https://www.wikidoc.org/api.php?action=feedcontributions&user=Rim+Halaby&feedformat=atomwikidoc - User contributions [en]2024-03-28T10:31:30ZUser contributionsMediaWiki 1.40.0https://www.wikidoc.org/index.php?title=Chelation_therapy_for_cardiovascular_disease&diff=1274907Chelation therapy for cardiovascular disease2016-12-08T00:47:47Z<p>Rim Halaby: </p>
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<div>__NOTOC__<br />
'''Editor-In-Chief:''' Gervasio Lamas, M.D., [[User:C Michael Gibson|C. Michael Gibson, M.S., M.D.]]; {{AE}} {{Rim}}, Ian Ergui, B.Sc.<br />
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'''[[Chelation therapy|To read more about chelation therapy click here.]]'''<br><br />
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{{SK}} Chelation therapy, EDTA, post-myocardial infarction, diabetes<br />
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==Overview==<br />
[[Chelation]] is a process by which an organic molecule with a negatively charged “pocket” complexes with a metal ion of opposite charge, inactivates it, and then permits its physiological mobilization and excretion, usually by a renal route. [[Chelation therapy]], which involves multiple administrations of a chelating agent, helps eliminate stored toxic metal ions from the body.<ref name="pmid11794513">{{cite journal| author=Waters RS, Bryden NA, Patterson KY, Veillon C, Anderson RA| title=EDTA chelation effects on urinary losses of cadmium, calcium, chromium, cobalt, copper, lead, magnesium, and zinc. | journal=Biol Trace Elem Res | year= 2001 | volume= 83 | issue= 3 | pages= 207-21 | pmid=11794513 | doi=10.1385/BTER:83:3:207 | pmc= | url=https://www.ncbi.nlm.nih.gov/entrez/eutils/elink.fcgi?dbfrom=pubmed&tool=sumsearch.org/cite&retmode=ref&cmd=prlinks&id=11794513 }} </ref><ref name="arenas">Arenas I.A., Navas-Acien A., Lamas G.A.; Enhanced vasculotoxic metal excretionin post-MI patients after edetate disodium therapy (abstr). J Am Coll Cardiol. 2016;67:A2125</ref> Common chelators include [[penicillamine]], which binds copper and can be used to treat [[Wilson’s disease]], [[deferoxamine]], which binds iron and is used in the treatment of [[thalassemia]] and iron overload, succimer, also used in the treatment of lead poisoning, and the edetates, non-specific chelators of metals and other ions with valences of +2 to +6. Chelation therapy is, in many cases, guideline mandated, such as in children with elevated blood lead levels,<ref name="CDC">CDC. Low Level Lead Exposure Harms Children: A Renewed Call for Primary Prevention. Atlanta, GA:Advisory Committee on Childhood Lead Poisoning Prevention, U.S. Centers for Disease Control and Prevention (4 Jan 2012). Available: [http://www.cdc.gov/nceh/lead/acclpp/final_document_010412.pdf]</ref> patients with iron overload and dyserythropoietic syndromes or chronic [[hemolytic anemia]],<ref name="pmid21452290">{{cite journal| author=Bacon BR, Adams PC, Kowdley KV, Powell LW, Tavill AS, American Association for the Study of Liver Diseases| title=Diagnosis and management of hemochromatosis: 2011 practice guideline by the American Association for the Study of Liver Diseases. | journal=Hepatology | year= 2011 | volume= 54 | issue= 1 | pages= 328-43 | pmid=21452290 | doi=10.1002/hep.24330 | pmc=3149125 | url=https://www.ncbi.nlm.nih.gov/entrez/eutils/elink.fcgi?dbfrom=pubmed&tool=sumsearch.org/cite&retmode=ref&cmd=prlinks&id=21452290 }} </ref> or [[sickle cell disease]] and transfusion acquired iron-overload,<ref name="NHLBI">NHLBI. Transfusion in Sickle Cell Disease: A Systematic Review of Benefits, Complications, and Management of Complications. Prepared for the National Heart, Lung, and Blood Institute and by the Knowledge and Evaluation Research Unit, Mayo Clinic Rochester (2012)</ref> to name a few instances.<br />
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[[Ethylene diamine tetraacetic acid]] ([[EDTA]], edetate) and its salts (most commonly disodium or calcium disodium), commonly used chelating agents patented in 1938, bind to and permit the urinary excretion of divalent cations such as calcium, and metals such as [[lead]], [[cadmium]], [[nickel]], [[cobalt]], [[iron]], [[aluminum]], and others. The initial medical use for [[EDTA]] began after World War II for the treatment of [[lead]]-exposed naval workers. In addition to its use for the treatment of metal poisoning, since the 1950s chelation therapy has been considered an alternative or add-on therapy for the prevention and treatment of [[atherosclerotic disease]]. The use of edetate disodium (Na2EDTA) has been most prominent in the alternative medicine treatment of [[atherosclerosis]] primarily because of the still-unproven hypothesis that the [[hypocalcemia]] it induces might lead to the decalcification of atherosclerotic lesions. In fact, the most current research suggests that the probable mechanism of benefit centers on enhancement of toxic metal excretion.<br />
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==Chelation Therapy and CVD==<br />
The use of chelation therapy as a treatment for [[atherosclerotic disease]] dates back to the 1950’s when Clarke et al investigated the use of EDTA for the treatment of [[angina pectoris]] and reported improvement in 19 of 20 patients.<ref name="pmid13372537">{{cite journal| author=CLARKE CN, CLARKE NE, MOSHER RE| title=Treatment of angina pectoris with disodium ethylene diamine tetraacetic acid. | journal=Am J Med Sci | year= 1956 | volume= 232 | issue= 6 | pages= 654-66 | pmid=13372537 | doi= | pmc= | url=http://www.ncbi.nlm.nih.gov/entrez/eutils/elink.fcgi?dbfrom=pubmed&tool=sumsearch.org/cite&retmode=ref&cmd=prlinks&id=13372537 }} </ref> Later studies by Kitchell were less positive,<ref name="pmid13756462">{{cite journal| author=KITCHELL JR, MELTZER LE, SEVEN MJ| title=Potential uses of chelation methods in the treatment of cardiovascular diseases. | journal=Prog Cardiovasc Dis | year= 1961 | volume= 3 | issue= | pages= 338-49 | pmid=13756462 | doi= | pmc= | url=https://www.ncbi.nlm.nih.gov/entrez/eutils/elink.fcgi?dbfrom=pubmed&tool=sumsearch.org/cite&retmode=ref&cmd=prlinks&id=13756462 }} </ref><ref name="pmid14033183">{{cite journal| author=KITCHELL JR, PALMON F, AYTAN N, MELTZER LE| title=The treatment of coronary artery disease with disodium EDTA. A reappraisal. | journal=Am J Cardiol | year= 1963 | volume= 11 | issue= | pages= 501-6 | pmid=14033183 | doi= | pmc= | url=https://www.ncbi.nlm.nih.gov/entrez/eutils/elink.fcgi?dbfrom=pubmed&tool=sumsearch.org/cite&retmode=ref&cmd=prlinks&id=14033183 }} </ref> and in an era without modern clinical trials methodology nor effective concomitant therapies, opinions regarding the use of [[chelation therapy]] for [[cardiovascular disease]] (CVD) tilted towards the negative. To be fair, from the 1970’s to 1990’s the preponderance of the scientific literature on [[chelation therapy]] for [[atherosclerosis]] consisted of case reports, case series, and small clinical trials with surrogate endpoints, poor-quality evidence from which to draw a conclusion of efficacy or harm.<ref name="pmid12519577">{{cite journal| author=Villarruz MV, Dans A, Tan F| title=Chelation therapy for atherosclerotic cardiovascular disease. | journal=Cochrane Database Syst Rev | year= 2002 | volume= | issue= 4 | pages= CD002785 | pmid=12519577 | doi=10.1002/14651858.CD002785 | pmc= | url=http://www.ncbi.nlm.nih.gov/entrez/eutils/elink.fcgi?dbfrom=pubmed&tool=sumsearch.org/cite&retmode=ref&cmd=prlinks&id=12519577 }} </ref><br />
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For example, one extensive case series reported an association between EDTA chelation therapy and improvement of [[ischemic heart disease]] and [[peripheral artery disease]].<ref name="pmid3144646">{{cite journal| author=Olszewer E, Carter JP| title=EDTA chelation therapy in chronic degenerative disease. | journal=Med Hypotheses | year= 1988 | volume= 27 | issue= 1 | pages= 41-9 | pmid=3144646 | doi= | pmc= | url=http://www.ncbi.nlm.nih.gov/entrez/eutils/elink.fcgi?dbfrom=pubmed&tool=sumsearch.org/cite&retmode=ref&cmd=prlinks&id=3144646 }} </ref> Another study demonstrated that EDTA supplemented with several B vitamins (vitamin B1, B2, B6 and B12) but not EDTA alone was effective in improving [[endothelium]]-dependent forearm blood flow.<ref name="pmid10561804">{{cite journal| author=Green DJ, O'Driscoll JG, Maiorana A, Scrimgeour NB, Weerasooriya R, Taylor RR| title=Effects of chelation with EDTA and vitamin B therapy on nitric oxide-related endothelial vasodilator function. | journal=Clin Exp Pharmacol Physiol | year= 1999 | volume= 26 | issue= 11 | pages= 853-6 | pmid=10561804 | doi= | pmc= | url=http://www.ncbi.nlm.nih.gov/entrez/eutils/elink.fcgi?dbfrom=pubmed&tool=sumsearch.org/cite&retmode=ref&cmd=prlinks&id=10561804 }} </ref> A systematic review of four [[randomized clinical trial]]s on chelation therapy and [[peripheral artery occlusive disease]] reported no benefit associated with [[chelation therapy]].<ref name="pmid9264515">{{cite journal| author=Ernst E| title=Chelation therapy for peripheral arterial occlusive disease: a systematic review. | journal=Circulation | year= 1997 | volume= 96 | issue= 3 | pages= 1031-3 | pmid=9264515 | doi= | pmc= | url=http://www.ncbi.nlm.nih.gov/entrez/eutils/elink.fcgi?dbfrom=pubmed&tool=sumsearch.org/cite&retmode=ref&cmd=prlinks&id=9264515 }} </ref> The studies, however, individually and in aggregate, were too small to exclude a small to moderate benefit of therapy. Moreover, follow up was short and surrogate physiologic endpoints, such as walking distance, were used. A Cochrane systematic review on the role of chelation therapy to treat [[coronary heart disease]] in 2002 concluded that the data were insufficient to recommend for or against chelation.<ref name="pmid10874275">{{cite journal| author=Ernst E| title=Chelation therapy for coronary heart disease: An overview of all clinical investigations. | journal=Am Heart J | year= 2000 | volume= 140 | issue= 1 | pages= 139-41 | pmid=10874275 | doi=10.1067/mhj.2000.107548 | pmc= | url=http://www.ncbi.nlm.nih.gov/entrez/eutils/elink.fcgi?dbfrom=pubmed&tool=sumsearch.org/cite&retmode=ref&cmd=prlinks&id=10874275 }} </ref> The medical community concluded that the absence of high quality evidence of efficacy equated with evidence of absence of efficacy. Professional organizations recommended against [[chelation therapy]].<ref name="pmid9205980">{{cite journal| author=Lewin MR| title=Chelation therapy for cardiovascular disease. Review and commentary. | journal=Tex Heart Inst J | year= 1997 | volume= 24 | issue= 2 | pages= 81-9 | pmid=9205980 | doi= | pmc=325409 | url=https://www.ncbi.nlm.nih.gov/entrez/eutils/elink.fcgi?dbfrom=pubmed&tool=sumsearch.org/cite&retmode=ref&cmd=prlinks&id=9205980 }} </ref> Interestingly, patients continued to seek, and practitioners to administer, chelation infusions for [[cardiovascular disease]] and other diagnoses.<br />
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In light of the persistent controversy regarding the benefits of chelation therapy and the absence of any previous large clinical trial investigating its use in coronary artery disease, the National Center for Complementary and Alternative Medicine and the National Heart Lung and Blood Institute released a $30 million Request for Applications (RFA) to develop a definitive trial. In 2002, the RFA was awarded to Mount Sinai Medical Center in Miami Beach FL (G Lamas MD, Principal Investigator). The Trial to Assess Chelation Therapy (TACT), a randomized, double blind, placebo controlled 2x2 factorial trial, investigated the efficacy and safety of disodium EDTA based infusions and high-dose oral vitamins and minerals in 1708 stable post-myocardial infarction (MI) patients more than 50 years of age and with fairly normal kidney function ([[creatinine]] 2.0 mg/dL or less). The active treatment consisted of 40 infusions consisted of disodium [[EDTA]] combined with [[ascorbic acid]], B vitamins, and other components. The median age of patients was 65 years, and they were treated with evidence-based post-MI medicines. The primary endpoint of this trial was a composite of all-cause mortality, [[stroke]], [[MI]], coronary revascularization, and hospitalization for [[angina]]. A follow up period of 55 months revealed a statistically significant decrease in the primary endpoint (HR: 0.82; 95% CI: 0.69-0.99; p= 0.035). There was an absolute reduction in the 5-year Kaplan-Meier estimate, from 38% to 33%, resulting in a 5-year number needed to treat (NNT) of 18 patients to avoid one adverse cardiovascular outcome. This is comparable to the 5-year NNT for [[statins]] in post-[[MI]] patients (NNT=16 for the secondary prevention of a major coronary event). The point estimate for the risk of each of the components of the primary endpoint was <1, consistent with the aggregate result. The Investigators concluded that chelation should not yet be adopted for routine post-[[MI]] use in all patients, but the results of TACT should inform further studies to confirm or refute these unexpected results.<ref name="pmid23532240">{{cite journal| author=Lamas GA, Goertz C, Boineau R, Mark DB, Rozema T, Nahin RL et al.| title=Effect of disodium EDTA chelation regimen on cardiovascular events in patients with previous myocardial infarction: the TACT randomized trial. | journal=JAMA | year= 2013 | volume= 309 | issue= 12 | pages= 1241-50 | pmid=23532240 | doi=10.1001/jama.2013.2107 | pmc= | url=http://www.ncbi.nlm.nih.gov/entrez/eutils/elink.fcgi?dbfrom=pubmed&tool=sumsearch.org/cite&retmode=ref&cmd=prlinks&id=23532240 }} </ref><br />
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TACT prespecified several subgroups for analysis and found a significant interaction between edetate disodium treatment and [[diabetes]] (p for interaction =0.0037). Among subjects enrolled in TACT, there were 633 [[diabetic]] patients, defined as patients with self-reported [[diabetes]], taking medications for [[diabetes]], or having a fasting blood glucose of at least 126 mg/dL at enrollment. The administration of chelation infusions among post-[[MI]] [[diabetic]] patients was associated with a marked reduction in the primary end point when compared with placebo. The primary end point occurred in 25% of [[diabetic]] patients who were administered chelation therapy compared to 38% in those who received placebo infusions (HR, 0.59; 95% CI, 0.44–0.79; P<0.001). The 5-year NNT to prevent one event was 6.5. In addition, chelation therapy was significantly associated with decreased all-cause mortality (43% reduction, p=0.011) and reinfarction (52% reduction, p=0.015).<ref name="pmid24254885">{{cite journal| author=Escolar E, Lamas GA, Mark DB, Boineau R, Goertz C, Rosenberg Y et al.| title=The effect of an EDTA-based chelation regimen on patients with diabetes mellitus and prior myocardial infarction in the Trial to Assess Chelation Therapy (TACT). | journal=Circ Cardiovasc Qual Outcomes | year= 2014 | volume= 7 | issue= 1 | pages= 15-24 | pmid=24254885 | doi=10.1161/CIRCOUTCOMES.113.000663 | pmc=4111470 | url=https://www.ncbi.nlm.nih.gov/entrez/eutils/elink.fcgi?dbfrom=pubmed&tool=sumsearch.org/cite&retmode=ref&cmd=prlinks&id=24254885 }} </ref> Again, the investigators concluded that these findings supported future research, but did not constitute sufficient evidence to indicate the routine use of [[chelation therapy]] for all post–[[MI]] patients with [[diabetes]], leaving open the clinician’s choice to use this novel therapy in occasional, or non-routine patients.<br />
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These results catalyzed a wave of increased public and scientific interest in disodium [[EDTA]] treatment for patients with established [[coronary disease]], particularly in [[diabetes]], and hypotheses regarding potential mechanisms of benefit. As a capstone to the published analyses, the ACC/AHA Guidelines for Chronic Ischemic Heart Disease changed to reflect the TACT data and upgraded disodium EDTA treatment from a Class III indication to a Class IIB indication. While Class III therapeutics are considered not beneficial or useful, Class IIB treatments can be considered in some patients and require additional research to establish efficacy.<ref name="pmid25077860">{{cite journal| author=Fihn SD, Blankenship JC, Alexander KP, Bittl JA, Byrne JG, Fletcher BJ et al.| title=2014 ACC/AHA/AATS/PCNA/SCAI/STS focused update of the guideline for the diagnosis and management of patients with stable ischemic heart disease: a report of the American College of Cardiology/American Heart Association Task Force on Practice Guidelines, and the American Association for Thoracic Surgery, Preventive Cardiovascular Nurses Association, Society for Cardiovascular Angiography and Interventions, and Society of Thoracic Surgeons. | journal=J Am Coll Cardiol | year= 2014 | volume= 64 | issue= 18 | pages= 1929-49 | pmid=25077860 | doi=10.1016/j.jacc.2014.07.017 | pmc= | url=https://www.ncbi.nlm.nih.gov/entrez/eutils/elink.fcgi?dbfrom=pubmed&tool=sumsearch.org/cite&retmode=ref&cmd=prlinks&id=25077860 }} </ref> The change in the guidelines signaled a major shift in the perception of chelation therapy among the medical establishment. The TACT data led clinicians to reconsider chelation objectively, and the investigators and many other academic cardiologists called for TACT2, a new trial to test the results of TACT, to be funded by the [[NIH]].<br />
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==Mechanism of Action==<br />
[[Edetate disodium]] binds to metals and forms soluble complexes facilitating their subsequent excretion in the [[urine]].<ref name="pmid14000694">{{cite journal| author=WILDER LW, DE JODE LR, MILSTEIN SW, HOWARD JM| title=Mobilization of atherosclerotic plaque calcium with EDTA utilizing the isolation-perfusion principle. | journal=Surgery | year= 1962 | volume= 52 | issue= | pages= 793-5 | pmid=14000694 | doi= | pmc= | url=http://www.ncbi.nlm.nih.gov/entrez/eutils/elink.fcgi?dbfrom=pubmed&tool=sumsearch.org/cite&retmode=ref&cmd=prlinks&id=14000694 }} </ref> Hence, chelation therapy results in the elimination of stored toxic and essential metals. In an experiment performed on 24 patients, age 50 or older, and with a prior MI and a creatinine of 2.0 or less, patients had urine toxic metals measured at baseline, 1 day after an infusion of placebo, and 1 day after an infusion of the edetate disodium-based TACT solution. Placebo did not increase the excretion of toxic metals. Following an infusion of the edetate disodium-based TACT solution, lead excretion increased by nearly 3900%, and cadmium by nearly 700%. Other toxic metals whose excretion was enhanced by edetate disodium were aluminum (by ~250%), nickel (by ~150%), thallium (by ~60%), and gadolinium. A similar experiment performed earlier by Waters et al, reported urinary lead concentrations approximately 35 times greater than in pre-chelation urine.<ref name="pmid11794513">{{cite journal| author=Waters RS, Bryden NA, Patterson KY, Veillon C, Anderson RA| title=EDTA chelation effects on urinary losses of cadmium, calcium, chromium, cobalt, copper, lead, magnesium, and zinc. | journal=Biol Trace Elem Res | year= 2001 | volume= 83 | issue= 3 | pages= 207-21 | pmid=11794513 | doi=10.1385/BTER:83:3:207 | pmc= | url=https://www.ncbi.nlm.nih.gov/entrez/eutils/elink.fcgi?dbfrom=pubmed&tool=sumsearch.org/cite&retmode=ref&cmd=prlinks&id=11794513 }} </ref><br />
While enhanced lead and cadmium is interesting, the critical link to cardiovascular events is provided by epidemiological studies, which provide robust evidence linking toxic metals with [[cardiovascular disease]].<ref name="pmid21421632">{{cite journal| author=Agarwal S, Zaman T, Tuzcu EM, Kapadia SR| title=Heavy metals and cardiovascular disease: results from the National Health and Nutrition Examination Survey (NHANES) 1999-2006. | journal=Angiology | year= 2011 | volume= 62 | issue= 5 | pages= 422-9 | pmid=21421632 | doi=10.1177/0003319710395562 | pmc= | url=http://www.ncbi.nlm.nih.gov/entrez/eutils/elink.fcgi?dbfrom=pubmed&tool=sumsearch.org/cite&retmode=ref&cmd=prlinks&id=21421632 }} </ref> This evidence is strongest for lead and cadmium.<ref name="pmid16982939">{{cite journal| author=Menke A, Muntner P, Batuman V, Silbergeld EK, Guallar E| title=Blood lead below 0.48 micromol/L (10 microg/dL) and mortality among US adults. | journal=Circulation | year= 2006 | volume= 114 | issue= 13 | pages= 1388-94 | pmid=16982939 | doi=10.1161/CIRCULATIONAHA.106.628321 | pmc= | url=https://www.ncbi.nlm.nih.gov/entrez/eutils/elink.fcgi?dbfrom=pubmed&tool=sumsearch.org/cite&retmode=ref&cmd=prlinks&id=16982939 }} </ref><ref name="pmid15184277">{{cite journal| author=Navas-Acien A, Selvin E, Sharrett AR, Calderon-Aranda E, Silbergeld E, Guallar E| title=Lead, cadmium, smoking, and increased risk of peripheral arterial disease. | journal=Circulation | year= 2004 | volume= 109 | issue= 25 | pages= 3196-201 | pmid=15184277 | doi=10.1161/01.CIR.0000130848.18636.B2 | pmc= | url=http://www.ncbi.nlm.nih.gov/entrez/eutils/elink.fcgi?dbfrom=pubmed&tool=sumsearch.org/cite&retmode=ref&cmd=prlinks&id=15184277 }} </ref><ref name="pmid23514838">{{cite journal| author=Tellez-Plaza M, Guallar E, Howard BV, Umans JG, Francesconi KA, Goessler W et al.| title=Cadmium exposure and incident cardiovascular disease. | journal=Epidemiology | year= 2013 | volume= 24 | issue= 3 | pages= 421-9 | pmid=23514838 | doi=10.1097/EDE.0b013e31828b0631 | pmc= | url=http://www.ncbi.nlm.nih.gov/entrez/eutils/elink.fcgi?dbfrom=pubmed&tool=sumsearch.org/cite&retmode=ref&cmd=prlinks&id=23514838 }} </ref> Elevated blood concentration of [[lead]] is associated with increased all-cause mortality [HR 1.25 (95% CI 1.04 to 1.51) for the highest versus lowest tertile of blood lead, P trend across the tertiles=0.002) and cardiovascular mortality [HR 1.55 (95% CI 1.08 to 2.24) for the highest versus lowest tertile, P trend <0.003].<ref name="pmid16982939">{{cite journal| author=Menke A, Muntner P, Batuman V, Silbergeld EK, Guallar E| title=Blood lead below 0.48 micromol/L (10 microg/dL) and mortality among US adults. | journal=Circulation | year= 2006 | volume= 114 | issue= 13 | pages= 1388-94 | pmid=16982939 | doi=10.1161/CIRCULATIONAHA.106.628321 | pmc= | url=https://www.ncbi.nlm.nih.gov/entrez/eutils/elink.fcgi?dbfrom=pubmed&tool=sumsearch.org/cite&retmode=ref&cmd=prlinks&id=16982939 }} </ref> Also, cardiovascular mortality is greater among subjects with elevated [[cadmium]] concentrations in the blood and urine [HR 1.69 (95% CI: 1.03, 2.77) and 1.74 (95% CI: 1.07, 2.83) for the 80th and 20th percentiles of blood and urine cadmium, respectively].<ref name="pmid22472185">{{cite journal| author=Tellez-Plaza M, Navas-Acien A, Menke A, Crainiceanu CM, Pastor-Barriuso R, Guallar E| title=Cadmium exposure and all-cause and cardiovascular mortality in the U.S. general population. | journal=Environ Health Perspect | year= 2012 | volume= 120 | issue= 7 | pages= 1017-22 | pmid=22472185 | doi=10.1289/ehp.1104352 | pmc=3404657 | url=https://www.ncbi.nlm.nih.gov/entrez/eutils/elink.fcgi?dbfrom=pubmed&tool=sumsearch.org/cite&retmode=ref&cmd=prlinks&id=22472185 }} </ref> <br />
Heavy metals may play a role in the development of [[cardiovascular disease]] through a number of different mechanisms.<ref name="pmid17645641">{{cite journal| author=Vaziri ND, Khan M| title=Interplay of reactive oxygen species and nitric oxide in the pathogenesis of experimental lead-induced hypertension. | journal=Clin Exp Pharmacol Physiol | year= 2007 | volume= 34 | issue= 9 | pages= 920-5 | pmid=17645641 | doi=10.1111/j.1440-1681.2007.04644.x | pmc= | url=https://www.ncbi.nlm.nih.gov/entrez/eutils/elink.fcgi?dbfrom=pubmed&tool=sumsearch.org/cite&retmode=ref&cmd=prlinks&id=17645641 }} </ref> Heavy metals include transition metals such as [[cadmium]], [[mercury]], [[manganese]], [[chromium]], [[cobalt]], [[nickel]], [[iron]], and [[copper]], metalloids such as antimony and arsenic, and post- transition metals such as [[thallium]] and [[lead]]. These metals all have unique toxicities, as well as toxicities that are common to all of them. Heavy metals in the [[endothelium]] promote oxygen free radical formation, resulting in increased [[oxidative stress]], [[inflammation]], and tissue damage. [[Lead]] and [[cadmium]] may interfere with calcium signaling channels. Transition metals promote modifications of [[low-density lipoprotein]] by [[endothelial cell]]s through lipid peroxidation and degradation of low-density lipoprotein phospholipids.<ref name="pmid6587396">{{cite journal| author=Steinbrecher UP, Parthasarathy S, Leake DS, Witztum JL, Steinberg D| title=Modification of low density lipoprotein by endothelial cells involves lipid peroxidation and degradation of low density lipoprotein phospholipids. | journal=Proc Natl Acad Sci U S A | year= 1984 | volume= 81 | issue= 12 | pages= 3883-7 | pmid=6587396 | doi= | pmc=345326 | url=https://www.ncbi.nlm.nih.gov/entrez/eutils/elink.fcgi?dbfrom=pubmed&tool=sumsearch.org/cite&retmode=ref&cmd=prlinks&id=6587396 }} </ref><ref name="pmid6501577">{{cite journal| author=Heinecke JW, Rosen H, Chait A| title=Iron and copper promote modification of low density lipoprotein by human arterial smooth muscle cells in culture. | journal=J Clin Invest | year= 1984 | volume= 74 | issue= 5 | pages= 1890-4 | pmid=6501577 | doi=10.1172/JCI111609 | pmc=425370 | url=https://www.ncbi.nlm.nih.gov/entrez/eutils/elink.fcgi?dbfrom=pubmed&tool=sumsearch.org/cite&retmode=ref&cmd=prlinks&id=6501577 }} </ref><ref name="pmid8847477">{{cite journal| author=Morgan J, Leake DS| title=Oxidation of low density lipoprotein by iron or copper at acidic pH. | journal=J Lipid Res | year= 1995 | volume= 36 | issue= 12 | pages= 2504-12 | pmid=8847477 | doi= | pmc= | url=https://www.ncbi.nlm.nih.gov/entrez/eutils/elink.fcgi?dbfrom=pubmed&tool=sumsearch.org/cite&retmode=ref&cmd=prlinks&id=8847477 }} </ref> Exposure to non-transition metals, such as lead, has also been associated with impaired nitric oxide signaling and availability,<ref name="pmid15894814">{{cite journal| author=Dursun N, Arifoglu C, Süer C, Keskinol L| title=Blood pressure relationship to nitric oxide, lipid peroxidation, renal function, and renal blood flow in rats exposed to low lead levels. | journal=Biol Trace Elem Res | year= 2005 | volume= 104 | issue= 2 | pages= 141-9 | pmid=15894814 | doi=10.1385/BTER:104:2:141 | pmc= | url=https://www.ncbi.nlm.nih.gov/entrez/eutils/elink.fcgi?dbfrom=pubmed&tool=sumsearch.org/cite&retmode=ref&cmd=prlinks&id=15894814 }} </ref> endothelial cell dysfunction,<ref name="pmid7710289">{{cite journal| author=Kaji T, Suzuki M, Yamamoto C, Mishima A, Sakamoto M, Kozuka H| title=Severe damage of cultured vascular endothelial cell monolayer after simultaneous exposure to cadmium and lead. | journal=Arch Environ Contam Toxicol | year= 1995 | volume= 28 | issue= 2 | pages= 168-72 | pmid=7710289 | doi= | pmc= | url=https://www.ncbi.nlm.nih.gov/entrez/eutils/elink.fcgi?dbfrom=pubmed&tool=sumsearch.org/cite&retmode=ref&cmd=prlinks&id=7710289 }} </ref> and hypertension.<ref name="pmid18567711">{{cite journal| author=Vaziri ND| title=Mechanisms of lead-induced hypertension and cardiovascular disease. | journal=Am J Physiol Heart Circ Physiol | year= 2008 | volume= 295 | issue= 2 | pages= H454-65 | pmid=18567711 | doi=10.1152/ajpheart.00158.2008 | pmc=2519216 | url=https://www.ncbi.nlm.nih.gov/entrez/eutils/elink.fcgi?dbfrom=pubmed&tool=sumsearch.org/cite&retmode=ref&cmd=prlinks&id=18567711 }} </ref> [[Heavy metal]] exposure is also associated with genetic and [[epigenetic]] manifestations. [[Cadmium]] promotes atherosclerosis and endothelial dysfunction through multiple [[genetic]] changes.<ref name="pmid19556524">{{cite journal| author=Messner B, Knoflach M, Seubert A, Ritsch A, Pfaller K, Henderson B et al.| title=Cadmium is a novel and independent risk factor for early atherosclerosis mechanisms and in vivo relevance. | journal=Arterioscler Thromb Vasc Biol | year= 2009 | volume= 29 | issue= 9 | pages= 1392-8 | pmid=19556524 | doi=10.1161/ATVBAHA.109.190082 | pmc= | url=https://www.ncbi.nlm.nih.gov/entrez/eutils/elink.fcgi?dbfrom=pubmed&tool=sumsearch.org/cite&retmode=ref&cmd=prlinks&id=19556524 }} </ref> One of the mechanisms involves [[DNA]] strand breaks and damage with subsequent apoptosis in [[endothelial cell]]s.<ref name="pmid19556524">{{cite journal| author=Messner B, Knoflach M, Seubert A, Ritsch A, Pfaller K, Henderson B et al.| title=Cadmium is a novel and independent risk factor for early atherosclerosis mechanisms and in vivo relevance. | journal=Arterioscler Thromb Vasc Biol | year= 2009 | volume= 29 | issue= 9 | pages= 1392-8 | pmid=19556524 | doi=10.1161/ATVBAHA.109.190082 | pmc= | url=https://www.ncbi.nlm.nih.gov/entrez/eutils/elink.fcgi?dbfrom=pubmed&tool=sumsearch.org/cite&retmode=ref&cmd=prlinks&id=19556524 }} </ref> Also, maternal [[lead]] exposure during pregnancy may be associated with epigenetic consequences in grandchildren through alteration of [[DNA methylation]] early in life.<ref name="pmid26417717">{{cite journal| author=Sen A, Heredia N, Senut MC, Land S, Hollocher K, Lu X et al.| title=Multigenerational epigenetic inheritance in humans: DNA methylation changes associated with maternal exposure to lead can be transmitted to the grandchildren. | journal=Sci Rep | year= 2015 | volume= 5 | issue= | pages= 14466 | pmid=26417717 | doi=10.1038/srep14466 | pmc=4586440 | url=https://www.ncbi.nlm.nih.gov/entrez/eutils/elink.fcgi?dbfrom=pubmed&tool=sumsearch.org/cite&retmode=ref&cmd=prlinks&id=26417717 }} </ref><br />
<br />
Current mechanistic understanding, albeit rudimentary, supports the concept that the cardiovascular benefits of [[chelation therapy]] may result from enhanced excretion of [[heavy metals]], and subsequent reduction in processes listed above. Additionally, in patients with [[diabetes]], a reduction in the metal-catalyzed formation of [[reactive oxygen species]], formation of advanced glycation end-products, and lipid [[peroxidation]] has been postulated.<ref name="pmid10874253">{{cite journal| author=Lamas GA, Ackermann A| title=Clinical evaluation of chelation therapy: is there any wheat amidst the chaff? | journal=Am Heart J | year= 2000 | volume= 140 | issue= 1 | pages= 4-5 | pmid=10874253 | doi=10.1067/mhj.2000.107549 | pmc= | url=http://www.ncbi.nlm.nih.gov/entrez/eutils/elink.fcgi?dbfrom=pubmed&tool=sumsearch.org/cite&retmode=ref&cmd=prlinks&id=10874253 }} </ref> Metal detoxification in the context of [[diabetes]] possibly decreases [[inflammation]] and [[oxidative stress]] that characterize atherosclerosis.<ref>Escolar E, Lamas G, Mark D et al(2013) "The Effect of an EDTA-based Chelation Regimen on Patients With Diabetes Mellitus and Prior Myocardial Infarction in the Trial to Assess Chelation Therapy (TACT)". Circulation. 2013</ref> Recent research, including chelation-activity assays, indicates that many common [[diabetes]] drugs, such as [[metformin]] and aldose reductase inhibitors, could possibly have some chelating properties.<ref name="pmid22354928">{{cite journal| author=Nagai R, Murray DB, Metz TO, Baynes JW| title=Chelation: a fundamental mechanism of action of AGE inhibitors, AGE breakers, and other inhibitors of diabetes complications. | journal=Diabetes | year= 2012 | volume= 61 | issue= 3 | pages= 549-59 | pmid=22354928 | doi=10.2337/db11-1120 | pmc=3282805 | url=https://www.ncbi.nlm.nih.gov/entrez/eutils/elink.fcgi?dbfrom=pubmed&tool=sumsearch.org/cite&retmode=ref&cmd=prlinks&id=22354928 }} </ref><ref name="pmid23612664">{{cite journal| author=Frizzell N, Baynes JW| title=Chelation therapy for the management of diabetic complications: a hypothesis and a proposal for clinical laboratory assessment of metal ion homeostasis in plasma. | journal=Clin Chem Lab Med | year= 2014 | volume= 52 | issue= 1 | pages= 69-75 | pmid=23612664 | doi=10.1515/cclm-2012-0881 | pmc= | url=https://www.ncbi.nlm.nih.gov/entrez/eutils/elink.fcgi?dbfrom=pubmed&tool=sumsearch.org/cite&retmode=ref&cmd=prlinks&id=23612664 }} </ref><ref name="pmid22492524">{{cite journal| author=Logie L, Harthill J, Patel K, Bacon S, Hamilton DL, Macrae K et al.| title=Cellular responses to the metal-binding properties of metformin. | journal=Diabetes | year= 2012 | volume= 61 | issue= 6 | pages= 1423-33 | pmid=22492524 | doi=10.2337/db11-0961 | pmc=3357267 | url=https://www.ncbi.nlm.nih.gov/entrez/eutils/elink.fcgi?dbfrom=pubmed&tool=sumsearch.org/cite&retmode=ref&cmd=prlinks&id=22492524 }} </ref><br />
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The TACT chelation infusion, however, did not contain edetate disodium alone. The standard chelation infusion formula used in TACT was formulated to be identical with the most prevalent infusion in use. This formulation had developed organically over decades and had been modified by clinical practitioners to have additives such as [[ascorbic acid]], B-vitamins and [[magnesium]], thought to have a protective effect on [[endothelial cells]],<ref>Rozema, Theodore C. "The protocol for the safe and effective administration of EDTA and other chelating agents for vascular disease, degenerative disease, and metal toxicity." Journal of Advancement in Medicine 10.1 (1997): 5-100.</ref> making the results of clinical application more difficult to understand, and emphasizing the need for mechanistic work.<br />
<br />
==Future Studies==<br />
TACT was a unique study with an unexpected result that could have vast public health implications. In order to consider its broad applicability, the medical and scientific community require the results reproduced. TACT2, scheduled to begin in October 2016 (press release), is a replicative study in post-MI diabetic patients. If the TACT2 results confirm the results of TACT, then chelation is poised to become the next major development in the treatment of vascular complications of diabetes and vascular disease. TACT2 is currently recruiting sites, and interested investigators should visit www.TACT2.org for additional information.<br />
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==Side Effects==<br />
Shown below is a list of the labelled toxicities of EDTA-based chelation therapy. However, TACT delivered 55,222 infusions of EDTA or placebo, and found no differences between groups in adverse events, serious or otherwise.<br />
* [[Arrhythmias]]<br />
* [[Autoimmune diseases]]<br />
* [[Bone marrow]]<br />
* [[Convulsions]]<br />
* [[Depression]]<br />
* [[Fever]]<br />
* [[Heart failure]]<br />
* [[Hypocalcemia]]<br />
* [[Hypoglycemia]]<br />
* [[Hypotension]]<br />
* [[Bleeding time|Prolonged bleeding time]]<br />
* [[Renal failure]]<br />
* [[Respiratory arrest]]<br />
* [[Tetany]]<br />
* [[Trace metal|Trace metal deficiency]]<br />
* [[Vitamin deficiency]]<ref name="pmid10874275">{{cite journal| author=Ernst E| title=Chelation therapy for coronary heart disease: An overview of all clinical investigations. | journal=Am Heart J | year= 2000 | volume= 140 | issue= 1 | pages= 139-41 | pmid=10874275 | doi=10.1067/mhj.2000.107548 | pmc= | url=http://www.ncbi.nlm.nih.gov/entrez/eutils/elink.fcgi?dbfrom=pubmed&tool=sumsearch.org/cite&retmode=ref&cmd=prlinks&id=10874275 }} </ref><ref name="pmid23532240">{{cite journal| author=Lamas GA, Goertz C, Boineau R, Mark DB, Rozema T, Nahin RL et al.| title=Effect of disodium EDTA chelation regimen on cardiovascular events in patients with previous myocardial infarction: the TACT randomized trial. | journal=JAMA | year= 2013 | volume= 309 | issue= 12 | pages= 1241-50 | pmid=23532240 | doi=10.1001/jama.2013.2107 | pmc= | url=http://www.ncbi.nlm.nih.gov/entrez/eutils/elink.fcgi?dbfrom=pubmed&tool=sumsearch.org/cite&retmode=ref&cmd=prlinks&id=23532240 }} </ref><br />
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==Landmark Trials==<br />
* [[TACT]] <br><br />
* TACT 2 [http://www.TACT2.org] (link to press release [http://www.prnewswire.com/news-releases/tact2-clinical-trial-receives-national-institutes-of-health-funding-300334174.html])<br />
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==References==<br />
{{Reflist|2}}<br />
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[[Category:Cardiology]]<br />
[[Category:Diabetes]]<br />
[[Category:Up-To-Date]]<br />
<br />
{{WikiDoc Help Menu}}<br />
{{WikiDoc Sources}}</div>Rim Halabyhttps://www.wikidoc.org/index.php?title=Chelation_therapy_for_cardiovascular_disease&diff=1274905Chelation therapy for cardiovascular disease2016-12-08T00:43:18Z<p>Rim Halaby: </p>
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<div>__NOTOC__<br />
'''Editor-In-Chief:''' Gervasio Lamas, M.D., C. Michael Gibson, M.S., M.D.; {{AE}} {{Rim}}, Ian Ergui, B.Sc.<br />
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'''[[Chelation therapy|To read more about chelation therapy click here.]]'''<br><br />
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{{SK}} Chelation therapy, EDTA, post-myocardial infarction, diabetes<br />
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==Overview==<br />
[[Chelation]] is a process by which an organic molecule with a negatively charged “pocket” complexes with a metal ion of opposite charge, inactivates it, and then permits its physiological mobilization and excretion, usually by a renal route. [[Chelation therapy]], which involves multiple administrations of a chelating agent, helps eliminate stored toxic metal ions from the body.<ref name="pmid11794513">{{cite journal| author=Waters RS, Bryden NA, Patterson KY, Veillon C, Anderson RA| title=EDTA chelation effects on urinary losses of cadmium, calcium, chromium, cobalt, copper, lead, magnesium, and zinc. | journal=Biol Trace Elem Res | year= 2001 | volume= 83 | issue= 3 | pages= 207-21 | pmid=11794513 | doi=10.1385/BTER:83:3:207 | pmc= | url=https://www.ncbi.nlm.nih.gov/entrez/eutils/elink.fcgi?dbfrom=pubmed&tool=sumsearch.org/cite&retmode=ref&cmd=prlinks&id=11794513 }} </ref><ref name="arenas">Arenas I.A., Navas-Acien A., Lamas G.A.; Enhanced vasculotoxic metal excretionin post-MI patients after edetate disodium therapy (abstr). J Am Coll Cardiol. 2016;67:A2125</ref> Common chelators include [[penicillamine]], which binds copper and can be used to treat [[Wilson’s disease]], [[deferoxamine]], which binds iron and is used in the treatment of [[thalassemia]] and iron overload, succimer, also used in the treatment of lead poisoning, and the edetates, non-specific chelators of metals and other ions with valences of +2 to +6. Chelation therapy is, in many cases, guideline mandated, such as in children with elevated blood lead levels,<ref name="CDC">CDC. Low Level Lead Exposure Harms Children: A Renewed Call for Primary Prevention. Atlanta, GA:Advisory Committee on Childhood Lead Poisoning Prevention, U.S. Centers for Disease Control and Prevention (4 Jan 2012). Available: [http://www.cdc.gov/nceh/lead/acclpp/final_document_010412.pdf]</ref> patients with iron overload and dyserythropoietic syndromes or chronic [[hemolytic anemia]],<ref name="pmid21452290">{{cite journal| author=Bacon BR, Adams PC, Kowdley KV, Powell LW, Tavill AS, American Association for the Study of Liver Diseases| title=Diagnosis and management of hemochromatosis: 2011 practice guideline by the American Association for the Study of Liver Diseases. | journal=Hepatology | year= 2011 | volume= 54 | issue= 1 | pages= 328-43 | pmid=21452290 | doi=10.1002/hep.24330 | pmc=3149125 | url=https://www.ncbi.nlm.nih.gov/entrez/eutils/elink.fcgi?dbfrom=pubmed&tool=sumsearch.org/cite&retmode=ref&cmd=prlinks&id=21452290 }} </ref> or [[sickle cell disease]] and transfusion acquired iron-overload,<ref name="NHLBI">NHLBI. Transfusion in Sickle Cell Disease: A Systematic Review of Benefits, Complications, and Management of Complications. Prepared for the National Heart, Lung, and Blood Institute and by the Knowledge and Evaluation Research Unit, Mayo Clinic Rochester (2012)</ref> to name a few instances.<br />
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[[Ethylene diamine tetraacetic acid]] ([[EDTA]], edetate) and its salts (most commonly disodium or calcium disodium), commonly used chelating agents patented in 1938, bind to and permit the urinary excretion of divalent cations such as calcium, and metals such as [[lead]], [[cadmium]], [[nickel]], [[cobalt]], [[iron]], [[aluminum]], and others. The initial medical use for [[EDTA]] began after World War II for the treatment of [[lead]]-exposed naval workers. In addition to its use for the treatment of metal poisoning, since the 1950s chelation therapy has been considered an alternative or add-on therapy for the prevention and treatment of [[atherosclerotic disease]]. The use of edetate disodium (Na2EDTA) has been most prominent in the alternative medicine treatment of [[atherosclerosis]] primarily because of the still-unproven hypothesis that the [[hypocalcemia]] it induces might lead to the decalcification of atherosclerotic lesions. In fact, the most current research suggests that the probable mechanism of benefit centers on enhancement of toxic metal excretion.<br />
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==Chelation Therapy and CVD==<br />
The use of chelation therapy as a treatment for [[atherosclerotic disease]] dates back to the 1950’s when Clarke et al investigated the use of EDTA for the treatment of [[angina pectoris]] and reported improvement in 19 of 20 patients.<ref name="pmid13372537">{{cite journal| author=CLARKE CN, CLARKE NE, MOSHER RE| title=Treatment of angina pectoris with disodium ethylene diamine tetraacetic acid. | journal=Am J Med Sci | year= 1956 | volume= 232 | issue= 6 | pages= 654-66 | pmid=13372537 | doi= | pmc= | url=http://www.ncbi.nlm.nih.gov/entrez/eutils/elink.fcgi?dbfrom=pubmed&tool=sumsearch.org/cite&retmode=ref&cmd=prlinks&id=13372537 }} </ref> Later studies by Kitchell were less positive,<ref name="pmid13756462">{{cite journal| author=KITCHELL JR, MELTZER LE, SEVEN MJ| title=Potential uses of chelation methods in the treatment of cardiovascular diseases. | journal=Prog Cardiovasc Dis | year= 1961 | volume= 3 | issue= | pages= 338-49 | pmid=13756462 | doi= | pmc= | url=https://www.ncbi.nlm.nih.gov/entrez/eutils/elink.fcgi?dbfrom=pubmed&tool=sumsearch.org/cite&retmode=ref&cmd=prlinks&id=13756462 }} </ref><ref name="pmid14033183">{{cite journal| author=KITCHELL JR, PALMON F, AYTAN N, MELTZER LE| title=The treatment of coronary artery disease with disodium EDTA. A reappraisal. | journal=Am J Cardiol | year= 1963 | volume= 11 | issue= | pages= 501-6 | pmid=14033183 | doi= | pmc= | url=https://www.ncbi.nlm.nih.gov/entrez/eutils/elink.fcgi?dbfrom=pubmed&tool=sumsearch.org/cite&retmode=ref&cmd=prlinks&id=14033183 }} </ref> and in an era without modern clinical trials methodology nor effective concomitant therapies, opinions regarding the use of [[chelation therapy]] for [[cardiovascular disease]] (CVD) tilted towards the negative. To be fair, from the 1970’s to 1990’s the preponderance of the scientific literature on [[chelation therapy]] for [[atherosclerosis]] consisted of case reports, case series, and small clinical trials with surrogate endpoints, poor-quality evidence from which to draw a conclusion of efficacy or harm.<ref name="pmid12519577">{{cite journal| author=Villarruz MV, Dans A, Tan F| title=Chelation therapy for atherosclerotic cardiovascular disease. | journal=Cochrane Database Syst Rev | year= 2002 | volume= | issue= 4 | pages= CD002785 | pmid=12519577 | doi=10.1002/14651858.CD002785 | pmc= | url=http://www.ncbi.nlm.nih.gov/entrez/eutils/elink.fcgi?dbfrom=pubmed&tool=sumsearch.org/cite&retmode=ref&cmd=prlinks&id=12519577 }} </ref><br />
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For example, one extensive case series reported an association between EDTA chelation therapy and improvement of [[ischemic heart disease]] and [[peripheral artery disease]].<ref name="pmid3144646">{{cite journal| author=Olszewer E, Carter JP| title=EDTA chelation therapy in chronic degenerative disease. | journal=Med Hypotheses | year= 1988 | volume= 27 | issue= 1 | pages= 41-9 | pmid=3144646 | doi= | pmc= | url=http://www.ncbi.nlm.nih.gov/entrez/eutils/elink.fcgi?dbfrom=pubmed&tool=sumsearch.org/cite&retmode=ref&cmd=prlinks&id=3144646 }} </ref> Another study demonstrated that EDTA supplemented with several B vitamins (vitamin B1, B2, B6 and B12) but not EDTA alone was effective in improving [[endothelium]]-dependent forearm blood flow.<ref name="pmid10561804">{{cite journal| author=Green DJ, O'Driscoll JG, Maiorana A, Scrimgeour NB, Weerasooriya R, Taylor RR| title=Effects of chelation with EDTA and vitamin B therapy on nitric oxide-related endothelial vasodilator function. | journal=Clin Exp Pharmacol Physiol | year= 1999 | volume= 26 | issue= 11 | pages= 853-6 | pmid=10561804 | doi= | pmc= | url=http://www.ncbi.nlm.nih.gov/entrez/eutils/elink.fcgi?dbfrom=pubmed&tool=sumsearch.org/cite&retmode=ref&cmd=prlinks&id=10561804 }} </ref> A systematic review of four [[randomized clinical trial]]s on chelation therapy and [[peripheral artery occlusive disease]] reported no benefit associated with [[chelation therapy]].<ref name="pmid9264515">{{cite journal| author=Ernst E| title=Chelation therapy for peripheral arterial occlusive disease: a systematic review. | journal=Circulation | year= 1997 | volume= 96 | issue= 3 | pages= 1031-3 | pmid=9264515 | doi= | pmc= | url=http://www.ncbi.nlm.nih.gov/entrez/eutils/elink.fcgi?dbfrom=pubmed&tool=sumsearch.org/cite&retmode=ref&cmd=prlinks&id=9264515 }} </ref> The studies, however, individually and in aggregate, were too small to exclude a small to moderate benefit of therapy. Moreover, follow up was short and surrogate physiologic endpoints, such as walking distance, were used. A Cochrane systematic review on the role of chelation therapy to treat [[coronary heart disease]] in 2002 concluded that the data were insufficient to recommend for or against chelation.<ref name="pmid10874275">{{cite journal| author=Ernst E| title=Chelation therapy for coronary heart disease: An overview of all clinical investigations. | journal=Am Heart J | year= 2000 | volume= 140 | issue= 1 | pages= 139-41 | pmid=10874275 | doi=10.1067/mhj.2000.107548 | pmc= | url=http://www.ncbi.nlm.nih.gov/entrez/eutils/elink.fcgi?dbfrom=pubmed&tool=sumsearch.org/cite&retmode=ref&cmd=prlinks&id=10874275 }} </ref> The medical community concluded that the absence of high quality evidence of efficacy equated with evidence of absence of efficacy. Professional organizations recommended against [[chelation therapy]].<ref name="pmid9205980">{{cite journal| author=Lewin MR| title=Chelation therapy for cardiovascular disease. Review and commentary. | journal=Tex Heart Inst J | year= 1997 | volume= 24 | issue= 2 | pages= 81-9 | pmid=9205980 | doi= | pmc=325409 | url=https://www.ncbi.nlm.nih.gov/entrez/eutils/elink.fcgi?dbfrom=pubmed&tool=sumsearch.org/cite&retmode=ref&cmd=prlinks&id=9205980 }} </ref> Interestingly, patients continued to seek, and practitioners to administer, chelation infusions for [[cardiovascular disease]] and other diagnoses.<br />
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In light of the persistent controversy regarding the benefits of chelation therapy and the absence of any previous large clinical trial investigating its use in coronary artery disease, the National Center for Complementary and Alternative Medicine and the National Heart Lung and Blood Institute released a $30 million Request for Applications (RFA) to develop a definitive trial. In 2002, the RFA was awarded to Mount Sinai Medical Center in Miami Beach FL (G Lamas MD, Principal Investigator). The Trial to Assess Chelation Therapy (TACT), a randomized, double blind, placebo controlled 2x2 factorial trial, investigated the efficacy and safety of disodium EDTA based infusions and high-dose oral vitamins and minerals in 1708 stable post-myocardial infarction (MI) patients more than 50 years of age and with fairly normal kidney function ([[creatinine]] 2.0 mg/dL or less). The active treatment consisted of 40 infusions consisted of disodium [[EDTA]] combined with [[ascorbic acid]], B vitamins, and other components. The median age of patients was 65 years, and they were treated with evidence-based post-MI medicines. The primary endpoint of this trial was a composite of all-cause mortality, [[stroke]], [[MI]], coronary revascularization, and hospitalization for [[angina]]. A follow up period of 55 months revealed a statistically significant decrease in the primary endpoint (HR: 0.82; 95% CI: 0.69-0.99; p= 0.035). There was an absolute reduction in the 5-year Kaplan-Meier estimate, from 38% to 33%, resulting in a 5-year number needed to treat (NNT) of 18 patients to avoid one adverse cardiovascular outcome. This is comparable to the 5-year NNT for [[statins]] in post-[[MI]] patients (NNT=16 for the secondary prevention of a major coronary event). The point estimate for the risk of each of the components of the primary endpoint was <1, consistent with the aggregate result. The Investigators concluded that chelation should not yet be adopted for routine post-[[MI]] use in all patients, but the results of TACT should inform further studies to confirm or refute these unexpected results.<ref name="pmid23532240">{{cite journal| author=Lamas GA, Goertz C, Boineau R, Mark DB, Rozema T, Nahin RL et al.| title=Effect of disodium EDTA chelation regimen on cardiovascular events in patients with previous myocardial infarction: the TACT randomized trial. | journal=JAMA | year= 2013 | volume= 309 | issue= 12 | pages= 1241-50 | pmid=23532240 | doi=10.1001/jama.2013.2107 | pmc= | url=http://www.ncbi.nlm.nih.gov/entrez/eutils/elink.fcgi?dbfrom=pubmed&tool=sumsearch.org/cite&retmode=ref&cmd=prlinks&id=23532240 }} </ref><br />
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TACT prespecified several subgroups for analysis and found a significant interaction between edetate disodium treatment and [[diabetes]] (p for interaction =0.0037). Among subjects enrolled in TACT, there were 633 [[diabetic]] patients, defined as patients with self-reported [[diabetes]], taking medications for [[diabetes]], or having a fasting blood glucose of at least 126 mg/dL at enrollment. The administration of chelation infusions among post-[[MI]] [[diabetic]] patients was associated with a marked reduction in the primary end point when compared with placebo. The primary end point occurred in 25% of [[diabetic]] patients who were administered chelation therapy compared to 38% in those who received placebo infusions (HR, 0.59; 95% CI, 0.44–0.79; P<0.001). The 5-year NNT to prevent one event was 6.5. In addition, chelation therapy was significantly associated with decreased all-cause mortality (43% reduction, p=0.011) and reinfarction (52% reduction, p=0.015).<ref name="pmid24254885">{{cite journal| author=Escolar E, Lamas GA, Mark DB, Boineau R, Goertz C, Rosenberg Y et al.| title=The effect of an EDTA-based chelation regimen on patients with diabetes mellitus and prior myocardial infarction in the Trial to Assess Chelation Therapy (TACT). | journal=Circ Cardiovasc Qual Outcomes | year= 2014 | volume= 7 | issue= 1 | pages= 15-24 | pmid=24254885 | doi=10.1161/CIRCOUTCOMES.113.000663 | pmc=4111470 | url=https://www.ncbi.nlm.nih.gov/entrez/eutils/elink.fcgi?dbfrom=pubmed&tool=sumsearch.org/cite&retmode=ref&cmd=prlinks&id=24254885 }} </ref> Again, the investigators concluded that these findings supported future research, but did not constitute sufficient evidence to indicate the routine use of [[chelation therapy]] for all post–[[MI]] patients with [[diabetes]], leaving open the clinician’s choice to use this novel therapy in occasional, or non-routine patients.<br />
<br />
These results catalyzed a wave of increased public and scientific interest in disodium [[EDTA]] treatment for patients with established [[coronary disease]], particularly in [[diabetes]], and hypotheses regarding potential mechanisms of benefit. As a capstone to the published analyses, the ACC/AHA Guidelines for Chronic Ischemic Heart Disease changed to reflect the TACT data and upgraded disodium EDTA treatment from a Class III indication to a Class IIB indication. While Class III therapeutics are considered not beneficial or useful, Class IIB treatments can be considered in some patients and require additional research to establish efficacy.<ref name="pmid25077860">{{cite journal| author=Fihn SD, Blankenship JC, Alexander KP, Bittl JA, Byrne JG, Fletcher BJ et al.| title=2014 ACC/AHA/AATS/PCNA/SCAI/STS focused update of the guideline for the diagnosis and management of patients with stable ischemic heart disease: a report of the American College of Cardiology/American Heart Association Task Force on Practice Guidelines, and the American Association for Thoracic Surgery, Preventive Cardiovascular Nurses Association, Society for Cardiovascular Angiography and Interventions, and Society of Thoracic Surgeons. | journal=J Am Coll Cardiol | year= 2014 | volume= 64 | issue= 18 | pages= 1929-49 | pmid=25077860 | doi=10.1016/j.jacc.2014.07.017 | pmc= | url=https://www.ncbi.nlm.nih.gov/entrez/eutils/elink.fcgi?dbfrom=pubmed&tool=sumsearch.org/cite&retmode=ref&cmd=prlinks&id=25077860 }} </ref> The change in the guidelines signaled a major shift in the perception of chelation therapy among the medical establishment. The TACT data led clinicians to reconsider chelation objectively, and the investigators and many other academic cardiologists called for TACT2, a new trial to test the results of TACT, to be funded by the [[NIH]].<br />
<br />
==Mechanism of Action==<br />
[[Edetate disodium]] binds to metals and forms soluble complexes facilitating their subsequent excretion in the [[urine]].<ref name="pmid14000694">{{cite journal| author=WILDER LW, DE JODE LR, MILSTEIN SW, HOWARD JM| title=Mobilization of atherosclerotic plaque calcium with EDTA utilizing the isolation-perfusion principle. | journal=Surgery | year= 1962 | volume= 52 | issue= | pages= 793-5 | pmid=14000694 | doi= | pmc= | url=http://www.ncbi.nlm.nih.gov/entrez/eutils/elink.fcgi?dbfrom=pubmed&tool=sumsearch.org/cite&retmode=ref&cmd=prlinks&id=14000694 }} </ref> Hence, chelation therapy results in the elimination of stored toxic and essential metals. In an experiment performed on 24 patients, age 50 or older, and with a prior MI and a creatinine of 2.0 or less, patients had urine toxic metals measured at baseline, 1 day after an infusion of placebo, and 1 day after an infusion of the edetate disodium-based TACT solution. Placebo did not increase the excretion of toxic metals. Following an infusion of the edetate disodium-based TACT solution, lead excretion increased by nearly 3900%, and cadmium by nearly 700%. Other toxic metals whose excretion was enhanced by edetate disodium were aluminum (by ~250%), nickel (by ~150%), thallium (by ~60%), and gadolinium. A similar experiment performed earlier by Waters et al, reported urinary lead concentrations approximately 35 times greater than in pre-chelation urine.<ref name="pmid11794513">{{cite journal| author=Waters RS, Bryden NA, Patterson KY, Veillon C, Anderson RA| title=EDTA chelation effects on urinary losses of cadmium, calcium, chromium, cobalt, copper, lead, magnesium, and zinc. | journal=Biol Trace Elem Res | year= 2001 | volume= 83 | issue= 3 | pages= 207-21 | pmid=11794513 | doi=10.1385/BTER:83:3:207 | pmc= | url=https://www.ncbi.nlm.nih.gov/entrez/eutils/elink.fcgi?dbfrom=pubmed&tool=sumsearch.org/cite&retmode=ref&cmd=prlinks&id=11794513 }} </ref><br />
While enhanced lead and cadmium is interesting, the critical link to cardiovascular events is provided by epidemiological studies, which provide robust evidence linking toxic metals with [[cardiovascular disease]].<ref name="pmid21421632">{{cite journal| author=Agarwal S, Zaman T, Tuzcu EM, Kapadia SR| title=Heavy metals and cardiovascular disease: results from the National Health and Nutrition Examination Survey (NHANES) 1999-2006. | journal=Angiology | year= 2011 | volume= 62 | issue= 5 | pages= 422-9 | pmid=21421632 | doi=10.1177/0003319710395562 | pmc= | url=http://www.ncbi.nlm.nih.gov/entrez/eutils/elink.fcgi?dbfrom=pubmed&tool=sumsearch.org/cite&retmode=ref&cmd=prlinks&id=21421632 }} </ref> This evidence is strongest for lead and cadmium.<ref name="pmid16982939">{{cite journal| author=Menke A, Muntner P, Batuman V, Silbergeld EK, Guallar E| title=Blood lead below 0.48 micromol/L (10 microg/dL) and mortality among US adults. | journal=Circulation | year= 2006 | volume= 114 | issue= 13 | pages= 1388-94 | pmid=16982939 | doi=10.1161/CIRCULATIONAHA.106.628321 | pmc= | url=https://www.ncbi.nlm.nih.gov/entrez/eutils/elink.fcgi?dbfrom=pubmed&tool=sumsearch.org/cite&retmode=ref&cmd=prlinks&id=16982939 }} </ref><ref name="pmid15184277">{{cite journal| author=Navas-Acien A, Selvin E, Sharrett AR, Calderon-Aranda E, Silbergeld E, Guallar E| title=Lead, cadmium, smoking, and increased risk of peripheral arterial disease. | journal=Circulation | year= 2004 | volume= 109 | issue= 25 | pages= 3196-201 | pmid=15184277 | doi=10.1161/01.CIR.0000130848.18636.B2 | pmc= | url=http://www.ncbi.nlm.nih.gov/entrez/eutils/elink.fcgi?dbfrom=pubmed&tool=sumsearch.org/cite&retmode=ref&cmd=prlinks&id=15184277 }} </ref><ref name="pmid23514838">{{cite journal| author=Tellez-Plaza M, Guallar E, Howard BV, Umans JG, Francesconi KA, Goessler W et al.| title=Cadmium exposure and incident cardiovascular disease. | journal=Epidemiology | year= 2013 | volume= 24 | issue= 3 | pages= 421-9 | pmid=23514838 | doi=10.1097/EDE.0b013e31828b0631 | pmc= | url=http://www.ncbi.nlm.nih.gov/entrez/eutils/elink.fcgi?dbfrom=pubmed&tool=sumsearch.org/cite&retmode=ref&cmd=prlinks&id=23514838 }} </ref> Elevated blood concentration of [[lead]] is associated with increased all-cause mortality [HR 1.25 (95% CI 1.04 to 1.51) for the highest versus lowest tertile of blood lead, P trend across the tertiles=0.002) and cardiovascular mortality [HR 1.55 (95% CI 1.08 to 2.24) for the highest versus lowest tertile, P trend <0.003].<ref name="pmid16982939">{{cite journal| author=Menke A, Muntner P, Batuman V, Silbergeld EK, Guallar E| title=Blood lead below 0.48 micromol/L (10 microg/dL) and mortality among US adults. | journal=Circulation | year= 2006 | volume= 114 | issue= 13 | pages= 1388-94 | pmid=16982939 | doi=10.1161/CIRCULATIONAHA.106.628321 | pmc= | url=https://www.ncbi.nlm.nih.gov/entrez/eutils/elink.fcgi?dbfrom=pubmed&tool=sumsearch.org/cite&retmode=ref&cmd=prlinks&id=16982939 }} </ref> Also, cardiovascular mortality is greater among subjects with elevated [[cadmium]] concentrations in the blood and urine [HR 1.69 (95% CI: 1.03, 2.77) and 1.74 (95% CI: 1.07, 2.83) for the 80th and 20th percentiles of blood and urine cadmium, respectively].<ref name="pmid22472185">{{cite journal| author=Tellez-Plaza M, Navas-Acien A, Menke A, Crainiceanu CM, Pastor-Barriuso R, Guallar E| title=Cadmium exposure and all-cause and cardiovascular mortality in the U.S. general population. | journal=Environ Health Perspect | year= 2012 | volume= 120 | issue= 7 | pages= 1017-22 | pmid=22472185 | doi=10.1289/ehp.1104352 | pmc=3404657 | url=https://www.ncbi.nlm.nih.gov/entrez/eutils/elink.fcgi?dbfrom=pubmed&tool=sumsearch.org/cite&retmode=ref&cmd=prlinks&id=22472185 }} </ref> <br />
Heavy metals may play a role in the development of [[cardiovascular disease]] through a number of different mechanisms.<ref name="pmid17645641">{{cite journal| author=Vaziri ND, Khan M| title=Interplay of reactive oxygen species and nitric oxide in the pathogenesis of experimental lead-induced hypertension. | journal=Clin Exp Pharmacol Physiol | year= 2007 | volume= 34 | issue= 9 | pages= 920-5 | pmid=17645641 | doi=10.1111/j.1440-1681.2007.04644.x | pmc= | url=https://www.ncbi.nlm.nih.gov/entrez/eutils/elink.fcgi?dbfrom=pubmed&tool=sumsearch.org/cite&retmode=ref&cmd=prlinks&id=17645641 }} </ref> Heavy metals include transition metals such as [[cadmium]], [[mercury]], [[manganese]], [[chromium]], [[cobalt]], [[nickel]], [[iron]], and [[copper]], metalloids such as antimony and arsenic, and post- transition metals such as [[thallium]] and [[lead]]. These metals all have unique toxicities, as well as toxicities that are common to all of them. Heavy metals in the [[endothelium]] promote oxygen free radical formation, resulting in increased [[oxidative stress]], [[inflammation]], and tissue damage. [[Lead]] and [[cadmium]] may interfere with calcium signaling channels. Transition metals promote modifications of [[low-density lipoprotein]] by [[endothelial cell]]s through lipid peroxidation and degradation of low-density lipoprotein phospholipids.<ref name="pmid6587396">{{cite journal| author=Steinbrecher UP, Parthasarathy S, Leake DS, Witztum JL, Steinberg D| title=Modification of low density lipoprotein by endothelial cells involves lipid peroxidation and degradation of low density lipoprotein phospholipids. | journal=Proc Natl Acad Sci U S A | year= 1984 | volume= 81 | issue= 12 | pages= 3883-7 | pmid=6587396 | doi= | pmc=345326 | url=https://www.ncbi.nlm.nih.gov/entrez/eutils/elink.fcgi?dbfrom=pubmed&tool=sumsearch.org/cite&retmode=ref&cmd=prlinks&id=6587396 }} </ref><ref name="pmid6501577">{{cite journal| author=Heinecke JW, Rosen H, Chait A| title=Iron and copper promote modification of low density lipoprotein by human arterial smooth muscle cells in culture. | journal=J Clin Invest | year= 1984 | volume= 74 | issue= 5 | pages= 1890-4 | pmid=6501577 | doi=10.1172/JCI111609 | pmc=425370 | url=https://www.ncbi.nlm.nih.gov/entrez/eutils/elink.fcgi?dbfrom=pubmed&tool=sumsearch.org/cite&retmode=ref&cmd=prlinks&id=6501577 }} </ref><ref name="pmid8847477">{{cite journal| author=Morgan J, Leake DS| title=Oxidation of low density lipoprotein by iron or copper at acidic pH. | journal=J Lipid Res | year= 1995 | volume= 36 | issue= 12 | pages= 2504-12 | pmid=8847477 | doi= | pmc= | url=https://www.ncbi.nlm.nih.gov/entrez/eutils/elink.fcgi?dbfrom=pubmed&tool=sumsearch.org/cite&retmode=ref&cmd=prlinks&id=8847477 }} </ref> Exposure to non-transition metals, such as lead, has also been associated with impaired nitric oxide signaling and availability,<ref name="pmid15894814">{{cite journal| author=Dursun N, Arifoglu C, Süer C, Keskinol L| title=Blood pressure relationship to nitric oxide, lipid peroxidation, renal function, and renal blood flow in rats exposed to low lead levels. | journal=Biol Trace Elem Res | year= 2005 | volume= 104 | issue= 2 | pages= 141-9 | pmid=15894814 | doi=10.1385/BTER:104:2:141 | pmc= | url=https://www.ncbi.nlm.nih.gov/entrez/eutils/elink.fcgi?dbfrom=pubmed&tool=sumsearch.org/cite&retmode=ref&cmd=prlinks&id=15894814 }} </ref> endothelial cell dysfunction,<ref name="pmid7710289">{{cite journal| author=Kaji T, Suzuki M, Yamamoto C, Mishima A, Sakamoto M, Kozuka H| title=Severe damage of cultured vascular endothelial cell monolayer after simultaneous exposure to cadmium and lead. | journal=Arch Environ Contam Toxicol | year= 1995 | volume= 28 | issue= 2 | pages= 168-72 | pmid=7710289 | doi= | pmc= | url=https://www.ncbi.nlm.nih.gov/entrez/eutils/elink.fcgi?dbfrom=pubmed&tool=sumsearch.org/cite&retmode=ref&cmd=prlinks&id=7710289 }} </ref> and hypertension.<ref name="pmid18567711">{{cite journal| author=Vaziri ND| title=Mechanisms of lead-induced hypertension and cardiovascular disease. | journal=Am J Physiol Heart Circ Physiol | year= 2008 | volume= 295 | issue= 2 | pages= H454-65 | pmid=18567711 | doi=10.1152/ajpheart.00158.2008 | pmc=2519216 | url=https://www.ncbi.nlm.nih.gov/entrez/eutils/elink.fcgi?dbfrom=pubmed&tool=sumsearch.org/cite&retmode=ref&cmd=prlinks&id=18567711 }} </ref> [[Heavy metal]] exposure is also associated with genetic and [[epigenetic]] manifestations. [[Cadmium]] promotes atherosclerosis and endothelial dysfunction through multiple [[genetic]] changes.<ref name="pmid19556524">{{cite journal| author=Messner B, Knoflach M, Seubert A, Ritsch A, Pfaller K, Henderson B et al.| title=Cadmium is a novel and independent risk factor for early atherosclerosis mechanisms and in vivo relevance. | journal=Arterioscler Thromb Vasc Biol | year= 2009 | volume= 29 | issue= 9 | pages= 1392-8 | pmid=19556524 | doi=10.1161/ATVBAHA.109.190082 | pmc= | url=https://www.ncbi.nlm.nih.gov/entrez/eutils/elink.fcgi?dbfrom=pubmed&tool=sumsearch.org/cite&retmode=ref&cmd=prlinks&id=19556524 }} </ref> One of the mechanisms involves [[DNA]] strand breaks and damage with subsequent apoptosis in [[endothelial cell]]s.<ref name="pmid19556524">{{cite journal| author=Messner B, Knoflach M, Seubert A, Ritsch A, Pfaller K, Henderson B et al.| title=Cadmium is a novel and independent risk factor for early atherosclerosis mechanisms and in vivo relevance. | journal=Arterioscler Thromb Vasc Biol | year= 2009 | volume= 29 | issue= 9 | pages= 1392-8 | pmid=19556524 | doi=10.1161/ATVBAHA.109.190082 | pmc= | url=https://www.ncbi.nlm.nih.gov/entrez/eutils/elink.fcgi?dbfrom=pubmed&tool=sumsearch.org/cite&retmode=ref&cmd=prlinks&id=19556524 }} </ref> Also, maternal [[lead]] exposure during pregnancy may be associated with epigenetic consequences in grandchildren through alteration of [[DNA methylation]] early in life.<ref name="pmid26417717">{{cite journal| author=Sen A, Heredia N, Senut MC, Land S, Hollocher K, Lu X et al.| title=Multigenerational epigenetic inheritance in humans: DNA methylation changes associated with maternal exposure to lead can be transmitted to the grandchildren. | journal=Sci Rep | year= 2015 | volume= 5 | issue= | pages= 14466 | pmid=26417717 | doi=10.1038/srep14466 | pmc=4586440 | url=https://www.ncbi.nlm.nih.gov/entrez/eutils/elink.fcgi?dbfrom=pubmed&tool=sumsearch.org/cite&retmode=ref&cmd=prlinks&id=26417717 }} </ref><br />
<br />
Current mechanistic understanding, albeit rudimentary, supports the concept that the cardiovascular benefits of [[chelation therapy]] may result from enhanced excretion of [[heavy metals]], and subsequent reduction in processes listed above. Additionally, in patients with [[diabetes]], a reduction in the metal-catalyzed formation of [[reactive oxygen species]], formation of advanced glycation end-products, and lipid [[peroxidation]] has been postulated.<ref name="pmid10874253">{{cite journal| author=Lamas GA, Ackermann A| title=Clinical evaluation of chelation therapy: is there any wheat amidst the chaff? | journal=Am Heart J | year= 2000 | volume= 140 | issue= 1 | pages= 4-5 | pmid=10874253 | doi=10.1067/mhj.2000.107549 | pmc= | url=http://www.ncbi.nlm.nih.gov/entrez/eutils/elink.fcgi?dbfrom=pubmed&tool=sumsearch.org/cite&retmode=ref&cmd=prlinks&id=10874253 }} </ref> Metal detoxification in the context of [[diabetes]] possibly decreases [[inflammation]] and [[oxidative stress]] that characterize atherosclerosis.<ref>Escolar E, Lamas G, Mark D et al(2013) "The Effect of an EDTA-based Chelation Regimen on Patients With Diabetes Mellitus and Prior Myocardial Infarction in the Trial to Assess Chelation Therapy (TACT)". Circulation. 2013</ref> Recent research, including chelation-activity assays, indicates that many common [[diabetes]] drugs, such as [[metformin]] and aldose reductase inhibitors, could possibly have some chelating properties.<ref name="pmid22354928">{{cite journal| author=Nagai R, Murray DB, Metz TO, Baynes JW| title=Chelation: a fundamental mechanism of action of AGE inhibitors, AGE breakers, and other inhibitors of diabetes complications. | journal=Diabetes | year= 2012 | volume= 61 | issue= 3 | pages= 549-59 | pmid=22354928 | doi=10.2337/db11-1120 | pmc=3282805 | url=https://www.ncbi.nlm.nih.gov/entrez/eutils/elink.fcgi?dbfrom=pubmed&tool=sumsearch.org/cite&retmode=ref&cmd=prlinks&id=22354928 }} </ref><ref name="pmid23612664">{{cite journal| author=Frizzell N, Baynes JW| title=Chelation therapy for the management of diabetic complications: a hypothesis and a proposal for clinical laboratory assessment of metal ion homeostasis in plasma. | journal=Clin Chem Lab Med | year= 2014 | volume= 52 | issue= 1 | pages= 69-75 | pmid=23612664 | doi=10.1515/cclm-2012-0881 | pmc= | url=https://www.ncbi.nlm.nih.gov/entrez/eutils/elink.fcgi?dbfrom=pubmed&tool=sumsearch.org/cite&retmode=ref&cmd=prlinks&id=23612664 }} </ref><ref name="pmid22492524">{{cite journal| author=Logie L, Harthill J, Patel K, Bacon S, Hamilton DL, Macrae K et al.| title=Cellular responses to the metal-binding properties of metformin. | journal=Diabetes | year= 2012 | volume= 61 | issue= 6 | pages= 1423-33 | pmid=22492524 | doi=10.2337/db11-0961 | pmc=3357267 | url=https://www.ncbi.nlm.nih.gov/entrez/eutils/elink.fcgi?dbfrom=pubmed&tool=sumsearch.org/cite&retmode=ref&cmd=prlinks&id=22492524 }} </ref><br />
<br />
The TACT chelation infusion, however, did not contain edetate disodium alone. The standard chelation infusion formula used in TACT was formulated to be identical with the most prevalent infusion in use. This formulation had developed organically over decades and had been modified by clinical practitioners to have additives such as [[ascorbic acid]], B-vitamins and [[magnesium]], thought to have a protective effect on [[endothelial cells]],<ref>Rozema, Theodore C. "The protocol for the safe and effective administration of EDTA and other chelating agents for vascular disease, degenerative disease, and metal toxicity." Journal of Advancement in Medicine 10.1 (1997): 5-100.</ref> making the results of clinical application more difficult to understand, and emphasizing the need for mechanistic work.<br />
<br />
==Future Studies==<br />
TACT was a unique study with an unexpected result that could have vast public health implications. In order to consider its broad applicability, the medical and scientific community require the results reproduced. TACT2, scheduled to begin in October 2016 (press release), is a replicative study in post-MI diabetic patients. If the TACT2 results confirm the results of TACT, then chelation is poised to become the next major development in the treatment of vascular complications of diabetes and vascular disease. TACT2 is currently recruiting sites, and interested investigators should visit www.TACT2.org for additional information.<br />
<br />
==Side Effects==<br />
Shown below is a list of the labelled toxicities of EDTA-based chelation therapy. However, TACT delivered 55,222 infusions of EDTA or placebo, and found no differences between groups in adverse events, serious or otherwise.<br />
* [[Arrhythmias]]<br />
* [[Autoimmune diseases]]<br />
* [[Bone marrow]]<br />
* [[Convulsions]]<br />
* [[Depression]]<br />
* [[Fever]]<br />
* [[Heart failure]]<br />
* [[Hypocalcemia]]<br />
* [[Hypoglycemia]]<br />
* [[Hypotension]]<br />
* [[Bleeding time|Prolonged bleeding time]]<br />
* [[Renal failure]]<br />
* [[Respiratory arrest]]<br />
* [[Tetany]]<br />
* [[Trace metal|Trace metal deficiency]]<br />
* [[Vitamin deficiency]]<ref name="pmid10874275">{{cite journal| author=Ernst E| title=Chelation therapy for coronary heart disease: An overview of all clinical investigations. | journal=Am Heart J | year= 2000 | volume= 140 | issue= 1 | pages= 139-41 | pmid=10874275 | doi=10.1067/mhj.2000.107548 | pmc= | url=http://www.ncbi.nlm.nih.gov/entrez/eutils/elink.fcgi?dbfrom=pubmed&tool=sumsearch.org/cite&retmode=ref&cmd=prlinks&id=10874275 }} </ref><ref name="pmid23532240">{{cite journal| author=Lamas GA, Goertz C, Boineau R, Mark DB, Rozema T, Nahin RL et al.| title=Effect of disodium EDTA chelation regimen on cardiovascular events in patients with previous myocardial infarction: the TACT randomized trial. | journal=JAMA | year= 2013 | volume= 309 | issue= 12 | pages= 1241-50 | pmid=23532240 | doi=10.1001/jama.2013.2107 | pmc= | url=http://www.ncbi.nlm.nih.gov/entrez/eutils/elink.fcgi?dbfrom=pubmed&tool=sumsearch.org/cite&retmode=ref&cmd=prlinks&id=23532240 }} </ref><br />
<br />
==Landmark Trials==<br />
* [[TACT]] <br><br />
* TACT 2 [http://www.TACT2.org] (link to press release [http://www.prnewswire.com/news-releases/tact2-clinical-trial-receives-national-institutes-of-health-funding-300334174.html])<br />
<br />
==References==<br />
{{Reflist|2}}<br />
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[[Category:Cardiology]]<br />
[[Category:Diabetes]]<br />
[[Category:Up-To-Date]]<br />
<br />
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{{WikiDoc Sources}}</div>Rim Halabyhttps://www.wikidoc.org/index.php?title=Chelation_therapy_for_cardiovascular_disease&diff=1274904Chelation therapy for cardiovascular disease2016-12-08T00:42:29Z<p>Rim Halaby: </p>
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<div>__NOTOC__<br />
'''Editor-In-Chief:''' Gervasio Lamas, M.D., C. Michael Gibson, M.S., M.D.; {{AE}} {{Rim}}, Ian Ergui, B.Sc.<br />
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'''[[Chelation therapy|To read more about chelation therapy click here.]]'''<br><br />
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{{SK}} Chelation therapy, EDTA, post-myocardial infarction, diabetes<br />
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==Overview==<br />
[[Chelation]] is a process by which an organic molecule with a negatively charged “pocket” complexes with a metal ion of opposite charge, inactivates it, and then permits its physiological mobilization and excretion, usually by a renal route. [[Chelation therapy]], which involves multiple administrations of a chelating agent, helps eliminate stored toxic metal ions from the body.<ref name="pmid11794513">{{cite journal| author=Waters RS, Bryden NA, Patterson KY, Veillon C, Anderson RA| title=EDTA chelation effects on urinary losses of cadmium, calcium, chromium, cobalt, copper, lead, magnesium, and zinc. | journal=Biol Trace Elem Res | year= 2001 | volume= 83 | issue= 3 | pages= 207-21 | pmid=11794513 | doi=10.1385/BTER:83:3:207 | pmc= | url=https://www.ncbi.nlm.nih.gov/entrez/eutils/elink.fcgi?dbfrom=pubmed&tool=sumsearch.org/cite&retmode=ref&cmd=prlinks&id=11794513 }} </ref><ref name="arenas">Arenas I.A., Navas-Acien A., Lamas G.A.; Enhanced vasculotoxic metal excretionin post-MI patients after edetate disodium therapy (abstr). J Am Coll Cardiol. 2016;67:A2125</ref> Common chelators include [[penicillamine]], which binds copper and can be used to treat [[Wilson’s disease]], [[deferoxamine]], which binds iron and is used in the treatment of [[thalassemia]] and iron overload, succimer, also used in the treatment of lead poisoning, and the edetates, non-specific chelators of metals and other ions with valences of +2 to +6. Chelation therapy is, in many cases, guideline mandated, such as in children with elevated blood lead levels,<ref name="CDC">CDC. Low Level Lead Exposure Harms Children: A Renewed Call for Primary Prevention. Atlanta, GA:Advisory Committee on Childhood Lead Poisoning Prevention, U.S. Centers for Disease Control and Prevention (4 Jan 2012). Available: [http://www.cdc.gov/nceh/lead/acclpp/final_document_010412.pdf]</ref> patients with iron overload and dyserythropoietic syndromes or chronic [[hemolytic anemia]],<ref name="pmid21452290">{{cite journal| author=Bacon BR, Adams PC, Kowdley KV, Powell LW, Tavill AS, American Association for the Study of Liver Diseases| title=Diagnosis and management of hemochromatosis: 2011 practice guideline by the American Association for the Study of Liver Diseases. | journal=Hepatology | year= 2011 | volume= 54 | issue= 1 | pages= 328-43 | pmid=21452290 | doi=10.1002/hep.24330 | pmc=3149125 | url=https://www.ncbi.nlm.nih.gov/entrez/eutils/elink.fcgi?dbfrom=pubmed&tool=sumsearch.org/cite&retmode=ref&cmd=prlinks&id=21452290 }} </ref> or [[sickle cell disease]] and transfusion acquired iron-overload,<ref name="NHLBI">NHLBI. Transfusion in Sickle Cell Disease: A Systematic Review of Benefits, Complications, and Management of Complications. Prepared for the National Heart, Lung, and Blood Institute and by the Knowledge and Evaluation Research Unit, Mayo Clinic Rochester (2012)</ref> to name a few instances.<br />
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[[Ethylene diamine tetraacetic acid]] ([[EDTA]], [[edetate]]) and its salts (most commonly disodium or calcium disodium), commonly used chelating agents patented in 1938, bind to and permit the urinary excretion of divalent cations such as calcium, and metals such as [[lead]], [[cadmium]], [[nickel]], [[cobalt]], [[iron]], [[aluminum]], and others. The initial medical use for [[EDTA]] began after World War II for the treatment of [[lead]]-exposed naval workers. In addition to its use for the treatment of metal poisoning, since the 1950s chelation therapy has been considered an alternative or add-on therapy for the prevention and treatment of [[atherosclerotic disease]]. The use of edetate disodium (Na2EDTA) has been most prominent in the alternative medicine treatment of [[atherosclerosis]] primarily because of the still-unproven hypothesis that the [[hypocalcemia]] it induces might lead to the decalcification of atherosclerotic lesions. In fact, the most current research suggests that the probable mechanism of benefit centers on enhancement of toxic metal excretion.<br />
<br />
==Chelation Therapy and CVD==<br />
The use of chelation therapy as a treatment for [[atherosclerotic disease]] dates back to the 1950’s when Clarke et al investigated the use of EDTA for the treatment of [[angina pectoris]] and reported improvement in 19 of 20 patients.<ref name="pmid13372537">{{cite journal| author=CLARKE CN, CLARKE NE, MOSHER RE| title=Treatment of angina pectoris with disodium ethylene diamine tetraacetic acid. | journal=Am J Med Sci | year= 1956 | volume= 232 | issue= 6 | pages= 654-66 | pmid=13372537 | doi= | pmc= | url=http://www.ncbi.nlm.nih.gov/entrez/eutils/elink.fcgi?dbfrom=pubmed&tool=sumsearch.org/cite&retmode=ref&cmd=prlinks&id=13372537 }} </ref> Later studies by Kitchell were less positive,<ref name="pmid13756462">{{cite journal| author=KITCHELL JR, MELTZER LE, SEVEN MJ| title=Potential uses of chelation methods in the treatment of cardiovascular diseases. | journal=Prog Cardiovasc Dis | year= 1961 | volume= 3 | issue= | pages= 338-49 | pmid=13756462 | doi= | pmc= | url=https://www.ncbi.nlm.nih.gov/entrez/eutils/elink.fcgi?dbfrom=pubmed&tool=sumsearch.org/cite&retmode=ref&cmd=prlinks&id=13756462 }} </ref><ref name="pmid14033183">{{cite journal| author=KITCHELL JR, PALMON F, AYTAN N, MELTZER LE| title=The treatment of coronary artery disease with disodium EDTA. A reappraisal. | journal=Am J Cardiol | year= 1963 | volume= 11 | issue= | pages= 501-6 | pmid=14033183 | doi= | pmc= | url=https://www.ncbi.nlm.nih.gov/entrez/eutils/elink.fcgi?dbfrom=pubmed&tool=sumsearch.org/cite&retmode=ref&cmd=prlinks&id=14033183 }} </ref> and in an era without modern clinical trials methodology nor effective concomitant therapies, opinions regarding the use of [[chelation therapy]] for [[cardiovascular disease]] (CVD) tilted towards the negative. To be fair, from the 1970’s to 1990’s the preponderance of the scientific literature on [[chelation therapy]] for [[atherosclerosis]] consisted of case reports, case series, and small clinical trials with surrogate endpoints, poor-quality evidence from which to draw a conclusion of efficacy or harm.<ref name="pmid12519577">{{cite journal| author=Villarruz MV, Dans A, Tan F| title=Chelation therapy for atherosclerotic cardiovascular disease. | journal=Cochrane Database Syst Rev | year= 2002 | volume= | issue= 4 | pages= CD002785 | pmid=12519577 | doi=10.1002/14651858.CD002785 | pmc= | url=http://www.ncbi.nlm.nih.gov/entrez/eutils/elink.fcgi?dbfrom=pubmed&tool=sumsearch.org/cite&retmode=ref&cmd=prlinks&id=12519577 }} </ref><br />
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For example, one extensive case series reported an association between EDTA chelation therapy and improvement of [[ischemic heart disease]] and [[peripheral artery disease]].<ref name="pmid3144646">{{cite journal| author=Olszewer E, Carter JP| title=EDTA chelation therapy in chronic degenerative disease. | journal=Med Hypotheses | year= 1988 | volume= 27 | issue= 1 | pages= 41-9 | pmid=3144646 | doi= | pmc= | url=http://www.ncbi.nlm.nih.gov/entrez/eutils/elink.fcgi?dbfrom=pubmed&tool=sumsearch.org/cite&retmode=ref&cmd=prlinks&id=3144646 }} </ref> Another study demonstrated that EDTA supplemented with several B vitamins (vitamin B1, B2, B6 and B12) but not EDTA alone was effective in improving [[endothelium]]-dependent forearm blood flow.<ref name="pmid10561804">{{cite journal| author=Green DJ, O'Driscoll JG, Maiorana A, Scrimgeour NB, Weerasooriya R, Taylor RR| title=Effects of chelation with EDTA and vitamin B therapy on nitric oxide-related endothelial vasodilator function. | journal=Clin Exp Pharmacol Physiol | year= 1999 | volume= 26 | issue= 11 | pages= 853-6 | pmid=10561804 | doi= | pmc= | url=http://www.ncbi.nlm.nih.gov/entrez/eutils/elink.fcgi?dbfrom=pubmed&tool=sumsearch.org/cite&retmode=ref&cmd=prlinks&id=10561804 }} </ref> A systematic review of four [[randomized clinical trial]]s on chelation therapy and [[peripheral artery occlusive disease]] reported no benefit associated with [[chelation therapy]].<ref name="pmid9264515">{{cite journal| author=Ernst E| title=Chelation therapy for peripheral arterial occlusive disease: a systematic review. | journal=Circulation | year= 1997 | volume= 96 | issue= 3 | pages= 1031-3 | pmid=9264515 | doi= | pmc= | url=http://www.ncbi.nlm.nih.gov/entrez/eutils/elink.fcgi?dbfrom=pubmed&tool=sumsearch.org/cite&retmode=ref&cmd=prlinks&id=9264515 }} </ref> The studies, however, individually and in aggregate, were too small to exclude a small to moderate benefit of therapy. Moreover, follow up was short and surrogate physiologic endpoints, such as walking distance, were used. A Cochrane systematic review on the role of chelation therapy to treat [[coronary heart disease]] in 2002 concluded that the data were insufficient to recommend for or against chelation.<ref name="pmid10874275">{{cite journal| author=Ernst E| title=Chelation therapy for coronary heart disease: An overview of all clinical investigations. | journal=Am Heart J | year= 2000 | volume= 140 | issue= 1 | pages= 139-41 | pmid=10874275 | doi=10.1067/mhj.2000.107548 | pmc= | url=http://www.ncbi.nlm.nih.gov/entrez/eutils/elink.fcgi?dbfrom=pubmed&tool=sumsearch.org/cite&retmode=ref&cmd=prlinks&id=10874275 }} </ref> The medical community concluded that the absence of high quality evidence of efficacy equated with evidence of absence of efficacy. Professional organizations recommended against [[chelation therapy]].<ref name="pmid9205980">{{cite journal| author=Lewin MR| title=Chelation therapy for cardiovascular disease. Review and commentary. | journal=Tex Heart Inst J | year= 1997 | volume= 24 | issue= 2 | pages= 81-9 | pmid=9205980 | doi= | pmc=325409 | url=https://www.ncbi.nlm.nih.gov/entrez/eutils/elink.fcgi?dbfrom=pubmed&tool=sumsearch.org/cite&retmode=ref&cmd=prlinks&id=9205980 }} </ref> Interestingly, patients continued to seek, and practitioners to administer, chelation infusions for [[cardiovascular disease]] and other diagnoses.<br />
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In light of the persistent controversy regarding the benefits of chelation therapy and the absence of any previous large clinical trial investigating its use in coronary artery disease, the National Center for Complementary and Alternative Medicine and the National Heart Lung and Blood Institute released a $30 million Request for Applications (RFA) to develop a definitive trial. In 2002, the RFA was awarded to Mount Sinai Medical Center in Miami Beach FL (G Lamas MD, Principal Investigator). The Trial to Assess Chelation Therapy (TACT), a randomized, double blind, placebo controlled 2x2 factorial trial, investigated the efficacy and safety of disodium EDTA based infusions and high-dose oral vitamins and minerals in 1708 stable post-myocardial infarction (MI) patients more than 50 years of age and with fairly normal kidney function ([[creatinine]] 2.0 mg/dL or less). The active treatment consisted of 40 infusions consisted of disodium [[EDTA]] combined with [[ascorbic acid]], B vitamins, and other components. The median age of patients was 65 years, and they were treated with evidence-based post-MI medicines. The primary endpoint of this trial was a composite of all-cause mortality, [[stroke]], [[MI]], coronary revascularization, and hospitalization for [[angina]]. A follow up period of 55 months revealed a statistically significant decrease in the primary endpoint (HR: 0.82; 95% CI: 0.69-0.99; p= 0.035). There was an absolute reduction in the 5-year Kaplan-Meier estimate, from 38% to 33%, resulting in a 5-year number needed to treat (NNT) of 18 patients to avoid one adverse cardiovascular outcome. This is comparable to the 5-year NNT for [[statins]] in post-[[MI]] patients (NNT=16 for the secondary prevention of a major coronary event). The point estimate for the risk of each of the components of the primary endpoint was <1, consistent with the aggregate result. The Investigators concluded that chelation should not yet be adopted for routine post-[[MI]] use in all patients, but the results of TACT should inform further studies to confirm or refute these unexpected results.<ref name="pmid23532240">{{cite journal| author=Lamas GA, Goertz C, Boineau R, Mark DB, Rozema T, Nahin RL et al.| title=Effect of disodium EDTA chelation regimen on cardiovascular events in patients with previous myocardial infarction: the TACT randomized trial. | journal=JAMA | year= 2013 | volume= 309 | issue= 12 | pages= 1241-50 | pmid=23532240 | doi=10.1001/jama.2013.2107 | pmc= | url=http://www.ncbi.nlm.nih.gov/entrez/eutils/elink.fcgi?dbfrom=pubmed&tool=sumsearch.org/cite&retmode=ref&cmd=prlinks&id=23532240 }} </ref><br />
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TACT prespecified several subgroups for analysis and found a significant interaction between edetate disodium treatment and [[diabetes]] (p for interaction =0.0037). Among subjects enrolled in TACT, there were 633 [[diabetic]] patients, defined as patients with self-reported [[diabetes]], taking medications for [[diabetes]], or having a fasting blood glucose of at least 126 mg/dL at enrollment. The administration of chelation infusions among post-[[MI]] [[diabetic]] patients was associated with a marked reduction in the primary end point when compared with placebo. The primary end point occurred in 25% of [[diabetic]] patients who were administered chelation therapy compared to 38% in those who received placebo infusions (HR, 0.59; 95% CI, 0.44–0.79; P<0.001). The 5-year NNT to prevent one event was 6.5. In addition, chelation therapy was significantly associated with decreased all-cause mortality (43% reduction, p=0.011) and reinfarction (52% reduction, p=0.015).<ref name="pmid24254885">{{cite journal| author=Escolar E, Lamas GA, Mark DB, Boineau R, Goertz C, Rosenberg Y et al.| title=The effect of an EDTA-based chelation regimen on patients with diabetes mellitus and prior myocardial infarction in the Trial to Assess Chelation Therapy (TACT). | journal=Circ Cardiovasc Qual Outcomes | year= 2014 | volume= 7 | issue= 1 | pages= 15-24 | pmid=24254885 | doi=10.1161/CIRCOUTCOMES.113.000663 | pmc=4111470 | url=https://www.ncbi.nlm.nih.gov/entrez/eutils/elink.fcgi?dbfrom=pubmed&tool=sumsearch.org/cite&retmode=ref&cmd=prlinks&id=24254885 }} </ref> Again, the investigators concluded that these findings supported future research, but did not constitute sufficient evidence to indicate the routine use of [[chelation therapy]] for all post–[[MI]] patients with [[diabetes]], leaving open the clinician’s choice to use this novel therapy in occasional, or non-routine patients.<br />
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These results catalyzed a wave of increased public and scientific interest in disodium [[EDTA]] treatment for patients with established [[coronary disease]], particularly in [[diabetes]], and hypotheses regarding potential mechanisms of benefit. As a capstone to the published analyses, the ACC/AHA Guidelines for Chronic Ischemic Heart Disease changed to reflect the TACT data and upgraded disodium EDTA treatment from a Class III indication to a Class IIB indication. While Class III therapeutics are considered not beneficial or useful, Class IIB treatments can be considered in some patients and require additional research to establish efficacy.<ref name="pmid25077860">{{cite journal| author=Fihn SD, Blankenship JC, Alexander KP, Bittl JA, Byrne JG, Fletcher BJ et al.| title=2014 ACC/AHA/AATS/PCNA/SCAI/STS focused update of the guideline for the diagnosis and management of patients with stable ischemic heart disease: a report of the American College of Cardiology/American Heart Association Task Force on Practice Guidelines, and the American Association for Thoracic Surgery, Preventive Cardiovascular Nurses Association, Society for Cardiovascular Angiography and Interventions, and Society of Thoracic Surgeons. | journal=J Am Coll Cardiol | year= 2014 | volume= 64 | issue= 18 | pages= 1929-49 | pmid=25077860 | doi=10.1016/j.jacc.2014.07.017 | pmc= | url=https://www.ncbi.nlm.nih.gov/entrez/eutils/elink.fcgi?dbfrom=pubmed&tool=sumsearch.org/cite&retmode=ref&cmd=prlinks&id=25077860 }} </ref> The change in the guidelines signaled a major shift in the perception of chelation therapy among the medical establishment. The TACT data led clinicians to reconsider chelation objectively, and the investigators and many other academic cardiologists called for TACT2, a new trial to test the results of TACT, to be funded by the [[NIH]].<br />
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==Mechanism of Action==<br />
[[Edetate disodium]] binds to metals and forms soluble complexes facilitating their subsequent excretion in the [[urine]].<ref name="pmid14000694">{{cite journal| author=WILDER LW, DE JODE LR, MILSTEIN SW, HOWARD JM| title=Mobilization of atherosclerotic plaque calcium with EDTA utilizing the isolation-perfusion principle. | journal=Surgery | year= 1962 | volume= 52 | issue= | pages= 793-5 | pmid=14000694 | doi= | pmc= | url=http://www.ncbi.nlm.nih.gov/entrez/eutils/elink.fcgi?dbfrom=pubmed&tool=sumsearch.org/cite&retmode=ref&cmd=prlinks&id=14000694 }} </ref> Hence, chelation therapy results in the elimination of stored toxic and essential metals. In an experiment performed on 24 patients, age 50 or older, and with a prior MI and a creatinine of 2.0 or less, patients had urine toxic metals measured at baseline, 1 day after an infusion of placebo, and 1 day after an infusion of the edetate disodium-based TACT solution. Placebo did not increase the excretion of toxic metals. Following an infusion of the edetate disodium-based TACT solution, lead excretion increased by nearly 3900%, and cadmium by nearly 700%. Other toxic metals whose excretion was enhanced by edetate disodium were aluminum (by ~250%), nickel (by ~150%), thallium (by ~60%), and gadolinium. A similar experiment performed earlier by Waters et al, reported urinary lead concentrations approximately 35 times greater than in pre-chelation urine.<ref name="pmid11794513">{{cite journal| author=Waters RS, Bryden NA, Patterson KY, Veillon C, Anderson RA| title=EDTA chelation effects on urinary losses of cadmium, calcium, chromium, cobalt, copper, lead, magnesium, and zinc. | journal=Biol Trace Elem Res | year= 2001 | volume= 83 | issue= 3 | pages= 207-21 | pmid=11794513 | doi=10.1385/BTER:83:3:207 | pmc= | url=https://www.ncbi.nlm.nih.gov/entrez/eutils/elink.fcgi?dbfrom=pubmed&tool=sumsearch.org/cite&retmode=ref&cmd=prlinks&id=11794513 }} </ref><br />
While enhanced lead and cadmium is interesting, the critical link to cardiovascular events is provided by epidemiological studies, which provide robust evidence linking toxic metals with [[cardiovascular disease]].<ref name="pmid21421632">{{cite journal| author=Agarwal S, Zaman T, Tuzcu EM, Kapadia SR| title=Heavy metals and cardiovascular disease: results from the National Health and Nutrition Examination Survey (NHANES) 1999-2006. | journal=Angiology | year= 2011 | volume= 62 | issue= 5 | pages= 422-9 | pmid=21421632 | doi=10.1177/0003319710395562 | pmc= | url=http://www.ncbi.nlm.nih.gov/entrez/eutils/elink.fcgi?dbfrom=pubmed&tool=sumsearch.org/cite&retmode=ref&cmd=prlinks&id=21421632 }} </ref> This evidence is strongest for lead and cadmium.<ref name="pmid16982939">{{cite journal| author=Menke A, Muntner P, Batuman V, Silbergeld EK, Guallar E| title=Blood lead below 0.48 micromol/L (10 microg/dL) and mortality among US adults. | journal=Circulation | year= 2006 | volume= 114 | issue= 13 | pages= 1388-94 | pmid=16982939 | doi=10.1161/CIRCULATIONAHA.106.628321 | pmc= | url=https://www.ncbi.nlm.nih.gov/entrez/eutils/elink.fcgi?dbfrom=pubmed&tool=sumsearch.org/cite&retmode=ref&cmd=prlinks&id=16982939 }} </ref><ref name="pmid15184277">{{cite journal| author=Navas-Acien A, Selvin E, Sharrett AR, Calderon-Aranda E, Silbergeld E, Guallar E| title=Lead, cadmium, smoking, and increased risk of peripheral arterial disease. | journal=Circulation | year= 2004 | volume= 109 | issue= 25 | pages= 3196-201 | pmid=15184277 | doi=10.1161/01.CIR.0000130848.18636.B2 | pmc= | url=http://www.ncbi.nlm.nih.gov/entrez/eutils/elink.fcgi?dbfrom=pubmed&tool=sumsearch.org/cite&retmode=ref&cmd=prlinks&id=15184277 }} </ref><ref name="pmid23514838">{{cite journal| author=Tellez-Plaza M, Guallar E, Howard BV, Umans JG, Francesconi KA, Goessler W et al.| title=Cadmium exposure and incident cardiovascular disease. | journal=Epidemiology | year= 2013 | volume= 24 | issue= 3 | pages= 421-9 | pmid=23514838 | doi=10.1097/EDE.0b013e31828b0631 | pmc= | url=http://www.ncbi.nlm.nih.gov/entrez/eutils/elink.fcgi?dbfrom=pubmed&tool=sumsearch.org/cite&retmode=ref&cmd=prlinks&id=23514838 }} </ref> Elevated blood concentration of [[lead]] is associated with increased all-cause mortality [HR 1.25 (95% CI 1.04 to 1.51) for the highest versus lowest tertile of blood lead, P trend across the tertiles=0.002) and cardiovascular mortality [HR 1.55 (95% CI 1.08 to 2.24) for the highest versus lowest tertile, P trend <0.003].<ref name="pmid16982939">{{cite journal| author=Menke A, Muntner P, Batuman V, Silbergeld EK, Guallar E| title=Blood lead below 0.48 micromol/L (10 microg/dL) and mortality among US adults. | journal=Circulation | year= 2006 | volume= 114 | issue= 13 | pages= 1388-94 | pmid=16982939 | doi=10.1161/CIRCULATIONAHA.106.628321 | pmc= | url=https://www.ncbi.nlm.nih.gov/entrez/eutils/elink.fcgi?dbfrom=pubmed&tool=sumsearch.org/cite&retmode=ref&cmd=prlinks&id=16982939 }} </ref> Also, cardiovascular mortality is greater among subjects with elevated [[cadmium]] concentrations in the blood and urine [HR 1.69 (95% CI: 1.03, 2.77) and 1.74 (95% CI: 1.07, 2.83) for the 80th and 20th percentiles of blood and urine cadmium, respectively].<ref name="pmid22472185">{{cite journal| author=Tellez-Plaza M, Navas-Acien A, Menke A, Crainiceanu CM, Pastor-Barriuso R, Guallar E| title=Cadmium exposure and all-cause and cardiovascular mortality in the U.S. general population. | journal=Environ Health Perspect | year= 2012 | volume= 120 | issue= 7 | pages= 1017-22 | pmid=22472185 | doi=10.1289/ehp.1104352 | pmc=3404657 | url=https://www.ncbi.nlm.nih.gov/entrez/eutils/elink.fcgi?dbfrom=pubmed&tool=sumsearch.org/cite&retmode=ref&cmd=prlinks&id=22472185 }} </ref> <br />
Heavy metals may play a role in the development of [[cardiovascular disease]] through a number of different mechanisms.<ref name="pmid17645641">{{cite journal| author=Vaziri ND, Khan M| title=Interplay of reactive oxygen species and nitric oxide in the pathogenesis of experimental lead-induced hypertension. | journal=Clin Exp Pharmacol Physiol | year= 2007 | volume= 34 | issue= 9 | pages= 920-5 | pmid=17645641 | doi=10.1111/j.1440-1681.2007.04644.x | pmc= | url=https://www.ncbi.nlm.nih.gov/entrez/eutils/elink.fcgi?dbfrom=pubmed&tool=sumsearch.org/cite&retmode=ref&cmd=prlinks&id=17645641 }} </ref> Heavy metals include transition metals such as [[cadmium]], [[mercury]], [[manganese]], [[chromium]], [[cobalt]], [[nickel]], [[iron]], and [[copper]], metalloids such as antimony and arsenic, and post- transition metals such as [[thallium]] and [[lead]]. These metals all have unique toxicities, as well as toxicities that are common to all of them. Heavy metals in the [[endothelium]] promote oxygen free radical formation, resulting in increased [[oxidative stress]], [[inflammation]], and tissue damage. [[Lead]] and [[cadmium]] may interfere with calcium signaling channels. Transition metals promote modifications of [[low-density lipoprotein]] by [[endothelial cell]]s through lipid peroxidation and degradation of low-density lipoprotein phospholipids.<ref name="pmid6587396">{{cite journal| author=Steinbrecher UP, Parthasarathy S, Leake DS, Witztum JL, Steinberg D| title=Modification of low density lipoprotein by endothelial cells involves lipid peroxidation and degradation of low density lipoprotein phospholipids. | journal=Proc Natl Acad Sci U S A | year= 1984 | volume= 81 | issue= 12 | pages= 3883-7 | pmid=6587396 | doi= | pmc=345326 | url=https://www.ncbi.nlm.nih.gov/entrez/eutils/elink.fcgi?dbfrom=pubmed&tool=sumsearch.org/cite&retmode=ref&cmd=prlinks&id=6587396 }} </ref><ref name="pmid6501577">{{cite journal| author=Heinecke JW, Rosen H, Chait A| title=Iron and copper promote modification of low density lipoprotein by human arterial smooth muscle cells in culture. | journal=J Clin Invest | year= 1984 | volume= 74 | issue= 5 | pages= 1890-4 | pmid=6501577 | doi=10.1172/JCI111609 | pmc=425370 | url=https://www.ncbi.nlm.nih.gov/entrez/eutils/elink.fcgi?dbfrom=pubmed&tool=sumsearch.org/cite&retmode=ref&cmd=prlinks&id=6501577 }} </ref><ref name="pmid8847477">{{cite journal| author=Morgan J, Leake DS| title=Oxidation of low density lipoprotein by iron or copper at acidic pH. | journal=J Lipid Res | year= 1995 | volume= 36 | issue= 12 | pages= 2504-12 | pmid=8847477 | doi= | pmc= | url=https://www.ncbi.nlm.nih.gov/entrez/eutils/elink.fcgi?dbfrom=pubmed&tool=sumsearch.org/cite&retmode=ref&cmd=prlinks&id=8847477 }} </ref> Exposure to non-transition metals, such as lead, has also been associated with impaired nitric oxide signaling and availability,<ref name="pmid15894814">{{cite journal| author=Dursun N, Arifoglu C, Süer C, Keskinol L| title=Blood pressure relationship to nitric oxide, lipid peroxidation, renal function, and renal blood flow in rats exposed to low lead levels. | journal=Biol Trace Elem Res | year= 2005 | volume= 104 | issue= 2 | pages= 141-9 | pmid=15894814 | doi=10.1385/BTER:104:2:141 | pmc= | url=https://www.ncbi.nlm.nih.gov/entrez/eutils/elink.fcgi?dbfrom=pubmed&tool=sumsearch.org/cite&retmode=ref&cmd=prlinks&id=15894814 }} </ref> endothelial cell dysfunction,<ref name="pmid7710289">{{cite journal| author=Kaji T, Suzuki M, Yamamoto C, Mishima A, Sakamoto M, Kozuka H| title=Severe damage of cultured vascular endothelial cell monolayer after simultaneous exposure to cadmium and lead. | journal=Arch Environ Contam Toxicol | year= 1995 | volume= 28 | issue= 2 | pages= 168-72 | pmid=7710289 | doi= | pmc= | url=https://www.ncbi.nlm.nih.gov/entrez/eutils/elink.fcgi?dbfrom=pubmed&tool=sumsearch.org/cite&retmode=ref&cmd=prlinks&id=7710289 }} </ref> and hypertension.<ref name="pmid18567711">{{cite journal| author=Vaziri ND| title=Mechanisms of lead-induced hypertension and cardiovascular disease. | journal=Am J Physiol Heart Circ Physiol | year= 2008 | volume= 295 | issue= 2 | pages= H454-65 | pmid=18567711 | doi=10.1152/ajpheart.00158.2008 | pmc=2519216 | url=https://www.ncbi.nlm.nih.gov/entrez/eutils/elink.fcgi?dbfrom=pubmed&tool=sumsearch.org/cite&retmode=ref&cmd=prlinks&id=18567711 }} </ref> [[Heavy metal]] exposure is also associated with genetic and [[epigenetic]] manifestations. [[Cadmium]] promotes atherosclerosis and endothelial dysfunction through multiple [[genetic]] changes.<ref name="pmid19556524">{{cite journal| author=Messner B, Knoflach M, Seubert A, Ritsch A, Pfaller K, Henderson B et al.| title=Cadmium is a novel and independent risk factor for early atherosclerosis mechanisms and in vivo relevance. | journal=Arterioscler Thromb Vasc Biol | year= 2009 | volume= 29 | issue= 9 | pages= 1392-8 | pmid=19556524 | doi=10.1161/ATVBAHA.109.190082 | pmc= | url=https://www.ncbi.nlm.nih.gov/entrez/eutils/elink.fcgi?dbfrom=pubmed&tool=sumsearch.org/cite&retmode=ref&cmd=prlinks&id=19556524 }} </ref> One of the mechanisms involves [[DNA]] strand breaks and damage with subsequent apoptosis in [[endothelial cell]]s.<ref name="pmid19556524">{{cite journal| author=Messner B, Knoflach M, Seubert A, Ritsch A, Pfaller K, Henderson B et al.| title=Cadmium is a novel and independent risk factor for early atherosclerosis mechanisms and in vivo relevance. | journal=Arterioscler Thromb Vasc Biol | year= 2009 | volume= 29 | issue= 9 | pages= 1392-8 | pmid=19556524 | doi=10.1161/ATVBAHA.109.190082 | pmc= | url=https://www.ncbi.nlm.nih.gov/entrez/eutils/elink.fcgi?dbfrom=pubmed&tool=sumsearch.org/cite&retmode=ref&cmd=prlinks&id=19556524 }} </ref> Also, maternal [[lead]] exposure during pregnancy may be associated with epigenetic consequences in grandchildren through alteration of [[DNA methylation]] early in life.<ref name="pmid26417717">{{cite journal| author=Sen A, Heredia N, Senut MC, Land S, Hollocher K, Lu X et al.| title=Multigenerational epigenetic inheritance in humans: DNA methylation changes associated with maternal exposure to lead can be transmitted to the grandchildren. | journal=Sci Rep | year= 2015 | volume= 5 | issue= | pages= 14466 | pmid=26417717 | doi=10.1038/srep14466 | pmc=4586440 | url=https://www.ncbi.nlm.nih.gov/entrez/eutils/elink.fcgi?dbfrom=pubmed&tool=sumsearch.org/cite&retmode=ref&cmd=prlinks&id=26417717 }} </ref><br />
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Current mechanistic understanding, albeit rudimentary, supports the concept that the cardiovascular benefits of [[chelation therapy]] may result from enhanced excretion of [[heavy metals]], and subsequent reduction in processes listed above. Additionally, in patients with [[diabetes]], a reduction in the metal-catalyzed formation of [[reactive oxygen species]], formation of advanced glycation end-products, and lipid [[peroxidation]] has been postulated.<ref name="pmid10874253">{{cite journal| author=Lamas GA, Ackermann A| title=Clinical evaluation of chelation therapy: is there any wheat amidst the chaff? | journal=Am Heart J | year= 2000 | volume= 140 | issue= 1 | pages= 4-5 | pmid=10874253 | doi=10.1067/mhj.2000.107549 | pmc= | url=http://www.ncbi.nlm.nih.gov/entrez/eutils/elink.fcgi?dbfrom=pubmed&tool=sumsearch.org/cite&retmode=ref&cmd=prlinks&id=10874253 }} </ref> Metal detoxification in the context of [[diabetes]] possibly decreases [[inflammation]] and [[oxidative stress]] that characterize atherosclerosis.<ref>Escolar E, Lamas G, Mark D et al(2013) "The Effect of an EDTA-based Chelation Regimen on Patients With Diabetes Mellitus and Prior Myocardial Infarction in the Trial to Assess Chelation Therapy (TACT)". Circulation. 2013</ref> Recent research, including chelation-activity assays, indicates that many common [[diabetes]] drugs, such as [[metformin]] and aldose reductase inhibitors, could possibly have some chelating properties.<ref name="pmid22354928">{{cite journal| author=Nagai R, Murray DB, Metz TO, Baynes JW| title=Chelation: a fundamental mechanism of action of AGE inhibitors, AGE breakers, and other inhibitors of diabetes complications. | journal=Diabetes | year= 2012 | volume= 61 | issue= 3 | pages= 549-59 | pmid=22354928 | doi=10.2337/db11-1120 | pmc=3282805 | url=https://www.ncbi.nlm.nih.gov/entrez/eutils/elink.fcgi?dbfrom=pubmed&tool=sumsearch.org/cite&retmode=ref&cmd=prlinks&id=22354928 }} </ref><ref name="pmid23612664">{{cite journal| author=Frizzell N, Baynes JW| title=Chelation therapy for the management of diabetic complications: a hypothesis and a proposal for clinical laboratory assessment of metal ion homeostasis in plasma. | journal=Clin Chem Lab Med | year= 2014 | volume= 52 | issue= 1 | pages= 69-75 | pmid=23612664 | doi=10.1515/cclm-2012-0881 | pmc= | url=https://www.ncbi.nlm.nih.gov/entrez/eutils/elink.fcgi?dbfrom=pubmed&tool=sumsearch.org/cite&retmode=ref&cmd=prlinks&id=23612664 }} </ref><ref name="pmid22492524">{{cite journal| author=Logie L, Harthill J, Patel K, Bacon S, Hamilton DL, Macrae K et al.| title=Cellular responses to the metal-binding properties of metformin. | journal=Diabetes | year= 2012 | volume= 61 | issue= 6 | pages= 1423-33 | pmid=22492524 | doi=10.2337/db11-0961 | pmc=3357267 | url=https://www.ncbi.nlm.nih.gov/entrez/eutils/elink.fcgi?dbfrom=pubmed&tool=sumsearch.org/cite&retmode=ref&cmd=prlinks&id=22492524 }} </ref><br />
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The TACT chelation infusion, however, did not contain edetate disodium alone. The standard chelation infusion formula used in TACT was formulated to be identical with the most prevalent infusion in use. This formulation had developed organically over decades and had been modified by clinical practitioners to have additives such as [[ascorbic acid]], B-vitamins and [[magnesium]], thought to have a protective effect on [[endothelial cells]],<ref>Rozema, Theodore C. "The protocol for the safe and effective administration of EDTA and other chelating agents for vascular disease, degenerative disease, and metal toxicity." Journal of Advancement in Medicine 10.1 (1997): 5-100.</ref> making the results of clinical application more difficult to understand, and emphasizing the need for mechanistic work.<br />
<br />
==Future Studies==<br />
TACT was a unique study with an unexpected result that could have vast public health implications. In order to consider its broad applicability, the medical and scientific community require the results reproduced. TACT2, scheduled to begin in October 2016 (press release), is a replicative study in post-MI diabetic patients. If the TACT2 results confirm the results of TACT, then chelation is poised to become the next major development in the treatment of vascular complications of diabetes and vascular disease. TACT2 is currently recruiting sites, and interested investigators should visit www.TACT2.org for additional information.<br />
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==Side Effects==<br />
Shown below is a list of the labelled toxicities of EDTA-based chelation therapy. However, TACT delivered 55,222 infusions of EDTA or placebo, and found no differences between groups in adverse events, serious or otherwise.<br />
* [[Arrhythmias]]<br />
* [[Autoimmune diseases]]<br />
* [[Bone marrow]]<br />
* [[Convulsions]]<br />
* [[Depression]]<br />
* [[Fever]]<br />
* [[Heart failure]]<br />
* [[Hypocalcemia]]<br />
* [[Hypoglycemia]]<br />
* [[Hypotension]]<br />
* [[Bleeding time|Prolonged bleeding time]]<br />
* [[Renal failure]]<br />
* [[Respiratory arrest]]<br />
* [[Tetany]]<br />
* [[Trace metal|Trace metal deficiency]]<br />
* [[Vitamin deficiency]]<ref name="pmid10874275">{{cite journal| author=Ernst E| title=Chelation therapy for coronary heart disease: An overview of all clinical investigations. | journal=Am Heart J | year= 2000 | volume= 140 | issue= 1 | pages= 139-41 | pmid=10874275 | doi=10.1067/mhj.2000.107548 | pmc= | url=http://www.ncbi.nlm.nih.gov/entrez/eutils/elink.fcgi?dbfrom=pubmed&tool=sumsearch.org/cite&retmode=ref&cmd=prlinks&id=10874275 }} </ref><ref name="pmid23532240">{{cite journal| author=Lamas GA, Goertz C, Boineau R, Mark DB, Rozema T, Nahin RL et al.| title=Effect of disodium EDTA chelation regimen on cardiovascular events in patients with previous myocardial infarction: the TACT randomized trial. | journal=JAMA | year= 2013 | volume= 309 | issue= 12 | pages= 1241-50 | pmid=23532240 | doi=10.1001/jama.2013.2107 | pmc= | url=http://www.ncbi.nlm.nih.gov/entrez/eutils/elink.fcgi?dbfrom=pubmed&tool=sumsearch.org/cite&retmode=ref&cmd=prlinks&id=23532240 }} </ref><br />
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==Landmark Trials==<br />
* [[TACT]] <br><br />
* TACT 2 [http://www.TACT2.org] (link to press release [http://www.prnewswire.com/news-releases/tact2-clinical-trial-receives-national-institutes-of-health-funding-300334174.html])<br />
<br />
==References==<br />
{{Reflist|2}}<br />
<br />
[[Category:Cardiology]]<br />
[[Category:Diabetes]]<br />
[[Category:Up-To-Date]]<br />
<br />
{{WikiDoc Help Menu}}<br />
{{WikiDoc Sources}}</div>Rim Halabyhttps://www.wikidoc.org/index.php?title=Chelation_therapy_for_cardiovascular_disease&diff=1274903Chelation therapy for cardiovascular disease2016-12-08T00:41:18Z<p>Rim Halaby: </p>
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<div>__NOTOC__<br />
'''Editor-In-Chief:''' Gervasio Lamas, M.D., C. Michael Gibson, M.S., M.D.; {{AE}} {{Rim}}, Ian Ergui, B.Sc.<br />
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'''[[Chelation therapy|To read more about chelation therapy click here.]]'''<br><br />
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{{SK}} Chelation therapy, EDTA, post-myocardial infarction, diabetes<br />
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==Overview==<br />
[[Chelation]] is a process by which an organic molecule with a negatively charged “pocket” complexes with a metal ion of opposite charge, inactivates it, and then permits its physiological mobilization and excretion, usually by a renal route. [[Chelation therapy]], which involves multiple administrations of a chelating agent, helps eliminate stored toxic metal ions from the body.<ref name="pmid11794513">{{cite journal| author=Waters RS, Bryden NA, Patterson KY, Veillon C, Anderson RA| title=EDTA chelation effects on urinary losses of cadmium, calcium, chromium, cobalt, copper, lead, magnesium, and zinc. | journal=Biol Trace Elem Res | year= 2001 | volume= 83 | issue= 3 | pages= 207-21 | pmid=11794513 | doi=10.1385/BTER:83:3:207 | pmc= | url=https://www.ncbi.nlm.nih.gov/entrez/eutils/elink.fcgi?dbfrom=pubmed&tool=sumsearch.org/cite&retmode=ref&cmd=prlinks&id=11794513 }} </ref><ref name="arenas">Arenas I.A., Navas-Acien A., Lamas G.A.; Enhanced vasculotoxic metal excretionin post-MI patients after edetate disodium therapy (abstr). J Am Coll Cardiol. 2016;67:A2125</ref> Common chelators include [[penicillamine]], which binds copper and can be used to treat [[Wilson’s disease]], [[deferoxamine]], which binds iron and is used in the treatment of [[thalassemia]] and iron overload, succimer, also used in the treatment of lead poisoning, and the edetates, non-specific chelators of metals and other ions with valences of +2 to +6. Chelation therapy is, in many cases, guideline mandated, such as in children with elevated blood lead levels,<ref name="CDC">CDC. Low Level Lead Exposure Harms Children: A Renewed Call for Primary Prevention. Atlanta, GA:Advisory Committee on Childhood Lead Poisoning Prevention, U.S. Centers for Disease Control and Prevention (4 Jan 2012). Available: [http://www.cdc.gov/nceh/lead/acclpp/final_document_010412.pdf]</ref> patients with iron overload and dyserythropoietic syndromes or chronic [[hemolytic anemia]],<ref name="pmid21452290">{{cite journal| author=Bacon BR, Adams PC, Kowdley KV, Powell LW, Tavill AS, American Association for the Study of Liver Diseases| title=Diagnosis and management of hemochromatosis: 2011 practice guideline by the American Association for the Study of Liver Diseases. | journal=Hepatology | year= 2011 | volume= 54 | issue= 1 | pages= 328-43 | pmid=21452290 | doi=10.1002/hep.24330 | pmc=3149125 | url=https://www.ncbi.nlm.nih.gov/entrez/eutils/elink.fcgi?dbfrom=pubmed&tool=sumsearch.org/cite&retmode=ref&cmd=prlinks&id=21452290 }} </ref> or [[sickle cell disease]] and transfusion acquired iron-overload,<ref name="NHLBI">NHLBI. Transfusion in Sickle Cell Disease: A Systematic Review of Benefits, Complications, and Management of Complications. Prepared for the National Heart, Lung, and Blood Institute and by the Knowledge and Evaluation Research Unit, Mayo Clinic Rochester (2012)</ref> to name a few instances.<br />
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[[Ethylene diamine tetraacetic acid]] ([[EDTA]], edetate) and its salts (most commonly disodium or calcium disodium), commonly used chelating agents patented in 1938, bind to and permit the urinary excretion of divalent cations such as calcium, and metals such as [[lead]], [[cadmium]], [[nickel]], [[cobalt]], [[iron]], [[aluminum]], and others. The initial medical use for [[EDTA]] began after World War II for the treatment of [[lead]]-exposed naval workers. In addition to its use for the treatment of metal poisoning, since the 1950s chelation therapy has been considered an alternative or add-on therapy for the prevention and treatment of [[atherosclerotic disease]]. The use of edetate disodium (Na2EDTA) has been most prominent in the alternative medicine treatment of [[atherosclerosis]] primarily because of the still-unproven hypothesis that the [[hypocalcemia]] it induces might lead to the decalcification of atherosclerotic lesions. In fact, the most current research suggests that the probable mechanism of benefit centers on enhancement of toxic metal excretion.<br />
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==Chelation Therapy and CVD==<br />
The use of chelation therapy as a treatment for [[atherosclerotic disease]] dates back to the 1950’s when Clarke et al investigated the use of EDTA for the treatment of [[angina pectoris]] and reported improvement in 19 of 20 patients.<ref name="pmid13372537">{{cite journal| author=CLARKE CN, CLARKE NE, MOSHER RE| title=Treatment of angina pectoris with disodium ethylene diamine tetraacetic acid. | journal=Am J Med Sci | year= 1956 | volume= 232 | issue= 6 | pages= 654-66 | pmid=13372537 | doi= | pmc= | url=http://www.ncbi.nlm.nih.gov/entrez/eutils/elink.fcgi?dbfrom=pubmed&tool=sumsearch.org/cite&retmode=ref&cmd=prlinks&id=13372537 }} </ref> Later studies by Kitchell were less positive,<ref name="pmid13756462">{{cite journal| author=KITCHELL JR, MELTZER LE, SEVEN MJ| title=Potential uses of chelation methods in the treatment of cardiovascular diseases. | journal=Prog Cardiovasc Dis | year= 1961 | volume= 3 | issue= | pages= 338-49 | pmid=13756462 | doi= | pmc= | url=https://www.ncbi.nlm.nih.gov/entrez/eutils/elink.fcgi?dbfrom=pubmed&tool=sumsearch.org/cite&retmode=ref&cmd=prlinks&id=13756462 }} </ref><ref name="pmid14033183">{{cite journal| author=KITCHELL JR, PALMON F, AYTAN N, MELTZER LE| title=The treatment of coronary artery disease with disodium EDTA. A reappraisal. | journal=Am J Cardiol | year= 1963 | volume= 11 | issue= | pages= 501-6 | pmid=14033183 | doi= | pmc= | url=https://www.ncbi.nlm.nih.gov/entrez/eutils/elink.fcgi?dbfrom=pubmed&tool=sumsearch.org/cite&retmode=ref&cmd=prlinks&id=14033183 }} </ref> and in an era without modern clinical trials methodology nor effective concomitant therapies, opinions regarding the use of [[chelation therapy]] for [[cardiovascular disease]] (CVD) tilted towards the negative. To be fair, from the 1970’s to 1990’s the preponderance of the scientific literature on [[chelation therapy]] for [[atherosclerosis]] consisted of case reports, case series, and small clinical trials with surrogate endpoints, poor-quality evidence from which to draw a conclusion of efficacy or harm.<ref name="pmid12519577">{{cite journal| author=Villarruz MV, Dans A, Tan F| title=Chelation therapy for atherosclerotic cardiovascular disease. | journal=Cochrane Database Syst Rev | year= 2002 | volume= | issue= 4 | pages= CD002785 | pmid=12519577 | doi=10.1002/14651858.CD002785 | pmc= | url=http://www.ncbi.nlm.nih.gov/entrez/eutils/elink.fcgi?dbfrom=pubmed&tool=sumsearch.org/cite&retmode=ref&cmd=prlinks&id=12519577 }} </ref><br />
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For example, one extensive case series reported an association between EDTA chelation therapy and improvement of [[ischemic heart disease]] and [[peripheral artery disease]].<ref name="pmid3144646">{{cite journal| author=Olszewer E, Carter JP| title=EDTA chelation therapy in chronic degenerative disease. | journal=Med Hypotheses | year= 1988 | volume= 27 | issue= 1 | pages= 41-9 | pmid=3144646 | doi= | pmc= | url=http://www.ncbi.nlm.nih.gov/entrez/eutils/elink.fcgi?dbfrom=pubmed&tool=sumsearch.org/cite&retmode=ref&cmd=prlinks&id=3144646 }} </ref> Another study demonstrated that EDTA supplemented with several B vitamins (vitamin B1, B2, B6 and B12) but not EDTA alone was effective in improving [[endothelium]]-dependent forearm blood flow.<ref name="pmid10561804">{{cite journal| author=Green DJ, O'Driscoll JG, Maiorana A, Scrimgeour NB, Weerasooriya R, Taylor RR| title=Effects of chelation with EDTA and vitamin B therapy on nitric oxide-related endothelial vasodilator function. | journal=Clin Exp Pharmacol Physiol | year= 1999 | volume= 26 | issue= 11 | pages= 853-6 | pmid=10561804 | doi= | pmc= | url=http://www.ncbi.nlm.nih.gov/entrez/eutils/elink.fcgi?dbfrom=pubmed&tool=sumsearch.org/cite&retmode=ref&cmd=prlinks&id=10561804 }} </ref> A systematic review of four [[randomized clinical trial]]s on chelation therapy and [[peripheral artery occlusive disease]] reported no benefit associated with [[chelation therapy]].<ref name="pmid9264515">{{cite journal| author=Ernst E| title=Chelation therapy for peripheral arterial occlusive disease: a systematic review. | journal=Circulation | year= 1997 | volume= 96 | issue= 3 | pages= 1031-3 | pmid=9264515 | doi= | pmc= | url=http://www.ncbi.nlm.nih.gov/entrez/eutils/elink.fcgi?dbfrom=pubmed&tool=sumsearch.org/cite&retmode=ref&cmd=prlinks&id=9264515 }} </ref> The studies, however, individually and in aggregate, were too small to exclude a small to moderate benefit of therapy. Moreover, follow up was short and surrogate physiologic endpoints, such as walking distance, were used. A Cochrane systematic review on the role of chelation therapy to treat [[coronary heart disease]] in 2002 concluded that the data were insufficient to recommend for or against chelation.<ref name="pmid10874275">{{cite journal| author=Ernst E| title=Chelation therapy for coronary heart disease: An overview of all clinical investigations. | journal=Am Heart J | year= 2000 | volume= 140 | issue= 1 | pages= 139-41 | pmid=10874275 | doi=10.1067/mhj.2000.107548 | pmc= | url=http://www.ncbi.nlm.nih.gov/entrez/eutils/elink.fcgi?dbfrom=pubmed&tool=sumsearch.org/cite&retmode=ref&cmd=prlinks&id=10874275 }} </ref> The medical community concluded that the absence of high quality evidence of efficacy equated with evidence of absence of efficacy. Professional organizations recommended against [[chelation therapy]].<ref name="pmid9205980">{{cite journal| author=Lewin MR| title=Chelation therapy for cardiovascular disease. Review and commentary. | journal=Tex Heart Inst J | year= 1997 | volume= 24 | issue= 2 | pages= 81-9 | pmid=9205980 | doi= | pmc=325409 | url=https://www.ncbi.nlm.nih.gov/entrez/eutils/elink.fcgi?dbfrom=pubmed&tool=sumsearch.org/cite&retmode=ref&cmd=prlinks&id=9205980 }} </ref> Interestingly, patients continued to seek, and practitioners to administer, chelation infusions for [[cardiovascular disease]] and other diagnoses.<br />
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In light of the persistent controversy regarding the benefits of chelation therapy and the absence of any previous large clinical trial investigating its use in coronary artery disease, the National Center for Complementary and Alternative Medicine and the National Heart Lung and Blood Institute released a $30 million Request for Applications (RFA) to develop a definitive trial. In 2002, the RFA was awarded to Mount Sinai Medical Center in Miami Beach FL (G Lamas MD, Principal Investigator). The Trial to Assess Chelation Therapy (TACT), a randomized, double blind, placebo controlled 2x2 factorial trial, investigated the efficacy and safety of disodium EDTA based infusions and high-dose oral vitamins and minerals in 1708 stable post-myocardial infarction (MI) patients more than 50 years of age and with fairly normal kidney function ([[creatinine]] 2.0 mg/dL or less). The active treatment consisted of 40 infusions consisted of disodium [[EDTA]] combined with [[ascorbic acid]], B vitamins, and other components. The median age of patients was 65 years, and they were treated with evidence-based post-MI medicines. The primary endpoint of this trial was a composite of all-cause mortality, [[stroke]], [[MI]], coronary revascularization, and hospitalization for [[angina]]. A follow up period of 55 months revealed a statistically significant decrease in the primary endpoint (HR: 0.82; 95% CI: 0.69-0.99; p= 0.035). There was an absolute reduction in the 5-year Kaplan-Meier estimate, from 38% to 33%, resulting in a 5-year number needed to treat (NNT) of 18 patients to avoid one adverse cardiovascular outcome. This is comparable to the 5-year NNT for [[statins]] in post-[[MI]] patients (NNT=16 for the secondary prevention of a major coronary event). The point estimate for the risk of each of the components of the primary endpoint was <1, consistent with the aggregate result. The Investigators concluded that chelation should not yet be adopted for routine post-[[MI]] use in all patients, but the results of TACT should inform further studies to confirm or refute these unexpected results.<ref name="pmid23532240">{{cite journal| author=Lamas GA, Goertz C, Boineau R, Mark DB, Rozema T, Nahin RL et al.| title=Effect of disodium EDTA chelation regimen on cardiovascular events in patients with previous myocardial infarction: the TACT randomized trial. | journal=JAMA | year= 2013 | volume= 309 | issue= 12 | pages= 1241-50 | pmid=23532240 | doi=10.1001/jama.2013.2107 | pmc= | url=http://www.ncbi.nlm.nih.gov/entrez/eutils/elink.fcgi?dbfrom=pubmed&tool=sumsearch.org/cite&retmode=ref&cmd=prlinks&id=23532240 }} </ref><br />
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TACT prespecified several subgroups for analysis and found a significant interaction between edetate disodium treatment and [[diabetes]] (p for interaction =0.0037). Among subjects enrolled in TACT, there were 633 [[diabetic]] patients, defined as patients with self-reported [[diabetes]], taking medications for [[diabetes]], or having a fasting blood glucose of at least 126 mg/dL at enrollment. The administration of chelation infusions among post-[[MI]] [[diabetic]] patients was associated with a marked reduction in the primary end point when compared with placebo. The primary end point occurred in 25% of [[diabetic]] patients who were administered chelation therapy compared to 38% in those who received placebo infusions (HR, 0.59; 95% CI, 0.44–0.79; P<0.001). The 5-year NNT to prevent one event was 6.5. In addition, chelation therapy was significantly associated with decreased all-cause mortality (43% reduction, p=0.011) and reinfarction (52% reduction, p=0.015).<ref name="pmid24254885">{{cite journal| author=Escolar E, Lamas GA, Mark DB, Boineau R, Goertz C, Rosenberg Y et al.| title=The effect of an EDTA-based chelation regimen on patients with diabetes mellitus and prior myocardial infarction in the Trial to Assess Chelation Therapy (TACT). | journal=Circ Cardiovasc Qual Outcomes | year= 2014 | volume= 7 | issue= 1 | pages= 15-24 | pmid=24254885 | doi=10.1161/CIRCOUTCOMES.113.000663 | pmc=4111470 | url=https://www.ncbi.nlm.nih.gov/entrez/eutils/elink.fcgi?dbfrom=pubmed&tool=sumsearch.org/cite&retmode=ref&cmd=prlinks&id=24254885 }} </ref> Again, the investigators concluded that these findings supported future research, but did not constitute sufficient evidence to indicate the routine use of [[chelation therapy]] for all post–[[MI]] patients with [[diabetes]], leaving open the clinician’s choice to use this novel therapy in occasional, or non-routine patients.<br />
<br />
These results catalyzed a wave of increased public and scientific interest in disodium [[EDTA]] treatment for patients with established [[coronary disease]], particularly in [[diabetes]], and hypotheses regarding potential mechanisms of benefit. As a capstone to the published analyses, the ACC/AHA Guidelines for Chronic Ischemic Heart Disease changed to reflect the TACT data and upgraded disodium EDTA treatment from a Class III indication to a Class IIB indication. While Class III therapeutics are considered not beneficial or useful, Class IIB treatments can be considered in some patients and require additional research to establish efficacy.<ref name="pmid25077860">{{cite journal| author=Fihn SD, Blankenship JC, Alexander KP, Bittl JA, Byrne JG, Fletcher BJ et al.| title=2014 ACC/AHA/AATS/PCNA/SCAI/STS focused update of the guideline for the diagnosis and management of patients with stable ischemic heart disease: a report of the American College of Cardiology/American Heart Association Task Force on Practice Guidelines, and the American Association for Thoracic Surgery, Preventive Cardiovascular Nurses Association, Society for Cardiovascular Angiography and Interventions, and Society of Thoracic Surgeons. | journal=J Am Coll Cardiol | year= 2014 | volume= 64 | issue= 18 | pages= 1929-49 | pmid=25077860 | doi=10.1016/j.jacc.2014.07.017 | pmc= | url=https://www.ncbi.nlm.nih.gov/entrez/eutils/elink.fcgi?dbfrom=pubmed&tool=sumsearch.org/cite&retmode=ref&cmd=prlinks&id=25077860 }} </ref> The change in the guidelines signaled a major shift in the perception of chelation therapy among the medical establishment. The TACT data led clinicians to reconsider chelation objectively, and the investigators and many other academic cardiologists called for TACT2, a new trial to test the results of TACT, to be funded by the [[NIH]].<br />
<br />
==Mechanism of Action==<br />
[[Edetate disodium]] binds to metals and forms soluble complexes facilitating their subsequent excretion in the [[urine]].<ref name="pmid14000694">{{cite journal| author=WILDER LW, DE JODE LR, MILSTEIN SW, HOWARD JM| title=Mobilization of atherosclerotic plaque calcium with EDTA utilizing the isolation-perfusion principle. | journal=Surgery | year= 1962 | volume= 52 | issue= | pages= 793-5 | pmid=14000694 | doi= | pmc= | url=http://www.ncbi.nlm.nih.gov/entrez/eutils/elink.fcgi?dbfrom=pubmed&tool=sumsearch.org/cite&retmode=ref&cmd=prlinks&id=14000694 }} </ref> Hence, chelation therapy results in the elimination of stored toxic and essential metals. In an experiment performed on 24 patients, age 50 or older, and with a prior MI and a creatinine of 2.0 or less, patients had urine toxic metals measured at baseline, 1 day after an infusion of placebo, and 1 day after an infusion of the edetate disodium-based TACT solution. Placebo did not increase the excretion of toxic metals. Following an infusion of the edetate disodium-based TACT solution, lead excretion increased by nearly 3900%, and cadmium by nearly 700%. Other toxic metals whose excretion was enhanced by edetate disodium were aluminum (by ~250%), nickel (by ~150%), thallium (by ~60%), and gadolinium. A similar experiment performed earlier by Waters et al, reported urinary lead concentrations approximately 35 times greater than in pre-chelation urine.<ref name="pmid11794513">{{cite journal| author=Waters RS, Bryden NA, Patterson KY, Veillon C, Anderson RA| title=EDTA chelation effects on urinary losses of cadmium, calcium, chromium, cobalt, copper, lead, magnesium, and zinc. | journal=Biol Trace Elem Res | year= 2001 | volume= 83 | issue= 3 | pages= 207-21 | pmid=11794513 | doi=10.1385/BTER:83:3:207 | pmc= | url=https://www.ncbi.nlm.nih.gov/entrez/eutils/elink.fcgi?dbfrom=pubmed&tool=sumsearch.org/cite&retmode=ref&cmd=prlinks&id=11794513 }} </ref><br />
While enhanced lead and cadmium is interesting, the critical link to cardiovascular events is provided by epidemiological studies, which provide robust evidence linking toxic metals with [[cardiovascular disease]].<ref name="pmid21421632">{{cite journal| author=Agarwal S, Zaman T, Tuzcu EM, Kapadia SR| title=Heavy metals and cardiovascular disease: results from the National Health and Nutrition Examination Survey (NHANES) 1999-2006. | journal=Angiology | year= 2011 | volume= 62 | issue= 5 | pages= 422-9 | pmid=21421632 | doi=10.1177/0003319710395562 | pmc= | url=http://www.ncbi.nlm.nih.gov/entrez/eutils/elink.fcgi?dbfrom=pubmed&tool=sumsearch.org/cite&retmode=ref&cmd=prlinks&id=21421632 }} </ref> This evidence is strongest for lead and cadmium.<ref name="pmid16982939">{{cite journal| author=Menke A, Muntner P, Batuman V, Silbergeld EK, Guallar E| title=Blood lead below 0.48 micromol/L (10 microg/dL) and mortality among US adults. | journal=Circulation | year= 2006 | volume= 114 | issue= 13 | pages= 1388-94 | pmid=16982939 | doi=10.1161/CIRCULATIONAHA.106.628321 | pmc= | url=https://www.ncbi.nlm.nih.gov/entrez/eutils/elink.fcgi?dbfrom=pubmed&tool=sumsearch.org/cite&retmode=ref&cmd=prlinks&id=16982939 }} </ref><ref name="pmid15184277">{{cite journal| author=Navas-Acien A, Selvin E, Sharrett AR, Calderon-Aranda E, Silbergeld E, Guallar E| title=Lead, cadmium, smoking, and increased risk of peripheral arterial disease. | journal=Circulation | year= 2004 | volume= 109 | issue= 25 | pages= 3196-201 | pmid=15184277 | doi=10.1161/01.CIR.0000130848.18636.B2 | pmc= | url=http://www.ncbi.nlm.nih.gov/entrez/eutils/elink.fcgi?dbfrom=pubmed&tool=sumsearch.org/cite&retmode=ref&cmd=prlinks&id=15184277 }} </ref><ref name="pmid23514838">{{cite journal| author=Tellez-Plaza M, Guallar E, Howard BV, Umans JG, Francesconi KA, Goessler W et al.| title=Cadmium exposure and incident cardiovascular disease. | journal=Epidemiology | year= 2013 | volume= 24 | issue= 3 | pages= 421-9 | pmid=23514838 | doi=10.1097/EDE.0b013e31828b0631 | pmc= | url=http://www.ncbi.nlm.nih.gov/entrez/eutils/elink.fcgi?dbfrom=pubmed&tool=sumsearch.org/cite&retmode=ref&cmd=prlinks&id=23514838 }} </ref> Elevated blood concentration of [[lead]] is associated with increased all-cause mortality [HR 1.25 (95% CI 1.04 to 1.51) for the highest versus lowest tertile of blood lead, P trend across the tertiles=0.002) and cardiovascular mortality [HR 1.55 (95% CI 1.08 to 2.24) for the highest versus lowest tertile, P trend <0.003].<ref name="pmid16982939">{{cite journal| author=Menke A, Muntner P, Batuman V, Silbergeld EK, Guallar E| title=Blood lead below 0.48 micromol/L (10 microg/dL) and mortality among US adults. | journal=Circulation | year= 2006 | volume= 114 | issue= 13 | pages= 1388-94 | pmid=16982939 | doi=10.1161/CIRCULATIONAHA.106.628321 | pmc= | url=https://www.ncbi.nlm.nih.gov/entrez/eutils/elink.fcgi?dbfrom=pubmed&tool=sumsearch.org/cite&retmode=ref&cmd=prlinks&id=16982939 }} </ref> Also, cardiovascular mortality is greater among subjects with elevated [[cadmium]] concentrations in the blood and urine [HR 1.69 (95% CI: 1.03, 2.77) and 1.74 (95% CI: 1.07, 2.83) for the 80th and 20th percentiles of blood and urine cadmium, respectively].<ref name="pmid22472185">{{cite journal| author=Tellez-Plaza M, Navas-Acien A, Menke A, Crainiceanu CM, Pastor-Barriuso R, Guallar E| title=Cadmium exposure and all-cause and cardiovascular mortality in the U.S. general population. | journal=Environ Health Perspect | year= 2012 | volume= 120 | issue= 7 | pages= 1017-22 | pmid=22472185 | doi=10.1289/ehp.1104352 | pmc=3404657 | url=https://www.ncbi.nlm.nih.gov/entrez/eutils/elink.fcgi?dbfrom=pubmed&tool=sumsearch.org/cite&retmode=ref&cmd=prlinks&id=22472185 }} </ref> <br />
Heavy metals may play a role in the development of [[cardiovascular disease]] through a number of different mechanisms.<ref name="pmid17645641">{{cite journal| author=Vaziri ND, Khan M| title=Interplay of reactive oxygen species and nitric oxide in the pathogenesis of experimental lead-induced hypertension. | journal=Clin Exp Pharmacol Physiol | year= 2007 | volume= 34 | issue= 9 | pages= 920-5 | pmid=17645641 | doi=10.1111/j.1440-1681.2007.04644.x | pmc= | url=https://www.ncbi.nlm.nih.gov/entrez/eutils/elink.fcgi?dbfrom=pubmed&tool=sumsearch.org/cite&retmode=ref&cmd=prlinks&id=17645641 }} </ref> Heavy metals include transition metals such as [[cadmium]], [[mercury]], [[manganese]], [[chromium]], [[cobalt]], [[nickel]], [[iron]], and [[copper]], metalloids such as antimony and arsenic, and post- transition metals such as [[thallium]] and [[lead]]. These metals all have unique toxicities, as well as toxicities that are common to all of them. Heavy metals in the [[endothelium]] promote oxygen free radical formation, resulting in increased [[oxidative stress]], [[inflammation]], and tissue damage. [[Lead]] and [[cadmium]] may interfere with calcium signaling channels. Transition metals promote modifications of [[low-density lipoprotein]] by [[endothelial cell]]s through lipid peroxidation and degradation of low-density lipoprotein phospholipids.<ref name="pmid6587396">{{cite journal| author=Steinbrecher UP, Parthasarathy S, Leake DS, Witztum JL, Steinberg D| title=Modification of low density lipoprotein by endothelial cells involves lipid peroxidation and degradation of low density lipoprotein phospholipids. | journal=Proc Natl Acad Sci U S A | year= 1984 | volume= 81 | issue= 12 | pages= 3883-7 | pmid=6587396 | doi= | pmc=345326 | url=https://www.ncbi.nlm.nih.gov/entrez/eutils/elink.fcgi?dbfrom=pubmed&tool=sumsearch.org/cite&retmode=ref&cmd=prlinks&id=6587396 }} </ref><ref name="pmid6501577">{{cite journal| author=Heinecke JW, Rosen H, Chait A| title=Iron and copper promote modification of low density lipoprotein by human arterial smooth muscle cells in culture. | journal=J Clin Invest | year= 1984 | volume= 74 | issue= 5 | pages= 1890-4 | pmid=6501577 | doi=10.1172/JCI111609 | pmc=425370 | url=https://www.ncbi.nlm.nih.gov/entrez/eutils/elink.fcgi?dbfrom=pubmed&tool=sumsearch.org/cite&retmode=ref&cmd=prlinks&id=6501577 }} </ref><ref name="pmid8847477">{{cite journal| author=Morgan J, Leake DS| title=Oxidation of low density lipoprotein by iron or copper at acidic pH. | journal=J Lipid Res | year= 1995 | volume= 36 | issue= 12 | pages= 2504-12 | pmid=8847477 | doi= | pmc= | url=https://www.ncbi.nlm.nih.gov/entrez/eutils/elink.fcgi?dbfrom=pubmed&tool=sumsearch.org/cite&retmode=ref&cmd=prlinks&id=8847477 }} </ref> Exposure to non-transition metals, such as lead, has also been associated with impaired nitric oxide signaling and availability,<ref name="pmid15894814">{{cite journal| author=Dursun N, Arifoglu C, Süer C, Keskinol L| title=Blood pressure relationship to nitric oxide, lipid peroxidation, renal function, and renal blood flow in rats exposed to low lead levels. | journal=Biol Trace Elem Res | year= 2005 | volume= 104 | issue= 2 | pages= 141-9 | pmid=15894814 | doi=10.1385/BTER:104:2:141 | pmc= | url=https://www.ncbi.nlm.nih.gov/entrez/eutils/elink.fcgi?dbfrom=pubmed&tool=sumsearch.org/cite&retmode=ref&cmd=prlinks&id=15894814 }} </ref> endothelial cell dysfunction,<ref name="pmid7710289">{{cite journal| author=Kaji T, Suzuki M, Yamamoto C, Mishima A, Sakamoto M, Kozuka H| title=Severe damage of cultured vascular endothelial cell monolayer after simultaneous exposure to cadmium and lead. | journal=Arch Environ Contam Toxicol | year= 1995 | volume= 28 | issue= 2 | pages= 168-72 | pmid=7710289 | doi= | pmc= | url=https://www.ncbi.nlm.nih.gov/entrez/eutils/elink.fcgi?dbfrom=pubmed&tool=sumsearch.org/cite&retmode=ref&cmd=prlinks&id=7710289 }} </ref> and hypertension.<ref name="pmid18567711">{{cite journal| author=Vaziri ND| title=Mechanisms of lead-induced hypertension and cardiovascular disease. | journal=Am J Physiol Heart Circ Physiol | year= 2008 | volume= 295 | issue= 2 | pages= H454-65 | pmid=18567711 | doi=10.1152/ajpheart.00158.2008 | pmc=2519216 | url=https://www.ncbi.nlm.nih.gov/entrez/eutils/elink.fcgi?dbfrom=pubmed&tool=sumsearch.org/cite&retmode=ref&cmd=prlinks&id=18567711 }} </ref> [[Heavy metal]] exposure is also associated with genetic and [[epigenetic]] manifestations. [[Cadmium]] promotes atherosclerosis and endothelial dysfunction through multiple [[genetic]] changes.<ref name="pmid19556524">{{cite journal| author=Messner B, Knoflach M, Seubert A, Ritsch A, Pfaller K, Henderson B et al.| title=Cadmium is a novel and independent risk factor for early atherosclerosis mechanisms and in vivo relevance. | journal=Arterioscler Thromb Vasc Biol | year= 2009 | volume= 29 | issue= 9 | pages= 1392-8 | pmid=19556524 | doi=10.1161/ATVBAHA.109.190082 | pmc= | url=https://www.ncbi.nlm.nih.gov/entrez/eutils/elink.fcgi?dbfrom=pubmed&tool=sumsearch.org/cite&retmode=ref&cmd=prlinks&id=19556524 }} </ref> One of the mechanisms involves [[DNA]] strand breaks and damage with subsequent apoptosis in [[endothelial cell]]s.<ref name="pmid19556524">{{cite journal| author=Messner B, Knoflach M, Seubert A, Ritsch A, Pfaller K, Henderson B et al.| title=Cadmium is a novel and independent risk factor for early atherosclerosis mechanisms and in vivo relevance. | journal=Arterioscler Thromb Vasc Biol | year= 2009 | volume= 29 | issue= 9 | pages= 1392-8 | pmid=19556524 | doi=10.1161/ATVBAHA.109.190082 | pmc= | url=https://www.ncbi.nlm.nih.gov/entrez/eutils/elink.fcgi?dbfrom=pubmed&tool=sumsearch.org/cite&retmode=ref&cmd=prlinks&id=19556524 }} </ref> Also, maternal [[lead]] exposure during pregnancy may be associated with epigenetic consequences in grandchildren through alteration of [[DNA methylation]] early in life.<ref name="pmid26417717">{{cite journal| author=Sen A, Heredia N, Senut MC, Land S, Hollocher K, Lu X et al.| title=Multigenerational epigenetic inheritance in humans: DNA methylation changes associated with maternal exposure to lead can be transmitted to the grandchildren. | journal=Sci Rep | year= 2015 | volume= 5 | issue= | pages= 14466 | pmid=26417717 | doi=10.1038/srep14466 | pmc=4586440 | url=https://www.ncbi.nlm.nih.gov/entrez/eutils/elink.fcgi?dbfrom=pubmed&tool=sumsearch.org/cite&retmode=ref&cmd=prlinks&id=26417717 }} </ref><br />
<br />
Current mechanistic understanding, albeit rudimentary, supports the concept that the cardiovascular benefits of [[chelation therapy]] may result from enhanced excretion of [[heavy metals]], and subsequent reduction in processes listed above. Additionally, in patients with [[diabetes]], a reduction in the metal-catalyzed formation of [[reactive oxygen species]], formation of advanced glycation end-products, and lipid [[peroxidation]] has been postulated.<ref name="pmid10874253">{{cite journal| author=Lamas GA, Ackermann A| title=Clinical evaluation of chelation therapy: is there any wheat amidst the chaff? | journal=Am Heart J | year= 2000 | volume= 140 | issue= 1 | pages= 4-5 | pmid=10874253 | doi=10.1067/mhj.2000.107549 | pmc= | url=http://www.ncbi.nlm.nih.gov/entrez/eutils/elink.fcgi?dbfrom=pubmed&tool=sumsearch.org/cite&retmode=ref&cmd=prlinks&id=10874253 }} </ref> Metal detoxification in the context of [[diabetes]] possibly decreases [[inflammation]] and [[oxidative stress]] that characterize atherosclerosis.<ref>Escolar E, Lamas G, Mark D et al(2013) "The Effect of an EDTA-based Chelation Regimen on Patients With Diabetes Mellitus and Prior Myocardial Infarction in the Trial to Assess Chelation Therapy (TACT)". Circulation. 2013</ref> Recent research, including chelation-activity assays, indicates that many common [[diabetes]] drugs, such as [[metformin]] and aldose reductase inhibitors, could possibly have some chelating properties.<ref name="pmid22354928">{{cite journal| author=Nagai R, Murray DB, Metz TO, Baynes JW| title=Chelation: a fundamental mechanism of action of AGE inhibitors, AGE breakers, and other inhibitors of diabetes complications. | journal=Diabetes | year= 2012 | volume= 61 | issue= 3 | pages= 549-59 | pmid=22354928 | doi=10.2337/db11-1120 | pmc=3282805 | url=https://www.ncbi.nlm.nih.gov/entrez/eutils/elink.fcgi?dbfrom=pubmed&tool=sumsearch.org/cite&retmode=ref&cmd=prlinks&id=22354928 }} </ref><ref name="pmid23612664">{{cite journal| author=Frizzell N, Baynes JW| title=Chelation therapy for the management of diabetic complications: a hypothesis and a proposal for clinical laboratory assessment of metal ion homeostasis in plasma. | journal=Clin Chem Lab Med | year= 2014 | volume= 52 | issue= 1 | pages= 69-75 | pmid=23612664 | doi=10.1515/cclm-2012-0881 | pmc= | url=https://www.ncbi.nlm.nih.gov/entrez/eutils/elink.fcgi?dbfrom=pubmed&tool=sumsearch.org/cite&retmode=ref&cmd=prlinks&id=23612664 }} </ref><ref name="pmid22492524">{{cite journal| author=Logie L, Harthill J, Patel K, Bacon S, Hamilton DL, Macrae K et al.| title=Cellular responses to the metal-binding properties of metformin. | journal=Diabetes | year= 2012 | volume= 61 | issue= 6 | pages= 1423-33 | pmid=22492524 | doi=10.2337/db11-0961 | pmc=3357267 | url=https://www.ncbi.nlm.nih.gov/entrez/eutils/elink.fcgi?dbfrom=pubmed&tool=sumsearch.org/cite&retmode=ref&cmd=prlinks&id=22492524 }} </ref><br />
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The TACT chelation infusion, however, did not contain edetate disodium alone. The standard chelation infusion formula used in TACT was formulated to be identical with the most prevalent infusion in use. This formulation had developed organically over decades and had been modified by clinical practitioners to have additives such as [[ascorbic acid]], B-vitamins and [[magnesium]], thought to have a protective effect on [[endothelial cells]],<ref>Rozema, Theodore C. "The protocol for the safe and effective administration of EDTA and other chelating agents for vascular disease, degenerative disease, and metal toxicity." Journal of Advancement in Medicine 10.1 (1997): 5-100.</ref> making the results of clinical application more difficult to understand, and emphasizing the need for mechanistic work.<br />
<br />
==Future Studies==<br />
TACT was a unique study with an unexpected result that could have vast public health implications. In order to consider its broad applicability, the medical and scientific community require the results reproduced. TACT2, scheduled to begin in October 2016 (press release), is a replicative study in post-MI diabetic patients. If the TACT2 results confirm the results of TACT, then chelation is poised to become the next major development in the treatment of vascular complications of diabetes and vascular disease. TACT2 is currently recruiting sites, and interested investigators should visit www.TACT2.org for additional information.<br />
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==Side Effects==<br />
Shown below is a list of the labelled toxicities of EDTA-based chelation therapy. However, TACT delivered 55,222 infusions of EDTA or placebo, and found no differences between groups in adverse events, serious or otherwise.<br />
* [[Arrhythmias]]<br />
* [[Autoimmune diseases]]<br />
* [[Bone marrow]]<br />
* [[Convulsions]]<br />
* [[Depression]]<br />
* [[Fever]]<br />
* [[Heart failure]]<br />
* [[Hypocalcemia]]<br />
* [[Hypoglycemia]]<br />
* [[Hypotension]]<br />
* [[Bleeding time|Prolonged bleeding time]]<br />
* [[Renal failure]]<br />
* [[Respiratory arrest]]<br />
* [[Tetany]]<br />
* [[Trace metal|Trace metal deficiency]]<br />
* [[Vitamin deficiency]]<ref name="pmid10874275">{{cite journal| author=Ernst E| title=Chelation therapy for coronary heart disease: An overview of all clinical investigations. | journal=Am Heart J | year= 2000 | volume= 140 | issue= 1 | pages= 139-41 | pmid=10874275 | doi=10.1067/mhj.2000.107548 | pmc= | url=http://www.ncbi.nlm.nih.gov/entrez/eutils/elink.fcgi?dbfrom=pubmed&tool=sumsearch.org/cite&retmode=ref&cmd=prlinks&id=10874275 }} </ref><ref name="pmid23532240">{{cite journal| author=Lamas GA, Goertz C, Boineau R, Mark DB, Rozema T, Nahin RL et al.| title=Effect of disodium EDTA chelation regimen on cardiovascular events in patients with previous myocardial infarction: the TACT randomized trial. | journal=JAMA | year= 2013 | volume= 309 | issue= 12 | pages= 1241-50 | pmid=23532240 | doi=10.1001/jama.2013.2107 | pmc= | url=http://www.ncbi.nlm.nih.gov/entrez/eutils/elink.fcgi?dbfrom=pubmed&tool=sumsearch.org/cite&retmode=ref&cmd=prlinks&id=23532240 }} </ref><br />
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==Landmark Trials==<br />
* [[TACT]] <br><br />
* TACT 2 [http://www.TACT2.org] (link to press release [http://www.prnewswire.com/news-releases/tact2-clinical-trial-receives-national-institutes-of-health-funding-300334174.html])<br />
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==References==<br />
{{Reflist|2}}<br />
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[[Category:Cardiology]]<br />
[[Category:Diabetes]]<br />
[[Category:Up-To-Date]]<br />
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{{WikiDoc Sources}}</div>Rim Halabyhttps://www.wikidoc.org/index.php?title=Chelation_therapy_for_cardiovascular_disease&diff=1274816Chelation therapy for cardiovascular disease2016-12-07T17:58:22Z<p>Rim Halaby: </p>
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<div>__NOTOC__<br />
'''Editor-In-Chief:''' Gervasio Lamas, M.D., C. Michael Gibson, M.S., M.D.; {{AE}} {{Rim}}, Ian Ergui, B.Sc.<br />
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'''[[Chelation therapy|To read more about chelation therapy click here.]]'''<br><br />
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{{SK}} Chelation therapy, EDTA, post-myocardial infarction, diabetes<br />
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==Overview==<br />
[[Chelation]] is a process by which an organic molecule with a negatively charged “pocket” complexes with a metal ion of opposite charge, inactivates it, and then permits its physiological mobilization and excretion, usually by a renal route. [[Chelation therapy]], which involves multiple administrations of a chelating agent, helps eliminate stored toxic metal ions from the body.<ref name="pmid11794513">{{cite journal| author=Waters RS, Bryden NA, Patterson KY, Veillon C, Anderson RA| title=EDTA chelation effects on urinary losses of cadmium, calcium, chromium, cobalt, copper, lead, magnesium, and zinc. | journal=Biol Trace Elem Res | year= 2001 | volume= 83 | issue= 3 | pages= 207-21 | pmid=11794513 | doi=10.1385/BTER:83:3:207 | pmc= | url=https://www.ncbi.nlm.nih.gov/entrez/eutils/elink.fcgi?dbfrom=pubmed&tool=sumsearch.org/cite&retmode=ref&cmd=prlinks&id=11794513 }} </ref><ref name="arenas">Arenas I.A., Navas-Acien A., Lamas G.A.; Enhanced vasculotoxic metal excretionin post-MI patients after edetate disodium therapy (abstr). J Am Coll Cardiol. 2016;67:A2125</ref> Common chelators include [[penicillamine]], which binds copper and can be used to treat [[Wilson’s disease]], [[deferoxamine]], which binds iron and is used in the treatment of [[thalassemia]] and iron overload, succimer, also used in the treatment of lead poisoning, and the edetates, non-specific chelators of metals and other ions with valences of +2 to +6. Chelation therapy is, in many cases, guideline mandated, such as in children with elevated blood lead levels,<ref name="CDC">CDC. Low Level Lead Exposure Harms Children: A Renewed Call for Primary Prevention. Atlanta, GA:Advisory Committee on Childhood Lead Poisoning Prevention, U.S. Centers for Disease Control and Prevention (4 Jan 2012). Available: [http://www.cdc.gov/nceh/lead/acclpp/final_document_010412.pdf]</ref> patients with iron overload and dyserythropoietic syndromes or chronic hemolytic anemia,<ref name="pmid21452290">{{cite journal| author=Bacon BR, Adams PC, Kowdley KV, Powell LW, Tavill AS, American Association for the Study of Liver Diseases| title=Diagnosis and management of hemochromatosis: 2011 practice guideline by the American Association for the Study of Liver Diseases. | journal=Hepatology | year= 2011 | volume= 54 | issue= 1 | pages= 328-43 | pmid=21452290 | doi=10.1002/hep.24330 | pmc=3149125 | url=https://www.ncbi.nlm.nih.gov/entrez/eutils/elink.fcgi?dbfrom=pubmed&tool=sumsearch.org/cite&retmode=ref&cmd=prlinks&id=21452290 }} </ref> or [[sickle cell disease]] and transfusion acquired iron-overload,<ref name="NHLBI">NHLBI. Transfusion in Sickle Cell Disease: A Systematic Review of Benefits, Complications, and Management of Complications. Prepared for the National Heart, Lung, and Blood Institute and by the Knowledge and Evaluation Research Unit, Mayo Clinic Rochester (2012)</ref> to name a few instances.<br />
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[[Ethylene diamine tetraacetic acid]] ([[EDTA]], edetate) and its salts (most commonly disodium or calcium disodium), commonly used chelating agents patented in 1938, bind to and permit the urinary excretion of divalent cations such as calcium, and metals such as [[lead]], [[cadmium]], [[nickel]], [[cobalt]], [[iron]], [[aluminum]], and others. The initial medical use for [[EDTA]] began after World War II for the treatment of [[lead]]-exposed naval workers. In addition to its use for the treatment of metal poisoning, since the 1950s chelation therapy has been considered an alternative or add-on therapy for the prevention and treatment of [[atherosclerotic disease]]. The use of edetate disodium (Na2EDTA) has been most prominent in the alternative medicine treatment of atherosclerosis primarily because of the still-unproven hypothesis that the [[hypocalcemia]] it induces might lead to the decalcification of atherosclerotic lesions. In fact, the most current research suggests that the probable mechanism of benefit centers on enhancement of toxic metal excretion.<br />
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==Chelation Therapy and CVD==<br />
The use of chelation therapy as a treatment for [[atherosclerotic disease]] dates back to the 1950’s when Clarke et al investigated the use of EDTA for the treatment of angina pectoris and reported improvement in 19 of 20 patients.<ref name="pmid13372537">{{cite journal| author=CLARKE CN, CLARKE NE, MOSHER RE| title=Treatment of angina pectoris with disodium ethylene diamine tetraacetic acid. | journal=Am J Med Sci | year= 1956 | volume= 232 | issue= 6 | pages= 654-66 | pmid=13372537 | doi= | pmc= | url=http://www.ncbi.nlm.nih.gov/entrez/eutils/elink.fcgi?dbfrom=pubmed&tool=sumsearch.org/cite&retmode=ref&cmd=prlinks&id=13372537 }} </ref> Later studies by Kitchell were less positive,<ref name="pmid13756462">{{cite journal| author=KITCHELL JR, MELTZER LE, SEVEN MJ| title=Potential uses of chelation methods in the treatment of cardiovascular diseases. | journal=Prog Cardiovasc Dis | year= 1961 | volume= 3 | issue= | pages= 338-49 | pmid=13756462 | doi= | pmc= | url=https://www.ncbi.nlm.nih.gov/entrez/eutils/elink.fcgi?dbfrom=pubmed&tool=sumsearch.org/cite&retmode=ref&cmd=prlinks&id=13756462 }} </ref><ref name="pmid14033183">{{cite journal| author=KITCHELL JR, PALMON F, AYTAN N, MELTZER LE| title=The treatment of coronary artery disease with disodium EDTA. A reappraisal. | journal=Am J Cardiol | year= 1963 | volume= 11 | issue= | pages= 501-6 | pmid=14033183 | doi= | pmc= | url=https://www.ncbi.nlm.nih.gov/entrez/eutils/elink.fcgi?dbfrom=pubmed&tool=sumsearch.org/cite&retmode=ref&cmd=prlinks&id=14033183 }} </ref> and in an era without modern clinical trials methodology nor effective concomitant therapies, opinions regarding the use of [[chelation therapy]] for [[cardiovascular disease]] (CVD) tilted towards the negative. To be fair, from the 1970’s to 1990’s the preponderance of the scientific literature on chelation therapy for atherosclerosis consisted of case reports, case series, and small clinical trials with surrogate endpoints, poor-quality evidence from which to draw a conclusion of efficacy or harm.<ref name="pmid12519577">{{cite journal| author=Villarruz MV, Dans A, Tan F| title=Chelation therapy for atherosclerotic cardiovascular disease. | journal=Cochrane Database Syst Rev | year= 2002 | volume= | issue= 4 | pages= CD002785 | pmid=12519577 | doi=10.1002/14651858.CD002785 | pmc= | url=http://www.ncbi.nlm.nih.gov/entrez/eutils/elink.fcgi?dbfrom=pubmed&tool=sumsearch.org/cite&retmode=ref&cmd=prlinks&id=12519577 }} </ref><br />
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For example, one extensive case series reported an association between EDTA chelation therapy and improvement of ischemic heart disease and peripheral artery disease.<ref name="pmid3144646">{{cite journal| author=Olszewer E, Carter JP| title=EDTA chelation therapy in chronic degenerative disease. | journal=Med Hypotheses | year= 1988 | volume= 27 | issue= 1 | pages= 41-9 | pmid=3144646 | doi= | pmc= | url=http://www.ncbi.nlm.nih.gov/entrez/eutils/elink.fcgi?dbfrom=pubmed&tool=sumsearch.org/cite&retmode=ref&cmd=prlinks&id=3144646 }} </ref> Another study demonstrated that EDTA supplemented with several B vitamins (vitamin B1, B2, B6 and B12) but not EDTA alone was effective in improving [[endothelium]]-dependent forearm blood flow.<ref name="pmid10561804">{{cite journal| author=Green DJ, O'Driscoll JG, Maiorana A, Scrimgeour NB, Weerasooriya R, Taylor RR| title=Effects of chelation with EDTA and vitamin B therapy on nitric oxide-related endothelial vasodilator function. | journal=Clin Exp Pharmacol Physiol | year= 1999 | volume= 26 | issue= 11 | pages= 853-6 | pmid=10561804 | doi= | pmc= | url=http://www.ncbi.nlm.nih.gov/entrez/eutils/elink.fcgi?dbfrom=pubmed&tool=sumsearch.org/cite&retmode=ref&cmd=prlinks&id=10561804 }} </ref> A systematic review of four randomized clinical trials on chelation therapy and [[peripheral artery occlusive disease]] reported no benefit associated with chelation therapy.<ref name="pmid9264515">{{cite journal| author=Ernst E| title=Chelation therapy for peripheral arterial occlusive disease: a systematic review. | journal=Circulation | year= 1997 | volume= 96 | issue= 3 | pages= 1031-3 | pmid=9264515 | doi= | pmc= | url=http://www.ncbi.nlm.nih.gov/entrez/eutils/elink.fcgi?dbfrom=pubmed&tool=sumsearch.org/cite&retmode=ref&cmd=prlinks&id=9264515 }} </ref> The studies, however, individually and in aggregate, were too small to exclude a small to moderate benefit of therapy. Moreover, followup was short and surrogate physiologic endpoints, such as walking distance, were used. A Cochrane systematic review on the role of chelation therapy to treat coronary heart disease in 2002 concluded that the data were insufficient to recommend for or against chelation.<ref name="pmid10874275">{{cite journal| author=Ernst E| title=Chelation therapy for coronary heart disease: An overview of all clinical investigations. | journal=Am Heart J | year= 2000 | volume= 140 | issue= 1 | pages= 139-41 | pmid=10874275 | doi=10.1067/mhj.2000.107548 | pmc= | url=http://www.ncbi.nlm.nih.gov/entrez/eutils/elink.fcgi?dbfrom=pubmed&tool=sumsearch.org/cite&retmode=ref&cmd=prlinks&id=10874275 }} </ref> <br />
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The medical community concluded that the absence of high quality evidence of efficacy equated with evidence of absence of efficacy. Professional organizations recommended against chelation therapy.<ref name="pmid9205980">{{cite journal| author=Lewin MR| title=Chelation therapy for cardiovascular disease. Review and commentary. | journal=Tex Heart Inst J | year= 1997 | volume= 24 | issue= 2 | pages= 81-9 | pmid=9205980 | doi= | pmc=325409 | url=https://www.ncbi.nlm.nih.gov/entrez/eutils/elink.fcgi?dbfrom=pubmed&tool=sumsearch.org/cite&retmode=ref&cmd=prlinks&id=9205980 }} </ref> Interestingly, patients continued to seek, and practitioners to administer, chelation infusions for [[cardiovascular disease]] and other diagnoses.<br />
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In light of the persistent controversy regarding the benefits of chelation therapy and the absence of any previous large clinical trial investigating its use in coronary artery disease, the National Center for Complementary and Alternative Medicine and the National Heart Lung and Blood Institute released a $30 million Request for Applications (RFA) to develop a definitive trial. In 2002, the RFA was awarded to Mount Sinai Medical Center in Miami Beach FL (G Lamas MD, Principal Investigator). The Trial to Assess Chelation Therapy (TACT), a randomized, double blind, placebo controlled 2x2 factorial trial, investigated the efficacy and safety of disodium EDTA based infusions and high-dose oral vitamins and minerals in 1708 stable post-myocardial infarction (MI) patients more than 50 years of age and with fairly normal kidney function ([[creatinine]] 2.0 mg/dL or less). The active treatment consisted of 40 infusions consisted of disodium [[EDTA]] combined with [[ascorbic acid]], B vitamins, and other components. The median age of patients was 65 years, and they were treated with evidence-based post-MI medicines. The primary endpoint of this trial was a composite of all-cause mortality, [[stroke]], [[MI]], coronary revascularization, and hospitalization for [[angina]].<ref name="pmid16585050">{{cite journal| author=Costa J, Borges M, David C, Vaz Carneiro A| title=Efficacy of lipid lowering drug treatment for diabetic and non-diabetic patients: meta-analysis of randomised controlled trials. | journal=BMJ | year= 2006 | volume= 332 | issue= 7550 | pages= 1115-24 | pmid=16585050 | doi=10.1136/bmj.38793.468449.AE | pmc=PMC1459619 | url=http://www.ncbi.nlm.nih.gov/entrez/eutils/elink.fcgi?dbfrom=pubmed&tool=sumsearch.org/cite&retmode=ref&cmd=prlinks&id=16585050 }} </ref><br />
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A follow up period of 55 months revealed a statistically significant decrease in the primary endpoint (HR: 0.82; 95% CI: 0.69-0.99; p= 0.035). There was an absolute reduction in the 5-year Kaplan-Meier estimate, from 38% to 33%, resulting in a 5-year number needed to treat (NNT) of 18 patients to avoid one adverse cardiovascular outcome. This is comparable to the 5-year NNT for [[statins]] in post-[[MI]] patients (NNT=16 for the secondary prevention of a major coronary event).<ref name="pmid16585050">{{cite journal| author=Costa J, Borges M, David C, Vaz Carneiro A| title=Efficacy of lipid lowering drug treatment for diabetic and non-diabetic patients: meta-analysis of randomised controlled trials. | journal=BMJ | year= 2006 | volume= 332 | issue= 7550 | pages= 1115-24 | pmid=16585050 | doi=10.1136/bmj.38793.468449.AE | pmc=PMC1459619 | url=http://www.ncbi.nlm.nih.gov/entrez/eutils/elink.fcgi?dbfrom=pubmed&tool=sumsearch.org/cite&retmode=ref&cmd=prlinks&id=16585050 }} </ref> The point estimate for the risk of each of the components of the primary endpoint was <1, consistent with the aggregate result. The Investigators concluded that chelation should not yet be adopted for routine post-MI use in all patients, but the results of TACT should inform further studies to confirm or refute these unexpected results.<ref name="pmid23532240">{{cite journal| author=Lamas GA, Goertz C, Boineau R, Mark DB, Rozema T, Nahin RL et al.| title=Effect of disodium EDTA chelation regimen on cardiovascular events in patients with previous myocardial infarction: the TACT randomized trial. | journal=JAMA | year= 2013 | volume= 309 | issue= 12 | pages= 1241-50 | pmid=23532240 | doi=10.1001/jama.2013.2107 | pmc= | url=http://www.ncbi.nlm.nih.gov/entrez/eutils/elink.fcgi?dbfrom=pubmed&tool=sumsearch.org/cite&retmode=ref&cmd=prlinks&id=23532240 }} </ref><br />
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TACT prespecified several subgroups for analysis and found a significant interaction between edetate disodium treatment and [[diabetes]] (p for interaction =0.0037). Among subjects enrolled in TACT, there were 633 diabetic patients, defined as patients with self-reported diabetes, taking medications for diabetes, or having a fasting blood glucose of at least 126 mg/dL at enrollment. The administration of chelation infusions among post-MI diabetic patients was associated with a marked reduction in the primary end point when compared with placebo. The primary end point occurred in 25% of diabetic patients who were administered chelation therapy compared to 38% in those who received placebo infusions (HR, 0.59; 95% CI, 0.44–0.79; P<0.001). The 5-year NNT to prevent one event was 6.5. In addition, chelation therapy was significantly associated with decreased all-cause mortality (43% reduction, p=0.011) and reinfarction (52% reduction, p=0.015). Again, the investigators concluded that these findings supported future research, but did not constitute sufficient evidence to indicate the routine use of chelation therapy for all post–myocardial infarction patients with diabetes, leaving open the clinician’s choice to use this novel therapy in occasional, or non-routine patients.<br />
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These results catalyzed a wave of increased public and scientific interest in disodium EDTA treatment for patients with established coronary disease, particularly in diabetes, and hypotheses regarding potential mechanisms of benefit. As a capstone to the published analyses, the ACC/AHA Guidelines for Chronic Ischemic Heart Disease changed to reflect the TACT data and upgraded disodium EDTA treatment from a Class III indication to a Class IIB indication. While Class III therapeutics are considered not beneficial or useful, Class IIB treatments can be considered in some patients and require additional research to establish efficacy.<ref name="pmid25077860">{{cite journal| author=Fihn SD, Blankenship JC, Alexander KP, Bittl JA, Byrne JG, Fletcher BJ et al.| title=2014 ACC/AHA/AATS/PCNA/SCAI/STS focused update of the guideline for the diagnosis and management of patients with stable ischemic heart disease: a report of the American College of Cardiology/American Heart Association Task Force on Practice Guidelines, and the American Association for Thoracic Surgery, Preventive Cardiovascular Nurses Association, Society for Cardiovascular Angiography and Interventions, and Society of Thoracic Surgeons. | journal=J Am Coll Cardiol | year= 2014 | volume= 64 | issue= 18 | pages= 1929-49 | pmid=25077860 | doi=10.1016/j.jacc.2014.07.017 | pmc= | url=https://www.ncbi.nlm.nih.gov/entrez/eutils/elink.fcgi?dbfrom=pubmed&tool=sumsearch.org/cite&retmode=ref&cmd=prlinks&id=25077860 }} </ref> The change in the guidelines signaled a major shift in the perception of chelation therapy among the medical establishment. The TACT data led clinicians to reconsider chelation objectively, and the investigators and many other academic cardiologists called for TACT2, a new trial to test the results of TACT, to be funded by the [[NIH]].<br />
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==Mechanism of Action==<br />
Edetate disodium binds to metals and forms soluble complexes facilitating their subsequent excretion in the urine.<ref name="pmid14000694">{{cite journal| author=WILDER LW, DE JODE LR, MILSTEIN SW, HOWARD JM| title=Mobilization of atherosclerotic plaque calcium with EDTA utilizing the isolation-perfusion principle. | journal=Surgery | year= 1962 | volume= 52 | issue= | pages= 793-5 | pmid=14000694 | doi= | pmc= | url=http://www.ncbi.nlm.nih.gov/entrez/eutils/elink.fcgi?dbfrom=pubmed&tool=sumsearch.org/cite&retmode=ref&cmd=prlinks&id=14000694 }} </ref> Hence, chelation therapy results in the elimination of stored toxic and essential metals. In an experiment performed on 24 patients, age 50 or older, and with a prior MI and a creatinine of 2.0 or less, patients had urine toxic metals measured at baseline, 1 day after an infusion of placebo, and 1 day after an infusion of the edetate disodium-based TACT solution. Placebo did not increase the excretion of toxic metals. Following an infusion of the edetate disodium-based TACT solution, lead excretion increased by nearly 3900%, and cadmium by nearly 700%. Other toxic metals whose excretion was enhanced by edetate disodium were aluminum (by ~250%), nickel (by ~150%), thallium (by ~60%), and gadolinium. A similar experiment performed earlier by Waters et al, reported urinary lead concentrations approximately 35 times greater than in pre-chelation urine.<ref name="pmid11794513">{{cite journal| author=Waters RS, Bryden NA, Patterson KY, Veillon C, Anderson RA| title=EDTA chelation effects on urinary losses of cadmium, calcium, chromium, cobalt, copper, lead, magnesium, and zinc. | journal=Biol Trace Elem Res | year= 2001 | volume= 83 | issue= 3 | pages= 207-21 | pmid=11794513 | doi=10.1385/BTER:83:3:207 | pmc= | url=https://www.ncbi.nlm.nih.gov/entrez/eutils/elink.fcgi?dbfrom=pubmed&tool=sumsearch.org/cite&retmode=ref&cmd=prlinks&id=11794513 }} </ref><br />
While enhanced lead and cadmium is interesting, the critical link to cardiovascular events is provided by epidemiological studies, which provide robust evidence linking toxic metals with cardiovascular disease.<ref name="pmid21421632">{{cite journal| author=Agarwal S, Zaman T, Tuzcu EM, Kapadia SR| title=Heavy metals and cardiovascular disease: results from the National Health and Nutrition Examination Survey (NHANES) 1999-2006. | journal=Angiology | year= 2011 | volume= 62 | issue= 5 | pages= 422-9 | pmid=21421632 | doi=10.1177/0003319710395562 | pmc= | url=http://www.ncbi.nlm.nih.gov/entrez/eutils/elink.fcgi?dbfrom=pubmed&tool=sumsearch.org/cite&retmode=ref&cmd=prlinks&id=21421632 }} </ref> This evidence is strongest for lead and cadmium.<ref name="pmid16982939">{{cite journal| author=Menke A, Muntner P, Batuman V, Silbergeld EK, Guallar E| title=Blood lead below 0.48 micromol/L (10 microg/dL) and mortality among US adults. | journal=Circulation | year= 2006 | volume= 114 | issue= 13 | pages= 1388-94 | pmid=16982939 | doi=10.1161/CIRCULATIONAHA.106.628321 | pmc= | url=https://www.ncbi.nlm.nih.gov/entrez/eutils/elink.fcgi?dbfrom=pubmed&tool=sumsearch.org/cite&retmode=ref&cmd=prlinks&id=16982939 }} </ref><ref name="pmid15184277">{{cite journal| author=Navas-Acien A, Selvin E, Sharrett AR, Calderon-Aranda E, Silbergeld E, Guallar E| title=Lead, cadmium, smoking, and increased risk of peripheral arterial disease. | journal=Circulation | year= 2004 | volume= 109 | issue= 25 | pages= 3196-201 | pmid=15184277 | doi=10.1161/01.CIR.0000130848.18636.B2 | pmc= | url=http://www.ncbi.nlm.nih.gov/entrez/eutils/elink.fcgi?dbfrom=pubmed&tool=sumsearch.org/cite&retmode=ref&cmd=prlinks&id=15184277 }} </ref><ref name="pmid23514838">{{cite journal| author=Tellez-Plaza M, Guallar E, Howard BV, Umans JG, Francesconi KA, Goessler W et al.| title=Cadmium exposure and incident cardiovascular disease. | journal=Epidemiology | year= 2013 | volume= 24 | issue= 3 | pages= 421-9 | pmid=23514838 | doi=10.1097/EDE.0b013e31828b0631 | pmc= | url=http://www.ncbi.nlm.nih.gov/entrez/eutils/elink.fcgi?dbfrom=pubmed&tool=sumsearch.org/cite&retmode=ref&cmd=prlinks&id=23514838 }} </ref> Elevated blood concentration of lead is associated with increased all-cause mortality [HR 1.25 (95% CI 1.04 to 1.51) for the highest versus lowest tertile of blood lead, P trend across the tertiles=0.002) and cardiovascular mortality [HR 1.55 (95% CI 1.08 to 2.24) for the highest versus lowest tertile, P trend <0.003].<ref name="pmid16982939">{{cite journal| author=Menke A, Muntner P, Batuman V, Silbergeld EK, Guallar E| title=Blood lead below 0.48 micromol/L (10 microg/dL) and mortality among US adults. | journal=Circulation | year= 2006 | volume= 114 | issue= 13 | pages= 1388-94 | pmid=16982939 | doi=10.1161/CIRCULATIONAHA.106.628321 | pmc= | url=https://www.ncbi.nlm.nih.gov/entrez/eutils/elink.fcgi?dbfrom=pubmed&tool=sumsearch.org/cite&retmode=ref&cmd=prlinks&id=16982939 }} </ref> Also, cardiovascular mortality is greater among subjects with elevated cadmium concentrations in the blood and urine [HR 1.69 (95% CI: 1.03, 2.77) and 1.74 (95% CI: 1.07, 2.83) for the 80th and 20th percentiles of blood and urine cadmium, respectively].<ref name="pmid22472185">{{cite journal| author=Tellez-Plaza M, Navas-Acien A, Menke A, Crainiceanu CM, Pastor-Barriuso R, Guallar E| title=Cadmium exposure and all-cause and cardiovascular mortality in the U.S. general population. | journal=Environ Health Perspect | year= 2012 | volume= 120 | issue= 7 | pages= 1017-22 | pmid=22472185 | doi=10.1289/ehp.1104352 | pmc=3404657 | url=https://www.ncbi.nlm.nih.gov/entrez/eutils/elink.fcgi?dbfrom=pubmed&tool=sumsearch.org/cite&retmode=ref&cmd=prlinks&id=22472185 }} </ref> <br />
Heavy metals may play a role in the development of [[cardiovascular disease]] through a number of different mechanisms.<ref name="pmid17645641">{{cite journal| author=Vaziri ND, Khan M| title=Interplay of reactive oxygen species and nitric oxide in the pathogenesis of experimental lead-induced hypertension. | journal=Clin Exp Pharmacol Physiol | year= 2007 | volume= 34 | issue= 9 | pages= 920-5 | pmid=17645641 | doi=10.1111/j.1440-1681.2007.04644.x | pmc= | url=https://www.ncbi.nlm.nih.gov/entrez/eutils/elink.fcgi?dbfrom=pubmed&tool=sumsearch.org/cite&retmode=ref&cmd=prlinks&id=17645641 }} </ref> Heavy metals include transition metals such as [[cadmium]], [[mercury]], [[manganese]], [[chromium]], [[cobalt]], [[nickel]], [[iron]], and [[copper]], metalloids such as antimony and arsenic, and post- transition metals such as thallium and lead. These metals all have unique toxicities, as well as toxicities that are common to all of them. Heavy metals in the endothelium promote oxygen free radical formation, resulting in increased oxidative stress, inflammation, and tissue damage. Lead and cadmium may interfere with calcium signaling channels. Transition metals promote modifications of low-density lipoprotein by endothelial cells through lipid peroxidation and degradation of low-density lipoprotein phospholipids.<ref name="pmid6587396">{{cite journal| author=Steinbrecher UP, Parthasarathy S, Leake DS, Witztum JL, Steinberg D| title=Modification of low density lipoprotein by endothelial cells involves lipid peroxidation and degradation of low density lipoprotein phospholipids. | journal=Proc Natl Acad Sci U S A | year= 1984 | volume= 81 | issue= 12 | pages= 3883-7 | pmid=6587396 | doi= | pmc=345326 | url=https://www.ncbi.nlm.nih.gov/entrez/eutils/elink.fcgi?dbfrom=pubmed&tool=sumsearch.org/cite&retmode=ref&cmd=prlinks&id=6587396 }} </ref><ref name="pmid6501577">{{cite journal| author=Heinecke JW, Rosen H, Chait A| title=Iron and copper promote modification of low density lipoprotein by human arterial smooth muscle cells in culture. | journal=J Clin Invest | year= 1984 | volume= 74 | issue= 5 | pages= 1890-4 | pmid=6501577 | doi=10.1172/JCI111609 | pmc=425370 | url=https://www.ncbi.nlm.nih.gov/entrez/eutils/elink.fcgi?dbfrom=pubmed&tool=sumsearch.org/cite&retmode=ref&cmd=prlinks&id=6501577 }} </ref><ref name="pmid8847477">{{cite journal| author=Morgan J, Leake DS| title=Oxidation of low density lipoprotein by iron or copper at acidic pH. | journal=J Lipid Res | year= 1995 | volume= 36 | issue= 12 | pages= 2504-12 | pmid=8847477 | doi= | pmc= | url=https://www.ncbi.nlm.nih.gov/entrez/eutils/elink.fcgi?dbfrom=pubmed&tool=sumsearch.org/cite&retmode=ref&cmd=prlinks&id=8847477 }} </ref> Exposure to non-transition metals, such as lead, has also been associated with impaired nitric oxide signaling and availability,<ref name="pmid15894814">{{cite journal| author=Dursun N, Arifoglu C, Süer C, Keskinol L| title=Blood pressure relationship to nitric oxide, lipid peroxidation, renal function, and renal blood flow in rats exposed to low lead levels. | journal=Biol Trace Elem Res | year= 2005 | volume= 104 | issue= 2 | pages= 141-9 | pmid=15894814 | doi=10.1385/BTER:104:2:141 | pmc= | url=https://www.ncbi.nlm.nih.gov/entrez/eutils/elink.fcgi?dbfrom=pubmed&tool=sumsearch.org/cite&retmode=ref&cmd=prlinks&id=15894814 }} </ref> endothelial cell dysfunction,<ref name="pmid7710289">{{cite journal| author=Kaji T, Suzuki M, Yamamoto C, Mishima A, Sakamoto M, Kozuka H| title=Severe damage of cultured vascular endothelial cell monolayer after simultaneous exposure to cadmium and lead. | journal=Arch Environ Contam Toxicol | year= 1995 | volume= 28 | issue= 2 | pages= 168-72 | pmid=7710289 | doi= | pmc= | url=https://www.ncbi.nlm.nih.gov/entrez/eutils/elink.fcgi?dbfrom=pubmed&tool=sumsearch.org/cite&retmode=ref&cmd=prlinks&id=7710289 }} </ref> and hypertension.<ref name="pmid18567711">{{cite journal| author=Vaziri ND| title=Mechanisms of lead-induced hypertension and cardiovascular disease. | journal=Am J Physiol Heart Circ Physiol | year= 2008 | volume= 295 | issue= 2 | pages= H454-65 | pmid=18567711 | doi=10.1152/ajpheart.00158.2008 | pmc=2519216 | url=https://www.ncbi.nlm.nih.gov/entrez/eutils/elink.fcgi?dbfrom=pubmed&tool=sumsearch.org/cite&retmode=ref&cmd=prlinks&id=18567711 }} </ref> [[Heavy metal]] exposure is also associated with genetic and [[epigenetic]] manifestations. [[Cadmium]] promotes atherosclerosis and endothelial dysfunction through multiple [[genetic]] changes.<ref name="pmid19556524">{{cite journal| author=Messner B, Knoflach M, Seubert A, Ritsch A, Pfaller K, Henderson B et al.| title=Cadmium is a novel and independent risk factor for early atherosclerosis mechanisms and in vivo relevance. | journal=Arterioscler Thromb Vasc Biol | year= 2009 | volume= 29 | issue= 9 | pages= 1392-8 | pmid=19556524 | doi=10.1161/ATVBAHA.109.190082 | pmc= | url=https://www.ncbi.nlm.nih.gov/entrez/eutils/elink.fcgi?dbfrom=pubmed&tool=sumsearch.org/cite&retmode=ref&cmd=prlinks&id=19556524 }} </ref> One of the mechanisms involves [[DNA]] strand breaks and damage with subsequent apoptosis in [[endothelial cell]]s.<ref name="pmid19556524">{{cite journal| author=Messner B, Knoflach M, Seubert A, Ritsch A, Pfaller K, Henderson B et al.| title=Cadmium is a novel and independent risk factor for early atherosclerosis mechanisms and in vivo relevance. | journal=Arterioscler Thromb Vasc Biol | year= 2009 | volume= 29 | issue= 9 | pages= 1392-8 | pmid=19556524 | doi=10.1161/ATVBAHA.109.190082 | pmc= | url=https://www.ncbi.nlm.nih.gov/entrez/eutils/elink.fcgi?dbfrom=pubmed&tool=sumsearch.org/cite&retmode=ref&cmd=prlinks&id=19556524 }} </ref> Also, maternal [[lead]] exposure during pregnancy may be associated with epigenetic consequences in grandchildren through alteration of [[DNA methylation]] early in life.<ref name="pmid26417717">{{cite journal| author=Sen A, Heredia N, Senut MC, Land S, Hollocher K, Lu X et al.| title=Multigenerational epigenetic inheritance in humans: DNA methylation changes associated with maternal exposure to lead can be transmitted to the grandchildren. | journal=Sci Rep | year= 2015 | volume= 5 | issue= | pages= 14466 | pmid=26417717 | doi=10.1038/srep14466 | pmc=4586440 | url=https://www.ncbi.nlm.nih.gov/entrez/eutils/elink.fcgi?dbfrom=pubmed&tool=sumsearch.org/cite&retmode=ref&cmd=prlinks&id=26417717 }} </ref><br />
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Current mechanistic understanding, albeit rudimentary, supports the concept that the cardiovascular benefits of [[chelation therapy]] may result from enhanced excretion of [[heavy metals]], and subsequent reduction in processes listed above. Additionally, in patients with [[diabetes]], a reduction in the metal-catalyzed formation of [[reactive oxygen species]], formation of advanced glycation end-products, and lipid [[peroxidation]] has been postulated.<ref name="pmid10874253">{{cite journal| author=Lamas GA, Ackermann A| title=Clinical evaluation of chelation therapy: is there any wheat amidst the chaff? | journal=Am Heart J | year= 2000 | volume= 140 | issue= 1 | pages= 4-5 | pmid=10874253 | doi=10.1067/mhj.2000.107549 | pmc= | url=http://www.ncbi.nlm.nih.gov/entrez/eutils/elink.fcgi?dbfrom=pubmed&tool=sumsearch.org/cite&retmode=ref&cmd=prlinks&id=10874253 }} </ref> Metal detoxification in the context of diabetes possibly decreases [[inflammation]] and [[oxidative stress]] that characterize atherosclerosis.<ref>Escolar E, Lamas G, Mark D et al(2013) "The Effect of an EDTA-based Chelation Regimen on Patients With Diabetes Mellitus and Prior Myocardial Infarction in the Trial to Assess Chelation Therapy (TACT)". Circulation. 2013</ref> Recent research, including chelation-activity assays, indicates that many common [[diabetes]] drugs, such as [[metformin]] and aldose reductase inhibitors, could possibly have some chelating properties.<ref name="pmid22354928">{{cite journal| author=Nagai R, Murray DB, Metz TO, Baynes JW| title=Chelation: a fundamental mechanism of action of AGE inhibitors, AGE breakers, and other inhibitors of diabetes complications. | journal=Diabetes | year= 2012 | volume= 61 | issue= 3 | pages= 549-59 | pmid=22354928 | doi=10.2337/db11-1120 | pmc=3282805 | url=https://www.ncbi.nlm.nih.gov/entrez/eutils/elink.fcgi?dbfrom=pubmed&tool=sumsearch.org/cite&retmode=ref&cmd=prlinks&id=22354928 }} </ref><ref name="pmid23612664">{{cite journal| author=Frizzell N, Baynes JW| title=Chelation therapy for the management of diabetic complications: a hypothesis and a proposal for clinical laboratory assessment of metal ion homeostasis in plasma. | journal=Clin Chem Lab Med | year= 2014 | volume= 52 | issue= 1 | pages= 69-75 | pmid=23612664 | doi=10.1515/cclm-2012-0881 | pmc= | url=https://www.ncbi.nlm.nih.gov/entrez/eutils/elink.fcgi?dbfrom=pubmed&tool=sumsearch.org/cite&retmode=ref&cmd=prlinks&id=23612664 }} </ref><ref name="pmid22492524">{{cite journal| author=Logie L, Harthill J, Patel K, Bacon S, Hamilton DL, Macrae K et al.| title=Cellular responses to the metal-binding properties of metformin. | journal=Diabetes | year= 2012 | volume= 61 | issue= 6 | pages= 1423-33 | pmid=22492524 | doi=10.2337/db11-0961 | pmc=3357267 | url=https://www.ncbi.nlm.nih.gov/entrez/eutils/elink.fcgi?dbfrom=pubmed&tool=sumsearch.org/cite&retmode=ref&cmd=prlinks&id=22492524 }} </ref><br />
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The TACT chelation infusion, however, did not contain edetate disodium alone. The standard chelation infusion formula used in TACT was formulated to be identical with the most prevalent infusion in use. This formulation had developed organically over decades and had been modified by clinical practitioners to have additives such as [[ascorbic acid]], B-vitamins and [[magnesium]], thought to have a protective effect on [[endothelial cells]],<ref>Rozema, Theodore C. "The protocol for the safe and effective administration of EDTA and other chelating agents for vascular disease, degenerative disease, and metal toxicity." Journal of Advancement in Medicine 10.1 (1997): 5-100.</ref> making the results of clinical application more difficult to understand, and emphasizing the need for mechanistic work.<br />
<br />
==Future Studies==<br />
TACT was a unique study with an unexpected result that could have vast public health implications. In order to consider its broad applicability, the medical and scientific community require the results reproduced. TACT2, scheduled to begin in October 2016 (press release), is a replicative study in post-MI diabetic patients. If the TACT2 results confirm the results of TACT, then chelation is poised to become the next major development in the treatment of vascular complications of diabetes and vascular disease. TACT2 is currently recruiting sites, and interested investigators should visit www.TACT2.org for additional information.<br />
<br />
==Side Effects==<br />
Shown below is a list of the labelled toxicities of EDTA-based chelation therapy. However, TACT delivered 55,222 infusions of EDTA or placebo, and found no differences between groups in adverse events, serious or otherwise.<br />
* [[Arrhythmias]]<br />
* [[Autoimmune diseases]]<br />
* [[Bone marrow]]<br />
* [[Convulsions]]<br />
* [[Depression]]<br />
* [[Fever]]<br />
* [[Heart failure]]<br />
* [[Hypocalcemia]]<br />
* [[Hypoglycemia]]<br />
* [[Hypotension]]<br />
* [[Bleeding time|Prolonged bleeding time]]<br />
* [[Renal failure]]<br />
* [[Respiratory arrest]]<br />
* [[Tetany]]<br />
* [[Trace metal|Trace metal deficiency]]<br />
* [[Vitamin deficiency]]<ref name="pmid10874275">{{cite journal| author=Ernst E| title=Chelation therapy for coronary heart disease: An overview of all clinical investigations. | journal=Am Heart J | year= 2000 | volume= 140 | issue= 1 | pages= 139-41 | pmid=10874275 | doi=10.1067/mhj.2000.107548 | pmc= | url=http://www.ncbi.nlm.nih.gov/entrez/eutils/elink.fcgi?dbfrom=pubmed&tool=sumsearch.org/cite&retmode=ref&cmd=prlinks&id=10874275 }} </ref><ref name="pmid23532240">{{cite journal| author=Lamas GA, Goertz C, Boineau R, Mark DB, Rozema T, Nahin RL et al.| title=Effect of disodium EDTA chelation regimen on cardiovascular events in patients with previous myocardial infarction: the TACT randomized trial. | journal=JAMA | year= 2013 | volume= 309 | issue= 12 | pages= 1241-50 | pmid=23532240 | doi=10.1001/jama.2013.2107 | pmc= | url=http://www.ncbi.nlm.nih.gov/entrez/eutils/elink.fcgi?dbfrom=pubmed&tool=sumsearch.org/cite&retmode=ref&cmd=prlinks&id=23532240 }} </ref><br />
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==Landmark Trials==<br />
[[TACT]] <br><br />
TACT 2 [http://www.TACT2.org] (link to press release [http://www.prnewswire.com/news-releases/tact2-clinical-trial-receives-national-institutes-of-health-funding-300334174.html])<br />
<br />
==References==<br />
{{Reflist|2}}<br />
<br />
[[Category:Cardiology]]<br />
[[Category:Diabetes]]<br />
[[Category:Up-To-Date]]<br />
<br />
{{WikiDoc Help Menu}}<br />
{{WikiDoc Sources}}</div>Rim Halabyhttps://www.wikidoc.org/index.php?title=Chelation_therapy_for_cardiovascular_disease&diff=1274811Chelation therapy for cardiovascular disease2016-12-07T17:54:52Z<p>Rim Halaby: /* Mechanism of Action */</p>
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<div>__NOTOC__<br />
'''Editor-In-Chief:''' Gervasio Lamas, M.D., C. Michael Gibson, M.S., M.D.; {{AE}} {{Rim}}, Ian Ergui, B.Sc.<br />
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'''[[Chelation therapy|To read more about chelation therapy click here.]]'''<br><br />
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{{SK}} Chelation therapy, EDTA, post-myocardial infarction, diabetes<br />
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==Overview==<br />
[[Chelation]] is a process by which an organic molecule with a negatively charged “pocket” complexes with a metal ion of opposite charge, inactivates it, and then permits its physiological mobilization and excretion, usually by a renal route. [[Chelation therapy]], which involves multiple administrations of a chelating agent, helps eliminate stored toxic metal ions from the body.<ref name="pmid11794513">{{cite journal| author=Waters RS, Bryden NA, Patterson KY, Veillon C, Anderson RA| title=EDTA chelation effects on urinary losses of cadmium, calcium, chromium, cobalt, copper, lead, magnesium, and zinc. | journal=Biol Trace Elem Res | year= 2001 | volume= 83 | issue= 3 | pages= 207-21 | pmid=11794513 | doi=10.1385/BTER:83:3:207 | pmc= | url=https://www.ncbi.nlm.nih.gov/entrez/eutils/elink.fcgi?dbfrom=pubmed&tool=sumsearch.org/cite&retmode=ref&cmd=prlinks&id=11794513 }} </ref><ref name="arenas">Arenas I.A., Navas-Acien A., Lamas G.A.; Enhanced vasculotoxic metal excretionin post-MI patients after edetate disodium therapy (abstr). J Am Coll Cardiol. 2016;67:A2125</ref> Common chelators include [[penicillamine]], which binds copper and can be used to treat [[Wilson’s disease]], [[deferoxamine]], which binds iron and is used in the treatment of [[thalassemia]] and iron overload, succimer, also used in the treatment of lead poisoning, and the edetates, non-specific chelators of metals and other ions with valences of +2 to +6. Chelation therapy is, in many cases, guideline mandated, such as in children with elevated blood lead levels,<ref name="CDC">CDC. Low Level Lead Exposure Harms Children: A Renewed Call for Primary Prevention. Atlanta, GA:Advisory Committee on Childhood Lead Poisoning Prevention, U.S. Centers for Disease Control and Prevention (4 Jan 2012). Available: [http://www.cdc.gov/nceh/lead/acclpp/final_document_010412.pdf]</ref> patients with iron overload and dyserythropoietic syndromes or chronic hemolytic anemia,<ref name="pmid21452290">{{cite journal| author=Bacon BR, Adams PC, Kowdley KV, Powell LW, Tavill AS, American Association for the Study of Liver Diseases| title=Diagnosis and management of hemochromatosis: 2011 practice guideline by the American Association for the Study of Liver Diseases. | journal=Hepatology | year= 2011 | volume= 54 | issue= 1 | pages= 328-43 | pmid=21452290 | doi=10.1002/hep.24330 | pmc=3149125 | url=https://www.ncbi.nlm.nih.gov/entrez/eutils/elink.fcgi?dbfrom=pubmed&tool=sumsearch.org/cite&retmode=ref&cmd=prlinks&id=21452290 }} </ref> or [[sickle cell disease]] and transfusion acquired iron-overload,<ref name="NHLBI">NHLBI. Transfusion in Sickle Cell Disease: A Systematic Review of Benefits, Complications, and Management of Complications. Prepared for the National Heart, Lung, and Blood Institute and by the Knowledge and Evaluation Research Unit, Mayo Clinic Rochester (2012)</ref> to name a few instances.<br />
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[[Ethylene diamine tetraacetic acid]] ([[EDTA]], edetate) and its salts (most commonly disodium or calcium disodium), commonly used chelating agents patented in 1938, bind to and permit the urinary excretion of divalent cations such as calcium, and metals such as [[lead]], [[cadmium]], [[nickel]], [[cobalt]], [[iron]], [[aluminum]], and others. The initial medical use for [[EDTA]] began after World War II for the treatment of [[lead]]-exposed naval workers. In addition to its use for the treatment of metal poisoning, since the 1950s chelation therapy has been considered an alternative or add-on therapy for the prevention and treatment of [[atherosclerotic disease]]. The use of edetate disodium (Na2EDTA) has been most prominent in the alternative medicine treatment of atherosclerosis primarily because of the still-unproven hypothesis that the [[hypocalcemia]] it induces might lead to the decalcification of atherosclerotic lesions. In fact, the most current research suggests that the probable mechanism of benefit centers on enhancement of toxic metal excretion.<br />
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==Chelation Therapy and CVD==<br />
The use of chelation therapy as a treatment for [[atherosclerotic disease]] dates back to the 1950’s when Clarke et al investigated the use of EDTA for the treatment of angina pectoris and reported improvement in 19 of 20 patients.<ref name="pmid13372537">{{cite journal| author=CLARKE CN, CLARKE NE, MOSHER RE| title=Treatment of angina pectoris with disodium ethylene diamine tetraacetic acid. | journal=Am J Med Sci | year= 1956 | volume= 232 | issue= 6 | pages= 654-66 | pmid=13372537 | doi= | pmc= | url=http://www.ncbi.nlm.nih.gov/entrez/eutils/elink.fcgi?dbfrom=pubmed&tool=sumsearch.org/cite&retmode=ref&cmd=prlinks&id=13372537 }} </ref> Later studies by Kitchell were less positive,<ref name="pmid13756462">{{cite journal| author=KITCHELL JR, MELTZER LE, SEVEN MJ| title=Potential uses of chelation methods in the treatment of cardiovascular diseases. | journal=Prog Cardiovasc Dis | year= 1961 | volume= 3 | issue= | pages= 338-49 | pmid=13756462 | doi= | pmc= | url=https://www.ncbi.nlm.nih.gov/entrez/eutils/elink.fcgi?dbfrom=pubmed&tool=sumsearch.org/cite&retmode=ref&cmd=prlinks&id=13756462 }} </ref><ref name="pmid14033183">{{cite journal| author=KITCHELL JR, PALMON F, AYTAN N, MELTZER LE| title=The treatment of coronary artery disease with disodium EDTA. A reappraisal. | journal=Am J Cardiol | year= 1963 | volume= 11 | issue= | pages= 501-6 | pmid=14033183 | doi= | pmc= | url=https://www.ncbi.nlm.nih.gov/entrez/eutils/elink.fcgi?dbfrom=pubmed&tool=sumsearch.org/cite&retmode=ref&cmd=prlinks&id=14033183 }} </ref> and in an era without modern clinical trials methodology nor effective concomitant therapies, opinions regarding the use of [[chelation therapy]] for [[cardiovascular disease]] (CVD) tilted towards the negative. To be fair, from the 1970’s to 1990’s the preponderance of the scientific literature on chelation therapy for atherosclerosis consisted of case reports, case series, and small clinical trials with surrogate endpoints, poor-quality evidence from which to draw a conclusion of efficacy or harm.<ref name="pmid12519577">{{cite journal| author=Villarruz MV, Dans A, Tan F| title=Chelation therapy for atherosclerotic cardiovascular disease. | journal=Cochrane Database Syst Rev | year= 2002 | volume= | issue= 4 | pages= CD002785 | pmid=12519577 | doi=10.1002/14651858.CD002785 | pmc= | url=http://www.ncbi.nlm.nih.gov/entrez/eutils/elink.fcgi?dbfrom=pubmed&tool=sumsearch.org/cite&retmode=ref&cmd=prlinks&id=12519577 }} </ref><br />
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For example, one extensive case series reported an association between EDTA chelation therapy and improvement of ischemic heart disease and peripheral artery disease.<ref name="pmid3144646">{{cite journal| author=Olszewer E, Carter JP| title=EDTA chelation therapy in chronic degenerative disease. | journal=Med Hypotheses | year= 1988 | volume= 27 | issue= 1 | pages= 41-9 | pmid=3144646 | doi= | pmc= | url=http://www.ncbi.nlm.nih.gov/entrez/eutils/elink.fcgi?dbfrom=pubmed&tool=sumsearch.org/cite&retmode=ref&cmd=prlinks&id=3144646 }} </ref> Another study demonstrated that EDTA supplemented with several B vitamins (vitamin B1, B2, B6 and B12) but not EDTA alone was effective in improving [[endothelium]]-dependent forearm blood flow.<ref name="pmid10561804">{{cite journal| author=Green DJ, O'Driscoll JG, Maiorana A, Scrimgeour NB, Weerasooriya R, Taylor RR| title=Effects of chelation with EDTA and vitamin B therapy on nitric oxide-related endothelial vasodilator function. | journal=Clin Exp Pharmacol Physiol | year= 1999 | volume= 26 | issue= 11 | pages= 853-6 | pmid=10561804 | doi= | pmc= | url=http://www.ncbi.nlm.nih.gov/entrez/eutils/elink.fcgi?dbfrom=pubmed&tool=sumsearch.org/cite&retmode=ref&cmd=prlinks&id=10561804 }} </ref> A systematic review of four randomized clinical trials on chelation therapy and [[peripheral artery occlusive disease]] reported no benefit associated with chelation therapy.<ref name="pmid9264515">{{cite journal| author=Ernst E| title=Chelation therapy for peripheral arterial occlusive disease: a systematic review. | journal=Circulation | year= 1997 | volume= 96 | issue= 3 | pages= 1031-3 | pmid=9264515 | doi= | pmc= | url=http://www.ncbi.nlm.nih.gov/entrez/eutils/elink.fcgi?dbfrom=pubmed&tool=sumsearch.org/cite&retmode=ref&cmd=prlinks&id=9264515 }} </ref> The studies, however, individually and in aggregate, were too small to exclude a small to moderate benefit of therapy. Moreover, followup was short and surrogate physiologic endpoints, such as walking distance, were used. A Cochrane systematic review on the role of chelation therapy to treat coronary heart disease in 2002 concluded that the data were insufficient to recommend for or against chelation.<ref name="pmid10874275">{{cite journal| author=Ernst E| title=Chelation therapy for coronary heart disease: An overview of all clinical investigations. | journal=Am Heart J | year= 2000 | volume= 140 | issue= 1 | pages= 139-41 | pmid=10874275 | doi=10.1067/mhj.2000.107548 | pmc= | url=http://www.ncbi.nlm.nih.gov/entrez/eutils/elink.fcgi?dbfrom=pubmed&tool=sumsearch.org/cite&retmode=ref&cmd=prlinks&id=10874275 }} </ref> <br />
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The medical community concluded that the absence of high quality evidence of efficacy equated with evidence of absence of efficacy. Professional organizations recommended against chelation therapy.<ref name="pmid9205980">{{cite journal| author=Lewin MR| title=Chelation therapy for cardiovascular disease. Review and commentary. | journal=Tex Heart Inst J | year= 1997 | volume= 24 | issue= 2 | pages= 81-9 | pmid=9205980 | doi= | pmc=325409 | url=https://www.ncbi.nlm.nih.gov/entrez/eutils/elink.fcgi?dbfrom=pubmed&tool=sumsearch.org/cite&retmode=ref&cmd=prlinks&id=9205980 }} </ref> Interestingly, patients continued to seek, and practitioners to administer, chelation infusions for [[cardiovascular disease]] and other diagnoses.<br />
<br />
In light of the persistent controversy regarding the benefits of chelation therapy and the absence of any previous large clinical trial investigating its use in coronary artery disease, the National Center for Complementary and Alternative Medicine and the National Heart Lung and Blood Institute released a $30 million Request for Applications (RFA) to develop a definitive trial. In 2002, the RFA was awarded to Mount Sinai Medical Center in Miami Beach FL (G Lamas MD, Principal Investigator). The Trial to Assess Chelation Therapy (TACT), a randomized, double blind, placebo controlled 2x2 factorial trial, investigated the efficacy and safety of disodium EDTA based infusions and high-dose oral vitamins and minerals in 1708 stable post-myocardial infarction (MI) patients more than 50 years of age and with fairly normal kidney function ([[creatinine]] 2.0 mg/dL or less). The active treatment consisted of 40 infusions consisted of disodium [[EDTA]] combined with [[ascorbic acid]], B vitamins, and other components. The median age of patients was 65 years, and they were treated with evidence-based post-MI medicines. The primary endpoint of this trial was a composite of all-cause mortality, [[stroke]], [[MI]], coronary revascularization, and hospitalization for [[angina]].<ref name="pmid16585050">{{cite journal| author=Costa J, Borges M, David C, Vaz Carneiro A| title=Efficacy of lipid lowering drug treatment for diabetic and non-diabetic patients: meta-analysis of randomised controlled trials. | journal=BMJ | year= 2006 | volume= 332 | issue= 7550 | pages= 1115-24 | pmid=16585050 | doi=10.1136/bmj.38793.468449.AE | pmc=PMC1459619 | url=http://www.ncbi.nlm.nih.gov/entrez/eutils/elink.fcgi?dbfrom=pubmed&tool=sumsearch.org/cite&retmode=ref&cmd=prlinks&id=16585050 }} </ref><br />
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A follow up period of 55 months revealed a statistically significant decrease in the primary endpoint (HR: 0.82; 95% CI: 0.69-0.99; p= 0.035). There was an absolute reduction in the 5-year Kaplan-Meier estimate, from 38% to 33%, resulting in a 5-year number needed to treat (NNT) of 18 patients to avoid one adverse cardiovascular outcome. This is comparable to the 5-year NNT for [[statins]] in post-[[MI]] patients (NNT=16 for the secondary prevention of a major coronary event).<ref name="pmid16585050">{{cite journal| author=Costa J, Borges M, David C, Vaz Carneiro A| title=Efficacy of lipid lowering drug treatment for diabetic and non-diabetic patients: meta-analysis of randomised controlled trials. | journal=BMJ | year= 2006 | volume= 332 | issue= 7550 | pages= 1115-24 | pmid=16585050 | doi=10.1136/bmj.38793.468449.AE | pmc=PMC1459619 | url=http://www.ncbi.nlm.nih.gov/entrez/eutils/elink.fcgi?dbfrom=pubmed&tool=sumsearch.org/cite&retmode=ref&cmd=prlinks&id=16585050 }} </ref> The point estimate for the risk of each of the components of the primary endpoint was <1, consistent with the aggregate result. The Investigators concluded that chelation should not yet be adopted for routine post-MI use in all patients, but the results of TACT should inform further studies to confirm or refute these unexpected results.<ref name="pmid23532240">{{cite journal| author=Lamas GA, Goertz C, Boineau R, Mark DB, Rozema T, Nahin RL et al.| title=Effect of disodium EDTA chelation regimen on cardiovascular events in patients with previous myocardial infarction: the TACT randomized trial. | journal=JAMA | year= 2013 | volume= 309 | issue= 12 | pages= 1241-50 | pmid=23532240 | doi=10.1001/jama.2013.2107 | pmc= | url=http://www.ncbi.nlm.nih.gov/entrez/eutils/elink.fcgi?dbfrom=pubmed&tool=sumsearch.org/cite&retmode=ref&cmd=prlinks&id=23532240 }} </ref><br />
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TACT prespecified several subgroups for analysis and found a significant interaction between edetate disodium treatment and [[diabetes]] (p for interaction =0.0037). Among subjects enrolled in TACT, there were 633 diabetic patients, defined as patients with self-reported diabetes, taking medications for diabetes, or having a fasting blood glucose of at least 126 mg/dL at enrollment. The administration of chelation infusions among post-MI diabetic patients was associated with a marked reduction in the primary end point when compared with placebo. The primary end point occurred in 25% of diabetic patients who were administered chelation therapy compared to 38% in those who received placebo infusions (HR, 0.59; 95% CI, 0.44–0.79; P<0.001). The 5-year NNT to prevent one event was 6.5. In addition, chelation therapy was significantly associated with decreased all-cause mortality (43% reduction, p=0.011) and reinfarction (52% reduction, p=0.015). Again, the investigators concluded that these findings supported future research, but did not constitute sufficient evidence to indicate the routine use of chelation therapy for all post–myocardial infarction patients with diabetes, leaving open the clinician’s choice to use this novel therapy in occasional, or non-routine patients.<br />
<br />
These results catalyzed a wave of increased public and scientific interest in disodium EDTA treatment for patients with established coronary disease, particularly in diabetes, and hypotheses regarding potential mechanisms of benefit. As a capstone to the published analyses, the ACC/AHA Guidelines for Chronic Ischemic Heart Disease changed to reflect the TACT data and upgraded disodium EDTA treatment from a Class III indication to a Class IIB indication. While Class III therapeutics are considered not beneficial or useful, Class IIB treatments can be considered in some patients and require additional research to establish efficacy.<ref name="pmid25077860">{{cite journal| author=Fihn SD, Blankenship JC, Alexander KP, Bittl JA, Byrne JG, Fletcher BJ et al.| title=2014 ACC/AHA/AATS/PCNA/SCAI/STS focused update of the guideline for the diagnosis and management of patients with stable ischemic heart disease: a report of the American College of Cardiology/American Heart Association Task Force on Practice Guidelines, and the American Association for Thoracic Surgery, Preventive Cardiovascular Nurses Association, Society for Cardiovascular Angiography and Interventions, and Society of Thoracic Surgeons. | journal=J Am Coll Cardiol | year= 2014 | volume= 64 | issue= 18 | pages= 1929-49 | pmid=25077860 | doi=10.1016/j.jacc.2014.07.017 | pmc= | url=https://www.ncbi.nlm.nih.gov/entrez/eutils/elink.fcgi?dbfrom=pubmed&tool=sumsearch.org/cite&retmode=ref&cmd=prlinks&id=25077860 }} </ref> The change in the guidelines signaled a major shift in the perception of chelation therapy among the medical establishment. The TACT data led clinicians to reconsider chelation objectively, and the investigators and many other academic cardiologists called for TACT2, a new trial to test the results of TACT, to be funded by the [[NIH]].<br />
<br />
==Mechanism of Action==<br />
Edetate disodium binds to metals and forms soluble complexes facilitating their subsequent excretion in the urine.<ref name="pmid14000694">{{cite journal| author=WILDER LW, DE JODE LR, MILSTEIN SW, HOWARD JM| title=Mobilization of atherosclerotic plaque calcium with EDTA utilizing the isolation-perfusion principle. | journal=Surgery | year= 1962 | volume= 52 | issue= | pages= 793-5 | pmid=14000694 | doi= | pmc= | url=http://www.ncbi.nlm.nih.gov/entrez/eutils/elink.fcgi?dbfrom=pubmed&tool=sumsearch.org/cite&retmode=ref&cmd=prlinks&id=14000694 }} </ref> Hence, chelation therapy results in the elimination of stored toxic and essential metals. In an experiment performed on 24 patients, age 50 or older, and with a prior MI and a creatinine of 2.0 or less, patients had urine toxic metals measured at baseline, 1 day after an infusion of placebo, and 1 day after an infusion of the edetate disodium-based TACT solution. Placebo did not increase the excretion of toxic metals. Following an infusion of the edetate disodium-based TACT solution, lead excretion increased by nearly 3900%, and cadmium by nearly 700%. Other toxic metals whose excretion was enhanced by edetate disodium were aluminum (by ~250%), nickel (by ~150%), thallium (by ~60%), and gadolinium. A similar experiment performed earlier by Waters et al, reported urinary lead concentrations approximately 35 times greater than in pre-chelation urine.<ref name="pmid11794513">{{cite journal| author=Waters RS, Bryden NA, Patterson KY, Veillon C, Anderson RA| title=EDTA chelation effects on urinary losses of cadmium, calcium, chromium, cobalt, copper, lead, magnesium, and zinc. | journal=Biol Trace Elem Res | year= 2001 | volume= 83 | issue= 3 | pages= 207-21 | pmid=11794513 | doi=10.1385/BTER:83:3:207 | pmc= | url=https://www.ncbi.nlm.nih.gov/entrez/eutils/elink.fcgi?dbfrom=pubmed&tool=sumsearch.org/cite&retmode=ref&cmd=prlinks&id=11794513 }} </ref><br />
While enhanced lead and cadmium is interesting, the critical link to cardiovascular events is provided by epidemiological studies, which provide robust evidence linking toxic metals with cardiovascular disease.<ref name="pmid21421632">{{cite journal| author=Agarwal S, Zaman T, Tuzcu EM, Kapadia SR| title=Heavy metals and cardiovascular disease: results from the National Health and Nutrition Examination Survey (NHANES) 1999-2006. | journal=Angiology | year= 2011 | volume= 62 | issue= 5 | pages= 422-9 | pmid=21421632 | doi=10.1177/0003319710395562 | pmc= | url=http://www.ncbi.nlm.nih.gov/entrez/eutils/elink.fcgi?dbfrom=pubmed&tool=sumsearch.org/cite&retmode=ref&cmd=prlinks&id=21421632 }} </ref> This evidence is strongest for lead and cadmium.<ref name="pmid16982939">{{cite journal| author=Menke A, Muntner P, Batuman V, Silbergeld EK, Guallar E| title=Blood lead below 0.48 micromol/L (10 microg/dL) and mortality among US adults. | journal=Circulation | year= 2006 | volume= 114 | issue= 13 | pages= 1388-94 | pmid=16982939 | doi=10.1161/CIRCULATIONAHA.106.628321 | pmc= | url=http://www.ncbi.nlm.nih.gov/entrez/eutils/elink.fcgi?dbfrom=pubmed&tool=sumsearch.org/cite&retmode=ref&cmd=prlinks&id=16982939 }} </ref><ref name="pmid15184277">{{cite journal| author=Navas-Acien A, Selvin E, Sharrett AR, Calderon-Aranda E, Silbergeld E, Guallar E| title=Lead, cadmium, smoking, and increased risk of peripheral arterial disease. | journal=Circulation | year= 2004 | volume= 109 | issue= 25 | pages= 3196-201 | pmid=15184277 | doi=10.1161/01.CIR.0000130848.18636.B2 | pmc= | url=http://www.ncbi.nlm.nih.gov/entrez/eutils/elink.fcgi?dbfrom=pubmed&tool=sumsearch.org/cite&retmode=ref&cmd=prlinks&id=15184277 }} </ref><ref name="pmid23514838">{{cite journal| author=Tellez-Plaza M, Guallar E, Howard BV, Umans JG, Francesconi KA, Goessler W et al.| title=Cadmium exposure and incident cardiovascular disease. | journal=Epidemiology | year= 2013 | volume= 24 | issue= 3 | pages= 421-9 | pmid=23514838 | doi=10.1097/EDE.0b013e31828b0631 | pmc= | url=http://www.ncbi.nlm.nih.gov/entrez/eutils/elink.fcgi?dbfrom=pubmed&tool=sumsearch.org/cite&retmode=ref&cmd=prlinks&id=23514838 }} </ref> Elevated blood concentration of lead is associated with increased all-cause mortality [HR 1.25 (95% CI 1.04 to 1.51) for the highest versus lowest tertile of blood lead, P trend across the tertiles=0.002) and cardiovascular mortality [HR 1.55 (95% CI 1.08 to 2.24) for the highest versus lowest tertile, P trend <0.003].<ref name="pmid16982939">{{cite journal| author=Menke A, Muntner P, Batuman V, Silbergeld EK, Guallar E| title=Blood lead below 0.48 micromol/L (10 microg/dL) and mortality among US adults. | journal=Circulation | year= 2006 | volume= 114 | issue= 13 | pages= 1388-94 | pmid=16982939 | doi=10.1161/CIRCULATIONAHA.106.628321 | pmc= | url=https://www.ncbi.nlm.nih.gov/entrez/eutils/elink.fcgi?dbfrom=pubmed&tool=sumsearch.org/cite&retmode=ref&cmd=prlinks&id=16982939 }} </ref> Also, cardiovascular mortality is greater among subjects with elevated cadmium concentrations in the blood and urine [HR 1.69 (95% CI: 1.03, 2.77) and 1.74 (95% CI: 1.07, 2.83) for the 80th and 20th percentiles of blood and urine cadmium, respectively].<ref name="pmid22472185">{{cite journal| author=Tellez-Plaza M, Navas-Acien A, Menke A, Crainiceanu CM, Pastor-Barriuso R, Guallar E| title=Cadmium exposure and all-cause and cardiovascular mortality in the U.S. general population. | journal=Environ Health Perspect | year= 2012 | volume= 120 | issue= 7 | pages= 1017-22 | pmid=22472185 | doi=10.1289/ehp.1104352 | pmc=3404657 | url=https://www.ncbi.nlm.nih.gov/entrez/eutils/elink.fcgi?dbfrom=pubmed&tool=sumsearch.org/cite&retmode=ref&cmd=prlinks&id=22472185 }} </ref> <br />
Heavy metals may play a role in the development of [[cardiovascular disease]] through a number of different mechanisms.<ref name="pmid17645641">{{cite journal| author=Vaziri ND, Khan M| title=Interplay of reactive oxygen species and nitric oxide in the pathogenesis of experimental lead-induced hypertension. | journal=Clin Exp Pharmacol Physiol | year= 2007 | volume= 34 | issue= 9 | pages= 920-5 | pmid=17645641 | doi=10.1111/j.1440-1681.2007.04644.x | pmc= | url=https://www.ncbi.nlm.nih.gov/entrez/eutils/elink.fcgi?dbfrom=pubmed&tool=sumsearch.org/cite&retmode=ref&cmd=prlinks&id=17645641 }} </ref> Heavy metals include transition metals such as [[cadmium]], [[mercury]], [[manganese]], [[chromium]], [[cobalt]], [[nickel]], [[iron]], and [[copper]], metalloids such as antimony and arsenic, and post- transition metals such as thallium and lead. These metals all have unique toxicities, as well as toxicities that are common to all of them. Heavy metals in the endothelium promote oxygen free radical formation, resulting in increased oxidative stress, inflammation, and tissue damage. Lead and cadmium may interfere with calcium signaling channels. Transition metals promote modifications of low-density lipoprotein by endothelial cells through lipid peroxidation and degradation of low-density lipoprotein phospholipids.<ref name="pmid6587396">{{cite journal| author=Steinbrecher UP, Parthasarathy S, Leake DS, Witztum JL, Steinberg D| title=Modification of low density lipoprotein by endothelial cells involves lipid peroxidation and degradation of low density lipoprotein phospholipids. | journal=Proc Natl Acad Sci U S A | year= 1984 | volume= 81 | issue= 12 | pages= 3883-7 | pmid=6587396 | doi= | pmc=345326 | url=https://www.ncbi.nlm.nih.gov/entrez/eutils/elink.fcgi?dbfrom=pubmed&tool=sumsearch.org/cite&retmode=ref&cmd=prlinks&id=6587396 }} </ref><ref name="pmid6501577">{{cite journal| author=Heinecke JW, Rosen H, Chait A| title=Iron and copper promote modification of low density lipoprotein by human arterial smooth muscle cells in culture. | journal=J Clin Invest | year= 1984 | volume= 74 | issue= 5 | pages= 1890-4 | pmid=6501577 | doi=10.1172/JCI111609 | pmc=425370 | url=https://www.ncbi.nlm.nih.gov/entrez/eutils/elink.fcgi?dbfrom=pubmed&tool=sumsearch.org/cite&retmode=ref&cmd=prlinks&id=6501577 }} </ref><ref name="pmid8847477">{{cite journal| author=Morgan J, Leake DS| title=Oxidation of low density lipoprotein by iron or copper at acidic pH. | journal=J Lipid Res | year= 1995 | volume= 36 | issue= 12 | pages= 2504-12 | pmid=8847477 | doi= | pmc= | url=https://www.ncbi.nlm.nih.gov/entrez/eutils/elink.fcgi?dbfrom=pubmed&tool=sumsearch.org/cite&retmode=ref&cmd=prlinks&id=8847477 }} </ref> Exposure to non-transition metals, such as lead, has also been associated with impaired nitric oxide signaling and availability,<ref name="pmid15894814">{{cite journal| author=Dursun N, Arifoglu C, Süer C, Keskinol L| title=Blood pressure relationship to nitric oxide, lipid peroxidation, renal function, and renal blood flow in rats exposed to low lead levels. | journal=Biol Trace Elem Res | year= 2005 | volume= 104 | issue= 2 | pages= 141-9 | pmid=15894814 | doi=10.1385/BTER:104:2:141 | pmc= | url=https://www.ncbi.nlm.nih.gov/entrez/eutils/elink.fcgi?dbfrom=pubmed&tool=sumsearch.org/cite&retmode=ref&cmd=prlinks&id=15894814 }} </ref> endothelial cell dysfunction,<ref name="pmid7710289">{{cite journal| author=Kaji T, Suzuki M, Yamamoto C, Mishima A, Sakamoto M, Kozuka H| title=Severe damage of cultured vascular endothelial cell monolayer after simultaneous exposure to cadmium and lead. | journal=Arch Environ Contam Toxicol | year= 1995 | volume= 28 | issue= 2 | pages= 168-72 | pmid=7710289 | doi= | pmc= | url=https://www.ncbi.nlm.nih.gov/entrez/eutils/elink.fcgi?dbfrom=pubmed&tool=sumsearch.org/cite&retmode=ref&cmd=prlinks&id=7710289 }} </ref> and hypertension.<ref name="pmid18567711">{{cite journal| author=Vaziri ND| title=Mechanisms of lead-induced hypertension and cardiovascular disease. | journal=Am J Physiol Heart Circ Physiol | year= 2008 | volume= 295 | issue= 2 | pages= H454-65 | pmid=18567711 | doi=10.1152/ajpheart.00158.2008 | pmc=2519216 | url=https://www.ncbi.nlm.nih.gov/entrez/eutils/elink.fcgi?dbfrom=pubmed&tool=sumsearch.org/cite&retmode=ref&cmd=prlinks&id=18567711 }} </ref> [[Heavy metal]] exposure is also associated with genetic and [[epigenetic]] manifestations. [[Cadmium]] promotes atherosclerosis and endothelial dysfunction through multiple [[genetic]] changes.<ref name="pmid19556524">{{cite journal| author=Messner B, Knoflach M, Seubert A, Ritsch A, Pfaller K, Henderson B et al.| title=Cadmium is a novel and independent risk factor for early atherosclerosis mechanisms and in vivo relevance. | journal=Arterioscler Thromb Vasc Biol | year= 2009 | volume= 29 | issue= 9 | pages= 1392-8 | pmid=19556524 | doi=10.1161/ATVBAHA.109.190082 | pmc= | url=https://www.ncbi.nlm.nih.gov/entrez/eutils/elink.fcgi?dbfrom=pubmed&tool=sumsearch.org/cite&retmode=ref&cmd=prlinks&id=19556524 }} </ref> One of the mechanisms involves [[DNA]] strand breaks and damage with subsequent apoptosis in [[endothelial cell]]s.<ref name="pmid19556524">{{cite journal| author=Messner B, Knoflach M, Seubert A, Ritsch A, Pfaller K, Henderson B et al.| title=Cadmium is a novel and independent risk factor for early atherosclerosis mechanisms and in vivo relevance. | journal=Arterioscler Thromb Vasc Biol | year= 2009 | volume= 29 | issue= 9 | pages= 1392-8 | pmid=19556524 | doi=10.1161/ATVBAHA.109.190082 | pmc= | url=https://www.ncbi.nlm.nih.gov/entrez/eutils/elink.fcgi?dbfrom=pubmed&tool=sumsearch.org/cite&retmode=ref&cmd=prlinks&id=19556524 }} </ref> Also, maternal [[lead]] exposure during pregnancy may be associated with epigenetic consequences in grandchildren through alteration of [[DNA methylation]] early in life.<ref name="pmid26417717">{{cite journal| author=Sen A, Heredia N, Senut MC, Land S, Hollocher K, Lu X et al.| title=Multigenerational epigenetic inheritance in humans: DNA methylation changes associated with maternal exposure to lead can be transmitted to the grandchildren. | journal=Sci Rep | year= 2015 | volume= 5 | issue= | pages= 14466 | pmid=26417717 | doi=10.1038/srep14466 | pmc=4586440 | url=https://www.ncbi.nlm.nih.gov/entrez/eutils/elink.fcgi?dbfrom=pubmed&tool=sumsearch.org/cite&retmode=ref&cmd=prlinks&id=26417717 }} </ref><br />
<br />
Current mechanistic understanding, albeit rudimentary, supports the concept that the cardiovascular benefits of [[chelation therapy]] may result from enhanced excretion of [[heavy metals]], and subsequent reduction in processes listed above. Additionally, in patients with [[diabetes]], a reduction in the metal-catalyzed formation of [[reactive oxygen species]], formation of advanced glycation end-products, and lipid [[peroxidation]] has been postulated.<ref name="pmid10874253">{{cite journal| author=Lamas GA, Ackermann A| title=Clinical evaluation of chelation therapy: is there any wheat amidst the chaff? | journal=Am Heart J | year= 2000 | volume= 140 | issue= 1 | pages= 4-5 | pmid=10874253 | doi=10.1067/mhj.2000.107549 | pmc= | url=http://www.ncbi.nlm.nih.gov/entrez/eutils/elink.fcgi?dbfrom=pubmed&tool=sumsearch.org/cite&retmode=ref&cmd=prlinks&id=10874253 }} </ref> Metal detoxification in the context of diabetes possibly decreases [[inflammation]] and [[oxidative stress]] that characterize atherosclerosis.<ref>Escolar E, Lamas G, Mark D et al(2013) "The Effect of an EDTA-based Chelation Regimen on Patients With Diabetes Mellitus and Prior Myocardial Infarction in the Trial to Assess Chelation Therapy (TACT)". Circulation. 2013</ref> Recent research, including chelation-activity assays, indicates that many common [[diabetes]] drugs, such as [[metformin]] and aldose reductase inhibitors, could possibly have some chelating properties.<ref name="pmid22354928">{{cite journal| author=Nagai R, Murray DB, Metz TO, Baynes JW| title=Chelation: a fundamental mechanism of action of AGE inhibitors, AGE breakers, and other inhibitors of diabetes complications. | journal=Diabetes | year= 2012 | volume= 61 | issue= 3 | pages= 549-59 | pmid=22354928 | doi=10.2337/db11-1120 | pmc=3282805 | url=https://www.ncbi.nlm.nih.gov/entrez/eutils/elink.fcgi?dbfrom=pubmed&tool=sumsearch.org/cite&retmode=ref&cmd=prlinks&id=22354928 }} </ref><ref name="pmid23612664">{{cite journal| author=Frizzell N, Baynes JW| title=Chelation therapy for the management of diabetic complications: a hypothesis and a proposal for clinical laboratory assessment of metal ion homeostasis in plasma. | journal=Clin Chem Lab Med | year= 2014 | volume= 52 | issue= 1 | pages= 69-75 | pmid=23612664 | doi=10.1515/cclm-2012-0881 | pmc= | url=https://www.ncbi.nlm.nih.gov/entrez/eutils/elink.fcgi?dbfrom=pubmed&tool=sumsearch.org/cite&retmode=ref&cmd=prlinks&id=23612664 }} </ref><ref name="pmid22492524">{{cite journal| author=Logie L, Harthill J, Patel K, Bacon S, Hamilton DL, Macrae K et al.| title=Cellular responses to the metal-binding properties of metformin. | journal=Diabetes | year= 2012 | volume= 61 | issue= 6 | pages= 1423-33 | pmid=22492524 | doi=10.2337/db11-0961 | pmc=3357267 | url=https://www.ncbi.nlm.nih.gov/entrez/eutils/elink.fcgi?dbfrom=pubmed&tool=sumsearch.org/cite&retmode=ref&cmd=prlinks&id=22492524 }} </ref><br />
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The TACT chelation infusion, however, did not contain edetate disodium alone. The standard chelation infusion formula used in TACT was formulated to be identical with the most prevalent infusion in use. This formulation had developed organically over decades and had been modified by clinical practitioners to have additives such as [[ascorbic acid]], B-vitamins and [[magnesium]], thought to have a protective effect on [[endothelial cells]],<ref>Rozema, Theodore C. "The protocol for the safe and effective administration of EDTA and other chelating agents for vascular disease, degenerative disease, and metal toxicity." Journal of Advancement in Medicine 10.1 (1997): 5-100.</ref> making the results of clinical application more difficult to understand, and emphasizing the need for mechanistic work.<br />
<br />
==Future Studies==<br />
TACT was a unique study with an unexpected result that could have vast public health implications. In order to consider its broad applicability, the medical and scientific community require the results reproduced. TACT2, scheduled to begin in October 2016 (press release), is a replicative study in post-MI diabetic patients. If the TACT2 results confirm the results of TACT, then chelation is poised to become the next major development in the treatment of vascular complications of diabetes and vascular disease. TACT2 is currently recruiting sites, and interested investigators should visit www.TACT2.org for additional information.<br />
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==Side Effects==<br />
Shown below is a list of the labelled toxicities of EDTA-based chelation therapy. However, TACT delivered 55,222 infusions of EDTA or placebo, and found no differences between groups in adverse events, serious or otherwise.<br />
* [[Arrhythmias]]<br />
* [[Autoimmune diseases]]<br />
* [[Bone marrow]]<br />
* [[Convulsions]]<br />
* [[Depression]]<br />
* [[Fever]]<br />
* [[Heart failure]]<br />
* [[Hypocalcemia]]<br />
* [[Hypoglycemia]]<br />
* [[Hypotension]]<br />
* [[Bleeding time|Prolonged bleeding time]]<br />
* [[Renal failure]]<br />
* [[Respiratory arrest]]<br />
* [[Tetany]]<br />
* [[Trace metal|Trace metal deficiency]]<br />
* [[Vitamin deficiency]]<ref name="pmid10874275">{{cite journal| author=Ernst E| title=Chelation therapy for coronary heart disease: An overview of all clinical investigations. | journal=Am Heart J | year= 2000 | volume= 140 | issue= 1 | pages= 139-41 | pmid=10874275 | doi=10.1067/mhj.2000.107548 | pmc= | url=http://www.ncbi.nlm.nih.gov/entrez/eutils/elink.fcgi?dbfrom=pubmed&tool=sumsearch.org/cite&retmode=ref&cmd=prlinks&id=10874275 }} </ref><ref name="pmid23532240">{{cite journal| author=Lamas GA, Goertz C, Boineau R, Mark DB, Rozema T, Nahin RL et al.| title=Effect of disodium EDTA chelation regimen on cardiovascular events in patients with previous myocardial infarction: the TACT randomized trial. | journal=JAMA | year= 2013 | volume= 309 | issue= 12 | pages= 1241-50 | pmid=23532240 | doi=10.1001/jama.2013.2107 | pmc= | url=http://www.ncbi.nlm.nih.gov/entrez/eutils/elink.fcgi?dbfrom=pubmed&tool=sumsearch.org/cite&retmode=ref&cmd=prlinks&id=23532240 }} </ref><br />
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==Landmark Trials==<br />
[[TACT]] <br><br />
TACT 2 [http://www.TACT2.org] (link to press release [http://www.prnewswire.com/news-releases/tact2-clinical-trial-receives-national-institutes-of-health-funding-300334174.html])<br />
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==References==<br />
{{Reflist|2}}<br />
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[[Category:Cardiology]]<br />
[[Category:Diabetes]]<br />
[[Category:Up-To-Date]]<br />
<br />
{{WikiDoc Help Menu}}<br />
{{WikiDoc Sources}}</div>Rim Halabyhttps://www.wikidoc.org/index.php?title=Chelation_therapy_for_cardiovascular_disease&diff=1274810Chelation therapy for cardiovascular disease2016-12-07T17:54:19Z<p>Rim Halaby: /* Mechanism of Action */</p>
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<div>__NOTOC__<br />
'''Editor-In-Chief:''' Gervasio Lamas, M.D., C. Michael Gibson, M.S., M.D.; {{AE}} {{Rim}}, Ian Ergui, B.Sc.<br />
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'''[[Chelation therapy|To read more about chelation therapy click here.]]'''<br><br />
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{{SK}} Chelation therapy, EDTA, post-myocardial infarction, diabetes<br />
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==Overview==<br />
[[Chelation]] is a process by which an organic molecule with a negatively charged “pocket” complexes with a metal ion of opposite charge, inactivates it, and then permits its physiological mobilization and excretion, usually by a renal route. [[Chelation therapy]], which involves multiple administrations of a chelating agent, helps eliminate stored toxic metal ions from the body.<ref name="pmid11794513">{{cite journal| author=Waters RS, Bryden NA, Patterson KY, Veillon C, Anderson RA| title=EDTA chelation effects on urinary losses of cadmium, calcium, chromium, cobalt, copper, lead, magnesium, and zinc. | journal=Biol Trace Elem Res | year= 2001 | volume= 83 | issue= 3 | pages= 207-21 | pmid=11794513 | doi=10.1385/BTER:83:3:207 | pmc= | url=https://www.ncbi.nlm.nih.gov/entrez/eutils/elink.fcgi?dbfrom=pubmed&tool=sumsearch.org/cite&retmode=ref&cmd=prlinks&id=11794513 }} </ref><ref name="arenas">Arenas I.A., Navas-Acien A., Lamas G.A.; Enhanced vasculotoxic metal excretionin post-MI patients after edetate disodium therapy (abstr). J Am Coll Cardiol. 2016;67:A2125</ref> Common chelators include [[penicillamine]], which binds copper and can be used to treat [[Wilson’s disease]], [[deferoxamine]], which binds iron and is used in the treatment of [[thalassemia]] and iron overload, succimer, also used in the treatment of lead poisoning, and the edetates, non-specific chelators of metals and other ions with valences of +2 to +6. Chelation therapy is, in many cases, guideline mandated, such as in children with elevated blood lead levels,<ref name="CDC">CDC. Low Level Lead Exposure Harms Children: A Renewed Call for Primary Prevention. Atlanta, GA:Advisory Committee on Childhood Lead Poisoning Prevention, U.S. Centers for Disease Control and Prevention (4 Jan 2012). Available: [http://www.cdc.gov/nceh/lead/acclpp/final_document_010412.pdf]</ref> patients with iron overload and dyserythropoietic syndromes or chronic hemolytic anemia,<ref name="pmid21452290">{{cite journal| author=Bacon BR, Adams PC, Kowdley KV, Powell LW, Tavill AS, American Association for the Study of Liver Diseases| title=Diagnosis and management of hemochromatosis: 2011 practice guideline by the American Association for the Study of Liver Diseases. | journal=Hepatology | year= 2011 | volume= 54 | issue= 1 | pages= 328-43 | pmid=21452290 | doi=10.1002/hep.24330 | pmc=3149125 | url=https://www.ncbi.nlm.nih.gov/entrez/eutils/elink.fcgi?dbfrom=pubmed&tool=sumsearch.org/cite&retmode=ref&cmd=prlinks&id=21452290 }} </ref> or [[sickle cell disease]] and transfusion acquired iron-overload,<ref name="NHLBI">NHLBI. Transfusion in Sickle Cell Disease: A Systematic Review of Benefits, Complications, and Management of Complications. Prepared for the National Heart, Lung, and Blood Institute and by the Knowledge and Evaluation Research Unit, Mayo Clinic Rochester (2012)</ref> to name a few instances.<br />
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[[Ethylene diamine tetraacetic acid]] ([[EDTA]], edetate) and its salts (most commonly disodium or calcium disodium), commonly used chelating agents patented in 1938, bind to and permit the urinary excretion of divalent cations such as calcium, and metals such as [[lead]], [[cadmium]], [[nickel]], [[cobalt]], [[iron]], [[aluminum]], and others. The initial medical use for [[EDTA]] began after World War II for the treatment of [[lead]]-exposed naval workers. In addition to its use for the treatment of metal poisoning, since the 1950s chelation therapy has been considered an alternative or add-on therapy for the prevention and treatment of [[atherosclerotic disease]]. The use of edetate disodium (Na2EDTA) has been most prominent in the alternative medicine treatment of atherosclerosis primarily because of the still-unproven hypothesis that the [[hypocalcemia]] it induces might lead to the decalcification of atherosclerotic lesions. In fact, the most current research suggests that the probable mechanism of benefit centers on enhancement of toxic metal excretion.<br />
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==Chelation Therapy and CVD==<br />
The use of chelation therapy as a treatment for [[atherosclerotic disease]] dates back to the 1950’s when Clarke et al investigated the use of EDTA for the treatment of angina pectoris and reported improvement in 19 of 20 patients.<ref name="pmid13372537">{{cite journal| author=CLARKE CN, CLARKE NE, MOSHER RE| title=Treatment of angina pectoris with disodium ethylene diamine tetraacetic acid. | journal=Am J Med Sci | year= 1956 | volume= 232 | issue= 6 | pages= 654-66 | pmid=13372537 | doi= | pmc= | url=http://www.ncbi.nlm.nih.gov/entrez/eutils/elink.fcgi?dbfrom=pubmed&tool=sumsearch.org/cite&retmode=ref&cmd=prlinks&id=13372537 }} </ref> Later studies by Kitchell were less positive,<ref name="pmid13756462">{{cite journal| author=KITCHELL JR, MELTZER LE, SEVEN MJ| title=Potential uses of chelation methods in the treatment of cardiovascular diseases. | journal=Prog Cardiovasc Dis | year= 1961 | volume= 3 | issue= | pages= 338-49 | pmid=13756462 | doi= | pmc= | url=https://www.ncbi.nlm.nih.gov/entrez/eutils/elink.fcgi?dbfrom=pubmed&tool=sumsearch.org/cite&retmode=ref&cmd=prlinks&id=13756462 }} </ref><ref name="pmid14033183">{{cite journal| author=KITCHELL JR, PALMON F, AYTAN N, MELTZER LE| title=The treatment of coronary artery disease with disodium EDTA. A reappraisal. | journal=Am J Cardiol | year= 1963 | volume= 11 | issue= | pages= 501-6 | pmid=14033183 | doi= | pmc= | url=https://www.ncbi.nlm.nih.gov/entrez/eutils/elink.fcgi?dbfrom=pubmed&tool=sumsearch.org/cite&retmode=ref&cmd=prlinks&id=14033183 }} </ref> and in an era without modern clinical trials methodology nor effective concomitant therapies, opinions regarding the use of [[chelation therapy]] for [[cardiovascular disease]] (CVD) tilted towards the negative. To be fair, from the 1970’s to 1990’s the preponderance of the scientific literature on chelation therapy for atherosclerosis consisted of case reports, case series, and small clinical trials with surrogate endpoints, poor-quality evidence from which to draw a conclusion of efficacy or harm.<ref name="pmid12519577">{{cite journal| author=Villarruz MV, Dans A, Tan F| title=Chelation therapy for atherosclerotic cardiovascular disease. | journal=Cochrane Database Syst Rev | year= 2002 | volume= | issue= 4 | pages= CD002785 | pmid=12519577 | doi=10.1002/14651858.CD002785 | pmc= | url=http://www.ncbi.nlm.nih.gov/entrez/eutils/elink.fcgi?dbfrom=pubmed&tool=sumsearch.org/cite&retmode=ref&cmd=prlinks&id=12519577 }} </ref><br />
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For example, one extensive case series reported an association between EDTA chelation therapy and improvement of ischemic heart disease and peripheral artery disease.<ref name="pmid3144646">{{cite journal| author=Olszewer E, Carter JP| title=EDTA chelation therapy in chronic degenerative disease. | journal=Med Hypotheses | year= 1988 | volume= 27 | issue= 1 | pages= 41-9 | pmid=3144646 | doi= | pmc= | url=http://www.ncbi.nlm.nih.gov/entrez/eutils/elink.fcgi?dbfrom=pubmed&tool=sumsearch.org/cite&retmode=ref&cmd=prlinks&id=3144646 }} </ref> Another study demonstrated that EDTA supplemented with several B vitamins (vitamin B1, B2, B6 and B12) but not EDTA alone was effective in improving [[endothelium]]-dependent forearm blood flow.<ref name="pmid10561804">{{cite journal| author=Green DJ, O'Driscoll JG, Maiorana A, Scrimgeour NB, Weerasooriya R, Taylor RR| title=Effects of chelation with EDTA and vitamin B therapy on nitric oxide-related endothelial vasodilator function. | journal=Clin Exp Pharmacol Physiol | year= 1999 | volume= 26 | issue= 11 | pages= 853-6 | pmid=10561804 | doi= | pmc= | url=http://www.ncbi.nlm.nih.gov/entrez/eutils/elink.fcgi?dbfrom=pubmed&tool=sumsearch.org/cite&retmode=ref&cmd=prlinks&id=10561804 }} </ref> A systematic review of four randomized clinical trials on chelation therapy and [[peripheral artery occlusive disease]] reported no benefit associated with chelation therapy.<ref name="pmid9264515">{{cite journal| author=Ernst E| title=Chelation therapy for peripheral arterial occlusive disease: a systematic review. | journal=Circulation | year= 1997 | volume= 96 | issue= 3 | pages= 1031-3 | pmid=9264515 | doi= | pmc= | url=http://www.ncbi.nlm.nih.gov/entrez/eutils/elink.fcgi?dbfrom=pubmed&tool=sumsearch.org/cite&retmode=ref&cmd=prlinks&id=9264515 }} </ref> The studies, however, individually and in aggregate, were too small to exclude a small to moderate benefit of therapy. Moreover, followup was short and surrogate physiologic endpoints, such as walking distance, were used. A Cochrane systematic review on the role of chelation therapy to treat coronary heart disease in 2002 concluded that the data were insufficient to recommend for or against chelation.<ref name="pmid10874275">{{cite journal| author=Ernst E| title=Chelation therapy for coronary heart disease: An overview of all clinical investigations. | journal=Am Heart J | year= 2000 | volume= 140 | issue= 1 | pages= 139-41 | pmid=10874275 | doi=10.1067/mhj.2000.107548 | pmc= | url=http://www.ncbi.nlm.nih.gov/entrez/eutils/elink.fcgi?dbfrom=pubmed&tool=sumsearch.org/cite&retmode=ref&cmd=prlinks&id=10874275 }} </ref> <br />
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The medical community concluded that the absence of high quality evidence of efficacy equated with evidence of absence of efficacy. Professional organizations recommended against chelation therapy.<ref name="pmid9205980">{{cite journal| author=Lewin MR| title=Chelation therapy for cardiovascular disease. Review and commentary. | journal=Tex Heart Inst J | year= 1997 | volume= 24 | issue= 2 | pages= 81-9 | pmid=9205980 | doi= | pmc=325409 | url=https://www.ncbi.nlm.nih.gov/entrez/eutils/elink.fcgi?dbfrom=pubmed&tool=sumsearch.org/cite&retmode=ref&cmd=prlinks&id=9205980 }} </ref> Interestingly, patients continued to seek, and practitioners to administer, chelation infusions for [[cardiovascular disease]] and other diagnoses.<br />
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In light of the persistent controversy regarding the benefits of chelation therapy and the absence of any previous large clinical trial investigating its use in coronary artery disease, the National Center for Complementary and Alternative Medicine and the National Heart Lung and Blood Institute released a $30 million Request for Applications (RFA) to develop a definitive trial. In 2002, the RFA was awarded to Mount Sinai Medical Center in Miami Beach FL (G Lamas MD, Principal Investigator). The Trial to Assess Chelation Therapy (TACT), a randomized, double blind, placebo controlled 2x2 factorial trial, investigated the efficacy and safety of disodium EDTA based infusions and high-dose oral vitamins and minerals in 1708 stable post-myocardial infarction (MI) patients more than 50 years of age and with fairly normal kidney function ([[creatinine]] 2.0 mg/dL or less). The active treatment consisted of 40 infusions consisted of disodium [[EDTA]] combined with [[ascorbic acid]], B vitamins, and other components. The median age of patients was 65 years, and they were treated with evidence-based post-MI medicines. The primary endpoint of this trial was a composite of all-cause mortality, [[stroke]], [[MI]], coronary revascularization, and hospitalization for [[angina]].<ref name="pmid16585050">{{cite journal| author=Costa J, Borges M, David C, Vaz Carneiro A| title=Efficacy of lipid lowering drug treatment for diabetic and non-diabetic patients: meta-analysis of randomised controlled trials. | journal=BMJ | year= 2006 | volume= 332 | issue= 7550 | pages= 1115-24 | pmid=16585050 | doi=10.1136/bmj.38793.468449.AE | pmc=PMC1459619 | url=http://www.ncbi.nlm.nih.gov/entrez/eutils/elink.fcgi?dbfrom=pubmed&tool=sumsearch.org/cite&retmode=ref&cmd=prlinks&id=16585050 }} </ref><br />
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A follow up period of 55 months revealed a statistically significant decrease in the primary endpoint (HR: 0.82; 95% CI: 0.69-0.99; p= 0.035). There was an absolute reduction in the 5-year Kaplan-Meier estimate, from 38% to 33%, resulting in a 5-year number needed to treat (NNT) of 18 patients to avoid one adverse cardiovascular outcome. This is comparable to the 5-year NNT for [[statins]] in post-[[MI]] patients (NNT=16 for the secondary prevention of a major coronary event).<ref name="pmid16585050">{{cite journal| author=Costa J, Borges M, David C, Vaz Carneiro A| title=Efficacy of lipid lowering drug treatment for diabetic and non-diabetic patients: meta-analysis of randomised controlled trials. | journal=BMJ | year= 2006 | volume= 332 | issue= 7550 | pages= 1115-24 | pmid=16585050 | doi=10.1136/bmj.38793.468449.AE | pmc=PMC1459619 | url=http://www.ncbi.nlm.nih.gov/entrez/eutils/elink.fcgi?dbfrom=pubmed&tool=sumsearch.org/cite&retmode=ref&cmd=prlinks&id=16585050 }} </ref> The point estimate for the risk of each of the components of the primary endpoint was <1, consistent with the aggregate result. The Investigators concluded that chelation should not yet be adopted for routine post-MI use in all patients, but the results of TACT should inform further studies to confirm or refute these unexpected results.<ref name="pmid23532240">{{cite journal| author=Lamas GA, Goertz C, Boineau R, Mark DB, Rozema T, Nahin RL et al.| title=Effect of disodium EDTA chelation regimen on cardiovascular events in patients with previous myocardial infarction: the TACT randomized trial. | journal=JAMA | year= 2013 | volume= 309 | issue= 12 | pages= 1241-50 | pmid=23532240 | doi=10.1001/jama.2013.2107 | pmc= | url=http://www.ncbi.nlm.nih.gov/entrez/eutils/elink.fcgi?dbfrom=pubmed&tool=sumsearch.org/cite&retmode=ref&cmd=prlinks&id=23532240 }} </ref><br />
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TACT prespecified several subgroups for analysis and found a significant interaction between edetate disodium treatment and [[diabetes]] (p for interaction =0.0037). Among subjects enrolled in TACT, there were 633 diabetic patients, defined as patients with self-reported diabetes, taking medications for diabetes, or having a fasting blood glucose of at least 126 mg/dL at enrollment. The administration of chelation infusions among post-MI diabetic patients was associated with a marked reduction in the primary end point when compared with placebo. The primary end point occurred in 25% of diabetic patients who were administered chelation therapy compared to 38% in those who received placebo infusions (HR, 0.59; 95% CI, 0.44–0.79; P<0.001). The 5-year NNT to prevent one event was 6.5. In addition, chelation therapy was significantly associated with decreased all-cause mortality (43% reduction, p=0.011) and reinfarction (52% reduction, p=0.015). Again, the investigators concluded that these findings supported future research, but did not constitute sufficient evidence to indicate the routine use of chelation therapy for all post–myocardial infarction patients with diabetes, leaving open the clinician’s choice to use this novel therapy in occasional, or non-routine patients.<br />
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These results catalyzed a wave of increased public and scientific interest in disodium EDTA treatment for patients with established coronary disease, particularly in diabetes, and hypotheses regarding potential mechanisms of benefit. As a capstone to the published analyses, the ACC/AHA Guidelines for Chronic Ischemic Heart Disease changed to reflect the TACT data and upgraded disodium EDTA treatment from a Class III indication to a Class IIB indication. While Class III therapeutics are considered not beneficial or useful, Class IIB treatments can be considered in some patients and require additional research to establish efficacy.<ref name="pmid25077860">{{cite journal| author=Fihn SD, Blankenship JC, Alexander KP, Bittl JA, Byrne JG, Fletcher BJ et al.| title=2014 ACC/AHA/AATS/PCNA/SCAI/STS focused update of the guideline for the diagnosis and management of patients with stable ischemic heart disease: a report of the American College of Cardiology/American Heart Association Task Force on Practice Guidelines, and the American Association for Thoracic Surgery, Preventive Cardiovascular Nurses Association, Society for Cardiovascular Angiography and Interventions, and Society of Thoracic Surgeons. | journal=J Am Coll Cardiol | year= 2014 | volume= 64 | issue= 18 | pages= 1929-49 | pmid=25077860 | doi=10.1016/j.jacc.2014.07.017 | pmc= | url=https://www.ncbi.nlm.nih.gov/entrez/eutils/elink.fcgi?dbfrom=pubmed&tool=sumsearch.org/cite&retmode=ref&cmd=prlinks&id=25077860 }} </ref> The change in the guidelines signaled a major shift in the perception of chelation therapy among the medical establishment. The TACT data led clinicians to reconsider chelation objectively, and the investigators and many other academic cardiologists called for TACT2, a new trial to test the results of TACT, to be funded by the [[NIH]].<br />
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==Mechanism of Action==<br />
Edetate disodium binds to metals and forms soluble complexes facilitating their subsequent excretion in the urine.<ref name="pmid14000694">{{cite journal| author=WILDER LW, DE JODE LR, MILSTEIN SW, HOWARD JM| title=Mobilization of atherosclerotic plaque calcium with EDTA utilizing the isolation-perfusion principle. | journal=Surgery | year= 1962 | volume= 52 | issue= | pages= 793-5 | pmid=14000694 | doi= | pmc= | url=http://www.ncbi.nlm.nih.gov/entrez/eutils/elink.fcgi?dbfrom=pubmed&tool=sumsearch.org/cite&retmode=ref&cmd=prlinks&id=14000694 }} </ref> Hence, chelation therapy results in the elimination of stored toxic and essential metals. In an experiment performed on 24 patients, age 50 or older, and with a prior MI and a creatinine of 2.0 or less, patients had urine toxic metals measured at baseline, 1 day after an infusion of placebo, and 1 day after an infusion of the edetate disodium-based TACT solution. Placebo did not increase the excretion of toxic metals. Following an infusion of the edetate disodium-based TACT solution, lead excretion increased by nearly 3900%, and cadmium by nearly 700%. Other toxic metals whose excretion was enhanced by edetate disodium were aluminum (by ~250%), nickel (by ~150%), thallium (by ~60%), and gadolinium. A similar experiment performed earlier by Waters et al, reported urinary lead concentrations approximately 35 times greater than in pre-chelation urine.<ref name="pmid11794513">{{cite journal| author=Waters RS, Bryden NA, Patterson KY, Veillon C, Anderson RA| title=EDTA chelation effects on urinary losses of cadmium, calcium, chromium, cobalt, copper, lead, magnesium, and zinc. | journal=Biol Trace Elem Res | year= 2001 | volume= 83 | issue= 3 | pages= 207-21 | pmid=11794513 | doi=10.1385/BTER:83:3:207 | pmc= | url=https://www.ncbi.nlm.nih.gov/entrez/eutils/elink.fcgi?dbfrom=pubmed&tool=sumsearch.org/cite&retmode=ref&cmd=prlinks&id=11794513 }} </ref><br />
While enhanced lead and cadmium is interesting, the critical link to cardiovascular events is provided by epidemiological studies, which provide robust evidence linking toxic metals with cardiovascular disease.<ref name="pmid21421632">{{cite journal| author=Agarwal S, Zaman T, Tuzcu EM, Kapadia SR| title=Heavy metals and cardiovascular disease: results from the National Health and Nutrition Examination Survey (NHANES) 1999-2006. | journal=Angiology | year= 2011 | volume= 62 | issue= 5 | pages= 422-9 | pmid=21421632 | doi=10.1177/0003319710395562 | pmc= | url=http://www.ncbi.nlm.nih.gov/entrez/eutils/elink.fcgi?dbfrom=pubmed&tool=sumsearch.org/cite&retmode=ref&cmd=prlinks&id=21421632 }} </ref> This evidence is strongest for lead and cadmium.<ref name="pmid16982939">{{cite journal| author=Menke A, Muntner P, Batuman V, Silbergeld EK, Guallar E| title=Blood lead below 0.48 micromol/L (10 microg/dL) and mortality among US adults. | journal=Circulation | year= 2006 | volume= 114 | issue= 13 | pages= 1388-94 | pmid=16982939 | doi=10.1161/CIRCULATIONAHA.106.628321 | pmc= | url=http://www.ncbi.nlm.nih.gov/entrez/eutils/elink.fcgi?dbfrom=pubmed&tool=sumsearch.org/cite&retmode=ref&cmd=prlinks&id=16982939 }} </ref><ref name="pmid15184277">{{cite journal| author=Navas-Acien A, Selvin E, Sharrett AR, Calderon-Aranda E, Silbergeld E, Guallar E| title=Lead, cadmium, smoking, and increased risk of peripheral arterial disease. | journal=Circulation | year= 2004 | volume= 109 | issue= 25 | pages= 3196-201 | pmid=15184277 | doi=10.1161/01.CIR.0000130848.18636.B2 | pmc= | url=http://www.ncbi.nlm.nih.gov/entrez/eutils/elink.fcgi?dbfrom=pubmed&tool=sumsearch.org/cite&retmode=ref&cmd=prlinks&id=15184277 }} </ref><ref name="pmid23514838">{{cite journal| author=Tellez-Plaza M, Guallar E, Howard BV, Umans JG, Francesconi KA, Goessler W et al.| title=Cadmium exposure and incident cardiovascular disease. | journal=Epidemiology | year= 2013 | volume= 24 | issue= 3 | pages= 421-9 | pmid=23514838 | doi=10.1097/EDE.0b013e31828b0631 | pmc= | url=http://www.ncbi.nlm.nih.gov/entrez/eutils/elink.fcgi?dbfrom=pubmed&tool=sumsearch.org/cite&retmode=ref&cmd=prlinks&id=23514838 }} </ref> Elevated blood concentration of lead is associated with increased all-cause mortality [HR 1.25 (95% CI 1.04 to 1.51) for the highest versus lowest tertile of blood lead, P trend across the tertiles=0.002) and cardiovascular mortality [HR 1.55 (95% CI 1.08 to 2.24) for the highest versus lowest tertile, P trend <0.003].<ref name="pmid16982939">{{cite journal| author=Menke A, Muntner P, Batuman V, Silbergeld EK, Guallar E| title=Blood lead below 0.48 micromol/L (10 microg/dL) and mortality among US adults. | journal=Circulation | year= 2006 | volume= 114 | issue= 13 | pages= 1388-94 | pmid=16982939 | doi=10.1161/CIRCULATIONAHA.106.628321 | pmc= | url=https://www.ncbi.nlm.nih.gov/entrez/eutils/elink.fcgi?dbfrom=pubmed&tool=sumsearch.org/cite&retmode=ref&cmd=prlinks&id=16982939 }} </ref> Also, cardiovascular mortality is greater among subjects with elevated cadmium concentrations in the blood and urine [HR 1.69 (95% CI: 1.03, 2.77) and 1.74 (95% CI: 1.07, 2.83) for the 80th and 20th percentiles of blood and urine cadmium, respectively].<ref name="pmid22472185">{{cite journal| author=Tellez-Plaza M, Navas-Acien A, Menke A, Crainiceanu CM, Pastor-Barriuso R, Guallar E| title=Cadmium exposure and all-cause and cardiovascular mortality in the U.S. general population. | journal=Environ Health Perspect | year= 2012 | volume= 120 | issue= 7 | pages= 1017-22 | pmid=22472185 | doi=10.1289/ehp.1104352 | pmc=3404657 | url=https://www.ncbi.nlm.nih.gov/entrez/eutils/elink.fcgi?dbfrom=pubmed&tool=sumsearch.org/cite&retmode=ref&cmd=prlinks&id=22472185 }} </ref> <br />
Heavy metals may play a role in the development of [[cardiovascular disease]] through a number of different mechanisms.<ref name="pmid17645641">{{cite journal| author=Vaziri ND, Khan M| title=Interplay of reactive oxygen species and nitric oxide in the pathogenesis of experimental lead-induced hypertension. | journal=Clin Exp Pharmacol Physiol | year= 2007 | volume= 34 | issue= 9 | pages= 920-5 | pmid=17645641 | doi=10.1111/j.1440-1681.2007.04644.x | pmc= | url=https://www.ncbi.nlm.nih.gov/entrez/eutils/elink.fcgi?dbfrom=pubmed&tool=sumsearch.org/cite&retmode=ref&cmd=prlinks&id=17645641 }} </ref> Heavy metals include transition metals such as [[cadmium]], [[mercury]], [[manganese]], [[chromium]], [[cobalt]], [[nickel]], [[iron]], and [[copper]], metalloids such as antimony and arsenic, and post- transition metals such as thallium and lead. These metals all have unique toxicities, as well as toxicities that are common to all of them. Heavy metals in the endothelium promote oxygen free radical formation, resulting in increased oxidative stress, inflammation, and tissue damage. Lead and cadmium may interfere with calcium signaling channels. Transition metals promote modifications of low-density lipoprotein by endothelial cells through lipid peroxidation and degradation of low-density lipoprotein phospholipids.<ref name="pmid6587396">{{cite journal| author=Steinbrecher UP, Parthasarathy S, Leake DS, Witztum JL, Steinberg D| title=Modification of low density lipoprotein by endothelial cells involves lipid peroxidation and degradation of low density lipoprotein phospholipids. | journal=Proc Natl Acad Sci U S A | year= 1984 | volume= 81 | issue= 12 | pages= 3883-7 | pmid=6587396 | doi= | pmc=345326 | url=https://www.ncbi.nlm.nih.gov/entrez/eutils/elink.fcgi?dbfrom=pubmed&tool=sumsearch.org/cite&retmode=ref&cmd=prlinks&id=6587396 }} </ref><ref name="pmid6501577">{{cite journal| author=Heinecke JW, Rosen H, Chait A| title=Iron and copper promote modification of low density lipoprotein by human arterial smooth muscle cells in culture. | journal=J Clin Invest | year= 1984 | volume= 74 | issue= 5 | pages= 1890-4 | pmid=6501577 | doi=10.1172/JCI111609 | pmc=425370 | url=https://www.ncbi.nlm.nih.gov/entrez/eutils/elink.fcgi?dbfrom=pubmed&tool=sumsearch.org/cite&retmode=ref&cmd=prlinks&id=6501577 }} </ref><ref name="pmid8847477">{{cite journal| author=Morgan J, Leake DS| title=Oxidation of low density lipoprotein by iron or copper at acidic pH. | journal=J Lipid Res | year= 1995 | volume= 36 | issue= 12 | pages= 2504-12 | pmid=8847477 | doi= | pmc= | url=https://www.ncbi.nlm.nih.gov/entrez/eutils/elink.fcgi?dbfrom=pubmed&tool=sumsearch.org/cite&retmode=ref&cmd=prlinks&id=8847477 }} </ref> Exposure to non-transition metals, such as lead, has also been associated with impaired nitric oxide signaling and availability,<ref name="pmid15894814">{{cite journal| author=Dursun N, Arifoglu C, Süer C, Keskinol L| title=Blood pressure relationship to nitric oxide, lipid peroxidation, renal function, and renal blood flow in rats exposed to low lead levels. | journal=Biol Trace Elem Res | year= 2005 | volume= 104 | issue= 2 | pages= 141-9 | pmid=15894814 | doi=10.1385/BTER:104:2:141 | pmc= | url=https://www.ncbi.nlm.nih.gov/entrez/eutils/elink.fcgi?dbfrom=pubmed&tool=sumsearch.org/cite&retmode=ref&cmd=prlinks&id=15894814 }} </ref> endothelial cell dysfunction,<ref name="pmid7710289">{{cite journal| author=Kaji T, Suzuki M, Yamamoto C, Mishima A, Sakamoto M, Kozuka H| title=Severe damage of cultured vascular endothelial cell monolayer after simultaneous exposure to cadmium and lead. | journal=Arch Environ Contam Toxicol | year= 1995 | volume= 28 | issue= 2 | pages= 168-72 | pmid=7710289 | doi= | pmc= | url=https://www.ncbi.nlm.nih.gov/entrez/eutils/elink.fcgi?dbfrom=pubmed&tool=sumsearch.org/cite&retmode=ref&cmd=prlinks&id=7710289 }} </ref> and hypertension.<ref name="pmid18567711">{{cite journal| author=Vaziri ND| title=Mechanisms of lead-induced hypertension and cardiovascular disease. | journal=Am J Physiol Heart Circ Physiol | year= 2008 | volume= 295 | issue= 2 | pages= H454-65 | pmid=18567711 | doi=10.1152/ajpheart.00158.2008 | pmc=2519216 | url=https://www.ncbi.nlm.nih.gov/entrez/eutils/elink.fcgi?dbfrom=pubmed&tool=sumsearch.org/cite&retmode=ref&cmd=prlinks&id=18567711 }} </ref> [[Heavy metal]] exposure is also associated with genetic and [[epigenetic]] manifestations. [[Cadmium]] promotes atherosclerosis and endothelial dysfunction through multiple [[genetic]] changes.<ref name="pmid19556524">{{cite journal| author=Messner B, Knoflach M, Seubert A, Ritsch A, Pfaller K, Henderson B et al.| title=Cadmium is a novel and independent risk factor for early atherosclerosis mechanisms and in vivo relevance. | journal=Arterioscler Thromb Vasc Biol | year= 2009 | volume= 29 | issue= 9 | pages= 1392-8 | pmid=19556524 | doi=10.1161/ATVBAHA.109.190082 | pmc= | url=https://www.ncbi.nlm.nih.gov/entrez/eutils/elink.fcgi?dbfrom=pubmed&tool=sumsearch.org/cite&retmode=ref&cmd=prlinks&id=19556524 }} </ref> One of the mechanisms involves [[DNA]] strand breaks and damage with subsequent apoptosis in [[endothelial cell]]s.<ref name="pmid19556524">{{cite journal| author=Messner B, Knoflach M, Seubert A, Ritsch A, Pfaller K, Henderson B et al.| title=Cadmium is a novel and independent risk factor for early atherosclerosis mechanisms and in vivo relevance. | journal=Arterioscler Thromb Vasc Biol | year= 2009 | volume= 29 | issue= 9 | pages= 1392-8 | pmid=19556524 | doi=10.1161/ATVBAHA.109.190082 | pmc= | url=https://www.ncbi.nlm.nih.gov/entrez/eutils/elink.fcgi?dbfrom=pubmed&tool=sumsearch.org/cite&retmode=ref&cmd=prlinks&id=19556524 }} </ref> Also, maternal [[lead]] exposure during pregnancy may be associated with epigenetic consequences in grandchildren through alteration of [[DNA methylation]] early in life.<ref name="pmid26417717">{{cite journal| author=Sen A, Heredia N, Senut MC, Land S, Hollocher K, Lu X et al.| title=Multigenerational epigenetic inheritance in humans: DNA methylation changes associated with maternal exposure to lead can be transmitted to the grandchildren. | journal=Sci Rep | year= 2015 | volume= 5 | issue= | pages= 14466 | pmid=26417717 | doi=10.1038/srep14466 | pmc=4586440 | url=https://www.ncbi.nlm.nih.gov/entrez/eutils/elink.fcgi?dbfrom=pubmed&tool=sumsearch.org/cite&retmode=ref&cmd=prlinks&id=26417717 }} </ref><br />
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Current mechanistic understanding, albeit rudimentary, supports the concept that the cardiovascular benefits of [[chelation therapy]] may result from enhanced excretion of [[heavy metals]], and subsequent reduction in processes listed above. Additionally, in patients with [[diabetes]], a reduction in the metal-catalyzed formation of [[reactive oxygen species]], formation of advanced glycation end-products, and lipid [[peroxidation]] has been postulated.<ref name="pmid10874253">{{cite journal| author=Lamas GA, Ackermann A| title=Clinical evaluation of chelation therapy: is there any wheat amidst the chaff? | journal=Am Heart J | year= 2000 | volume= 140 | issue= 1 | pages= 4-5 | pmid=10874253 | doi=10.1067/mhj.2000.107549 | pmc= | url=http://www.ncbi.nlm.nih.gov/entrez/eutils/elink.fcgi?dbfrom=pubmed&tool=sumsearch.org/cite&retmode=ref&cmd=prlinks&id=10874253 }} </ref> Metal detoxification in the context of diabetes possibly decreases [[inflammation]] and [[oxidative stress]] that characterize atherosclerosis.<ref>Escolar E, Lamas G, Mark D et al(2013) "The Effect of an EDTA-based Chelation Regimen on Patients With Diabetes Mellitus and Prior Myocardial Infarction in the Trial to Assess Chelation Therapy (TACT)". Circulation. 2013</ref> Recent research, including chelation-activity assays, indicates that many common [[diabetes]] drugs, such as [[metformin]] and aldose reductase inhibitors, could possibly have some chelating properties.<ref name="pmid22354928">{{cite journal| author=Nagai R, Murray DB, Metz TO, Baynes JW| title=Chelation: a fundamental mechanism of action of AGE inhibitors, AGE breakers, and other inhibitors of diabetes complications. | journal=Diabetes | year= 2012 | volume= 61 | issue= 3 | pages= 549-59 | pmid=22354928 | doi=10.2337/db11-1120 | pmc=3282805 | url=https://www.ncbi.nlm.nih.gov/entrez/eutils/elink.fcgi?dbfrom=pubmed&tool=sumsearch.org/cite&retmode=ref&cmd=prlinks&id=22354928 }} </ref><ref name="pmid23612664">{{cite journal| author=Frizzell N, Baynes JW| title=Chelation therapy for the management of diabetic complications: a hypothesis and a proposal for clinical laboratory assessment of metal ion homeostasis in plasma. | journal=Clin Chem Lab Med | year= 2014 | volume= 52 | issue= 1 | pages= 69-75 | pmid=23612664 | doi=10.1515/cclm-2012-0881 | pmc= | url=https://www.ncbi.nlm.nih.gov/entrez/eutils/elink.fcgi?dbfrom=pubmed&tool=sumsearch.org/cite&retmode=ref&cmd=prlinks&id=23612664 }} </ref><ref name="pmid22492524">{{cite journal| author=Logie L, Harthill J, Patel K, Bacon S, Hamilton DL, Macrae K et al.| title=Cellular responses to the metal-binding properties of metformin. | journal=Diabetes | year= 2012 | volume= 61 | issue= 6 | pages= 1423-33 | pmid=22492524 | doi=10.2337/db11-0961 | pmc=3357267 | url=https://www.ncbi.nlm.nih.gov/entrez/eutils/elink.fcgi?dbfrom=pubmed&tool=sumsearch.org/cite&retmode=ref&cmd=prlinks&id=22492524 }} </ref><br />
<br />
<br />
<br />
The TACT chelation infusion, however, did not contain edetate disodium alone. The standard chelation infusion formula used in TACT was formulated to be identical with the most prevalent infusion in use. This formulation had developed organically over decades and had been modified by clinical practitioners to have additives such as [[ascorbic acid]], B-vitamins and [[magnesium]], thought to have a protective effect on [[endothelial cells]],<ref>Rozema, Theodore C. "The protocol for the safe and effective administration of EDTA and other chelating agents for vascular disease, degenerative disease, and metal toxicity." Journal of Advancement in Medicine 10.1 (1997): 5-100.</ref> making the results of clinical application more difficult to understand, and emphasizing the need for mechanistic work.<br />
<br />
==Future Studies==<br />
TACT was a unique study with an unexpected result that could have vast public health implications. In order to consider its broad applicability, the medical and scientific community require the results reproduced. TACT2, scheduled to begin in October 2016 (press release), is a replicative study in post-MI diabetic patients. If the TACT2 results confirm the results of TACT, then chelation is poised to become the next major development in the treatment of vascular complications of diabetes and vascular disease. TACT2 is currently recruiting sites, and interested investigators should visit www.TACT2.org for additional information.<br />
<br />
==Side Effects==<br />
Shown below is a list of the labelled toxicities of EDTA-based chelation therapy. However, TACT delivered 55,222 infusions of EDTA or placebo, and found no differences between groups in adverse events, serious or otherwise.<br />
* [[Arrhythmias]]<br />
* [[Autoimmune diseases]]<br />
* [[Bone marrow]]<br />
* [[Convulsions]]<br />
* [[Depression]]<br />
* [[Fever]]<br />
* [[Heart failure]]<br />
* [[Hypocalcemia]]<br />
* [[Hypoglycemia]]<br />
* [[Hypotension]]<br />
* [[Bleeding time|Prolonged bleeding time]]<br />
* [[Renal failure]]<br />
* [[Respiratory arrest]]<br />
* [[Tetany]]<br />
* [[Trace metal|Trace metal deficiency]]<br />
* [[Vitamin deficiency]]<ref name="pmid10874275">{{cite journal| author=Ernst E| title=Chelation therapy for coronary heart disease: An overview of all clinical investigations. | journal=Am Heart J | year= 2000 | volume= 140 | issue= 1 | pages= 139-41 | pmid=10874275 | doi=10.1067/mhj.2000.107548 | pmc= | url=http://www.ncbi.nlm.nih.gov/entrez/eutils/elink.fcgi?dbfrom=pubmed&tool=sumsearch.org/cite&retmode=ref&cmd=prlinks&id=10874275 }} </ref><ref name="pmid23532240">{{cite journal| author=Lamas GA, Goertz C, Boineau R, Mark DB, Rozema T, Nahin RL et al.| title=Effect of disodium EDTA chelation regimen on cardiovascular events in patients with previous myocardial infarction: the TACT randomized trial. | journal=JAMA | year= 2013 | volume= 309 | issue= 12 | pages= 1241-50 | pmid=23532240 | doi=10.1001/jama.2013.2107 | pmc= | url=http://www.ncbi.nlm.nih.gov/entrez/eutils/elink.fcgi?dbfrom=pubmed&tool=sumsearch.org/cite&retmode=ref&cmd=prlinks&id=23532240 }} </ref><br />
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==Landmark Trials==<br />
[[TACT]] <br><br />
TACT 2 [http://www.TACT2.org] (link to press release [http://www.prnewswire.com/news-releases/tact2-clinical-trial-receives-national-institutes-of-health-funding-300334174.html])<br />
<br />
==References==<br />
{{Reflist|2}}<br />
<br />
[[Category:Cardiology]]<br />
[[Category:Diabetes]]<br />
[[Category:Up-To-Date]]<br />
<br />
{{WikiDoc Help Menu}}<br />
{{WikiDoc Sources}}</div>Rim Halabyhttps://www.wikidoc.org/index.php?title=Chelation_therapy_for_cardiovascular_disease&diff=1274797Chelation therapy for cardiovascular disease2016-12-07T17:45:37Z<p>Rim Halaby: /* Mechanism of Action */</p>
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<div>__NOTOC__<br />
'''Editor-In-Chief:''' Gervasio Lamas, M.D., C. Michael Gibson, M.S., M.D.; {{AE}} {{Rim}}, Ian Ergui, B.Sc.<br />
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'''[[Chelation therapy|To read more about chelation therapy click here.]]'''<br><br />
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{{SK}} Chelation therapy, EDTA, post-myocardial infarction, diabetes<br />
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==Overview==<br />
[[Chelation]] is a process by which an organic molecule with a negatively charged “pocket” complexes with a metal ion of opposite charge, inactivates it, and then permits its physiological mobilization and excretion, usually by a renal route. [[Chelation therapy]], which involves multiple administrations of a chelating agent, helps eliminate stored toxic metal ions from the body.<ref name="pmid11794513">{{cite journal| author=Waters RS, Bryden NA, Patterson KY, Veillon C, Anderson RA| title=EDTA chelation effects on urinary losses of cadmium, calcium, chromium, cobalt, copper, lead, magnesium, and zinc. | journal=Biol Trace Elem Res | year= 2001 | volume= 83 | issue= 3 | pages= 207-21 | pmid=11794513 | doi=10.1385/BTER:83:3:207 | pmc= | url=https://www.ncbi.nlm.nih.gov/entrez/eutils/elink.fcgi?dbfrom=pubmed&tool=sumsearch.org/cite&retmode=ref&cmd=prlinks&id=11794513 }} </ref><ref name="arenas">Arenas I.A., Navas-Acien A., Lamas G.A.; Enhanced vasculotoxic metal excretionin post-MI patients after edetate disodium therapy (abstr). J Am Coll Cardiol. 2016;67:A2125</ref> Common chelators include [[penicillamine]], which binds copper and can be used to treat [[Wilson’s disease]], [[deferoxamine]], which binds iron and is used in the treatment of [[thalassemia]] and iron overload, succimer, also used in the treatment of lead poisoning, and the edetates, non-specific chelators of metals and other ions with valences of +2 to +6. Chelation therapy is, in many cases, guideline mandated, such as in children with elevated blood lead levels,<ref name="CDC">CDC. Low Level Lead Exposure Harms Children: A Renewed Call for Primary Prevention. Atlanta, GA:Advisory Committee on Childhood Lead Poisoning Prevention, U.S. Centers for Disease Control and Prevention (4 Jan 2012). Available: [http://www.cdc.gov/nceh/lead/acclpp/final_document_010412.pdf]</ref> patients with iron overload and dyserythropoietic syndromes or chronic hemolytic anemia,<ref name="pmid21452290">{{cite journal| author=Bacon BR, Adams PC, Kowdley KV, Powell LW, Tavill AS, American Association for the Study of Liver Diseases| title=Diagnosis and management of hemochromatosis: 2011 practice guideline by the American Association for the Study of Liver Diseases. | journal=Hepatology | year= 2011 | volume= 54 | issue= 1 | pages= 328-43 | pmid=21452290 | doi=10.1002/hep.24330 | pmc=3149125 | url=https://www.ncbi.nlm.nih.gov/entrez/eutils/elink.fcgi?dbfrom=pubmed&tool=sumsearch.org/cite&retmode=ref&cmd=prlinks&id=21452290 }} </ref> or [[sickle cell disease]] and transfusion acquired iron-overload,<ref name="NHLBI">NHLBI. Transfusion in Sickle Cell Disease: A Systematic Review of Benefits, Complications, and Management of Complications. Prepared for the National Heart, Lung, and Blood Institute and by the Knowledge and Evaluation Research Unit, Mayo Clinic Rochester (2012)</ref> to name a few instances.<br />
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[[Ethylene diamine tetraacetic acid]] ([[EDTA]], edetate) and its salts (most commonly disodium or calcium disodium), commonly used chelating agents patented in 1938, bind to and permit the urinary excretion of divalent cations such as calcium, and metals such as [[lead]], [[cadmium]], [[nickel]], [[cobalt]], [[iron]], [[aluminum]], and others. The initial medical use for [[EDTA]] began after World War II for the treatment of [[lead]]-exposed naval workers. In addition to its use for the treatment of metal poisoning, since the 1950s chelation therapy has been considered an alternative or add-on therapy for the prevention and treatment of [[atherosclerotic disease]]. The use of edetate disodium (Na2EDTA) has been most prominent in the alternative medicine treatment of atherosclerosis primarily because of the still-unproven hypothesis that the [[hypocalcemia]] it induces might lead to the decalcification of atherosclerotic lesions. In fact, the most current research suggests that the probable mechanism of benefit centers on enhancement of toxic metal excretion.<br />
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==Chelation Therapy and CVD==<br />
The use of chelation therapy as a treatment for [[atherosclerotic disease]] dates back to the 1950’s when Clarke et al investigated the use of EDTA for the treatment of angina pectoris and reported improvement in 19 of 20 patients.<ref name="pmid13372537">{{cite journal| author=CLARKE CN, CLARKE NE, MOSHER RE| title=Treatment of angina pectoris with disodium ethylene diamine tetraacetic acid. | journal=Am J Med Sci | year= 1956 | volume= 232 | issue= 6 | pages= 654-66 | pmid=13372537 | doi= | pmc= | url=http://www.ncbi.nlm.nih.gov/entrez/eutils/elink.fcgi?dbfrom=pubmed&tool=sumsearch.org/cite&retmode=ref&cmd=prlinks&id=13372537 }} </ref> Later studies by Kitchell were less positive,<ref name="pmid13756462">{{cite journal| author=KITCHELL JR, MELTZER LE, SEVEN MJ| title=Potential uses of chelation methods in the treatment of cardiovascular diseases. | journal=Prog Cardiovasc Dis | year= 1961 | volume= 3 | issue= | pages= 338-49 | pmid=13756462 | doi= | pmc= | url=https://www.ncbi.nlm.nih.gov/entrez/eutils/elink.fcgi?dbfrom=pubmed&tool=sumsearch.org/cite&retmode=ref&cmd=prlinks&id=13756462 }} </ref><ref name="pmid14033183">{{cite journal| author=KITCHELL JR, PALMON F, AYTAN N, MELTZER LE| title=The treatment of coronary artery disease with disodium EDTA. A reappraisal. | journal=Am J Cardiol | year= 1963 | volume= 11 | issue= | pages= 501-6 | pmid=14033183 | doi= | pmc= | url=https://www.ncbi.nlm.nih.gov/entrez/eutils/elink.fcgi?dbfrom=pubmed&tool=sumsearch.org/cite&retmode=ref&cmd=prlinks&id=14033183 }} </ref> and in an era without modern clinical trials methodology nor effective concomitant therapies, opinions regarding the use of [[chelation therapy]] for [[cardiovascular disease]] (CVD) tilted towards the negative. To be fair, from the 1970’s to 1990’s the preponderance of the scientific literature on chelation therapy for atherosclerosis consisted of case reports, case series, and small clinical trials with surrogate endpoints, poor-quality evidence from which to draw a conclusion of efficacy or harm.<ref name="pmid12519577">{{cite journal| author=Villarruz MV, Dans A, Tan F| title=Chelation therapy for atherosclerotic cardiovascular disease. | journal=Cochrane Database Syst Rev | year= 2002 | volume= | issue= 4 | pages= CD002785 | pmid=12519577 | doi=10.1002/14651858.CD002785 | pmc= | url=http://www.ncbi.nlm.nih.gov/entrez/eutils/elink.fcgi?dbfrom=pubmed&tool=sumsearch.org/cite&retmode=ref&cmd=prlinks&id=12519577 }} </ref><br />
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For example, one extensive case series reported an association between EDTA chelation therapy and improvement of ischemic heart disease and peripheral artery disease.<ref name="pmid3144646">{{cite journal| author=Olszewer E, Carter JP| title=EDTA chelation therapy in chronic degenerative disease. | journal=Med Hypotheses | year= 1988 | volume= 27 | issue= 1 | pages= 41-9 | pmid=3144646 | doi= | pmc= | url=http://www.ncbi.nlm.nih.gov/entrez/eutils/elink.fcgi?dbfrom=pubmed&tool=sumsearch.org/cite&retmode=ref&cmd=prlinks&id=3144646 }} </ref> Another study demonstrated that EDTA supplemented with several B vitamins (vitamin B1, B2, B6 and B12) but not EDTA alone was effective in improving [[endothelium]]-dependent forearm blood flow.<ref name="pmid10561804">{{cite journal| author=Green DJ, O'Driscoll JG, Maiorana A, Scrimgeour NB, Weerasooriya R, Taylor RR| title=Effects of chelation with EDTA and vitamin B therapy on nitric oxide-related endothelial vasodilator function. | journal=Clin Exp Pharmacol Physiol | year= 1999 | volume= 26 | issue= 11 | pages= 853-6 | pmid=10561804 | doi= | pmc= | url=http://www.ncbi.nlm.nih.gov/entrez/eutils/elink.fcgi?dbfrom=pubmed&tool=sumsearch.org/cite&retmode=ref&cmd=prlinks&id=10561804 }} </ref> A systematic review of four randomized clinical trials on chelation therapy and [[peripheral artery occlusive disease]] reported no benefit associated with chelation therapy.<ref name="pmid9264515">{{cite journal| author=Ernst E| title=Chelation therapy for peripheral arterial occlusive disease: a systematic review. | journal=Circulation | year= 1997 | volume= 96 | issue= 3 | pages= 1031-3 | pmid=9264515 | doi= | pmc= | url=http://www.ncbi.nlm.nih.gov/entrez/eutils/elink.fcgi?dbfrom=pubmed&tool=sumsearch.org/cite&retmode=ref&cmd=prlinks&id=9264515 }} </ref> The studies, however, individually and in aggregate, were too small to exclude a small to moderate benefit of therapy. Moreover, followup was short and surrogate physiologic endpoints, such as walking distance, were used. A Cochrane systematic review on the role of chelation therapy to treat coronary heart disease in 2002 concluded that the data were insufficient to recommend for or against chelation.<ref name="pmid10874275">{{cite journal| author=Ernst E| title=Chelation therapy for coronary heart disease: An overview of all clinical investigations. | journal=Am Heart J | year= 2000 | volume= 140 | issue= 1 | pages= 139-41 | pmid=10874275 | doi=10.1067/mhj.2000.107548 | pmc= | url=http://www.ncbi.nlm.nih.gov/entrez/eutils/elink.fcgi?dbfrom=pubmed&tool=sumsearch.org/cite&retmode=ref&cmd=prlinks&id=10874275 }} </ref> <br />
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The medical community concluded that the absence of high quality evidence of efficacy equated with evidence of absence of efficacy. Professional organizations recommended against chelation therapy.<ref name="pmid9205980">{{cite journal| author=Lewin MR| title=Chelation therapy for cardiovascular disease. Review and commentary. | journal=Tex Heart Inst J | year= 1997 | volume= 24 | issue= 2 | pages= 81-9 | pmid=9205980 | doi= | pmc=325409 | url=https://www.ncbi.nlm.nih.gov/entrez/eutils/elink.fcgi?dbfrom=pubmed&tool=sumsearch.org/cite&retmode=ref&cmd=prlinks&id=9205980 }} </ref> Interestingly, patients continued to seek, and practitioners to administer, chelation infusions for [[cardiovascular disease]] and other diagnoses.<br />
<br />
In light of the persistent controversy regarding the benefits of chelation therapy and the absence of any previous large clinical trial investigating its use in coronary artery disease, the National Center for Complementary and Alternative Medicine and the National Heart Lung and Blood Institute released a $30 million Request for Applications (RFA) to develop a definitive trial. In 2002, the RFA was awarded to Mount Sinai Medical Center in Miami Beach FL (G Lamas MD, Principal Investigator). The Trial to Assess Chelation Therapy (TACT), a randomized, double blind, placebo controlled 2x2 factorial trial, investigated the efficacy and safety of disodium EDTA based infusions and high-dose oral vitamins and minerals in 1708 stable post-myocardial infarction (MI) patients more than 50 years of age and with fairly normal kidney function ([[creatinine]] 2.0 mg/dL or less). The active treatment consisted of 40 infusions consisted of disodium [[EDTA]] combined with [[ascorbic acid]], B vitamins, and other components. The median age of patients was 65 years, and they were treated with evidence-based post-MI medicines. The primary endpoint of this trial was a composite of all-cause mortality, [[stroke]], [[MI]], coronary revascularization, and hospitalization for [[angina]].<ref name="pmid16585050">{{cite journal| author=Costa J, Borges M, David C, Vaz Carneiro A| title=Efficacy of lipid lowering drug treatment for diabetic and non-diabetic patients: meta-analysis of randomised controlled trials. | journal=BMJ | year= 2006 | volume= 332 | issue= 7550 | pages= 1115-24 | pmid=16585050 | doi=10.1136/bmj.38793.468449.AE | pmc=PMC1459619 | url=http://www.ncbi.nlm.nih.gov/entrez/eutils/elink.fcgi?dbfrom=pubmed&tool=sumsearch.org/cite&retmode=ref&cmd=prlinks&id=16585050 }} </ref><br />
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A follow up period of 55 months revealed a statistically significant decrease in the primary endpoint (HR: 0.82; 95% CI: 0.69-0.99; p= 0.035). There was an absolute reduction in the 5-year Kaplan-Meier estimate, from 38% to 33%, resulting in a 5-year number needed to treat (NNT) of 18 patients to avoid one adverse cardiovascular outcome. This is comparable to the 5-year NNT for [[statins]] in post-[[MI]] patients (NNT=16 for the secondary prevention of a major coronary event).<ref name="pmid16585050">{{cite journal| author=Costa J, Borges M, David C, Vaz Carneiro A| title=Efficacy of lipid lowering drug treatment for diabetic and non-diabetic patients: meta-analysis of randomised controlled trials. | journal=BMJ | year= 2006 | volume= 332 | issue= 7550 | pages= 1115-24 | pmid=16585050 | doi=10.1136/bmj.38793.468449.AE | pmc=PMC1459619 | url=http://www.ncbi.nlm.nih.gov/entrez/eutils/elink.fcgi?dbfrom=pubmed&tool=sumsearch.org/cite&retmode=ref&cmd=prlinks&id=16585050 }} </ref> The point estimate for the risk of each of the components of the primary endpoint was <1, consistent with the aggregate result. The Investigators concluded that chelation should not yet be adopted for routine post-MI use in all patients, but the results of TACT should inform further studies to confirm or refute these unexpected results.<ref name="pmid23532240">{{cite journal| author=Lamas GA, Goertz C, Boineau R, Mark DB, Rozema T, Nahin RL et al.| title=Effect of disodium EDTA chelation regimen on cardiovascular events in patients with previous myocardial infarction: the TACT randomized trial. | journal=JAMA | year= 2013 | volume= 309 | issue= 12 | pages= 1241-50 | pmid=23532240 | doi=10.1001/jama.2013.2107 | pmc= | url=http://www.ncbi.nlm.nih.gov/entrez/eutils/elink.fcgi?dbfrom=pubmed&tool=sumsearch.org/cite&retmode=ref&cmd=prlinks&id=23532240 }} </ref><br />
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TACT prespecified several subgroups for analysis and found a significant interaction between edetate disodium treatment and [[diabetes]] (p for interaction =0.0037). Among subjects enrolled in TACT, there were 633 diabetic patients, defined as patients with self-reported diabetes, taking medications for diabetes, or having a fasting blood glucose of at least 126 mg/dL at enrollment. The administration of chelation infusions among post-MI diabetic patients was associated with a marked reduction in the primary end point when compared with placebo. The primary end point occurred in 25% of diabetic patients who were administered chelation therapy compared to 38% in those who received placebo infusions (HR, 0.59; 95% CI, 0.44–0.79; P<0.001). The 5-year NNT to prevent one event was 6.5. In addition, chelation therapy was significantly associated with decreased all-cause mortality (43% reduction, p=0.011) and reinfarction (52% reduction, p=0.015). Again, the investigators concluded that these findings supported future research, but did not constitute sufficient evidence to indicate the routine use of chelation therapy for all post–myocardial infarction patients with diabetes, leaving open the clinician’s choice to use this novel therapy in occasional, or non-routine patients.<br />
<br />
These results catalyzed a wave of increased public and scientific interest in disodium EDTA treatment for patients with established coronary disease, particularly in diabetes, and hypotheses regarding potential mechanisms of benefit. As a capstone to the published analyses, the ACC/AHA Guidelines for Chronic Ischemic Heart Disease changed to reflect the TACT data and upgraded disodium EDTA treatment from a Class III indication to a Class IIB indication. While Class III therapeutics are considered not beneficial or useful, Class IIB treatments can be considered in some patients and require additional research to establish efficacy.<ref name="pmid25077860">{{cite journal| author=Fihn SD, Blankenship JC, Alexander KP, Bittl JA, Byrne JG, Fletcher BJ et al.| title=2014 ACC/AHA/AATS/PCNA/SCAI/STS focused update of the guideline for the diagnosis and management of patients with stable ischemic heart disease: a report of the American College of Cardiology/American Heart Association Task Force on Practice Guidelines, and the American Association for Thoracic Surgery, Preventive Cardiovascular Nurses Association, Society for Cardiovascular Angiography and Interventions, and Society of Thoracic Surgeons. | journal=J Am Coll Cardiol | year= 2014 | volume= 64 | issue= 18 | pages= 1929-49 | pmid=25077860 | doi=10.1016/j.jacc.2014.07.017 | pmc= | url=https://www.ncbi.nlm.nih.gov/entrez/eutils/elink.fcgi?dbfrom=pubmed&tool=sumsearch.org/cite&retmode=ref&cmd=prlinks&id=25077860 }} </ref> The change in the guidelines signaled a major shift in the perception of chelation therapy among the medical establishment. The TACT data led clinicians to reconsider chelation objectively, and the investigators and many other academic cardiologists called for TACT2, a new trial to test the results of TACT, to be funded by the [[NIH]].<br />
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==Mechanism of Action==<br />
Edetate disodium binds to metals and forms soluble complexes facilitating their subsequent excretion in the urine.<ref name="pmid14000694">{{cite journal| author=WILDER LW, DE JODE LR, MILSTEIN SW, HOWARD JM| title=Mobilization of atherosclerotic plaque calcium with EDTA utilizing the isolation-perfusion principle. | journal=Surgery | year= 1962 | volume= 52 | issue= | pages= 793-5 | pmid=14000694 | doi= | pmc= | url=http://www.ncbi.nlm.nih.gov/entrez/eutils/elink.fcgi?dbfrom=pubmed&tool=sumsearch.org/cite&retmode=ref&cmd=prlinks&id=14000694 }} </ref> Hence, chelation therapy results in the elimination of stored toxic and essential metals. In an experiment performed on 24 patients, age 50 or older, and with a prior MI and a creatinine of 2.0 or less, patients had urine toxic metals measured at baseline, 1 day after an infusion of placebo, and 1 day after an infusion of the edetate disodium-based TACT solution. Placebo did not increase the excretion of toxic metals. Following an infusion of the edetate disodium-based TACT solution, lead excretion increased by nearly 3900%, and cadmium by nearly 700%. Other toxic metals whose excretion was enhanced by edetate disodium were aluminum (by ~250%), nickel (by ~150%), thallium (by ~60%), and gadolinium. A similar experiment performed earlier by Waters et al, reported urinary lead concentrations approximately 35 times greater than in pre-chelation urine.<ref name="pmid11794513">{{cite journal| author=Waters RS, Bryden NA, Patterson KY, Veillon C, Anderson RA| title=EDTA chelation effects on urinary losses of cadmium, calcium, chromium, cobalt, copper, lead, magnesium, and zinc. | journal=Biol Trace Elem Res | year= 2001 | volume= 83 | issue= 3 | pages= 207-21 | pmid=11794513 | doi=10.1385/BTER:83:3:207 | pmc= | url=https://www.ncbi.nlm.nih.gov/entrez/eutils/elink.fcgi?dbfrom=pubmed&tool=sumsearch.org/cite&retmode=ref&cmd=prlinks&id=11794513 }} </ref><br />
While enhanced lead and cadmium is interesting, the critical link to cardiovascular events is provided by epidemiological studies, which provide robust evidence linking toxic metals with cardiovascular disease.<ref name="pmid21421632">{{cite journal| author=Agarwal S, Zaman T, Tuzcu EM, Kapadia SR| title=Heavy metals and cardiovascular disease: results from the National Health and Nutrition Examination Survey (NHANES) 1999-2006. | journal=Angiology | year= 2011 | volume= 62 | issue= 5 | pages= 422-9 | pmid=21421632 | doi=10.1177/0003319710395562 | pmc= | url=http://www.ncbi.nlm.nih.gov/entrez/eutils/elink.fcgi?dbfrom=pubmed&tool=sumsearch.org/cite&retmode=ref&cmd=prlinks&id=21421632 }} </ref> This evidence is strongest for lead and cadmium.<ref name="pmid16982939">{{cite journal| author=Menke A, Muntner P, Batuman V, Silbergeld EK, Guallar E| title=Blood lead below 0.48 micromol/L (10 microg/dL) and mortality among US adults. | journal=Circulation | year= 2006 | volume= 114 | issue= 13 | pages= 1388-94 | pmid=16982939 | doi=10.1161/CIRCULATIONAHA.106.628321 | pmc= | url=http://www.ncbi.nlm.nih.gov/entrez/eutils/elink.fcgi?dbfrom=pubmed&tool=sumsearch.org/cite&retmode=ref&cmd=prlinks&id=16982939 }} </ref><ref name="pmid15184277">{{cite journal| author=Navas-Acien A, Selvin E, Sharrett AR, Calderon-Aranda E, Silbergeld E, Guallar E| title=Lead, cadmium, smoking, and increased risk of peripheral arterial disease. | journal=Circulation | year= 2004 | volume= 109 | issue= 25 | pages= 3196-201 | pmid=15184277 | doi=10.1161/01.CIR.0000130848.18636.B2 | pmc= | url=http://www.ncbi.nlm.nih.gov/entrez/eutils/elink.fcgi?dbfrom=pubmed&tool=sumsearch.org/cite&retmode=ref&cmd=prlinks&id=15184277 }} </ref><ref name="pmid23514838">{{cite journal| author=Tellez-Plaza M, Guallar E, Howard BV, Umans JG, Francesconi KA, Goessler W et al.| title=Cadmium exposure and incident cardiovascular disease. | journal=Epidemiology | year= 2013 | volume= 24 | issue= 3 | pages= 421-9 | pmid=23514838 | doi=10.1097/EDE.0b013e31828b0631 | pmc= | url=http://www.ncbi.nlm.nih.gov/entrez/eutils/elink.fcgi?dbfrom=pubmed&tool=sumsearch.org/cite&retmode=ref&cmd=prlinks&id=23514838 }} </ref> Elevated blood concentration of lead is associated with increased all-cause mortality [HR 1.25 (95% CI 1.04 to 1.51) for the highest versus lowest tertile of blood lead, P trend across the tertiles=0.002) and cardiovascular mortality [HR 1.55 (95% CI 1.08 to 2.24) for the highest versus lowest tertile, P trend <0.003] ((Menke, Muntner, Batuman, Silbergeld, & Guallar, 2006)). Also, cardiovascular mortality is greater among subjects with elevated cadmium concentrations in the blood and urine [HR 1.69 (95% CI: 1.03, 2.77) and 1.74 (95% CI: 1.07, 2.83) for the 80th and 20th percentiles of blood and urine cadmium, respectively] (cadmium exposure and all cause cardiovascular mortality, Navas-Acien, Tellez-Plaza). <br />
Heavy metals may play a role in the development of [[cardiovascular disease]] through a number of different mechanisms (Navas Nature) (Vaziri Khan Interplay of ROS). Heavy metals include transition metals such as [[cadmium]], [[mercury]], [[manganese]], [[chromium]], [[cobalt]], [[nickel]], [[iron]], and [[copper]], metalloids such as antimony and arsenic, and post- transition metals such as thallium and lead. These metals all have unique toxicities, as well as toxicities that are common to all of them. Heavy metals in the endothelium promote oxygen free radical formation, resulting in increased oxidative stress, inflammation, and tissue damage. Lead and cadmium may interfere with calcium signaling channels. Transition metals promote modifications of low-density lipoprotein by endothelial cells through lipid peroxidation and degradation of low-density lipoprotein phospholipids.<ref name="pmid6587396">{{cite journal| author=Steinbrecher UP, Parthasarathy S, Leake DS, Witztum JL, Steinberg D| title=Modification of low density lipoprotein by endothelial cells involves lipid peroxidation and degradation of low density lipoprotein phospholipids. | journal=Proc Natl Acad Sci U S A | year= 1984 | volume= 81 | issue= 12 | pages= 3883-7 | pmid=6587396 | doi= | pmc=345326 | url=https://www.ncbi.nlm.nih.gov/entrez/eutils/elink.fcgi?dbfrom=pubmed&tool=sumsearch.org/cite&retmode=ref&cmd=prlinks&id=6587396 }} </ref><ref name="pmid6501577">{{cite journal| author=Heinecke JW, Rosen H, Chait A| title=Iron and copper promote modification of low density lipoprotein by human arterial smooth muscle cells in culture. | journal=J Clin Invest | year= 1984 | volume= 74 | issue= 5 | pages= 1890-4 | pmid=6501577 | doi=10.1172/JCI111609 | pmc=425370 | url=https://www.ncbi.nlm.nih.gov/entrez/eutils/elink.fcgi?dbfrom=pubmed&tool=sumsearch.org/cite&retmode=ref&cmd=prlinks&id=6501577 }} </ref><ref name="pmid8847477">{{cite journal| author=Morgan J, Leake DS| title=Oxidation of low density lipoprotein by iron or copper at acidic pH. | journal=J Lipid Res | year= 1995 | volume= 36 | issue= 12 | pages= 2504-12 | pmid=8847477 | doi= | pmc= | url=https://www.ncbi.nlm.nih.gov/entrez/eutils/elink.fcgi?dbfrom=pubmed&tool=sumsearch.org/cite&retmode=ref&cmd=prlinks&id=8847477 }} </ref> Exposure to non-transition metals, such as lead, has also been associated with impaired nitric oxide signaling and availability,<ref name="pmid15894814">{{cite journal| author=Dursun N, Arifoglu C, Süer C, Keskinol L| title=Blood pressure relationship to nitric oxide, lipid peroxidation, renal function, and renal blood flow in rats exposed to low lead levels. | journal=Biol Trace Elem Res | year= 2005 | volume= 104 | issue= 2 | pages= 141-9 | pmid=15894814 | doi=10.1385/BTER:104:2:141 | pmc= | url=https://www.ncbi.nlm.nih.gov/entrez/eutils/elink.fcgi?dbfrom=pubmed&tool=sumsearch.org/cite&retmode=ref&cmd=prlinks&id=15894814 }} </ref> endothelial cell dysfunction,<ref name="pmid7710289">{{cite journal| author=Kaji T, Suzuki M, Yamamoto C, Mishima A, Sakamoto M, Kozuka H| title=Severe damage of cultured vascular endothelial cell monolayer after simultaneous exposure to cadmium and lead. | journal=Arch Environ Contam Toxicol | year= 1995 | volume= 28 | issue= 2 | pages= 168-72 | pmid=7710289 | doi= | pmc= | url=https://www.ncbi.nlm.nih.gov/entrez/eutils/elink.fcgi?dbfrom=pubmed&tool=sumsearch.org/cite&retmode=ref&cmd=prlinks&id=7710289 }} </ref> and hypertension.<ref name="pmid18567711">{{cite journal| author=Vaziri ND| title=Mechanisms of lead-induced hypertension and cardiovascular disease. | journal=Am J Physiol Heart Circ Physiol | year= 2008 | volume= 295 | issue= 2 | pages= H454-65 | pmid=18567711 | doi=10.1152/ajpheart.00158.2008 | pmc=2519216 | url=https://www.ncbi.nlm.nih.gov/entrez/eutils/elink.fcgi?dbfrom=pubmed&tool=sumsearch.org/cite&retmode=ref&cmd=prlinks&id=18567711 }} </ref> [[Heavy metal]] exposure is also associated with genetic and [[epigenetic]] manifestations. [[Cadmium]] promotes atherosclerosis and endothelial dysfunction through multiple [[genetic]] changes.<ref name="pmid19556524">{{cite journal| author=Messner B, Knoflach M, Seubert A, Ritsch A, Pfaller K, Henderson B et al.| title=Cadmium is a novel and independent risk factor for early atherosclerosis mechanisms and in vivo relevance. | journal=Arterioscler Thromb Vasc Biol | year= 2009 | volume= 29 | issue= 9 | pages= 1392-8 | pmid=19556524 | doi=10.1161/ATVBAHA.109.190082 | pmc= | url=https://www.ncbi.nlm.nih.gov/entrez/eutils/elink.fcgi?dbfrom=pubmed&tool=sumsearch.org/cite&retmode=ref&cmd=prlinks&id=19556524 }} </ref> One of the mechanisms involves [[DNA]] strand breaks and damage with subsequent apoptosis in [[endothelial cell]]s.<ref name="pmid19556524">{{cite journal| author=Messner B, Knoflach M, Seubert A, Ritsch A, Pfaller K, Henderson B et al.| title=Cadmium is a novel and independent risk factor for early atherosclerosis mechanisms and in vivo relevance. | journal=Arterioscler Thromb Vasc Biol | year= 2009 | volume= 29 | issue= 9 | pages= 1392-8 | pmid=19556524 | doi=10.1161/ATVBAHA.109.190082 | pmc= | url=https://www.ncbi.nlm.nih.gov/entrez/eutils/elink.fcgi?dbfrom=pubmed&tool=sumsearch.org/cite&retmode=ref&cmd=prlinks&id=19556524 }} </ref> Also, maternal [[lead]] exposure during pregnancy may be associated with epigenetic consequences in grandchildren through alteration of [[DNA methylation]] early in life.<ref name="pmid26417717">{{cite journal| author=Sen A, Heredia N, Senut MC, Land S, Hollocher K, Lu X et al.| title=Multigenerational epigenetic inheritance in humans: DNA methylation changes associated with maternal exposure to lead can be transmitted to the grandchildren. | journal=Sci Rep | year= 2015 | volume= 5 | issue= | pages= 14466 | pmid=26417717 | doi=10.1038/srep14466 | pmc=4586440 | url=https://www.ncbi.nlm.nih.gov/entrez/eutils/elink.fcgi?dbfrom=pubmed&tool=sumsearch.org/cite&retmode=ref&cmd=prlinks&id=26417717 }} </ref><br />
<br />
Current mechanistic understanding, albeit rudimentary, supports the concept that the cardiovascular benefits of [[chelation therapy]] may result from enhanced excretion of [[heavy metals]], and subsequent reduction in processes listed above. Additionally, in patients with [[diabetes]], a reduction in the metal-catalyzed formation of [[reactive oxygen species]], formation of advanced glycation end-products, and lipid [[peroxidation]] has been postulated.<ref name="pmid10874253">{{cite journal| author=Lamas GA, Ackermann A| title=Clinical evaluation of chelation therapy: is there any wheat amidst the chaff? | journal=Am Heart J | year= 2000 | volume= 140 | issue= 1 | pages= 4-5 | pmid=10874253 | doi=10.1067/mhj.2000.107549 | pmc= | url=http://www.ncbi.nlm.nih.gov/entrez/eutils/elink.fcgi?dbfrom=pubmed&tool=sumsearch.org/cite&retmode=ref&cmd=prlinks&id=10874253 }} </ref> Metal detoxification in the context of diabetes possibly decreases [[inflammation]] and [[oxidative stress]] that characterize atherosclerosis.<ref>Escolar E, Lamas G, Mark D et al(2013) "The Effect of an EDTA-based Chelation Regimen on Patients With Diabetes Mellitus and Prior Myocardial Infarction in the Trial to Assess Chelation Therapy (TACT)". Circulation. 2013</ref> Recent research, including chelation-activity assays, indicates that many common [[diabetes]] drugs, such as [[metformin]] and aldose reductase inhibitors, could possibly have some chelating properties.<ref name="pmid22354928">{{cite journal| author=Nagai R, Murray DB, Metz TO, Baynes JW| title=Chelation: a fundamental mechanism of action of AGE inhibitors, AGE breakers, and other inhibitors of diabetes complications. | journal=Diabetes | year= 2012 | volume= 61 | issue= 3 | pages= 549-59 | pmid=22354928 | doi=10.2337/db11-1120 | pmc=3282805 | url=https://www.ncbi.nlm.nih.gov/entrez/eutils/elink.fcgi?dbfrom=pubmed&tool=sumsearch.org/cite&retmode=ref&cmd=prlinks&id=22354928 }} </ref><ref name="pmid23612664">{{cite journal| author=Frizzell N, Baynes JW| title=Chelation therapy for the management of diabetic complications: a hypothesis and a proposal for clinical laboratory assessment of metal ion homeostasis in plasma. | journal=Clin Chem Lab Med | year= 2014 | volume= 52 | issue= 1 | pages= 69-75 | pmid=23612664 | doi=10.1515/cclm-2012-0881 | pmc= | url=https://www.ncbi.nlm.nih.gov/entrez/eutils/elink.fcgi?dbfrom=pubmed&tool=sumsearch.org/cite&retmode=ref&cmd=prlinks&id=23612664 }} </ref><ref name="pmid22492524">{{cite journal| author=Logie L, Harthill J, Patel K, Bacon S, Hamilton DL, Macrae K et al.| title=Cellular responses to the metal-binding properties of metformin. | journal=Diabetes | year= 2012 | volume= 61 | issue= 6 | pages= 1423-33 | pmid=22492524 | doi=10.2337/db11-0961 | pmc=3357267 | url=https://www.ncbi.nlm.nih.gov/entrez/eutils/elink.fcgi?dbfrom=pubmed&tool=sumsearch.org/cite&retmode=ref&cmd=prlinks&id=22492524 }} </ref><br />
<br />
<br />
<br />
The TACT chelation infusion, however, did not contain edetate disodium alone. The standard chelation infusion formula used in TACT was formulated to be identical with the most prevalent infusion in use. This formulation had developed organically over decades and had been modified by clinical practitioners to have additives such as [[ascorbic acid]], B-vitamins and [[magnesium]], thought to have a protective effect on [[endothelial cells]],<ref>Rozema, Theodore C. "The protocol for the safe and effective administration of EDTA and other chelating agents for vascular disease, degenerative disease, and metal toxicity." Journal of Advancement in Medicine 10.1 (1997): 5-100.</ref> making the results of clinical application more difficult to understand, and emphasizing the need for mechanistic work.<br />
<br />
==Future Studies==<br />
TACT was a unique study with an unexpected result that could have vast public health implications. In order to consider its broad applicability, the medical and scientific community require the results reproduced. TACT2, scheduled to begin in October 2016 (press release), is a replicative study in post-MI diabetic patients. If the TACT2 results confirm the results of TACT, then chelation is poised to become the next major development in the treatment of vascular complications of diabetes and vascular disease. TACT2 is currently recruiting sites, and interested investigators should visit www.TACT2.org for additional information.<br />
<br />
==Side Effects==<br />
Shown below is a list of the labelled toxicities of EDTA-based chelation therapy. However, TACT delivered 55,222 infusions of EDTA or placebo, and found no differences between groups in adverse events, serious or otherwise.<br />
* [[Arrhythmias]]<br />
* [[Autoimmune diseases]]<br />
* [[Bone marrow]]<br />
* [[Convulsions]]<br />
* [[Depression]]<br />
* [[Fever]]<br />
* [[Heart failure]]<br />
* [[Hypocalcemia]]<br />
* [[Hypoglycemia]]<br />
* [[Hypotension]]<br />
* [[Bleeding time|Prolonged bleeding time]]<br />
* [[Renal failure]]<br />
* [[Respiratory arrest]]<br />
* [[Tetany]]<br />
* [[Trace metal|Trace metal deficiency]]<br />
* [[Vitamin deficiency]]<ref name="pmid10874275">{{cite journal| author=Ernst E| title=Chelation therapy for coronary heart disease: An overview of all clinical investigations. | journal=Am Heart J | year= 2000 | volume= 140 | issue= 1 | pages= 139-41 | pmid=10874275 | doi=10.1067/mhj.2000.107548 | pmc= | url=http://www.ncbi.nlm.nih.gov/entrez/eutils/elink.fcgi?dbfrom=pubmed&tool=sumsearch.org/cite&retmode=ref&cmd=prlinks&id=10874275 }} </ref><ref name="pmid23532240">{{cite journal| author=Lamas GA, Goertz C, Boineau R, Mark DB, Rozema T, Nahin RL et al.| title=Effect of disodium EDTA chelation regimen on cardiovascular events in patients with previous myocardial infarction: the TACT randomized trial. | journal=JAMA | year= 2013 | volume= 309 | issue= 12 | pages= 1241-50 | pmid=23532240 | doi=10.1001/jama.2013.2107 | pmc= | url=http://www.ncbi.nlm.nih.gov/entrez/eutils/elink.fcgi?dbfrom=pubmed&tool=sumsearch.org/cite&retmode=ref&cmd=prlinks&id=23532240 }} </ref><br />
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==Landmark Trials==<br />
[[TACT]] <br><br />
TACT 2 [http://www.TACT2.org] (link to press release [http://www.prnewswire.com/news-releases/tact2-clinical-trial-receives-national-institutes-of-health-funding-300334174.html])<br />
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==References==<br />
{{Reflist|2}}<br />
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[[Category:Cardiology]]<br />
[[Category:Diabetes]]<br />
[[Category:Up-To-Date]]<br />
<br />
{{WikiDoc Help Menu}}<br />
{{WikiDoc Sources}}</div>Rim Halabyhttps://www.wikidoc.org/index.php?title=Chelation_therapy_for_cardiovascular_disease&diff=1274683Chelation therapy for cardiovascular disease2016-12-07T00:17:25Z<p>Rim Halaby: </p>
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<div>__NOTOC__<br />
'''Editor-In-Chief:''' Gervasio Lamas, M.D., C. Michael Gibson, M.S., M.D.; {{AE}} {{Rim}}, Ian Ergui, B.Sc.<br />
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'''[[Chelation therapy|To read more about chelation therapy click here.]]'''<br><br />
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{{SK}} Chelation therapy, EDTA, post-myocardial infarction, diabetes<br />
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==Overview==<br />
[[Chelation]] is a process by which an organic molecule with a negatively charged “pocket” complexes with a metal ion of opposite charge, inactivates it, and then permits its physiological mobilization and excretion, usually by a renal route. [[Chelation therapy]], which involves multiple administrations of a chelating agent, helps eliminate stored toxic metal ions from the body.<ref name="pmid11794513">{{cite journal| author=Waters RS, Bryden NA, Patterson KY, Veillon C, Anderson RA| title=EDTA chelation effects on urinary losses of cadmium, calcium, chromium, cobalt, copper, lead, magnesium, and zinc. | journal=Biol Trace Elem Res | year= 2001 | volume= 83 | issue= 3 | pages= 207-21 | pmid=11794513 | doi=10.1385/BTER:83:3:207 | pmc= | url=https://www.ncbi.nlm.nih.gov/entrez/eutils/elink.fcgi?dbfrom=pubmed&tool=sumsearch.org/cite&retmode=ref&cmd=prlinks&id=11794513 }} </ref><ref name="arenas">Arenas I.A., Navas-Acien A., Lamas G.A.; Enhanced vasculotoxic metal excretionin post-MI patients after edetate disodium therapy (abstr). J Am Coll Cardiol. 2016;67:A2125</ref> Common chelators include [[penicillamine]], which binds copper and can be used to treat [[Wilson’s disease]], [[deferoxamine]], which binds iron and is used in the treatment of [[thalassemia]] and iron overload, succimer, also used in the treatment of lead poisoning, and the edetates, non-specific chelators of metals and other ions with valences of +2 to +6. Chelation therapy is, in many cases, guideline mandated, such as in children with elevated blood lead levels,<ref name="CDC">CDC. Low Level Lead Exposure Harms Children: A Renewed Call for Primary Prevention. Atlanta, GA:Advisory Committee on Childhood Lead Poisoning Prevention, U.S. Centers for Disease Control and Prevention (4 Jan 2012). Available: [http://www.cdc.gov/nceh/lead/acclpp/final_document_010412.pdf]</ref> patients with iron overload and dyserythropoietic syndromes or chronic hemolytic anemia,<ref name="pmid21452290">{{cite journal| author=Bacon BR, Adams PC, Kowdley KV, Powell LW, Tavill AS, American Association for the Study of Liver Diseases| title=Diagnosis and management of hemochromatosis: 2011 practice guideline by the American Association for the Study of Liver Diseases. | journal=Hepatology | year= 2011 | volume= 54 | issue= 1 | pages= 328-43 | pmid=21452290 | doi=10.1002/hep.24330 | pmc=3149125 | url=https://www.ncbi.nlm.nih.gov/entrez/eutils/elink.fcgi?dbfrom=pubmed&tool=sumsearch.org/cite&retmode=ref&cmd=prlinks&id=21452290 }} </ref> or [[sickle cell disease]] and transfusion acquired iron-overload,<ref name="NHLBI">NHLBI. Transfusion in Sickle Cell Disease: A Systematic Review of Benefits, Complications, and Management of Complications. Prepared for the National Heart, Lung, and Blood Institute and by the Knowledge and Evaluation Research Unit, Mayo Clinic Rochester (2012)</ref> to name a few instances.<br />
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[[Ethylene diamine tetraacetic acid]] ([[EDTA]], edetate) and its salts (most commonly disodium or calcium disodium), commonly used chelating agents patented in 1938, bind to and permit the urinary excretion of divalent cations such as calcium, and metals such as [[lead]], [[cadmium]], [[nickel]], [[cobalt]], [[iron]], [[aluminum]], and others. The initial medical use for [[EDTA]] began after World War II for the treatment of [[lead]]-exposed naval workers. In addition to its use for the treatment of metal poisoning, since the 1950s chelation therapy has been considered an alternative or add-on therapy for the prevention and treatment of [[atherosclerotic disease]]. The use of edetate disodium (Na2EDTA) has been most prominent in the alternative medicine treatment of atherosclerosis primarily because of the still-unproven hypothesis that the [[hypocalcemia]] it induces might lead to the decalcification of atherosclerotic lesions. In fact, the most current research suggests that the probable mechanism of benefit centers on enhancement of toxic metal excretion.<br />
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==Chelation Therapy and CVD==<br />
The use of chelation therapy as a treatment for [[atherosclerotic disease]] dates back to the 1950’s when Clarke et al investigated the use of EDTA for the treatment of angina pectoris and reported improvement in 19 of 20 patients.<ref name="pmid13372537">{{cite journal| author=CLARKE CN, CLARKE NE, MOSHER RE| title=Treatment of angina pectoris with disodium ethylene diamine tetraacetic acid. | journal=Am J Med Sci | year= 1956 | volume= 232 | issue= 6 | pages= 654-66 | pmid=13372537 | doi= | pmc= | url=http://www.ncbi.nlm.nih.gov/entrez/eutils/elink.fcgi?dbfrom=pubmed&tool=sumsearch.org/cite&retmode=ref&cmd=prlinks&id=13372537 }} </ref> Later studies by Kitchell were less positive,<ref name="pmid13756462">{{cite journal| author=KITCHELL JR, MELTZER LE, SEVEN MJ| title=Potential uses of chelation methods in the treatment of cardiovascular diseases. | journal=Prog Cardiovasc Dis | year= 1961 | volume= 3 | issue= | pages= 338-49 | pmid=13756462 | doi= | pmc= | url=https://www.ncbi.nlm.nih.gov/entrez/eutils/elink.fcgi?dbfrom=pubmed&tool=sumsearch.org/cite&retmode=ref&cmd=prlinks&id=13756462 }} </ref><ref name="pmid14033183">{{cite journal| author=KITCHELL JR, PALMON F, AYTAN N, MELTZER LE| title=The treatment of coronary artery disease with disodium EDTA. A reappraisal. | journal=Am J Cardiol | year= 1963 | volume= 11 | issue= | pages= 501-6 | pmid=14033183 | doi= | pmc= | url=https://www.ncbi.nlm.nih.gov/entrez/eutils/elink.fcgi?dbfrom=pubmed&tool=sumsearch.org/cite&retmode=ref&cmd=prlinks&id=14033183 }} </ref> and in an era without modern clinical trials methodology nor effective concomitant therapies, opinions regarding the use of [[chelation therapy]] for [[cardiovascular disease]] (CVD) tilted towards the negative. To be fair, from the 1970’s to 1990’s the preponderance of the scientific literature on chelation therapy for atherosclerosis consisted of case reports, case series, and small clinical trials with surrogate endpoints, poor-quality evidence from which to draw a conclusion of efficacy or harm.<ref name="pmid12519577">{{cite journal| author=Villarruz MV, Dans A, Tan F| title=Chelation therapy for atherosclerotic cardiovascular disease. | journal=Cochrane Database Syst Rev | year= 2002 | volume= | issue= 4 | pages= CD002785 | pmid=12519577 | doi=10.1002/14651858.CD002785 | pmc= | url=http://www.ncbi.nlm.nih.gov/entrez/eutils/elink.fcgi?dbfrom=pubmed&tool=sumsearch.org/cite&retmode=ref&cmd=prlinks&id=12519577 }} </ref><br />
<br />
For example, one extensive case series reported an association between EDTA chelation therapy and improvement of ischemic heart disease and peripheral artery disease.<ref name="pmid3144646">{{cite journal| author=Olszewer E, Carter JP| title=EDTA chelation therapy in chronic degenerative disease. | journal=Med Hypotheses | year= 1988 | volume= 27 | issue= 1 | pages= 41-9 | pmid=3144646 | doi= | pmc= | url=http://www.ncbi.nlm.nih.gov/entrez/eutils/elink.fcgi?dbfrom=pubmed&tool=sumsearch.org/cite&retmode=ref&cmd=prlinks&id=3144646 }} </ref> Another study demonstrated that EDTA supplemented with several B vitamins (vitamin B1, B2, B6 and B12) but not EDTA alone was effective in improving [[endothelium]]-dependent forearm blood flow.<ref name="pmid10561804">{{cite journal| author=Green DJ, O'Driscoll JG, Maiorana A, Scrimgeour NB, Weerasooriya R, Taylor RR| title=Effects of chelation with EDTA and vitamin B therapy on nitric oxide-related endothelial vasodilator function. | journal=Clin Exp Pharmacol Physiol | year= 1999 | volume= 26 | issue= 11 | pages= 853-6 | pmid=10561804 | doi= | pmc= | url=http://www.ncbi.nlm.nih.gov/entrez/eutils/elink.fcgi?dbfrom=pubmed&tool=sumsearch.org/cite&retmode=ref&cmd=prlinks&id=10561804 }} </ref> A systematic review of four randomized clinical trials on chelation therapy and [[peripheral artery occlusive disease]] reported no benefit associated with chelation therapy.<ref name="pmid9264515">{{cite journal| author=Ernst E| title=Chelation therapy for peripheral arterial occlusive disease: a systematic review. | journal=Circulation | year= 1997 | volume= 96 | issue= 3 | pages= 1031-3 | pmid=9264515 | doi= | pmc= | url=http://www.ncbi.nlm.nih.gov/entrez/eutils/elink.fcgi?dbfrom=pubmed&tool=sumsearch.org/cite&retmode=ref&cmd=prlinks&id=9264515 }} </ref> The studies, however, individually and in aggregate, were too small to exclude a small to moderate benefit of therapy. Moreover, followup was short and surrogate physiologic endpoints, such as walking distance, were used. A Cochrane systematic review on the role of chelation therapy to treat coronary heart disease in 2002 concluded that the data were insufficient to recommend for or against chelation.<ref name="pmid10874275">{{cite journal| author=Ernst E| title=Chelation therapy for coronary heart disease: An overview of all clinical investigations. | journal=Am Heart J | year= 2000 | volume= 140 | issue= 1 | pages= 139-41 | pmid=10874275 | doi=10.1067/mhj.2000.107548 | pmc= | url=http://www.ncbi.nlm.nih.gov/entrez/eutils/elink.fcgi?dbfrom=pubmed&tool=sumsearch.org/cite&retmode=ref&cmd=prlinks&id=10874275 }} </ref> <br />
<br />
The medical community concluded that the absence of high quality evidence of efficacy equated with evidence of absence of efficacy. Professional organizations recommended against chelation therapy.<ref name="pmid9205980">{{cite journal| author=Lewin MR| title=Chelation therapy for cardiovascular disease. Review and commentary. | journal=Tex Heart Inst J | year= 1997 | volume= 24 | issue= 2 | pages= 81-9 | pmid=9205980 | doi= | pmc=325409 | url=https://www.ncbi.nlm.nih.gov/entrez/eutils/elink.fcgi?dbfrom=pubmed&tool=sumsearch.org/cite&retmode=ref&cmd=prlinks&id=9205980 }} </ref> Interestingly, patients continued to seek, and practitioners to administer, chelation infusions for [[cardiovascular disease]] and other diagnoses.<br />
<br />
In light of the persistent controversy regarding the benefits of chelation therapy and the absence of any previous large clinical trial investigating its use in coronary artery disease, the National Center for Complementary and Alternative Medicine and the National Heart Lung and Blood Institute released a $30 million Request for Applications (RFA) to develop a definitive trial. In 2002, the RFA was awarded to Mount Sinai Medical Center in Miami Beach FL (G Lamas MD, Principal Investigator). The Trial to Assess Chelation Therapy (TACT), a randomized, double blind, placebo controlled 2x2 factorial trial, investigated the efficacy and safety of disodium EDTA based infusions and high-dose oral vitamins and minerals in 1708 stable post-myocardial infarction (MI) patients more than 50 years of age and with fairly normal kidney function ([[creatinine]] 2.0 mg/dL or less). The active treatment consisted of 40 infusions consisted of disodium [[EDTA]] combined with [[ascorbic acid]], B vitamins, and other components. The median age of patients was 65 years, and they were treated with evidence-based post-MI medicines. The primary endpoint of this trial was a composite of all-cause mortality, [[stroke]], [[MI]], coronary revascularization, and hospitalization for [[angina]].<ref name="pmid16585050">{{cite journal| author=Costa J, Borges M, David C, Vaz Carneiro A| title=Efficacy of lipid lowering drug treatment for diabetic and non-diabetic patients: meta-analysis of randomised controlled trials. | journal=BMJ | year= 2006 | volume= 332 | issue= 7550 | pages= 1115-24 | pmid=16585050 | doi=10.1136/bmj.38793.468449.AE | pmc=PMC1459619 | url=http://www.ncbi.nlm.nih.gov/entrez/eutils/elink.fcgi?dbfrom=pubmed&tool=sumsearch.org/cite&retmode=ref&cmd=prlinks&id=16585050 }} </ref><br />
<br />
A follow up period of 55 months revealed a statistically significant decrease in the primary endpoint (HR: 0.82; 95% CI: 0.69-0.99; p= 0.035). There was an absolute reduction in the 5-year Kaplan-Meier estimate, from 38% to 33%, resulting in a 5-year number needed to treat (NNT) of 18 patients to avoid one adverse cardiovascular outcome. This is comparable to the 5-year NNT for [[statins]] in post-[[MI]] patients (NNT=16 for the secondary prevention of a major coronary event).<ref name="pmid16585050">{{cite journal| author=Costa J, Borges M, David C, Vaz Carneiro A| title=Efficacy of lipid lowering drug treatment for diabetic and non-diabetic patients: meta-analysis of randomised controlled trials. | journal=BMJ | year= 2006 | volume= 332 | issue= 7550 | pages= 1115-24 | pmid=16585050 | doi=10.1136/bmj.38793.468449.AE | pmc=PMC1459619 | url=http://www.ncbi.nlm.nih.gov/entrez/eutils/elink.fcgi?dbfrom=pubmed&tool=sumsearch.org/cite&retmode=ref&cmd=prlinks&id=16585050 }} </ref> The point estimate for the risk of each of the components of the primary endpoint was <1, consistent with the aggregate result. The Investigators concluded that chelation should not yet be adopted for routine post-MI use in all patients, but the results of TACT should inform further studies to confirm or refute these unexpected results.<ref name="pmid23532240">{{cite journal| author=Lamas GA, Goertz C, Boineau R, Mark DB, Rozema T, Nahin RL et al.| title=Effect of disodium EDTA chelation regimen on cardiovascular events in patients with previous myocardial infarction: the TACT randomized trial. | journal=JAMA | year= 2013 | volume= 309 | issue= 12 | pages= 1241-50 | pmid=23532240 | doi=10.1001/jama.2013.2107 | pmc= | url=http://www.ncbi.nlm.nih.gov/entrez/eutils/elink.fcgi?dbfrom=pubmed&tool=sumsearch.org/cite&retmode=ref&cmd=prlinks&id=23532240 }} </ref><br />
<br />
TACT prespecified several subgroups for analysis and found a significant interaction between edetate disodium treatment and [[diabetes]] (p for interaction =0.0037). Among subjects enrolled in TACT, there were 633 diabetic patients, defined as patients with self-reported diabetes, taking medications for diabetes, or having a fasting blood glucose of at least 126 mg/dL at enrollment. The administration of chelation infusions among post-MI diabetic patients was associated with a marked reduction in the primary end point when compared with placebo. The primary end point occurred in 25% of diabetic patients who were administered chelation therapy compared to 38% in those who received placebo infusions (HR, 0.59; 95% CI, 0.44–0.79; P<0.001). The 5-year NNT to prevent one event was 6.5. In addition, chelation therapy was significantly associated with decreased all-cause mortality (43% reduction, p=0.011) and reinfarction (52% reduction, p=0.015). Again, the investigators concluded that these findings supported future research, but did not constitute sufficient evidence to indicate the routine use of chelation therapy for all post–myocardial infarction patients with diabetes, leaving open the clinician’s choice to use this novel therapy in occasional, or non-routine patients.<br />
<br />
These results catalyzed a wave of increased public and scientific interest in disodium EDTA treatment for patients with established coronary disease, particularly in diabetes, and hypotheses regarding potential mechanisms of benefit. As a capstone to the published analyses, the ACC/AHA Guidelines for Chronic Ischemic Heart Disease changed to reflect the TACT data and upgraded disodium EDTA treatment from a Class III indication to a Class IIB indication. While Class III therapeutics are considered not beneficial or useful, Class IIB treatments can be considered in some patients and require additional research to establish efficacy.<ref name="pmid25077860">{{cite journal| author=Fihn SD, Blankenship JC, Alexander KP, Bittl JA, Byrne JG, Fletcher BJ et al.| title=2014 ACC/AHA/AATS/PCNA/SCAI/STS focused update of the guideline for the diagnosis and management of patients with stable ischemic heart disease: a report of the American College of Cardiology/American Heart Association Task Force on Practice Guidelines, and the American Association for Thoracic Surgery, Preventive Cardiovascular Nurses Association, Society for Cardiovascular Angiography and Interventions, and Society of Thoracic Surgeons. | journal=J Am Coll Cardiol | year= 2014 | volume= 64 | issue= 18 | pages= 1929-49 | pmid=25077860 | doi=10.1016/j.jacc.2014.07.017 | pmc= | url=https://www.ncbi.nlm.nih.gov/entrez/eutils/elink.fcgi?dbfrom=pubmed&tool=sumsearch.org/cite&retmode=ref&cmd=prlinks&id=25077860 }} </ref> The change in the guidelines signaled a major shift in the perception of chelation therapy among the medical establishment. The TACT data led clinicians to reconsider chelation objectively, and the investigators and many other academic cardiologists called for TACT2, a new trial to test the results of TACT, to be funded by the [[NIH]].<br />
<br />
==Mechanism of Action==<br />
Edetate disodium binds to metals and forms soluble complexes facilitating their subsequent excretion in the urine.<ref name="pmid14000694">{{cite journal| author=WILDER LW, DE JODE LR, MILSTEIN SW, HOWARD JM| title=Mobilization of atherosclerotic plaque calcium with EDTA utilizing the isolation-perfusion principle. | journal=Surgery | year= 1962 | volume= 52 | issue= | pages= 793-5 | pmid=14000694 | doi= | pmc= | url=http://www.ncbi.nlm.nih.gov/entrez/eutils/elink.fcgi?dbfrom=pubmed&tool=sumsearch.org/cite&retmode=ref&cmd=prlinks&id=14000694 }} </ref> Hence, chelation therapy results in the elimination of stored toxic and essential metals. In an experiment performed on 24 patients, age 50 or older, and with a prior MI and a creatinine of 2.0 or less, patients had urine toxic metals measured at baseline, 1 day after an infusion of placebo, and 1 day after an infusion of the edetate disodium-based TACT solution. Placebo did not increase the excretion of toxic metals. Following an infusion of the edetate disodium-based TACT solution, lead excretion increased by nearly 3900%, and cadmium by nearly 700%. Other toxic metals whose excretion was enhanced by edetate disodium were aluminum (by ~250%), nickel (by ~150%), thallium (by ~60%), and gadolinium. A similar experiment performed earlier by Waters et al, reported urinary lead concentrations approximately 35 times greater than in pre-chelation urine.<ref name="pmid11794513">{{cite journal| author=Waters RS, Bryden NA, Patterson KY, Veillon C, Anderson RA| title=EDTA chelation effects on urinary losses of cadmium, calcium, chromium, cobalt, copper, lead, magnesium, and zinc. | journal=Biol Trace Elem Res | year= 2001 | volume= 83 | issue= 3 | pages= 207-21 | pmid=11794513 | doi=10.1385/BTER:83:3:207 | pmc= | url=https://www.ncbi.nlm.nih.gov/entrez/eutils/elink.fcgi?dbfrom=pubmed&tool=sumsearch.org/cite&retmode=ref&cmd=prlinks&id=11794513 }} </ref><br />
While enhanced lead and cadmium is interesting, the critical link to cardiovascular events is provided by epidemiological studies, which provide robust evidence linking toxic metals with cardiovascular disease.<ref name="pmid21421632">{{cite journal| author=Agarwal S, Zaman T, Tuzcu EM, Kapadia SR| title=Heavy metals and cardiovascular disease: results from the National Health and Nutrition Examination Survey (NHANES) 1999-2006. | journal=Angiology | year= 2011 | volume= 62 | issue= 5 | pages= 422-9 | pmid=21421632 | doi=10.1177/0003319710395562 | pmc= | url=http://www.ncbi.nlm.nih.gov/entrez/eutils/elink.fcgi?dbfrom=pubmed&tool=sumsearch.org/cite&retmode=ref&cmd=prlinks&id=21421632 }} </ref> This evidence is strongest for lead and cadmium.<ref name="pmid16982939">{{cite journal| author=Menke A, Muntner P, Batuman V, Silbergeld EK, Guallar E| title=Blood lead below 0.48 micromol/L (10 microg/dL) and mortality among US adults. | journal=Circulation | year= 2006 | volume= 114 | issue= 13 | pages= 1388-94 | pmid=16982939 | doi=10.1161/CIRCULATIONAHA.106.628321 | pmc= | url=http://www.ncbi.nlm.nih.gov/entrez/eutils/elink.fcgi?dbfrom=pubmed&tool=sumsearch.org/cite&retmode=ref&cmd=prlinks&id=16982939 }} </ref><ref name="pmid15184277">{{cite journal| author=Navas-Acien A, Selvin E, Sharrett AR, Calderon-Aranda E, Silbergeld E, Guallar E| title=Lead, cadmium, smoking, and increased risk of peripheral arterial disease. | journal=Circulation | year= 2004 | volume= 109 | issue= 25 | pages= 3196-201 | pmid=15184277 | doi=10.1161/01.CIR.0000130848.18636.B2 | pmc= | url=http://www.ncbi.nlm.nih.gov/entrez/eutils/elink.fcgi?dbfrom=pubmed&tool=sumsearch.org/cite&retmode=ref&cmd=prlinks&id=15184277 }} </ref><ref name="pmid23514838">{{cite journal| author=Tellez-Plaza M, Guallar E, Howard BV, Umans JG, Francesconi KA, Goessler W et al.| title=Cadmium exposure and incident cardiovascular disease. | journal=Epidemiology | year= 2013 | volume= 24 | issue= 3 | pages= 421-9 | pmid=23514838 | doi=10.1097/EDE.0b013e31828b0631 | pmc= | url=http://www.ncbi.nlm.nih.gov/entrez/eutils/elink.fcgi?dbfrom=pubmed&tool=sumsearch.org/cite&retmode=ref&cmd=prlinks&id=23514838 }} </ref> Elevated blood concentration of lead is associated with increased all-cause mortality [HR 1.25 (95% CI 1.04 to 1.51) for the highest versus lowest tertile of blood lead, P trend across the tertiles=0.002) and cardiovascular mortality [HR 1.55 (95% CI 1.08 to 2.24) for the highest versus lowest tertile, P trend <0.003] ((Menke, Muntner, Batuman, Silbergeld, & Guallar, 2006)). Also, cardiovascular mortality is greater among subjects with elevated cadmium concentrations in the blood and urine [HR 1.69 (95% CI: 1.03, 2.77) and 1.74 (95% CI: 1.07, 2.83) for the 80th and 20th percentiles of blood and urine cadmium, respectively] (cadmium exposure and all cause cardiovascular mortality, Navas-Acien, Tellez-Plaza). <br />
Heavy metals may play a role in the development of [[cardiovascular disease]] through a number of different mechanisms (Navas Nature) (Vaziri Khan Interplay of ROS). Heavy metals include transition metals such as [[cadmium]], [[mercury]], [[manganese]], [[chromium]], [[cobalt]], [[nickel]], [[iron]], and [[copper]], metalloids such as antimony and arsenic, and post- transition metals such as thallium and lead. These metals all have unique toxicities, as well as toxicities that are common to all of them. Heavy metals in the endothelium promote oxygen free radical formation, resulting in increased oxidative stress, inflammation, and tissue damage. Lead and cadmium may interfere with calcium signaling channels. Transition metals promote modifications of low-density lipoprotein by endothelial cells through lipid peroxidation and degradation of low-density lipoprotein phospholipids.<ref name="pmid6587396">{{cite journal| author=Steinbrecher UP, Parthasarathy S, Leake DS, Witztum JL, Steinberg D| title=Modification of low density lipoprotein by endothelial cells involves lipid peroxidation and degradation of low density lipoprotein phospholipids. | journal=Proc Natl Acad Sci U S A | year= 1984 | volume= 81 | issue= 12 | pages= 3883-7 | pmid=6587396 | doi= | pmc=345326 | url=https://www.ncbi.nlm.nih.gov/entrez/eutils/elink.fcgi?dbfrom=pubmed&tool=sumsearch.org/cite&retmode=ref&cmd=prlinks&id=6587396 }} </ref><ref name="pmid6501577">{{cite journal| author=Heinecke JW, Rosen H, Chait A| title=Iron and copper promote modification of low density lipoprotein by human arterial smooth muscle cells in culture. | journal=J Clin Invest | year= 1984 | volume= 74 | issue= 5 | pages= 1890-4 | pmid=6501577 | doi=10.1172/JCI111609 | pmc=425370 | url=https://www.ncbi.nlm.nih.gov/entrez/eutils/elink.fcgi?dbfrom=pubmed&tool=sumsearch.org/cite&retmode=ref&cmd=prlinks&id=6501577 }} </ref><ref name="pmid8847477">{{cite journal| author=Morgan J, Leake DS| title=Oxidation of low density lipoprotein by iron or copper at acidic pH. | journal=J Lipid Res | year= 1995 | volume= 36 | issue= 12 | pages= 2504-12 | pmid=8847477 | doi= | pmc= | url=https://www.ncbi.nlm.nih.gov/entrez/eutils/elink.fcgi?dbfrom=pubmed&tool=sumsearch.org/cite&retmode=ref&cmd=prlinks&id=8847477 }} </ref> Exposure to non-transition metals, such as lead, has also been associated with impaired nitric oxide signaling and availability,<ref name="pmid15894814">{{cite journal| author=Dursun N, Arifoglu C, Süer C, Keskinol L| title=Blood pressure relationship to nitric oxide, lipid peroxidation, renal function, and renal blood flow in rats exposed to low lead levels. | journal=Biol Trace Elem Res | year= 2005 | volume= 104 | issue= 2 | pages= 141-9 | pmid=15894814 | doi=10.1385/BTER:104:2:141 | pmc= | url=https://www.ncbi.nlm.nih.gov/entrez/eutils/elink.fcgi?dbfrom=pubmed&tool=sumsearch.org/cite&retmode=ref&cmd=prlinks&id=15894814 }} </ref> endothelial cell dysfunction,<ref name="pmid7710289">{{cite journal| author=Kaji T, Suzuki M, Yamamoto C, Mishima A, Sakamoto M, Kozuka H| title=Severe damage of cultured vascular endothelial cell monolayer after simultaneous exposure to cadmium and lead. | journal=Arch Environ Contam Toxicol | year= 1995 | volume= 28 | issue= 2 | pages= 168-72 | pmid=7710289 | doi= | pmc= | url=https://www.ncbi.nlm.nih.gov/entrez/eutils/elink.fcgi?dbfrom=pubmed&tool=sumsearch.org/cite&retmode=ref&cmd=prlinks&id=7710289 }} </ref> and hypertension.<ref name="pmid18567711">{{cite journal| author=Vaziri ND| title=Mechanisms of lead-induced hypertension and cardiovascular disease. | journal=Am J Physiol Heart Circ Physiol | year= 2008 | volume= 295 | issue= 2 | pages= H454-65 | pmid=18567711 | doi=10.1152/ajpheart.00158.2008 | pmc=2519216 | url=https://www.ncbi.nlm.nih.gov/entrez/eutils/elink.fcgi?dbfrom=pubmed&tool=sumsearch.org/cite&retmode=ref&cmd=prlinks&id=18567711 }} </ref> [[Heavy metal]] exposure is also associated with genetic and [[epigenetic]] manifestations. [[Cadmium]] promotes atherosclerosis and endothelial dysfunction through multiple [[genetic]] changes.<ref name="pmid19556524">{{cite journal| author=Messner B, Knoflach M, Seubert A, Ritsch A, Pfaller K, Henderson B et al.| title=Cadmium is a novel and independent risk factor for early atherosclerosis mechanisms and in vivo relevance. | journal=Arterioscler Thromb Vasc Biol | year= 2009 | volume= 29 | issue= 9 | pages= 1392-8 | pmid=19556524 | doi=10.1161/ATVBAHA.109.190082 | pmc= | url=https://www.ncbi.nlm.nih.gov/entrez/eutils/elink.fcgi?dbfrom=pubmed&tool=sumsearch.org/cite&retmode=ref&cmd=prlinks&id=19556524 }} </ref> One of the mechanisms involves [[DNA]] strand breaks and damage with subsequent apoptosis in [[endothelial cell]]s.<ref name="pmid19556524">{{cite journal| author=Messner B, Knoflach M, Seubert A, Ritsch A, Pfaller K, Henderson B et al.| title=Cadmium is a novel and independent risk factor for early atherosclerosis mechanisms and in vivo relevance. | journal=Arterioscler Thromb Vasc Biol | year= 2009 | volume= 29 | issue= 9 | pages= 1392-8 | pmid=19556524 | doi=10.1161/ATVBAHA.109.190082 | pmc= | url=https://www.ncbi.nlm.nih.gov/entrez/eutils/elink.fcgi?dbfrom=pubmed&tool=sumsearch.org/cite&retmode=ref&cmd=prlinks&id=19556524 }} </ref> Also, maternal [[lead]] exposure during pregnancy may be associated with epigenetic consequences in grandchildren through alteration of [[DNA methylation]] early in life.<ref name="pmid26417717">{{cite journal| author=Sen A, Heredia N, Senut MC, Land S, Hollocher K, Lu X et al.| title=Multigenerational epigenetic inheritance in humans: DNA methylation changes associated with maternal exposure to lead can be transmitted to the grandchildren. | journal=Sci Rep | year= 2015 | volume= 5 | issue= | pages= 14466 | pmid=26417717 | doi=10.1038/srep14466 | pmc=4586440 | url=https://www.ncbi.nlm.nih.gov/entrez/eutils/elink.fcgi?dbfrom=pubmed&tool=sumsearch.org/cite&retmode=ref&cmd=prlinks&id=26417717 }} </ref><br />
<br />
Current mechanistic understanding, albeit rudimentary, supports the concept that the cardiovascular benefits of [[chelation therapy]] may result from enhanced excretion of [[heavy metals]], and subsequent reduction in processes listed above. Additionally, in patients with [[diabetes]], a reduction in the metal-catalyzed formation of [[reactive oxygen species]], formation of advanced glycation end-products, and lipid [[peroxidation]] has been postulated.<ref name="pmid10874253">{{cite journal| author=Lamas GA, Ackermann A| title=Clinical evaluation of chelation therapy: is there any wheat amidst the chaff? | journal=Am Heart J | year= 2000 | volume= 140 | issue= 1 | pages= 4-5 | pmid=10874253 | doi=10.1067/mhj.2000.107549 | pmc= | url=http://www.ncbi.nlm.nih.gov/entrez/eutils/elink.fcgi?dbfrom=pubmed&tool=sumsearch.org/cite&retmode=ref&cmd=prlinks&id=10874253 }} </ref> Metal detoxification in the context of diabetes possibly decreases [[inflammation]] and [[oxidative stress]] that characterize atherosclerosis.<ref>Escolar E, Lamas G, Mark D et al(2013) "The Effect of an EDTA-based Chelation Regimen on Patients With Diabetes Mellitus and Prior Myocardial Infarction in the Trial to Assess Chelation Therapy (TACT)". Circulation. 2013</ref> Recent research, including chelation-activity assays, indicates that many common [[diabetes]] drugs, such as [[metformin]] and aldose reductase inhibitors, could possibly have some chelating properties (Frizzell, Baynes) (Nagai Murray Chelation: a fundamental mechanism of action of AGE inhibitors, Frizell Baynes Chelation therapy for management of diabetic complications)(pubmed ID: 22492524).<br />
The TACT chelation infusion, however, did not contain edetate disodium alone. The standard chelation infusion formula used in TACT was formulated to be identical with the most prevalent infusion in use. This formulation had developed organically over decades and had been modified by clinical practitioners to have additives such as [[ascorbic acid]], B-vitamins and [[magnesium]], thought to have a protective effect on [[endothelial cells]],<ref>Rozema, Theodore C. "The protocol for the safe and effective administration of EDTA and other chelating agents for vascular disease, degenerative disease, and metal toxicity." Journal of Advancement in Medicine 10.1 (1997): 5-100.</ref> making the results of clinical application more difficult to understand, and emphasizing the need for mechanistic work.<br />
<br />
==Future Studies==<br />
TACT was a unique study with an unexpected result that could have vast public health implications. In order to consider its broad applicability, the medical and scientific community require the results reproduced. TACT2, scheduled to begin in October 2016 (press release), is a replicative study in post-MI diabetic patients. If the TACT2 results confirm the results of TACT, then chelation is poised to become the next major development in the treatment of vascular complications of diabetes and vascular disease. TACT2 is currently recruiting sites, and interested investigators should visit www.TACT2.org for additional information.<br />
<br />
==Side Effects==<br />
Shown below is a list of the labelled toxicities of EDTA-based chelation therapy. However, TACT delivered 55,222 infusions of EDTA or placebo, and found no differences between groups in adverse events, serious or otherwise.<br />
* [[Arrhythmias]]<br />
* [[Autoimmune diseases]]<br />
* [[Bone marrow]]<br />
* [[Convulsions]]<br />
* [[Depression]]<br />
* [[Fever]]<br />
* [[Heart failure]]<br />
* [[Hypocalcemia]]<br />
* [[Hypoglycemia]]<br />
* [[Hypotension]]<br />
* [[Bleeding time|Prolonged bleeding time]]<br />
* [[Renal failure]]<br />
* [[Respiratory arrest]]<br />
* [[Tetany]]<br />
* [[Trace metal|Trace metal deficiency]]<br />
* [[Vitamin deficiency]]<ref name="pmid10874275">{{cite journal| author=Ernst E| title=Chelation therapy for coronary heart disease: An overview of all clinical investigations. | journal=Am Heart J | year= 2000 | volume= 140 | issue= 1 | pages= 139-41 | pmid=10874275 | doi=10.1067/mhj.2000.107548 | pmc= | url=http://www.ncbi.nlm.nih.gov/entrez/eutils/elink.fcgi?dbfrom=pubmed&tool=sumsearch.org/cite&retmode=ref&cmd=prlinks&id=10874275 }} </ref><ref name="pmid23532240">{{cite journal| author=Lamas GA, Goertz C, Boineau R, Mark DB, Rozema T, Nahin RL et al.| title=Effect of disodium EDTA chelation regimen on cardiovascular events in patients with previous myocardial infarction: the TACT randomized trial. | journal=JAMA | year= 2013 | volume= 309 | issue= 12 | pages= 1241-50 | pmid=23532240 | doi=10.1001/jama.2013.2107 | pmc= | url=http://www.ncbi.nlm.nih.gov/entrez/eutils/elink.fcgi?dbfrom=pubmed&tool=sumsearch.org/cite&retmode=ref&cmd=prlinks&id=23532240 }} </ref><br />
<br />
==Landmark Trials==<br />
[[TACT]] <br><br />
TACT 2 [http://www.TACT2.org] (link to press release [http://www.prnewswire.com/news-releases/tact2-clinical-trial-receives-national-institutes-of-health-funding-300334174.html])<br />
<br />
==References==<br />
{{Reflist|2}}<br />
<br />
[[Category:Cardiology]]<br />
[[Category:Diabetes]]<br />
[[Category:Up-To-Date]]<br />
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{{WikiDoc Sources}}</div>Rim Halabyhttps://www.wikidoc.org/index.php?title=Chelation_therapy_for_cardiovascular_disease&diff=1274682Chelation therapy for cardiovascular disease2016-12-07T00:09:14Z<p>Rim Halaby: /* Mechanism of Action */</p>
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<div>__NOTOC__<br />
'''Editor-In-Chief:''' Gervasio Lamas, M.D., C. Michael Gibson, M.S., M.D.; {{AE}} {{Rim}}, Ian Ergui, B.Sc.<br />
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'''[[Chelation therapy|To read more about chelation therapy click here.]]'''<br><br />
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{{SK}} Chelation therapy, EDTA, post-myocardial infarction, diabetes<br />
<br />
==Overview==<br />
[[Chelation]] is a process by which an organic molecule with a negatively charged “pocket” complexes with a metal ion of opposite charge, inactivates it, and then permits its physiological mobilization and excretion, usually by a renal route. [[Chelation therapy]], which involves multiple administrations of a chelating agent, helps eliminate stored toxic metal ions from the body (Waters paper, Arenas abstract).<ref name="pmid11794513">{{cite journal| author=Waters RS, Bryden NA, Patterson KY, Veillon C, Anderson RA| title=EDTA chelation effects on urinary losses of cadmium, calcium, chromium, cobalt, copper, lead, magnesium, and zinc. | journal=Biol Trace Elem Res | year= 2001 | volume= 83 | issue= 3 | pages= 207-21 | pmid=11794513 | doi=10.1385/BTER:83:3:207 | pmc= | url=https://www.ncbi.nlm.nih.gov/entrez/eutils/elink.fcgi?dbfrom=pubmed&tool=sumsearch.org/cite&retmode=ref&cmd=prlinks&id=11794513 }} </ref><ref name="arenas">Arenas I.A., Navas-Acien A., Lamas G.A.; Enhanced vasculotoxic metal excretionin post-MI patients after edetate disodium therapy (abstr). J Am Coll Cardiol. 2016;67:A2125</ref> Common chelators include [[penicillamine]], which binds copper and can be used to treat [[Wilson’s disease]], [[deferoxamine]], which binds iron and is used in the treatment of [[thalassemia]] and iron overload, succimer, also used in the treatment of lead poisoning, and the edetates, non-specific chelators of metals and other ions with valences of +2 to +6. Chelation therapy is, in many cases, guideline mandated, such as in children with elevated blood lead levels,<ref name="CDC">CDC. Low Level Lead Exposure Harms Children: A Renewed Call for Primary Prevention. Atlanta, GA:Advisory Committee on Childhood Lead Poisoning Prevention, U.S. Centers for Disease Control and Prevention (4 Jan 2012). Available: [http://www.cdc.gov/nceh/lead/acclpp/final_document_010412.pdf]</ref> patients with iron overload and dyserythropoietic syndromes or chronic hemolytic anemia,<ref name="pmid21452290">{{cite journal| author=Bacon BR, Adams PC, Kowdley KV, Powell LW, Tavill AS, American Association for the Study of Liver Diseases| title=Diagnosis and management of hemochromatosis: 2011 practice guideline by the American Association for the Study of Liver Diseases. | journal=Hepatology | year= 2011 | volume= 54 | issue= 1 | pages= 328-43 | pmid=21452290 | doi=10.1002/hep.24330 | pmc=3149125 | url=https://www.ncbi.nlm.nih.gov/entrez/eutils/elink.fcgi?dbfrom=pubmed&tool=sumsearch.org/cite&retmode=ref&cmd=prlinks&id=21452290 }} </ref> or [[sickle cell disease]] and transfusion acquired iron-overload,<ref name="NHLBI">NHLBI. Transfusion in Sickle Cell Disease: A Systematic Review of Benefits, Complications, and Management of Complications. Prepared for the National Heart, Lung, and Blood Institute and by the Knowledge and Evaluation Research Unit, Mayo Clinic Rochester (2012)</ref> to name a few instances.<br />
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[[Ethylene diamine tetraacetic acid]] ([[EDTA]], edetate) and its salts (most commonly disodium or calcium disodium), commonly used chelating agents patented in 1938, bind to and permit the urinary excretion of divalent cations such as calcium, and metals such as [[lead]], [[cadmium]], [[nickel]], [[cobalt]], [[iron]], [[aluminum]], and others. The initial medical use for [[EDTA]] began after World War II for the treatment of [[lead]]-exposed naval workers. In addition to its use for the treatment of metal poisoning, since the 1950s chelation therapy has been considered an alternative or add-on therapy for the prevention and treatment of [[atherosclerotic disease]]. The use of edetate disodium (Na2EDTA) has been most prominent in the alternative medicine treatment of atherosclerosis primarily because of the still-unproven hypothesis that the [[hypocalcemia]] it induces might lead to the decalcification of atherosclerotic lesions. In fact, the most current research suggests that the probable mechanism of benefit centers on enhancement of toxic metal excretion.<br />
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==Chelation Therapy and CVD==<br />
The use of chelation therapy as a treatment for [[atherosclerotic disease]] dates back to the 1950’s when Clarke et al investigated the use of EDTA for the treatment of angina pectoris and reported improvement in 19 of 20 patients.<ref name="pmid13372537">{{cite journal| author=CLARKE CN, CLARKE NE, MOSHER RE| title=Treatment of angina pectoris with disodium ethylene diamine tetraacetic acid. | journal=Am J Med Sci | year= 1956 | volume= 232 | issue= 6 | pages= 654-66 | pmid=13372537 | doi= | pmc= | url=http://www.ncbi.nlm.nih.gov/entrez/eutils/elink.fcgi?dbfrom=pubmed&tool=sumsearch.org/cite&retmode=ref&cmd=prlinks&id=13372537 }} </ref> Later studies by Kitchell were less positive,<ref name="pmid13756462">{{cite journal| author=KITCHELL JR, MELTZER LE, SEVEN MJ| title=Potential uses of chelation methods in the treatment of cardiovascular diseases. | journal=Prog Cardiovasc Dis | year= 1961 | volume= 3 | issue= | pages= 338-49 | pmid=13756462 | doi= | pmc= | url=https://www.ncbi.nlm.nih.gov/entrez/eutils/elink.fcgi?dbfrom=pubmed&tool=sumsearch.org/cite&retmode=ref&cmd=prlinks&id=13756462 }} </ref><ref name="pmid14033183">{{cite journal| author=KITCHELL JR, PALMON F, AYTAN N, MELTZER LE| title=The treatment of coronary artery disease with disodium EDTA. A reappraisal. | journal=Am J Cardiol | year= 1963 | volume= 11 | issue= | pages= 501-6 | pmid=14033183 | doi= | pmc= | url=https://www.ncbi.nlm.nih.gov/entrez/eutils/elink.fcgi?dbfrom=pubmed&tool=sumsearch.org/cite&retmode=ref&cmd=prlinks&id=14033183 }} </ref> and in an era without modern clinical trials methodology nor effective concomitant therapies, opinions regarding the use of [[chelation therapy]] for [[cardiovascular disease]] (CVD) tilted towards the negative. To be fair, from the 1970’s to 1990’s the preponderance of the scientific literature on chelation therapy for atherosclerosis consisted of case reports, case series, and small clinical trials with surrogate endpoints, poor-quality evidence from which to draw a conclusion of efficacy or harm.<ref name="pmid12519577">{{cite journal| author=Villarruz MV, Dans A, Tan F| title=Chelation therapy for atherosclerotic cardiovascular disease. | journal=Cochrane Database Syst Rev | year= 2002 | volume= | issue= 4 | pages= CD002785 | pmid=12519577 | doi=10.1002/14651858.CD002785 | pmc= | url=http://www.ncbi.nlm.nih.gov/entrez/eutils/elink.fcgi?dbfrom=pubmed&tool=sumsearch.org/cite&retmode=ref&cmd=prlinks&id=12519577 }} </ref><br />
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For example, one extensive case series reported an association between EDTA chelation therapy and improvement of ischemic heart disease and peripheral artery disease.<ref name="pmid3144646">{{cite journal| author=Olszewer E, Carter JP| title=EDTA chelation therapy in chronic degenerative disease. | journal=Med Hypotheses | year= 1988 | volume= 27 | issue= 1 | pages= 41-9 | pmid=3144646 | doi= | pmc= | url=http://www.ncbi.nlm.nih.gov/entrez/eutils/elink.fcgi?dbfrom=pubmed&tool=sumsearch.org/cite&retmode=ref&cmd=prlinks&id=3144646 }} </ref> Another study demonstrated that EDTA supplemented with several B vitamins (vitamin B1, B2, B6 and B12) but not EDTA alone was effective in improving [[endothelium]]-dependent forearm blood flow.<ref name="pmid10561804">{{cite journal| author=Green DJ, O'Driscoll JG, Maiorana A, Scrimgeour NB, Weerasooriya R, Taylor RR| title=Effects of chelation with EDTA and vitamin B therapy on nitric oxide-related endothelial vasodilator function. | journal=Clin Exp Pharmacol Physiol | year= 1999 | volume= 26 | issue= 11 | pages= 853-6 | pmid=10561804 | doi= | pmc= | url=http://www.ncbi.nlm.nih.gov/entrez/eutils/elink.fcgi?dbfrom=pubmed&tool=sumsearch.org/cite&retmode=ref&cmd=prlinks&id=10561804 }} </ref> A systematic review of four randomized clinical trials on chelation therapy and [[peripheral artery occlusive disease]] reported no benefit associated with chelation therapy.<ref name="pmid9264515">{{cite journal| author=Ernst E| title=Chelation therapy for peripheral arterial occlusive disease: a systematic review. | journal=Circulation | year= 1997 | volume= 96 | issue= 3 | pages= 1031-3 | pmid=9264515 | doi= | pmc= | url=http://www.ncbi.nlm.nih.gov/entrez/eutils/elink.fcgi?dbfrom=pubmed&tool=sumsearch.org/cite&retmode=ref&cmd=prlinks&id=9264515 }} </ref> The studies, however, individually and in aggregate, were too small to exclude a small to moderate benefit of therapy. Moreover, followup was short and surrogate physiologic endpoints, such as walking distance, were used. A Cochrane systematic review on the role of chelation therapy to treat coronary heart disease in 2002 concluded that the data were insufficient to recommend for or against chelation.<ref name="pmid10874275">{{cite journal| author=Ernst E| title=Chelation therapy for coronary heart disease: An overview of all clinical investigations. | journal=Am Heart J | year= 2000 | volume= 140 | issue= 1 | pages= 139-41 | pmid=10874275 | doi=10.1067/mhj.2000.107548 | pmc= | url=http://www.ncbi.nlm.nih.gov/entrez/eutils/elink.fcgi?dbfrom=pubmed&tool=sumsearch.org/cite&retmode=ref&cmd=prlinks&id=10874275 }} </ref> <br />
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The medical community concluded that the absence of high quality evidence of efficacy equated with evidence of absence of efficacy. Professional organizations recommended against chelation therapy.<ref name="pmid9205980">{{cite journal| author=Lewin MR| title=Chelation therapy for cardiovascular disease. Review and commentary. | journal=Tex Heart Inst J | year= 1997 | volume= 24 | issue= 2 | pages= 81-9 | pmid=9205980 | doi= | pmc=325409 | url=https://www.ncbi.nlm.nih.gov/entrez/eutils/elink.fcgi?dbfrom=pubmed&tool=sumsearch.org/cite&retmode=ref&cmd=prlinks&id=9205980 }} </ref> Interestingly, patients continued to seek, and practitioners to administer, chelation infusions for [[cardiovascular disease]] and other diagnoses.<br />
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In light of the persistent controversy regarding the benefits of chelation therapy and the absence of any previous large clinical trial investigating its use in coronary artery disease, the National Center for Complementary and Alternative Medicine and the National Heart Lung and Blood Institute released a $30 million Request for Applications (RFA) to develop a definitive trial. In 2002, the RFA was awarded to Mount Sinai Medical Center in Miami Beach FL (G Lamas MD, Principal Investigator). The Trial to Assess Chelation Therapy (TACT), a randomized, double blind, placebo controlled 2x2 factorial trial, investigated the efficacy and safety of disodium EDTA based infusions and high-dose oral vitamins and minerals in 1708 stable post-myocardial infarction (MI) patients more than 50 years of age and with fairly normal kidney function ([[creatinine]] 2.0 mg/dL or less). The active treatment consisted of 40 infusions consisted of disodium [[EDTA]] combined with [[ascorbic acid]], B vitamins, and other components. The median age of patients was 65 years, and they were treated with evidence-based post-MI medicines. The primary endpoint of this trial was a composite of all-cause mortality, [[stroke]], [[MI]], coronary revascularization, and hospitalization for [[angina]].<ref name="pmid16585050">{{cite journal| author=Costa J, Borges M, David C, Vaz Carneiro A| title=Efficacy of lipid lowering drug treatment for diabetic and non-diabetic patients: meta-analysis of randomised controlled trials. | journal=BMJ | year= 2006 | volume= 332 | issue= 7550 | pages= 1115-24 | pmid=16585050 | doi=10.1136/bmj.38793.468449.AE | pmc=PMC1459619 | url=http://www.ncbi.nlm.nih.gov/entrez/eutils/elink.fcgi?dbfrom=pubmed&tool=sumsearch.org/cite&retmode=ref&cmd=prlinks&id=16585050 }} </ref><br />
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A follow up period of 55 months revealed a statistically significant decrease in the primary endpoint (HR: 0.82; 95% CI: 0.69-0.99; p= 0.035). There was an absolute reduction in the 5-year Kaplan-Meier estimate, from 38% to 33%, resulting in a 5-year number needed to treat (NNT) of 18 patients to avoid one adverse cardiovascular outcome. This is comparable to the 5-year NNT for [[statins]] in post-[[MI]] patients (NNT=16 for the secondary prevention of a major coronary event).<ref name="pmid16585050">{{cite journal| author=Costa J, Borges M, David C, Vaz Carneiro A| title=Efficacy of lipid lowering drug treatment for diabetic and non-diabetic patients: meta-analysis of randomised controlled trials. | journal=BMJ | year= 2006 | volume= 332 | issue= 7550 | pages= 1115-24 | pmid=16585050 | doi=10.1136/bmj.38793.468449.AE | pmc=PMC1459619 | url=http://www.ncbi.nlm.nih.gov/entrez/eutils/elink.fcgi?dbfrom=pubmed&tool=sumsearch.org/cite&retmode=ref&cmd=prlinks&id=16585050 }} </ref> The point estimate for the risk of each of the components of the primary endpoint was <1, consistent with the aggregate result. The Investigators concluded that chelation should not yet be adopted for routine post-MI use in all patients, but the results of TACT should inform further studies to confirm or refute these unexpected results.<ref name="pmid23532240">{{cite journal| author=Lamas GA, Goertz C, Boineau R, Mark DB, Rozema T, Nahin RL et al.| title=Effect of disodium EDTA chelation regimen on cardiovascular events in patients with previous myocardial infarction: the TACT randomized trial. | journal=JAMA | year= 2013 | volume= 309 | issue= 12 | pages= 1241-50 | pmid=23532240 | doi=10.1001/jama.2013.2107 | pmc= | url=http://www.ncbi.nlm.nih.gov/entrez/eutils/elink.fcgi?dbfrom=pubmed&tool=sumsearch.org/cite&retmode=ref&cmd=prlinks&id=23532240 }} </ref><br />
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TACT prespecified several subgroups for analysis and found a significant interaction between edetate disodium treatment and [[diabetes]] (p for interaction =0.0037). Among subjects enrolled in TACT, there were 633 diabetic patients, defined as patients with self-reported diabetes, taking medications for diabetes, or having a fasting blood glucose of at least 126 mg/dL at enrollment. The administration of chelation infusions among post-MI diabetic patients was associated with a marked reduction in the primary end point when compared with placebo. The primary end point occurred in 25% of diabetic patients who were administered chelation therapy compared to 38% in those who received placebo infusions (HR, 0.59; 95% CI, 0.44–0.79; P<0.001). The 5-year NNT to prevent one event was 6.5. In addition, chelation therapy was significantly associated with decreased all-cause mortality (43% reduction, p=0.011) and reinfarction (52% reduction, p=0.015). Again, the investigators concluded that these findings supported future research, but did not constitute sufficient evidence to indicate the routine use of chelation therapy for all post–myocardial infarction patients with diabetes, leaving open the clinician’s choice to use this novel therapy in occasional, or non-routine patients.<br />
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These results catalyzed a wave of increased public and scientific interest in disodium EDTA treatment for patients with established coronary disease, particularly in diabetes, and hypotheses regarding potential mechanisms of benefit. As a capstone to the published analyses, the ACC/AHA Guidelines for Chronic Ischemic Heart Disease changed to reflect the TACT data and upgraded disodium EDTA treatment from a Class III indication to a Class IIB indication. While Class III therapeutics are considered not beneficial or useful, Class IIB treatments can be considered in some patients and require additional research to establish efficacy.<ref name="pmid25077860">{{cite journal| author=Fihn SD, Blankenship JC, Alexander KP, Bittl JA, Byrne JG, Fletcher BJ et al.| title=2014 ACC/AHA/AATS/PCNA/SCAI/STS focused update of the guideline for the diagnosis and management of patients with stable ischemic heart disease: a report of the American College of Cardiology/American Heart Association Task Force on Practice Guidelines, and the American Association for Thoracic Surgery, Preventive Cardiovascular Nurses Association, Society for Cardiovascular Angiography and Interventions, and Society of Thoracic Surgeons. | journal=J Am Coll Cardiol | year= 2014 | volume= 64 | issue= 18 | pages= 1929-49 | pmid=25077860 | doi=10.1016/j.jacc.2014.07.017 | pmc= | url=https://www.ncbi.nlm.nih.gov/entrez/eutils/elink.fcgi?dbfrom=pubmed&tool=sumsearch.org/cite&retmode=ref&cmd=prlinks&id=25077860 }} </ref> The change in the guidelines signaled a major shift in the perception of chelation therapy among the medical establishment. The TACT data led clinicians to reconsider chelation objectively, and the investigators and many other academic cardiologists called for TACT2, a new trial to test the results of TACT, to be funded by the [[NIH]].<br />
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==Mechanism of Action==<br />
Edetate disodium binds to metals and forms soluble complexes facilitating their subsequent excretion in the urine.<ref name="pmid14000694">{{cite journal| author=WILDER LW, DE JODE LR, MILSTEIN SW, HOWARD JM| title=Mobilization of atherosclerotic plaque calcium with EDTA utilizing the isolation-perfusion principle. | journal=Surgery | year= 1962 | volume= 52 | issue= | pages= 793-5 | pmid=14000694 | doi= | pmc= | url=http://www.ncbi.nlm.nih.gov/entrez/eutils/elink.fcgi?dbfrom=pubmed&tool=sumsearch.org/cite&retmode=ref&cmd=prlinks&id=14000694 }} </ref> Hence, chelation therapy results in the elimination of stored toxic and essential metals. In an experiment performed on 24 patients, age 50 or older, and with a prior MI and a creatinine of 2.0 or less, patients had urine toxic metals measured at baseline, 1 day after an infusion of placebo, and 1 day after an infusion of the edetate disodium-based TACT solution. Placebo did not increase the excretion of toxic metals. Following an infusion of the edetate disodium-based TACT solution, lead excretion increased by nearly 3900%, and cadmium by nearly 700%. Other toxic metals whose excretion was enhanced by edetate disodium were aluminum (by ~250%), nickel (by ~150%), thallium (by ~60%), and gadolinium. A similar experiment performed earlierby Waters et al, reported urinary lead concentrations approximately 35 times greater than in pre-chelation urine (Waters et al).<br />
While enhanced lead and cadmium is interesting, the critical link to cardiovascular events is provided by epidemiological studies, which provide robust evidence linking toxic metals with cardiovascular disease.<ref name="pmid21421632">{{cite journal| author=Agarwal S, Zaman T, Tuzcu EM, Kapadia SR| title=Heavy metals and cardiovascular disease: results from the National Health and Nutrition Examination Survey (NHANES) 1999-2006. | journal=Angiology | year= 2011 | volume= 62 | issue= 5 | pages= 422-9 | pmid=21421632 | doi=10.1177/0003319710395562 | pmc= | url=http://www.ncbi.nlm.nih.gov/entrez/eutils/elink.fcgi?dbfrom=pubmed&tool=sumsearch.org/cite&retmode=ref&cmd=prlinks&id=21421632 }} </ref> This evidence is strongest for lead and cadmium.<ref name="pmid16982939">{{cite journal| author=Menke A, Muntner P, Batuman V, Silbergeld EK, Guallar E| title=Blood lead below 0.48 micromol/L (10 microg/dL) and mortality among US adults. | journal=Circulation | year= 2006 | volume= 114 | issue= 13 | pages= 1388-94 | pmid=16982939 | doi=10.1161/CIRCULATIONAHA.106.628321 | pmc= | url=http://www.ncbi.nlm.nih.gov/entrez/eutils/elink.fcgi?dbfrom=pubmed&tool=sumsearch.org/cite&retmode=ref&cmd=prlinks&id=16982939 }} </ref><ref name="pmid15184277">{{cite journal| author=Navas-Acien A, Selvin E, Sharrett AR, Calderon-Aranda E, Silbergeld E, Guallar E| title=Lead, cadmium, smoking, and increased risk of peripheral arterial disease. | journal=Circulation | year= 2004 | volume= 109 | issue= 25 | pages= 3196-201 | pmid=15184277 | doi=10.1161/01.CIR.0000130848.18636.B2 | pmc= | url=http://www.ncbi.nlm.nih.gov/entrez/eutils/elink.fcgi?dbfrom=pubmed&tool=sumsearch.org/cite&retmode=ref&cmd=prlinks&id=15184277 }} </ref><ref name="pmid23514838">{{cite journal| author=Tellez-Plaza M, Guallar E, Howard BV, Umans JG, Francesconi KA, Goessler W et al.| title=Cadmium exposure and incident cardiovascular disease. | journal=Epidemiology | year= 2013 | volume= 24 | issue= 3 | pages= 421-9 | pmid=23514838 | doi=10.1097/EDE.0b013e31828b0631 | pmc= | url=http://www.ncbi.nlm.nih.gov/entrez/eutils/elink.fcgi?dbfrom=pubmed&tool=sumsearch.org/cite&retmode=ref&cmd=prlinks&id=23514838 }} </ref> Elevated blood concentration of lead is associated with increased all-cause mortality [HR 1.25 (95% CI 1.04 to 1.51) for the highest versus lowest tertile of blood lead, P trend across the tertiles=0.002) and cardiovascular mortality [HR 1.55 (95% CI 1.08 to 2.24) for the highest versus lowest tertile, P trend <0.003] ((Menke, Muntner, Batuman, Silbergeld, & Guallar, 2006)). Also, cardiovascular mortality is greater among subjects with elevated cadmium concentrations in the blood and urine [HR 1.69 (95% CI: 1.03, 2.77) and 1.74 (95% CI: 1.07, 2.83) for the 80th and 20th percentiles of blood and urine cadmium, respectively] (cadmium exposure and all cause cardiovascular mortality, Navas-Acien, Tellez-Plaza). <br />
Heavy metals may play a role in the development of [[cardiovascular disease]] through a number of different mechanisms (Navas Nature) (Vaziri Khan Interplay of ROS). Heavy metals include transition metals such as [[cadmium]], [[mercury]], [[manganese]], [[chromium]], [[cobalt]], [[nickel]], [[iron]], and [[copper]], metalloids such as antimony and arsenic, and post- transition metals such as thallium and lead. These metals all have unique toxicities, as well as toxicities that are common to all of them. Heavy metals in the endothelium promote oxygen free radical formation, resulting in increased oxidative stress, inflammation, and tissue damage. Lead and cadmium may interfere with calcium signaling channels. Transition metals promote modifications of low-density lipoprotein by endothelial cells through lipid peroxidation and degradation of low-density lipoprotein phospholipids.<ref name="pmid6587396">{{cite journal| author=Steinbrecher UP, Parthasarathy S, Leake DS, Witztum JL, Steinberg D| title=Modification of low density lipoprotein by endothelial cells involves lipid peroxidation and degradation of low density lipoprotein phospholipids. | journal=Proc Natl Acad Sci U S A | year= 1984 | volume= 81 | issue= 12 | pages= 3883-7 | pmid=6587396 | doi= | pmc=345326 | url=https://www.ncbi.nlm.nih.gov/entrez/eutils/elink.fcgi?dbfrom=pubmed&tool=sumsearch.org/cite&retmode=ref&cmd=prlinks&id=6587396 }} </ref><ref name="pmid6501577">{{cite journal| author=Heinecke JW, Rosen H, Chait A| title=Iron and copper promote modification of low density lipoprotein by human arterial smooth muscle cells in culture. | journal=J Clin Invest | year= 1984 | volume= 74 | issue= 5 | pages= 1890-4 | pmid=6501577 | doi=10.1172/JCI111609 | pmc=425370 | url=https://www.ncbi.nlm.nih.gov/entrez/eutils/elink.fcgi?dbfrom=pubmed&tool=sumsearch.org/cite&retmode=ref&cmd=prlinks&id=6501577 }} </ref><ref name="pmid8847477">{{cite journal| author=Morgan J, Leake DS| title=Oxidation of low density lipoprotein by iron or copper at acidic pH. | journal=J Lipid Res | year= 1995 | volume= 36 | issue= 12 | pages= 2504-12 | pmid=8847477 | doi= | pmc= | url=https://www.ncbi.nlm.nih.gov/entrez/eutils/elink.fcgi?dbfrom=pubmed&tool=sumsearch.org/cite&retmode=ref&cmd=prlinks&id=8847477 }} </ref> Exposure to non-transition metals, such as lead, has also been associated with impaired nitric oxide signaling and availability,<ref name="pmid15894814">{{cite journal| author=Dursun N, Arifoglu C, Süer C, Keskinol L| title=Blood pressure relationship to nitric oxide, lipid peroxidation, renal function, and renal blood flow in rats exposed to low lead levels. | journal=Biol Trace Elem Res | year= 2005 | volume= 104 | issue= 2 | pages= 141-9 | pmid=15894814 | doi=10.1385/BTER:104:2:141 | pmc= | url=https://www.ncbi.nlm.nih.gov/entrez/eutils/elink.fcgi?dbfrom=pubmed&tool=sumsearch.org/cite&retmode=ref&cmd=prlinks&id=15894814 }} </ref> endothelial cell dysfunction,<ref name="pmid7710289">{{cite journal| author=Kaji T, Suzuki M, Yamamoto C, Mishima A, Sakamoto M, Kozuka H| title=Severe damage of cultured vascular endothelial cell monolayer after simultaneous exposure to cadmium and lead. | journal=Arch Environ Contam Toxicol | year= 1995 | volume= 28 | issue= 2 | pages= 168-72 | pmid=7710289 | doi= | pmc= | url=https://www.ncbi.nlm.nih.gov/entrez/eutils/elink.fcgi?dbfrom=pubmed&tool=sumsearch.org/cite&retmode=ref&cmd=prlinks&id=7710289 }} </ref> and hypertension.<ref name="pmid18567711">{{cite journal| author=Vaziri ND| title=Mechanisms of lead-induced hypertension and cardiovascular disease. | journal=Am J Physiol Heart Circ Physiol | year= 2008 | volume= 295 | issue= 2 | pages= H454-65 | pmid=18567711 | doi=10.1152/ajpheart.00158.2008 | pmc=2519216 | url=https://www.ncbi.nlm.nih.gov/entrez/eutils/elink.fcgi?dbfrom=pubmed&tool=sumsearch.org/cite&retmode=ref&cmd=prlinks&id=18567711 }} </ref> [[Heavy metal]] exposure is also associated with genetic and [[epigenetic]] manifestations. [[Cadmium]] promotes atherosclerosis and endothelial dysfunction through multiple [[genetic]] changes (19556524). One of the mechanisms involves [[DNA]] strand breaks and damage with subsequent apoptosis in [[endothelial cell]]s (Messner Knoflack ATVB). Also, maternal [[lead]] exposure during pregnancy may be associated with epigenetic consequences in grandchildren through alteration of [[DNA methylation]] early in life.<ref name="pmid26417717">{{cite journal| author=Sen A, Heredia N, Senut MC, Land S, Hollocher K, Lu X et al.| title=Multigenerational epigenetic inheritance in humans: DNA methylation changes associated with maternal exposure to lead can be transmitted to the grandchildren. | journal=Sci Rep | year= 2015 | volume= 5 | issue= | pages= 14466 | pmid=26417717 | doi=10.1038/srep14466 | pmc=4586440 | url=https://www.ncbi.nlm.nih.gov/entrez/eutils/elink.fcgi?dbfrom=pubmed&tool=sumsearch.org/cite&retmode=ref&cmd=prlinks&id=26417717 }} </ref><br />
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Current mechanistic understanding, albeit rudimentary, supports the concept that the cardiovascular benefits of [[chelation therapy]] may result from enhanced excretion of [[heavy metals]], and subsequent reduction in processes listed above. Additionally, in patients with [[diabetes]], a reduction in the metal-catalyzed formation of [[reactive oxygen species]], formation of advanced glycation end-products, and lipid [[peroxidation]] has been postulated.<ref name="pmid10874253">{{cite journal| author=Lamas GA, Ackermann A| title=Clinical evaluation of chelation therapy: is there any wheat amidst the chaff? | journal=Am Heart J | year= 2000 | volume= 140 | issue= 1 | pages= 4-5 | pmid=10874253 | doi=10.1067/mhj.2000.107549 | pmc= | url=http://www.ncbi.nlm.nih.gov/entrez/eutils/elink.fcgi?dbfrom=pubmed&tool=sumsearch.org/cite&retmode=ref&cmd=prlinks&id=10874253 }} </ref> Metal detoxification in the context of diabetes possibly decreases [[inflammation]] and [[oxidative stress]] that characterize atherosclerosis.<ref>Escolar E, Lamas G, Mark D et al(2013) "The Effect of an EDTA-based Chelation Regimen on Patients With Diabetes Mellitus and Prior Myocardial Infarction in the Trial to Assess Chelation Therapy (TACT)". Circulation. 2013</ref> Recent research, including chelation-activity assays, indicates that many common [[diabetes]] drugs, such as [[metformin]] and aldose reductase inhibitors, could possibly have some chelating properties (Frizzell, Baynes) (Nagai Murray Chelation: a fundamental mechanism of action of AGE inhibitors, Frizell Baynes Chelation therapy for management of diabetic complications)(pubmed ID: 22492524).<br />
The TACT chelation infusion, however, did not contain edetate disodium alone. The standard chelation infusion formula used in TACT was formulated to be identical with the most prevalent infusion in use. This formulation had developed organically over decades and had been modified by clinical practitioners to have additives such as [[ascorbic acid]], B-vitamins and [[magnesium]], thought to have a protective effect on [[endothelial cells]],<ref>Rozema, Theodore C. "The protocol for the safe and effective administration of EDTA and other chelating agents for vascular disease, degenerative disease, and metal toxicity." Journal of Advancement in Medicine 10.1 (1997): 5-100.</ref> making the results of clinical application more difficult to understand, and emphasizing the need for mechanistic work.<br />
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==Future Studies==<br />
TACT was a unique study with an unexpected result that could have vast public health implications. In order to consider its broad applicability, the medical and scientific community require the results reproduced. TACT2, scheduled to begin in October 2016 (press release), is a replicative study in post-MI diabetic patients. If the TACT2 results confirm the results of TACT, then chelation is poised to become the next major development in the treatment of vascular complications of diabetes and vascular disease. TACT2 is currently recruiting sites, and interested investigators should visit www.TACT2.org for additional information.<br />
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==Side Effects==<br />
Shown below is a list of the labelled toxicities of EDTA-based chelation therapy. However, TACT delivered 55,222 infusions of EDTA or placebo, and found no differences between groups in adverse events, serious or otherwise.<br />
* [[Arrhythmias]]<br />
* [[Autoimmune diseases]]<br />
* [[Bone marrow]]<br />
* [[Convulsions]]<br />
* [[Depression]]<br />
* [[Fever]]<br />
* [[Heart failure]]<br />
* [[Hypocalcemia]]<br />
* [[Hypoglycemia]]<br />
* [[Hypotension]]<br />
* [[Bleeding time|Prolonged bleeding time]]<br />
* [[Renal failure]]<br />
* [[Respiratory arrest]]<br />
* [[Tetany]]<br />
* [[Trace metal|Trace metal deficiency]]<br />
* [[Vitamin deficiency]]<ref name="pmid10874275">{{cite journal| author=Ernst E| title=Chelation therapy for coronary heart disease: An overview of all clinical investigations. | journal=Am Heart J | year= 2000 | volume= 140 | issue= 1 | pages= 139-41 | pmid=10874275 | doi=10.1067/mhj.2000.107548 | pmc= | url=http://www.ncbi.nlm.nih.gov/entrez/eutils/elink.fcgi?dbfrom=pubmed&tool=sumsearch.org/cite&retmode=ref&cmd=prlinks&id=10874275 }} </ref><ref name="pmid23532240">{{cite journal| author=Lamas GA, Goertz C, Boineau R, Mark DB, Rozema T, Nahin RL et al.| title=Effect of disodium EDTA chelation regimen on cardiovascular events in patients with previous myocardial infarction: the TACT randomized trial. | journal=JAMA | year= 2013 | volume= 309 | issue= 12 | pages= 1241-50 | pmid=23532240 | doi=10.1001/jama.2013.2107 | pmc= | url=http://www.ncbi.nlm.nih.gov/entrez/eutils/elink.fcgi?dbfrom=pubmed&tool=sumsearch.org/cite&retmode=ref&cmd=prlinks&id=23532240 }} </ref><br />
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==Landmark Trials==<br />
[[TACT]] <br><br />
TACT 2 [http://www.TACT2.org] (link to press release [http://www.prnewswire.com/news-releases/tact2-clinical-trial-receives-national-institutes-of-health-funding-300334174.html])<br />
<br />
==References==<br />
{{Reflist|2}}<br />
<br />
[[Category:Cardiology]]<br />
[[Category:Diabetes]]<br />
[[Category:Up-To-Date]]<br />
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{{WikiDoc Sources}}</div>Rim Halabyhttps://www.wikidoc.org/index.php?title=Chelation_therapy_for_cardiovascular_disease&diff=1274681Chelation therapy for cardiovascular disease2016-12-06T23:59:20Z<p>Rim Halaby: /* Chelation Therapy and CVD */</p>
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<div>__NOTOC__<br />
'''Editor-In-Chief:''' Gervasio Lamas, M.D., C. Michael Gibson, M.S., M.D.; {{AE}} {{Rim}}, Ian Ergui, B.Sc.<br />
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'''[[Chelation therapy|To read more about chelation therapy click here.]]'''<br><br />
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{{SK}} Chelation therapy, EDTA, post-myocardial infarction, diabetes<br />
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==Overview==<br />
[[Chelation]] is a process by which an organic molecule with a negatively charged “pocket” complexes with a metal ion of opposite charge, inactivates it, and then permits its physiological mobilization and excretion, usually by a renal route. [[Chelation therapy]], which involves multiple administrations of a chelating agent, helps eliminate stored toxic metal ions from the body (Waters paper, Arenas abstract).<ref name="pmid11794513">{{cite journal| author=Waters RS, Bryden NA, Patterson KY, Veillon C, Anderson RA| title=EDTA chelation effects on urinary losses of cadmium, calcium, chromium, cobalt, copper, lead, magnesium, and zinc. | journal=Biol Trace Elem Res | year= 2001 | volume= 83 | issue= 3 | pages= 207-21 | pmid=11794513 | doi=10.1385/BTER:83:3:207 | pmc= | url=https://www.ncbi.nlm.nih.gov/entrez/eutils/elink.fcgi?dbfrom=pubmed&tool=sumsearch.org/cite&retmode=ref&cmd=prlinks&id=11794513 }} </ref><ref name="arenas">Arenas I.A., Navas-Acien A., Lamas G.A.; Enhanced vasculotoxic metal excretionin post-MI patients after edetate disodium therapy (abstr). J Am Coll Cardiol. 2016;67:A2125</ref> Common chelators include [[penicillamine]], which binds copper and can be used to treat [[Wilson’s disease]], [[deferoxamine]], which binds iron and is used in the treatment of [[thalassemia]] and iron overload, succimer, also used in the treatment of lead poisoning, and the edetates, non-specific chelators of metals and other ions with valences of +2 to +6. Chelation therapy is, in many cases, guideline mandated, such as in children with elevated blood lead levels,<ref name="CDC">CDC. Low Level Lead Exposure Harms Children: A Renewed Call for Primary Prevention. Atlanta, GA:Advisory Committee on Childhood Lead Poisoning Prevention, U.S. Centers for Disease Control and Prevention (4 Jan 2012). Available: [http://www.cdc.gov/nceh/lead/acclpp/final_document_010412.pdf]</ref> patients with iron overload and dyserythropoietic syndromes or chronic hemolytic anemia,<ref name="pmid21452290">{{cite journal| author=Bacon BR, Adams PC, Kowdley KV, Powell LW, Tavill AS, American Association for the Study of Liver Diseases| title=Diagnosis and management of hemochromatosis: 2011 practice guideline by the American Association for the Study of Liver Diseases. | journal=Hepatology | year= 2011 | volume= 54 | issue= 1 | pages= 328-43 | pmid=21452290 | doi=10.1002/hep.24330 | pmc=3149125 | url=https://www.ncbi.nlm.nih.gov/entrez/eutils/elink.fcgi?dbfrom=pubmed&tool=sumsearch.org/cite&retmode=ref&cmd=prlinks&id=21452290 }} </ref> or [[sickle cell disease]] and transfusion acquired iron-overload,<ref name="NHLBI">NHLBI. Transfusion in Sickle Cell Disease: A Systematic Review of Benefits, Complications, and Management of Complications. Prepared for the National Heart, Lung, and Blood Institute and by the Knowledge and Evaluation Research Unit, Mayo Clinic Rochester (2012)</ref> to name a few instances.<br />
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[[Ethylene diamine tetraacetic acid]] ([[EDTA]], edetate) and its salts (most commonly disodium or calcium disodium), commonly used chelating agents patented in 1938, bind to and permit the urinary excretion of divalent cations such as calcium, and metals such as [[lead]], [[cadmium]], [[nickel]], [[cobalt]], [[iron]], [[aluminum]], and others. The initial medical use for [[EDTA]] began after World War II for the treatment of [[lead]]-exposed naval workers. In addition to its use for the treatment of metal poisoning, since the 1950s chelation therapy has been considered an alternative or add-on therapy for the prevention and treatment of [[atherosclerotic disease]]. The use of edetate disodium (Na2EDTA) has been most prominent in the alternative medicine treatment of atherosclerosis primarily because of the still-unproven hypothesis that the [[hypocalcemia]] it induces might lead to the decalcification of atherosclerotic lesions. In fact, the most current research suggests that the probable mechanism of benefit centers on enhancement of toxic metal excretion.<br />
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==Chelation Therapy and CVD==<br />
The use of chelation therapy as a treatment for [[atherosclerotic disease]] dates back to the 1950’s when Clarke et al investigated the use of EDTA for the treatment of angina pectoris and reported improvement in 19 of 20 patients.<ref name="pmid13372537">{{cite journal| author=CLARKE CN, CLARKE NE, MOSHER RE| title=Treatment of angina pectoris with disodium ethylene diamine tetraacetic acid. | journal=Am J Med Sci | year= 1956 | volume= 232 | issue= 6 | pages= 654-66 | pmid=13372537 | doi= | pmc= | url=http://www.ncbi.nlm.nih.gov/entrez/eutils/elink.fcgi?dbfrom=pubmed&tool=sumsearch.org/cite&retmode=ref&cmd=prlinks&id=13372537 }} </ref> Later studies by Kitchell were less positive,<ref name="pmid13756462">{{cite journal| author=KITCHELL JR, MELTZER LE, SEVEN MJ| title=Potential uses of chelation methods in the treatment of cardiovascular diseases. | journal=Prog Cardiovasc Dis | year= 1961 | volume= 3 | issue= | pages= 338-49 | pmid=13756462 | doi= | pmc= | url=https://www.ncbi.nlm.nih.gov/entrez/eutils/elink.fcgi?dbfrom=pubmed&tool=sumsearch.org/cite&retmode=ref&cmd=prlinks&id=13756462 }} </ref><ref name="pmid14033183">{{cite journal| author=KITCHELL JR, PALMON F, AYTAN N, MELTZER LE| title=The treatment of coronary artery disease with disodium EDTA. A reappraisal. | journal=Am J Cardiol | year= 1963 | volume= 11 | issue= | pages= 501-6 | pmid=14033183 | doi= | pmc= | url=https://www.ncbi.nlm.nih.gov/entrez/eutils/elink.fcgi?dbfrom=pubmed&tool=sumsearch.org/cite&retmode=ref&cmd=prlinks&id=14033183 }} </ref> and in an era without modern clinical trials methodology nor effective concomitant therapies, opinions regarding the use of [[chelation therapy]] for [[cardiovascular disease]] (CVD) tilted towards the negative. To be fair, from the 1970’s to 1990’s the preponderance of the scientific literature on chelation therapy for atherosclerosis consisted of case reports, case series, and small clinical trials with surrogate endpoints, poor-quality evidence from which to draw a conclusion of efficacy or harm.<ref name="pmid12519577">{{cite journal| author=Villarruz MV, Dans A, Tan F| title=Chelation therapy for atherosclerotic cardiovascular disease. | journal=Cochrane Database Syst Rev | year= 2002 | volume= | issue= 4 | pages= CD002785 | pmid=12519577 | doi=10.1002/14651858.CD002785 | pmc= | url=http://www.ncbi.nlm.nih.gov/entrez/eutils/elink.fcgi?dbfrom=pubmed&tool=sumsearch.org/cite&retmode=ref&cmd=prlinks&id=12519577 }} </ref><br />
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For example, one extensive case series reported an association between EDTA chelation therapy and improvement of ischemic heart disease and peripheral artery disease.<ref name="pmid3144646">{{cite journal| author=Olszewer E, Carter JP| title=EDTA chelation therapy in chronic degenerative disease. | journal=Med Hypotheses | year= 1988 | volume= 27 | issue= 1 | pages= 41-9 | pmid=3144646 | doi= | pmc= | url=http://www.ncbi.nlm.nih.gov/entrez/eutils/elink.fcgi?dbfrom=pubmed&tool=sumsearch.org/cite&retmode=ref&cmd=prlinks&id=3144646 }} </ref> Another study demonstrated that EDTA supplemented with several B vitamins (vitamin B1, B2, B6 and B12) but not EDTA alone was effective in improving [[endothelium]]-dependent forearm blood flow.<ref name="pmid10561804">{{cite journal| author=Green DJ, O'Driscoll JG, Maiorana A, Scrimgeour NB, Weerasooriya R, Taylor RR| title=Effects of chelation with EDTA and vitamin B therapy on nitric oxide-related endothelial vasodilator function. | journal=Clin Exp Pharmacol Physiol | year= 1999 | volume= 26 | issue= 11 | pages= 853-6 | pmid=10561804 | doi= | pmc= | url=http://www.ncbi.nlm.nih.gov/entrez/eutils/elink.fcgi?dbfrom=pubmed&tool=sumsearch.org/cite&retmode=ref&cmd=prlinks&id=10561804 }} </ref> A systematic review of four randomized clinical trials on chelation therapy and [[peripheral artery occlusive disease]] reported no benefit associated with chelation therapy.<ref name="pmid9264515">{{cite journal| author=Ernst E| title=Chelation therapy for peripheral arterial occlusive disease: a systematic review. | journal=Circulation | year= 1997 | volume= 96 | issue= 3 | pages= 1031-3 | pmid=9264515 | doi= | pmc= | url=http://www.ncbi.nlm.nih.gov/entrez/eutils/elink.fcgi?dbfrom=pubmed&tool=sumsearch.org/cite&retmode=ref&cmd=prlinks&id=9264515 }} </ref> The studies, however, individually and in aggregate, were too small to exclude a small to moderate benefit of therapy. Moreover, followup was short and surrogate physiologic endpoints, such as walking distance, were used. A Cochrane systematic review on the role of chelation therapy to treat coronary heart disease in 2002 concluded that the data were insufficient to recommend for or against chelation.<ref name="pmid10874275">{{cite journal| author=Ernst E| title=Chelation therapy for coronary heart disease: An overview of all clinical investigations. | journal=Am Heart J | year= 2000 | volume= 140 | issue= 1 | pages= 139-41 | pmid=10874275 | doi=10.1067/mhj.2000.107548 | pmc= | url=http://www.ncbi.nlm.nih.gov/entrez/eutils/elink.fcgi?dbfrom=pubmed&tool=sumsearch.org/cite&retmode=ref&cmd=prlinks&id=10874275 }} </ref> <br />
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The medical community concluded that the absence of high quality evidence of efficacy equated with evidence of absence of efficacy. Professional organizations recommended against chelation therapy.<ref name="pmid9205980">{{cite journal| author=Lewin MR| title=Chelation therapy for cardiovascular disease. Review and commentary. | journal=Tex Heart Inst J | year= 1997 | volume= 24 | issue= 2 | pages= 81-9 | pmid=9205980 | doi= | pmc=325409 | url=https://www.ncbi.nlm.nih.gov/entrez/eutils/elink.fcgi?dbfrom=pubmed&tool=sumsearch.org/cite&retmode=ref&cmd=prlinks&id=9205980 }} </ref> Interestingly, patients continued to seek, and practitioners to administer, chelation infusions for [[cardiovascular disease]] and other diagnoses.<br />
<br />
In light of the persistent controversy regarding the benefits of chelation therapy and the absence of any previous large clinical trial investigating its use in coronary artery disease, the National Center for Complementary and Alternative Medicine and the National Heart Lung and Blood Institute released a $30 million Request for Applications (RFA) to develop a definitive trial. In 2002, the RFA was awarded to Mount Sinai Medical Center in Miami Beach FL (G Lamas MD, Principal Investigator). The Trial to Assess Chelation Therapy (TACT), a randomized, double blind, placebo controlled 2x2 factorial trial, investigated the efficacy and safety of disodium EDTA based infusions and high-dose oral vitamins and minerals in 1708 stable post-myocardial infarction (MI) patients more than 50 years of age and with fairly normal kidney function ([[creatinine]] 2.0 mg/dL or less). The active treatment consisted of 40 infusions consisted of disodium [[EDTA]] combined with [[ascorbic acid]], B vitamins, and other components. The median age of patients was 65 years, and they were treated with evidence-based post-MI medicines. The primary endpoint of this trial was a composite of all-cause mortality, [[stroke]], [[MI]], coronary revascularization, and hospitalization for [[angina]].<ref name="pmid16585050">{{cite journal| author=Costa J, Borges M, David C, Vaz Carneiro A| title=Efficacy of lipid lowering drug treatment for diabetic and non-diabetic patients: meta-analysis of randomised controlled trials. | journal=BMJ | year= 2006 | volume= 332 | issue= 7550 | pages= 1115-24 | pmid=16585050 | doi=10.1136/bmj.38793.468449.AE | pmc=PMC1459619 | url=http://www.ncbi.nlm.nih.gov/entrez/eutils/elink.fcgi?dbfrom=pubmed&tool=sumsearch.org/cite&retmode=ref&cmd=prlinks&id=16585050 }} </ref><br />
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A follow up period of 55 months revealed a statistically significant decrease in the primary endpoint (HR: 0.82; 95% CI: 0.69-0.99; p= 0.035). There was an absolute reduction in the 5-year Kaplan-Meier estimate, from 38% to 33%, resulting in a 5-year number needed to treat (NNT) of 18 patients to avoid one adverse cardiovascular outcome. This is comparable to the 5-year NNT for [[statins]] in post-[[MI]] patients (NNT=16 for the secondary prevention of a major coronary event).<ref name="pmid16585050">{{cite journal| author=Costa J, Borges M, David C, Vaz Carneiro A| title=Efficacy of lipid lowering drug treatment for diabetic and non-diabetic patients: meta-analysis of randomised controlled trials. | journal=BMJ | year= 2006 | volume= 332 | issue= 7550 | pages= 1115-24 | pmid=16585050 | doi=10.1136/bmj.38793.468449.AE | pmc=PMC1459619 | url=http://www.ncbi.nlm.nih.gov/entrez/eutils/elink.fcgi?dbfrom=pubmed&tool=sumsearch.org/cite&retmode=ref&cmd=prlinks&id=16585050 }} </ref> The point estimate for the risk of each of the components of the primary endpoint was <1, consistent with the aggregate result. The Investigators concluded that chelation should not yet be adopted for routine post-MI use in all patients, but the results of TACT should inform further studies to confirm or refute these unexpected results.<ref name="pmid23532240">{{cite journal| author=Lamas GA, Goertz C, Boineau R, Mark DB, Rozema T, Nahin RL et al.| title=Effect of disodium EDTA chelation regimen on cardiovascular events in patients with previous myocardial infarction: the TACT randomized trial. | journal=JAMA | year= 2013 | volume= 309 | issue= 12 | pages= 1241-50 | pmid=23532240 | doi=10.1001/jama.2013.2107 | pmc= | url=http://www.ncbi.nlm.nih.gov/entrez/eutils/elink.fcgi?dbfrom=pubmed&tool=sumsearch.org/cite&retmode=ref&cmd=prlinks&id=23532240 }} </ref><br />
<br />
TACT prespecified several subgroups for analysis and found a significant interaction between edetate disodium treatment and [[diabetes]] (p for interaction =0.0037). Among subjects enrolled in TACT, there were 633 diabetic patients, defined as patients with self-reported diabetes, taking medications for diabetes, or having a fasting blood glucose of at least 126 mg/dL at enrollment. The administration of chelation infusions among post-MI diabetic patients was associated with a marked reduction in the primary end point when compared with placebo. The primary end point occurred in 25% of diabetic patients who were administered chelation therapy compared to 38% in those who received placebo infusions (HR, 0.59; 95% CI, 0.44–0.79; P<0.001). The 5-year NNT to prevent one event was 6.5. In addition, chelation therapy was significantly associated with decreased all-cause mortality (43% reduction, p=0.011) and reinfarction (52% reduction, p=0.015). Again, the investigators concluded that these findings supported future research, but did not constitute sufficient evidence to indicate the routine use of chelation therapy for all post–myocardial infarction patients with diabetes, leaving open the clinician’s choice to use this novel therapy in occasional, or non-routine patients.<br />
<br />
These results catalyzed a wave of increased public and scientific interest in disodium EDTA treatment for patients with established coronary disease, particularly in diabetes, and hypotheses regarding potential mechanisms of benefit. As a capstone to the published analyses, the ACC/AHA Guidelines for Chronic Ischemic Heart Disease changed to reflect the TACT data and upgraded disodium EDTA treatment from a Class III indication to a Class IIB indication. While Class III therapeutics are considered not beneficial or useful, Class IIB treatments can be considered in some patients and require additional research to establish efficacy.<ref name="pmid25077860">{{cite journal| author=Fihn SD, Blankenship JC, Alexander KP, Bittl JA, Byrne JG, Fletcher BJ et al.| title=2014 ACC/AHA/AATS/PCNA/SCAI/STS focused update of the guideline for the diagnosis and management of patients with stable ischemic heart disease: a report of the American College of Cardiology/American Heart Association Task Force on Practice Guidelines, and the American Association for Thoracic Surgery, Preventive Cardiovascular Nurses Association, Society for Cardiovascular Angiography and Interventions, and Society of Thoracic Surgeons. | journal=J Am Coll Cardiol | year= 2014 | volume= 64 | issue= 18 | pages= 1929-49 | pmid=25077860 | doi=10.1016/j.jacc.2014.07.017 | pmc= | url=https://www.ncbi.nlm.nih.gov/entrez/eutils/elink.fcgi?dbfrom=pubmed&tool=sumsearch.org/cite&retmode=ref&cmd=prlinks&id=25077860 }} </ref> The change in the guidelines signaled a major shift in the perception of chelation therapy among the medical establishment. The TACT data led clinicians to reconsider chelation objectively, and the investigators and many other academic cardiologists called for TACT2, a new trial to test the results of TACT, to be funded by the [[NIH]].<br />
<br />
==Mechanism of Action==<br />
Edetate disodium binds to metals and forms soluble complexes facilitating their subsequent excretion in the urine.<ref name="pmid14000694">{{cite journal| author=WILDER LW, DE JODE LR, MILSTEIN SW, HOWARD JM| title=Mobilization of atherosclerotic plaque calcium with EDTA utilizing the isolation-perfusion principle. | journal=Surgery | year= 1962 | volume= 52 | issue= | pages= 793-5 | pmid=14000694 | doi= | pmc= | url=http://www.ncbi.nlm.nih.gov/entrez/eutils/elink.fcgi?dbfrom=pubmed&tool=sumsearch.org/cite&retmode=ref&cmd=prlinks&id=14000694 }} </ref> Hence, chelation therapy results in the elimination of stored toxic and essential metals. In an experiment performed on 24 patients, age 50 or older, and with a prior MI and a creatinine of 2.0 or less, patients had urine toxic metals measured at baseline, 1 day after an infusion of placebo, and 1 day after an infusion of the edetate disodium-based TACT solution. Placebo did not increase the excretion of toxic metals. Following an infusion of the edetate disodium-based TACT solution, lead excretion increased by nearly 3900%, and cadmium by nearly 700%. Other toxic metals whose excretion was enhanced by edetate disodium were aluminum (by ~250%), nickel (by ~150%), thallium (by ~60%), and gadolinium. A similar experiment performed earlierby Waters et al, reported urinary lead concentrations approximately 35 times greater than in pre-chelation urine (Waters et al).<br />
While enhanced lead and cadmium is interesting, the critical link to cardiovascular events is provided by epidemiological studies, which provide robust evidence linking toxic metals with cardiovascular disease.<ref name="pmid21421632">{{cite journal| author=Agarwal S, Zaman T, Tuzcu EM, Kapadia SR| title=Heavy metals and cardiovascular disease: results from the National Health and Nutrition Examination Survey (NHANES) 1999-2006. | journal=Angiology | year= 2011 | volume= 62 | issue= 5 | pages= 422-9 | pmid=21421632 | doi=10.1177/0003319710395562 | pmc= | url=http://www.ncbi.nlm.nih.gov/entrez/eutils/elink.fcgi?dbfrom=pubmed&tool=sumsearch.org/cite&retmode=ref&cmd=prlinks&id=21421632 }} </ref> This evidence is strongest for lead and cadmium.<ref name="pmid16982939">{{cite journal| author=Menke A, Muntner P, Batuman V, Silbergeld EK, Guallar E| title=Blood lead below 0.48 micromol/L (10 microg/dL) and mortality among US adults. | journal=Circulation | year= 2006 | volume= 114 | issue= 13 | pages= 1388-94 | pmid=16982939 | doi=10.1161/CIRCULATIONAHA.106.628321 | pmc= | url=http://www.ncbi.nlm.nih.gov/entrez/eutils/elink.fcgi?dbfrom=pubmed&tool=sumsearch.org/cite&retmode=ref&cmd=prlinks&id=16982939 }} </ref><ref name="pmid15184277">{{cite journal| author=Navas-Acien A, Selvin E, Sharrett AR, Calderon-Aranda E, Silbergeld E, Guallar E| title=Lead, cadmium, smoking, and increased risk of peripheral arterial disease. | journal=Circulation | year= 2004 | volume= 109 | issue= 25 | pages= 3196-201 | pmid=15184277 | doi=10.1161/01.CIR.0000130848.18636.B2 | pmc= | url=http://www.ncbi.nlm.nih.gov/entrez/eutils/elink.fcgi?dbfrom=pubmed&tool=sumsearch.org/cite&retmode=ref&cmd=prlinks&id=15184277 }} </ref><ref name="pmid23514838">{{cite journal| author=Tellez-Plaza M, Guallar E, Howard BV, Umans JG, Francesconi KA, Goessler W et al.| title=Cadmium exposure and incident cardiovascular disease. | journal=Epidemiology | year= 2013 | volume= 24 | issue= 3 | pages= 421-9 | pmid=23514838 | doi=10.1097/EDE.0b013e31828b0631 | pmc= | url=http://www.ncbi.nlm.nih.gov/entrez/eutils/elink.fcgi?dbfrom=pubmed&tool=sumsearch.org/cite&retmode=ref&cmd=prlinks&id=23514838 }} </ref> Elevated blood concentration of lead is associated with increased all-cause mortality [HR 1.25 (95% CI 1.04 to 1.51) for the highest versus lowest tertile of blood lead, P trend across the tertiles=0.002) and cardiovascular mortality [HR 1.55 (95% CI 1.08 to 2.24) for the highest versus lowest tertile, P trend <0.003] ((Menke, Muntner, Batuman, Silbergeld, & Guallar, 2006)). Also, cardiovascular mortality is greater among subjects with elevated cadmium concentrations in the blood and urine [HR 1.69 (95% CI: 1.03, 2.77) and 1.74 (95% CI: 1.07, 2.83) for the 80th and 20th percentiles of blood and urine cadmium, respectively] (cadmium exposure and all cause cardiovascular mortality, Navas-Acien, Tellez-Plaza). <br />
Heavy metals may play a role in the development of [[cardiovascular disease]] through a number of different mechanisms (Navas Nature) (Vaziri Khan Interplay of ROS). Heavy metals include transition metals such as [[cadmium]], [[mercury]], [[manganese]], [[chromium]], [[cobalt]], [[nickel]], [[iron]], and [[copper]], metalloids such as antimony and arsenic, and post- transition metals such as thallium and lead. These metals all have unique toxicities, as well as toxicities that are common to all of them. Heavy metals in the endothelium promote oxygen free radical formation, resulting in increased oxidative stress, inflammation, and tissue damage. Lead and cadmium may interfere with calcium signaling channels. Transition metals promote modifications of low-density lipoprotein by endothelial cells through lipid peroxidation and degradation of low-density lipoprotein phospholipids (pubmed ID: PMC345326, PMC425370, 8847477). Exposure to non-transition metals, such as lead, has also been associated with impaired nitric oxide signaling and availability (15894814), endothelial cell dysfunction (7710289), and hypertension (18567711). [[Heavy metal]] exposure is also associated with genetic and [[epigenetic]] manifestations. [[Cadmium]] promotes atherosclerosis and endothelial dysfunction through multiple [[genetic]] changes (19556524). One of the mechanisms involves [[DNA]] strand breaks and damage with subsequent apoptosis in [[endothelial cell]]s (Messner Knoflack ATVB). Also, maternal [[lead]] exposure during pregnancy may be associated with epigenetic consequences in grandchildren through alteration of [[DNA methylation]] early in life (Sen, Heredia, Senut et al, Nature Scientific Reports Jan 2015).<br />
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Current mechanistic understanding, albeit rudimentary, supports the concept that the cardiovascular benefits of [[chelation therapy]] may result from enhanced excretion of [[heavy metals]], and subsequent reduction in processes listed above. Additionally, in patients with [[diabetes]], a reduction in the metal-catalyzed formation of [[reactive oxygen species]], formation of advanced glycation end-products, and lipid [[peroxidation]] has been postulated.<ref name="pmid10874253">{{cite journal| author=Lamas GA, Ackermann A| title=Clinical evaluation of chelation therapy: is there any wheat amidst the chaff? | journal=Am Heart J | year= 2000 | volume= 140 | issue= 1 | pages= 4-5 | pmid=10874253 | doi=10.1067/mhj.2000.107549 | pmc= | url=http://www.ncbi.nlm.nih.gov/entrez/eutils/elink.fcgi?dbfrom=pubmed&tool=sumsearch.org/cite&retmode=ref&cmd=prlinks&id=10874253 }} </ref> Metal detoxification in the context of diabetes possibly decreases [[inflammation]] and [[oxidative stress]] that characterize atherosclerosis.<ref>Escolar E, Lamas G, Mark D et al(2013) "The Effect of an EDTA-based Chelation Regimen on Patients With Diabetes Mellitus and Prior Myocardial Infarction in the Trial to Assess Chelation Therapy (TACT)". Circulation. 2013</ref> Recent research, including chelation-activity assays, indicates that many common [[diabetes]] drugs, such as [[metformin]] and aldose reductase inhibitors, could possibly have some chelating properties (Frizzell, Baynes) (Nagai Murray Chelation: a fundamental mechanism of action of AGE inhibitors, Frizell Baynes Chelation therapy for management of diabetic complications)(pubmed ID: 22492524).<br />
The TACT chelation infusion, however, did not contain edetate disodium alone. The standard chelation infusion formula used in TACT was formulated to be identical with the most prevalent infusion in use. This formulation had developed organically over decades and had been modified by clinical practitioners to have additives such as [[ascorbic acid]], B-vitamins and [[magnesium]], thought to have a protective effect on [[endothelial cells]],<ref>Rozema, Theodore C. "The protocol for the safe and effective administration of EDTA and other chelating agents for vascular disease, degenerative disease, and metal toxicity." Journal of Advancement in Medicine 10.1 (1997): 5-100.</ref> making the results of clinical application more difficult to understand, and emphasizing the need for mechanistic work. <br />
<br />
==Future Studies==<br />
TACT was a unique study with an unexpected result that could have vast public health implications. In order to consider its broad applicability, the medical and scientific community require the results reproduced. TACT2, scheduled to begin in October 2016 (press release), is a replicative study in post-MI diabetic patients. If the TACT2 results confirm the results of TACT, then chelation is poised to become the next major development in the treatment of vascular complications of diabetes and vascular disease. TACT2 is currently recruiting sites, and interested investigators should visit www.TACT2.org for additional information.<br />
<br />
==Side Effects==<br />
Shown below is a list of the labelled toxicities of EDTA-based chelation therapy. However, TACT delivered 55,222 infusions of EDTA or placebo, and found no differences between groups in adverse events, serious or otherwise.<br />
* [[Arrhythmias]]<br />
* [[Autoimmune diseases]]<br />
* [[Bone marrow]]<br />
* [[Convulsions]]<br />
* [[Depression]]<br />
* [[Fever]]<br />
* [[Heart failure]]<br />
* [[Hypocalcemia]]<br />
* [[Hypoglycemia]]<br />
* [[Hypotension]]<br />
* [[Bleeding time|Prolonged bleeding time]]<br />
* [[Renal failure]]<br />
* [[Respiratory arrest]]<br />
* [[Tetany]]<br />
* [[Trace metal|Trace metal deficiency]]<br />
* [[Vitamin deficiency]]<ref name="pmid10874275">{{cite journal| author=Ernst E| title=Chelation therapy for coronary heart disease: An overview of all clinical investigations. | journal=Am Heart J | year= 2000 | volume= 140 | issue= 1 | pages= 139-41 | pmid=10874275 | doi=10.1067/mhj.2000.107548 | pmc= | url=http://www.ncbi.nlm.nih.gov/entrez/eutils/elink.fcgi?dbfrom=pubmed&tool=sumsearch.org/cite&retmode=ref&cmd=prlinks&id=10874275 }} </ref><ref name="pmid23532240">{{cite journal| author=Lamas GA, Goertz C, Boineau R, Mark DB, Rozema T, Nahin RL et al.| title=Effect of disodium EDTA chelation regimen on cardiovascular events in patients with previous myocardial infarction: the TACT randomized trial. | journal=JAMA | year= 2013 | volume= 309 | issue= 12 | pages= 1241-50 | pmid=23532240 | doi=10.1001/jama.2013.2107 | pmc= | url=http://www.ncbi.nlm.nih.gov/entrez/eutils/elink.fcgi?dbfrom=pubmed&tool=sumsearch.org/cite&retmode=ref&cmd=prlinks&id=23532240 }} </ref><br />
<br />
==Landmark Trials==<br />
[[TACT]] <br><br />
TACT 2 [http://www.TACT2.org] (link to press release [http://www.prnewswire.com/news-releases/tact2-clinical-trial-receives-national-institutes-of-health-funding-300334174.html])<br />
<br />
==References==<br />
{{Reflist|2}}<br />
<br />
[[Category:Cardiology]]<br />
[[Category:Diabetes]]<br />
[[Category:Up-To-Date]]<br />
<br />
{{WikiDoc Help Menu}}<br />
{{WikiDoc Sources}}</div>Rim Halabyhttps://www.wikidoc.org/index.php?title=Chelation_therapy_for_cardiovascular_disease&diff=1274680Chelation therapy for cardiovascular disease2016-12-06T23:44:44Z<p>Rim Halaby: /* Overview */</p>
<hr />
<div>__NOTOC__<br />
'''Editor-In-Chief:''' Gervasio Lamas, M.D., C. Michael Gibson, M.S., M.D.; {{AE}} {{Rim}}, Ian Ergui, B.Sc.<br />
<br />
'''[[Chelation therapy|To read more about chelation therapy click here.]]'''<br><br />
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{{SK}} Chelation therapy, EDTA, post-myocardial infarction, diabetes<br />
<br />
==Overview==<br />
[[Chelation]] is a process by which an organic molecule with a negatively charged “pocket” complexes with a metal ion of opposite charge, inactivates it, and then permits its physiological mobilization and excretion, usually by a renal route. [[Chelation therapy]], which involves multiple administrations of a chelating agent, helps eliminate stored toxic metal ions from the body (Waters paper, Arenas abstract).<ref name="pmid11794513">{{cite journal| author=Waters RS, Bryden NA, Patterson KY, Veillon C, Anderson RA| title=EDTA chelation effects on urinary losses of cadmium, calcium, chromium, cobalt, copper, lead, magnesium, and zinc. | journal=Biol Trace Elem Res | year= 2001 | volume= 83 | issue= 3 | pages= 207-21 | pmid=11794513 | doi=10.1385/BTER:83:3:207 | pmc= | url=https://www.ncbi.nlm.nih.gov/entrez/eutils/elink.fcgi?dbfrom=pubmed&tool=sumsearch.org/cite&retmode=ref&cmd=prlinks&id=11794513 }} </ref><ref name="arenas">Arenas I.A., Navas-Acien A., Lamas G.A.; Enhanced vasculotoxic metal excretionin post-MI patients after edetate disodium therapy (abstr). J Am Coll Cardiol. 2016;67:A2125</ref> Common chelators include [[penicillamine]], which binds copper and can be used to treat [[Wilson’s disease]], [[deferoxamine]], which binds iron and is used in the treatment of [[thalassemia]] and iron overload, succimer, also used in the treatment of lead poisoning, and the edetates, non-specific chelators of metals and other ions with valences of +2 to +6. Chelation therapy is, in many cases, guideline mandated, such as in children with elevated blood lead levels,<ref name="CDC">CDC. Low Level Lead Exposure Harms Children: A Renewed Call for Primary Prevention. Atlanta, GA:Advisory Committee on Childhood Lead Poisoning Prevention, U.S. Centers for Disease Control and Prevention (4 Jan 2012). Available: [http://www.cdc.gov/nceh/lead/acclpp/final_document_010412.pdf]</ref> patients with iron overload and dyserythropoietic syndromes or chronic hemolytic anemia,<ref name="pmid21452290">{{cite journal| author=Bacon BR, Adams PC, Kowdley KV, Powell LW, Tavill AS, American Association for the Study of Liver Diseases| title=Diagnosis and management of hemochromatosis: 2011 practice guideline by the American Association for the Study of Liver Diseases. | journal=Hepatology | year= 2011 | volume= 54 | issue= 1 | pages= 328-43 | pmid=21452290 | doi=10.1002/hep.24330 | pmc=3149125 | url=https://www.ncbi.nlm.nih.gov/entrez/eutils/elink.fcgi?dbfrom=pubmed&tool=sumsearch.org/cite&retmode=ref&cmd=prlinks&id=21452290 }} </ref> or [[sickle cell disease]] and transfusion acquired iron-overload,<ref name="NHLBI">NHLBI. Transfusion in Sickle Cell Disease: A Systematic Review of Benefits, Complications, and Management of Complications. Prepared for the National Heart, Lung, and Blood Institute and by the Knowledge and Evaluation Research Unit, Mayo Clinic Rochester (2012)</ref> to name a few instances.<br />
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[[Ethylene diamine tetraacetic acid]] ([[EDTA]], edetate) and its salts (most commonly disodium or calcium disodium), commonly used chelating agents patented in 1938, bind to and permit the urinary excretion of divalent cations such as calcium, and metals such as [[lead]], [[cadmium]], [[nickel]], [[cobalt]], [[iron]], [[aluminum]], and others. The initial medical use for [[EDTA]] began after World War II for the treatment of [[lead]]-exposed naval workers. In addition to its use for the treatment of metal poisoning, since the 1950s chelation therapy has been considered an alternative or add-on therapy for the prevention and treatment of [[atherosclerotic disease]]. The use of edetate disodium (Na2EDTA) has been most prominent in the alternative medicine treatment of atherosclerosis primarily because of the still-unproven hypothesis that the [[hypocalcemia]] it induces might lead to the decalcification of atherosclerotic lesions. In fact, the most current research suggests that the probable mechanism of benefit centers on enhancement of toxic metal excretion.<br />
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==Chelation Therapy and CVD==<br />
The use of chelation therapy as a treatment for [[atherosclerotic disease]] dates back to the 1950’s when Clarke et al investigated the use of EDTA for the treatment of angina pectoris and reported improvement in 19 of 20 patients.<ref name="pmid13372537">{{cite journal| author=CLARKE CN, CLARKE NE, MOSHER RE| title=Treatment of angina pectoris with disodium ethylene diamine tetraacetic acid. | journal=Am J Med Sci | year= 1956 | volume= 232 | issue= 6 | pages= 654-66 | pmid=13372537 | doi= | pmc= | url=http://www.ncbi.nlm.nih.gov/entrez/eutils/elink.fcgi?dbfrom=pubmed&tool=sumsearch.org/cite&retmode=ref&cmd=prlinks&id=13372537 }} </ref> Later studies by Kitchell (Kitchell, Meltzer, & Seven, 1961; Kitchell, Palmon, Aytan, & Meltzer, 1963) were less positive, and in an era without modern clinical trials methodology nor effective concomitant therapies, opinions regarding the use of [[chelation therapy]] for [[cardiovascular disease]] (CVD) tilted towards the negative. To be fair, from the 1970’s to 1990’s the preponderance of the scientific literature on chelation therapy for atherosclerosis consisted of case reports, case series, and small clinical trials with surrogate endpoints, poor-quality evidence from which to draw a conclusion of efficacy or harm.<ref name="pmid12519577">{{cite journal| author=Villarruz MV, Dans A, Tan F| title=Chelation therapy for atherosclerotic cardiovascular disease. | journal=Cochrane Database Syst Rev | year= 2002 | volume= | issue= 4 | pages= CD002785 | pmid=12519577 | doi=10.1002/14651858.CD002785 | pmc= | url=http://www.ncbi.nlm.nih.gov/entrez/eutils/elink.fcgi?dbfrom=pubmed&tool=sumsearch.org/cite&retmode=ref&cmd=prlinks&id=12519577 }} </ref><br />
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For example, one extensive case series reported an association between EDTA chelation therapy and improvement of ischemic heart disease and peripheral artery disease.<ref name="pmid3144646">{{cite journal| author=Olszewer E, Carter JP| title=EDTA chelation therapy in chronic degenerative disease. | journal=Med Hypotheses | year= 1988 | volume= 27 | issue= 1 | pages= 41-9 | pmid=3144646 | doi= | pmc= | url=http://www.ncbi.nlm.nih.gov/entrez/eutils/elink.fcgi?dbfrom=pubmed&tool=sumsearch.org/cite&retmode=ref&cmd=prlinks&id=3144646 }} </ref> Another study demonstrated that EDTA supplemented with several B vitamins (vitamin B1, B2, B6 and B12) but not EDTA alone was effective in improving [[endothelium]]-dependent forearm blood flow.<ref name="pmid10561804">{{cite journal| author=Green DJ, O'Driscoll JG, Maiorana A, Scrimgeour NB, Weerasooriya R, Taylor RR| title=Effects of chelation with EDTA and vitamin B therapy on nitric oxide-related endothelial vasodilator function. | journal=Clin Exp Pharmacol Physiol | year= 1999 | volume= 26 | issue= 11 | pages= 853-6 | pmid=10561804 | doi= | pmc= | url=http://www.ncbi.nlm.nih.gov/entrez/eutils/elink.fcgi?dbfrom=pubmed&tool=sumsearch.org/cite&retmode=ref&cmd=prlinks&id=10561804 }} </ref> A systematic review of four randomized clinical trials on chelation therapy and [[peripheral artery occlusive disease]] reported no benefit associated with chelation therapy.<ref name="pmid9264515">{{cite journal| author=Ernst E| title=Chelation therapy for peripheral arterial occlusive disease: a systematic review. | journal=Circulation | year= 1997 | volume= 96 | issue= 3 | pages= 1031-3 | pmid=9264515 | doi= | pmc= | url=http://www.ncbi.nlm.nih.gov/entrez/eutils/elink.fcgi?dbfrom=pubmed&tool=sumsearch.org/cite&retmode=ref&cmd=prlinks&id=9264515 }} </ref> The studies, however, individually and in aggregate, were too small to exclude a small to moderate benefit of therapy. Moreover, followup was short and surrogate physiologic endpoints, such as walking distance, were used. A Cochrane systematic review on the role of chelation therapy to treat coronary heart disease in 2002 concluded that the data were insufficient to recommend for or against chelation.<ref name="pmid10874275">{{cite journal| author=Ernst E| title=Chelation therapy for coronary heart disease: An overview of all clinical investigations. | journal=Am Heart J | year= 2000 | volume= 140 | issue= 1 | pages= 139-41 | pmid=10874275 | doi=10.1067/mhj.2000.107548 | pmc= | url=http://www.ncbi.nlm.nih.gov/entrez/eutils/elink.fcgi?dbfrom=pubmed&tool=sumsearch.org/cite&retmode=ref&cmd=prlinks&id=10874275 }} </ref> <br />
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The medical community concluded that the absence of high quality evidence of efficacy equated with evidence of absence of efficacy. Professional organizations recommended against chelation therapy (Lewin, 1997). Interestingly, patients continued to seek, and practitioners to administer, chelation infusions for [[cardiovascular disease]] and other diagnoses.<br />
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In light of the persistent controversy regarding the benefits of chelation therapy and the absence of any previous large clinical trial investigating its use in coronary artery disease, the National Center for Complementary and Alternative Medicine and the National Heart Lung and Blood Institute released a $30 million Request for Applications (RFA) to develop a definitive trial. In 2002, the RFA was awarded to Mount Sinai Medical Center in Miami Beach FL (G Lamas MD, Principal Investigator). The Trial to Assess Chelation Therapy (TACT), a randomized, double blind, placebo controlled 2x2 factorial trial, investigated the efficacy and safety of disodium EDTA based infusions and high-dose oral vitamins and minerals in 1708 stable post-myocardial infarction (MI) patients more than 50 years of age and with fairly normal kidney function ([[creatinine]] 2.0 mg/dL or less). The active treatment consisted of 40 infusions consisted of disodium [[EDTA]] combined with [[ascorbic acid]], B vitamins, and other components. The median age of patients was 65 years, and they were treated with evidence-based post-MI medicines. The primary endpoint of this trial was a composite of all-cause mortality, [[stroke]], [[MI]], coronary revascularization, and hospitalization for [[angina]].<ref name="pmid16585050">{{cite journal| author=Costa J, Borges M, David C, Vaz Carneiro A| title=Efficacy of lipid lowering drug treatment for diabetic and non-diabetic patients: meta-analysis of randomised controlled trials. | journal=BMJ | year= 2006 | volume= 332 | issue= 7550 | pages= 1115-24 | pmid=16585050 | doi=10.1136/bmj.38793.468449.AE | pmc=PMC1459619 | url=http://www.ncbi.nlm.nih.gov/entrez/eutils/elink.fcgi?dbfrom=pubmed&tool=sumsearch.org/cite&retmode=ref&cmd=prlinks&id=16585050 }} </ref><br />
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A follow up period of 55 months revealed a statistically significant decrease in the primary endpoint (HR: 0.82; 95% CI: 0.69-0.99; p= 0.035). There was an absolute reduction in the 5-year Kaplan-Meier estimate, from 38% to 33%, resulting in a 5-year number needed to treat (NNT) of 18 patients to avoid one adverse cardiovascular outcome. This is comparable to the 5-year NNT for [[statins]] in post-[[MI]] patients (NNT=16 for the secondary prevention of a major coronary event).<ref name="pmid16585050">{{cite journal| author=Costa J, Borges M, David C, Vaz Carneiro A| title=Efficacy of lipid lowering drug treatment for diabetic and non-diabetic patients: meta-analysis of randomised controlled trials. | journal=BMJ | year= 2006 | volume= 332 | issue= 7550 | pages= 1115-24 | pmid=16585050 | doi=10.1136/bmj.38793.468449.AE | pmc=PMC1459619 | url=http://www.ncbi.nlm.nih.gov/entrez/eutils/elink.fcgi?dbfrom=pubmed&tool=sumsearch.org/cite&retmode=ref&cmd=prlinks&id=16585050 }} </ref> The point estimate for the risk of each of the components of the primary endpoint was <1, consistent with the aggregate result. The Investigators concluded that chelation should not yet be adopted for routine post-MI use in all patients, but the results of TACT should inform further studies to confirm or refute these unexpected results.<ref name="pmid23532240">{{cite journal| author=Lamas GA, Goertz C, Boineau R, Mark DB, Rozema T, Nahin RL et al.| title=Effect of disodium EDTA chelation regimen on cardiovascular events in patients with previous myocardial infarction: the TACT randomized trial. | journal=JAMA | year= 2013 | volume= 309 | issue= 12 | pages= 1241-50 | pmid=23532240 | doi=10.1001/jama.2013.2107 | pmc= | url=http://www.ncbi.nlm.nih.gov/entrez/eutils/elink.fcgi?dbfrom=pubmed&tool=sumsearch.org/cite&retmode=ref&cmd=prlinks&id=23532240 }} </ref><br />
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TACT prespecified several subgroups for analysis and found a significant interaction between edetate disodium treatment and [[diabetes]] (p for interaction =0.0037). Among subjects enrolled in TACT, there were 633 diabetic patients, defined as patients with self-reported diabetes, taking medications for diabetes, or having a fasting blood glucose of at least 126 mg/dL at enrollment. The administration of chelation infusions among post-MI diabetic patients was associated with a marked reduction in the primary end point when compared with placebo. The primary end point occurred in 25% of diabetic patients who were administered chelation therapy compared to 38% in those who received placebo infusions (HR, 0.59; 95% CI, 0.44–0.79; P<0.001). The 5-year NNT to prevent one event was 6.5. In addition, chelation therapy was significantly associated with decreased all-cause mortality (43% reduction, p=0.011) and reinfarction (52% reduction, p=0.015). Again, the investigators concluded that these findings supported future research, but did not constitute sufficient evidence to indicate the routine use of chelation therapy for all post–myocardial infarction patients with diabetes, leaving open the clinician’s choice to use this novel therapy in occasional, or non-routine patients.<br />
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These results catalyzed a wave of increased public and scientific interest in disodium EDTA treatment for patients with established coronary disease, particularly in diabetes, and hypotheses regarding potential mechanisms of benefit. As a capstone to the published analyses, the ACC/AHA Guidelines for Chronic Ischemic Heart Disease changed to reflect the TACT data and upgraded disodium EDTA treatment from a Class III indication to a Class IIB indication. While Class III therapeutics are considered not beneficial or useful, Class IIB treatments can be considered in some patients and require additional research to establish efficacy (ACC/AHA 2014 SIHD guidelines). The change in the guidelines signaled a major shift in the perception of chelation therapy among the medical establishment. The TACT data led clinicians to reconsider chelation objectively, and the investigators and many other academic cardiologists called for TACT2, a new trial to test the results of TACT, to be funded by the [[NIH]]. <br />
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==Mechanism of Action==<br />
Edetate disodium binds to metals and forms soluble complexes facilitating their subsequent excretion in the urine.<ref name="pmid14000694">{{cite journal| author=WILDER LW, DE JODE LR, MILSTEIN SW, HOWARD JM| title=Mobilization of atherosclerotic plaque calcium with EDTA utilizing the isolation-perfusion principle. | journal=Surgery | year= 1962 | volume= 52 | issue= | pages= 793-5 | pmid=14000694 | doi= | pmc= | url=http://www.ncbi.nlm.nih.gov/entrez/eutils/elink.fcgi?dbfrom=pubmed&tool=sumsearch.org/cite&retmode=ref&cmd=prlinks&id=14000694 }} </ref> Hence, chelation therapy results in the elimination of stored toxic and essential metals. In an experiment performed on 24 patients, age 50 or older, and with a prior MI and a creatinine of 2.0 or less, patients had urine toxic metals measured at baseline, 1 day after an infusion of placebo, and 1 day after an infusion of the edetate disodium-based TACT solution. Placebo did not increase the excretion of toxic metals. Following an infusion of the edetate disodium-based TACT solution, lead excretion increased by nearly 3900%, and cadmium by nearly 700%. Other toxic metals whose excretion was enhanced by edetate disodium were aluminum (by ~250%), nickel (by ~150%), thallium (by ~60%), and gadolinium. A similar experiment performed earlierby Waters et al, reported urinary lead concentrations approximately 35 times greater than in pre-chelation urine (Waters et al).<br />
While enhanced lead and cadmium is interesting, the critical link to cardiovascular events is provided by epidemiological studies, which provide robust evidence linking toxic metals with cardiovascular disease.<ref name="pmid21421632">{{cite journal| author=Agarwal S, Zaman T, Tuzcu EM, Kapadia SR| title=Heavy metals and cardiovascular disease: results from the National Health and Nutrition Examination Survey (NHANES) 1999-2006. | journal=Angiology | year= 2011 | volume= 62 | issue= 5 | pages= 422-9 | pmid=21421632 | doi=10.1177/0003319710395562 | pmc= | url=http://www.ncbi.nlm.nih.gov/entrez/eutils/elink.fcgi?dbfrom=pubmed&tool=sumsearch.org/cite&retmode=ref&cmd=prlinks&id=21421632 }} </ref> This evidence is strongest for lead and cadmium.<ref name="pmid16982939">{{cite journal| author=Menke A, Muntner P, Batuman V, Silbergeld EK, Guallar E| title=Blood lead below 0.48 micromol/L (10 microg/dL) and mortality among US adults. | journal=Circulation | year= 2006 | volume= 114 | issue= 13 | pages= 1388-94 | pmid=16982939 | doi=10.1161/CIRCULATIONAHA.106.628321 | pmc= | url=http://www.ncbi.nlm.nih.gov/entrez/eutils/elink.fcgi?dbfrom=pubmed&tool=sumsearch.org/cite&retmode=ref&cmd=prlinks&id=16982939 }} </ref><ref name="pmid15184277">{{cite journal| author=Navas-Acien A, Selvin E, Sharrett AR, Calderon-Aranda E, Silbergeld E, Guallar E| title=Lead, cadmium, smoking, and increased risk of peripheral arterial disease. | journal=Circulation | year= 2004 | volume= 109 | issue= 25 | pages= 3196-201 | pmid=15184277 | doi=10.1161/01.CIR.0000130848.18636.B2 | pmc= | url=http://www.ncbi.nlm.nih.gov/entrez/eutils/elink.fcgi?dbfrom=pubmed&tool=sumsearch.org/cite&retmode=ref&cmd=prlinks&id=15184277 }} </ref><ref name="pmid23514838">{{cite journal| author=Tellez-Plaza M, Guallar E, Howard BV, Umans JG, Francesconi KA, Goessler W et al.| title=Cadmium exposure and incident cardiovascular disease. | journal=Epidemiology | year= 2013 | volume= 24 | issue= 3 | pages= 421-9 | pmid=23514838 | doi=10.1097/EDE.0b013e31828b0631 | pmc= | url=http://www.ncbi.nlm.nih.gov/entrez/eutils/elink.fcgi?dbfrom=pubmed&tool=sumsearch.org/cite&retmode=ref&cmd=prlinks&id=23514838 }} </ref> Elevated blood concentration of lead is associated with increased all-cause mortality [HR 1.25 (95% CI 1.04 to 1.51) for the highest versus lowest tertile of blood lead, P trend across the tertiles=0.002) and cardiovascular mortality [HR 1.55 (95% CI 1.08 to 2.24) for the highest versus lowest tertile, P trend <0.003] ((Menke, Muntner, Batuman, Silbergeld, & Guallar, 2006)). Also, cardiovascular mortality is greater among subjects with elevated cadmium concentrations in the blood and urine [HR 1.69 (95% CI: 1.03, 2.77) and 1.74 (95% CI: 1.07, 2.83) for the 80th and 20th percentiles of blood and urine cadmium, respectively] (cadmium exposure and all cause cardiovascular mortality, Navas-Acien, Tellez-Plaza). <br />
Heavy metals may play a role in the development of [[cardiovascular disease]] through a number of different mechanisms (Navas Nature) (Vaziri Khan Interplay of ROS). Heavy metals include transition metals such as [[cadmium]], [[mercury]], [[manganese]], [[chromium]], [[cobalt]], [[nickel]], [[iron]], and [[copper]], metalloids such as antimony and arsenic, and post- transition metals such as thallium and lead. These metals all have unique toxicities, as well as toxicities that are common to all of them. Heavy metals in the endothelium promote oxygen free radical formation, resulting in increased oxidative stress, inflammation, and tissue damage. Lead and cadmium may interfere with calcium signaling channels. Transition metals promote modifications of low-density lipoprotein by endothelial cells through lipid peroxidation and degradation of low-density lipoprotein phospholipids (pubmed ID: PMC345326, PMC425370, 8847477). Exposure to non-transition metals, such as lead, has also been associated with impaired nitric oxide signaling and availability (15894814), endothelial cell dysfunction (7710289), and hypertension (18567711). [[Heavy metal]] exposure is also associated with genetic and [[epigenetic]] manifestations. [[Cadmium]] promotes atherosclerosis and endothelial dysfunction through multiple [[genetic]] changes (19556524). One of the mechanisms involves [[DNA]] strand breaks and damage with subsequent apoptosis in [[endothelial cell]]s (Messner Knoflack ATVB). Also, maternal [[lead]] exposure during pregnancy may be associated with epigenetic consequences in grandchildren through alteration of [[DNA methylation]] early in life (Sen, Heredia, Senut et al, Nature Scientific Reports Jan 2015).<br />
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Current mechanistic understanding, albeit rudimentary, supports the concept that the cardiovascular benefits of [[chelation therapy]] may result from enhanced excretion of [[heavy metals]], and subsequent reduction in processes listed above. Additionally, in patients with [[diabetes]], a reduction in the metal-catalyzed formation of [[reactive oxygen species]], formation of advanced glycation end-products, and lipid [[peroxidation]] has been postulated.<ref name="pmid10874253">{{cite journal| author=Lamas GA, Ackermann A| title=Clinical evaluation of chelation therapy: is there any wheat amidst the chaff? | journal=Am Heart J | year= 2000 | volume= 140 | issue= 1 | pages= 4-5 | pmid=10874253 | doi=10.1067/mhj.2000.107549 | pmc= | url=http://www.ncbi.nlm.nih.gov/entrez/eutils/elink.fcgi?dbfrom=pubmed&tool=sumsearch.org/cite&retmode=ref&cmd=prlinks&id=10874253 }} </ref> Metal detoxification in the context of diabetes possibly decreases [[inflammation]] and [[oxidative stress]] that characterize atherosclerosis.<ref>Escolar E, Lamas G, Mark D et al(2013) "The Effect of an EDTA-based Chelation Regimen on Patients With Diabetes Mellitus and Prior Myocardial Infarction in the Trial to Assess Chelation Therapy (TACT)". Circulation. 2013</ref> Recent research, including chelation-activity assays, indicates that many common [[diabetes]] drugs, such as [[metformin]] and aldose reductase inhibitors, could possibly have some chelating properties (Frizzell, Baynes) (Nagai Murray Chelation: a fundamental mechanism of action of AGE inhibitors, Frizell Baynes Chelation therapy for management of diabetic complications)(pubmed ID: 22492524).<br />
The TACT chelation infusion, however, did not contain edetate disodium alone. The standard chelation infusion formula used in TACT was formulated to be identical with the most prevalent infusion in use. This formulation had developed organically over decades and had been modified by clinical practitioners to have additives such as [[ascorbic acid]], B-vitamins and [[magnesium]], thought to have a protective effect on [[endothelial cells]],<ref>Rozema, Theodore C. "The protocol for the safe and effective administration of EDTA and other chelating agents for vascular disease, degenerative disease, and metal toxicity." Journal of Advancement in Medicine 10.1 (1997): 5-100.</ref> making the results of clinical application more difficult to understand, and emphasizing the need for mechanistic work. <br />
<br />
==Future Studies==<br />
TACT was a unique study with an unexpected result that could have vast public health implications. In order to consider its broad applicability, the medical and scientific community require the results reproduced. TACT2, scheduled to begin in October 2016 (press release), is a replicative study in post-MI diabetic patients. If the TACT2 results confirm the results of TACT, then chelation is poised to become the next major development in the treatment of vascular complications of diabetes and vascular disease. TACT2 is currently recruiting sites, and interested investigators should visit www.TACT2.org for additional information.<br />
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==Side Effects==<br />
Shown below is a list of the labelled toxicities of EDTA-based chelation therapy. However, TACT delivered 55,222 infusions of EDTA or placebo, and found no differences between groups in adverse events, serious or otherwise.<br />
* [[Arrhythmias]]<br />
* [[Autoimmune diseases]]<br />
* [[Bone marrow]]<br />
* [[Convulsions]]<br />
* [[Depression]]<br />
* [[Fever]]<br />
* [[Heart failure]]<br />
* [[Hypocalcemia]]<br />
* [[Hypoglycemia]]<br />
* [[Hypotension]]<br />
* [[Bleeding time|Prolonged bleeding time]]<br />
* [[Renal failure]]<br />
* [[Respiratory arrest]]<br />
* [[Tetany]]<br />
* [[Trace metal|Trace metal deficiency]]<br />
* [[Vitamin deficiency]]<ref name="pmid10874275">{{cite journal| author=Ernst E| title=Chelation therapy for coronary heart disease: An overview of all clinical investigations. | journal=Am Heart J | year= 2000 | volume= 140 | issue= 1 | pages= 139-41 | pmid=10874275 | doi=10.1067/mhj.2000.107548 | pmc= | url=http://www.ncbi.nlm.nih.gov/entrez/eutils/elink.fcgi?dbfrom=pubmed&tool=sumsearch.org/cite&retmode=ref&cmd=prlinks&id=10874275 }} </ref><ref name="pmid23532240">{{cite journal| author=Lamas GA, Goertz C, Boineau R, Mark DB, Rozema T, Nahin RL et al.| title=Effect of disodium EDTA chelation regimen on cardiovascular events in patients with previous myocardial infarction: the TACT randomized trial. | journal=JAMA | year= 2013 | volume= 309 | issue= 12 | pages= 1241-50 | pmid=23532240 | doi=10.1001/jama.2013.2107 | pmc= | url=http://www.ncbi.nlm.nih.gov/entrez/eutils/elink.fcgi?dbfrom=pubmed&tool=sumsearch.org/cite&retmode=ref&cmd=prlinks&id=23532240 }} </ref><br />
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==Landmark Trials==<br />
[[TACT]] <br><br />
TACT 2 [http://www.TACT2.org] (link to press release [http://www.prnewswire.com/news-releases/tact2-clinical-trial-receives-national-institutes-of-health-funding-300334174.html])<br />
<br />
==References==<br />
{{Reflist|2}}<br />
<br />
[[Category:Cardiology]]<br />
[[Category:Diabetes]]<br />
[[Category:Up-To-Date]]<br />
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{{WikiDoc Sources}}</div>Rim Halabyhttps://www.wikidoc.org/index.php?title=Chelation_therapy_for_cardiovascular_disease&diff=1274679Chelation therapy for cardiovascular disease2016-12-06T23:39:48Z<p>Rim Halaby: </p>
<hr />
<div>__NOTOC__<br />
'''Editor-In-Chief:''' Gervasio Lamas, M.D., C. Michael Gibson, M.S., M.D.; {{AE}} {{Rim}}, Ian Ergui, B.Sc.<br />
<br />
'''[[Chelation therapy|To read more about chelation therapy click here.]]'''<br><br />
<br />
{{SK}} Chelation therapy, EDTA, post-myocardial infarction, diabetes<br />
<br />
==Overview==<br />
[[Chelation]] is a process by which an organic molecule with a negatively charged “pocket” complexes with a metal ion of opposite charge, inactivates it, and then permits its physiological mobilization and excretion, usually by a renal route. [[Chelation therapy]], which involves multiple administrations of a chelating agent, helps eliminate stored toxic metal ions from the body (Waters paper, Arenas abstract). Common chelators include [[penicillamine]], which binds copper and can be used to treat [[Wilson’s disease]], [[deferoxamine]], which binds iron and is used in the treatment of [[thalassemia]] and iron overload, succimer, also used in the treatment of lead poisoning, and the edetates, non-specific chelators of metals and other ions with valences of +2 to +6. Chelation therapy is, in many cases, guideline mandated, such as in children with elevated blood lead levels,<ref name="CDC">CDC. Low Level Lead Exposure Harms Children: A Renewed Call for Primary Prevention. Atlanta, GA:Advisory Committee on Childhood Lead Poisoning Prevention, U.S. Centers for Disease Control and Prevention (4 Jan 2012). Available: [http://www.cdc.gov/nceh/lead/acclpp/final_document_010412.pdf]</ref> patients with iron overload and dyserythropoietic syndromes or chronic hemolytic anemia (PMC3149125), or [[sickle cell disease]] and transfusion acquired iron-overload (NHLBI Transfusion Guidelines),<ref name="NHLBI">NHLBI. Transfusion in Sickle Cell Disease: A Systematic Review of Benefits, Complications, and Management of Complications. Prepared for the National Heart, Lung, and Blood Institute and by the Knowledge and Evaluation Research Unit, Mayo Clinic Rochester (2012)</ref> to name a few instances.<br />
<br />
[[Ethylene diamine tetraacetic acid]] (EDTA, edetate) and its salts (most commonly disodium or calcium disodium), commonly used chelating agents patented in 1938, bind to and permit the urinary excretion of divalent cations such as calcium, and metals such as lead, cadmium, nickel, cobalt, iron, aluminum, and others. The initial medical use for EDTA began after World War II for the treatment of lead-exposed naval workers. In addition to its use for the treatment of metal poisoning, since the 1950s chelation therapy has been considered an alternative or add-on therapy for the prevention and treatment of [[atherosclerotic disease]]. The use of edetate disodium (Na2EDTA) has been most prominent in the alternative medicine treatment of atherosclerosis primarily because of the still-unproven hypothesis that the hypocalcemia it induces might lead to the decalcification of atherosclerotic lesions. In fact, the most current research suggests that the probable mechanism of benefit centers on enhancement of toxic metal excretion.<br />
<br />
==Chelation Therapy and CVD==<br />
The use of chelation therapy as a treatment for [[atherosclerotic disease]] dates back to the 1950’s when Clarke et al investigated the use of EDTA for the treatment of angina pectoris and reported improvement in 19 of 20 patients.<ref name="pmid13372537">{{cite journal| author=CLARKE CN, CLARKE NE, MOSHER RE| title=Treatment of angina pectoris with disodium ethylene diamine tetraacetic acid. | journal=Am J Med Sci | year= 1956 | volume= 232 | issue= 6 | pages= 654-66 | pmid=13372537 | doi= | pmc= | url=http://www.ncbi.nlm.nih.gov/entrez/eutils/elink.fcgi?dbfrom=pubmed&tool=sumsearch.org/cite&retmode=ref&cmd=prlinks&id=13372537 }} </ref> Later studies by Kitchell (Kitchell, Meltzer, & Seven, 1961; Kitchell, Palmon, Aytan, & Meltzer, 1963) were less positive, and in an era without modern clinical trials methodology nor effective concomitant therapies, opinions regarding the use of [[chelation therapy]] for [[cardiovascular disease]] (CVD) tilted towards the negative. To be fair, from the 1970’s to 1990’s the preponderance of the scientific literature on chelation therapy for atherosclerosis consisted of case reports, case series, and small clinical trials with surrogate endpoints, poor-quality evidence from which to draw a conclusion of efficacy or harm.<ref name="pmid12519577">{{cite journal| author=Villarruz MV, Dans A, Tan F| title=Chelation therapy for atherosclerotic cardiovascular disease. | journal=Cochrane Database Syst Rev | year= 2002 | volume= | issue= 4 | pages= CD002785 | pmid=12519577 | doi=10.1002/14651858.CD002785 | pmc= | url=http://www.ncbi.nlm.nih.gov/entrez/eutils/elink.fcgi?dbfrom=pubmed&tool=sumsearch.org/cite&retmode=ref&cmd=prlinks&id=12519577 }} </ref><br />
<br />
For example, one extensive case series reported an association between EDTA chelation therapy and improvement of ischemic heart disease and peripheral artery disease.<ref name="pmid3144646">{{cite journal| author=Olszewer E, Carter JP| title=EDTA chelation therapy in chronic degenerative disease. | journal=Med Hypotheses | year= 1988 | volume= 27 | issue= 1 | pages= 41-9 | pmid=3144646 | doi= | pmc= | url=http://www.ncbi.nlm.nih.gov/entrez/eutils/elink.fcgi?dbfrom=pubmed&tool=sumsearch.org/cite&retmode=ref&cmd=prlinks&id=3144646 }} </ref> Another study demonstrated that EDTA supplemented with several B vitamins (vitamin B1, B2, B6 and B12) but not EDTA alone was effective in improving [[endothelium]]-dependent forearm blood flow.<ref name="pmid10561804">{{cite journal| author=Green DJ, O'Driscoll JG, Maiorana A, Scrimgeour NB, Weerasooriya R, Taylor RR| title=Effects of chelation with EDTA and vitamin B therapy on nitric oxide-related endothelial vasodilator function. | journal=Clin Exp Pharmacol Physiol | year= 1999 | volume= 26 | issue= 11 | pages= 853-6 | pmid=10561804 | doi= | pmc= | url=http://www.ncbi.nlm.nih.gov/entrez/eutils/elink.fcgi?dbfrom=pubmed&tool=sumsearch.org/cite&retmode=ref&cmd=prlinks&id=10561804 }} </ref> A systematic review of four randomized clinical trials on chelation therapy and [[peripheral artery occlusive disease]] reported no benefit associated with chelation therapy.<ref name="pmid9264515">{{cite journal| author=Ernst E| title=Chelation therapy for peripheral arterial occlusive disease: a systematic review. | journal=Circulation | year= 1997 | volume= 96 | issue= 3 | pages= 1031-3 | pmid=9264515 | doi= | pmc= | url=http://www.ncbi.nlm.nih.gov/entrez/eutils/elink.fcgi?dbfrom=pubmed&tool=sumsearch.org/cite&retmode=ref&cmd=prlinks&id=9264515 }} </ref> The studies, however, individually and in aggregate, were too small to exclude a small to moderate benefit of therapy. Moreover, followup was short and surrogate physiologic endpoints, such as walking distance, were used. A Cochrane systematic review on the role of chelation therapy to treat coronary heart disease in 2002 concluded that the data were insufficient to recommend for or against chelation.<ref name="pmid10874275">{{cite journal| author=Ernst E| title=Chelation therapy for coronary heart disease: An overview of all clinical investigations. | journal=Am Heart J | year= 2000 | volume= 140 | issue= 1 | pages= 139-41 | pmid=10874275 | doi=10.1067/mhj.2000.107548 | pmc= | url=http://www.ncbi.nlm.nih.gov/entrez/eutils/elink.fcgi?dbfrom=pubmed&tool=sumsearch.org/cite&retmode=ref&cmd=prlinks&id=10874275 }} </ref> <br />
<br />
The medical community concluded that the absence of high quality evidence of efficacy equated with evidence of absence of efficacy. Professional organizations recommended against chelation therapy (Lewin, 1997). Interestingly, patients continued to seek, and practitioners to administer, chelation infusions for [[cardiovascular disease]] and other diagnoses.<br />
<br />
In light of the persistent controversy regarding the benefits of chelation therapy and the absence of any previous large clinical trial investigating its use in coronary artery disease, the National Center for Complementary and Alternative Medicine and the National Heart Lung and Blood Institute released a $30 million Request for Applications (RFA) to develop a definitive trial. In 2002, the RFA was awarded to Mount Sinai Medical Center in Miami Beach FL (G Lamas MD, Principal Investigator). The Trial to Assess Chelation Therapy (TACT), a randomized, double blind, placebo controlled 2x2 factorial trial, investigated the efficacy and safety of disodium EDTA based infusions and high-dose oral vitamins and minerals in 1708 stable post-myocardial infarction (MI) patients more than 50 years of age and with fairly normal kidney function ([[creatinine]] 2.0 mg/dL or less). The active treatment consisted of 40 infusions consisted of disodium [[EDTA]] combined with [[ascorbic acid]], B vitamins, and other components. The median age of patients was 65 years, and they were treated with evidence-based post-MI medicines. The primary endpoint of this trial was a composite of all-cause mortality, [[stroke]], [[MI]], coronary revascularization, and hospitalization for [[angina]].<ref name="pmid16585050">{{cite journal| author=Costa J, Borges M, David C, Vaz Carneiro A| title=Efficacy of lipid lowering drug treatment for diabetic and non-diabetic patients: meta-analysis of randomised controlled trials. | journal=BMJ | year= 2006 | volume= 332 | issue= 7550 | pages= 1115-24 | pmid=16585050 | doi=10.1136/bmj.38793.468449.AE | pmc=PMC1459619 | url=http://www.ncbi.nlm.nih.gov/entrez/eutils/elink.fcgi?dbfrom=pubmed&tool=sumsearch.org/cite&retmode=ref&cmd=prlinks&id=16585050 }} </ref><br />
<br />
A follow up period of 55 months revealed a statistically significant decrease in the primary endpoint (HR: 0.82; 95% CI: 0.69-0.99; p= 0.035). There was an absolute reduction in the 5-year Kaplan-Meier estimate, from 38% to 33%, resulting in a 5-year number needed to treat (NNT) of 18 patients to avoid one adverse cardiovascular outcome. This is comparable to the 5-year NNT for [[statins]] in post-[[MI]] patients (NNT=16 for the secondary prevention of a major coronary event).<ref name="pmid16585050">{{cite journal| author=Costa J, Borges M, David C, Vaz Carneiro A| title=Efficacy of lipid lowering drug treatment for diabetic and non-diabetic patients: meta-analysis of randomised controlled trials. | journal=BMJ | year= 2006 | volume= 332 | issue= 7550 | pages= 1115-24 | pmid=16585050 | doi=10.1136/bmj.38793.468449.AE | pmc=PMC1459619 | url=http://www.ncbi.nlm.nih.gov/entrez/eutils/elink.fcgi?dbfrom=pubmed&tool=sumsearch.org/cite&retmode=ref&cmd=prlinks&id=16585050 }} </ref> The point estimate for the risk of each of the components of the primary endpoint was <1, consistent with the aggregate result. The Investigators concluded that chelation should not yet be adopted for routine post-MI use in all patients, but the results of TACT should inform further studies to confirm or refute these unexpected results.<ref name="pmid23532240">{{cite journal| author=Lamas GA, Goertz C, Boineau R, Mark DB, Rozema T, Nahin RL et al.| title=Effect of disodium EDTA chelation regimen on cardiovascular events in patients with previous myocardial infarction: the TACT randomized trial. | journal=JAMA | year= 2013 | volume= 309 | issue= 12 | pages= 1241-50 | pmid=23532240 | doi=10.1001/jama.2013.2107 | pmc= | url=http://www.ncbi.nlm.nih.gov/entrez/eutils/elink.fcgi?dbfrom=pubmed&tool=sumsearch.org/cite&retmode=ref&cmd=prlinks&id=23532240 }} </ref><br />
<br />
TACT prespecified several subgroups for analysis and found a significant interaction between edetate disodium treatment and [[diabetes]] (p for interaction =0.0037). Among subjects enrolled in TACT, there were 633 diabetic patients, defined as patients with self-reported diabetes, taking medications for diabetes, or having a fasting blood glucose of at least 126 mg/dL at enrollment. The administration of chelation infusions among post-MI diabetic patients was associated with a marked reduction in the primary end point when compared with placebo. The primary end point occurred in 25% of diabetic patients who were administered chelation therapy compared to 38% in those who received placebo infusions (HR, 0.59; 95% CI, 0.44–0.79; P<0.001). The 5-year NNT to prevent one event was 6.5. In addition, chelation therapy was significantly associated with decreased all-cause mortality (43% reduction, p=0.011) and reinfarction (52% reduction, p=0.015). Again, the investigators concluded that these findings supported future research, but did not constitute sufficient evidence to indicate the routine use of chelation therapy for all post–myocardial infarction patients with diabetes, leaving open the clinician’s choice to use this novel therapy in occasional, or non-routine patients.<br />
<br />
These results catalyzed a wave of increased public and scientific interest in disodium EDTA treatment for patients with established coronary disease, particularly in diabetes, and hypotheses regarding potential mechanisms of benefit. As a capstone to the published analyses, the ACC/AHA Guidelines for Chronic Ischemic Heart Disease changed to reflect the TACT data and upgraded disodium EDTA treatment from a Class III indication to a Class IIB indication. While Class III therapeutics are considered not beneficial or useful, Class IIB treatments can be considered in some patients and require additional research to establish efficacy (ACC/AHA 2014 SIHD guidelines). The change in the guidelines signaled a major shift in the perception of chelation therapy among the medical establishment. The TACT data led clinicians to reconsider chelation objectively, and the investigators and many other academic cardiologists called for TACT2, a new trial to test the results of TACT, to be funded by the [[NIH]]. <br />
<br />
==Mechanism of Action==<br />
Edetate disodium binds to metals and forms soluble complexes facilitating their subsequent excretion in the urine.<ref name="pmid14000694">{{cite journal| author=WILDER LW, DE JODE LR, MILSTEIN SW, HOWARD JM| title=Mobilization of atherosclerotic plaque calcium with EDTA utilizing the isolation-perfusion principle. | journal=Surgery | year= 1962 | volume= 52 | issue= | pages= 793-5 | pmid=14000694 | doi= | pmc= | url=http://www.ncbi.nlm.nih.gov/entrez/eutils/elink.fcgi?dbfrom=pubmed&tool=sumsearch.org/cite&retmode=ref&cmd=prlinks&id=14000694 }} </ref> Hence, chelation therapy results in the elimination of stored toxic and essential metals. In an experiment performed on 24 patients, age 50 or older, and with a prior MI and a creatinine of 2.0 or less, patients had urine toxic metals measured at baseline, 1 day after an infusion of placebo, and 1 day after an infusion of the edetate disodium-based TACT solution. Placebo did not increase the excretion of toxic metals. Following an infusion of the edetate disodium-based TACT solution, lead excretion increased by nearly 3900%, and cadmium by nearly 700%. Other toxic metals whose excretion was enhanced by edetate disodium were aluminum (by ~250%), nickel (by ~150%), thallium (by ~60%), and gadolinium. A similar experiment performed earlierby Waters et al, reported urinary lead concentrations approximately 35 times greater than in pre-chelation urine (Waters et al).<br />
While enhanced lead and cadmium is interesting, the critical link to cardiovascular events is provided by epidemiological studies, which provide robust evidence linking toxic metals with cardiovascular disease.<ref name="pmid21421632">{{cite journal| author=Agarwal S, Zaman T, Tuzcu EM, Kapadia SR| title=Heavy metals and cardiovascular disease: results from the National Health and Nutrition Examination Survey (NHANES) 1999-2006. | journal=Angiology | year= 2011 | volume= 62 | issue= 5 | pages= 422-9 | pmid=21421632 | doi=10.1177/0003319710395562 | pmc= | url=http://www.ncbi.nlm.nih.gov/entrez/eutils/elink.fcgi?dbfrom=pubmed&tool=sumsearch.org/cite&retmode=ref&cmd=prlinks&id=21421632 }} </ref> This evidence is strongest for lead and cadmium.<ref name="pmid16982939">{{cite journal| author=Menke A, Muntner P, Batuman V, Silbergeld EK, Guallar E| title=Blood lead below 0.48 micromol/L (10 microg/dL) and mortality among US adults. | journal=Circulation | year= 2006 | volume= 114 | issue= 13 | pages= 1388-94 | pmid=16982939 | doi=10.1161/CIRCULATIONAHA.106.628321 | pmc= | url=http://www.ncbi.nlm.nih.gov/entrez/eutils/elink.fcgi?dbfrom=pubmed&tool=sumsearch.org/cite&retmode=ref&cmd=prlinks&id=16982939 }} </ref><ref name="pmid15184277">{{cite journal| author=Navas-Acien A, Selvin E, Sharrett AR, Calderon-Aranda E, Silbergeld E, Guallar E| title=Lead, cadmium, smoking, and increased risk of peripheral arterial disease. | journal=Circulation | year= 2004 | volume= 109 | issue= 25 | pages= 3196-201 | pmid=15184277 | doi=10.1161/01.CIR.0000130848.18636.B2 | pmc= | url=http://www.ncbi.nlm.nih.gov/entrez/eutils/elink.fcgi?dbfrom=pubmed&tool=sumsearch.org/cite&retmode=ref&cmd=prlinks&id=15184277 }} </ref><ref name="pmid23514838">{{cite journal| author=Tellez-Plaza M, Guallar E, Howard BV, Umans JG, Francesconi KA, Goessler W et al.| title=Cadmium exposure and incident cardiovascular disease. | journal=Epidemiology | year= 2013 | volume= 24 | issue= 3 | pages= 421-9 | pmid=23514838 | doi=10.1097/EDE.0b013e31828b0631 | pmc= | url=http://www.ncbi.nlm.nih.gov/entrez/eutils/elink.fcgi?dbfrom=pubmed&tool=sumsearch.org/cite&retmode=ref&cmd=prlinks&id=23514838 }} </ref> Elevated blood concentration of lead is associated with increased all-cause mortality [HR 1.25 (95% CI 1.04 to 1.51) for the highest versus lowest tertile of blood lead, P trend across the tertiles=0.002) and cardiovascular mortality [HR 1.55 (95% CI 1.08 to 2.24) for the highest versus lowest tertile, P trend <0.003] ((Menke, Muntner, Batuman, Silbergeld, & Guallar, 2006)). Also, cardiovascular mortality is greater among subjects with elevated cadmium concentrations in the blood and urine [HR 1.69 (95% CI: 1.03, 2.77) and 1.74 (95% CI: 1.07, 2.83) for the 80th and 20th percentiles of blood and urine cadmium, respectively] (cadmium exposure and all cause cardiovascular mortality, Navas-Acien, Tellez-Plaza). <br />
Heavy metals may play a role in the development of [[cardiovascular disease]] through a number of different mechanisms (Navas Nature) (Vaziri Khan Interplay of ROS). Heavy metals include transition metals such as [[cadmium]], [[mercury]], [[manganese]], [[chromium]], [[cobalt]], [[nickel]], [[iron]], and [[copper]], metalloids such as antimony and arsenic, and post- transition metals such as thallium and lead. These metals all have unique toxicities, as well as toxicities that are common to all of them. Heavy metals in the endothelium promote oxygen free radical formation, resulting in increased oxidative stress, inflammation, and tissue damage. Lead and cadmium may interfere with calcium signaling channels. Transition metals promote modifications of low-density lipoprotein by endothelial cells through lipid peroxidation and degradation of low-density lipoprotein phospholipids (pubmed ID: PMC345326, PMC425370, 8847477). Exposure to non-transition metals, such as lead, has also been associated with impaired nitric oxide signaling and availability (15894814), endothelial cell dysfunction (7710289), and hypertension (18567711). [[Heavy metal]] exposure is also associated with genetic and [[epigenetic]] manifestations. [[Cadmium]] promotes atherosclerosis and endothelial dysfunction through multiple [[genetic]] changes (19556524). One of the mechanisms involves [[DNA]] strand breaks and damage with subsequent apoptosis in [[endothelial cell]]s (Messner Knoflack ATVB). Also, maternal [[lead]] exposure during pregnancy may be associated with epigenetic consequences in grandchildren through alteration of [[DNA methylation]] early in life (Sen, Heredia, Senut et al, Nature Scientific Reports Jan 2015).<br />
<br />
Current mechanistic understanding, albeit rudimentary, supports the concept that the cardiovascular benefits of [[chelation therapy]] may result from enhanced excretion of [[heavy metals]], and subsequent reduction in processes listed above. Additionally, in patients with [[diabetes]], a reduction in the metal-catalyzed formation of [[reactive oxygen species]], formation of advanced glycation end-products, and lipid [[peroxidation]] has been postulated.<ref name="pmid10874253">{{cite journal| author=Lamas GA, Ackermann A| title=Clinical evaluation of chelation therapy: is there any wheat amidst the chaff? | journal=Am Heart J | year= 2000 | volume= 140 | issue= 1 | pages= 4-5 | pmid=10874253 | doi=10.1067/mhj.2000.107549 | pmc= | url=http://www.ncbi.nlm.nih.gov/entrez/eutils/elink.fcgi?dbfrom=pubmed&tool=sumsearch.org/cite&retmode=ref&cmd=prlinks&id=10874253 }} </ref> Metal detoxification in the context of diabetes possibly decreases [[inflammation]] and [[oxidative stress]] that characterize atherosclerosis.<ref>Escolar E, Lamas G, Mark D et al(2013) "The Effect of an EDTA-based Chelation Regimen on Patients With Diabetes Mellitus and Prior Myocardial Infarction in the Trial to Assess Chelation Therapy (TACT)". Circulation. 2013</ref> Recent research, including chelation-activity assays, indicates that many common [[diabetes]] drugs, such as [[metformin]] and aldose reductase inhibitors, could possibly have some chelating properties (Frizzell, Baynes) (Nagai Murray Chelation: a fundamental mechanism of action of AGE inhibitors, Frizell Baynes Chelation therapy for management of diabetic complications)(pubmed ID: 22492524).<br />
The TACT chelation infusion, however, did not contain edetate disodium alone. The standard chelation infusion formula used in TACT was formulated to be identical with the most prevalent infusion in use. This formulation had developed organically over decades and had been modified by clinical practitioners to have additives such as [[ascorbic acid]], B-vitamins and [[magnesium]], thought to have a protective effect on [[endothelial cells]],<ref>Rozema, Theodore C. "The protocol for the safe and effective administration of EDTA and other chelating agents for vascular disease, degenerative disease, and metal toxicity." Journal of Advancement in Medicine 10.1 (1997): 5-100.</ref> making the results of clinical application more difficult to understand, and emphasizing the need for mechanistic work. <br />
<br />
==Future Studies==<br />
TACT was a unique study with an unexpected result that could have vast public health implications. In order to consider its broad applicability, the medical and scientific community require the results reproduced. TACT2, scheduled to begin in October 2016 (press release), is a replicative study in post-MI diabetic patients. If the TACT2 results confirm the results of TACT, then chelation is poised to become the next major development in the treatment of vascular complications of diabetes and vascular disease. TACT2 is currently recruiting sites, and interested investigators should visit www.TACT2.org for additional information.<br />
<br />
==Side Effects==<br />
Shown below is a list of the labelled toxicities of EDTA-based chelation therapy. However, TACT delivered 55,222 infusions of EDTA or placebo, and found no differences between groups in adverse events, serious or otherwise.<br />
* [[Arrhythmias]]<br />
* [[Autoimmune diseases]]<br />
* [[Bone marrow]]<br />
* [[Convulsions]]<br />
* [[Depression]]<br />
* [[Fever]]<br />
* [[Heart failure]]<br />
* [[Hypocalcemia]]<br />
* [[Hypoglycemia]]<br />
* [[Hypotension]]<br />
* [[Bleeding time|Prolonged bleeding time]]<br />
* [[Renal failure]]<br />
* [[Respiratory arrest]]<br />
* [[Tetany]]<br />
* [[Trace metal|Trace metal deficiency]]<br />
* [[Vitamin deficiency]]<ref name="pmid10874275">{{cite journal| author=Ernst E| title=Chelation therapy for coronary heart disease: An overview of all clinical investigations. | journal=Am Heart J | year= 2000 | volume= 140 | issue= 1 | pages= 139-41 | pmid=10874275 | doi=10.1067/mhj.2000.107548 | pmc= | url=http://www.ncbi.nlm.nih.gov/entrez/eutils/elink.fcgi?dbfrom=pubmed&tool=sumsearch.org/cite&retmode=ref&cmd=prlinks&id=10874275 }} </ref><ref name="pmid23532240">{{cite journal| author=Lamas GA, Goertz C, Boineau R, Mark DB, Rozema T, Nahin RL et al.| title=Effect of disodium EDTA chelation regimen on cardiovascular events in patients with previous myocardial infarction: the TACT randomized trial. | journal=JAMA | year= 2013 | volume= 309 | issue= 12 | pages= 1241-50 | pmid=23532240 | doi=10.1001/jama.2013.2107 | pmc= | url=http://www.ncbi.nlm.nih.gov/entrez/eutils/elink.fcgi?dbfrom=pubmed&tool=sumsearch.org/cite&retmode=ref&cmd=prlinks&id=23532240 }} </ref><br />
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==Landmark Trials==<br />
[[TACT]] <br><br />
TACT 2 [http://www.TACT2.org] (link to press release [http://www.prnewswire.com/news-releases/tact2-clinical-trial-receives-national-institutes-of-health-funding-300334174.html])<br />
<br />
==References==<br />
{{Reflist|2}}<br />
<br />
[[Category:Cardiology]]<br />
[[Category:Diabetes]]<br />
[[Category:Up-To-Date]]<br />
<br />
{{WikiDoc Help Menu}}<br />
{{WikiDoc Sources}}</div>Rim Halabyhttps://www.wikidoc.org/index.php?title=Chelation_therapy_for_cardiovascular_disease&diff=1274474Chelation therapy for cardiovascular disease2016-12-06T15:29:43Z<p>Rim Halaby: </p>
<hr />
<div>__NOTOC__<br />
'''Editor-In-Chief:''' Gervasio Lamas, M.D., C. Michael Gibson, M.S., M.D.; {{AE}} {{Rim}}, Ian Ergui, B.Sc.<br />
<br />
'''[[Chelation therapy|To read more about chelation therapy click here.]]'''<br><br />
<br />
{{SK}} Chelation therapy, EDTA, post-myocardial infarction, diabetes<br />
<br />
==Overview==<br />
[[Chelation]] is a process by which an organic molecule with a negatively charged “pocket” complexes with a metal ion of opposite charge, inactivates it, and then permits its physiological mobilization and excretion, usually by a renal route. [[Chelation therapy]], which involves multiple administrations of a chelating agent, helps eliminate stored toxic metal ions from the body (Waters paper, Arenas abstract). Common chelators include [[penicillamine]], which binds copper and can be used to treat [[Wilson’s disease]], [[deferoxamine]], which binds iron and is used in the treatment of [[thalassemia]] and iron overload, succimer, also used in the treatment of lead poisoning, and the edetates, non-specific chelators of metals and other ions with valences of +2 to +6. Chelation therapy is, in many cases, guideline mandated, such as in children with elevated blood lead levels (2012 CDC recommendations), patients with iron overload and dyserythropoietic syndromes or chronic hemolytic anemia (American Association for the Study of Liver Diseases Guidelines), or [[sickle cell disease]] and transfusion acquired iron-overload (NHLBI Transfusion Guidelines), to name a few instances.<br />
<br />
[[Ethylene diamine tetraacetic acid]] (EDTA, edetate) and its salts (most commonly disodium or calcium disodium), commonly used chelating agents patented in 1938, bind to and permit the urinary excretion of divalent cations such as calcium, and metals such as lead, cadmium, nickel, cobalt, iron, aluminum, and others. The initial medical use for EDTA began after World War II for the treatment of lead-exposed naval workers. In addition to its use for the treatment of metal poisoning, since the 1950s chelation therapy has been considered an alternative or add-on therapy for the prevention and treatment of [[atherosclerotic disease]]. The use of edetate disodium (Na2EDTA) has been most prominent in the alternative medicine treatment of atherosclerosis primarily because of the still-unproven hypothesis that the hypocalcemia it induces might lead to the decalcification of atherosclerotic lesions. In fact, the most current research suggests that the probable mechanism of benefit centers on enhancement of toxic metal excretion.<br />
<br />
==Chelation Therapy and CVD==<br />
The use of chelation therapy as a treatment for [[atherosclerotic disease]] dates back to the 1950’s when Clarke et al investigated the use of EDTA for the treatment of angina pectoris and reported improvement in 19 of 20 patients.<ref name="pmid13372537">{{cite journal| author=CLARKE CN, CLARKE NE, MOSHER RE| title=Treatment of angina pectoris with disodium ethylene diamine tetraacetic acid. | journal=Am J Med Sci | year= 1956 | volume= 232 | issue= 6 | pages= 654-66 | pmid=13372537 | doi= | pmc= | url=http://www.ncbi.nlm.nih.gov/entrez/eutils/elink.fcgi?dbfrom=pubmed&tool=sumsearch.org/cite&retmode=ref&cmd=prlinks&id=13372537 }} </ref> Later studies by Kitchell (Kitchell, Meltzer, & Seven, 1961; Kitchell, Palmon, Aytan, & Meltzer, 1963) were less positive, and in an era without modern clinical trials methodology nor effective concomitant therapies, opinions regarding the use of [[chelation therapy]] for [[cardiovascular disease]] (CVD) tilted towards the negative. To be fair, from the 1970’s to 1990’s the preponderance of the scientific literature on chelation therapy for atherosclerosis consisted of case reports, case series, and small clinical trials with surrogate endpoints, poor-quality evidence from which to draw a conclusion of efficacy or harm.<ref name="pmid12519577">{{cite journal| author=Villarruz MV, Dans A, Tan F| title=Chelation therapy for atherosclerotic cardiovascular disease. | journal=Cochrane Database Syst Rev | year= 2002 | volume= | issue= 4 | pages= CD002785 | pmid=12519577 | doi=10.1002/14651858.CD002785 | pmc= | url=http://www.ncbi.nlm.nih.gov/entrez/eutils/elink.fcgi?dbfrom=pubmed&tool=sumsearch.org/cite&retmode=ref&cmd=prlinks&id=12519577 }} </ref><br />
<br />
For example, one extensive case series reported an association between EDTA chelation therapy and improvement of ischemic heart disease and peripheral artery disease.<ref name="pmid3144646">{{cite journal| author=Olszewer E, Carter JP| title=EDTA chelation therapy in chronic degenerative disease. | journal=Med Hypotheses | year= 1988 | volume= 27 | issue= 1 | pages= 41-9 | pmid=3144646 | doi= | pmc= | url=http://www.ncbi.nlm.nih.gov/entrez/eutils/elink.fcgi?dbfrom=pubmed&tool=sumsearch.org/cite&retmode=ref&cmd=prlinks&id=3144646 }} </ref> Another study demonstrated that EDTA supplemented with several B vitamins (vitamin B1, B2, B6 and B12) but not EDTA alone was effective in improving [[endothelium]]-dependent forearm blood flow.<ref name="pmid10561804">{{cite journal| author=Green DJ, O'Driscoll JG, Maiorana A, Scrimgeour NB, Weerasooriya R, Taylor RR| title=Effects of chelation with EDTA and vitamin B therapy on nitric oxide-related endothelial vasodilator function. | journal=Clin Exp Pharmacol Physiol | year= 1999 | volume= 26 | issue= 11 | pages= 853-6 | pmid=10561804 | doi= | pmc= | url=http://www.ncbi.nlm.nih.gov/entrez/eutils/elink.fcgi?dbfrom=pubmed&tool=sumsearch.org/cite&retmode=ref&cmd=prlinks&id=10561804 }} </ref> A systematic review of four randomized clinical trials on chelation therapy and [[peripheral artery occlusive disease]] reported no benefit associated with chelation therapy.<ref name="pmid9264515">{{cite journal| author=Ernst E| title=Chelation therapy for peripheral arterial occlusive disease: a systematic review. | journal=Circulation | year= 1997 | volume= 96 | issue= 3 | pages= 1031-3 | pmid=9264515 | doi= | pmc= | url=http://www.ncbi.nlm.nih.gov/entrez/eutils/elink.fcgi?dbfrom=pubmed&tool=sumsearch.org/cite&retmode=ref&cmd=prlinks&id=9264515 }} </ref> The studies, however, individually and in aggregate, were too small to exclude a small to moderate benefit of therapy. Moreover, followup was short and surrogate physiologic endpoints, such as walking distance, were used. A Cochrane systematic review on the role of chelation therapy to treat coronary heart disease in 2002 concluded that the data were insufficient to recommend for or against chelation.<ref name="pmid10874275">{{cite journal| author=Ernst E| title=Chelation therapy for coronary heart disease: An overview of all clinical investigations. | journal=Am Heart J | year= 2000 | volume= 140 | issue= 1 | pages= 139-41 | pmid=10874275 | doi=10.1067/mhj.2000.107548 | pmc= | url=http://www.ncbi.nlm.nih.gov/entrez/eutils/elink.fcgi?dbfrom=pubmed&tool=sumsearch.org/cite&retmode=ref&cmd=prlinks&id=10874275 }} </ref> <br />
<br />
The medical community concluded that the absence of high quality evidence of efficacy equated with evidence of absence of efficacy. Professional organizations recommended against chelation therapy (Lewin, 1997). Interestingly, patients continued to seek, and practitioners to administer, chelation infusions for [[cardiovascular disease]] and other diagnoses.<br />
<br />
In light of the persistent controversy regarding the benefits of chelation therapy and the absence of any previous large clinical trial investigating its use in coronary artery disease, the National Center for Complementary and Alternative Medicine and the National Heart Lung and Blood Institute released a $30 million Request for Applications (RFA) to develop a definitive trial. In 2002, the RFA was awarded to Mount Sinai Medical Center in Miami Beach FL (G Lamas MD, Principal Investigator). The Trial to Assess Chelation Therapy (TACT), a randomized, double blind, placebo controlled 2x2 factorial trial, investigated the efficacy and safety of disodium EDTA based infusions and high-dose oral vitamins and minerals in 1708 stable post-myocardial infarction (MI) patients more than 50 years of age and with fairly normal kidney function ([[creatinine]] 2.0 mg/dL or less). The active treatment consisted of 40 infusions consisted of disodium [[EDTA]] combined with [[ascorbic acid]], B vitamins, and other components. The median age of patients was 65 years, and they were treated with evidence-based post-MI medicines. The primary endpoint of this trial was a composite of all-cause mortality, [[stroke]], [[MI]], coronary revascularization, and hospitalization for [[angina]].<ref name="pmid16585050">{{cite journal| author=Costa J, Borges M, David C, Vaz Carneiro A| title=Efficacy of lipid lowering drug treatment for diabetic and non-diabetic patients: meta-analysis of randomised controlled trials. | journal=BMJ | year= 2006 | volume= 332 | issue= 7550 | pages= 1115-24 | pmid=16585050 | doi=10.1136/bmj.38793.468449.AE | pmc=PMC1459619 | url=http://www.ncbi.nlm.nih.gov/entrez/eutils/elink.fcgi?dbfrom=pubmed&tool=sumsearch.org/cite&retmode=ref&cmd=prlinks&id=16585050 }} </ref><br />
<br />
A follow up period of 55 months revealed a statistically significant decrease in the primary endpoint (HR: 0.82; 95% CI: 0.69-0.99; p= 0.035). There was an absolute reduction in the 5-year Kaplan-Meier estimate, from 38% to 33%, resulting in a 5-year number needed to treat (NNT) of 18 patients to avoid one adverse cardiovascular outcome. This is comparable to the 5-year NNT for [[statins]] in post-[[MI]] patients (NNT=16 for the secondary prevention of a major coronary event).<ref name="pmid16585050">{{cite journal| author=Costa J, Borges M, David C, Vaz Carneiro A| title=Efficacy of lipid lowering drug treatment for diabetic and non-diabetic patients: meta-analysis of randomised controlled trials. | journal=BMJ | year= 2006 | volume= 332 | issue= 7550 | pages= 1115-24 | pmid=16585050 | doi=10.1136/bmj.38793.468449.AE | pmc=PMC1459619 | url=http://www.ncbi.nlm.nih.gov/entrez/eutils/elink.fcgi?dbfrom=pubmed&tool=sumsearch.org/cite&retmode=ref&cmd=prlinks&id=16585050 }} </ref> The point estimate for the risk of each of the components of the primary endpoint was <1, consistent with the aggregate result. The Investigators concluded that chelation should not yet be adopted for routine post-MI use in all patients, but the results of TACT should inform further studies to confirm or refute these unexpected results.<ref name="pmid23532240">{{cite journal| author=Lamas GA, Goertz C, Boineau R, Mark DB, Rozema T, Nahin RL et al.| title=Effect of disodium EDTA chelation regimen on cardiovascular events in patients with previous myocardial infarction: the TACT randomized trial. | journal=JAMA | year= 2013 | volume= 309 | issue= 12 | pages= 1241-50 | pmid=23532240 | doi=10.1001/jama.2013.2107 | pmc= | url=http://www.ncbi.nlm.nih.gov/entrez/eutils/elink.fcgi?dbfrom=pubmed&tool=sumsearch.org/cite&retmode=ref&cmd=prlinks&id=23532240 }} </ref><br />
<br />
TACT prespecified several subgroups for analysis and found a significant interaction between edetate disodium treatment and [[diabetes]] (p for interaction =0.0037). Among subjects enrolled in TACT, there were 633 diabetic patients, defined as patients with self-reported diabetes, taking medications for diabetes, or having a fasting blood glucose of at least 126 mg/dL at enrollment. The administration of chelation infusions among post-MI diabetic patients was associated with a marked reduction in the primary end point when compared with placebo. The primary end point occurred in 25% of diabetic patients who were administered chelation therapy compared to 38% in those who received placebo infusions (HR, 0.59; 95% CI, 0.44–0.79; P<0.001). The 5-year NNT to prevent one event was 6.5. In addition, chelation therapy was significantly associated with decreased all-cause mortality (43% reduction, p=0.011) and reinfarction (52% reduction, p=0.015). Again, the investigators concluded that these findings supported future research, but did not constitute sufficient evidence to indicate the routine use of chelation therapy for all post–myocardial infarction patients with diabetes, leaving open the clinician’s choice to use this novel therapy in occasional, or non-routine patients.<br />
<br />
These results catalyzed a wave of increased public and scientific interest in disodium EDTA treatment for patients with established coronary disease, particularly in diabetes, and hypotheses regarding potential mechanisms of benefit. As a capstone to the published analyses, the ACC/AHA Guidelines for Chronic Ischemic Heart Disease changed to reflect the TACT data and upgraded disodium EDTA treatment from a Class III indication to a Class IIB indication. While Class III therapeutics are considered not beneficial or useful, Class IIB treatments can be considered in some patients and require additional research to establish efficacy (ACC/AHA 2014 SIHD guidelines). The change in the guidelines signaled a major shift in the perception of chelation therapy among the medical establishment. The TACT data led clinicians to reconsider chelation objectively, and the investigators and many other academic cardiologists called for TACT2, a new trial to test the results of TACT, to be funded by the [[NIH]]. <br />
<br />
==Mechanism of Action==<br />
Edetate disodium binds to metals and forms soluble complexes facilitating their subsequent excretion in the urine.<ref name="pmid14000694">{{cite journal| author=WILDER LW, DE JODE LR, MILSTEIN SW, HOWARD JM| title=Mobilization of atherosclerotic plaque calcium with EDTA utilizing the isolation-perfusion principle. | journal=Surgery | year= 1962 | volume= 52 | issue= | pages= 793-5 | pmid=14000694 | doi= | pmc= | url=http://www.ncbi.nlm.nih.gov/entrez/eutils/elink.fcgi?dbfrom=pubmed&tool=sumsearch.org/cite&retmode=ref&cmd=prlinks&id=14000694 }} </ref> Hence, chelation therapy results in the elimination of stored toxic and essential metals. In an experiment performed on 24 patients, age 50 or older, and with a prior MI and a creatinine of 2.0 or less, patients had urine toxic metals measured at baseline, 1 day after an infusion of placebo, and 1 day after an infusion of the edetate disodium-based TACT solution. Placebo did not increase the excretion of toxic metals. Following an infusion of the edetate disodium-based TACT solution, lead excretion increased by nearly 3900%, and cadmium by nearly 700%. Other toxic metals whose excretion was enhanced by edetate disodium were aluminum (by ~250%), nickel (by ~150%), thallium (by ~60%), and gadolinium. A similar experiment performed earlierby Waters et al, reported urinary lead concentrations approximately 35 times greater than in pre-chelation urine (Waters et al).<br />
While enhanced lead and cadmium is interesting, the critical link to cardiovascular events is provided by epidemiological studies, which provide robust evidence linking toxic metals with cardiovascular disease.<ref name="pmid21421632">{{cite journal| author=Agarwal S, Zaman T, Tuzcu EM, Kapadia SR| title=Heavy metals and cardiovascular disease: results from the National Health and Nutrition Examination Survey (NHANES) 1999-2006. | journal=Angiology | year= 2011 | volume= 62 | issue= 5 | pages= 422-9 | pmid=21421632 | doi=10.1177/0003319710395562 | pmc= | url=http://www.ncbi.nlm.nih.gov/entrez/eutils/elink.fcgi?dbfrom=pubmed&tool=sumsearch.org/cite&retmode=ref&cmd=prlinks&id=21421632 }} </ref> This evidence is strongest for lead and cadmium.<ref name="pmid16982939">{{cite journal| author=Menke A, Muntner P, Batuman V, Silbergeld EK, Guallar E| title=Blood lead below 0.48 micromol/L (10 microg/dL) and mortality among US adults. | journal=Circulation | year= 2006 | volume= 114 | issue= 13 | pages= 1388-94 | pmid=16982939 | doi=10.1161/CIRCULATIONAHA.106.628321 | pmc= | url=http://www.ncbi.nlm.nih.gov/entrez/eutils/elink.fcgi?dbfrom=pubmed&tool=sumsearch.org/cite&retmode=ref&cmd=prlinks&id=16982939 }} </ref><ref name="pmid15184277">{{cite journal| author=Navas-Acien A, Selvin E, Sharrett AR, Calderon-Aranda E, Silbergeld E, Guallar E| title=Lead, cadmium, smoking, and increased risk of peripheral arterial disease. | journal=Circulation | year= 2004 | volume= 109 | issue= 25 | pages= 3196-201 | pmid=15184277 | doi=10.1161/01.CIR.0000130848.18636.B2 | pmc= | url=http://www.ncbi.nlm.nih.gov/entrez/eutils/elink.fcgi?dbfrom=pubmed&tool=sumsearch.org/cite&retmode=ref&cmd=prlinks&id=15184277 }} </ref><ref name="pmid23514838">{{cite journal| author=Tellez-Plaza M, Guallar E, Howard BV, Umans JG, Francesconi KA, Goessler W et al.| title=Cadmium exposure and incident cardiovascular disease. | journal=Epidemiology | year= 2013 | volume= 24 | issue= 3 | pages= 421-9 | pmid=23514838 | doi=10.1097/EDE.0b013e31828b0631 | pmc= | url=http://www.ncbi.nlm.nih.gov/entrez/eutils/elink.fcgi?dbfrom=pubmed&tool=sumsearch.org/cite&retmode=ref&cmd=prlinks&id=23514838 }} </ref> Elevated blood concentration of lead is associated with increased all-cause mortality [HR 1.25 (95% CI 1.04 to 1.51) for the highest versus lowest tertile of blood lead, P trend across the tertiles=0.002) and cardiovascular mortality [HR 1.55 (95% CI 1.08 to 2.24) for the highest versus lowest tertile, P trend <0.003] ((Menke, Muntner, Batuman, Silbergeld, & Guallar, 2006)). Also, cardiovascular mortality is greater among subjects with elevated cadmium concentrations in the blood and urine [HR 1.69 (95% CI: 1.03, 2.77) and 1.74 (95% CI: 1.07, 2.83) for the 80th and 20th percentiles of blood and urine cadmium, respectively] (cadmium exposure and all cause cardiovascular mortality, Navas-Acien, Tellez-Plaza). <br />
Heavy metals may play a role in the development of [[cardiovascular disease]] through a number of different mechanisms (Navas Nature) (Vaziri Khan Interplay of ROS). Heavy metals include transition metals such as [[cadmium]], [[mercury]], [[manganese]], [[chromium]], [[cobalt]], [[nickel]], [[iron]], and [[copper]], metalloids such as antimony and arsenic, and post- transition metals such as thallium and lead. These metals all have unique toxicities, as well as toxicities that are common to all of them. Heavy metals in the endothelium promote oxygen free radical formation, resulting in increased oxidative stress, inflammation, and tissue damage. Lead and cadmium may interfere with calcium signaling channels. Transition metals promote modifications of low-density lipoprotein by endothelial cells through lipid peroxidation and degradation of low-density lipoprotein phospholipids (pubmed ID: PMC345326, PMC425370, 8847477). Exposure to non-transition metals, such as lead, has also been associated with impaired nitric oxide signaling and availability (15894814), endothelial cell dysfunction (7710289), and hypertension (18567711). [[Heavy metal]] exposure is also associated with genetic and [[epigenetic]] manifestations. [[Cadmium]] promotes atherosclerosis and endothelial dysfunction through multiple [[genetic]] changes (19556524). One of the mechanisms involves [[DNA]] strand breaks and damage with subsequent apoptosis in [[endothelial cell]]s (Messner Knoflack ATVB). Also, maternal [[lead]] exposure during pregnancy may be associated with epigenetic consequences in grandchildren through alteration of [[DNA methylation]] early in life (Sen, Heredia, Senut et al, Nature Scientific Reports Jan 2015).<br />
<br />
Current mechanistic understanding, albeit rudimentary, supports the concept that the cardiovascular benefits of [[chelation therapy]] may result from enhanced excretion of [[heavy metals]], and subsequent reduction in processes listed above. Additionally, in patients with [[diabetes]], a reduction in the metal-catalyzed formation of [[reactive oxygen species]], formation of advanced glycation end-products, and lipid [[peroxidation]] has been postulated.<ref name="pmid10874253">{{cite journal| author=Lamas GA, Ackermann A| title=Clinical evaluation of chelation therapy: is there any wheat amidst the chaff? | journal=Am Heart J | year= 2000 | volume= 140 | issue= 1 | pages= 4-5 | pmid=10874253 | doi=10.1067/mhj.2000.107549 | pmc= | url=http://www.ncbi.nlm.nih.gov/entrez/eutils/elink.fcgi?dbfrom=pubmed&tool=sumsearch.org/cite&retmode=ref&cmd=prlinks&id=10874253 }} </ref> Metal detoxification in the context of diabetes possibly decreases [[inflammation]] and [[oxidative stress]] that characterize atherosclerosis.<ref>Escolar E, Lamas G, Mark D et al(2013) "The Effect of an EDTA-based Chelation Regimen on Patients With Diabetes Mellitus and Prior Myocardial Infarction in the Trial to Assess Chelation Therapy (TACT)". Circulation. 2013</ref> Recent research, including chelation-activity assays, indicates that many common [[diabetes]] drugs, such as [[metformin]] and aldose reductase inhibitors, could possibly have some chelating properties (Frizzell, Baynes) (Nagai Murray Chelation: a fundamental mechanism of action of AGE inhibitors, Frizell Baynes Chelation therapy for management of diabetic complications)(pubmed ID: 22492524).<br />
The TACT chelation infusion, however, did not contain edetate disodium alone. The standard chelation infusion formula used in TACT was formulated to be identical with the most prevalent infusion in use. This formulation had developed organically over decades and had been modified by clinical practitioners to have additives such as [[ascorbic acid]], B-vitamins and [[magnesium]], thought to have a protective effect on [[endothelial cells]],<ref>Rozema, Theodore C. "The protocol for the safe and effective administration of EDTA and other chelating agents for vascular disease, degenerative disease, and metal toxicity." Journal of Advancement in Medicine 10.1 (1997): 5-100.</ref> making the results of clinical application more difficult to understand, and emphasizing the need for mechanistic work. <br />
<br />
==Future Studies==<br />
TACT was a unique study with an unexpected result that could have vast public health implications. In order to consider its broad applicability, the medical and scientific community require the results reproduced. TACT2, scheduled to begin in October 2016 (press release), is a replicative study in post-MI diabetic patients. If the TACT2 results confirm the results of TACT, then chelation is poised to become the next major development in the treatment of vascular complications of diabetes and vascular disease. TACT2 is currently recruiting sites, and interested investigators should visit www.TACT2.org for additional information.<br />
<br />
==Side Effects==<br />
Shown below is a list of the labelled toxicities of EDTA-based chelation therapy. However, TACT delivered 55,222 infusions of EDTA or placebo, and found no differences between groups in adverse events, serious or otherwise.<br />
* [[Arrhythmias]]<br />
* [[Autoimmune diseases]]<br />
* [[Bone marrow]]<br />
* [[Convulsions]]<br />
* [[Depression]]<br />
* [[Fever]]<br />
* [[Heart failure]]<br />
* [[Hypocalcemia]]<br />
* [[Hypoglycemia]]<br />
* [[Hypotension]]<br />
* [[Bleeding time|Prolonged bleeding time]]<br />
* [[Renal failure]]<br />
* [[Respiratory arrest]]<br />
* [[Tetany]]<br />
* [[Trace metal|Trace metal deficiency]]<br />
* [[Vitamin deficiency]]<ref name="pmid10874275">{{cite journal| author=Ernst E| title=Chelation therapy for coronary heart disease: An overview of all clinical investigations. | journal=Am Heart J | year= 2000 | volume= 140 | issue= 1 | pages= 139-41 | pmid=10874275 | doi=10.1067/mhj.2000.107548 | pmc= | url=http://www.ncbi.nlm.nih.gov/entrez/eutils/elink.fcgi?dbfrom=pubmed&tool=sumsearch.org/cite&retmode=ref&cmd=prlinks&id=10874275 }} </ref><ref name="pmid23532240">{{cite journal| author=Lamas GA, Goertz C, Boineau R, Mark DB, Rozema T, Nahin RL et al.| title=Effect of disodium EDTA chelation regimen on cardiovascular events in patients with previous myocardial infarction: the TACT randomized trial. | journal=JAMA | year= 2013 | volume= 309 | issue= 12 | pages= 1241-50 | pmid=23532240 | doi=10.1001/jama.2013.2107 | pmc= | url=http://www.ncbi.nlm.nih.gov/entrez/eutils/elink.fcgi?dbfrom=pubmed&tool=sumsearch.org/cite&retmode=ref&cmd=prlinks&id=23532240 }} </ref><br />
<br />
==Landmark Trials==<br />
[[TACT]] <br><br />
TACT 2 [http://www.TACT2.org] (link to press release [http://www.prnewswire.com/news-releases/tact2-clinical-trial-receives-national-institutes-of-health-funding-300334174.html])<br />
<br />
==References==<br />
{{Reflist|2}}<br />
<br />
[[Category:Cardiology]]<br />
[[Category:Diabetes]]<br />
[[Category:Up-To-Date]]<br />
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{{WikiDoc Sources}}</div>Rim Halabyhttps://www.wikidoc.org/index.php?title=Chelation_therapy_for_cardiovascular_disease&diff=1274470Chelation therapy for cardiovascular disease2016-12-06T15:22:24Z<p>Rim Halaby: </p>
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<div>__NOTOC__<br />
'''Editor-In-Chief:''' Gervasio Lamas, M.D., C. Michael Gibson, M.S., M.D.; {{AE}} {{Rim}}, Ian Ergui, B.Sc.<br />
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'''[[Chelation therapy|To read more about chelation therapy click here.]]'''<br><br />
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{{SK}} Chelation therapy, EDTA, post-myocardial infarction, diabetes<br />
<br />
==Overview==<br />
[[Chelation]] is a process by which an organic molecule with a negatively charged “pocket” complexes with a metal ion of opposite charge, inactivates it, and then permits its physiological mobilization and excretion, usually by a renal route. [[Chelation therapy]], which involves multiple administrations of a chelating agent, helps eliminate stored toxic metal ions from the body (Waters paper, Arenas abstract). Common chelators include [[penicillamine]], which binds copper and can be used to treat [[Wilson’s disease]], [[deferoxamine]], which binds iron and is used in the treatment of [[thalassemia]] and iron overload, succimer, also used in the treatment of lead poisoning, and the edetates, non-specific chelators of metals and other ions with valences of +2 to +6. Chelation therapy is, in many cases, guideline mandated, such as in children with elevated blood lead levels (2012 CDC recommendations), patients with iron overload and dyserythropoietic syndromes or chronic hemolytic anemia (American Association for the Study of Liver Diseases Guidelines), or [[sickle cell disease]] and transfusion acquired iron-overload (NHLBI Transfusion Guidelines), to name a few instances.<br />
<br />
[[Ethylene diamine tetraacetic acid]] (EDTA, edetate) and its salts (most commonly disodium or calcium disodium), commonly used chelating agents patented in 1938, bind to and permit the urinary excretion of divalent cations such as calcium, and metals such as lead, cadmium, nickel, cobalt, iron, aluminum, and others. The initial medical use for EDTA began after World War II for the treatment of lead-exposed naval workers. In addition to its use for the treatment of metal poisoning, since the 1950s chelation therapy has been considered an alternative or add-on therapy for the prevention and treatment of [[atherosclerotic disease]]. The use of edetate disodium (Na2EDTA) has been most prominent in the alternative medicine treatment of atherosclerosis primarily because of the still-unproven hypothesis that the hypocalcemia it induces might lead to the decalcification of atherosclerotic lesions. In fact, the most current research suggests that the probable mechanism of benefit centers on enhancement of toxic metal excretion.<br />
<br />
==Chelation Therapy and CVD==<br />
The use of chelation therapy as a treatment for [[atherosclerotic disease]] dates back to the 1950’s when Clarke et al investigated the use of EDTA for the treatment of angina pectoris and reported improvement in 19 of 20 patients.<ref name="pmid13372537">{{cite journal| author=CLARKE CN, CLARKE NE, MOSHER RE| title=Treatment of angina pectoris with disodium ethylene diamine tetraacetic acid. | journal=Am J Med Sci | year= 1956 | volume= 232 | issue= 6 | pages= 654-66 | pmid=13372537 | doi= | pmc= | url=http://www.ncbi.nlm.nih.gov/entrez/eutils/elink.fcgi?dbfrom=pubmed&tool=sumsearch.org/cite&retmode=ref&cmd=prlinks&id=13372537 }} </ref> Later studies by Kitchell (Kitchell, Meltzer, & Seven, 1961; Kitchell, Palmon, Aytan, & Meltzer, 1963) were less positive, and in an era without modern clinical trials methodology nor effective concomitant therapies, opinions regarding the use of [[chelation therapy]] for [[cardiovascular disease]] (CVD) tilted towards the negative. To be fair, from the 1970’s to 1990’s the preponderance of the scientific literature on chelation therapy for atherosclerosis consisted of case reports, case series, and small clinical trials with surrogate endpoints, poor-quality evidence from which to draw a conclusion of efficacy or harm.<ref name="pmid12519577">{{cite journal| author=Villarruz MV, Dans A, Tan F| title=Chelation therapy for atherosclerotic cardiovascular disease. | journal=Cochrane Database Syst Rev | year= 2002 | volume= | issue= 4 | pages= CD002785 | pmid=12519577 | doi=10.1002/14651858.CD002785 | pmc= | url=http://www.ncbi.nlm.nih.gov/entrez/eutils/elink.fcgi?dbfrom=pubmed&tool=sumsearch.org/cite&retmode=ref&cmd=prlinks&id=12519577 }} </ref><br />
<br />
For example, one extensive case series reported an association between EDTA chelation therapy and improvement of ischemic heart disease and peripheral artery disease.<ref name="pmid3144646">{{cite journal| author=Olszewer E, Carter JP| title=EDTA chelation therapy in chronic degenerative disease. | journal=Med Hypotheses | year= 1988 | volume= 27 | issue= 1 | pages= 41-9 | pmid=3144646 | doi= | pmc= | url=http://www.ncbi.nlm.nih.gov/entrez/eutils/elink.fcgi?dbfrom=pubmed&tool=sumsearch.org/cite&retmode=ref&cmd=prlinks&id=3144646 }} </ref> Another study demonstrated that EDTA supplemented with several B vitamins (vitamin B1, B2, B6 and B12) but not EDTA alone was effective in improving [[endothelium]]-dependent forearm blood flow.<ref name="pmid10561804">{{cite journal| author=Green DJ, O'Driscoll JG, Maiorana A, Scrimgeour NB, Weerasooriya R, Taylor RR| title=Effects of chelation with EDTA and vitamin B therapy on nitric oxide-related endothelial vasodilator function. | journal=Clin Exp Pharmacol Physiol | year= 1999 | volume= 26 | issue= 11 | pages= 853-6 | pmid=10561804 | doi= | pmc= | url=http://www.ncbi.nlm.nih.gov/entrez/eutils/elink.fcgi?dbfrom=pubmed&tool=sumsearch.org/cite&retmode=ref&cmd=prlinks&id=10561804 }} </ref> A systematic review of four randomized clinical trials on chelation therapy and [[peripheral artery occlusive disease]] reported no benefit associated with chelation therapy.<ref name="pmid9264515">{{cite journal| author=Ernst E| title=Chelation therapy for peripheral arterial occlusive disease: a systematic review. | journal=Circulation | year= 1997 | volume= 96 | issue= 3 | pages= 1031-3 | pmid=9264515 | doi= | pmc= | url=http://www.ncbi.nlm.nih.gov/entrez/eutils/elink.fcgi?dbfrom=pubmed&tool=sumsearch.org/cite&retmode=ref&cmd=prlinks&id=9264515 }} </ref> The studies, however, individually and in aggregate, were too small to exclude a small to moderate benefit of therapy. Moreover, followup was short and surrogate physiologic endpoints, such as walking distance, were used. A Cochrane systematic review on the role of chelation therapy to treat coronary heart disease in 2002 concluded that the data were insufficient to recommend for or against chelation.<ref name="pmid10874275">{{cite journal| author=Ernst E| title=Chelation therapy for coronary heart disease: An overview of all clinical investigations. | journal=Am Heart J | year= 2000 | volume= 140 | issue= 1 | pages= 139-41 | pmid=10874275 | doi=10.1067/mhj.2000.107548 | pmc= | url=http://www.ncbi.nlm.nih.gov/entrez/eutils/elink.fcgi?dbfrom=pubmed&tool=sumsearch.org/cite&retmode=ref&cmd=prlinks&id=10874275 }} </ref> <br />
<br />
The medical community concluded that the absence of high quality evidence of efficacy equated with evidence of absence of efficacy. Professional organizations recommended against chelation therapy (Lewin, 1997). Interestingly, patients continued to seek, and practitioners to administer, chelation infusions for [[cardiovascular disease]] and other diagnoses.<br />
<br />
In light of the persistent controversy regarding the benefits of chelation therapy and the absence of any previous large clinical trial investigating its use in coronary artery disease, the National Center for Complementary and Alternative Medicine and the National Heart Lung and Blood Institute released a $30 million Request for Applications (RFA) to develop a definitive trial. In 2002, the RFA was awarded to Mount Sinai Medical Center in Miami Beach FL (G Lamas MD, Principal Investigator). The Trial to Assess Chelation Therapy (TACT), a randomized, double blind, placebo controlled 2x2 factorial trial, investigated the efficacy and safety of disodium EDTA based infusions and high-dose oral vitamins and minerals in 1708 stable post-myocardial infarction (MI) patients more than 50 years of age and with fairly normal kidney function ([[creatinine]] 2.0 mg/dL or less). The active treatment consisted of 40 infusions consisted of disodium [[EDTA]] combined with [[ascorbic acid]], B vitamins, and other components. The median age of patients was 65 years, and they were treated with evidence-based post-MI medicines. The primary endpoint of this trial was a composite of all-cause mortality, [[stroke]], [[MI]], coronary revascularization, and hospitalization for [[angina]].<ref name="pmid16585050">{{cite journal| author=Costa J, Borges M, David C, Vaz Carneiro A| title=Efficacy of lipid lowering drug treatment for diabetic and non-diabetic patients: meta-analysis of randomised controlled trials. | journal=BMJ | year= 2006 | volume= 332 | issue= 7550 | pages= 1115-24 | pmid=16585050 | doi=10.1136/bmj.38793.468449.AE | pmc=PMC1459619 | url=http://www.ncbi.nlm.nih.gov/entrez/eutils/elink.fcgi?dbfrom=pubmed&tool=sumsearch.org/cite&retmode=ref&cmd=prlinks&id=16585050 }} </ref><br />
<br />
A follow up period of 55 months revealed a statistically significant decrease in the primary endpoint (HR: 0.82; 95% CI: 0.69-0.99; p= 0.035). There was an absolute reduction in the 5-year Kaplan-Meier estimate, from 38% to 33%, resulting in a 5-year number needed to treat (NNT) of 18 patients to avoid one adverse cardiovascular outcome. This is comparable to the 5-year NNT for [[statins]] in post-[[MI]] patients (NNT=16 for the secondary prevention of a major coronary event).<ref name="pmid16585050">{{cite journal| author=Costa J, Borges M, David C, Vaz Carneiro A| title=Efficacy of lipid lowering drug treatment for diabetic and non-diabetic patients: meta-analysis of randomised controlled trials. | journal=BMJ | year= 2006 | volume= 332 | issue= 7550 | pages= 1115-24 | pmid=16585050 | doi=10.1136/bmj.38793.468449.AE | pmc=PMC1459619 | url=http://www.ncbi.nlm.nih.gov/entrez/eutils/elink.fcgi?dbfrom=pubmed&tool=sumsearch.org/cite&retmode=ref&cmd=prlinks&id=16585050 }} </ref> The point estimate for the risk of each of the components of the primary endpoint was <1, consistent with the aggregate result. The Investigators concluded that chelation should not yet be adopted for routine post-MI use in all patients, but the results of TACT should inform further studies to confirm or refute these unexpected results.<ref name="pmid23532240">{{cite journal| author=Lamas GA, Goertz C, Boineau R, Mark DB, Rozema T, Nahin RL et al.| title=Effect of disodium EDTA chelation regimen on cardiovascular events in patients with previous myocardial infarction: the TACT randomized trial. | journal=JAMA | year= 2013 | volume= 309 | issue= 12 | pages= 1241-50 | pmid=23532240 | doi=10.1001/jama.2013.2107 | pmc= | url=http://www.ncbi.nlm.nih.gov/entrez/eutils/elink.fcgi?dbfrom=pubmed&tool=sumsearch.org/cite&retmode=ref&cmd=prlinks&id=23532240 }} </ref><br />
<br />
TACT prespecified several subgroups for analysis and found a significant interaction between edetate disodium treatment and [[diabetes]] (p for interaction =0.0037). Among subjects enrolled in TACT, there were 633 diabetic patients, defined as patients with self-reported diabetes, taking medications for diabetes, or having a fasting blood glucose of at least 126 mg/dL at enrollment. The administration of chelation infusions among post-MI diabetic patients was associated with a marked reduction in the primary end point when compared with placebo. The primary end point occurred in 25% of diabetic patients who were administered chelation therapy compared to 38% in those who received placebo infusions (HR, 0.59; 95% CI, 0.44–0.79; P<0.001). The 5-year NNT to prevent one event was 6.5. In addition, chelation therapy was significantly associated with decreased all-cause mortality (43% reduction, p=0.011) and reinfarction (52% reduction, p=0.015). Again, the investigators concluded that these findings supported future research, but did not constitute sufficient evidence to indicate the routine use of chelation therapy for all post–myocardial infarction patients with diabetes, leaving open the clinician’s choice to use this novel therapy in occasional, or non-routine patients.<br />
<br />
These results catalyzed a wave of increased public and scientific interest in disodium EDTA treatment for patients with established coronary disease, particularly in diabetes, and hypotheses regarding potential mechanisms of benefit. As a capstone to the published analyses, the ACC/AHA Guidelines for Chronic Ischemic Heart Disease changed to reflect the TACT data and upgraded disodium EDTA treatment from a Class III indication to a Class IIB indication. While Class III therapeutics are considered not beneficial or useful, Class IIB treatments can be considered in some patients and require additional research to establish efficacy (ACC/AHA 2014 SIHD guidelines). The change in the guidelines signaled a major shift in the perception of chelation therapy among the medical establishment. The TACT data led clinicians to reconsider chelation objectively, and the investigators and many other academic cardiologists called for TACT2, a new trial to test the results of TACT, to be funded by the [[NIH]]. <br />
<br />
==Mechanism of Action==<br />
Edetate disodium binds to metals and forms soluble complexes facilitating their subsequent excretion in the urine.<ref name="pmid14000694">{{cite journal| author=WILDER LW, DE JODE LR, MILSTEIN SW, HOWARD JM| title=Mobilization of atherosclerotic plaque calcium with EDTA utilizing the isolation-perfusion principle. | journal=Surgery | year= 1962 | volume= 52 | issue= | pages= 793-5 | pmid=14000694 | doi= | pmc= | url=http://www.ncbi.nlm.nih.gov/entrez/eutils/elink.fcgi?dbfrom=pubmed&tool=sumsearch.org/cite&retmode=ref&cmd=prlinks&id=14000694 }} </ref> Hence, chelation therapy results in the elimination of stored toxic and essential metals. In an experiment performed on 24 patients, age 50 or older, and with a prior MI and a creatinine of 2.0 or less, patients had urine toxic metals measured at baseline, 1 day after an infusion of placebo, and 1 day after an infusion of the edetate disodium-based TACT solution. Placebo did not increase the excretion of toxic metals. Following an infusion of the edetate disodium-based TACT solution, lead excretion increased by nearly 3900%, and cadmium by nearly 700%. Other toxic metals whose excretion was enhanced by edetate disodium were aluminum (by ~250%), nickel (by ~150%), thallium (by ~60%), and gadolinium. A similar experiment performed earlierby Waters et al, reported urinary lead concentrations approximately 35 times greater than in pre-chelation urine (Waters et al).<br />
While enhanced lead and cadmium is interesting, the critical link to cardiovascular events is provided by epidemiological studies, which provide robust evidence linking toxic metals with cardiovascular disease.<ref name="pmid21421632">{{cite journal| author=Agarwal S, Zaman T, Tuzcu EM, Kapadia SR| title=Heavy metals and cardiovascular disease: results from the National Health and Nutrition Examination Survey (NHANES) 1999-2006. | journal=Angiology | year= 2011 | volume= 62 | issue= 5 | pages= 422-9 | pmid=21421632 | doi=10.1177/0003319710395562 | pmc= | url=http://www.ncbi.nlm.nih.gov/entrez/eutils/elink.fcgi?dbfrom=pubmed&tool=sumsearch.org/cite&retmode=ref&cmd=prlinks&id=21421632 }} </ref> This evidence is strongest for lead and cadmium.<ref name="pmid16982939">{{cite journal| author=Menke A, Muntner P, Batuman V, Silbergeld EK, Guallar E| title=Blood lead below 0.48 micromol/L (10 microg/dL) and mortality among US adults. | journal=Circulation | year= 2006 | volume= 114 | issue= 13 | pages= 1388-94 | pmid=16982939 | doi=10.1161/CIRCULATIONAHA.106.628321 | pmc= | url=http://www.ncbi.nlm.nih.gov/entrez/eutils/elink.fcgi?dbfrom=pubmed&tool=sumsearch.org/cite&retmode=ref&cmd=prlinks&id=16982939 }} </ref><ref name="pmid15184277">{{cite journal| author=Navas-Acien A, Selvin E, Sharrett AR, Calderon-Aranda E, Silbergeld E, Guallar E| title=Lead, cadmium, smoking, and increased risk of peripheral arterial disease. | journal=Circulation | year= 2004 | volume= 109 | issue= 25 | pages= 3196-201 | pmid=15184277 | doi=10.1161/01.CIR.0000130848.18636.B2 | pmc= | url=http://www.ncbi.nlm.nih.gov/entrez/eutils/elink.fcgi?dbfrom=pubmed&tool=sumsearch.org/cite&retmode=ref&cmd=prlinks&id=15184277 }} </ref><ref name="pmid23514838">{{cite journal| author=Tellez-Plaza M, Guallar E, Howard BV, Umans JG, Francesconi KA, Goessler W et al.| title=Cadmium exposure and incident cardiovascular disease. | journal=Epidemiology | year= 2013 | volume= 24 | issue= 3 | pages= 421-9 | pmid=23514838 | doi=10.1097/EDE.0b013e31828b0631 | pmc= | url=http://www.ncbi.nlm.nih.gov/entrez/eutils/elink.fcgi?dbfrom=pubmed&tool=sumsearch.org/cite&retmode=ref&cmd=prlinks&id=23514838 }} </ref> Elevated blood concentration of lead is associated with increased all-cause mortality [HR 1.25 (95% CI 1.04 to 1.51) for the highest versus lowest tertile of blood lead, P trend across the tertiles=0.002) and cardiovascular mortality [HR 1.55 (95% CI 1.08 to 2.24) for the highest versus lowest tertile, P trend <0.003] ((Menke, Muntner, Batuman, Silbergeld, & Guallar, 2006)). Also, cardiovascular mortality is greater among subjects with elevated cadmium concentrations in the blood and urine [HR 1.69 (95% CI: 1.03, 2.77) and 1.74 (95% CI: 1.07, 2.83) for the 80th and 20th percentiles of blood and urine cadmium, respectively] (cadmium exposure and all cause cardiovascular mortality, Navas-Acien, Tellez-Plaza). <br />
Heavy metals may play a role in the development of cardiovascular disease through a number of different mechanisms (Navas Nature) (Vaziri Khan Interplay of ROS). Heavy metals include transition metals such as cadmium, mercury, manganese, chromium, cobalt, nickel, iron, and copper, metalloids such as antimony and arsenic, and post- transition metals such as thallium and lead. These metals all have unique toxicities, as well as toxicities that are common to all of them. Heavy metals in the endothelium promote oxygen free radical formation, resulting in increased oxidative stress, inflammation, and tissue damage. Lead and cadmium may interfere with calcium signaling channels. Transition metals promote modifications of low-density lipoprotein by endothelial cells through lipid peroxidation and degradation of low-density lipoprotein phospholipids (pubmed ID: PMC345326, PMC425370, 8847477). Exposure to non-transition metals, such as lead, has also been associated with impaired nitric oxide signaling and availability (15894814), endothelial cell dysfunction (7710289), and hypertension (18567711). Heavy metal exposure is also associated with genetic and epigenetic manifestations. Cadmium promotes atherosclerosis and endothelial dysfunction through multiple genetic changes (19556524). One of the mechanisms involves DNA strand breaks and damage with subsequent apoptosis in endothelial cells (Messner Knoflack ATVB). Also, maternal lead exposure during pregnancy may be associated with epigenetic consequences in grandchildren through alteration of DNA methylation early in life (Sen, Heredia, Senut et al, Nature Scientific Reports Jan 2015).<br />
<br />
Current mechanistic understanding, albeit rudimentary, supports the concept that the cardiovascular benefits of chelation therapy may result from enhanced excretion of heavy metals, and subsequent reduction in processes listed above. Additionally, in patients with diabetes, a reduction in the metal-catalyzed formation of reactive oxygen species, formation of advanced glycation end-products, and lipid peroxidation has been postulated.<ref name="pmid10874253">{{cite journal| author=Lamas GA, Ackermann A| title=Clinical evaluation of chelation therapy: is there any wheat amidst the chaff? | journal=Am Heart J | year= 2000 | volume= 140 | issue= 1 | pages= 4-5 | pmid=10874253 | doi=10.1067/mhj.2000.107549 | pmc= | url=http://www.ncbi.nlm.nih.gov/entrez/eutils/elink.fcgi?dbfrom=pubmed&tool=sumsearch.org/cite&retmode=ref&cmd=prlinks&id=10874253 }} </ref> Metal detoxification in the context of diabetes possibly decreases inflammation and oxidative stress that characterize atherosclerosis.<ref>Escolar E, Lamas G, Mark D et al(2013) "The Effect of an EDTA-based Chelation Regimen on Patients With Diabetes Mellitus and Prior Myocardial Infarction in the Trial to Assess Chelation Therapy (TACT)". Circulation. 2013</ref> Recent research, including chelation-activity assays, indicates that many common diabetes drugs, such as metformin and aldose reductase inhibitors, could possibly have some chelating properties (Frizzell, Baynes) (Nagai Murray Chelation: a fundamental mechanism of action of AGE inhibitors, Frizell Baynes Chelation therapy for management of diabetic complications)(pubmed ID: 22492524).<br />
The TACT chelation infusion, however, did not contain edetate disodium alone. The standard chelation infusion formula used in TACT was formulated to be identical with the most prevalent infusion in use. This formulation had developed organically over decades and had been modified by clinical practitioners to have additives such as ascorbic acid, B-vitamins and magnesium, thought to have a protective effect on endothelial cells,<ref>Rozema, Theodore C. "The protocol for the safe and effective administration of EDTA and other chelating agents for vascular disease, degenerative disease, and metal toxicity." Journal of Advancement in Medicine 10.1 (1997): 5-100.</ref> making the results of clinical application more difficult to understand, and emphasizing the need for mechanistic work. <br />
<br />
==Future Studies==<br />
TACT was a unique study with an unexpected result that could have vast public health implications. In order to consider its broad applicability, the medical and scientific community require the results reproduced. TACT2, scheduled to begin in October 2016 (press release), is a replicative study in post-MI diabetic patients. If the TACT2 results confirm the results of TACT, then chelation is poised to become the next major development in the treatment of vascular complications of diabetes and vascular disease. TACT2 is currently recruiting sites, and interested investigators should visit www.TACT2.org for additional information.<br />
<br />
==Side Effects==<br />
Shown below is a list of the labelled toxicities of EDTA-based chelation therapy. However, TACT delivered 55,222 infusions of EDTA or placebo, and found no differences between groups in adverse events, serious or otherwise.<br />
* [[Arrhythmias]]<br />
* [[Autoimmune diseases]]<br />
* [[Bone marrow]]<br />
* [[Convulsions]]<br />
* [[Depression]]<br />
* [[Fever]]<br />
* [[Heart failure]]<br />
* [[Hypocalcemia]]<br />
* [[Hypoglycemia]]<br />
* [[Hypotension]]<br />
* [[Bleeding time|Prolonged bleeding time]]<br />
* [[Renal failure]]<br />
* [[Respiratory arrest]]<br />
* [[Tetany]]<br />
* [[Trace metal|Trace metal deficiency]]<br />
* [[Vitamin deficiency]]<ref name="pmid10874275">{{cite journal| author=Ernst E| title=Chelation therapy for coronary heart disease: An overview of all clinical investigations. | journal=Am Heart J | year= 2000 | volume= 140 | issue= 1 | pages= 139-41 | pmid=10874275 | doi=10.1067/mhj.2000.107548 | pmc= | url=http://www.ncbi.nlm.nih.gov/entrez/eutils/elink.fcgi?dbfrom=pubmed&tool=sumsearch.org/cite&retmode=ref&cmd=prlinks&id=10874275 }} </ref><ref name="pmid23532240">{{cite journal| author=Lamas GA, Goertz C, Boineau R, Mark DB, Rozema T, Nahin RL et al.| title=Effect of disodium EDTA chelation regimen on cardiovascular events in patients with previous myocardial infarction: the TACT randomized trial. | journal=JAMA | year= 2013 | volume= 309 | issue= 12 | pages= 1241-50 | pmid=23532240 | doi=10.1001/jama.2013.2107 | pmc= | url=http://www.ncbi.nlm.nih.gov/entrez/eutils/elink.fcgi?dbfrom=pubmed&tool=sumsearch.org/cite&retmode=ref&cmd=prlinks&id=23532240 }} </ref><br />
<br />
==Landmark Trials==<br />
[[TACT]] <br><br />
TACT 2 [http://www.TACT2.org] (link to press release [http://www.prnewswire.com/news-releases/tact2-clinical-trial-receives-national-institutes-of-health-funding-300334174.html])<br />
<br />
==References==<br />
{{Reflist|2}}<br />
<br />
[[Category:Cardiology]]<br />
[[Category:Diabetes]]<br />
[[Category:Up-To-Date]]<br />
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Any of the trademarks, service marks, collective marks, design rights, personality rights or similar rights that are mentioned, used or cited in the articles of the WikiDoc are the property of their respective owners. Their use here does not imply that you may use them for any other purpose other than for the same or a similar informational use as contemplated by the original authors of these WikiDoc articles under the GFDL licensing scheme. Unless otherwise stated WikiDoc and Wikimedia sites are neither endorsed nor affiliated with any of the holders of any such rights and as such WikiDoc can not grant any rights to use any otherwise protected materials. Your use of any such or similar incorporeal property is at your own risk. <br />
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13. COPYRIGHT INFRINGEMENT:<br />
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Should you as a user of the site post material that infringes upon another entities copyright, you are responsible. WikiDoc is not responsible for your negligence in posting copyrighted materials. <br />
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14. NOT PROFESSIONAL ADVICE: <br />
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If you need specific advice (for example, medical, legal, financial, or risk management) please seek a professional who is licensed or knowledgeable in that area. <br />
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'''Thank you for taking the time to read this page, and please enjoy your use of WikiDoc.''' <br />
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'''Examples of other encyclopedia disclaimers.''' While other encyclopedias, unlike WikiDoc, are professionally peer reviewed, they still do not guarantee their content. <br />
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The britannica.com disclaimer (from the site hosting the Encyclopædia Britannica online): "YOUR USE OF BRITANNICA.COM IS AT YOUR SOLE RISK." The MSN.com disclaimer (from the site hosting Microsoft's Encarta Encyclopedia) "...AND THE ENTIRE RISK AS TO SATISFACTORY QUALITY, PERFORMANCE, ACCURACY, AND EFFORT IS WITH YOU." The bartleby.com disclaimer (from the site hosting the Columbia Encyclopedia) "YOU EXPRESSLY AGREE THAT USE OF THE SERVICE IS AT YOUR SOLE RISK." <br />
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'''Global attribution:''' The language describing WikiDoc throughout these pages is often borrowed and modified with global attribution to Wikipedia and with links to Wikipedia. This statement is a global attribution to wikipedia consistent with copyleft policies.</div>Rim Halabyhttps://www.wikidoc.org/index.php?title=Quick_Start_Guide_-_Create_a_username&diff=1088912Quick Start Guide - Create a username2015-04-17T18:56:24Z<p>Rim Halaby: </p>
<hr />
<div><div style="text-align:center;"><br />
<div style="float:left; padding: .5ex 0; font-weight:bold; background-color:#eee; border:2px solid #999; border-bottom:0; font-size:130%">&nbsp;&nbsp;1. [[WikiDoc:Quick Start Guide - Introduction|Introduction]]&nbsp;&nbsp;</div><br />
<div style="float:left; padding: .5ex 0; font-weight:bold; background-color:#ff9; border:2px solid #fc0; border-bottom:0; font-size:130%">&nbsp;&nbsp;2. [[WikiDoc:Quick Start Guide - Create a username|Create a username]]&nbsp;&nbsp;</div><br />
<div style="float:left; padding: .5ex 0; font-weight:bold; background-color:#eee; border:2px solid #999; border-bottom:0; font-size:130%">&nbsp;&nbsp;3. [[WikiDoc:Quick Start Guide - Introduce yourself|Introduce yourself]]&nbsp;&nbsp;</div><br />
<div style="float:left; padding: .5ex 0; font-weight:bold; background-color:#eee; border:2px solid #999; border-bottom:0; font-size:130%">&nbsp;&nbsp;4. [[WikiDoc:Quick Start Guide - Join in|Join in!]]&nbsp;&nbsp;</div><br />
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<div style="float: left; width: 90%; margin-left: 4.5%; margin-bottom: 2%;"><br />
<div style="float: left; padding-right: 8%;"><br />
<h3 style="font-size: 100%; margin: 0;">What is a username...</h3><br />
* A username identifies you on WikiDoc.<br />
* It's '''very easy''' to set up, and all we will need is you to create a username and a password.<br />
* Once you create a username, you'll be able to contribute content and get credit for your contributions (your username will appear in the page history), view all of your contributions, and you will be able to create a user page to tell others about you. Other users will be able to contact you on your user talk page.<br />
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<div style="width: 80%; margin: 0 auto; clear: both; white-space: nowrap; text-align: left; border-bottom: 1px solid #c0c0c0; margin-bottom: 1%;"> </div><br />
<br />
{|<br />
|<br />
{{divbox|navy|Step 1|Click on the '''create an account or log in''' link at the top of any WikiDoc page.}}<br />
<br />
<br />
{{divbox|navy|Step 2|Pick a username and password and fill out the form.}}<br />
|[[Image:Sign_up.PNG|300px|frame||'''Step 1''' - Select this link]]<br />
|[[Image:Login.PNG|100px|frame|right|'''Step 2''' - Fill out the simple form]]<br />
|}<br />
<br />
</div><br />
<div style="width: 17em; margin: 0 auto; clear: both; white-space: nowrap; text-align: left;"> </div><br />
<br />
<div style="border-top:1px solid #fc0;padding:.3em 0;text-align:center;background-color:#ff9;margin-top:.5em;font-size:140%">next step: [[WikiDoc:Quick Start Guide - Introduce yourself|'''Introduce yourself &gt;&gt;''']]<br />
</div><br />
</div><br />
<br />
{{WikiDoc Help Menu}}<br />
{{WikiDoc Sources}}<br />
[[Category:Help]]</div>Rim Halabyhttps://www.wikidoc.org/index.php?title=File:Login.PNG&diff=1088911File:Login.PNG2015-04-17T18:54:51Z<p>Rim Halaby: </p>
<hr />
<div></div>Rim Halabyhttps://www.wikidoc.org/index.php?title=Resident_survival_guide_checklist&diff=1088692Resident survival guide checklist2015-04-17T14:56:23Z<p>Rim Halaby: /* FIRE */</p>
<hr />
<div>__NOTOC__<br />
{{Resident survival guide project}}<br />
[[Image:Main_help_page_small.PNG|100px|link=Help]][[Image:Projects.PNG|100px|link=Projects]][[Image:Editor's_Tools.PNG|100px|link=Help Menu]]<br />
{{CMG}}; {{AE}} {{Rim}}; {{VR}}<br />
<br />
==Overview==<br />
The following items in this checklist describe in detail the resident survival guide pages. All these items should be present for a page to be complete and ready for quality check.<br />
<br />
==Checklist==<br />
===General Structure===<br />
* In general, each page contains the following titles in order:<br />
** Overview<br />
** Classification (if needed for the management)<br />
** Causes<br />
** FIRE<br />
** Complete Diagnostic Approach<br />
** Treatment<br />
** Do's<br />
** Dont's<br />
** References<br />
<br />
* The treatment for some diseases is extensive or it can be subdivided into sections. In this case, appropriate headings are used to organize the treatment. Click '''[[STEMI resident survival guide|here]]''' for an example.<br />
<br />
===Floating Navigation Bar===<br />
* A navigation bar is present on every resident survival guide page. Click '''[[Template:Resident_survival_guide|here]]''' for a template.<br />
* For an example of a page with a floating navigation bar, check [[STEMI resident survival guide]].<br />
* The navigation bar should contain the following items: overview, classification (if applicable), causes, FIRE, complete diagnostic approach, treatment, do's and don'ts. However, the content of the navigation bar is flexible.<br />
** If you have added an additional title or subtitle on your page make sure to add it in the navigation bar.<br />
** If the therapy is divided into several sections, modify the content of the navigation bar to fit the order of the titles of the resident survival page. Click '''[[STEMI resident survival guide|here]]''' for an example.<br />
<br />
===Overview===<br />
* The overview section is a short and straight to the point statement that summarizes the disease and its management in few sentences, particularly the immediate management.<br />
* The overview section should include the disease name in the first sentence.<br />
* To see an example of an overview section on the resident survival guide, click '''[[Cardiac tamponade resident survival guide|here]]'''.<br />
<br />
===Classification===<br />
* The classification section should be included only when the classification of the disease is needed for the management plan.<br />
* This section provides either a table or a list of subheadings of categories with content that the disease can be classified under.<br />
* To see an example of a classification section on the resident survival guide, click '''[[Atrial fibrillation resident survival guide|here]]'''.<br />
<br />
===Causes===<br />
* The causes section contains two subheadings:<br />
** Life Threatening Causes<br />
** Common Causes<br />
* Under life threatening causes, the following definition of life threatening is provided: Life-threatening causes include conditions which may result in death or permanent disability within 24 hours if left untreated.<br />
** If the disease itself is life threatening, the following sentence is written: <nowiki>[[Name of the disease]]</nowiki> is life threatening and should be treated as such irrespective of the underlying cause.<br />
* Under common causes, only the '''common''' causes are provided, without including rare etiologies.<br />
* The causes are listed in alphabetical order.<br />
* The causes are all hyperlinked.<br />
<br />
===FIRE===<br />
* This section begins with the following sentence: A Focused Initial Rapid Evaluation (FIRE) should be performed to identify patients in need of immediate intervention.<br />
* A list of abbreviated terms is provided '''above''' the algorithm as follows:<br />
<nowiki><span style="font-size:85%">'''Abbreviations:''' '''BUN''': Blood urea nitrogen; '''CAD''': Coronary artery disease; '''CBC''': Complete blood count; '''EKG''': Electrocardiogram; '''Hb''': Hemoglobin; '''ICU''': Intensive care unit; '''INR''': International normalized ratio; '''IV''': Intravenous; '''GI''': Gastrointestinal; '''NPO''': Nil per os; '''NSAIDs''': Non steroid anti-inflammatory drugs</span></nowiki><br />
<br />
And it will appear this way:<br><br />
<span style="font-size:85%">'''Abbreviations:''' '''BUN''': Blood urea nitrogen; '''CAD''': Coronary artery disease; '''CBC''': Complete blood count; '''EKG''': Electrocardiogram; '''Hb''': Hemoglobin; '''ICU''': Intensive care unit; '''INR''': International normalized ratio; '''IV''': Intravenous; '''GI''': Gastrointestinal; '''NPO''': Nil per os; '''NSAIDs''': Non steroid anti-inflammatory drugs</span><br />
<br />
* The algorithm for FIRE contains at least the following:<br />
**Identify cardinal findings that increase the pretest probability of [insert name of disease here]<br />
** Rule out life-threatening diagnoses<br />
<br />
* The boxes that require immediate attention and management are colored in red/salmon (background: #FA8072). Boxes are colored in white when they don't require immediate management.<br />
* When boxes are in red/salmon, the font color is white (color: #F8F8FF). In order to make sure that the hyperlinks are also shown as white and not blue, the following code is used: <nowiki>[[word to be hyperlinked|<span style="color:white;">word to be hyoperlinked</span>]]</nowiki><br />
<br />
===Complete Diagnostic Approach===<br />
* The complete diagnostic approach section contains the diagnostic algorithm(s).<br />
* If the diagnostic approach is very big and the algorithm is complicated, the algorithm is divided into more than one.<br />
* If more than one algorithm is provided, a subtitle is given for each.<br />
* When more than one algorithm are provided, separate them with <nowiki><br></nowiki>.<br />
* The algorithm for diagnosis contains at least the following<br />
**Characterize the symptoms<br />
**Obtain a detailed history<br />
**Examine the patient<br />
**Order labs<br />
**Order imaging studies<br />
**Consider alternative diagnoses<br />
<br />
===Treatment===<br />
* The treatment section contains the therapeutic algorithm(s).<br />
* The number of algorithms depends on each topic.<br />
* If the therapeutic approach is very big and the algorithm is complicated, the algorithm is divided into more than one.<br />
* If more than one algorithm is provided, a subtitle is given for each.<br />
* When more than one algorithm are provided, they are separated with <nowiki><br></nowiki>.<br />
* Details about the dosage, route, and frequency of the medications are provided.<br />
* Major contraindications for the medications are provided in red. Click '''[[STEMI resident survival guide|here]]''' for an example.<br />
* Action verbs are used before medications or treatment, for example: "Administer aspirin" instead of aspirin.<br />
* Check-boxes “❑” are placed in front of every action. <br />
* Urgent or Immediately are added when an action should be taken as soon as possible.<br />
* When the algorithm contains a big management plan already developed on another resident survival page, the management should not be replicated but rather redirected to the other resident survival guide page. <br />
<br />
===Description of The Algorithm===<br />
* Before starting the algorithm, the following sentence is written and the main reference(s) of the algorithm are cited:<br><br />
Shown below is an algorithm depicting [...] based on [...].(references)<br />
<br />
* Abbreviations should be avoided, example: hour and not hr, minute and not min.<br />
** If abbreviations are used, provide a list of abbreviated terms '''above''' the algorithm as follows:<br />
<nowiki><span style="font-size:85%">'''Abbreviations:''' '''BUN''': Blood urea nitrogen; '''CAD''': Coronary artery disease; '''CBC''': Complete blood count; '''EKG''': Electrocardiogram; '''Hb''': Hemoglobin; '''ICU''': Intensive care unit; '''INR''': International normalized ratio; '''IV''': Intravenous; '''GI''': Gastrointestinal; '''NPO''': Nil per os; '''NSAIDs''': Non steroid anti-inflammatory drugs</span></nowiki><br />
<br />
And it will appear this way:<br><br />
<span style="font-size:85%">'''Abbreviations:''' '''BUN''': Blood urea nitrogen; '''CAD''': Coronary artery disease; '''CBC''': Complete blood count; '''EKG''': Electrocardiogram; '''Hb''': Hemoglobin; '''ICU''': Intensive care unit; '''INR''': International normalized ratio; '''IV''': Intravenous; '''GI''': Gastrointestinal; '''NPO''': Nil per os; '''NSAIDs''': Non steroid anti-inflammatory drugs</span><br />
<br />
Click '''[[STEMI resident survival guide|here]]''' for an example.<br />
<br />
<br />
* The algorithm should be drawn on a paper then replicated on WikiDoc in a way that the algorithm is minimally spaced.<br />
* The algorithm and content are aligned to the left, and the size of each box is adjusted using the following formula:<br />
** <nowiki><div style="float: left; text-align: left; width: 25em; padding:1em;"> [content of the box] </div> </nowiki><br />
* The algorithm should contain the following:<br />
** Characterize the symptoms:<br />
** Obtain a detailed history:<br />
** Examine the patient:<br />
** Order labs:<br />
** Order imaging studies:<br />
**Consider alternative diagnoses:<br />
<br />
* Action verbs are used before medications or treatment, for example: "Administer aspirin" instead of aspirin<br />
* Check-boxes ❑ are placed in front of every action.<br />
* '''Urgent''' or '''Immediately''' are added when an action should be taken as soon as possible.<br />
* When a medication is to be administered, the dose and mode of administration are included.<br />
<br />
* When the algorithm contains a big management plan already developed on another resident survival page, the management should not be replicated but rather redirected to the other reisdent survival guide page.<br />
<br />
===Do's===<br />
* Extra information and details about the management are provided in this section.<br />
* Each sentence is written as an order, for example:<br />
** Order an EKG. (correct)<br />
** An EKG should be ordered. (incorrect)<br />
* Write the important do’s within the algorithms. <br />
<br />
===Dont's===<br />
* Extra information and details about what should be avoided in the management are provided in this section.<br />
* Each sentence is written as an order, for example:<br />
** Do not administer beta blockers. (correct)<br />
** Beta blockers should not be administered. (incorrect)<br />
<br />
===References===<br />
* Make sure to use the latest guidelines and recommendations as references.<br />
* Make sure that the links of the references are working.<br />
<br />
===General Notes===<br />
* When more that one associate editors are included, separate the names by a a semicolon followed by a space.<br />
* Expand buttons should be avoided as much as possible.<br />
* Hyperlinks through <nowiki> [[ ]] </nowiki> are used to link key words to their pages.<br />
* The page should be reviewed for typographical errors and capitalization.<br />
* Add '''categories''' for each section. Make sure that <nowiki>[[category:Resident survival guide]]</nowiki> is present among others, for example: <nowiki>[[Category:Cardiology]]</nowiki>.<br />
* Make sure that a siren is present on all the pages of each of the resident survival guide's topics.<br />
* Contributors who are not native English speakers and require help in writing should add the Category:Grammar to their pages.<br />
<br />
===Example of Pages===<br />
For examples of high quality pages, please check:<br />
* [[STEMI resident survival guide]]<br />
* [[Bradycardia resident survival guide]]<br />
* [[Cardiac tamponade resident survival guide]]</div>Rim Halabyhttps://www.wikidoc.org/index.php?title=Resident_survival_guide_checklist&diff=1088690Resident survival guide checklist2015-04-17T14:54:05Z<p>Rim Halaby: /* FIRE */</p>
<hr />
<div>__NOTOC__<br />
{{Resident survival guide project}}<br />
[[Image:Main_help_page_small.PNG|100px|link=Help]][[Image:Projects.PNG|100px|link=Projects]][[Image:Editor's_Tools.PNG|100px|link=Help Menu]]<br />
{{CMG}}; {{AE}} {{Rim}}; {{VR}}<br />
<br />
==Overview==<br />
The following items in this checklist describe in detail the resident survival guide pages. All these items should be present for a page to be complete and ready for quality check.<br />
<br />
==Checklist==<br />
===General Structure===<br />
* In general, each page contains the following titles in order:<br />
** Overview<br />
** Classification (if needed for the management)<br />
** Causes<br />
** FIRE<br />
** Complete Diagnostic Approach<br />
** Treatment<br />
** Do's<br />
** Dont's<br />
** References<br />
<br />
* The treatment for some diseases is extensive or it can be subdivided into sections. In this case, appropriate headings are used to organize the treatment. Click '''[[STEMI resident survival guide|here]]''' for an example.<br />
<br />
===Floating Navigation Bar===<br />
* A navigation bar is present on every resident survival guide page. Click '''[[Template:Resident_survival_guide|here]]''' for a template.<br />
* For an example of a page with a floating navigation bar, check [[STEMI resident survival guide]].<br />
* The navigation bar should contain the following items: overview, classification (if applicable), causes, FIRE, complete diagnostic approach, treatment, do's and don'ts. However, the content of the navigation bar is flexible.<br />
** If you have added an additional title or subtitle on your page make sure to add it in the navigation bar.<br />
** If the therapy is divided into several sections, modify the content of the navigation bar to fit the order of the titles of the resident survival page. Click '''[[STEMI resident survival guide|here]]''' for an example.<br />
<br />
===Overview===<br />
* The overview section is a short and straight to the point statement that summarizes the disease and its management in few sentences, particularly the immediate management.<br />
* The overview section should include the disease name in the first sentence.<br />
* To see an example of an overview section on the resident survival guide, click '''[[Cardiac tamponade resident survival guide|here]]'''.<br />
<br />
===Classification===<br />
* The classification section should be included only when the classification of the disease is needed for the management plan.<br />
* This section provides either a table or a list of subheadings of categories with content that the disease can be classified under.<br />
* To see an example of a classification section on the resident survival guide, click '''[[Atrial fibrillation resident survival guide|here]]'''.<br />
<br />
===Causes===<br />
* The causes section contains two subheadings:<br />
** Life Threatening Causes<br />
** Common Causes<br />
* Under life threatening causes, the following definition of life threatening is provided: Life-threatening causes include conditions which may result in death or permanent disability within 24 hours if left untreated.<br />
** If the disease itself is life threatening, the following sentence is written: <nowiki>[[Name of the disease]]</nowiki> is life threatening and should be treated as such irrespective of the underlying cause.<br />
* Under common causes, only the '''common''' causes are provided, without including rare etiologies.<br />
* The causes are listed in alphabetical order.<br />
* The causes are all hyperlinked.<br />
<br />
===FIRE===<br />
* This section begins with the following sentence: A Focused Initial Rapid Evaluation (FIRE) should be performed to identify patients in need of immediate intervention.<br />
* A list of abbreviated terms is provided '''above''' the algorithm as follows:<br />
<nowiki><span style="font-size:85%">'''Abbreviations:''' '''BUN''': Blood urea nitrogen; '''CAD''': Coronary artery disease; '''CBC''': Complete blood count; '''EKG''': Electrocardiogram; '''Hb''': Hemoglobin; '''ICU''': Intensive care unit; '''INR''': International normalized ratio; '''IV''': Intravenous; '''GI''': Gastrointestinal; '''NPO''': Nil per os; '''NSAIDs''': Non steroid anti-inflammatory drugs</span></nowiki><br />
<br />
And it will appear this way:<br><br />
<span style="font-size:85%">'''Abbreviations:''' '''BUN''': Blood urea nitrogen; '''CAD''': Coronary artery disease; '''CBC''': Complete blood count; '''EKG''': Electrocardiogram; '''Hb''': Hemoglobin; '''ICU''': Intensive care unit; '''INR''': International normalized ratio; '''IV''': Intravenous; '''GI''': Gastrointestinal; '''NPO''': Nil per os; '''NSAIDs''': Non steroid anti-inflammatory drugs</span><br />
<br />
* The algorithm for FIRE contains at least the following:<br />
**Identify cardinal findings that increase the pretest probability of [insert name of disease here]<br />
** Rule out life-threatening diagnoses<br />
<br />
* The boxes that require immediate attention and management are colored in red/salmon (background: #FA8072). Boxes are colored in white when they don't require immediate management.<br />
<br />
===Complete Diagnostic Approach===<br />
* The complete diagnostic approach section contains the diagnostic algorithm(s).<br />
* If the diagnostic approach is very big and the algorithm is complicated, the algorithm is divided into more than one.<br />
* If more than one algorithm is provided, a subtitle is given for each.<br />
* When more than one algorithm are provided, separate them with <nowiki><br></nowiki>.<br />
* The algorithm for diagnosis contains at least the following<br />
**Characterize the symptoms<br />
**Obtain a detailed history<br />
**Examine the patient<br />
**Order labs<br />
**Order imaging studies<br />
**Consider alternative diagnoses<br />
<br />
===Treatment===<br />
* The treatment section contains the therapeutic algorithm(s).<br />
* The number of algorithms depends on each topic.<br />
* If the therapeutic approach is very big and the algorithm is complicated, the algorithm is divided into more than one.<br />
* If more than one algorithm is provided, a subtitle is given for each.<br />
* When more than one algorithm are provided, they are separated with <nowiki><br></nowiki>.<br />
* Details about the dosage, route, and frequency of the medications are provided.<br />
* Major contraindications for the medications are provided in red. Click '''[[STEMI resident survival guide|here]]''' for an example.<br />
* Action verbs are used before medications or treatment, for example: "Administer aspirin" instead of aspirin.<br />
* Check-boxes “❑” are placed in front of every action. <br />
* Urgent or Immediately are added when an action should be taken as soon as possible.<br />
* When the algorithm contains a big management plan already developed on another resident survival page, the management should not be replicated but rather redirected to the other resident survival guide page. <br />
<br />
===Description of The Algorithm===<br />
* Before starting the algorithm, the following sentence is written and the main reference(s) of the algorithm are cited:<br><br />
Shown below is an algorithm depicting [...] based on [...].(references)<br />
<br />
* Abbreviations should be avoided, example: hour and not hr, minute and not min.<br />
** If abbreviations are used, provide a list of abbreviated terms '''above''' the algorithm as follows:<br />
<nowiki><span style="font-size:85%">'''Abbreviations:''' '''BUN''': Blood urea nitrogen; '''CAD''': Coronary artery disease; '''CBC''': Complete blood count; '''EKG''': Electrocardiogram; '''Hb''': Hemoglobin; '''ICU''': Intensive care unit; '''INR''': International normalized ratio; '''IV''': Intravenous; '''GI''': Gastrointestinal; '''NPO''': Nil per os; '''NSAIDs''': Non steroid anti-inflammatory drugs</span></nowiki><br />
<br />
And it will appear this way:<br><br />
<span style="font-size:85%">'''Abbreviations:''' '''BUN''': Blood urea nitrogen; '''CAD''': Coronary artery disease; '''CBC''': Complete blood count; '''EKG''': Electrocardiogram; '''Hb''': Hemoglobin; '''ICU''': Intensive care unit; '''INR''': International normalized ratio; '''IV''': Intravenous; '''GI''': Gastrointestinal; '''NPO''': Nil per os; '''NSAIDs''': Non steroid anti-inflammatory drugs</span><br />
<br />
Click '''[[STEMI resident survival guide|here]]''' for an example.<br />
<br />
<br />
* The algorithm should be drawn on a paper then replicated on WikiDoc in a way that the algorithm is minimally spaced.<br />
* The algorithm and content are aligned to the left, and the size of each box is adjusted using the following formula:<br />
** <nowiki><div style="float: left; text-align: left; width: 25em; padding:1em;"> [content of the box] </div> </nowiki><br />
* The algorithm should contain the following:<br />
** Characterize the symptoms:<br />
** Obtain a detailed history:<br />
** Examine the patient:<br />
** Order labs:<br />
** Order imaging studies:<br />
**Consider alternative diagnoses:<br />
<br />
* Action verbs are used before medications or treatment, for example: "Administer aspirin" instead of aspirin<br />
* Check-boxes ❑ are placed in front of every action.<br />
* '''Urgent''' or '''Immediately''' are added when an action should be taken as soon as possible.<br />
* When a medication is to be administered, the dose and mode of administration are included.<br />
<br />
* When the algorithm contains a big management plan already developed on another resident survival page, the management should not be replicated but rather redirected to the other reisdent survival guide page.<br />
<br />
===Do's===<br />
* Extra information and details about the management are provided in this section.<br />
* Each sentence is written as an order, for example:<br />
** Order an EKG. (correct)<br />
** An EKG should be ordered. (incorrect)<br />
* Write the important do’s within the algorithms. <br />
<br />
===Dont's===<br />
* Extra information and details about what should be avoided in the management are provided in this section.<br />
* Each sentence is written as an order, for example:<br />
** Do not administer beta blockers. (correct)<br />
** Beta blockers should not be administered. (incorrect)<br />
<br />
===References===<br />
* Make sure to use the latest guidelines and recommendations as references.<br />
* Make sure that the links of the references are working.<br />
<br />
===General Notes===<br />
* When more that one associate editors are included, separate the names by a a semicolon followed by a space.<br />
* Expand buttons should be avoided as much as possible.<br />
* Hyperlinks through <nowiki> [[ ]] </nowiki> are used to link key words to their pages.<br />
* The page should be reviewed for typographical errors and capitalization.<br />
* Add '''categories''' for each section. Make sure that <nowiki>[[category:Resident survival guide]]</nowiki> is present among others, for example: <nowiki>[[Category:Cardiology]]</nowiki>.<br />
* Make sure that a siren is present on all the pages of each of the resident survival guide's topics.<br />
* Contributors who are not native English speakers and require help in writing should add the Category:Grammar to their pages.<br />
<br />
===Example of Pages===<br />
For examples of high quality pages, please check:<br />
* [[STEMI resident survival guide]]<br />
* [[Bradycardia resident survival guide]]<br />
* [[Cardiac tamponade resident survival guide]]</div>Rim Halabyhttps://www.wikidoc.org/index.php?title=Resident_survival_guide_checklist&diff=1088683Resident survival guide checklist2015-04-17T14:41:43Z<p>Rim Halaby: /* Checklist */</p>
<hr />
<div>__NOTOC__<br />
{{Resident survival guide project}}<br />
[[Image:Main_help_page_small.PNG|100px|link=Help]][[Image:Projects.PNG|100px|link=Projects]][[Image:Editor's_Tools.PNG|100px|link=Help Menu]]<br />
{{CMG}}; {{AE}} {{Rim}}; {{VR}}<br />
<br />
==Overview==<br />
The following items in this checklist describe in detail the resident survival guide pages. All these items should be present for a page to be complete and ready for quality check.<br />
<br />
==Checklist==<br />
===General Structure===<br />
* In general, each page contains the following titles in order:<br />
** Overview<br />
** Classification (if needed for the management)<br />
** Causes<br />
** FIRE<br />
** Complete Diagnostic Approach<br />
** Treatment<br />
** Do's<br />
** Dont's<br />
** References<br />
<br />
* The treatment for some diseases is extensive or it can be subdivided into sections. In this case, appropriate headings are used to organize the treatment. Click '''[[STEMI resident survival guide|here]]''' for an example.<br />
<br />
===Floating Navigation Bar===<br />
* A navigation bar is present on every resident survival guide page. Click '''[[Template:Resident_survival_guide|here]]''' for a template.<br />
* For an example of a page with a floating navigation bar, check [[STEMI resident survival guide]].<br />
* The navigation bar should contain the following items: overview, classification (if applicable), causes, FIRE, complete diagnostic approach, treatment, do's and don'ts. However, the content of the navigation bar is flexible.<br />
** If you have added an additional title or subtitle on your page make sure to add it in the navigation bar.<br />
** If the therapy is divided into several sections, modify the content of the navigation bar to fit the order of the titles of the resident survival page. Click '''[[STEMI resident survival guide|here]]''' for an example.<br />
<br />
===Overview===<br />
* The overview section is a short and straight to the point statement that summarizes the disease and its management in few sentences, particularly the immediate management.<br />
* The overview section should include the disease name in the first sentence.<br />
* To see an example of an overview section on the resident survival guide, click '''[[Cardiac tamponade resident survival guide|here]]'''.<br />
<br />
===Classification===<br />
* The classification section should be included only when the classification of the disease is needed for the management plan.<br />
* This section provides either a table or a list of subheadings of categories with content that the disease can be classified under.<br />
* To see an example of a classification section on the resident survival guide, click '''[[Atrial fibrillation resident survival guide|here]]'''.<br />
<br />
===Causes===<br />
* The causes section contains two subheadings:<br />
** Life Threatening Causes<br />
** Common Causes<br />
* Under life threatening causes, the following definition of life threatening is provided: Life-threatening causes include conditions which may result in death or permanent disability within 24 hours if left untreated.<br />
** If the disease itself is life threatening, the following sentence is written: <nowiki>[[Name of the disease]]</nowiki> is life threatening and should be treated as such irrespective of the underlying cause.<br />
* Under common causes, only the '''common''' causes are provided, without including rare etiologies.<br />
* The causes are listed in alphabetical order.<br />
* The causes are all hyperlinked.<br />
<br />
===FIRE===<br />
* This section begins with the following sentence: A Focused Initial Rapid Evaluation (FIRE) should be performed to identify patients in need of immediate intervention.<br />
* A list of abbreviated terms is provided '''above''' the algorithm as follows:<br />
<nowiki><span style="font-size:85%">'''Abbreviations:''' '''BUN''': Blood urea nitrogen; '''CAD''': Coronary artery disease; '''CBC''': Complete blood count; '''EKG''': Electrocardiogram; '''Hb''': Hemoglobin; '''ICU''': Intensive care unit; '''INR''': International normalized ratio; '''IV''': Intravenous; '''GI''': Gastrointestinal; '''NPO''': Nil per os; '''NSAIDs''': Non steroid anti-inflammatory drugs</span></nowiki><br />
<br />
And it will appear this way:<br><br />
<span style="font-size:85%">'''Abbreviations:''' '''BUN''': Blood urea nitrogen; '''CAD''': Coronary artery disease; '''CBC''': Complete blood count; '''EKG''': Electrocardiogram; '''Hb''': Hemoglobin; '''ICU''': Intensive care unit; '''INR''': International normalized ratio; '''IV''': Intravenous; '''GI''': Gastrointestinal; '''NPO''': Nil per os; '''NSAIDs''': Non steroid anti-inflammatory drugs</span><br />
<br />
* The algorithm for FIRE contains at least the following:<br />
**Identify cardinal findings that increase the pretest probability of [insert name of disease here]]<br />
** Rule out life-threatening diagnoses<br />
<br />
* The boxes that require immediate attention and management are colored in red/salmon (background: #FA8072). Boxes that in white when they don't require immediate management.<br />
<br />
===Complete Diagnostic Approach===<br />
* The complete diagnostic approach section contains the diagnostic algorithm(s).<br />
* If the diagnostic approach is very big and the algorithm is complicated, the algorithm is divided into more than one.<br />
* If more than one algorithm is provided, a subtitle is given for each.<br />
* When more than one algorithm are provided, separate them with <nowiki><br></nowiki>.<br />
* The algorithm for diagnosis contains at least the following<br />
**Characterize the symptoms<br />
**Obtain a detailed history<br />
**Examine the patient<br />
**Order labs<br />
**Order imaging studies<br />
**Consider alternative diagnoses<br />
<br />
===Treatment===<br />
* The treatment section contains the therapeutic algorithm(s).<br />
* The number of algorithms depends on each topic.<br />
* If the therapeutic approach is very big and the algorithm is complicated, the algorithm is divided into more than one.<br />
* If more than one algorithm is provided, a subtitle is given for each.<br />
* When more than one algorithm are provided, they are separated with <nowiki><br></nowiki>.<br />
* Details about the dosage, route, and frequency of the medications are provided.<br />
* Major contraindications for the medications are provided in red. Click '''[[STEMI resident survival guide|here]]''' for an example.<br />
* Action verbs are used before medications or treatment, for example: "Administer aspirin" instead of aspirin.<br />
* Check-boxes “❑” are placed in front of every action. <br />
* Urgent or Immediately are added when an action should be taken as soon as possible.<br />
* When the algorithm contains a big management plan already developed on another resident survival page, the management should not be replicated but rather redirected to the other resident survival guide page. <br />
<br />
===Description of The Algorithm===<br />
* Before starting the algorithm, the following sentence is written and the main reference(s) of the algorithm are cited:<br><br />
Shown below is an algorithm depicting [...] based on [...].(references)<br />
<br />
* Abbreviations should be avoided, example: hour and not hr, minute and not min.<br />
** If abbreviations are used, provide a list of abbreviated terms '''above''' the algorithm as follows:<br />
<nowiki><span style="font-size:85%">'''Abbreviations:''' '''BUN''': Blood urea nitrogen; '''CAD''': Coronary artery disease; '''CBC''': Complete blood count; '''EKG''': Electrocardiogram; '''Hb''': Hemoglobin; '''ICU''': Intensive care unit; '''INR''': International normalized ratio; '''IV''': Intravenous; '''GI''': Gastrointestinal; '''NPO''': Nil per os; '''NSAIDs''': Non steroid anti-inflammatory drugs</span></nowiki><br />
<br />
And it will appear this way:<br><br />
<span style="font-size:85%">'''Abbreviations:''' '''BUN''': Blood urea nitrogen; '''CAD''': Coronary artery disease; '''CBC''': Complete blood count; '''EKG''': Electrocardiogram; '''Hb''': Hemoglobin; '''ICU''': Intensive care unit; '''INR''': International normalized ratio; '''IV''': Intravenous; '''GI''': Gastrointestinal; '''NPO''': Nil per os; '''NSAIDs''': Non steroid anti-inflammatory drugs</span><br />
<br />
Click '''[[STEMI resident survival guide|here]]''' for an example.<br />
<br />
<br />
* The algorithm should be drawn on a paper then replicated on WikiDoc in a way that the algorithm is minimally spaced.<br />
* The algorithm and content are aligned to the left, and the size of each box is adjusted using the following formula:<br />
** <nowiki><div style="float: left; text-align: left; width: 25em; padding:1em;"> [content of the box] </div> </nowiki><br />
* The algorithm should contain the following:<br />
** Characterize the symptoms:<br />
** Obtain a detailed history:<br />
** Examine the patient:<br />
** Order labs:<br />
** Order imaging studies:<br />
**Consider alternative diagnoses:<br />
<br />
* Action verbs are used before medications or treatment, for example: "Administer aspirin" instead of aspirin<br />
* Check-boxes ❑ are placed in front of every action.<br />
* '''Urgent''' or '''Immediately''' are added when an action should be taken as soon as possible.<br />
* When a medication is to be administered, the dose and mode of administration are included.<br />
<br />
* When the algorithm contains a big management plan already developed on another resident survival page, the management should not be replicated but rather redirected to the other reisdent survival guide page.<br />
<br />
===Do's===<br />
* Extra information and details about the management are provided in this section.<br />
* Each sentence is written as an order, for example:<br />
** Order an EKG. (correct)<br />
** An EKG should be ordered. (incorrect)<br />
* Write the important do’s within the algorithms. <br />
<br />
===Dont's===<br />
* Extra information and details about what should be avoided in the management are provided in this section.<br />
* Each sentence is written as an order, for example:<br />
** Do not administer beta blockers. (correct)<br />
** Beta blockers should not be administered. (incorrect)<br />
<br />
===References===<br />
* Make sure to use the latest guidelines and recommendations as references.<br />
* Make sure that the links of the references are working.<br />
<br />
===General Notes===<br />
* When more that one associate editors are included, separate the names by a a semicolon followed by a space.<br />
* Expand buttons should be avoided as much as possible.<br />
* Hyperlinks through <nowiki> [[ ]] </nowiki> are used to link key words to their pages.<br />
* The page should be reviewed for typographical errors and capitalization.<br />
* Add '''categories''' for each section. Make sure that <nowiki>[[category:Resident survival guide]]</nowiki> is present among others, for example: <nowiki>[[Category:Cardiology]]</nowiki>.<br />
* Make sure that a siren is present on all the pages of each of the resident survival guide's topics.<br />
* Contributors who are not native English speakers and require help in writing should add the Category:Grammar to their pages.<br />
<br />
===Example of Pages===<br />
For examples of high quality pages, please check:<br />
* [[STEMI resident survival guide]]<br />
* [[Bradycardia resident survival guide]]<br />
* [[Cardiac tamponade resident survival guide]]</div>Rim Halabyhttps://www.wikidoc.org/index.php?title=Resident_survival_guide_checklist&diff=1088679Resident survival guide checklist2015-04-17T14:26:52Z<p>Rim Halaby: </p>
<hr />
<div>__NOTOC__<br />
{{Resident survival guide project}}<br />
[[Image:Main_help_page_small.PNG|100px|link=Help]][[Image:Projects.PNG|100px|link=Projects]][[Image:Editor's_Tools.PNG|100px|link=Help Menu]]<br />
{{CMG}}; {{AE}} {{Rim}}; {{VR}}<br />
<br />
==Overview==<br />
The following items in this checklist describe in detail the resident survival guide pages. All these items should be present for a page to be complete and ready for quality check.<br />
<br />
==Checklist==<br />
===General Structure===<br />
* In general, each page contains the following titles in order:<br />
** Overview<br />
** Classification (if needed for the management)<br />
** Causes<br />
** FIRE<br />
** Complete Diagnostic Approach<br />
** Treatment<br />
** Do's<br />
** Dont's<br />
** References<br />
<br />
* The treatment for some diseases is extensive or it can be subdivided into sections. In this case, appropriate headings are used to organize the treatment. Click '''[[STEMI resident survival guide|here]]''' for an example.<br />
<br />
===Floating Navigation Bar===<br />
* A navigation bar is present on every resident survival guide page. Click '''[[Template:Resident_survival_guide|here]]''' for a template.<br />
* For an example of a page with a floating navigation bar, check [[STEMI resident survival guide]].<br />
* The navigation bar should contain the following items: overview, classification (if applicable), causes, FIRE, complete diagnostic approach, treatment, do's and don'ts. However, the content of the navigation bar is flexible.<br />
** If you have added an additional title or subtitle on your page make sure to add it in the navigation bar.<br />
** If the therapy is divided into several sections, modify the content of the navigation bar to fit the order of the titles of the resident survival page. Click '''[[STEMI resident survival guide|here]]''' for an example.<br />
<br />
===Overview===<br />
* The overview section is a short and straight to the point statement that summarizes the disease and its management in few sentences, particularly the immediate management.<br />
* The overview section should include the disease name in the first sentence.<br />
* To see an example of an overview section on the resident survival guide, click '''[[Cardiac tamponade resident survival guide|here]]'''.<br />
<br />
===Classification===<br />
* The classification section should be included only when the classification of the disease is needed for the management plan.<br />
* This section provides either a table or a list of subheadings of categories with content that the disease can be classified under.<br />
* To see an example of a classification section on the resident survival guide, click '''[[Atrial fibrillation resident survival guide|here]]'''.<br />
<br />
===Causes===<br />
* The causes section contains two subheadings:<br />
** Life Threatening Causes<br />
** Common Causes<br />
* Under life threatening causes, the following definition of life threatening is provided: Life-threatening causes include conditions which may result in death or permanent disability within 24 hours if left untreated.<br />
** If the disease itself is life threatening, the following sentence is written: <nowiki>[[Name of the disease]]</nowiki> is life threatening and should be treated as such irrespective of the underlying cause.<br />
* Under common causes, only the '''common''' causes are provided, without including rare etiologies.<br />
* The causes are listed in alphabetical order.<br />
* The causes are all hyperlinked.<br />
<br />
===FIRE===<br />
<br />
===Complete Diagnostic Approach===<br />
* The complete diagnostic approach section contains the diagnostic algorithm(s).<br />
* If the diagnostic approach is very big and the algorithm is complicated, the algorithm is divided into more than one.<br />
* If more than one algorithm is provided, a subtitle is given for each.<br />
* When more than one algorithm are provided, separate them with <nowiki><br></nowiki>.<br />
* The algorithm for diagnosis contains at least the following<br />
**Characterize the symptoms<br />
**Obtain a detailed history<br />
**Examine the patient<br />
**Order labs<br />
**Order imaging studies<br />
**Consider alternative diagnoses<br />
<br />
===Treatment===<br />
* The treatment section contains the therapeutic algorithm(s).<br />
* The number of algorithms depends on each topic.<br />
* If the therapeutic approach is very big and the algorithm is complicated, the algorithm is divided into more than one.<br />
* If more than one algorithm is provided, a subtitle is given for each.<br />
* When more than one algorithm are provided, they are separated with <nowiki><br></nowiki>.<br />
* Details about the dosage, route, and frequency of the medications are provided.<br />
* Major contraindications for the medications are provided in red. Click '''[[STEMI resident survival guide|here]]''' for an example.<br />
* Action verbs are used before medications or treatment, for example: "Administer aspirin" instead of aspirin.<br />
* Check-boxes “❑” are placed in front of every action. <br />
* Urgent or Immediately are added when an action should be taken as soon as possible.<br />
* When the algorithm contains a big management plan already developed on another resident survival page, the management should not be replicated but rather redirected to the other resident survival guide page. <br />
<br />
===Description of The Algorithm===<br />
* Before starting the algorithm, the following sentence is written and the main reference(s) of the algorithm are cited:<br><br />
Shown below is an algorithm depicting [...] based on [...].(references)<br />
<br />
* Abbreviations should be avoided, example: hour and not hr, minute and not min.<br />
** If abbreviations are used, provide a list of abbreviated terms '''above''' the algorithm as follows:<br />
<nowiki><span style="font-size:85%">'''Abbreviations:''' '''BUN''': Blood urea nitrogen; '''CAD''': Coronary artery disease; '''CBC''': Complete blood count; '''EKG''': Electrocardiogram; '''Hb''': Hemoglobin; '''ICU''': Intensive care unit; '''INR''': International normalized ratio; '''IV''': Intravenous; '''GI''': Gastrointestinal; '''NPO''': Nil per os; '''NSAIDs''': Non steroid anti-inflammatory drugs</span></nowiki><br />
<br />
And it will appear this way:<br><br />
<span style="font-size:85%">'''Abbreviations:''' '''BUN''': Blood urea nitrogen; '''CAD''': Coronary artery disease; '''CBC''': Complete blood count; '''EKG''': Electrocardiogram; '''Hb''': Hemoglobin; '''ICU''': Intensive care unit; '''INR''': International normalized ratio; '''IV''': Intravenous; '''GI''': Gastrointestinal; '''NPO''': Nil per os; '''NSAIDs''': Non steroid anti-inflammatory drugs</span><br />
<br />
Click '''[[STEMI resident survival guide|here]]''' for an example.<br />
<br />
<br />
* The algorithm should be drawn on a paper then replicated on WikiDoc in a way that the algorithm is minimally spaced.<br />
* The algorithm and content are aligned to the left, and the size of each box is adjusted using the following formula:<br />
** <nowiki><div style="float: left; text-align: left; width: 25em; padding:1em;"> [content of the box] </div> </nowiki><br />
* The algorithm should contain the following:<br />
** Characterize the symptoms:<br />
** Obtain a detailed history:<br />
** Examine the patient:<br />
** Order labs:<br />
** Order imaging studies:<br />
**Consider alternative diagnoses:<br />
<br />
* Action verbs are used before medications or treatment, for example: "Administer aspirin" instead of aspirin<br />
* Check-boxes ❑ are placed in front of every action.<br />
* '''Urgent''' or '''Immediately''' are added when an action should be taken as soon as possible.<br />
* When a medication is to be administered, the dose and mode of administration are included.<br />
<br />
* When the algorithm contains a big management plan already developed on another resident survival page, the management should not be replicated but rather redirected to the other reisdent survival guide page.<br />
<br />
===Do's===<br />
* Extra information and details about the management are provided in this section.<br />
* Each sentence is written as an order, for example:<br />
** Order an EKG. (correct)<br />
** An EKG should be ordered. (incorrect)<br />
* Write the important do’s within the algorithms. <br />
<br />
===Dont's===<br />
* Extra information and details about what should be avoided in the management are provided in this section.<br />
* Each sentence is written as an order, for example:<br />
** Do not administer beta blockers. (correct)<br />
** Beta blockers should not be administered. (incorrect)<br />
<br />
===References===<br />
* Make sure to use the latest guidelines and recommendations as references.<br />
* Make sure that the links of the references are working.<br />
<br />
===General Notes===<br />
* When more that one associate editors are included, separate the names by a a semicolon followed by a space.<br />
* Expand buttons should be avoided as much as possible.<br />
* Hyperlinks through <nowiki> [[ ]] </nowiki> are used to link key words to their pages.<br />
* The page should be reviewed for typographical errors and capitalization.<br />
* Add '''categories''' for each section. Make sure that <nowiki>[[category:Resident survival guide]]</nowiki> is present among others, for example: <nowiki>[[Category:Cardiology]]</nowiki>.<br />
* Make sure that a siren is present on all the pages of each of the resident survival guide's topics.<br />
* Contributors who are not native English speakers and require help in writing should add the Category:Grammar to their pages.<br />
<br />
===Example of Pages===<br />
For examples of high quality pages, please check:<br />
* [[STEMI resident survival guide]]<br />
* [[Bradycardia resident survival guide]]<br />
* [[Cardiac tamponade resident survival guide]]</div>Rim Halabyhttps://www.wikidoc.org/index.php?title=Resident_survival_guide_topics&diff=1088668Resident survival guide topics2015-04-17T14:18:07Z<p>Rim Halaby: /* List of All Topics */</p>
<hr />
<div>__NOTOC__<br />
{{Resident survival guide project}}<br />
[[Image:Main_help_page_small.PNG|100px|link=Help]][[Image:Projects.PNG|100px|link=Projects]][[Image:Editor's_Tools.PNG|100px|link=Help Menu]]<br />
<br />
{{WikiDoc CMG}}; {{AE}} {{MS}}; [[Priyamvada Singh|Priyamvada Singh, M.D.]] [mailto:psingh13579@gmail.com]; {{Rim}}<br />
<br />
==Overview==<br />
This section shows the list of topics available for the resident survival guide project and how to select a topic. You can also update the status of your chosen topic here by entering the authorship details so that your work is not overlapped by the work of other editors.<br />
<br />
==Select a Topic==<br />
*Select a topic from the list of resident survival guide topics shown below.<br />
*The topics that are completed or have been worked on by wikidoc scholars are highlighted in blue.<br />
*The topics in black are still available for scholars on campus or remote collaborators to work on.<br />
<br />
==List of All Topics==<br />
<br />
===Cardiology===<br />
<br />
{| class="wikitable sortable"<br />
! Specialty<br />
! Topic<br />
! Resident Survival Guide Page<br />
! Author<br />
! Status<br />
|-<br />
| Cardiology || [[Acute coronary syndrome]] || [[Acute coronary syndrome resident survival guide]] || ''Landing page'' || Complete<br />
|-<br />
| Cardiology || [[Heart failure]] || [[Heart failure resident survival guide]] || Mahmoud/Dr. Kay || Complete<br />
|-<br />
| Cardiology || [[Arrhythmia]] || [[Arrhythmia resident survival guide]] || Rim || Complete<br />
|-<br />
| Cardiology || [[Atrial fibrillation]] || [[Atrial fibrillation resident survival guide]] || Vidit|| Complete<br />
|-<br />
| Cardiology || [[Aortic aneurysm]] || [[Aortic aneurysm resident survival guide]] ||Landing page|| Complete<br />
|-<br />
| Cardiology || [[Abdominal aortic aneurysm]] || [[Abdominal aortic aneurysm resident survival guide]] ||Yaz|| Complete<br />
|-<br />
| Cardiology || [[Thoracic aortic aneurysm]] || [[Thoracic aortic aneurysm resident survival guide]] ||Yaz|| Complete<br />
|-<br />
| Cardiology || [[Aortic dissection]] || [[Aortic dissection resident survival guide]] || Chetan/Serge || Complete<br />
|-<br />
| Cardiology || [[Aortic regurgitation]] || [[Aortic regurgitation resident survival guide]] || Alejandro ||Complete<br />
|-<br />
| Cardiology || [[Aortic stenosis]] || [[Aortic stenosis resident survival guide]] || Alejandro ||Complete<br />
|-<br />
| Cardiology || [[Atrial flutter]] || [[Atrial flutter resident survival guide]] || Vidit ||<br />
|-<br />
| Cardiology || [[Bradycardia]] || [[Bradycardia resident survival guide]] || Ogheneochuko: Vidit ||Complete<br />
|-<br />
| Cardiology || [[Cardiac arrest]] || [[Cardiac arrest resident survival guide]] || Rim: Vidit ||Complete<br />
|-<br />
| Cardiology || [[Cardiogenic shock]] || [[Cardiogenic shock resident survival guide]] ||Gerry|| Complete<br />
|-<br />
| Cardiology || [[Chest pain]] || [[Chest pain resident survival guide]] || Rim/Alejandro || Complete<br />
|-<br />
| Cardiology || || [[Coronary angiography resident survival guide]] ||Yaz ||<br />
|-<br />
| Cardiology || [[Dyslipidemia]] || [[Dyslipidemia resident survival guide]] || ||<br />
|-<br />
| Cardiology || [[Electrocardiography]] || [[Electrocardiography resident survival guide]] ||Rim|| Complete<br />
|-<br />
| Cardiology || [[Endocarditis]] || [[Endocarditis resident survival guide]] ||Mohamed||Complete<br />
|-<br />
| Cardiology || [[Pericarditis]] || [[Pericarditis resident survival guide]] || Mugilan ||<br />
|-<br />
| Cardiology || [[Hypertension]] || [[Hypertension resident survival guide]] ||Landing page||Complete<br />
|-<br />
| Cardiology || [[Chronic hypertension]] || [[Chronic hypertension resident survival guide]] || Ayokunle||<br />
|-<br />
| Cardiology || [[Hypertensive crisis]] || [[Hypertensive crisis resident survival guide]]||Ayokunle|| Complete<br />
|-<br />
| Cardiology || [[Intracardiac device]] || [[Intracardiac device resident survival guide]] || ||<br />
|-<br />
| Cardiology || [[Supraventricular tachycardia|Narrow complex tachycardia]] || [[Narrow complex tachycardia resident survival guide]] || Hilda/Rim/Twinkle || Complete<br />
|-<br />
| Cardiology || [[Cardiac tamponade]] || [[Cardiac tamponade resident survival guide]] ||Ayokunle|| Complete<br />
|-<br />
| Cardiology || [[Low flow low gradient aortic stenosis]] || [[Low flow low gradient aortic stenosis resident survival guide]] || Rim || Complete<br />
|-<br />
| Cardiology || || [[Cardiac risk assessment prior to non-cardiac surgery resident survival guide]] ||Yaz||Complete<br />
|-<br />
| Cardiology || [[Dilated cardiomyopathy]] || [[Dilated cardiomyopathy resident survival guide]] || Steven ||<br />
|-<br />
| Cardiology || [[Restrictive cardiomyopathy]] || [[Restrictive cardiomyopathy resident survival guide]] || Steven ||<br />
|-<br />
| Cardiology || [[Hypertrophic cardiomyopathy]] || [[Hypertrophic cardiomyopathy resident survival guide]] || Steven ||<br />
|-<br />
| Cardiology || [[Arrhythmogenic right ventricular cardiomyopathy]] || [[Arrhythmogenic right ventricular cardiomyopathy resident survival guide]] || Steven ||<br />
|-<br />
| Cardiology || [[Claudication]] || [[Claudication resident survival guide]] ||Ochuko||<br />
|-<br />
| Cardiology || [[Mitral regurgitation]] || [[Mitral regurgitation resident survival guide]] ||Mugilan||<br />
|-<br />
| Cardiology || [[Mitral stenosis]] || [[Mitral stenosis resident survival guide]] ||Twinkle||Complete<br />
|-<br />
| Cardiology || [[Palpitations]] || [[Palpitations resident survival guide]] ||Serge||<br />
|-<br />
| Cardiology || [[Peripheral artery disease]] || [[Peripheral artery disease resident survival guide]] || Ogheneochuko ||<br />
|-<br />
| Cardiology || [[Shortness of breath]] || [[Shortness of breath resident survival guide]] || Steven ||<br />
|-<br />
| Cardiology || [[STEMI]] || [[STEMI resident survival guide]] || Alejandro||Complete<br />
|-<br />
| Cardiology || [[Pulmonary embolism]] || [[Pulmonary embolism resident survival guide]] ||Rim ||Complete<br />
|-<br />
| Cardiology || [[Right ventricular myocardial infarction]] || [[Right ventricular myocardial infarction resident survival guide]] || Jad ||<br />
|-<br />
| Cardiology || [[Syncope]] || [[Syncope resident survival guide]] || Karol/Alejandro || Complete<br />
|-<br />
| Cardiology || [[Unstable angina]] || [[Unstable angina/ NSTEMI resident survival guide]] || Andrea/Rim ||<br />
|-<br />
| Cardiology || [[Valvular diseases]] || [[Valvular diseases resident survival guide]] || Landing page||Complete<br />
|-<br />
| Cardiology || [[VTE prevention]] || [[VTE prevention resident survival guide]] || Rim||Complete<br />
|-<br />
| Cardiology || [[Wide complex tachycardia]] || [[Wide complex tachycardia resident survival guide]] || Rim || Complete<br />
|-<br />
| Cardiology || [[WPW|Wolff-Parkinson-White syndrome]] || [[Wolff-Parkinson-White syndrome resident survival guide]]|| Alonso||<br />
|-<br />
|}<br />
<br />
===Other Topics===<br />
{| class="wikitable sortable"<br />
! Specialty<br />
! Topic<br />
! Resident Survival Guide Page<br />
! Author<br />
! Status<br />
|-<br />
| Pulmonary || [[Acute respiratory distress syndrome]] || [[Acute respiratory distress syndrome resident survival guide]] ||Ayokunle||<br />
|-<br />
| Pulmonary || [[Anaphylaxis]] || [[Anaphylaxis resident survival guide]] || Vidit ||<br />
|-<br />
| Pulmonary || [[Asthma|Asthma exacerbation]] || [[Asthma exacerbation resident survival guide]] || Abdurahman, Vidit ||Complete<br />
|-<br />
| Pulmonary || [[Chronic obstructive pulmonary disease|COPD exacerbation]] || [[COPD exacerbation resident survival guide]] || Abdurahman: Vidit ||Complete<br />
|-<br />
| Pulmonary || [[Cough]] || [[Cough resident survival guide]] || ||<br />
|-<br />
| Pulmonary || [[Deep venous thrombosis]] || [[Deep vein thrombosis resident survival guide|Deep venous thrombosis resident survival guide]] || Rim|| Complete<br />
|-<br />
| Pulmonary || [[Dyspnea]] || [[Dyspnea resident survival guide]] ||Dyspnea||<br />
|-<br />
| Pulmonary || [[Hemoptysis]] || [[Hemoptysis resident survival guide]] ||Teresa||<br />
|-<br />
| Pulmonary || [[Mechanical ventilation]] || [[Mechanical ventilation resident survival guide]] || Ahmed ||<br />
|-<br />
| Pulmonary || [[Pleural effusion]] || [[Pleural effusion resident survival guide]] ||Twinkle||<br />
|-<br />
| Pulmonary || [[Pulmonary embolism]] || [[Pulmonary embolism resident survival guide]] ||||<br />
|-<br />
| Pulmonary || [[Pulmonary hypertension]] || [[Pulmonary hypertension resident survival guide]] || Vidit ||<br />
|-<br />
| Pulmonary || [[Respiratory failure]] || [[Respiratory failure resident survival guide]] ||||<br />
|-<br />
| Cardiology || [[Tension pneumothorax]] || [[Tension pneumothorax resident survival guide]] || Mohamad||Complete<br />
|-<br />
| Gastroenterology || [[Abdominal pain]] || [[Abdominal pain resident survival guide]] ||||<br />
|-<br />
| Gastroenterology || [[Abnormal liver tests]] || [[Abnormal liver tests resident survival guide]] ||||<br />
|-<br />
| Gastroenterology || [[Acetaminophen toxicity]] || [[Acetaminophen overdose resident survival guide|Acetaminophen toxicity resident survival guide]] || Vidit ||Complete<br />
|-<br />
| Gastroenterology || [[Diarrhea|Acute diarrhea]] || [[Acute diarrhea resident survival guide]] || Mugilan ||Complete<br />
|-<br />
| Gastroenterology || [[Acute liver failure]] || [[Acute liver failure resident survival guide]] || Vendhan ||<br />
|-<br />
| Gastroenterology || [[Acute pancreatitis]] || [[Acute pancreatitis resident survival guide]] || Vidit || Complete<br />
|-<br />
| Gastroenterology || [[Appendicitis]] || [[Appendicitis resident survival guide]] || Teresa || Complete<br />
|-<br />
| Gastroenterology || [[Ascites]] || [[Ascites resident survival guide]] || Twinkle/Steven ||<br />
|-<br />
| Gastroenterology || [[Biliary tract diseases]] || [[Biliary tract diseases resident survival guide]] || Vendhan ||<br />
|-<br />
| Gastroenterology || [[Cholangitis]] || [[Cholangitis resident survival guide]] || Vendhan || Complete<br />
|-<br />
| Gastroenterology || [[Cholecystitis]] || [[Cholecystitis resident survival guide]] || Vendhan || Complete<br />
|-<br />
| Gastroenterology || [[Acute cholecystitis|Cholecystitis]] || [[Acute cholecystitis resident survival guide]] || Vendhan || Complete<br />
|-<br />
| Gastroenterology || [[Chronic cholecystitis|Cholecystitis]] || [[Chronic cholecystitis resident survival guide]] || Vendhan || Complete<br />
|-<br />
| Gastroenterology || [[Choledocholithiasis]] || [[Choledocholithiasis resident survival guide]] || Vendhan ||Complete<br />
|-<br />
| Gastroenterology || [[Cholelithiasis]] || [[Cholelithiasis resident survival guide]] || Vendhan ||<br />
|-<br />
| Gastroenterology || [[Diarrhea|Chronic diarrhea]] || [[Chronic diarrhea resident survival guide]] || Mugilan || Complete<br />
|-<br />
| Gastroenterology || [[Clostridium difficile]] || [[Clostridium difficile infection resident survival guide]] || Mugilan ||<br />
|-<br />
| Gastroenterology || [[Constipation]] || [[Constipation resident survival guide]] ||Mugilan|| Complete<br />
|-<br />
| Gastroenterology || [[Crohn’s disease]] || [[Crohn's disease resident survival guide]] ||Mugilan||<br />
|-<br />
| Gastroenterology || [[Diarrhea]] || [[Diarrhea resident survival guide]] || Mugilan ||Complete<br />
|-<br />
| Gastroenterology || [[Esophageal rupture]] || [[Esophageal rupture resident survival guide]] || ||<br />
|-<br />
| Gastroenterology || [[Ileus]] || [[Ileus resident survival guide]] ||Mugilan||<br />
|-<br />
| Gastroenterology || [[Intestinal ischemia]] || [[Intestinal ischemia resident survival guide]] ||Mugilan||<br />
|-<br />
| Gastroenterology || [[Acute pancreatitis|Gallstone pancreatitis]] || [[Gallstone pancreatitis resident survival guide]] || Vendhan|| Complete<br />
|-<br />
| Gastroenterology || [[Lower gastrointestinal bleeding]] || [[Lower gastrointestinal bleeding resident survival guide]] || Twinkle ||Complete<br />
|-<br />
| Gastroenterology || [[Nutrition]] || [[Nutrition resident survival guide]] ||||<br />
|-<br />
| Gastroenterology || [[Ulcerative colitis]] || [[Ulcerative colitis resident survival guide]] ||Mugilan||<br />
|-<br />
| Gastroenterology || [[Upper gastrointestinal bleeding]] || [[Upper gastrointestinal bleeding resident survival guide]] || Twinkle ||<br />
|-<br />
| Gastroenterology || [[Varices]] || [[Varices and variceal bleed resident survival guide]] || Twinkle || Complete<br />
|-<br />
| Nephrology || [[Acidosis]] || [[Acidosis resident survival guide]] ||||<br />
|-<br />
| Nephrology || [[Acute kidney injury]] || [[Acute kidney failure resident survival guide]] || Vendhan ||<br />
|-<br />
| Nephrology ||[[Alkalosis]] || [[Alkalosis resident survival guide]] ||||<br />
|-<br />
| Nephrology || [[Hyperkalemia]] || [[Hyperkalemia resident survival guide]] || Mahmoud ||<br />
|-<br />
| Nephrology || [[Hypernatremia]] || [[Hypernatremia resident survival guide]] || Priyamvada ||<br />
|-<br />
| Nephrology || [[Hypokalemia]] || [[Hypokalemia resident survival guide]] ||||<br />
|-<br />
| Nephrology || [[Hyponatremia]] || [[Hyponatremia resident survival guide]] || Priyamvada ||<br />
|-<br />
| Nephrology || [[Metabolic acidosis]] || [[Metabolic acidosis resident survival guide]] || Ogheneochuko ||<br />
|-<br />
| Nephrology || [[Metabolic alkalosis]] || [[Metabolic alkalosis resident survival guide]] ||||<br />
|-<br />
| Nephrology || [[Nephrolithiasis]] || [[Nephrolithiasis resident survival guide]] ||||<br />
|-<br />
| Nephrology || [[Polyuria]] || [[Polyuria resident survival guide]] ||||<br />
|-<br />
| Nephrology || [[Renal artery stenosis]] || [[Renal artery stenosis resident survival guide]] ||Karol||Complete<br />
|-<br />
| Nephrology || [[Respiratory acidosis]] || [[Respiratory acidosis resident survival guide]] ||||<br />
|-<br />
| Nephrology || [[Respiratory alkalosis]] || [[Respiratory alkalosis resident survival guide]] ||||<br />
|-<br />
| Hematology-Oncology || [[Anemia]] || [[Anemia resident survival guide]] || Chetan ||<br />
|-<br />
| Hematology-Oncology || [[Aplastic anemia]] || [[Aplastic anemia resident survival guide]] || Chetan ||<br />
|-<br />
| Hematology-Oncology || [[Breast cancer screening]] || [[Breast cancer screening resident survival guide]] || Twinkle|| Complete<br />
|-<br />
| Hematology-Oncology || [[Hemolytic anemia]] || [[Hemolytic anemia resident survival guide]] ||||<br />
|-<br />
| Hematology-Oncology || [[Heparin induced thrombocytopenia]] || [[HIT resident survival guide]] || Karol|| Complete<br />
|-<br />
| Hematology-Oncology || [[Pancytopenia]] || [[Pancytopenia resident survival guide]] || ||<br />
|-<br />
| Hematology-Oncology || [[Bleeding disorders]] || [[Bleeding disorder resident survival guide]] ||||<br />
|-<br />
| Hematology-Oncology || [[Thrombocytopenia]] || [[Thrombocytopenia resident survival guide]] ||Ogheneochuko|| Complete<br />
|-<br />
| Hematology-Oncology || [[DIC]] || [[DIC resident survival guide]] ||Ogheneochuko|| Complete<br />
|-<br />
| Hematology-Oncology || [[Transfusion therapy]] || [[Transfusion therapy resident survival guide]] ||Ayokunle||<br />
|-<br />
| Hematology-Oncology || [[Febrile neutropenia]] || [[Febrile neutropenia resident survival guide]] || Rim ||<br />
|-<br />
| Hematology-Oncology || [[Tumor lysis syndrome]] || [[Tumor lysis syndrome resident survival guide]] ||Twinkle|| Complete<br />
|-<br />
| Infectious Diseases || [[Community acquired pneumonia]] || [[Community acquired pneumonia resident survival guide]] ||Chetan:Rim|| Complete<br />
|-<br />
| Infectious Diseases || [[Urinary tract infection]] || [[Urinary tract infection resident survival guide]] ||Ogheneochuko||<br />
|-<br />
| Infectious Diseases || [[Cellulitis]] || [[Cellulitis resident survival guide]] ||Ogheneochuko||<br />
|-<br />
| Infectious Diseases || [[Diabetic foot]] || [[Diabetic foot resident survival guide]] ||Ogheneochuko||<br />
|-<br />
| Infectious Diseases || [[Meningitis]] || [[Meningitis resident survival guide]] ||||<br />
|-<br />
| Infectious Diseases || [[Fever of unknown origin]] || [[Fever of unknown origin resident survival guide]] ||Ogheneochuko||<br />
|-<br />
| Infectious Diseases || [[Rash with fever|Fever and rash]] || [[Rash with fever resident survival guide]] ||||<br />
|-<br />
| Infectious Diseases || [[Fever after travel]] || [[Fever after travel resident survival guide]] ||||<br />
|-<br />
| Infectious Diseases || [[Norovirus infection]] || [[Norovirus outbreak resident survival guide]] ||Twinkle|| Complete<br />
|-<br />
| Infectious Diseases || [[Sepsis]] || [[Sepsis resident survival guide]] || Ahmed ||<br />
|-<br />
| Endocrinology || [[Hypercalcemia]] || [[Hypercalcemia resident survival guide]] ||||<br />
|-<br />
| Endocrinology ||[[Hypocalcemia]] || [[Hypocalcemia resident survival guide]] ||Ammu||<br />
|-<br />
| Endocrinology || [[Diabetic ketoacidosis]] || [[Hyperglycemic crises resident survival guide]] || Vidit ||Complete<br />
|-<br />
| Neurology || [[Altered mental status]] || [[Altered mental status resident survival guide]] ||||<br />
|-<br />
| Neurology || [[Seizure]] || [[Seizure resident survival guide]] || Vidit ||<br />
|-<br />
| Neurology || [[Status epilepticus]] || [[Status epilepticus resident survival guide]] || Vidit ||Complete<br />
|-<br />
| Neurology || [[Alcohol withdrawal]] || [[Alcohol withdrawal resident survival guide]] ||Vidit||Complete<br />
|-<br />
| Neurology || [[Opioid]] || [[Opioid resident survival guide]] || Vidit ||<br />
|-<br />
| Neurology || [[Opioid overdose]] || [[Opioid overdose resident survival guide]] || Vidit ||<br />
|-<br />
| Neurology || [[Opioid withdrawal]] || [[Opioid withdrawal resident survival guide]] || Vidit ||<br />
|-<br />
| Neurology || [[Stroke]] || [[Stroke resident survival guide]] || Ayokunle ||<br />
|-<br />
| Neurology || [[Headache]] || [[Headache resident survival guide]] ||||<br />
|-<br />
| Neurology || [[Back pain]] || [[Back pain resident survival guide]] || Hilda ||<br />
|-<br />
| Neurology || [[Vertigo]] || [[Vertigo resident survival guide]] || || High priority<br />
|-<br />
| Miscellaneous || [[ICU Medications]] || [[ICU medications resident survival guide]] || Ahmed ||<br />
|-<br />
| Miscellaneous || [[Shock]] || [[Shock resident survival guide]] || Ahmed ||<br />
|-<br />
| Miscellaneous || [[Anticoagulation therapy]] || [[Anticoagulation therapy resident survival guide]] || Priyamvada ||<br />
|-<br />
| Miscellaneous || [[Carbon monoxide poisoning]] || [[Carbon monoxide poisoning resident survival guide]] || Vidit ||<br />
|}<br />
<br />
[[Category:Help]]<br />
[[Category:Projects]]<br />
[[Category:Resident survival guide]]<br />
<br />
{{WikiDoc Help Menu}}<br />
{{WikiDoc Sources}}</div>Rim Halabyhttps://www.wikidoc.org/index.php?title=Resident_survival_guide_topics&diff=1088660Resident survival guide topics2015-04-17T14:09:52Z<p>Rim Halaby: /* List of All Topics */</p>
<hr />
<div>__NOTOC__<br />
{{Resident survival guide project}}<br />
[[Image:Main_help_page_small.PNG|100px|link=Help]][[Image:Projects.PNG|100px|link=Projects]][[Image:Editor's_Tools.PNG|100px|link=Help Menu]]<br />
<br />
{{WikiDoc CMG}}; {{AE}} {{MS}}; [[Priyamvada Singh|Priyamvada Singh, M.D.]] [mailto:psingh13579@gmail.com]; {{Rim}}<br />
<br />
==Overview==<br />
This section shows the list of topics available for the resident survival guide project and how to select a topic. You can also update the status of your chosen topic here by entering the authorship details so that your work is not overlapped by the work of other editors.<br />
<br />
==Select a Topic==<br />
*Select a topic from the list of resident survival guide topics shown below.<br />
*The topics that are completed or have been worked on by wikidoc scholars are highlighted in blue.<br />
*The topics in black are still available for scholars on campus or remote collaborators to work on.<br />
<br />
==List of All Topics==<br />
<br />
===Cardiology===<br />
<br />
{| class="wikitable sortable"<br />
! Specialty<br />
! Topic<br />
! Resident Survival Guide Page<br />
! Author<br />
! Status<br />
|-<br />
| Cardiology || [[Acute coronary syndrome]] || [[Acute coronary syndrome resident survival guide]] || ''Landing page'' || Complete<br />
|-<br />
| Cardiology || [[Heart failure]] || [[Heart failure resident survival guide]] || Mahmoud/Dr. Kay || Complete<br />
|-<br />
| Cardiology || [[Arrhythmia]] || [[Arrhythmia resident survival guide]] || Rim || Complete<br />
|-<br />
| Cardiology || [[Atrial fibrillation]] || [[Atrial fibrillation resident survival guide]] || Vidit|| Complete<br />
|-<br />
| Cardiology || [[Aortic aneurysm]] || [[Aortic aneurysm resident survival guide]] ||Landing page|| Complete<br />
|-<br />
| Cardiology || [[Abdominal aortic aneurysm]] || [[Abdominal aortic aneurysm resident survival guide]] ||Yaz||<br />
|-<br />
| Cardiology || [[Thoracic aortic aneurysm]] || [[Thoracic aortic aneurysm resident survival guide]] ||Yaz||<br />
|-<br />
| Cardiology || [[Aortic dissection]] || [[Aortic dissection resident survival guide]] || Chetan/Serge ||<br />
|-<br />
| Cardiology || [[Aortic regurgitation]] || [[Aortic regurgitation resident survival guide]] || Alejandro ||Complete<br />
|-<br />
| Cardiology || [[Aortic stenosis]] || [[Aortic stenosis resident survival guide]] || Alejandro ||Complete<br />
|-<br />
| Cardiology || [[Atrial flutter]] || [[Atrial flutter resident survival guide]] || Vidit ||<br />
|-<br />
| Cardiology || [[Bradycardia]] || [[Bradycardia resident survival guide]] || Ogheneochuko: Vidit ||Complete<br />
|-<br />
| Cardiology || [[Cardiac arrest]] || [[Cardiac arrest resident survival guide]] || Rim: Vidit ||Complete<br />
|-<br />
| Cardiology || [[Cardiogenic shock]] || [[Cardiogenic shock resident survival guide]] ||Gerry|| Complete<br />
|-<br />
| Cardiology || [[Chest pain]] || [[Chest pain resident survival guide]] || Rim/Alejandro || Complete<br />
|-<br />
| Cardiology || || [[Coronary angiography resident survival guide]] ||Yaz ||<br />
|-<br />
| Cardiology || [[Dyslipidemia]] || [[Dyslipidemia resident survival guide]] || ||<br />
|-<br />
| Cardiology || [[Electrocardiography]] || [[Electrocardiography resident survival guide]] ||Rim|| Complete<br />
|-<br />
| Cardiology || [[Endocarditis]] || [[Endocarditis resident survival guide]] ||Mohamed||Complete<br />
|-<br />
| Cardiology || [[Pericarditis]] || [[Pericarditis resident survival guide]] || Mugilan ||<br />
|-<br />
| Cardiology || [[Hypertension]] || [[Hypertension resident survival guide]] ||Landing page||Complete<br />
|-<br />
| Cardiology || [[Chronic hypertension]] || [[Chronic hypertension resident survival guide]] || Ayokunle||<br />
|-<br />
| Cardiology || [[Hypertensive crisis]] || [[Hypertensive crisis resident survival guide]]||Ayokunle|| Complete<br />
|-<br />
| Cardiology || [[Intracardiac device]] || [[Intracardiac device resident survival guide]] || ||<br />
|-<br />
| Cardiology || [[Supraventricular tachycardia|Narrow complex tachycardia]] || [[Narrow complex tachycardia resident survival guide]] || Hilda/Rim/Twinkle || Complete<br />
|-<br />
| Cardiology || [[Cardiac tamponade]] || [[Cardiac tamponade resident survival guide]] ||Ayokunle|| Complete<br />
|-<br />
| Cardiology || [[Low flow low gradient aortic stenosis]] || [[Low flow low gradient aortic stenosis resident survival guide]] || Rim || Complete<br />
|-<br />
| Cardiology || || [[Cardiac risk assessment prior to non-cardiac surgery resident survival guide]] ||Yaz||Complete<br />
|-<br />
| Cardiology || [[Dilated cardiomyopathy]] || [[Dilated cardiomyopathy resident survival guide]] || Steven ||<br />
|-<br />
| Cardiology || [[Restrictive cardiomyopathy]] || [[Restrictive cardiomyopathy resident survival guide]] || Steven ||<br />
|-<br />
| Cardiology || [[Hypertrophic cardiomyopathy]] || [[Hypertrophic cardiomyopathy resident survival guide]] || Steven ||<br />
|-<br />
| Cardiology || [[Arrhythmogenic right ventricular cardiomyopathy]] || [[Arrhythmogenic right ventricular cardiomyopathy resident survival guide]] || Steven ||<br />
|-<br />
| Cardiology || [[Claudication]] || [[Claudication resident survival guide]] ||Ochuko||<br />
|-<br />
| Cardiology || [[Mitral regurgitation]] || [[Mitral regurgitation resident survival guide]] ||Mugilan||<br />
|-<br />
| Cardiology || [[Mitral stenosis]] || [[Mitral stenosis resident survival guide]] ||Twinkle||Complete<br />
|-<br />
| Cardiology || [[Palpitations]] || [[Palpitations resident survival guide]] || ||<br />
|-<br />
| Cardiology || [[Peripheral artery disease]] || [[Peripheral artery disease resident survival guide]] || Ogheneochuko ||<br />
|-<br />
| Cardiology || [[Shortness of breath]] || [[Shortness of breath resident survival guide]] || Steven ||<br />
|-<br />
| Cardiology || [[STEMI]] || [[STEMI resident survival guide]] || Alejandro||Complete<br />
|-<br />
| Cardiology || [[Pulmonary embolism]] || [[Pulmonary embolism resident survival guide]] ||Rim ||Complete<br />
|-<br />
| Cardiology || [[Right ventricular myocardial infarction]] || [[Right ventricular myocardial infarction resident survival guide]] || Jad ||<br />
|-<br />
| Cardiology || [[Syncope]] || [[Syncope resident survival guide]] || Karol/Alejandro || Complete<br />
|-<br />
| Cardiology || [[Unstable angina]] || [[Unstable angina/ NSTEMI resident survival guide]] || Andrea/Rim ||<br />
|-<br />
| Cardiology || [[Valvular diseases]] || [[Valvular diseases resident survival guide]] || Landing page||Complete<br />
|-<br />
| Cardiology || [[VTE prevention]] || [[VTE prevention resident survival guide]] || Rim||Complete<br />
|-<br />
| Cardiology || [[Wide complex tachycardia]] || [[Wide complex tachycardia resident survival guide]] || Rim || Complete<br />
|-<br />
| Cardiology || [[WPW|Wolff-Parkinson-White syndrome]] || [[Wolff-Parkinson-White syndrome resident survival guide]]|| Alonso||<br />
|-<br />
|}<br />
<br />
===Other Topics===<br />
{| class="wikitable sortable"<br />
! Specialty<br />
! Topic<br />
! Resident Survival Guide Page<br />
! Author<br />
! Status<br />
|-<br />
| Pulmonary || [[Acute respiratory distress syndrome]] || [[Acute respiratory distress syndrome resident survival guide]] ||Ayokunle||<br />
|-<br />
| Pulmonary || [[Anaphylaxis]] || [[Anaphylaxis resident survival guide]] || Vidit ||<br />
|-<br />
| Pulmonary || [[Asthma|Asthma exacerbation]] || [[Asthma exacerbation resident survival guide]] || Abdurahman, Vidit ||Complete<br />
|-<br />
| Pulmonary || [[Chronic obstructive pulmonary disease|COPD exacerbation]] || [[COPD exacerbation resident survival guide]] || Abdurahman: Vidit ||Complete<br />
|-<br />
| Pulmonary || [[Cough]] || [[Cough resident survival guide]] || ||<br />
|-<br />
| Pulmonary || [[Deep venous thrombosis]] || [[Deep vein thrombosis resident survival guide|Deep venous thrombosis resident survival guide]] || Rim|| Complete<br />
|-<br />
| Pulmonary || [[Dyspnea]] || [[Dyspnea resident survival guide]] ||Dyspnea||<br />
|-<br />
| Pulmonary || [[Hemoptysis]] || [[Hemoptysis resident survival guide]] ||Teresa||<br />
|-<br />
| Pulmonary || [[Mechanical ventilation]] || [[Mechanical ventilation resident survival guide]] || Ahmed ||<br />
|-<br />
| Pulmonary || [[Pleural effusion]] || [[Pleural effusion resident survival guide]] ||Twinkle||<br />
|-<br />
| Pulmonary || [[Pulmonary embolism]] || [[Pulmonary embolism resident survival guide]] ||||<br />
|-<br />
| Pulmonary || [[Pulmonary hypertension]] || [[Pulmonary hypertension resident survival guide]] || Vidit ||<br />
|-<br />
| Pulmonary || [[Respiratory failure]] || [[Respiratory failure resident survival guide]] ||||<br />
|-<br />
| Cardiology || [[Tension pneumothorax]] || [[Tension pneumothorax resident survival guide]] || Mohamad||Complete<br />
|-<br />
| Gastroenterology || [[Abdominal pain]] || [[Abdominal pain resident survival guide]] ||||<br />
|-<br />
| Gastroenterology || [[Abnormal liver tests]] || [[Abnormal liver tests resident survival guide]] ||||<br />
|-<br />
| Gastroenterology || [[Acetaminophen toxicity]] || [[Acetaminophen overdose resident survival guide|Acetaminophen toxicity resident survival guide]] || Vidit ||Complete<br />
|-<br />
| Gastroenterology || [[Diarrhea|Acute diarrhea]] || [[Acute diarrhea resident survival guide]] || Mugilan ||Complete<br />
|-<br />
| Gastroenterology || [[Acute liver failure]] || [[Acute liver failure resident survival guide]] || Vendhan ||<br />
|-<br />
| Gastroenterology || [[Acute pancreatitis]] || [[Acute pancreatitis resident survival guide]] || Vidit || Complete<br />
|-<br />
| Gastroenterology || [[Appendicitis]] || [[Appendicitis resident survival guide]] || Teresa || Complete<br />
|-<br />
| Gastroenterology || [[Ascites]] || [[Ascites resident survival guide]] || Twinkle/Steven ||<br />
|-<br />
| Gastroenterology || [[Biliary tract diseases]] || [[Biliary tract diseases resident survival guide]] || Vendhan ||<br />
|-<br />
| Gastroenterology || [[Cholangitis]] || [[Cholangitis resident survival guide]] || Vendhan || Complete<br />
|-<br />
| Gastroenterology || [[Cholecystitis]] || [[Cholecystitis resident survival guide]] || Vendhan || Complete<br />
|-<br />
| Gastroenterology || [[Acute cholecystitis|Cholecystitis]] || [[Acute cholecystitis resident survival guide]] || Vendhan || Complete<br />
|-<br />
| Gastroenterology || [[Chronic cholecystitis|Cholecystitis]] || [[Chronic cholecystitis resident survival guide]] || Vendhan || Complete<br />
|-<br />
| Gastroenterology || [[Choledocholithiasis]] || [[Choledocholithiasis resident survival guide]] || Vendhan ||Complete<br />
|-<br />
| Gastroenterology || [[Cholelithiasis]] || [[Cholelithiasis resident survival guide]] || Vendhan ||<br />
|-<br />
| Gastroenterology || [[Diarrhea|Chronic diarrhea]] || [[Chronic diarrhea resident survival guide]] || Mugilan || Complete<br />
|-<br />
| Gastroenterology || [[Clostridium difficile]] || [[Clostridium difficile infection resident survival guide]] || Mugilan ||<br />
|-<br />
| Gastroenterology || [[Constipation]] || [[Constipation resident survival guide]] ||Mugilan|| Complete<br />
|-<br />
| Gastroenterology || [[Crohn’s disease]] || [[Crohn's disease resident survival guide]] ||Mugilan||<br />
|-<br />
| Gastroenterology || [[Diarrhea]] || [[Diarrhea resident survival guide]] || Mugilan ||Complete<br />
|-<br />
| Gastroenterology || [[Esophageal rupture]] || [[Esophageal rupture resident survival guide]] || ||<br />
|-<br />
| Gastroenterology || [[Ileus]] || [[Ileus resident survival guide]] ||Mugilan||<br />
|-<br />
| Gastroenterology || [[Intestinal ischemia]] || [[Intestinal ischemia resident survival guide]] ||Mugilan||<br />
|-<br />
| Gastroenterology || [[Acute pancreatitis|Gallstone pancreatitis]] || [[Gallstone pancreatitis resident survival guide]] || Vendhan|| Complete<br />
|-<br />
| Gastroenterology || [[Lower gastrointestinal bleeding]] || [[Lower gastrointestinal bleeding resident survival guide]] || Twinkle ||Complete<br />
|-<br />
| Gastroenterology || [[Nutrition]] || [[Nutrition resident survival guide]] ||||<br />
|-<br />
| Gastroenterology || [[Ulcerative colitis]] || [[Ulcerative colitis resident survival guide]] ||Mugilan||<br />
|-<br />
| Gastroenterology || [[Upper gastrointestinal bleeding]] || [[Upper gastrointestinal bleeding resident survival guide]] || Twinkle ||<br />
|-<br />
| Gastroenterology || [[Varices]] || [[Varices and variceal bleed resident survival guide]] || Twinkle || Complete<br />
|-<br />
| Nephrology || [[Acidosis]] || [[Acidosis resident survival guide]] ||||<br />
|-<br />
| Nephrology || [[Acute kidney injury]] || [[Acute kidney failure resident survival guide]] || Vendhan ||<br />
|-<br />
| Nephrology ||[[Alkalosis]] || [[Alkalosis resident survival guide]] ||||<br />
|-<br />
| Nephrology || [[Hyperkalemia]] || [[Hyperkalemia resident survival guide]] || Mahmoud ||<br />
|-<br />
| Nephrology || [[Hypernatremia]] || [[Hypernatremia resident survival guide]] || Priyamvada ||<br />
|-<br />
| Nephrology || [[Hypokalemia]] || [[Hypokalemia resident survival guide]] ||||<br />
|-<br />
| Nephrology || [[Hyponatremia]] || [[Hyponatremia resident survival guide]] || Priyamvada ||<br />
|-<br />
| Nephrology || [[Metabolic acidosis]] || [[Metabolic acidosis resident survival guide]] || Ogheneochuko ||<br />
|-<br />
| Nephrology || [[Metabolic alkalosis]] || [[Metabolic alkalosis resident survival guide]] ||||<br />
|-<br />
| Nephrology || [[Nephrolithiasis]] || [[Nephrolithiasis resident survival guide]] ||||<br />
|-<br />
| Nephrology || [[Polyuria]] || [[Polyuria resident survival guide]] ||||<br />
|-<br />
| Nephrology || [[Renal artery stenosis]] || [[Renal artery stenosis resident survival guide]] ||Karol||Complete<br />
|-<br />
| Nephrology || [[Respiratory acidosis]] || [[Respiratory acidosis resident survival guide]] ||||<br />
|-<br />
| Nephrology || [[Respiratory alkalosis]] || [[Respiratory alkalosis resident survival guide]] ||||<br />
|-<br />
| Hematology-Oncology || [[Anemia]] || [[Anemia resident survival guide]] || Chetan ||<br />
|-<br />
| Hematology-Oncology || [[Aplastic anemia]] || [[Aplastic anemia resident survival guide]] || Chetan ||<br />
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{{WikiDoc Sources}}</div>Rim Halabyhttps://www.wikidoc.org/index.php?title=wikidoc:General_disclaimer&diff=1088464wikidoc:General disclaimer2015-04-16T17:08:38Z<p>Rim Halaby: </p>
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'''Global attribution:''' The language describing WikiDoc throughout these pages is often borrowed and modified with global attribution to Wikipedia and with links to Wikipedia. This statement is a global attribution to wikipedia consistent with copyleft policies.</div>Rim Halabyhttps://www.wikidoc.org/index.php?title=Pregnancy_termination_complications&diff=1088400Pregnancy termination complications2015-04-16T15:57:03Z<p>Rim Halaby: /* Complications */</p>
<hr />
<div>__NOTOC__<br />
{{SI}}<br />
'''Editor-In-Chief:''' {{Rim}}<br />
<br />
{{SK}} Abortion complications, uterine evacuation complications<br />
<br />
==Overview==<br />
Complications of pregnancy termination include [[hemorrhage]], cervical laceration, uterine perforation, and [[infection]]s.<br />
<br />
==Complications==<br />
* Cervical laceration<br />
* Cervical stenosis<br />
* Continuing [[pregnancy]]<br />
* Death<br />
* [[Endometritis]]<br />
* [[Hematometra]]<br />
* [[Hemorrhage]]<br />
* Incomplete abortion<br />
* Mild [[infection]]<br />
* [[Pain]]<br />
* Retained products of conception<br />
* [[Sepsis]]<br />
* Uterine perforation<ref name="pmid18772098">{{cite journal| author=Grossman D, Blanchard K, Blumenthal P| title=Complications after second trimester surgical and medical abortion. | journal=Reprod Health Matters | year= 2008 | volume= 16 | issue= 31 Suppl | pages= 173-82 | pmid=18772098 | doi=10.1016/S0968-8080(08)31379-2 | pmc= | url=http://www.ncbi.nlm.nih.gov/entrez/eutils/elink.fcgi?dbfrom=pubmed&tool=sumsearch.org/cite&retmode=ref&cmd=prlinks&id=18772098 }} </ref><ref name="pmid6866362">{{cite journal| author=Peterson WF, Berry FN, Grace MR, Gulbranson CL| title=Second-trimester abortion by dilatation and evacuation: an analysis of 11,747 cases. | journal=Obstet Gynecol | year= 1983 | volume= 62 | issue= 2 | pages= 185-90 | pmid=6866362 | doi= | pmc= | url=http://www.ncbi.nlm.nih.gov/entrez/eutils/elink.fcgi?dbfrom=pubmed&tool=sumsearch.org/cite&retmode=ref&cmd=prlinks&id=6866362 }} </ref><ref name="pmid10944371">{{cite journal| author=Kruse B, Poppema S, Creinin MD, Paul M| title=Management of side effects and complications in medical abortion. | journal=Am J Obstet Gynecol | year= 2000 | volume= 183 | issue= 2 Suppl | pages= S65-75 | pmid=10944371 | doi= | pmc= | url=http://www.ncbi.nlm.nih.gov/entrez/eutils/elink.fcgi?dbfrom=pubmed&tool=sumsearch.org/cite&retmode=ref&cmd=prlinks&id=10944371 }} </ref><ref name="pmid12193931">{{cite journal| author=Autry AM, Hayes EC, Jacobson GF, Kirby RS| title=A comparison of medical induction and dilation and evacuation for second-trimester abortion. | journal=Am J Obstet Gynecol | year= 2002 | volume= 187 | issue= 2 | pages= 393-7 | pmid=12193931 | doi= | pmc= | url=http://www.ncbi.nlm.nih.gov/entrez/eutils/elink.fcgi?dbfrom=pubmed&tool=sumsearch.org/cite&retmode=ref&cmd=prlinks&id=12193931 }} </ref><br />
<br />
==References==<br />
{{Reflist|2}}<br />
<br />
[[Category:Obstetrics]]<br />
<br />
{{WikiDoc Help Menu}}<br />
{{WikiDoc Sources}}</div>Rim Halabyhttps://www.wikidoc.org/index.php?title=Pregnancy_termination_complications&diff=1088399Pregnancy termination complications2015-04-16T15:56:24Z<p>Rim Halaby: /* Complications */</p>
<hr />
<div>__NOTOC__<br />
{{SI}}<br />
'''Editor-In-Chief:''' {{Rim}}<br />
<br />
{{SK}} Abortion complications, uterine evacuation complications<br />
<br />
==Overview==<br />
Complications of pregnancy termination include [[hemorrhage]], cervical laceration, uterine perforation, and [[infection]]s.<br />
<br />
==Complications==<br />
* Cervical laceration<br />
* Cervical stenosis<br />
* Continuing [[pregnancy]]<br />
* Death<br />
* [[Endometritis]]<br />
* [[Hematometra]]<br />
* [[Hemorrhage]]<br />
* Incomplete abortion<br />
* Mild [[infection]]<br />
* [[Pain]]<br />
* Retained products of conception<ref name="pmid18772098">{{cite journal| author=Grossman D, Blanchard K, Blumenthal P| title=Complications after second trimester surgical and medical abortion. | journal=Reprod Health Matters | year= 2008 | volume= 16 | issue= 31 Suppl | pages= 173-82 | pmid=18772098 | doi=10.1016/S0968-8080(08)31379-2 | pmc= | url=http://www.ncbi.nlm.nih.gov/entrez/eutils/elink.fcgi?dbfrom=pubmed&tool=sumsearch.org/cite&retmode=ref&cmd=prlinks&id=18772098 }} </ref><ref name="pmid6866362">{{cite journal| author=Peterson WF, Berry FN, Grace MR, Gulbranson CL| title=Second-trimester abortion by dilatation and evacuation: an analysis of 11,747 cases. | journal=Obstet Gynecol | year= 1983 | volume= 62 | issue= 2 | pages= 185-90 | pmid=6866362 | doi= | pmc= | url=http://www.ncbi.nlm.nih.gov/entrez/eutils/elink.fcgi?dbfrom=pubmed&tool=sumsearch.org/cite&retmode=ref&cmd=prlinks&id=6866362 }} </ref><ref name="pmid10944371">{{cite journal| author=Kruse B, Poppema S, Creinin MD, Paul M| title=Management of side effects and complications in medical abortion. | journal=Am J Obstet Gynecol | year= 2000 | volume= 183 | issue= 2 Suppl | pages= S65-75 | pmid=10944371 | doi= | pmc= | url=http://www.ncbi.nlm.nih.gov/entrez/eutils/elink.fcgi?dbfrom=pubmed&tool=sumsearch.org/cite&retmode=ref&cmd=prlinks&id=10944371 }} </ref><ref name="pmid12193931">{{cite journal| author=Autry AM, Hayes EC, Jacobson GF, Kirby RS| title=A comparison of medical induction and dilation and evacuation for second-trimester abortion. | journal=Am J Obstet Gynecol | year= 2002 | volume= 187 | issue= 2 | pages= 393-7 | pmid=12193931 | doi= | pmc= | url=http://www.ncbi.nlm.nih.gov/entrez/eutils/elink.fcgi?dbfrom=pubmed&tool=sumsearch.org/cite&retmode=ref&cmd=prlinks&id=12193931 }} </ref><br />
* [[Sepsis]]<br />
* Uterine perforation<br />
<br />
==References==<br />
{{Reflist|2}}<br />
<br />
[[Category:Obstetrics]]<br />
<br />
{{WikiDoc Help Menu}}<br />
{{WikiDoc Sources}}</div>Rim Halabyhttps://www.wikidoc.org/index.php?title=Pregnancy_termination_complications&diff=1088398Pregnancy termination complications2015-04-16T15:55:30Z<p>Rim Halaby: /* Complications */</p>
<hr />
<div>__NOTOC__<br />
{{SI}}<br />
'''Editor-In-Chief:''' {{Rim}}<br />
<br />
{{SK}} Abortion complications, uterine evacuation complications<br />
<br />
==Overview==<br />
Complications of pregnancy termination include [[hemorrhage]], cervical laceration, uterine perforation, and [[infection]]s.<br />
<br />
==Complications==<br />
* Cervical laceration<br />
* Cervical stenosis<br />
* Continuing [[pregnancy]]<br />
* Death<br />
* [[Endometritis]]<br />
* [[Hematometra]]<br />
* [[Hemorrhage]]<br />
* Incomplete abortion<br />
* Incomplete abortion<br />
* Mild [[infection]]<br />
* [[Pain]]<br />
* Retained products of conception<ref name="pmid18772098">{{cite journal| author=Grossman D, Blanchard K, Blumenthal P| title=Complications after second trimester surgical and medical abortion. | journal=Reprod Health Matters | year= 2008 | volume= 16 | issue= 31 Suppl | pages= 173-82 | pmid=18772098 | doi=10.1016/S0968-8080(08)31379-2 | pmc= | url=http://www.ncbi.nlm.nih.gov/entrez/eutils/elink.fcgi?dbfrom=pubmed&tool=sumsearch.org/cite&retmode=ref&cmd=prlinks&id=18772098 }} </ref><ref name="pmid6866362">{{cite journal| author=Peterson WF, Berry FN, Grace MR, Gulbranson CL| title=Second-trimester abortion by dilatation and evacuation: an analysis of 11,747 cases. | journal=Obstet Gynecol | year= 1983 | volume= 62 | issue= 2 | pages= 185-90 | pmid=6866362 | doi= | pmc= | url=http://www.ncbi.nlm.nih.gov/entrez/eutils/elink.fcgi?dbfrom=pubmed&tool=sumsearch.org/cite&retmode=ref&cmd=prlinks&id=6866362 }} </ref><ref name="pmid10944371">{{cite journal| author=Kruse B, Poppema S, Creinin MD, Paul M| title=Management of side effects and complications in medical abortion. | journal=Am J Obstet Gynecol | year= 2000 | volume= 183 | issue= 2 Suppl | pages= S65-75 | pmid=10944371 | doi= | pmc= | url=http://www.ncbi.nlm.nih.gov/entrez/eutils/elink.fcgi?dbfrom=pubmed&tool=sumsearch.org/cite&retmode=ref&cmd=prlinks&id=10944371 }} </ref><ref name="pmid12193931">{{cite journal| author=Autry AM, Hayes EC, Jacobson GF, Kirby RS| title=A comparison of medical induction and dilation and evacuation for second-trimester abortion. | journal=Am J Obstet Gynecol | year= 2002 | volume= 187 | issue= 2 | pages= 393-7 | pmid=12193931 | doi= | pmc= | url=http://www.ncbi.nlm.nih.gov/entrez/eutils/elink.fcgi?dbfrom=pubmed&tool=sumsearch.org/cite&retmode=ref&cmd=prlinks&id=12193931 }} </ref><br />
* [[Sepsis]]<br />
* Uterine perforation<br />
<br />
==References==<br />
{{Reflist|2}}<br />
<br />
[[Category:Obstetrics]]<br />
<br />
{{WikiDoc Help Menu}}<br />
{{WikiDoc Sources}}</div>Rim Halabyhttps://www.wikidoc.org/index.php?title=Uterine_evacuation_complications&diff=1088394Uterine evacuation complications2015-04-16T15:52:24Z<p>Rim Halaby: ←Redirected page to Pregnancy termination complications</p>
<hr />
<div>#Redirect [[Pregnancy termination complications]]</div>Rim Halabyhttps://www.wikidoc.org/index.php?title=Abortion_complications&diff=1088393Abortion complications2015-04-16T15:51:59Z<p>Rim Halaby: ←Redirected page to Pregnancy termination complications</p>
<hr />
<div>#Redirect [[Pregnancy termination complications]]</div>Rim Halabyhttps://www.wikidoc.org/index.php?title=Uterine_evacuation&diff=1088392Uterine evacuation2015-04-16T15:51:40Z<p>Rim Halaby: ←Redirected page to Pregnancy termination complications</p>
<hr />
<div>#Redirect [[Pregnancy termination complications]]</div>Rim Halabyhttps://www.wikidoc.org/index.php?title=Abortion&diff=1088391Abortion2015-04-16T15:51:34Z<p>Rim Halaby: ←Redirected page to Pregnancy termination complications</p>
<hr />
<div>#Redirect [[Pregnancy termination complications]]</div>Rim Halabyhttps://www.wikidoc.org/index.php?title=Pregnancy_termination_complications&diff=1088388Pregnancy termination complications2015-04-16T15:50:55Z<p>Rim Halaby: </p>
<hr />
<div>__NOTOC__<br />
{{SI}}<br />
'''Editor-In-Chief:''' {{Rim}}<br />
<br />
{{SK}} Abortion complications, uterine evacuation complications<br />
<br />
==Overview==<br />
Complications of pregnancy termination include [[hemorrhage]], cervical laceration, uterine perforation, and [[infection]]s.<br />
<br />
==Complications==<br />
* [[Hemorrhage]]<br />
* Cervical laceration<br />
* Uterine perforation<br />
* Incomplete abortion<br />
* [[Sepsis]]<br />
* Cervical stenosis<br />
* Continuing [[pregnancy]]<br />
* [[Hematometra]]<br />
* Death<br />
* [[Endometritis]]<br />
* Incomplete abortion<br />
* Mild [[infection]]<br />
* [[Pain]]<br />
* Retained products of conception<ref name="pmid18772098">{{cite journal| author=Grossman D, Blanchard K, Blumenthal P| title=Complications after second trimester surgical and medical abortion. | journal=Reprod Health Matters | year= 2008 | volume= 16 | issue= 31 Suppl | pages= 173-82 | pmid=18772098 | doi=10.1016/S0968-8080(08)31379-2 | pmc= | url=http://www.ncbi.nlm.nih.gov/entrez/eutils/elink.fcgi?dbfrom=pubmed&tool=sumsearch.org/cite&retmode=ref&cmd=prlinks&id=18772098 }} </ref><ref name="pmid6866362">{{cite journal| author=Peterson WF, Berry FN, Grace MR, Gulbranson CL| title=Second-trimester abortion by dilatation and evacuation: an analysis of 11,747 cases. | journal=Obstet Gynecol | year= 1983 | volume= 62 | issue= 2 | pages= 185-90 | pmid=6866362 | doi= | pmc= | url=http://www.ncbi.nlm.nih.gov/entrez/eutils/elink.fcgi?dbfrom=pubmed&tool=sumsearch.org/cite&retmode=ref&cmd=prlinks&id=6866362 }} </ref><ref name="pmid10944371">{{cite journal| author=Kruse B, Poppema S, Creinin MD, Paul M| title=Management of side effects and complications in medical abortion. | journal=Am J Obstet Gynecol | year= 2000 | volume= 183 | issue= 2 Suppl | pages= S65-75 | pmid=10944371 | doi= | pmc= | url=http://www.ncbi.nlm.nih.gov/entrez/eutils/elink.fcgi?dbfrom=pubmed&tool=sumsearch.org/cite&retmode=ref&cmd=prlinks&id=10944371 }} </ref><ref name="pmid12193931">{{cite journal| author=Autry AM, Hayes EC, Jacobson GF, Kirby RS| title=A comparison of medical induction and dilation and evacuation for second-trimester abortion. | journal=Am J Obstet Gynecol | year= 2002 | volume= 187 | issue= 2 | pages= 393-7 | pmid=12193931 | doi= | pmc= | url=http://www.ncbi.nlm.nih.gov/entrez/eutils/elink.fcgi?dbfrom=pubmed&tool=sumsearch.org/cite&retmode=ref&cmd=prlinks&id=12193931 }} </ref><br />
<br />
==References==<br />
{{Reflist|2}}<br />
<br />
[[Category:Obstetrics]]<br />
<br />
{{WikiDoc Help Menu}}<br />
{{WikiDoc Sources}}</div>Rim Halabyhttps://www.wikidoc.org/index.php?title=Termination_of_pregnancy&diff=1088386Termination of pregnancy2015-04-16T15:49:42Z<p>Rim Halaby: Rim Halaby moved page Termination of pregnancy to Pregnancy termination complications</p>
<hr />
<div>#REDIRECT [[Pregnancy termination complications]]</div>Rim Halabyhttps://www.wikidoc.org/index.php?title=Pregnancy_termination_complications&diff=1088385Pregnancy termination complications2015-04-16T15:49:32Z<p>Rim Halaby: Rim Halaby moved page Termination of pregnancy to Pregnancy termination complications</p>
<hr />
<div>__NOTOC__<br />
{{SI}}<br />
'''Editor-In-Chief:''' {{Rim}}<br />
<br />
{{SK}} Abortion, uterine evacuation<br />
<br />
==Overview==<br />
Complications of termination of pregnancy include [[hemorrhage]], cervical laceration, uterine perforation, and [[infection]]s.<br />
<br />
==Complications==<br />
* [[Hemorrhage]]<br />
* Cervical laceration<br />
* Uterine perforation<br />
* Incomplete abortion<br />
* [[Sepsis]]<br />
* Cervical stenosis<br />
* Continuing [[pregnancy]]<br />
* [[Hematometra]]<br />
* Death<br />
* [[Endometritis]]<br />
* Incomplete abortion<br />
* Mild [[infection]]<br />
* [[Pain]]<br />
* Retained products of conception<ref name="pmid18772098">{{cite journal| author=Grossman D, Blanchard K, Blumenthal P| title=Complications after second trimester surgical and medical abortion. | journal=Reprod Health Matters | year= 2008 | volume= 16 | issue= 31 Suppl | pages= 173-82 | pmid=18772098 | doi=10.1016/S0968-8080(08)31379-2 | pmc= | url=http://www.ncbi.nlm.nih.gov/entrez/eutils/elink.fcgi?dbfrom=pubmed&tool=sumsearch.org/cite&retmode=ref&cmd=prlinks&id=18772098 }} </ref><ref name="pmid6866362">{{cite journal| author=Peterson WF, Berry FN, Grace MR, Gulbranson CL| title=Second-trimester abortion by dilatation and evacuation: an analysis of 11,747 cases. | journal=Obstet Gynecol | year= 1983 | volume= 62 | issue= 2 | pages= 185-90 | pmid=6866362 | doi= | pmc= | url=http://www.ncbi.nlm.nih.gov/entrez/eutils/elink.fcgi?dbfrom=pubmed&tool=sumsearch.org/cite&retmode=ref&cmd=prlinks&id=6866362 }} </ref><ref name="pmid10944371">{{cite journal| author=Kruse B, Poppema S, Creinin MD, Paul M| title=Management of side effects and complications in medical abortion. | journal=Am J Obstet Gynecol | year= 2000 | volume= 183 | issue= 2 Suppl | pages= S65-75 | pmid=10944371 | doi= | pmc= | url=http://www.ncbi.nlm.nih.gov/entrez/eutils/elink.fcgi?dbfrom=pubmed&tool=sumsearch.org/cite&retmode=ref&cmd=prlinks&id=10944371 }} </ref><ref name="pmid12193931">{{cite journal| author=Autry AM, Hayes EC, Jacobson GF, Kirby RS| title=A comparison of medical induction and dilation and evacuation for second-trimester abortion. | journal=Am J Obstet Gynecol | year= 2002 | volume= 187 | issue= 2 | pages= 393-7 | pmid=12193931 | doi= | pmc= | url=http://www.ncbi.nlm.nih.gov/entrez/eutils/elink.fcgi?dbfrom=pubmed&tool=sumsearch.org/cite&retmode=ref&cmd=prlinks&id=12193931 }} </ref><br />
<br />
==References==<br />
{{Reflist|2}}<br />
<br />
[[Category:Obstetrics]]<br />
<br />
{{WikiDoc Help Menu}}<br />
{{WikiDoc Sources}}</div>Rim Halabyhttps://www.wikidoc.org/index.php?title=Pregnancy_termination_complications&diff=1088377Pregnancy termination complications2015-04-16T15:46:24Z<p>Rim Halaby: /* Complications */</p>
<hr />
<div>__NOTOC__<br />
{{SI}}<br />
'''Editor-In-Chief:''' {{Rim}}<br />
<br />
{{SK}} Abortion, uterine evacuation<br />
<br />
==Overview==<br />
Complications of termination of pregnancy include [[hemorrhage]], cervical laceration, uterine perforation, and [[infection]]s.<br />
<br />
==Complications==<br />
* [[Hemorrhage]]<br />
* Cervical laceration<br />
* Uterine perforation<br />
* Incomplete abortion<br />
* [[Sepsis]]<br />
* Cervical stenosis<br />
* Continuing [[pregnancy]]<br />
* [[Hematometra]]<br />
* Death<br />
* [[Endometritis]]<br />
* Incomplete abortion<br />
* Mild [[infection]]<br />
* [[Pain]]<br />
* Retained products of conception<ref name="pmid18772098">{{cite journal| author=Grossman D, Blanchard K, Blumenthal P| title=Complications after second trimester surgical and medical abortion. | journal=Reprod Health Matters | year= 2008 | volume= 16 | issue= 31 Suppl | pages= 173-82 | pmid=18772098 | doi=10.1016/S0968-8080(08)31379-2 | pmc= | url=http://www.ncbi.nlm.nih.gov/entrez/eutils/elink.fcgi?dbfrom=pubmed&tool=sumsearch.org/cite&retmode=ref&cmd=prlinks&id=18772098 }} </ref><ref name="pmid6866362">{{cite journal| author=Peterson WF, Berry FN, Grace MR, Gulbranson CL| title=Second-trimester abortion by dilatation and evacuation: an analysis of 11,747 cases. | journal=Obstet Gynecol | year= 1983 | volume= 62 | issue= 2 | pages= 185-90 | pmid=6866362 | doi= | pmc= | url=http://www.ncbi.nlm.nih.gov/entrez/eutils/elink.fcgi?dbfrom=pubmed&tool=sumsearch.org/cite&retmode=ref&cmd=prlinks&id=6866362 }} </ref><ref name="pmid10944371">{{cite journal| author=Kruse B, Poppema S, Creinin MD, Paul M| title=Management of side effects and complications in medical abortion. | journal=Am J Obstet Gynecol | year= 2000 | volume= 183 | issue= 2 Suppl | pages= S65-75 | pmid=10944371 | doi= | pmc= | url=http://www.ncbi.nlm.nih.gov/entrez/eutils/elink.fcgi?dbfrom=pubmed&tool=sumsearch.org/cite&retmode=ref&cmd=prlinks&id=10944371 }} </ref><ref name="pmid12193931">{{cite journal| author=Autry AM, Hayes EC, Jacobson GF, Kirby RS| title=A comparison of medical induction and dilation and evacuation for second-trimester abortion. | journal=Am J Obstet Gynecol | year= 2002 | volume= 187 | issue= 2 | pages= 393-7 | pmid=12193931 | doi= | pmc= | url=http://www.ncbi.nlm.nih.gov/entrez/eutils/elink.fcgi?dbfrom=pubmed&tool=sumsearch.org/cite&retmode=ref&cmd=prlinks&id=12193931 }} </ref><br />
<br />
==References==<br />
{{Reflist|2}}<br />
<br />
[[Category:Obstetrics]]<br />
<br />
{{WikiDoc Help Menu}}<br />
{{WikiDoc Sources}}</div>Rim Halabyhttps://www.wikidoc.org/index.php?title=Uterine_evacuation&diff=1088368Uterine evacuation2015-04-16T15:44:41Z<p>Rim Halaby: ←Redirected page to Termination of pregnancy</p>
<hr />
<div>#Redirect [[Termination of pregnancy]]</div>Rim Halabyhttps://www.wikidoc.org/index.php?title=Abortion&diff=1088367Abortion2015-04-16T15:44:33Z<p>Rim Halaby: ←Redirected page to Termination of pregnancy</p>
<hr />
<div>#Redirect [[Termination of pregnancy]]</div>Rim Halabyhttps://www.wikidoc.org/index.php?title=Pregnancy_termination_complications&diff=1088365Pregnancy termination complications2015-04-16T15:43:55Z<p>Rim Halaby: Created page with "__NOTOC__ {{SI}} '''Editor-In-Chief:''' {{Rim}} {{SK}} Abortion, uterine evacuation ==Overview== Complications of termination of pregnancy include hemorrhage, cervical l..."</p>
<hr />
<div>__NOTOC__<br />
{{SI}}<br />
'''Editor-In-Chief:''' {{Rim}}<br />
<br />
{{SK}} Abortion, uterine evacuation<br />
<br />
==Overview==<br />
Complications of termination of pregnancy include [[hemorrhage]], cervical laceration, uterine perforation, and [[infection]]s.<br />
<br />
==Complications==<br />
* [[Hemorrhage]]<br />
* Cervical laceration<br />
* Uterine perforation<br />
* Incomplete abortion<br />
* [[Sepsis]]<br />
* Cervical stenosis<br />
* Continuing [[pregnancy]]<br />
* [[Hematometra]]<br />
* Death<br />
* [[Endometritis]]<br />
* Incomplete abortion<br />
* Mild [[infection]]<br />
* [[Pain]]<br />
* Retained products of conception<br />
* Side effects of medications ([[nausea]], [[vomiting]], [[diarrhea]])<ref name="pmid18772098">{{cite journal| author=Grossman D, Blanchard K, Blumenthal P| title=Complications after second trimester surgical and medical abortion. | journal=Reprod Health Matters | year= 2008 | volume= 16 | issue= 31 Suppl | pages= 173-82 | pmid=18772098 | doi=10.1016/S0968-8080(08)31379-2 | pmc= | url=http://www.ncbi.nlm.nih.gov/entrez/eutils/elink.fcgi?dbfrom=pubmed&tool=sumsearch.org/cite&retmode=ref&cmd=prlinks&id=18772098 }} </ref><ref name="pmid6866362">{{cite journal| author=Peterson WF, Berry FN, Grace MR, Gulbranson CL| title=Second-trimester abortion by dilatation and evacuation: an analysis of 11,747 cases. | journal=Obstet Gynecol | year= 1983 | volume= 62 | issue= 2 | pages= 185-90 | pmid=6866362 | doi= | pmc= | url=http://www.ncbi.nlm.nih.gov/entrez/eutils/elink.fcgi?dbfrom=pubmed&tool=sumsearch.org/cite&retmode=ref&cmd=prlinks&id=6866362 }} </ref><ref name="pmid10944371">{{cite journal| author=Kruse B, Poppema S, Creinin MD, Paul M| title=Management of side effects and complications in medical abortion. | journal=Am J Obstet Gynecol | year= 2000 | volume= 183 | issue= 2 Suppl | pages= S65-75 | pmid=10944371 | doi= | pmc= | url=http://www.ncbi.nlm.nih.gov/entrez/eutils/elink.fcgi?dbfrom=pubmed&tool=sumsearch.org/cite&retmode=ref&cmd=prlinks&id=10944371 }} </ref><ref name="pmid12193931">{{cite journal| author=Autry AM, Hayes EC, Jacobson GF, Kirby RS| title=A comparison of medical induction and dilation and evacuation for second-trimester abortion. | journal=Am J Obstet Gynecol | year= 2002 | volume= 187 | issue= 2 | pages= 393-7 | pmid=12193931 | doi= | pmc= | url=http://www.ncbi.nlm.nih.gov/entrez/eutils/elink.fcgi?dbfrom=pubmed&tool=sumsearch.org/cite&retmode=ref&cmd=prlinks&id=12193931 }} </ref><br />
<br />
==References==<br />
{{Reflist|2}}<br />
<br />
[[Category:Obstetrics]]<br />
<br />
{{WikiDoc Help Menu}}<br />
{{WikiDoc Sources}}</div>Rim Halabyhttps://www.wikidoc.org/index.php?title=Uterine_evacuation&diff=1088331Uterine evacuation2015-04-16T15:16:45Z<p>Rim Halaby: ←Redirected page to Pregnancy termination</p>
<hr />
<div>#Redirect [[Pregnancy termination]]</div>Rim Halabyhttps://www.wikidoc.org/index.php?title=Abortion&diff=1088315Abortion2015-04-16T14:58:52Z<p>Rim Halaby: ←Redirected page to Pregnancy termination</p>
<hr />
<div>#Redirect [[Pregnancy termination]]</div>Rim Halabyhttps://www.wikidoc.org/index.php?title=Miscarriage&diff=1088292Miscarriage2015-04-16T14:45:43Z<p>Rim Halaby: </p>
<hr />
<div>__NOTOC__<br />
'''For patient information, click [[Miscarriage (patient information)|here]]'''.<br />
<br />
{{Miscarriage}}<br />
{{CMG}}<br />
<br />
'''''Synonyms and Keywords:''''' Spontaneous abortion; Missed abortion; Incomplete abortion; Complete abortion; Inevitable abortion; Infected abortion<br />
<br />
<br />
==[[Miscarriage overview|Overview]]==<br />
<br />
==[[Miscarriage historical perspective|Historical Perspective]]==<br />
<br />
==[[Miscarriage classification|Classification]]==<br />
<br />
==[[Miscarriage pathophysiology|Pathophysiology]]==<br />
<br />
==[[Miscarriage causes|Causes]]==<br />
<br />
==[[Miscarriage differential diagnosis|Differentiating Miscarriage from other Diseases]]==<br />
<br />
==[[Miscarriage epidemiology and demographics|Epidemiology and Demographics]]==<br />
<br />
==[[Miscarriage risk factors|Risk Factors]]== <br />
<br />
==[[Miscarriage natural history, complications and prognosis|Natural History, Complications and Prognosis]]==<br />
<br />
==Diagnosis==<br />
[[Miscarriage history and symptoms|History and Symptoms]] | [[Miscarriage physical examination|Physical Examination]] | [[Miscarriage laboratory findings|Laboratory Findings]] | [[Miscarriage ultrasound|Ultrasound]] | [[Miscarriage other imaging findings|Other Imaging Findings]] | [[Miscarriage other diagnostic studies|Other Diagnostic Studies]]<br />
<br />
==Treatment==<br />
[[Miscarriage medical therapy|Medical Therapy]] | [[Miscarriage surgery|Surgery]] | [[Miscarriage primary prevention|Primary Prevention]] | [[Miscarriage secondary prevention|Secondary Prevention]] | [[Miscarriage cost-effectiveness of therapy|Cost-Effectiveness of Therapy]] | [[Miscarriage future or investigational therapies|Future or Investigational Therapies]]<br />
<br />
==Case Studies==<br />
[[Miscarriage case study one|Case #1]]<br />
<br />
==References==<br />
{{reflist|2}}<br />
[[Category:Abortion]]<br />
[[Category:Primary care]]<br />
[[Category:Obstetrics]]<br />
[[Category:Disease]]<br />
<br />
{{WH}}<br />
{{WikiDoc Sources}}</div>Rim Halabyhttps://www.wikidoc.org/index.php?title=Unstable_angina/_NSTEMI_resident_survival_guide&diff=1088094Unstable angina/ NSTEMI resident survival guide2015-04-15T21:12:19Z<p>Rim Halaby: Replaced content with "Work under progress. Please come back later to check this page."</p>
<hr />
<div>Work under progress.<br />
<br />
Please come back later to check this page.</div>Rim Halabyhttps://www.wikidoc.org/index.php?title=Resident_survival_guide_topics&diff=1088092Resident survival guide topics2015-04-15T21:11:11Z<p>Rim Halaby: /* List of All Topics */</p>
<hr />
<div>__NOTOC__<br />
{{Resident survival guide project}}<br />
[[Image:Main_help_page_small.PNG|100px|link=Help]][[Image:Projects.PNG|100px|link=Projects]][[Image:Editor's_Tools.PNG|100px|link=Help Menu]]<br />
<br />
{{WikiDoc CMG}}; {{AE}} {{MS}}; [[Priyamvada Singh|Priyamvada Singh, M.D.]] [mailto:psingh13579@gmail.com]; {{Rim}}<br />
<br />
==Overview==<br />
This section shows the list of topics available for the resident survival guide project and how to select a topic. You can also update the status of your chosen topic here by entering the authorship details so that your work is not overlapped by the work of other editors.<br />
<br />
==Select a Topic==<br />
*Select a topic from the list of resident survival guide topics shown below.<br />
*The topics that are completed or have been worked on by wikidoc scholars are highlighted in blue.<br />
*The topics in black are still available for scholars on campus or remote collaborators to work on.<br />
<br />
==List of All Topics==<br />
<br />
===Cardiology===<br />
<br />
{| class="wikitable sortable"<br />
! Specialty<br />
! Topic<br />
! Resident Survival Guide Page<br />
! Author<br />
! Status<br />
|-<br />
| Cardiology || [[Acute coronary syndrome]] || [[Acute coronary syndrome resident survival guide]] || Priyamvada/Rim || Complete<br />
|-<br />
| Cardiology || [[Heart failure]] || [[Heart failure resident survival guide]] || Mahmoud/Dr. Kay || Complete<br />
|-<br />
| Cardiology || [[Arrhythmia]] || [[Arrhythmia resident survival guide]] || Rim || Complete<br />
|-<br />
| Cardiology || [[Atrial fibrillation]] || [[Atrial fibrillation resident survival guide]] || Vidit|| Complete<br />
|-<br />
| Cardiology || [[Aortic aneurysm]] || [[Aortic aneurysm resident survival guide]] ||Landing page|| Complete<br />
|-<br />
| Cardiology || [[Abdominal aortic aneurysm]] || [[Abdominal aortic aneurysm resident survival guide]] ||Yaz||<br />
|-<br />
| Cardiology || [[Thoracic aortic aneurysm]] || [[Thoracic aortic aneurysm resident survival guide]] ||Yaz||<br />
|-<br />
| Cardiology || [[Aortic dissection]] || [[Aortic dissection resident survival guide]] || Chetan/Serge ||<br />
|-<br />
| Cardiology || [[Aortic regurgitation]] || [[Aortic regurgitation resident survival guide]] || Alejandro ||Complete<br />
|-<br />
| Cardiology || [[Aortic stenosis]] || [[Aortic stenosis resident survival guide]] || Alejandro ||Complete<br />
|-<br />
| Cardiology || [[Atrial flutter]] || [[Atrial flutter resident survival guide]] || Vidit ||<br />
|-<br />
| Cardiology || [[Bradycardia]] || [[Bradycardia resident survival guide]] || Ogheneochuko: Vidit ||Complete<br />
|-<br />
| Cardiology || [[Cardiac arrest]] || [[Cardiac arrest resident survival guide]] || Rim: Vidit ||Complete<br />
|-<br />
| Cardiology || [[Cardiogenic shock]] || [[Cardiogenic shock resident survival guide]] ||Gerry|| Complete<br />
|-<br />
| Cardiology || [[Chest pain]] || [[Chest pain resident survival guide]] || Rim/Alejandro || Complete<br />
|-<br />
| Cardiology || || [[Coronary angiography resident survival guide]] ||Yaz ||<br />
|-<br />
| Cardiology || [[Dyslipidemia]] || [[Dyslipidemia resident survival guide]] || ||<br />
|-<br />
| Cardiology || [[Electrocardiography]] || [[Electrocardiography resident survival guide]] ||Rim|| Complete<br />
|-<br />
| Cardiology || [[Endocarditis]] || [[Endocarditis resident survival guide]] ||Mohamed||Complete<br />
|-<br />
| Cardiology || [[Pericarditis]] || [[Pericarditis resident survival guide]] || Mugilan ||<br />
|-<br />
| Cardiology || [[Hypertension]] || [[Hypertension resident survival guide]] ||Landing page||Complete<br />
|-<br />
| Cardiology || [[Chronic hypertension]] || [[Chronic hypertension resident survival guide]] || Ayokunle||<br />
|-<br />
| Cardiology || [[Hypertensive crisis]] || [[Hypertensive crisis resident survival guide]]||Ayokunle|| Complete<br />
|-<br />
| Cardiology || [[Intracardiac device]] || [[Intracardiac device resident survival guide]] || ||<br />
|-<br />
| Cardiology || [[Supraventricular tachycardia|Narrow complex tachycardia]] || [[Narrow complex tachycardia resident survival guide]] || Hilda/Rim/Twinkle || Complete<br />
|-<br />
| Cardiology || [[Cardiac tamponade]] || [[Cardiac tamponade resident survival guide]] ||Ayokunle|| Complete<br />
|-<br />
| Cardiology || [[Low flow low gradient aortic stenosis]] || [[Low flow low gradient aortic stenosis resident survival guide]] || Rim || Complete<br />
|-<br />
| Cardiology || || [[Cardiac risk assessment prior to non-cardiac surgery resident survival guide]] ||Yaz||Complete<br />
|-<br />
| Cardiology || [[Dilated cardiomyopathy]] || [[Dilated cardiomyopathy resident survival guide]] || Steven ||<br />
|-<br />
| Cardiology || [[Restrictive cardiomyopathy]] || [[Restrictive cardiomyopathy resident survival guide]] || Steven ||<br />
|-<br />
| Cardiology || [[Hypertrophic cardiomyopathy]] || [[Hypertrophic cardiomyopathy resident survival guide]] || Steven ||<br />
|-<br />
| Cardiology || [[Arrhythmogenic right ventricular cardiomyopathy]] || [[Arrhythmogenic right ventricular cardiomyopathy resident survival guide]] || Steven ||<br />
|-<br />
| Cardiology || [[Claudication]] || [[Claudication resident survival guide]] ||Ochuko||<br />
|-<br />
| Cardiology || [[Mitral regurgitation]] || [[Mitral regurgitation resident survival guide]] ||Mugilan||<br />
|-<br />
| Cardiology || [[Mitral stenosis]] || [[Mitral stenosis resident survival guide]] ||Twinkle||Complete<br />
|-<br />
| Cardiology || [[Palpitations]] || [[Palpitations resident survival guide]] || ||<br />
|-<br />
| Cardiology || [[Peripheral artery disease]] || [[Peripheral artery disease resident survival guide]] || Ogheneochuko ||<br />
|-<br />
| Cardiology || [[Shortness of breath]] || [[Shortness of breath resident survival guide]] || Steven ||<br />
|-<br />
| Cardiology || [[STEMI]] || [[STEMI resident survival guide]] || Alejandro||Complete<br />
|-<br />
| Cardiology || [[Pulmonary embolism]] || [[Pulmonary embolism resident survival guide]] ||Rim ||Complete<br />
|-<br />
| Cardiology || [[Right ventricular myocardial infarction]] || [[Right ventricular myocardial infarction resident survival guide]] || Jad ||<br />
|-<br />
| Cardiology || [[Syncope]] || [[Syncope resident survival guide]] || Karol/Alejandro || Complete<br />
|-<br />
| Cardiology || [[Unstable angina]] || [[Unstable angina/ NSTEMI resident survival guide]] || Andrea ||<br />
|-<br />
| Cardiology || [[Valvular diseases]] || [[Valvular diseases resident survival guide]] || Landing page||Complete<br />
|-<br />
| Cardiology || [[VTE prevention]] || [[VTE prevention resident survival guide]] || Rim||Complete<br />
|-<br />
| Cardiology || [[Wide complex tachycardia]] || [[Wide complex tachycardia resident survival guide]] || Rim || Complete<br />
|-<br />
| Cardiology || [[WPW|Wolff-Parkinson-White syndrome]] || [[Wolff-Parkinson-White syndrome resident survival guide]]|| Alonso||<br />
|-<br />
|}<br />
<br />
===Other Topics===<br />
{| class="wikitable sortable"<br />
! Specialty<br />
! Topic<br />
! Resident Survival Guide Page<br />
! Author<br />
! Status<br />
|-<br />
| Pulmonary || [[Acute respiratory distress syndrome]] || [[Acute respiratory distress syndrome resident survival guide]] ||Ayokunle||<br />
|-<br />
| Pulmonary || [[Anaphylaxis]] || [[Anaphylaxis resident survival guide]] || Vidit ||<br />
|-<br />
| Pulmonary || [[Asthma|Asthma exacerbation]] || [[Asthma exacerbation resident survival guide]] || Abdurahman, Vidit ||Complete<br />
|-<br />
| Pulmonary || [[Chronic obstructive pulmonary disease|COPD exacerbation]] || [[COPD exacerbation resident survival guide]] || Abdurahman: Vidit ||Complete<br />
|-<br />
| Pulmonary || [[Cough]] || [[Cough resident survival guide]] || ||<br />
|-<br />
| Pulmonary || [[Deep venous thrombosis]] || [[Deep vein thrombosis resident survival guide|Deep venous thrombosis resident survival guide]] || Rim|| Complete<br />
|-<br />
| Pulmonary || [[Dyspnea]] || [[Dyspnea resident survival guide]] ||Dyspnea||<br />
|-<br />
| Pulmonary || [[Hemoptysis]] || [[Hemoptysis resident survival guide]] ||Teresa||<br />
|-<br />
| Pulmonary || [[Mechanical ventilation]] || [[Mechanical ventilation resident survival guide]] || Ahmed ||<br />
|-<br />
| Pulmonary || [[Pleural effusion]] || [[Pleural effusion resident survival guide]] ||Twinkle||<br />
|-<br />
| Pulmonary || [[Pulmonary embolism]] || [[Pulmonary embolism resident survival guide]] ||||<br />
|-<br />
| Pulmonary || [[Pulmonary hypertension]] || [[Pulmonary hypertension resident survival guide]] || Vidit ||<br />
|-<br />
| Pulmonary || [[Respiratory failure]] || [[Respiratory failure resident survival guide]] ||||<br />
|-<br />
| Cardiology || [[Tension pneumothorax]] || [[Tension pneumothorax resident survival guide]] || Mohamad||Complete<br />
|-<br />
| Gastroenterology || [[Abdominal pain]] || [[Abdominal pain resident survival guide]] ||||<br />
|-<br />
| Gastroenterology || [[Abnormal liver tests]] || [[Abnormal liver tests resident survival guide]] ||||<br />
|-<br />
| Gastroenterology || [[Acetaminophen toxicity]] || [[Acetaminophen overdose resident survival guide|Acetaminophen toxicity resident survival guide]] || Vidit ||Complete<br />
|-<br />
| Gastroenterology || [[Diarrhea|Acute diarrhea]] || [[Acute diarrhea resident survival guide]] || Mugilan ||Complete<br />
|-<br />
| Gastroenterology || [[Acute liver failure]] || [[Acute liver failure resident survival guide]] || Vendhan ||<br />
|-<br />
| Gastroenterology || [[Acute pancreatitis]] || [[Acute pancreatitis resident survival guide]] || Vidit || Complete<br />
|-<br />
| Gastroenterology || [[Appendicitis]] || [[Appendicitis resident survival guide]] || Teresa || Complete<br />
|-<br />
| Gastroenterology || [[Ascites]] || [[Ascites resident survival guide]] || Twinkle/Steven ||<br />
|-<br />
| Gastroenterology || [[Biliary tract diseases]] || [[Biliary tract diseases resident survival guide]] || Vendhan ||<br />
|-<br />
| Gastroenterology || [[Cholangitis]] || [[Cholangitis resident survival guide]] || Vendhan || Complete<br />
|-<br />
| Gastroenterology || [[Cholecystitis]] || [[Cholecystitis resident survival guide]] || Vendhan || Complete<br />
|-<br />
| Gastroenterology || [[Acute cholecystitis|Cholecystitis]] || [[Acute cholecystitis resident survival guide]] || Vendhan || Complete<br />
|-<br />
| Gastroenterology || [[Chronic cholecystitis|Cholecystitis]] || [[Chronic cholecystitis resident survival guide]] || Vendhan || Complete<br />
|-<br />
| Gastroenterology || [[Choledocholithiasis]] || [[Choledocholithiasis resident survival guide]] || Vendhan ||Complete<br />
|-<br />
| Gastroenterology || [[Cholelithiasis]] || [[Cholelithiasis resident survival guide]] || Vendhan ||<br />
|-<br />
| Gastroenterology || [[Diarrhea|Chronic diarrhea]] || [[Chronic diarrhea resident survival guide]] || Mugilan || Complete<br />
|-<br />
| Gastroenterology || [[Clostridium difficile]] || [[Clostridium difficile infection resident survival guide]] || Mugilan ||<br />
|-<br />
| Gastroenterology || [[Constipation]] || [[Constipation resident survival guide]] ||Mugilan|| Complete<br />
|-<br />
| Gastroenterology || [[Crohn’s disease]] || [[Crohn's disease resident survival guide]] ||Mugilan||<br />
|-<br />
| Gastroenterology || [[Diarrhea]] || [[Diarrhea resident survival guide]] || Mugilan ||Complete<br />
|-<br />
| Gastroenterology || [[Esophageal rupture]] || [[Esophageal rupture resident survival guide]] || ||<br />
|-<br />
| Gastroenterology || [[Ileus]] || [[Ileus resident survival guide]] ||Mugilan||<br />
|-<br />
| Gastroenterology || [[Intestinal ischemia]] || [[Intestinal ischemia resident survival guide]] ||Mugilan||<br />
|-<br />
| Gastroenterology || [[Acute pancreatitis|Gallstone pancreatitis]] || [[Gallstone pancreatitis resident survival guide]] || Vendhan|| Complete<br />
|-<br />
| Gastroenterology || [[Lower gastrointestinal bleeding]] || [[Lower gastrointestinal bleeding resident survival guide]] || Twinkle ||Complete<br />
|-<br />
| Gastroenterology || [[Nutrition]] || [[Nutrition resident survival guide]] ||||<br />
|-<br />
| Gastroenterology || [[Ulcerative colitis]] || [[Ulcerative colitis resident survival guide]] ||Mugilan||<br />
|-<br />
| Gastroenterology || [[Upper gastrointestinal bleeding]] || [[Upper gastrointestinal bleeding resident survival guide]] || Twinkle ||<br />
|-<br />
| Gastroenterology || [[Varices]] || [[Varices and variceal bleed resident survival guide]] || Twinkle || Complete<br />
|-<br />
| Nephrology || [[Acidosis]] || [[Acidosis resident survival guide]] ||||<br />
|-<br />
| Nephrology || [[Acute kidney injury]] || [[Acute kidney failure resident survival guide]] || Vendhan ||<br />
|-<br />
| Nephrology ||[[Alkalosis]] || [[Alkalosis resident survival guide]] ||||<br />
|-<br />
| Nephrology || [[Hyperkalemia]] || [[Hyperkalemia resident survival guide]] || Mahmoud ||<br />
|-<br />
| Nephrology || [[Hypernatremia]] || [[Hypernatremia resident survival guide]] || Priyamvada ||<br />
|-<br />
| Nephrology || [[Hypokalemia]] || [[Hypokalemia resident survival guide]] ||||<br />
|-<br />
| Nephrology || [[Hyponatremia]] || [[Hyponatremia resident survival guide]] || Priyamvada ||<br />
|-<br />
| Nephrology || [[Metabolic acidosis]] || [[Metabolic acidosis resident survival guide]] || Ogheneochuko ||<br />
|-<br />
| Nephrology || [[Metabolic alkalosis]] || [[Metabolic alkalosis resident survival guide]] ||||<br />
|-<br />
| Nephrology || [[Nephrolithiasis]] || [[Nephrolithiasis resident survival guide]] ||||<br />
|-<br />
| Nephrology || [[Polyuria]] || [[Polyuria resident survival guide]] ||||<br />
|-<br />
| Nephrology || [[Renal artery stenosis]] || [[Renal artery stenosis resident survival guide]] ||Karol||Complete<br />
|-<br />
| Nephrology || [[Respiratory acidosis]] || [[Respiratory acidosis resident survival guide]] ||||<br />
|-<br />
| Nephrology || [[Respiratory alkalosis]] || [[Respiratory alkalosis resident survival guide]] ||||<br />
|-<br />
| Hematology-Oncology || [[Anemia]] || [[Anemia resident survival guide]] || Chetan ||<br />
|-<br />
| Hematology-Oncology || [[Aplastic anemia]] || [[Aplastic anemia resident survival guide]] || Chetan ||<br />
|-<br />
| Hematology-Oncology || [[Breast cancer screening]] || [[Breast cancer screening resident survival guide]] || Twinkle|| Complete<br />
|-<br />
| Hematology-Oncology || [[Hemolytic anemia]] || [[Hemolytic anemia resident survival guide]] ||||<br />
|-<br />
| Hematology-Oncology || [[Heparin induced thrombocytopenia]] || [[HIT resident survival guide]] || Karol|| Complete<br />
|-<br />
| Hematology-Oncology || [[Pancytopenia]] || [[Pancytopenia resident survival guide]] || ||<br />
|-<br />
| Hematology-Oncology || [[Bleeding disorders]] || [[Bleeding disorder resident survival guide]] ||||<br />
|-<br />
| Hematology-Oncology || [[Thrombocytopenia]] || [[Thrombocytopenia resident survival guide]] ||Ogheneochuko|| Complete<br />
|-<br />
| Hematology-Oncology || [[DIC]] || [[DIC resident survival guide]] ||Ogheneochuko|| Complete<br />
|-<br />
| Hematology-Oncology || [[Transfusion therapy]] || [[Transfusion therapy resident survival guide]] ||Ayokunle||<br />
|-<br />
| Hematology-Oncology || [[Febrile neutropenia]] || [[Febrile neutropenia resident survival guide]] || Rim ||<br />
|-<br />
| Hematology-Oncology || [[Tumor lysis syndrome]] || [[Tumor lysis syndrome resident survival guide]] ||Twinkle|| Complete<br />
|-<br />
| Infectious Diseases || [[Community acquired pneumonia]] || [[Community acquired pneumonia resident survival guide]] ||Chetan:Rim|| Complete<br />
|-<br />
| Infectious Diseases || [[Urinary tract infection]] || [[Urinary tract infection resident survival guide]] ||Ogheneochuko||<br />
|-<br />
| Infectious Diseases || [[Cellulitis]] || [[Cellulitis resident survival guide]] ||Ogheneochuko||<br />
|-<br />
| Infectious Diseases || [[Diabetic foot]] || [[Diabetic foot resident survival guide]] ||Ogheneochuko||<br />
|-<br />
| Infectious Diseases || [[Meningitis]] || [[Meningitis resident survival guide]] ||||<br />
|-<br />
| Infectious Diseases || [[Fever of unknown origin]] || [[Fever of unknown origin resident survival guide]] ||Ogheneochuko||<br />
|-<br />
| Infectious Diseases || [[Rash with fever|Fever and rash]] || [[Rash with fever resident survival guide]] ||||<br />
|-<br />
| Infectious Diseases || [[Fever after travel]] || [[Fever after travel resident survival guide]] ||||<br />
|-<br />
| Infectious Diseases || [[Norovirus infection]] || [[Norovirus outbreak resident survival guide]] ||Twinkle|| Complete<br />
|-<br />
| Infectious Diseases || [[Sepsis]] || [[Sepsis resident survival guide]] || Ahmed ||<br />
|-<br />
| Endocrinology || [[Hypercalcemia]] || [[Hypercalcemia resident survival guide]] ||||<br />
|-<br />
| Endocrinology ||[[Hypocalcemia]] || [[Hypocalcemia resident survival guide]] ||Ammu||<br />
|-<br />
| Endocrinology || [[Diabetic ketoacidosis]] || [[Hyperglycemic crises resident survival guide]] || Vidit ||Complete<br />
|-<br />
| Neurology || [[Altered mental status]] || [[Altered mental status resident survival guide]] ||||<br />
|-<br />
| Neurology || [[Seizure]] || [[Seizure resident survival guide]] || Vidit ||<br />
|-<br />
| Neurology || [[Status epilepticus]] || [[Status epilepticus resident survival guide]] || Vidit ||Complete<br />
|-<br />
| Neurology || [[Alcohol withdrawal]] || [[Alcohol withdrawal resident survival guide]] ||Vidit||Complete<br />
|-<br />
| Neurology || [[Opioid]] || [[Opioid resident survival guide]] || Vidit ||<br />
|-<br />
| Neurology || [[Opioid overdose]] || [[Opioid overdose resident survival guide]] || Vidit ||<br />
|-<br />
| Neurology || [[Opioid withdrawal]] || [[Opioid withdrawal resident survival guide]] || Vidit ||<br />
|-<br />
| Neurology || [[Stroke]] || [[Stroke resident survival guide]] || Ayokunle ||<br />
|-<br />
| Neurology || [[Headache]] || [[Headache resident survival guide]] ||||<br />
|-<br />
| Neurology || [[Back pain]] || [[Back pain resident survival guide]] || Hilda ||<br />
|-<br />
| Neurology || [[Vertigo]] || [[Vertigo resident survival guide]] || || High priority<br />
|-<br />
| Miscellaneous || [[ICU Medications]] || [[ICU medications resident survival guide]] || Ahmed ||<br />
|-<br />
| Miscellaneous || [[Shock]] || [[Shock resident survival guide]] || Ahmed ||<br />
|-<br />
| Miscellaneous || [[Anticoagulation therapy]] || [[Anticoagulation therapy resident survival guide]] || Priyamvada ||<br />
|-<br />
| Miscellaneous || [[Carbon monoxide poisoning]] || [[Carbon monoxide poisoning resident survival guide]] || Vidit ||<br />
|}<br />
<br />
[[Category:Help]]<br />
[[Category:Projects]]<br />
[[Category:Resident survival guide]]<br />
<br />
{{WikiDoc Help Menu}}<br />
{{WikiDoc Sources}}</div>Rim Halabyhttps://www.wikidoc.org/index.php?title=Sandbox_Rim&diff=1088089Sandbox Rim2015-04-15T21:09:22Z<p>Rim Halaby: </p>
<hr />
<div><div style="width: 80%;"><br />
__NOTOC__<br />
{{CMG}}; {{AE}} {{ATS}}; {{Rim}}<br />
<br />
{| class="infobox" style="margin: 0 0 0 0; border: 0; float: right; width: 100px; background: #A8A8A8; position: fixed; top: 250px; right: 21px; border-radius: 0 0 10px 10px;" cellpadding="0" cellspacing="0";<br />
|-<br />
! style="padding: 0 5px; font-size: 85%; background: #A8A8A8" align=center| {{fontcolor|#2B3B44|Unstable angina/ NSTEMI Resident Survival Guide Microchapters}}<br />
|-<br />
! style="font-size: 80%; padding: 0 5px; background: #DCDCDC" align=left | [[Unstable angina/ NSTEMI resident survival guide#Overview|Overview]]<br />
|-<br />
! style="font-size: 80%; padding: 0 5px; background: #DCDCDC" align=left | [[Unstable angina/ NSTEMI resident survival guide#Causes|Causes]]<br />
|-<br />
! style="font-size: 80%; padding: 0 5px; background: #DCDCDC" align=left | [[Unstable angina/ NSTEMI resident survival guide#FIRE: Focused Initial Rapid Evaluation|FIRE]]<br />
|-<br />
! style="font-size: 80%; padding: 0 5px; background: #DCDCDC" align=left | [[Unstable angina/ NSTEMI resident survival guide#Complete Diagnostic Approach|Diagnosis]]<br />
|-<br />
! style="font-size: 80%; padding: 0 5px; background: #DCDCDC" align=left | [[Unstable angina/ NSTEMI resident survival guide#Treatment|Treatment]]<br />
: [[Unstable angina/ NSTEMI resident survival guide#Management Following Angiography|Management Following Angiography]]<br />
|-<br />
! style="font-size: 80%; padding: 0 5px; background: #DCDCDC" align=left | [[Unstable angina/ NSTEMI resident survival guide#Pre-Discharge Care|Pre-Discharge Care]]<br />
|-<br />
! style="font-size: 80%; padding: 0 5px; background: #DCDCDC" align=left | [[Unstable angina/ NSTEMI resident survival guide#Long Term Managemnet|Long Term Management]]<br />
|-<br />
! style="font-size: 80%; padding: 0 5px; background: #DCDCDC" align=left | [[Unstable angina/ NSTEMI resident survival guide#Do's|Do's]]<br />
|-<br />
! style="font-size: 80%; padding: 0 5px; background: #DCDCDC" align=left | [[Unstable angina/ NSTEMI resident survival guide#Don'ts|Don'ts]]<br />
|}<br />
<br />
==Overview==<br />
[[Unstable angina]] and [[non ST elevation myocardial infarction]] ([[NSTEMI]]) belong to two different ends of the spectrum of [[acute coronary syndrome]]. These conditions have a similar clinical presentation characterized by an acute onset of chest pain that starts on minimal exertion, rest or sleep, lasts at least 20 minutes (but usually less that half an hour) and, is not relieved by medications or rest. [[NSTEMI]] is differentiated from [[unstable angina]] by the presence of elevated cardiac biomarkers secondary to myocardial injury. [[Unstabel angina]] and [[NSTEMI]] might not be differentiated early following the occurrence of symptoms because [[cardiac biomarker]]s may require a few hours to rise.<br />
<br />
==Causes==<br />
<br />
===Life Threatening Causes===<br />
Life-threatening causes include conditions which may result in death or permanent disability within 24 hours if left untreated. [[Unstable angina]] and [[NSTEMI]] are life-threatening conditions and must be treated as such irrespective of the causes.<br />
<br />
===Common Causes===<br />
====Myocardial Infarction====<br />
* [[Atherosclerotic]] [[plaque rupture]] and subsequent [[coronary thrombus]] (most common cause)<br />
* [[Coronary artery spasm]]<br />
* [[Arrhythmia]]<br />
* [[MI|Post-myocardial infarction]]<br />
* [[PCI|Post-percutaneous coronary intervention]]<br />
** [[Abrupt closure]]<br />
** [[PCI complications: loss of side branch|Loss of side branch]]<br />
** [[Distal embolization]]<br />
** [[PCI complications: restenosis|Restenosis]]<br />
**[[Stent thrombosis]]<br />
* [[CABG|Post-coronary artery bypass graft]]<br />
** Graft closure<br />
** New lesion in the graft<br />
<br />
''For a complete list of causes, click [[Unstable angina pathophysiology|here]] for unstable angina and [[Non ST elevation myocardial infarction pathophysiology|here]] for NSTEMI.''<br />
<br />
==FIRE: Focused Initial Rapid Evaluation==<br />
A Focused Initial Rapid Evaluation (FIRE) should be performed to identify patients in need of immediate intervention based on the 2012 ACCF/AHA focused update of the guideline for the management of patients with unstable angina/non-ST-elevation myocardial infarction.<ref name="pmid22809746">{{cite journal| author=Jneid H, Anderson JL, Wright RS, Adams CD, Bridges CR, Casey DE et al.| title=2012 ACCF/AHA focused update of the guideline for the management of patients with unstable angina/non-ST-elevation myocardial infarction (updating the 2007 guideline and replacing the 2011 focused update): a report of the American College of Cardiology Foundation/American Heart Association Task Force on Practice Guidelines. | journal=J Am Coll Cardiol | year= 2012 | volume= 60 | issue= 7 | pages= 645-81 | pmid=22809746 | doi=10.1016/j.jacc.2012.06.004 | pmc= | url=http://www.ncbi.nlm.nih.gov/entrez/eutils/elink.fcgi?dbfrom=pubmed&tool=sumsearch.org/cite&retmode=ref&cmd=prlinks&id=22809746 }} </ref> An invasive strategy is defined as diagnostic angiography with the intention of revascularization.<br />
<br />
<span style="font-size:85%">Boxes in the red color signify that an urgent management is needed.</span><br />
{{Family tree/start}}<br />
{{familytree |boxstyle=background: #FA8072; color: #F8F8FF; | | | | A00 | | A00=<div style="float: left; text-align: left; width: 17em; padding:1em;"> '''Identify cardinal findings of unstable angina/ NSTEMI :''' <br><br />
❑ '''[[Chest pain|<span style="color:white;"> Chest pain</span>]] or [[chest discomfort|<span style="color:white;">chest discomfort</span>]]''' <br><br />
:❑ Sudden onset<br />
:❑ Sensation of heaviness, tightness, pressure, or squeezing<br />
:❑ Duration> 20 minutes (but usually less than half an hour) <br><br />
:❑ Radiation to the left arm, jaw, neck, right arm, back or [[epigastrium|<span style="color:white;">epigastrium</span>]]<br />
:❑ No relief with medications<br><br />
:❑ No relief with rest <br><br />
:❑ Worse with time <br><br />
:❑ Worse with exertion<br><br />
:❑ Associated symptoms of [[palpitations|<span style="color:white;">palpitations</span>]], [[nausea|<span style="color:white;">nausea</span>]], [[vomiting|<span style="color:white;">vomiting</span>]], [[sweating|<span style="color:white;">sweating</span>]], [[dyspnea|<span style="color:white;">dyspnea</span>]], and [[lightheadedness|<span style="color:white;">lightheadedness</span>]]<br><br />
❑ '''Characteristic [[ECG|<span style="color:white;">ECG</span>]] changes consistent with [[unstable angina|<span style="color:white;">unstable angina</span>]]/ [[NSTEMI|<span style="color:white;">NSTEMI</span>]] '''<br />
:❑ No changes <br><br />
:❑ Non specific ST / T wave changes <br> <br />
:❑ Flipped or inverted T waves <br><br />
:❑ ST depression (carries the poorest prognosis) <br><br />
❑ '''Increase in >99th percentile of upper limit of normal of [[troponin|<span style="color:white;">troponin</span>]] and / or [[CKMB|<span style="color:white;">CK MB</span>]]''', which is consistent with [[NSTEMI|<span style="color:white;">NSTEMI</span>]]</div>}}<br />
{{familytree |boxstyle=background: #FA8072; color: #F8F8FF; | | | | |!| | | }}<br />
{{familytree |boxstyle=background: #FA8072; color: #F8F8FF; | | | | G02 | G02= <div style="float: left; text-align: left; width: 17em; padding:1em;"> '''Rule out life threatening alternative diagnoses:'''<br><br />
❑ [[Aortic dissection|<span style="color:white;">Aortic dissection</span>]] <br> (suggestive findings: [[back pain|<span style="color:white;">back pain</span>]], [[interscapular pain|<span style="color:white;">interscapular pain</span>]], [[aortic regurgitation|<span style="color:white;">aortic regurgitation</span>]], [[pulsus paradoxus|<span style="color:white;">pulsus paradoxus</span>]], [[blood pressure|<span style="color:white;">blood pressure</span>]] discrepancy between the arms) <br><br />
❑ [[Pulmonary embolism|<span style="color:white;">Pulmonary embolism</span>]] <br> (suggestive findings: acute onset of [[dyspnea|<span style="color:white;">dyspnea</span>]], [[tachypnea|<span style="color:white;">tachypnea</span>]], [[hemoptysis|<span style="color:white;">hemoptysis</span>]], previous [[DVT|<span style="color:white;">DVT</span>]]) <br><br />
❑ [[Cardiac tamponade|<span style="color:white;">Cardiac tamponade</span>]] <br> (suggestive findings: [[hypotension|<span style="color:white;">hypotension</span>]], [[jugular venous distention|<span style="color:white;">jugular venous distention</span>]], [[muffled heart sounds|<span style="color:white;">muffled heart sounds</span>]], [[pulsus paradoxus|<span style="color:white;">pulsus paradoxus</span>]])<br><br />
❑ [[Tension pneumothorax|<span style="color:white;">Tension pneumothorax</span>]] <br> (suggestive findings: sudden [[dyspnea|<span style="color:white;">dyspnea</span>]], [[tachycardia|<span style="color:white;">tachycardia</span>]], [[trauma|<span style="color:white;">chest trauma</span>]], unilateral absence of [[breath sounds|<span style="color:white;">breath sound</span>]])<br><br />
❑ [[Esophageal rupture|<span style="color:white;">Esophageal rupture</span>]] <br> (suggestive findings: [[vomiting|<span style="color:white;">vomiting</span>]], [[subcutaneous emphysema|<span style="color:white;">subcutaneous emphysema</span>]])</div>}}<br />
{{familytree |boxstyle=background: #FA8072; color: #F8F8FF; | | | | |!| | | }}<br />
{{familytree |boxstyle=background: #FA8072; color: #F8F8FF; | | | | A01 | | | | | A01= <div style="float: left; text-align: left; width: 17em; padding:1em;">'''Begin initial treatment:'''<br> <br />
❑ Administer 162 to 325 mg of non enteric [[aspirin|<span style="color:white;">aspirin</span>]],orally, crushed or chewed (I-A)<br />
:''Among patients with either GI intolerance or hypersensitivity to aspirin, administer a loading dose (75 mg) followed by maintenance dose of clopidogrel (I-B)''<br />
❑ Administer 2-4 L/min [[oxygen|<span style="color:white;">oxygen</span>]] via nasal cannula when saturation <90% (I-C)<br />
:''Caution in [[COPD|<span style="color:white;">COPD</span>]] patients: maintain an oxygen saturation between 88% and 92%.''<br />
❑ Administer [[nitroglycerin|<span style="color:white;">nitroglycerin</span>]]<br />
:❑ Administer sublingual nitroglycerin (0.3 to 0.4 mg, every 5 minutes for a total of 3 doses) then assess for further need to IV nitroglycerin (I-C)<br />
:❑ Administer IV nitroglyerin in case of persistent chest pain despite PO nitroglycerin, heart failure, or hypertenion (I-B): 10 mcg/min, increase by 10 mcg/min every 3 to 5 minutes until symptom relief; in case no response at 20 mcg/min, can increase by 10 mcg/min and then by 20 mcg/min<br />
<span style="font-size:85%;">Contraindicated in suspected [[RVMI|<span style="color:white;">right ventricular MI</span>]], recent use of [[phosphodiesterase inhibitors|<span style="color:white;">phosphodiesterase inhibitors</span>]], decreased [[blood pressure|<span style="color:white;">blood pressure</span>]] 30 mmHg below baseline</span> <br><br />
❑ Administer [[beta-blockers|<span style="color:white;">beta-blockers</span>]] (unless contraindicated) and titrate to the [[heart rate|<span style="color:white;">heart rate</span>]] and [[blood pressure|<span style="color:white;">blood pressure</span>]] (I-A)<br><br />
: ''PO in general, IV if patient has hypertension or ongoing pain''<br />
: ''Beta blocker is contraindicated in heart failure and high risk of cardiogenic shock.''<br />
:❑ [[Metoprolol|<span style="color:white;">Metoprolol</span>]]:<br />
:PO: 25 to 50 mg every 6 hours<br />
:IV: 5 mg every 5 min, up to 3 doses, then 25 to 50 mg orally every 6 hours<br />
:❑ [[Carvedilol|<span style="color:white;">Carvedilol</span>]] IV, 25 mg, two times a day<br />
<span style="font-size:85%;">Contraindicated in [[heart failure|<span style="color:white;">heart failure</span>]], bradycardia, hypotension (SBP<90 mmHg), [[AV block |<span style="color:white;">second or third degree AV block</span>]], [[reactive airway disease|<span style="color:white;">reactive airway disease</span>]], high risk of [[cardiogenic shock|<span style="color:white;">cardiogenic shock</span>]] and low [[cardiac output|<span style="color:white;">cardiac output</span>]] state</span> <br><br />
❑ Administer IV [[morphine|<span style="color:white;">morphine</span>]] if persistent symptoms (IIb-B) or [[pulmonary edema|<span style="color:white;">pulmonary edema</span>]]<br />
:❑ Initial dose 4-8 mg<br />
:❑ 2-8 mg every 5 to 15 minutes, as needed <br><br />
❑ Administer 80 mg [[atorvastatin|<span style="color:white;">atorvastatin</span>]] (I-A)<br><br />
❑ Monitor with a 12-lead [[ECG|<span style="color:white;">ECG</span>]] all the time<br />
</div>}}<br />
{{familytree |boxstyle=background: #FA8072; color: #F8F8FF; | | | | |!| | | }}<br />
{{familytree |boxstyle=background: #FA8072; color: #F8F8FF; | | | | G01 | G01= <div style="float: left; text-align: left; width: 17em; padding:1em;"> {{fontcolor|#000000|'''TRIAGE FOR IMMEDIATE INTERVENTION'''}} <br>'''Does the patient have ANY of the following indications that require immediate angiography and revascularization ?'''<br />
❑ Hemodynamic instability or [[cardiogenic shock|<span style="color:white;">cardiogenic shock</span>]], '''OR''' <br><br />
❑ Severe left ventricular dysfunction or [[heart failure|<span style="color:white;">heart failure</span>]], '''OR''' <br><br />
❑ Recurrent or persistent rest angina despite intensive medical therapy, '''OR''' <br><br />
❑ New or worsening [[mitral regurgitation|<span style="color:white;">mitral regurgitation</span>]] or new [[VSD|<span style="color:white;">VSD</span>]], '''OR''' <br><br />
❑ Sustained [[VT|<span style="color:white;">VT</span>]] or [[VF|<span style="color:white;">VF</span>]], '''OR''' <br><br />
❑ Prior [[PCI|<span style="color:white;">PCI</span>]] within past 6 months or [[CABG|<span style="color:white;">CABG</span>]] <br> </div> }}<br />
{{familytree |boxstyle=background: #FA8072; color: #F8F8FF; | |,|-|-|^|-|-|.| | }}<br />
{{familytree |boxstyle=background: #FA8072; color: #F8F8FF; | C01 | | | | C02 | | | C01=<div style="float: left; text-align: center; width: 17em; padding:1em;">'''YES''' </div>| C02= <div style="float: left; text-align: center; width: 17em; padding:1em;">'''NO''' </div> }}<br />
{{familytree |boxstyle=background: #FA8072; color: #F8F8FF; | |!| | | | | |!| | | | }}<br />
{{familytree |boxstyle=background: #FA8072; color: #F8F8FF; | |!| | | | | C03 | | | C03=<div style="float: left; text-align: left; width: 17em; padding:1em;">Does the patient have no ECG changes '''AND''' no rise in cardiac biomarkers > 99th percentile of ULN?</div>}}<br />
{{familytree |boxstyle=background: #FA8072; color: #F8F8FF; | |!| | | |,|-|^|-|.| | }}<br />
{{familytree |boxstyle=background: #FA8072; color: #F8F8FF; | |!| | | C04 | | C05 | C04= <div style="float: left; text-align: left; width: 17em; padding:1em;">Yes. The patient has no ECG changes AND no rise in cardiac biomarkers > 99th percentile of ULN. </div>| C05= <div style="float: left; text-align: left; width: 17em; padding:1em;">No. The patient has either positive ECG changes, OR rise in cardiac biomarkers, OR both. </div>}}<br />
{{familytree |boxstyle=background: #FA8072; color: #F8F8FF; | |!| | | |!| | | |!| | }} <br />
{{familytree |boxstyle=background: #FA8072; color: #F8F8FF; | |!| | | C06 | | |!| | C06= <div style="float: left; text-align: left; width: 17em; padding:1em;">Repeat ECG and biomarkers within next 3 hours and 6 hours <br><br> '''Does the patient still have no ECG changes '''AND''' no rise in cardiac biomarkers?'''</div>}} <br />
{{familytree |boxstyle=background: #FA8072; color: #F8F8FF; | |!| |,|^|-|-|.| |!| }}<br />
{{familytree |boxstyle=background: #FA8072; color: #F8F8FF; | |!| C07 | | C08 |!| C07= <div style="float: left; text-align: left; width: 17em; padding:1em;">Yes. The patient has no ECG changes AND no rise in cardiac biomarkers.</div>| C08= <div style="float: left; text-align: left; width: 17em; padding:1em;">No. The patient has either positive ECG changes, OR rise in cardiac biomarkers, OR both.</div>}}<br />
{{familytree |boxstyle=background: #FA8072; color: #F8F8FF; | |!| |!| | | |!| |!| }}<br />
{{familytree |boxstyle=background: #FA8072; color: #F8F8FF; | |!|C09 | | | C10 | | | C09= <div style="float: left; text-align: left; width: 17em; padding:1em;">[[Chest pain resident survival guide#Complete Diagnostic Approach|Proceed to complete diagnostic approach of chest pain to rule out differential diagnoses]]</div>| C10=<div style="float: left; text-align: left; width: 17em; padding:1em;">{{fontcolor|#000000|''' TRIAGE FOR INITIAL CONSERVATIVE OR INVASIVE THERAPY'''}} <br>'''Calculate the risk of future adverse clinical outcomes:'''<br><br />
❑ [[TIMI risk score|<span style="color:white;">Thrombolysis in Myocardial Infarction (TIMI) risk score</span>]], '''OR'''<br />
❑ [[GRACE score|<span style="color:white;">GRACE score</span>]] </div>}}<br />
{{familytree |boxstyle=background: #FA8072; color: #F8F8FF; | |!| | | |,|-|-|^|.| | }}<br />
{{familytree |boxstyle=background: #FA8072; color: #F8F8FF; | |!| | | C11 | | C12 | C11= '''Intermediate or high risk''' | C12= '''Low risk'''}}<br />
{{familytree |boxstyle=background: #FA8072; color: #F8F8FF; | |!| | | |!| | | |!| | }}<br />
{{familytree |boxstyle=background: #FA8072; color: #F8F8FF; | D01 | | D02 | | D03 | |D01=<div style="float: left; text-align: center; width: 17em; padding:1em;"> '''INITIAL INVASIVE THERAPY (IMMEDIATELY)'''<br></div><br />
| D02= <div style="float: left; text-align: center; width: 17em; padding:1em;">'''INITIAL INVASIVE THERAPY (4 to 48 hours)''' </div>| D03= <div style="float: left; text-align: center; width: 17em; padding:1em;"> '''INITIAL CONSERVATIVE THERAPY ''' </div>}}<br />
{{familytree |boxstyle=background: #FA8072; color: #F8F8FF; | | |!| |!| | | | |!| | }}<br />
{{familytree |boxstyle=background: #FA8072; color: #F8F8FF; | | | E02 | | | | E03 | |E02=<div style="float: left; text-align: left; width: 17em; padding:1em;">'''Initiate ONE of the following anticoagulant therapy (I-A)'''<br> <br />
❑ Enoxaparin (I-A)<br><br />
:❑ SC 1 mg/kg every 12 hours if CrCL≥ 30 mL/min<br />
:❑ SC 1 mg/kg every 12 hours if CrCL< 30 mL/min<br />
:❑ Initial IV 30 mg loading dose in selected patients<br />
'''OR''' <br><br />
❑ IV [[UFH|<span style="color:white;">Unfractionated heparin</span>]] (and adjust dose for apTT) for 48 hours or until PCI is perfomed (I-B)<br><br />
:❑ Initial loading dose 60 IU/kg (max 40,000 IU) <br><br />
:❑ Initial infusion 12 IU/kg/h (max 10,000 IU)<br>'''OR''' <br><br />
❑ [[Bivalirudin|<span style="color:white;">Bivalirudin</span>]] (I-B)<br />
::❑ Loading dose 0.1-mg/kg IV bolus, then 0.25–mg/kg/h infusion<br />
<br>'''OR''' <br><br />
❑ Fondaparinux , SC 2.5 mg daily (I-B)<br />
<br><br>'''PLUS'''<br><br><br />
'''Administer ONE of the following antiplatelet agents (before OR at the time of PCI) (I-A)'''<br><br />
❑ Loading dose of [[P2Y12|<span style="color:white;">P2Y12</span>]] receptor inhibitors <br><br />
:❑ [[Clopidogrel|<span style="color:white;">Clopidogrel</span>]] (I-B if before PCI, I-A if at time of PCI)<br />
::Loading dose: 300 mg or 600 mg<br />
:: Maintenance dose: 75 mg OD<br />
<br>'''OR''' <br><br />
:❑ [[Ticagrelor|<span style="color:white;">Ticagrelor</span>]] (I-B)<br />
::Loading dose: 180 mg<br />
:: Maintenance dose: 90 mg BID<br />
<br>'''OR''' <br><br />
:❑ Prasugrel ONLY AT THE TIME OF PCI, AND NOT PRE-PCI (I-B)<br><br />
::Loading dose: 60 mg<br />
:: Maintenance dose: 10 mg OD<br />
<span style="font-size:85%;">Prasugrel is contraindicated in case of prior history of strokes or TIAs, active pathological bleeding, age ≥75 years, when urgent coronary artery bypass graft surgery (CABG) is likely, body weight <60 kg, propensity to bleed, concomitant use of medications that increase the risk of bleeding</span><br><br><br />
'''Consider adding IV [[GP IIb/IIIa|<span style="color:white;">GP IIb/IIIa</span>]] inhibitors in case of high risk patients (IIb-B)'''<br><br />
❑ [[Eptifibatide|<span style="color:white;">Eptifibatide</span>]]<br><br />
:❑ Loading dose 180 mcg/kg IV bolus followed by another bolus after 10 minutes<br><br />
:❑ Maintenance dose 2 mcg/kg/min<br>'''OR''' <br><br />
❑ [[Tirofiban|<span style="color:white;">Tirofiban</span>]] <br><br />
:❑ Loading dose 25 mcg/kg<br><br />
:❑ Maintenance dose 0.15 mcg/kg/min </div><br />
|E03=<div style="float: left; text-align: left; width: 17em; padding:1em;">'''Initiate ONE of the following anticoagulant therapy (I-A)'''<br><br />
❑ Enoxaparin (I-A)<br>'''OR''' <br><br />
❑ UFH (I-B)<br>'''OR''' <br><br />
❑ Fondaparinux (I-B)<br />
<br />
<br><br> '''PLUS'''<br><br><br />
'''Administer ONE of the following antiplatelet agents (I-B):'''<br><br />
❑ [[P2Y12]] receptor inhibitors <br><br />
:❑ [[Clopidogrel]]<br><br />
::❑ Loading dose (300 mg or 600 mg)<br><br />
::❑ Maintenance dose (75 mg)<br>'''OR''' <br><br />
:❑ [[Ticagrelor]]<br><br />
::❑ Loading dose (180 mg)<br><br />
::❑ Maintenance dose (90 mg twice daily)<br>'''OR''' <br><br />
</div>}}<br />
{{familytree |boxstyle=background: #FA8072; color: #F8F8FF; | | | |!| | | | | |!| | }}<br />
{{familytree |boxstyle=background: #FA8072; color: #F8F8FF; | | | |!| | | | | F01 | |F01=<div style="float: left; text-align: left; width: 17em; padding:1em;">{{fontcolor|#000000|'''TRIAGE FOR NEED OF INVASIVE THERAPY'''}} <br>'''Does the patient experience ANY of the following?''' <br><br />
❑ Recurrence of symptoms, OR<br><br />
❑ [[Heart failure|<span style="color:white;">Heart failure</span>]], OR<br><br />
❑ Serious [[arrhythmia|<span style="color:white;">arrhythmia</span>]], OR<br><br />
❑ Subsequent ischemia</div>}}<br />
{{familytree |boxstyle=background: #FA8072; color: #F8F8FF; | | | |!| |,|-|-|-|^|.| }}<br />
{{familytree |boxstyle=background: #FA8072; color: #F8F8FF; | | | |!| G01 | | G02 | G01= YES| G02= NO}}<br />
{{familytree |boxstyle=background: #FA8072; color: #F8F8FF; | | | |!| |!| | | |!| }}<br />
{{familytree |boxstyle=background: #FA8072; color: #F8F8FF; | | | |!| H01 | | H02 | H01= <div style="float: left; text-align: left; width: 17em; padding:1em;"> '''PROCEED TO INVASIVE THERAPY (I-A)''' <br><br />
'''Administer ONE of the following antiplatelet agents if not already administered (I-A):'''<br><br />
:''The antiplatelet should be administered upstream (I-C)''<br />
❑ [[P2Y12]] receptor inhibitors <br><br />
:❑ [[Clopidogrel]] (I-B)<br><br />
::❑ Loading dose (300 mg or 600 mg)<br><br />
::❑ Maintenance dose (75 mg)<br>'''OR''' <br><br />
:❑ [[Ticagrelor]] (I-B)<br><br />
::❑ Loading dose (180 mg)<br><br />
::❑ Maintenance dose (90 mg twice daily)<br>'''OR''' <br><br />
❑ IV [[GP IIb/IIIa]] inhibitors (I-A)<br><br />
:❑ [[Eptifibatide]]<br><br />
::❑ Loading dose 180 mcg/kg IV bolus followed by another bolus after 10 minutes<br><br />
::❑ Maintenance dose 2 mcg/kg/min<br>'''OR''' <br><br />
:❑ [[Tirofiban]] <br><br />
::❑ Loading dose 25 mcg/kg<br><br />
::❑ Maintenance dose 0.15 mcg/kg/min<br></div><br />
| H02= <div style="float: left; text-align: left; width: 17em; padding:1em;">{{fontcolor|#000000|'''TRIAGE PATIENTS BY RISK ON STRESS TEST'''}} <br>❑ Perform a [[stress test]] (I-B) </div>}}<br />
{{familytree |boxstyle=background: #FA8072; color: #F8F8FF; | | | |!|!| |,|-|-|^|.|}}<br />
{{familytree |boxstyle=background: #FA8072; color: #F8F8FF; | | | |!|!| I01 | | I02 | I01= <div style="float: left; text-align: left; width: 17em; padding:1em;">'''High risk on stress test''' </div>| I02= <div style="float: left; text-align: left; width: 17em; padding:1em;">'''Low risk on stress test OR did not undergo stress test''' </div>}}<br />
{{familytree |boxstyle=background: #FA8072; color: #F8F8FF; | | | |!|!| |!| | | |!| | }}<br />
{{familytree |boxstyle=background: #FA8072; color: #F8F8FF; | | | |!|!| J01 | | |!| | J01= <div style="float: left; text-align: left; width: 17em; padding:1em;"> '''INVASIVE THERAPY''' <br>❑ Perform diagnostic [[angiography]] (I-A) </div>}}<br />
{{familytree |boxstyle=background: #FA8072; color: #F8F8FF; | | | |!|!|!| | | | K01 | K01= <div style="float: left; text-align: left; width: 17em; padding:1em;"> ❑ Continue [[aspirin]] for life (I-A)<br> ❑ Continue [[P2Y12]] receptor inhibitors up to 12 months (I-B)<br><br />
:❑ [[Clopidogrel]] (75 mg once a day)<br>'''OR''' <br><br />
:❑ [[Ticagrelor]] (90 mg twice a day)<br><br />
❑ Discontinue [[GP IIb/IIIa]] inhibitors if administered earlier (I-A)<br><br />
❑ Continue [[antithrombotic]] therapy:<br><br />
:❑ [[UFH]] for 48 hours (I-A)<br>'''OR''' <br><br />
:❑ [[Enoxaparin]] for duration of hospitalization (up to 8 days) (I-A)<br>'''OR''' <br><br />
:❑ [[Fondaparinux]] for duration of hospitalization (up to 8 days) (I-B)<br />
❑ Measure LVEF (I-B)</div>}}<br />
{{familytree |boxstyle=background: #FA8072; color: #F8F8FF; | | | |!|!|!| | | | | |}}<br />
{{familytree |boxstyle=background: #FA8072; color: #F8F8FF; | | | | C01 | | | | | | | | C01= <div style="float: left; text-align: left; width: 17em; padding:1em;">{{fontcolor|#000000|'''TRIAGE FOR SUBSEQUENT THERAPY PLAN FOLLOWING ANGIOGRAPHY'''}} <br> Does the [[angiography]] show coronary vessel obstruction ?</div> }}<br />
{{familytree |boxstyle=background: #FA8072; color: #F8F8FF; | | |,|-|^|-|-|.| | | | | }}<br />
{{familytree |boxstyle=background: #FA8072; color: #F8F8FF; | | D01 | | | | D02 | | | | D01= '''No'''| D02= '''Yes'''}}<br />
{{familytree |boxstyle=background: #FA8072; color: #F8F8FF; | | |!| | | |,|-|^|-|-|-|-|-|.| | | }}<br />
{{familytree |boxstyle=background: #FA8072; color: #F8F8FF; | | |!| | | E01 | | E02 | | E03 | | E01=<div style="float: left; text-align: left; width: 17em; padding:1em;">❑ 1 or 2 vessel disease <br> ''[[CABG]] or medical therapy might also be considered'' </div>|E02=<div style="float: left; text-align: left; width: 17em; padding:1em;">❑ Left main coronary artery disease <br>❑ 3 vessel disease <br>❑ 2 vessel disease with proximal left anterior descending artery affection <br>❑ [[Left ventricular dysfunction]] <br> ❑Patient treated from [[diabetes]]</div>| E03= }}<br />
{{familytree |boxstyle=background: #FA8072; color: #F8F8FF; | | |!| | | |!| | | |!| | | |!| | |}}<br />
{{familytree |boxstyle=background: #FA8072; color: #F8F8FF; | | L03 | | L01 | | L02 | | L03 | | L01= '''[[PCI]]''' <br> <br />
| L02= '''[[CABG]]''' <BR><br />
| L03= '''Medical treatment'''}}<br />
{{familytree |boxstyle=background: #FA8072; color: #F8F8FF; | | |!| | | |!| | | |!| | | |!| | | }}<br />
{{familytree |boxstyle=background: #FA8072; color: #F8F8FF; | | M01 | | M02 | | M03 | | M04 | | M01= <div style="float: left; text-align: left; width: 17em; padding:1em;"><br />
❑ Administer aspirin indefinitely <br><br />
❑ Administer additional antiplatelet therapy ''at the discretion of the physician'' (I-C)<br><br />
❑ Administer anticoagulant therapy ''at the discretion of the physician'' (I-C)</div><br />
|M02= <div style="float: left; text-align: left; width: 17em; padding:1em;"><br />
❑ Administer [[aspirin]] for life (I-B)<br><br />
❑ Initiate/continue [[P2Y12]] receptor inhibitor:<br><br />
:❑ [[Clopidogrel]] (I-B)<br>'''OR''' <br><br />
:❑ [[Ticagrelor]] (I-B)<br>'''OR''' <br><br />
:❑ [[Prasugrel]] (I-B)<br>'''OR''' <br><br />
❑ Initiate/continue [[GPI]] (if not treated with bivalirudin at the time of PCI):<br><br />
: High risk patients without adequate clopidogrel pre-treatment (I-A)<br />
: High risk patients with adequate clopidogrel pre-treatment (I-B)<br />
❑ Initiate/Continue anticoagulant therapy:<br />
:❑ Enoxaparin (I-A)<br />
:❑ UFH (I-B)<br />
:❑ Bivalirudin (I-B)<br />
:❑ Fondaparinux (not as a sole agent)</div><br />
| M03=<div style="float: left; text-align: left; width: 17em; padding:1em;"><br />
❑ Continue [[aspirin]] (I-B)<br><br />
❑ Discontinue IV [[GP IIb/IIIa]] inhibitors (I-B):<br><br />
:❑ Discontinue eptifibatide/tirofiban if started before angiography (2 to 4 hours prior to CABG)<br><br />
:❑ Discontinue abciximab if started before angiography (≥ 12 hours prior to CABG)<br><br />
❑ Manage the P2Y12 receptor inhibitor therapy as follows:<br />
''If CABG can be delayed'':<br><br />
:❑ Discontinue clopidogrel if started before angiography (5 days prior to CABG)<br><br />
:❑ Discontinue ticagrelor if started before angiography (5 days prior to CABG)<br><br />
:❑ Discontinue prasugrel if started before angiography (7 days prior to CABG)<br><br />
''If CABG is urgent'':<br><br />
:❑ Discontinue clopidogrel if started before angiography (up to 24 hours prior to CABG)<br><br />
:❑ Discontinue ticagrelor if started before angiography (up to 24 hours prior to CABG)<br><br />
❑ Manage the [[anticoagulation]] therapy <br><br />
:❑ Continue [[UFH]] (I-B)<br />
:❑ Discontinue [[enoxaparin]] if started before angiography (12-24 hours prior to CABG) and dose with UFH (I-B)<br><br />
:❑ Discontinue [[fondaparinux]] if started before angiography (24 hours prior to CABG) and dose with UFH (I-B)<br><br />
:❑ Discontinue [[bivalirudin]] if started before angiography (3 hours prior to CABG) and dose with UFH (I-B)</div><br />
|M04= <div style="float: left; text-align: left; width: 17em; padding:1em;"> ❑ Continue [[aspirin]] (I-A)<br><br />
❑ Administer a loading dose of [[P2Y12]] receptor inhibitors ''if not given before angiography'' (I-B)<br />
:❑ [[Clopidogrel]] (300 mg or 600 mg)<br>'''OR''' <br><br />
:❑ [[Prasugrel]] (60 mg) <br><br />
❑ Discontinue IV [[GP IIb/IIIa]] inhibitors if started before angiography (I-B)<br><br />
❑ Manage [[antithrombotic]] therapy:<br />
:❑ Continue IV [[UFH]] for at least 48 hours or until discharge if started before angiography (I-A)<br><br />
:❑ Continue [[enoxaparin]] for entire hospital stay, up to 8 days if started before angiography (I-A)<br><br />
:❑ Continue [[fondaparinux]] for entire hospital stay, up to 8 days if started before angiography (I-B)<br><br />
:❑ Discontinue [[bivalirudin]] or continue at 0.25 mg/kg/hour for up to 72 hours (I-B)</div> }}<br />
{{familytree/end}}<br />
<br />
==Complete Diagnostic Approach==<br />
A complete diagnostic approach should be carried out after a focused initial rapid evaluation is conducted and following initiation of any urgent intervention.<ref name="pmid22809746">{{cite journal| author=Jneid H, Anderson JL, Wright RS, Adams CD, Bridges CR, Casey DE et al.| title=2012 ACCF/AHA focused update of the guideline for the management of patients with unstable angina/non-ST-elevation myocardial infarction (updating the 2007 guideline and replacing the 2011 focused update): a report of the American College of Cardiology Foundation/American Heart Association Task Force on Practice Guidelines. | journal=J Am Coll Cardiol | year= 2012 | volume= 60 | issue= 7 | pages= 645-81 | pmid=22809746 | doi=10.1016/j.jacc.2012.06.004 | pmc= | url=http://www.ncbi.nlm.nih.gov/entrez/eutils/elink.fcgi?dbfrom=pubmed&tool=sumsearch.org/cite&retmode=ref&cmd=prlinks&id=22809746 }} </ref><br />
<br />
<span style="font-size:85%"> '''Abbreviations:''' '''CABG:''' [[coronary artery bypass graft]]; '''ECG:''' [[electrocardiogram]]; '''LAD:''' [[LAD|left anterior descending]]; '''LBBB:''' [[left bundle branch block]]; '''MI:''' [[myocardial infarction]]; '''PCI:''' [[percutaneous coronary intervention]]; '''S3:''' [[S3|third heart sound]]; '''S4:''' [[S4|fourth heart sound]]; '''VSD:''' [[ventricular septal defect]] </span><br />
<br />
{{Family tree/start}}<br />
{{familytree | A01 | | A01=<div style="float: left; text-align: left; width: 28em; padding:1em;"> '''Characterize the symptoms:''' <br><br />
❑ [[Chest pain]] or [[chest discomfort]] <br><br />
:❑ Sudden onset<br />
:❑ Sensation of heaviness, tightness, pressure, or squeezing<br />
:❑ Duration> 20 minutes <br><br />
:❑ Radiation to the left arm, jaw, neck, right arm, back or [[epigastrium]]<br />
:❑ No relief with rest <br><br />
:❑ Worse with time <br><br />
:❑ Worse with exertion<br><br />
❑ [[Dyspnea]] <br><br />
❑ [[Weakness]] <br><br />
❑ [[Palpitations]] <br><br />
❑ [[Nausea]] <br><br />
❑ [[Vomiting]] <br><br />
❑ [[Sweating]] <br><br />
❑ [[Loss of consciousness]]<br><br />
❑ [[Fatigue]]<br />
</div>}}<br />
{{familytree | |!| | |}}<br />
{{familytree | B01 | | B01=<div style="float: left; text-align: left; width: 35em; padding:1em;"> '''Obtain a detailed history:''' <br><br />
❑ Age <br><br />
❑ Baseline [[blood pressure]] <br><br />
❑ Previous episodes of [[chest pain]] <br><br />
❑ Previous [[PCI]] or [[CABG]] <br><br />
❑ Cardiac risk factors<br><br />
:❑ [[Hypertension]] <br><br />
:❑ [[Diabetes]] <br><br />
:❑ [[Hypercholesterolemia]] <br><br />
:❑ [[Smoking]] <br><br />
:❑ [[Obesity]] <br><br />
❑ List of medications <br><br />
❑ Family history of premature [[coronary artery disease]]<br />
----<br />
'''Identify possible triggers:'''<br><br />
❑ Physical exertion <br><br />
❑ Air pollution or fine particulate matter <br><br />
❑ Antecedant infection <br><br />
❑ Heavy meal <br><br />
❑ [[Cocaine]] <br><br />
❑ [[Marijuana]]</div>}}<br />
{{familytree | |!| | | }}<br />
{{familytree | C01 | | C01=<div style="float: left; text-align: left; width: 35em; padding:1em;">'''Examine the patient:''' <br><br />
<br />
'''Vital signs''' <br><br />
❑ [[Blood pressure]] <br><br />
:❑ [[Blood pressure]] lower than baseline, suggestive of:<br />
:❑ Discrepancy between arms (suggestive of [[aortic dissection]])<br />
:❑ Narrow [[pulse pressure]] (suggestive of [[heart failure]])<br />
<br />
❑ [[Heart rate]] <br><br />
:❑ [[Tachycardia]] (suggestive of [[heart failure]])<br />
:❑ [[Bradycardia]] (suggestive of [[heart block]] or [[bradyarrhythmias]])<br />
<br />
'''Pulses''' <br><br />
❑ [[Femoral artery|Femoral pulse]] (if a patient is to undergo [[PCI]])<br><br />
:❑ Strength<br />
:❑ [[Bruits]]<br />
<br />
'''Skin''' <br><br />
❑ [[Xanthelasma]] (suggestive of [[dyslipidemia]]) <br><br />
❑ [[Xanthoma]] (suggestive of [[dyslipidemia]]) <br><br />
❑ [[Edema]] (suggestive of [[heart failure]])<br><br />
❑ [[Cyanosis|Cyanotic]] and cold skin, lips, nail bed (suggestive of [[cardiogenic shock]]) <br><br />
<br />
'''Heart''' <br><br />
❑ [[Heart sounds]]<br><br />
:❑ [[S3]] (suggestive of [[heart failure]])<br />
:❑ [[S4]] (associated with conditions that increase the stiffness of the ventricle)<br />
❑ [[Murmurs]]<br />
:❑ [[Aortic regurgitation]]: early diastolic high-pitched sound best heard at the left sternal border (suggestive of [[aortic dissection]] with propagation to the aortic arch)<br />
❑ [[Friction rub|Pericardial friction rub]] (suggestive of [[pericarditis]])<br />
<br />
'''Lungs''' <br><br />
❑ [[Rales]] (suggestive of [[heart failure]]) <br><br />
</div>}}<br />
{{familytree | |!| | }}<br />
{{familytree | E01 | E01= <div style="float: left; width: 28em; text-align: left;">'''Order labs and tests:''' <br><br />
❑ [[EKG]] <br><br />
❑ Biomarkers <br><br />
:❑ Troponin I<br><br />
:❑ CK-MB <br><br />
❑ [[Echocardiography]]<br />
❑ [[Creatinine]] <br><br />
❑ [[Glucose]] <br><br />
❑ [[Hemoglobin]]<br><br />
❑ Multislice CT coronary imaging (rule out [[CAD]] as cause of pain in<br />
patients with low to intermediate likelihood of [[CAD]] and when [[troponin]] and [[ECG]] are<br />
inconclusive)<ref>{{Cite web | last = | first = | title = http://eurheartj.oxfordjournals.org/content/32/23/2999.full.pdf | url = http://eurheartj.oxfordjournals.org/content/32/23/2999.full.pdf | publisher = | date = | accessdate = }}</ref> <br><br />
❑ [[MRI]] (integrate imaging of function, perfusion and necrosis)<ref>{{Cite web | last = | first = | title = http://eurheartj.oxfordjournals.org/content/32/23/2999.full.pdf | url = http://eurheartj.oxfordjournals.org/content/32/23/2999.full.pdf | publisher = | date = | accessdate = }}</ref><br />
</div>}}<br />
{{Family tree/end}}<br />
<br />
==Pre-Discharge Care==<br />
<span style="font-size:85%"> '''Abbreviations:''' '''ACE:''' [[angiotensin converting enzyme]]; '''LVEF:''' [[left ventricular ejection fraction]]; '''PCI:''' [[percutaneous coronary intervention]]; '''PO:''' per os; '''VF:''' [[ventricular fibrillation]]; '''VT:''' [[ventricular tachycardia]] </span><br />
<br />
{{Family tree/start}}<br />
{{familytree | A01 | | |A01= <div style="float: left; text-align: left; width: 30em; padding:1em;">'''Administer the following medications in patients without contraindications:'''<br><br />
❑ [[Aspirin]] 81-325 mg (indefinitely) (I-A)<br><br />
:''Among patients with either GI intolerance or hypersensitivity to aspirin, administer a loading dose followed by maintenance dose of either clopidogrel 75 mg OD (I-B), OR prasugrel 10 mg OD (only in PCI patients) (I-C), OR ticagrelor 90 mg BID (I-C)'' <br><br />
❑ [[Beta blockers]] <br><br />
<span style="font-size:85%;color:red">Contraindicated in heart failure, prolonged or high degree AV block, reactive airway disease, high risk of cardiogenic shock and low cardiac output state</span> :❑ [[Metoprolol tartrate]]<br />
::❑ Begin with 25 to 50 mg PO every 6 to 12 hour<br />
::❑ Then, [[metoprolol tartrate]] twice daily or [[metoprolol succinate]] once daily for 2-3 days<br />
::❑ Titate to 200 mg daily, OR<br />
:❑ [[Carvedilol]]<br />
::❑ Begin with 6.25 mg twice daily<br />
::❑ Titrate to 25 mg twice daily<br />
❑ [[Calcium channel blockers]] are used as anti-ischemic or antihypertensive drugs and also in [[atrial fibrillation]] when [[beta blockers]] are contraindicated <br><br />
<span style="font-size:85%;color:red">Contraindicated in heart failure and left ventricular dysfunction</span> <br><br />
❑ [[ACE]] inhibitors and [[ARBs]] may also be considered in selected patients (no enough information)<ref name="www.ncbi.nlm.nih.gov">{{Cite web | last = | first = | title = Therapeutic effects of captopril on ischemia and ... [Am Heart J. 1994] - PubMed - NCBI | url = http://www.ncbi.nlm.nih.gov/pubmed?term=8273728 | publisher = | date = | accessdate = }}</ref><br />
<br><br />
<span style="font-size:85%;color:red">Contraindicated in hypotension, renal failure and hyperkalemia</span> <br><br />
❑ [[Atorvastatin]] 80 mg daily<br />
----<br />
'''Administer ONE of the following antiplatelet therapy for a duration of:'''<br />
: '''Up to 12 months in medically treated with no stenting (I-B)'''<br />
: '''Up to 12 months in BMS (I-B)'''<br />
: '''At least 12 months in DES (I-B)'''<br />
❑ [[Clopidogrel]] 75 mg daily, OR <br><br />
❑ [[Ticagrelor]] 90 mg twice a day, OR <br><br />
❑ [[Prasugrel]] 10 mg daily '''only for patients who underwent PCI'''<br><br />
<br><br />
<br />
<span style="font-size:85%;color:red">Consider earlier discontinuation in case bleeding risk exceeds benefit of the antiplatelet therapy (I-C).</span> <br><br />
----<br />
'''Assess the patient for ischemia:'''<br><br />
❑ Perform non invasive testing before discharge for the evaluation of ischemia among patients who did not undergo [[coronary angiography]] and in whom [[coronary angiography]] is not warranted due to the absence of high risk features ([[ACC AHA guidelines classification scheme|Class I, level of evidence B]]) <br><br />
❑ Assess the [[LVEF]] ([[ACC AHA guidelines classification scheme|Class I, level of evidence C]])<br />
</div>}}<br />
{{familytree/end}}<br />
<br />
<br />
<span style="font-size:85%"> '''Abbreviations:''' '''ACE:''' [[angiotensin converting enzyme]]; '''ARB:''' [[angiotensin receptor blocker]];</span><br />
<br />
{{Family tree/start}}<br />
{{familytree | A01 | | A01= <div style="float: left; text-align: left; width: 30em; padding:1em;"> ❑ Prepare a list of all the home medications and educate the patient about compliance<br />
:❑ [[Aspirin]] 81-325 mg (indefinitely) <br />
:❑ [[Antiplatelet drug|Antiplatelet therapy]]<br />
:❑ [[Beta blockers]]<br />
:❑ [[ACE inhibitors]] or [[ARB]] (only in selected patients <ref name="ACE">{{Cite web | last = | first = | title = Therapeutic effects of captopril on ischemia and ... [Am Heart J. 1994] - PubMed - NCBI | url = http://www.ncbi.nlm.nih.gov/pubmed?term=8273728 | publisher = | date = | accessdate = }}</ref><br />
<br />
:❑ [[Atorvastatin]] 80 mg daily<br />
❑ Encourage lifestyle modification <br><br />
:❑ [[Smoking]] cessation<br />
:❑ Physical activity<br />
:❑ Dietary changes<br />
❑ Ensure the initiation of the management of comorbidities<br />
:❑ [[Obesity]]<br />
:❑ [[Dyslipidemia]]<br />
:❑ [[Hypertension]]<br />
:❑ [[Diabetes]]<br />
:❑ [[Heart failure]]<br />
❑ Educate the patient about the early recognition of symptoms of [[acute coronary syndrome]]<br />
❑ Educate the patient about the use of [[nitroglycerin]] 0.4 mg, sublingually, up to 3 doses every 5 minutes </div> }}<br />
{{Family tree/end}}<br />
<br />
==Do's==<br />
* Administer a loading dose followed by a maintenance dose of [[clopidogrel]], [[ticagrelor]] or [[prasugrel]] (if [[PCI]] is planned) as initial treatment instead of [[aspirin]] among patients with gastrointestinal intolerance or hypersensitivity reaction to [[aspirin]].<br />
<br />
* Administer sublingual [[nitroglycerin]] in patients with ischemic [[chest pain]]; however, administer IV [[nitroglycerin]] among patients with persistent [[chest pain]] after three sublingual [[nitroglycerin]].<ref name="pmid6402912">{{cite journal| author=Kaplan K, Davison R, Parker M, Przybylek J, Teagarden JR, Lesch M| title=Intravenous nitroglycerin for the treatment of angina at rest unresponsive to standard nitrate therapy. | journal=Am J Cardiol | year= 1983 | volume= 51 | issue= 5 | pages= 694-8 | pmid=6402912 | doi= | pmc= | url=http://www.ncbi.nlm.nih.gov/entrez/eutils/elink.fcgi?dbfrom=pubmed&tool=sumsearch.org/cite&retmode=ref&cmd=prlinks&id=6402912 }} </ref><br />
<br />
*Discontinue [[NSAID]] drugs immediately. <ref name="pmid21224324">{{cite journal| author=Trelle S, Reichenbach S, Wandel S, Hildebrand P, Tschannen B, Villiger PM et al.| title=Cardiovascular safety of non-steroidal anti-inflammatory drugs: network meta-analysis. | journal=BMJ | year= 2011 | volume= 342 | issue= | pages= c7086 | pmid=21224324 | doi=10.1136/bmj.c7086 | pmc=PMC3019238 | url=http://www.ncbi.nlm.nih.gov/entrez/eutils/elink.fcgi?dbfrom=pubmed&tool=sumsearch.org/cite&retmode=ref&cmd=prlinks&id=21224324 }} [http://www.ncbi.nlm.nih.gov/entrez/eutils/elink.fcgi?dbfrom=pubmed&tool=sumsearch.org/cite&retmode=ref&cmd=prlinks&id=21460398 Review in: Evid Based Med. 2011 Oct;16(5):142-3] </ref> <ref name="pmid23726390">{{cite journal| author=Coxib and traditional NSAID Trialists' (CNT) Collaboration. Bhala N, Emberson J, Merhi A, Abramson S, Arber N et al.| title=Vascular and upper gastrointestinal effects of non-steroidal anti-inflammatory drugs: meta-analyses of individual participant data from randomised trials. | journal=Lancet | year= 2013 | volume= 382 | issue= 9894 | pages= 769-79 | pmid=23726390 | doi=10.1016/S0140-6736(13)60900-9 | pmc=PMC3778977 | url=http://www.ncbi.nlm.nih.gov/entrez/eutils/elink.fcgi?dbfrom=pubmed&tool=sumsearch.org/cite&retmode=ref&cmd=prlinks&id=23726390 }} [http://www.ncbi.nlm.nih.gov/entrez/eutils/elink.fcgi?dbfrom=pubmed&tool=sumsearch.org/cite&retmode=ref&cmd=prlinks&id=24126661 Review in: Ann Intern Med. 2013 Oct 15;159(8):JC12] </ref><br />
<br />
* If fondaparinux is chosen to be administered ad the anticoagulant therapy during PCI, co-administer another antocoagulant with factor IIa activity such as UFH.<br />
<br />
==Don'ts==<br />
* Do not administer IV [[GP IIb/IIIa inhibitors]] to patients with low risk of ischemic events or at high risk of [[bleeding]] and who are already on [[aspirin]] and P2Y12 receptor inhibitors therapy.<br />
<br />
* Do not administer [[prasugrel]] among patients with prior history of [[strokes]] or [[TIAs]].<br />
<br />
* Do not administer IV [[beta-blockers]] among hemodynamically unstable patients.<br />
<br />
* Do not administer a complete dose of [[prasugrel]] among patients under 60kg (132lbs) due to high exposure to the active metabolite. They should receive half the dose of [[prasugrel]] although there is no evidence that half the dose is as effective as a complete dose.<br />
<br />
* Do not administer fibrinolytic therapy to patients with [[unstable angina]].<ref name="pmid7475596">{{cite journal| author=Anderson HV| title=Intravenous thrombolysis in refractory unstable angina pectoris. | journal=Lancet | year= 1995 | volume= 346 | issue= 8983 | pages= 1113-4 | pmid=7475596 | doi= | pmc= | url=http://www.ncbi.nlm.nih.gov/entrez/eutils/elink.fcgi?dbfrom=pubmed&tool=sumsearch.org/cite&retmode=ref&cmd=prlinks&id=7475596 }} </ref><br />
<br />
*Do not administer [[abciximab]] for patients not scheduled for [[PCI]]. <ref name="pmid22809746">{{cite journal| author=Jneid H, Anderson JL, Wright RS, Adams CD, Bridges CR, Casey DE et al.| title=2012 ACCF/AHA focused update of the guideline for the management of patients with unstable angina/non-ST-elevation myocardial infarction (updating the 2007 guideline and replacing the 2011 focused update): a report of the American College of Cardiology Foundation/American Heart Association Task Force on Practice Guidelines. | journal=J Am Coll Cardiol | year= 2012 | volume= 60 | issue= 7 | pages= 645-81 | pmid=22809746 | doi=10.1016/j.jacc.2012.06.004 | pmc= | url=http://www.ncbi.nlm.nih.gov/entrez/eutils/elink.fcgi?dbfrom=pubmed&tool=sumsearch.org/cite&retmode=ref&cmd=prlinks&id=22809746 }} </ref><br />
<br />
* Do not administer 2 P2Y12 receptor inhibitors, even in the presence of hypersensitivity or GI interoperability to aspirin.<br />
<br />
==References==<br />
{{reflist|2}}<br />
<br />
[[Category:Emergency medicine]]<br />
[[Category:Medicine]]<br />
[[Category:Resident survival guide]]<br />
[[Category:Cardiology]]<br />
<br />
{{WikiDoc Help Menu}}<br />
{{WikiDoc Sources}}<br />
</div></div>Rim Halabyhttps://www.wikidoc.org/index.php?title=Resident_survival_guide_topics&diff=1088088Resident survival guide topics2015-04-15T21:08:26Z<p>Rim Halaby: /* List of All Topics */</p>
<hr />
<div>__NOTOC__<br />
{{Resident survival guide project}}<br />
[[Image:Main_help_page_small.PNG|100px|link=Help]][[Image:Projects.PNG|100px|link=Projects]][[Image:Editor's_Tools.PNG|100px|link=Help Menu]]<br />
<br />
{{WikiDoc CMG}}; {{AE}} {{MS}}; [[Priyamvada Singh|Priyamvada Singh, M.D.]] [mailto:psingh13579@gmail.com]; {{Rim}}<br />
<br />
==Overview==<br />
This section shows the list of topics available for the resident survival guide project and how to select a topic. You can also update the status of your chosen topic here by entering the authorship details so that your work is not overlapped by the work of other editors.<br />
<br />
==Select a Topic==<br />
*Select a topic from the list of resident survival guide topics shown below.<br />
*The topics that are completed or have been worked on by wikidoc scholars are highlighted in blue.<br />
*The topics in black are still available for scholars on campus or remote collaborators to work on.<br />
<br />
==List of All Topics==<br />
<br />
===Cardiology===<br />
<br />
{| class="wikitable sortable"<br />
! Specialty<br />
! Topic<br />
! Resident Survival Guide Page<br />
! Author<br />
! Status<br />
|-<br />
| Cardiology || [[Acute coronary syndrome]] || [[Acute coronary syndrome resident survival guide]] || Priyamvada/Rim || Complete<br />
|-<br />
| Cardiology || [[Heart failure]] || [[Heart failure resident survival guide]] || Mahmoud/Dr. Kay || Complete<br />
|-<br />
| Cardiology || [[Arrhythmia]] || [[Arrhythmia resident survival guide]] || Rim || Complete<br />
|-<br />
| Cardiology || [[Atrial fibrillation]] || [[Atrial fibrillation resident survival guide]] || Vidit|| Complete<br />
|-<br />
| Cardiology || [[Aortic aneurysm]] || [[Aortic aneurysm resident survival guide]] ||Landing page|| Complete<br />
|-<br />
| Cardiology || [[Abdominal aortic aneurysm]] || [[Abdominal aortic aneurysm resident survival guide]] ||Yaz||<br />
|-<br />
| Cardiology || [[Thoracic aortic aneurysm]] || [[Thoracic aortic aneurysm resident survival guide]] ||Yaz||<br />
|-<br />
| Cardiology || [[Aortic dissection]] || [[Aortic dissection resident survival guide]] || Chetan/Serge ||<br />
|-<br />
| Cardiology || [[Aortic regurgitation]] || [[Aortic regurgitation resident survival guide]] || Alejandro ||Complete<br />
|-<br />
| Cardiology || [[Aortic stenosis]] || [[Aortic stenosis resident survival guide]] || Alejandro ||Complete<br />
|-<br />
| Cardiology || [[Atrial flutter]] || [[Atrial flutter resident survival guide]] || Vidit ||<br />
|-<br />
| Cardiology || [[Bradycardia]] || [[Bradycardia resident survival guide]] || Ogheneochuko: Vidit ||Complete<br />
|-<br />
| Cardiology || [[Cardiac arrest]] || [[Cardiac arrest resident survival guide]] || Rim: Vidit ||Complete<br />
|-<br />
| Cardiology || [[Cardiogenic shock]] || [[Cardiogenic shock resident survival guide]] ||Gerry|| Complete<br />
|-<br />
| Cardiology || [[Chest pain]] || [[Chest pain resident survival guide]] || Rim/Alejandro || Complete<br />
|-<br />
| Cardiology || || [[Coronary angiography resident survival guide]] ||Yazan ||<br />
|-<br />
| Cardiology || [[Dyslipidemia]] || [[Dyslipidemia resident survival guide]] || ||<br />
|-<br />
| Cardiology || [[Electrocardiography]] || [[Electrocardiography resident survival guide]] ||Rim|| Complete<br />
|-<br />
| Cardiology || [[Endocarditis]] || [[Endocarditis resident survival guide]] ||Mohamed||Complete<br />
|-<br />
| Cardiology || [[Pericarditis]] || [[Pericarditis resident survival guide]] || Mugilan ||<br />
|-<br />
| Cardiology || [[Hypertension]] || [[Hypertension resident survival guide]] ||Landing page||Complete<br />
|-<br />
| Cardiology || [[Chronic hypertension]] || [[Chronic hypertension resident survival guide]] || Ayokunle||<br />
|-<br />
| Cardiology || [[Hypertensive crisis]] || [[Hypertensive crisis resident survival guide]]||Ayokunle|| Complete<br />
|-<br />
| Cardiology || [[Intracardiac device]] || [[Intracardiac device resident survival guide]] || ||<br />
|-<br />
| Cardiology || [[Supraventricular tachycardia|Narrow complex tachycardia]] || [[Narrow complex tachycardia resident survival guide]] || Hilda/Rim/Twinkle || Complete<br />
|-<br />
| Cardiology || [[Cardiac tamponade]] || [[Cardiac tamponade resident survival guide]] ||Ayokunle|| Complete<br />
|-<br />
| Cardiology || [[Low flow low gradient aortic stenosis]] || [[Low flow low gradient aortic stenosis resident survival guide]] || Rim || Complete<br />
|-<br />
| Cardiology || || [[Cardiac risk assessment prior to non-cardiac surgery resident survival guide]] ||Yaz||Complete<br />
|-<br />
| Cardiology || [[Dilated cardiomyopathy]] || [[Dilated cardiomyopathy resident survival guide]] || Steven ||<br />
|-<br />
| Cardiology || [[Restrictive cardiomyopathy]] || [[Restrictive cardiomyopathy resident survival guide]] || Steven ||<br />
|-<br />
| Cardiology || [[Hypertrophic cardiomyopathy]] || [[Hypertrophic cardiomyopathy resident survival guide]] || Steven ||<br />
|-<br />
| Cardiology || [[Arrhythmogenic right ventricular cardiomyopathy]] || [[Arrhythmogenic right ventricular cardiomyopathy resident survival guide]] || Steven ||<br />
|-<br />
| Cardiology || [[Claudication]] || [[Claudication resident survival guide]] ||Ochuko||<br />
|-<br />
| Cardiology || [[Mitral regurgitation]] || [[Mitral regurgitation resident survival guide]] ||Mugilan||<br />
|-<br />
| Cardiology || [[Mitral stenosis]] || [[Mitral stenosis resident survival guide]] ||Twinkle||Complete<br />
|-<br />
| Cardiology || [[Palpitations]] || [[Palpitations resident survival guide]] || ||<br />
|-<br />
| Cardiology || [[Peripheral artery disease]] || [[Peripheral artery disease resident survival guide]] || Ogheneochuko ||<br />
|-<br />
| Cardiology || [[Shortness of breath]] || [[Shortness of breath resident survival guide]] || Steven ||<br />
|-<br />
| Cardiology || [[STEMI]] || [[STEMI resident survival guide]] || Alejandro||Complete<br />
|-<br />
| Cardiology || [[Pulmonary embolism]] || [[Pulmonary embolism resident survival guide]] ||Rim ||Complete<br />
|-<br />
| Cardiology || [[Right ventricular myocardial infarction]] || [[Right ventricular myocardial infarction resident survival guide]] || Jad ||<br />
|-<br />
| Cardiology || [[Syncope]] || [[Syncope resident survival guide]] || Karol/Alejandro || Complete<br />
|-<br />
| Cardiology || [[Unstable angina]] || [[Unstable angina/ NSTEMI resident survival guide]] || Andrea ||<br />
|-<br />
| Cardiology || [[Valvular diseases]] || [[Valvular diseases resident survival guide]] || Landing page||Complete<br />
|-<br />
| Cardiology || [[VTE prevention]] || [[VTE prevention resident survival guide]] || Rim||Complete<br />
|-<br />
| Cardiology || [[Wide complex tachycardia]] || [[Wide complex tachycardia resident survival guide]] || Rim || Complete<br />
|-<br />
| Cardiology || [[WPW|Wolff-Parkinson-White syndrome]] || [[Wolff-Parkinson-White syndrome resident survival guide]]|| Alonso||<br />
|-<br />
|}<br />
<br />
===Other Topics===<br />
{| class="wikitable sortable"<br />
! Specialty<br />
! Topic<br />
! Resident Survival Guide Page<br />
! Author<br />
! Status<br />
|-<br />
| Pulmonary || [[Acute respiratory distress syndrome]] || [[Acute respiratory distress syndrome resident survival guide]] ||Ayokunle||<br />
|-<br />
| Pulmonary || [[Anaphylaxis]] || [[Anaphylaxis resident survival guide]] || Vidit ||<br />
|-<br />
| Pulmonary || [[Asthma|Asthma exacerbation]] || [[Asthma exacerbation resident survival guide]] || Abdurahman, Vidit ||Complete<br />
|-<br />
| Pulmonary || [[Chronic obstructive pulmonary disease|COPD exacerbation]] || [[COPD exacerbation resident survival guide]] || Abdurahman: Vidit ||Complete<br />
|-<br />
| Pulmonary || [[Cough]] || [[Cough resident survival guide]] || ||<br />
|-<br />
| Pulmonary || [[Deep venous thrombosis]] || [[Deep vein thrombosis resident survival guide|Deep venous thrombosis resident survival guide]] || Rim|| Complete<br />
|-<br />
| Pulmonary || [[Dyspnea]] || [[Dyspnea resident survival guide]] ||Dyspnea||<br />
|-<br />
| Pulmonary || [[Hemoptysis]] || [[Hemoptysis resident survival guide]] ||Teresa||<br />
|-<br />
| Pulmonary || [[Mechanical ventilation]] || [[Mechanical ventilation resident survival guide]] || Ahmed ||<br />
|-<br />
| Pulmonary || [[Pleural effusion]] || [[Pleural effusion resident survival guide]] ||Twinkle||<br />
|-<br />
| Pulmonary || [[Pulmonary embolism]] || [[Pulmonary embolism resident survival guide]] ||||<br />
|-<br />
| Pulmonary || [[Pulmonary hypertension]] || [[Pulmonary hypertension resident survival guide]] || Vidit ||<br />
|-<br />
| Pulmonary || [[Respiratory failure]] || [[Respiratory failure resident survival guide]] ||||<br />
|-<br />
| Cardiology || [[Tension pneumothorax]] || [[Tension pneumothorax resident survival guide]] || Mohamad||Complete<br />
|-<br />
| Gastroenterology || [[Abdominal pain]] || [[Abdominal pain resident survival guide]] ||||<br />
|-<br />
| Gastroenterology || [[Abnormal liver tests]] || [[Abnormal liver tests resident survival guide]] ||||<br />
|-<br />
| Gastroenterology || [[Acetaminophen toxicity]] || [[Acetaminophen overdose resident survival guide|Acetaminophen toxicity resident survival guide]] || Vidit ||Complete<br />
|-<br />
| Gastroenterology || [[Diarrhea|Acute diarrhea]] || [[Acute diarrhea resident survival guide]] || Mugilan ||Complete<br />
|-<br />
| Gastroenterology || [[Acute liver failure]] || [[Acute liver failure resident survival guide]] || Vendhan ||<br />
|-<br />
| Gastroenterology || [[Acute pancreatitis]] || [[Acute pancreatitis resident survival guide]] || Vidit || Complete<br />
|-<br />
| Gastroenterology || [[Appendicitis]] || [[Appendicitis resident survival guide]] || Teresa || Complete<br />
|-<br />
| Gastroenterology || [[Ascites]] || [[Ascites resident survival guide]] || Twinkle/Steven ||<br />
|-<br />
| Gastroenterology || [[Biliary tract diseases]] || [[Biliary tract diseases resident survival guide]] || Vendhan ||<br />
|-<br />
| Gastroenterology || [[Cholangitis]] || [[Cholangitis resident survival guide]] || Vendhan || Complete<br />
|-<br />
| Gastroenterology || [[Cholecystitis]] || [[Cholecystitis resident survival guide]] || Vendhan || Complete<br />
|-<br />
| Gastroenterology || [[Acute cholecystitis|Cholecystitis]] || [[Acute cholecystitis resident survival guide]] || Vendhan || Complete<br />
|-<br />
| Gastroenterology || [[Chronic cholecystitis|Cholecystitis]] || [[Chronic cholecystitis resident survival guide]] || Vendhan || Complete<br />
|-<br />
| Gastroenterology || [[Choledocholithiasis]] || [[Choledocholithiasis resident survival guide]] || Vendhan ||Complete<br />
|-<br />
| Gastroenterology || [[Cholelithiasis]] || [[Cholelithiasis resident survival guide]] || Vendhan ||<br />
|-<br />
| Gastroenterology || [[Diarrhea|Chronic diarrhea]] || [[Chronic diarrhea resident survival guide]] || Mugilan || Complete<br />
|-<br />
| Gastroenterology || [[Clostridium difficile]] || [[Clostridium difficile infection resident survival guide]] || Mugilan ||<br />
|-<br />
| Gastroenterology || [[Constipation]] || [[Constipation resident survival guide]] ||Mugilan|| Complete<br />
|-<br />
| Gastroenterology || [[Crohn’s disease]] || [[Crohn's disease resident survival guide]] ||Mugilan||<br />
|-<br />
| Gastroenterology || [[Diarrhea]] || [[Diarrhea resident survival guide]] || Mugilan ||Complete<br />
|-<br />
| Gastroenterology || [[Esophageal rupture]] || [[Esophageal rupture resident survival guide]] || ||<br />
|-<br />
| Gastroenterology || [[Ileus]] || [[Ileus resident survival guide]] ||Mugilan||<br />
|-<br />
| Gastroenterology || [[Intestinal ischemia]] || [[Intestinal ischemia resident survival guide]] ||Mugilan||<br />
|-<br />
| Gastroenterology || [[Acute pancreatitis|Gallstone pancreatitis]] || [[Gallstone pancreatitis resident survival guide]] || Vendhan|| Complete<br />
|-<br />
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{{WikiDoc Sources}}</div>Rim Halabyhttps://www.wikidoc.org/index.php?title=Unstable_angina/_NSTEMI_resident_survival_guide&diff=1088084Unstable angina/ NSTEMI resident survival guide2015-04-15T20:57:06Z<p>Rim Halaby: /* FIRE: Focused Initial Rapid Evaluation */</p>
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__NOTOC__<br />
{{CMG}}; {{AE}} {{ATS}}; {{Rim}}<br />
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{| class="infobox" style="margin: 0 0 0 0; border: 0; float: right; width: 100px; background: #A8A8A8; position: fixed; top: 250px; right: 21px; border-radius: 0 0 10px 10px;" cellpadding="0" cellspacing="0";<br />
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! style="padding: 0 5px; font-size: 85%; background: #A8A8A8" align=center| {{fontcolor|#2B3B44|Unstable angina/ NSTEMI Resident Survival Guide Microchapters}}<br />
|-<br />
! style="font-size: 80%; padding: 0 5px; background: #DCDCDC" align=left | [[Unstable angina/ NSTEMI resident survival guide#Overview|Overview]]<br />
|-<br />
! style="font-size: 80%; padding: 0 5px; background: #DCDCDC" align=left | [[Unstable angina/ NSTEMI resident survival guide#Causes|Causes]]<br />
|-<br />
! style="font-size: 80%; padding: 0 5px; background: #DCDCDC" align=left | [[Unstable angina/ NSTEMI resident survival guide#FIRE: Focused Initial Rapid Evaluation|FIRE]]<br />
|-<br />
! style="font-size: 80%; padding: 0 5px; background: #DCDCDC" align=left | [[Unstable angina/ NSTEMI resident survival guide#Complete Diagnostic Approach|Diagnosis]]<br />
|-<br />
! style="font-size: 80%; padding: 0 5px; background: #DCDCDC" align=left | [[Unstable angina/ NSTEMI resident survival guide#Treatment|Treatment]]<br />
: [[Unstable angina/ NSTEMI resident survival guide#Management Following Angiography|Management Following Angiography]]<br />
|-<br />
! style="font-size: 80%; padding: 0 5px; background: #DCDCDC" align=left | [[Unstable angina/ NSTEMI resident survival guide#Pre-Discharge Care|Pre-Discharge Care]]<br />
|-<br />
! style="font-size: 80%; padding: 0 5px; background: #DCDCDC" align=left | [[Unstable angina/ NSTEMI resident survival guide#Long Term Managemnet|Long Term Management]]<br />
|-<br />
! style="font-size: 80%; padding: 0 5px; background: #DCDCDC" align=left | [[Unstable angina/ NSTEMI resident survival guide#Do's|Do's]]<br />
|-<br />
! style="font-size: 80%; padding: 0 5px; background: #DCDCDC" align=left | [[Unstable angina/ NSTEMI resident survival guide#Don'ts|Don'ts]]<br />
|}<br />
<br />
==Overview==<br />
[[Unstable angina]] and [[non ST elevation myocardial infarction]] ([[NSTEMI]]) belong to two different ends of the spectrum of [[acute coronary syndrome]]. These conditions have a similar clinical presentation characterized by an acute onset of chest pain that starts on minimal exertion, rest or sleep, lasts at least 20 minutes (but usually less that half an hour) and, is not relieved by medications or rest. [[NSTEMI]] is differentiated from [[unstable angina]] by the presence of elevated cardiac biomarkers secondary to myocardial injury. [[Unstabel angina]] and [[NSTEMI]] might not be differentiated early following the occurrence of symptoms because [[cardiac biomarker]]s may require a few hours to rise.<br />
<br />
==Causes==<br />
<br />
===Life Threatening Causes===<br />
Life-threatening causes include conditions which may result in death or permanent disability within 24 hours if left untreated. [[Unstable angina]] and [[NSTEMI]] are life-threatening conditions and must be treated as such irrespective of the causes.<br />
<br />
===Common Causes===<br />
====Myocardial Infarction====<br />
* [[Atherosclerotic]] [[plaque rupture]] and subsequent [[coronary thrombus]] (most common cause)<br />
* [[Coronary artery spasm]]<br />
* [[Arrhythmia]]<br />
* [[MI|Post-myocardial infarction]]<br />
* [[PCI|Post-percutaneous coronary intervention]]<br />
** [[Abrupt closure]]<br />
** [[PCI complications: loss of side branch|Loss of side branch]]<br />
** [[Distal embolization]]<br />
** [[PCI complications: restenosis|Restenosis]]<br />
**[[Stent thrombosis]]<br />
* [[CABG|Post-coronary artery bypass graft]]<br />
** Graft closure<br />
** New lesion in the graft<br />
<br />
''For a complete list of causes, click [[Unstable angina pathophysiology|here]] for unstable angina and [[Non ST elevation myocardial infarction pathophysiology|here]] for NSTEMI.''<br />
<br />
==FIRE: Focused Initial Rapid Evaluation==<br />
A Focused Initial Rapid Evaluation (FIRE) should be performed to identify patients in need of immediate intervention based on the 2012 ACCF/AHA focused update of the guideline for the management of patients with unstable angina/non-ST-elevation myocardial infarction.<ref name="pmid22809746">{{cite journal| author=Jneid H, Anderson JL, Wright RS, Adams CD, Bridges CR, Casey DE et al.| title=2012 ACCF/AHA focused update of the guideline for the management of patients with unstable angina/non-ST-elevation myocardial infarction (updating the 2007 guideline and replacing the 2011 focused update): a report of the American College of Cardiology Foundation/American Heart Association Task Force on Practice Guidelines. | journal=J Am Coll Cardiol | year= 2012 | volume= 60 | issue= 7 | pages= 645-81 | pmid=22809746 | doi=10.1016/j.jacc.2012.06.004 | pmc= | url=http://www.ncbi.nlm.nih.gov/entrez/eutils/elink.fcgi?dbfrom=pubmed&tool=sumsearch.org/cite&retmode=ref&cmd=prlinks&id=22809746 }} </ref> An invasive strategy is defined as diagnostic angiography with the intention of revascularization.<br />
<br />
<span style="font-size:85%">Boxes in the red color signify that an urgent management is needed.</span><br />
{{Family tree/start}}<br />
{{familytree |boxstyle=background: #FA8072; color: #F8F8FF; | | | | A00 | | A00=<div style="float: left; text-align: left; width: 17em; padding:1em;"> '''Identify cardinal findings of unstable angina/ NSTEMI :''' <br><br />
❑ '''[[Chest pain|<span style="color:white;"> Chest pain</span>]] or [[chest discomfort|<span style="color:white;">chest discomfort</span>]]''' <br><br />
:❑ Sudden onset<br />
:❑ Sensation of heaviness, tightness, pressure, or squeezing<br />
:❑ Duration> 20 minutes (but usually less than half an hour) <br><br />
:❑ Radiation to the left arm, jaw, neck, right arm, back or [[epigastrium|<span style="color:white;">epigastrium</span>]]<br />
:❑ No relief with medications<br><br />
:❑ No relief with rest <br><br />
:❑ Worse with time <br><br />
:❑ Worse with exertion<br><br />
:❑ Associated symptoms of [[palpitations|<span style="color:white;">palpitations</span>]], [[nausea|<span style="color:white;">nausea</span>]], [[vomiting|<span style="color:white;">vomiting</span>]], [[sweating|<span style="color:white;">sweating</span>]], [[dyspnea|<span style="color:white;">dyspnea</span>]], and [[lightheadedness|<span style="color:white;">lightheadedness</span>]]<br><br />
❑ '''Characteristic [[ECG|<span style="color:white;">ECG</span>]] changes consistent with [[unstable angina|<span style="color:white;">unstable angina</span>]]/ [[NSTEMI|<span style="color:white;">NSTEMI</span>]] '''<br />
:❑ No changes <br><br />
:❑ Non specific ST / T wave changes <br> <br />
:❑ Flipped or inverted T waves <br><br />
:❑ ST depression (carries the poorest prognosis) <br><br />
❑ '''Increase in >99th percentile of upper limit of normal of [[troponin|<span style="color:white;">troponin</span>]] and / or [[CKMB|<span style="color:white;">CK MB</span>]]''', which is consistent with [[NSTEMI|<span style="color:white;">NSTEMI</span>]]</div>}}<br />
{{familytree |boxstyle=background: #FA8072; color: #F8F8FF; | | | | |!| | | }}<br />
{{familytree |boxstyle=background: #FA8072; color: #F8F8FF; | | | | G02 | G02= <div style="float: left; text-align: left; width: 17em; padding:1em;"> '''Rule out life threatening alternative diagnoses:'''<br><br />
❑ [[Aortic dissection|<span style="color:white;">Aortic dissection</span>]] <br> (suggestive findings: [[back pain|<span style="color:white;">back pain</span>]], [[interscapular pain|<span style="color:white;">interscapular pain</span>]], [[aortic regurgitation|<span style="color:white;">aortic regurgitation</span>]], [[pulsus paradoxus|<span style="color:white;">pulsus paradoxus</span>]], [[blood pressure|<span style="color:white;">blood pressure</span>]] discrepancy between the arms) <br><br />
❑ [[Pulmonary embolism|<span style="color:white;">Pulmonary embolism</span>]] <br> (suggestive findings: acute onset of [[dyspnea|<span style="color:white;">dyspnea</span>]], [[tachypnea|<span style="color:white;">tachypnea</span>]], [[hemoptysis|<span style="color:white;">hemoptysis</span>]], previous [[DVT|<span style="color:white;">DVT</span>]]) <br><br />
❑ [[Cardiac tamponade|<span style="color:white;">Cardiac tamponade</span>]] <br> (suggestive findings: [[hypotension|<span style="color:white;">hypotension</span>]], [[jugular venous distention|<span style="color:white;">jugular venous distention</span>]], [[muffled heart sounds|<span style="color:white;">muffled heart sounds</span>]], [[pulsus paradoxus|<span style="color:white;">pulsus paradoxus</span>]])<br><br />
❑ [[Tension pneumothorax|<span style="color:white;">Tension pneumothorax</span>]] <br> (suggestive findings: sudden [[dyspnea|<span style="color:white;">dyspnea</span>]], [[tachycardia|<span style="color:white;">tachycardia</span>]], [[trauma|<span style="color:white;">chest trauma</span>]], unilateral absence of [[breath sounds|<span style="color:white;">breath sound</span>]])<br><br />
❑ [[Esophageal rupture|<span style="color:white;">Esophageal rupture</span>]] <br> (suggestive findings: [[vomiting|<span style="color:white;">vomiting</span>]], [[subcutaneous emphysema|<span style="color:white;">subcutaneous emphysema</span>]])</div>}}<br />
{{familytree |boxstyle=background: #FA8072; color: #F8F8FF; | | | | |!| | | }}<br />
{{familytree |boxstyle=background: #FA8072; color: #F8F8FF; | | | | A01 | | | | | A01= <div style="float: left; text-align: left; width: 17em; padding:1em;">'''Begin initial treatment:'''<br> <br />
❑ Administer 162 to 325 mg of non enteric [[aspirin|<span style="color:white;">aspirin</span>]],orally, crushed or chewed (I-A)<br />
:''Among patients with either GI intolerance or hypersensitivity to aspirin, administer a loading dose (75 mg) followed by maintenance dose of clopidogrel (I-B)''<br />
❑ Administer 2-4 L/min [[oxygen|<span style="color:white;">oxygen</span>]] via nasal cannula when saturation <90% (I-C)<br />
:''Caution in [[COPD|<span style="color:white;">COPD</span>]] patients: maintain an oxygen saturation between 88% and 92%.''<br />
❑ Administer [[nitroglycerin|<span style="color:white;">nitroglycerin</span>]]<br />
:❑ Administer sublingual nitroglycerin (0.3 to 0.4 mg, every 5 minutes for a total of 3 doses) then assess for further need to IV nitroglycerin (I-C)<br />
:❑ Administer IV nitroglyerin in case of persistent chest pain despite PO nitroglycerin, heart failure, or hypertenion (I-B): 10 mcg/min, increase by 10 mcg/min every 3 to 5 minutes until symptom relief; in case no response at 20 mcg/min, can increase by 10 mcg/min and then by 20 mcg/min<br />
<span style="font-size:85%;">Contraindicated in suspected [[RVMI|<span style="color:white;">right ventricular MI</span>]], recent use of [[phosphodiesterase inhibitors|<span style="color:white;">phosphodiesterase inhibitors</span>]], decreased [[blood pressure|<span style="color:white;">blood pressure</span>]] 30 mmHg below baseline</span> <br><br />
❑ Administer [[beta-blockers|<span style="color:white;">beta-blockers</span>]] (unless contraindicated) and titrate to the [[heart rate|<span style="color:white;">heart rate</span>]] and [[blood pressure|<span style="color:white;">blood pressure</span>]] (I-A)<br><br />
: ''PO in general, IV if patient has hypertension or ongoing pain''<br />
: ''Beta blocker is contraindicated in heart failure and high risk of cardiogenic shock.''<br />
:❑ [[Metoprolol|<span style="color:white;">Metoprolol</span>]]:<br />
:PO: 25 to 50 mg every 6 hours<br />
:IV: 5 mg every 5 min, up to 3 doses, then 25 to 50 mg orally every 6 hours<br />
:❑ [[Carvedilol|<span style="color:white;">Carvedilol</span>]] IV, 25 mg, two times a day<br />
<span style="font-size:85%;">Contraindicated in [[heart failure|<span style="color:white;">heart failure</span>]], bradycardia, hypotension (SBP<90 mmHg), [[AV block |<span style="color:white;">second or third degree AV block</span>]], [[reactive airway disease|<span style="color:white;">reactive airway disease</span>]], high risk of [[cardiogenic shock|<span style="color:white;">cardiogenic shock</span>]] and low [[cardiac output|<span style="color:white;">cardiac output</span>]] state</span> <br><br />
❑ Administer IV [[morphine|<span style="color:white;">morphine</span>]] if persistent symptoms (IIb-B) or [[pulmonary edema|<span style="color:white;">pulmonary edema</span>]]<br />
:❑ Initial dose 4-8 mg<br />
:❑ 2-8 mg every 5 to 15 minutes, as needed <br><br />
❑ Administer 80 mg [[atorvastatin|<span style="color:white;">atorvastatin</span>]] (I-A)<br><br />
❑ Monitor with a 12-lead [[ECG|<span style="color:white;">ECG</span>]] all the time<br />
</div>}}<br />
{{familytree |boxstyle=background: #FA8072; color: #F8F8FF; | | | | |!| | | }}<br />
{{familytree |boxstyle=background: #FA8072; color: #F8F8FF; | | | | G01 | G01= <div style="float: left; text-align: left; width: 17em; padding:1em;"> {{fontcolor|#000000|'''TRIAGE FOR IMMEDIATE INTERVENTION'''}} <br>'''Does the patient have ANY of the following indications that require immediate angiography and revascularization ?'''<br />
❑ Hemodynamic instability or [[cardiogenic shock|<span style="color:white;">cardiogenic shock</span>]], '''OR''' <br><br />
❑ Severe left ventricular dysfunction or [[heart failure|<span style="color:white;">heart failure</span>]], '''OR''' <br><br />
❑ Recurrent or persistent rest angina despite intensive medical therapy, '''OR''' <br><br />
❑ New or worsening [[mitral regurgitation|<span style="color:white;">mitral regurgitation</span>]] or new [[VSD|<span style="color:white;">VSD</span>]], '''OR''' <br><br />
❑ Sustained [[VT|<span style="color:white;">VT</span>]] or [[VF|<span style="color:white;">VF</span>]], '''OR''' <br><br />
❑ Prior [[PCI|<span style="color:white;">PCI</span>]] within past 6 months or [[CABG|<span style="color:white;">CABG</span>]] <br> </div> }}<br />
{{familytree |boxstyle=background: #FA8072; color: #F8F8FF; | |,|-|-|^|-|-|.| | }}<br />
{{familytree |boxstyle=background: #FA8072; color: #F8F8FF; | C01 | | | | C02 | | | C01=<div style="float: left; text-align: center; width: 17em; padding:1em;">'''YES''' </div>| C02= <div style="float: left; text-align: center; width: 17em; padding:1em;">'''NO''' </div> }}<br />
{{familytree |boxstyle=background: #FA8072; color: #F8F8FF; | |!| | | | | |!| | | | }}<br />
{{familytree |boxstyle=background: #FA8072; color: #F8F8FF; | |!| | | | | C03 | | | C03=<div style="float: left; text-align: left; width: 17em; padding:1em;">Does the patient have no ECG changes '''AND''' no rise in cardiac biomarkers > 99th percentile of ULN?</div>}}<br />
{{familytree |boxstyle=background: #FA8072; color: #F8F8FF; | |!| | | |,|-|^|-|.| | }}<br />
{{familytree |boxstyle=background: #FA8072; color: #F8F8FF; | |!| | | C04 | | C05 | C04= <div style="float: left; text-align: left; width: 17em; padding:1em;">Yes. The patient has no ECG changes AND no rise in cardiac biomarkers > 99th percentile of ULN. </div>| C05= <div style="float: left; text-align: left; width: 17em; padding:1em;">No. The patient has either positive ECG changes, OR rise in cardiac biomarkers, OR both. </div>}}<br />
{{familytree |boxstyle=background: #FA8072; color: #F8F8FF; | |!| | | |!| | | |!| | }} <br />
{{familytree |boxstyle=background: #FA8072; color: #F8F8FF; | |!| | | C06 | | |!| | C06= <div style="float: left; text-align: left; width: 17em; padding:1em;">Repeat ECG and biomarkers within next 3 hours and 6 hours <br><br> '''Does the patient still have no ECG changes '''AND''' no rise in cardiac biomarkers?'''</div>}} <br />
{{familytree |boxstyle=background: #FA8072; color: #F8F8FF; | |!| |,|^|-|-|.| |!| }}<br />
{{familytree |boxstyle=background: #FA8072; color: #F8F8FF; | |!| C07 | | C08 |!| C07= <div style="float: left; text-align: left; width: 17em; padding:1em;">Yes. The patient has no ECG changes AND no rise in cardiac biomarkers.</div>| C08= <div style="float: left; text-align: left; width: 17em; padding:1em;">No. The patient has either positive ECG changes, OR rise in cardiac biomarkers, OR both.</div>}}<br />
{{familytree |boxstyle=background: #FA8072; color: #F8F8FF; | |!| |!| | | |!| |!| }}<br />
{{familytree |boxstyle=background: #FA8072; color: #F8F8FF; | |!|C09 | | | C10 | | | C09= <div style="float: left; text-align: left; width: 17em; padding:1em;">[[Chest pain resident survival guide#Complete Diagnostic Approach|Proceed to complete diagnostic approach of chest pain to rule out differential diagnoses]]</div>| C10=<div style="float: left; text-align: left; width: 17em; padding:1em;">{{fontcolor|#000000|''' TRIAGE FOR INITIAL CONSERVATIVE OR INVASIVE THERAPY'''}} <br>'''Calculate the risk of future adverse clinical outcomes:'''<br><br />
❑ [[TIMI risk score|<span style="color:white;">Thrombolysis in Myocardial Infarction (TIMI) risk score</span>]], '''OR'''<br />
❑ [[GRACE score|<span style="color:white;">GRACE score</span>]] </div>}}<br />
{{familytree |boxstyle=background: #FA8072; color: #F8F8FF; | |!| | | |,|-|-|^|.| | }}<br />
{{familytree |boxstyle=background: #FA8072; color: #F8F8FF; | |!| | | C11 | | C12 | C11= '''Intermediate or high risk''' | C12= '''Low risk'''}}<br />
{{familytree |boxstyle=background: #FA8072; color: #F8F8FF; | |!| | | |!| | | |!| | }}<br />
{{familytree |boxstyle=background: #FA8072; color: #F8F8FF; | D01 | | D02 | | D03 | |D01=<div style="float: left; text-align: center; width: 17em; padding:1em;"> '''INITIAL INVASIVE THERAPY (IMMEDIATELY)'''<br></div><br />
| D02= <div style="float: left; text-align: center; width: 17em; padding:1em;">'''INITIAL INVASIVE THERAPY (4 to 48 hours)''' </div>| D03= <div style="float: left; text-align: center; width: 17em; padding:1em;"> '''INITIAL CONSERVATIVE THERAPY ''' </div>}}<br />
{{familytree |boxstyle=background: #FA8072; color: #F8F8FF; | | |!| |!| | | | |!| | }}<br />
{{familytree |boxstyle=background: #FA8072; color: #F8F8FF; | | | E02 | | | | E03 | |E02=<div style="float: left; text-align: left; width: 17em; padding:1em;">'''Initiate ONE of the following anticoagulant therapy (I-A)'''<br> <br />
❑ Enoxaparin (I-A)<br><br />
:❑ SC 1 mg/kg every 12 hours if CrCL≥ 30 mL/min<br />
:❑ SC 1 mg/kg every 12 hours if CrCL< 30 mL/min<br />
:❑ Initial IV 30 mg loading dose in selected patients<br />
'''OR''' <br><br />
❑ IV [[UFH|<span style="color:white;">Unfractionated heparin</span>]] (and adjust dose for apTT) for 48 hours or until PCI is perfomed (I-B)<br><br />
:❑ Initial loading dose 60 IU/kg (max 40,000 IU) <br><br />
:❑ Initial infusion 12 IU/kg/h (max 10,000 IU)<br>'''OR''' <br><br />
❑ [[Bivalirudin|<span style="color:white;">Bivalirudin</span>]] (I-B)<br />
::❑ Loading dose 0.1-mg/kg IV bolus, then 0.25–mg/kg/h infusion<br />
<br>'''OR''' <br><br />
❑ Fondaparinux , SC 2.5 mg daily (I-B)<br />
<br><br>'''PLUS'''<br><br><br />
'''Administer ONE of the following antiplatelet agents (before OR at the time of PCI) (I-A)'''<br><br />
❑ Loading dose of [[P2Y12|<span style="color:white;">P2Y12</span>]] receptor inhibitors <br><br />
:❑ [[Clopidogrel|<span style="color:white;">Clopidogrel</span>]] (I-B if before PCI, I-A if at time of PCI)<br />
::Loading dose: 300 mg or 600 mg<br />
:: Maintenance dose: 75 mg OD<br />
<br>'''OR''' <br><br />
:❑ [[Ticagrelor|<span style="color:white;">Ticagrelor</span>]] (I-B)<br />
::Loading dose: 180 mg<br />
:: Maintenance dose: 90 mg BID<br />
<br>'''OR''' <br><br />
:❑ Prasugrel ONLY AT THE TIME OF PCI, AND NOT PRE-PCI (I-B)<br><br />
::Loading dose: 60 mg<br />
:: Maintenance dose: 10 mg OD<br />
<span style="font-size:85%;">Prasugrel is contraindicated in case of prior history of strokes or TIAs, active pathological bleeding, age ≥75 years, when urgent coronary artery bypass graft surgery (CABG) is likely, body weight <60 kg, propensity to bleed, concomitant use of medications that increase the risk of bleeding</span><br><br><br />
'''Consider adding IV [[GP IIb/IIIa|<span style="color:white;">GP IIb/IIIa</span>]] inhibitors in case of high risk patients (IIb-B)'''<br><br />
❑ [[Eptifibatide|<span style="color:white;">Eptifibatide</span>]]<br><br />
:❑ Loading dose 180 mcg/kg IV bolus followed by another bolus after 10 minutes<br><br />
:❑ Maintenance dose 2 mcg/kg/min<br>'''OR''' <br><br />
❑ [[Tirofiban|<span style="color:white;">Tirofiban</span>]] <br><br />
:❑ Loading dose 25 mcg/kg<br><br />
:❑ Maintenance dose 0.15 mcg/kg/min </div><br />
|E03=<div style="float: left; text-align: left; width: 17em; padding:1em;">'''Initiate ONE of the following anticoagulant therapy (I-A)'''<br><br />
❑ Enoxaparin (I-A)<br>'''OR''' <br><br />
❑ UFH (I-B)<br>'''OR''' <br><br />
❑ Fondaparinux (I-B)<br />
<br />
<br><br> '''PLUS'''<br><br><br />
'''Administer ONE of the following antiplatelet agents (I-B):'''<br><br />
❑ [[P2Y12]] receptor inhibitors <br><br />
:❑ [[Clopidogrel]]<br><br />
::❑ Loading dose (300 mg or 600 mg)<br><br />
::❑ Maintenance dose (75 mg)<br>'''OR''' <br><br />
:❑ [[Ticagrelor]]<br><br />
::❑ Loading dose (180 mg)<br><br />
::❑ Maintenance dose (90 mg twice daily)<br>'''OR''' <br><br />
</div>}}<br />
{{familytree |boxstyle=background: #FA8072; color: #F8F8FF; | | | |!| | | | | |!| | }}<br />
{{familytree |boxstyle=background: #FA8072; color: #F8F8FF; | | | |!| | | | | F01 | |F01=<div style="float: left; text-align: left; width: 17em; padding:1em;">{{fontcolor|#000000|'''TRIAGE FOR NEED OF INVASIVE THERAPY'''}} <br>'''Does the patient experience ANY of the following?''' <br><br />
❑ Recurrence of symptoms, OR<br><br />
❑ [[Heart failure|<span style="color:white;">Heart failure</span>]], OR<br><br />
❑ Serious [[arrhythmia|<span style="color:white;">arrhythmia</span>]], OR<br><br />
❑ Subsequent ischemia</div>}}<br />
{{familytree |boxstyle=background: #FA8072; color: #F8F8FF; | | | |!| |,|-|-|-|^|.| }}<br />
{{familytree |boxstyle=background: #FA8072; color: #F8F8FF; | | | |!| G01 | | G02 | G01= YES| G02= NO}}<br />
{{familytree |boxstyle=background: #FA8072; color: #F8F8FF; | | | |!| |!| | | |!| }}<br />
{{familytree |boxstyle=background: #FA8072; color: #F8F8FF; | | | |!| H01 | | H02 | H01= <div style="float: left; text-align: left; width: 17em; padding:1em;"> '''PROCEED TO INVASIVE THERAPY (I-A)''' <br><br />
'''Administer ONE of the following antiplatelet agents if not already administered (I-A):'''<br><br />
:''The antiplatelet should be administered upstream (I-C)''<br />
❑ [[P2Y12]] receptor inhibitors <br><br />
:❑ [[Clopidogrel]] (I-B)<br><br />
::❑ Loading dose (300 mg or 600 mg)<br><br />
::❑ Maintenance dose (75 mg)<br>'''OR''' <br><br />
:❑ [[Ticagrelor]] (I-B)<br><br />
::❑ Loading dose (180 mg)<br><br />
::❑ Maintenance dose (90 mg twice daily)<br>'''OR''' <br><br />
❑ IV [[GP IIb/IIIa]] inhibitors (I-A)<br><br />
:❑ [[Eptifibatide]]<br><br />
::❑ Loading dose 180 mcg/kg IV bolus followed by another bolus after 10 minutes<br><br />
::❑ Maintenance dose 2 mcg/kg/min<br>'''OR''' <br><br />
:❑ [[Tirofiban]] <br><br />
::❑ Loading dose 25 mcg/kg<br><br />
::❑ Maintenance dose 0.15 mcg/kg/min<br></div><br />
| H02= <div style="float: left; text-align: left; width: 17em; padding:1em;">{{fontcolor|#000000|'''TRIAGE PATIENTS BY RISK ON STRESS TEST'''}} <br>❑ Perform a [[stress test]] (I-B) </div>}}<br />
{{familytree |boxstyle=background: #FA8072; color: #F8F8FF; | | | |!|!| |,|-|-|^|.|}}<br />
{{familytree |boxstyle=background: #FA8072; color: #F8F8FF; | | | |!|!| I01 | | I02 | I01= <div style="float: left; text-align: left; width: 17em; padding:1em;">'''High risk on stress test''' </div>| I02= <div style="float: left; text-align: left; width: 17em; padding:1em;">'''Low risk on stress test OR did not undergo stress test''' </div>}}<br />
{{familytree |boxstyle=background: #FA8072; color: #F8F8FF; | | | |!|!| |!| | | |!| | }}<br />
{{familytree |boxstyle=background: #FA8072; color: #F8F8FF; | | | |!|!| J01 | | |!| | J01= <div style="float: left; text-align: left; width: 17em; padding:1em;"> '''INVASIVE THERAPY''' <br>❑ Perform diagnostic [[angiography]] (I-A) </div>}}<br />
{{familytree |boxstyle=background: #FA8072; color: #F8F8FF; | | | |!|!|!| | | | K01 | K01= <div style="float: left; text-align: left; width: 17em; padding:1em;"> ❑ Continue [[aspirin]] for life (I-A)<br> ❑ Continue [[P2Y12]] receptor inhibitors up to 12 months (I-B)<br><br />
:❑ [[Clopidogrel]] (75 mg once a day)<br>'''OR''' <br><br />
:❑ [[Ticagrelor]] (90 mg twice a day)<br><br />
❑ Discontinue [[GP IIb/IIIa]] inhibitors if administered earlier (I-A)<br><br />
❑ Continue [[antithrombotic]] therapy:<br><br />
:❑ [[UFH]] for 48 hours (I-A)<br>'''OR''' <br><br />
:❑ [[Enoxaparin]] for duration of hospitalization (up to 8 days) (I-A)<br>'''OR''' <br><br />
:❑ [[Fondaparinux]] for duration of hospitalization (up to 8 days) (I-B)<br />
❑ Measure LVEF (I-B)</div>}}<br />
{{familytree |boxstyle=background: #FA8072; color: #F8F8FF; | | | |!|!|!| | | | | |}}<br />
{{familytree |boxstyle=background: #FA8072; color: #F8F8FF; | | | | C01 | | | | | | | | C01= <div style="float: left; text-align: left; width: 17em; padding:1em;">{{fontcolor|#000000|'''TRIAGE FOR SUBSEQUENT THERAPY PLAN FOLLOWING ANGIOGRAPHY'''}} <br> Does the [[angiography]] show coronary vessel obstruction ?</div> }}<br />
{{familytree |boxstyle=background: #FA8072; color: #F8F8FF; | | |,|-|^|-|-|.| | | | | }}<br />
{{familytree |boxstyle=background: #FA8072; color: #F8F8FF; | | D01 | | | | D02 | | | | D01= '''No'''| D02= '''Yes'''}}<br />
{{familytree |boxstyle=background: #FA8072; color: #F8F8FF; | | |!| | | |,|-|^|-|-|-|-|-|.| | | }}<br />
{{familytree |boxstyle=background: #FA8072; color: #F8F8FF; | | |!| | | E01 | | E02 | | E03 | | E01=<div style="float: left; text-align: left; width: 17em; padding:1em;">❑ 1 or 2 vessel disease <br> ''[[CABG]] or medical therapy might also be considered'' </div>|E02=<div style="float: left; text-align: left; width: 17em; padding:1em;">❑ Left main coronary artery disease <br>❑ 3 vessel disease <br>❑ 2 vessel disease with proximal left anterior descending artery affection <br>❑ [[Left ventricular dysfunction]] <br> ❑Patient treated from [[diabetes]]</div>| E03= }}<br />
{{familytree |boxstyle=background: #FA8072; color: #F8F8FF; | | |!| | | |!| | | |!| | | |!| | |}}<br />
{{familytree |boxstyle=background: #FA8072; color: #F8F8FF; | | L03 | | L01 | | L02 | | L03 | | L01= '''[[PCI]]''' <br> <br />
| L02= '''[[CABG]]''' <BR><br />
| L03= '''Medical treatment'''}}<br />
{{familytree |boxstyle=background: #FA8072; color: #F8F8FF; | | |!| | | |!| | | |!| | | |!| | | }}<br />
{{familytree |boxstyle=background: #FA8072; color: #F8F8FF; | | M01 | | M02 | | M03 | | M04 | | M01= <div style="float: left; text-align: left; width: 17em; padding:1em;"><br />
❑ Administer aspirin indefinitely <br><br />
❑ Administer additional antiplatelet therapy ''at the discretion of the physician'' (I-C)<br><br />
❑ Administer anticoagulant therapy ''at the discretion of the physician'' (I-C)</div><br />
|M02= <div style="float: left; text-align: left; width: 17em; padding:1em;"><br />
❑ Administer [[aspirin]] for life (I-B)<br><br />
❑ Initiate/continue [[P2Y12]] receptor inhibitor:<br><br />
:❑ [[Clopidogrel]] (I-B)<br>'''OR''' <br><br />
:❑ [[Ticagrelor]] (I-B)<br>'''OR''' <br><br />
:❑ [[Prasugrel]] (I-B)<br>'''OR''' <br><br />
❑ Initiate/continue [[GPI]] (if not treated with bivalirudin at the time of PCI):<br><br />
: High risk patients without adequate clopidogrel pre-treatment (I-A)<br />
: High risk patients with adequate clopidogrel pre-treatment (I-B)<br />
❑ Initiate/Continue anticoagulant therapy:<br />
:❑ Enoxaparin (I-A)<br />
:❑ UFH (I-B)<br />
:❑ Bivalirudin (I-B)<br />
:❑ Fondaparinux (not as a sole agent)</div><br />
| M03=<div style="float: left; text-align: left; width: 17em; padding:1em;"><br />
❑ Continue [[aspirin]] (I-B)<br><br />
❑ Discontinue IV [[GP IIb/IIIa]] inhibitors (I-B):<br><br />
:❑ Discontinue eptifibatide/tirofiban if started before angiography (2 to 4 hours prior to CABG)<br><br />
:❑ Discontinue abciximab if started before angiography (≥ 12 hours prior to CABG)<br><br />
❑ Manage the P2Y12 receptor inhibitor therapy as follows:<br />
''If CABG can be delayed'':<br><br />
:❑ Discontinue clopidogrel if started before angiography (5 days prior to CABG)<br><br />
:❑ Discontinue ticagrelor if started before angiography (5 days prior to CABG)<br><br />
:❑ Discontinue prasugrel if started before angiography (7 days prior to CABG)<br><br />
''If CABG is urgent'':<br><br />
:❑ Discontinue clopidogrel if started before angiography (up to 24 hours prior to CABG)<br><br />
:❑ Discontinue ticagrelor if started before angiography (up to 24 hours prior to CABG)<br><br />
❑ Manage the [[anticoagulation]] therapy <br><br />
:❑ Continue [[UFH]] (I-B)<br />
:❑ Discontinue [[enoxaparin]] if started before angiography (12-24 hours prior to CABG) and dose with UFH (I-B)<br><br />
:❑ Discontinue [[fondaparinux]] if started before angiography (24 hours prior to CABG) and dose with UFH (I-B)<br><br />
:❑ Discontinue [[bivalirudin]] if started before angiography (3 hours prior to CABG) and dose with UFH (I-B)</div><br />
|M04= <div style="float: left; text-align: left; width: 17em; padding:1em;"> ❑ Continue [[aspirin]] (I-A)<br><br />
❑ Administer a loading dose of [[P2Y12]] receptor inhibitors ''if not given before angiography'' (I-B)<br />
:❑ [[Clopidogrel]] (300 mg or 600 mg)<br>'''OR''' <br><br />
:❑ [[Prasugrel]] (60 mg) <br><br />
❑ Discontinue IV [[GP IIb/IIIa]] inhibitors if started before angiography (I-B)<br><br />
❑ Manage [[antithrombotic]] therapy:<br />
:❑ Continue IV [[UFH]] for at least 48 hours or until discharge if started before angiography (I-A)<br><br />
:❑ Continue [[enoxaparin]] for entire hospital stay, up to 8 days if started before angiography (I-A)<br><br />
:❑ Continue [[fondaparinux]] for entire hospital stay, up to 8 days if started before angiography (I-B)<br><br />
:❑ Discontinue [[bivalirudin]] or continue at 0.25 mg/kg/hour for up to 72 hours (I-B)</div> }}<br />
{{familytree/end}}<br />
<br />
==Complete Diagnostic Approach==<br />
A complete diagnostic approach should be carried out after a focused initial rapid evaluation is conducted and following initiation of any urgent intervention.<ref name="pmid22809746">{{cite journal| author=Jneid H, Anderson JL, Wright RS, Adams CD, Bridges CR, Casey DE et al.| title=2012 ACCF/AHA focused update of the guideline for the management of patients with unstable angina/non-ST-elevation myocardial infarction (updating the 2007 guideline and replacing the 2011 focused update): a report of the American College of Cardiology Foundation/American Heart Association Task Force on Practice Guidelines. | journal=J Am Coll Cardiol | year= 2012 | volume= 60 | issue= 7 | pages= 645-81 | pmid=22809746 | doi=10.1016/j.jacc.2012.06.004 | pmc= | url=http://www.ncbi.nlm.nih.gov/entrez/eutils/elink.fcgi?dbfrom=pubmed&tool=sumsearch.org/cite&retmode=ref&cmd=prlinks&id=22809746 }} </ref><br />
<br />
<span style="font-size:85%"> '''Abbreviations:''' '''CABG:''' [[coronary artery bypass graft]]; '''ECG:''' [[electrocardiogram]]; '''LAD:''' [[LAD|left anterior descending]]; '''LBBB:''' [[left bundle branch block]]; '''MI:''' [[myocardial infarction]]; '''PCI:''' [[percutaneous coronary intervention]]; '''S3:''' [[S3|third heart sound]]; '''S4:''' [[S4|fourth heart sound]]; '''VSD:''' [[ventricular septal defect]] </span><br />
<br />
{{Family tree/start}}<br />
{{familytree | A01 | | A01=<div style="float: left; text-align: left; width: 28em; padding:1em;"> '''Characterize the symptoms:''' <br><br />
❑ [[Chest pain]] or [[chest discomfort]] <br><br />
:❑ Sudden onset<br />
:❑ Sensation of heaviness, tightness, pressure, or squeezing<br />
:❑ Duration> 20 minutes <br><br />
:❑ Radiation to the left arm, jaw, neck, right arm, back or [[epigastrium]]<br />
:❑ No relief with rest <br><br />
:❑ Worse with time <br><br />
:❑ Worse with exertion<br><br />
❑ [[Dyspnea]] <br><br />
❑ [[Weakness]] <br><br />
❑ [[Palpitations]] <br><br />
❑ [[Nausea]] <br><br />
❑ [[Vomiting]] <br><br />
❑ [[Sweating]] <br><br />
❑ [[Loss of consciousness]]<br><br />
❑ [[Fatigue]]<br />
</div>}}<br />
{{familytree | |!| | |}}<br />
{{familytree | B01 | | B01=<div style="float: left; text-align: left; width: 35em; padding:1em;"> '''Obtain a detailed history:''' <br><br />
❑ Age <br><br />
❑ Baseline [[blood pressure]] <br><br />
❑ Previous episodes of [[chest pain]] <br><br />
❑ Previous [[PCI]] or [[CABG]] <br><br />
❑ Cardiac risk factors<br><br />
:❑ [[Hypertension]] <br><br />
:❑ [[Diabetes]] <br><br />
:❑ [[Hypercholesterolemia]] <br><br />
:❑ [[Smoking]] <br><br />
:❑ [[Obesity]] <br><br />
❑ List of medications <br><br />
❑ Family history of premature [[coronary artery disease]]<br />
----<br />
'''Identify possible triggers:'''<br><br />
❑ Physical exertion <br><br />
❑ Air pollution or fine particulate matter <br><br />
❑ Antecedant infection <br><br />
❑ Heavy meal <br><br />
❑ [[Cocaine]] <br><br />
❑ [[Marijuana]]</div>}}<br />
{{familytree | |!| | | }}<br />
{{familytree | C01 | | C01=<div style="float: left; text-align: left; width: 35em; padding:1em;">'''Examine the patient:''' <br><br />
<br />
'''Vital signs''' <br><br />
❑ [[Blood pressure]] <br><br />
:❑ [[Blood pressure]] lower than baseline, suggestive of:<br />
:❑ Discrepancy between arms (suggestive of [[aortic dissection]])<br />
:❑ Narrow [[pulse pressure]] (suggestive of [[heart failure]])<br />
<br />
❑ [[Heart rate]] <br><br />
:❑ [[Tachycardia]] (suggestive of [[heart failure]])<br />
:❑ [[Bradycardia]] (suggestive of [[heart block]] or [[bradyarrhythmias]])<br />
<br />
'''Pulses''' <br><br />
❑ [[Femoral artery|Femoral pulse]] (if a patient is to undergo [[PCI]])<br><br />
:❑ Strength<br />
:❑ [[Bruits]]<br />
<br />
'''Skin''' <br><br />
❑ [[Xanthelasma]] (suggestive of [[dyslipidemia]]) <br><br />
❑ [[Xanthoma]] (suggestive of [[dyslipidemia]]) <br><br />
❑ [[Edema]] (suggestive of [[heart failure]])<br><br />
❑ [[Cyanosis|Cyanotic]] and cold skin, lips, nail bed (suggestive of [[cardiogenic shock]]) <br><br />
<br />
'''Heart''' <br><br />
❑ [[Heart sounds]]<br><br />
:❑ [[S3]] (suggestive of [[heart failure]])<br />
:❑ [[S4]] (associated with conditions that increase the stiffness of the ventricle)<br />
❑ [[Murmurs]]<br />
:❑ [[Aortic regurgitation]]: early diastolic high-pitched sound best heard at the left sternal border (suggestive of [[aortic dissection]] with propagation to the aortic arch)<br />
❑ [[Friction rub|Pericardial friction rub]] (suggestive of [[pericarditis]])<br />
<br />
'''Lungs''' <br><br />
❑ [[Rales]] (suggestive of [[heart failure]]) <br><br />
</div>}}<br />
{{familytree | |!| | }}<br />
{{familytree | E01 | E01= <div style="float: left; width: 28em; text-align: left;">'''Order labs and tests:''' <br><br />
❑ [[EKG]] <br><br />
❑ Biomarkers <br><br />
:❑ Troponin I<br><br />
:❑ CK-MB <br><br />
❑ [[Echocardiography]]<br />
❑ [[Creatinine]] <br><br />
❑ [[Glucose]] <br><br />
❑ [[Hemoglobin]]<br><br />
❑ Multislice CT coronary imaging (rule out [[CAD]] as cause of pain in<br />
patients with low to intermediate likelihood of [[CAD]] and when [[troponin]] and [[ECG]] are<br />
inconclusive)<ref>{{Cite web | last = | first = | title = http://eurheartj.oxfordjournals.org/content/32/23/2999.full.pdf | url = http://eurheartj.oxfordjournals.org/content/32/23/2999.full.pdf | publisher = | date = | accessdate = }}</ref> <br><br />
❑ [[MRI]] (integrate imaging of function, perfusion and necrosis)<ref>{{Cite web | last = | first = | title = http://eurheartj.oxfordjournals.org/content/32/23/2999.full.pdf | url = http://eurheartj.oxfordjournals.org/content/32/23/2999.full.pdf | publisher = | date = | accessdate = }}</ref><br />
</div>}}<br />
{{Family tree/end}}<br />
<br />
==Pre-Discharge Care==<br />
<span style="font-size:85%"> '''Abbreviations:''' '''ACE:''' [[angiotensin converting enzyme]]; '''LVEF:''' [[left ventricular ejection fraction]]; '''PCI:''' [[percutaneous coronary intervention]]; '''PO:''' per os; '''VF:''' [[ventricular fibrillation]]; '''VT:''' [[ventricular tachycardia]] </span><br />
<br />
{{Family tree/start}}<br />
{{familytree | A01 | | |A01= <div style="float: left; text-align: left; width: 30em; padding:1em;">'''Administer the following medications in patients without contraindications:'''<br><br />
❑ [[Aspirin]] 81-325 mg (indefinitely) (I-A)<br><br />
:''Among patients with either GI intolerance or hypersensitivity to aspirin, administer a loading dose followed by maintenance dose of either clopidogrel 75 mg OD (I-B), OR prasugrel 10 mg OD (only in PCI patients) (I-C), OR ticagrelor 90 mg BID (I-C)'' <br><br />
❑ [[Beta blockers]] <br><br />
<span style="font-size:85%;color:red">Contraindicated in heart failure, prolonged or high degree AV block, reactive airway disease, high risk of cardiogenic shock and low cardiac output state</span> :❑ [[Metoprolol tartrate]]<br />
::❑ Begin with 25 to 50 mg PO every 6 to 12 hour<br />
::❑ Then, [[metoprolol tartrate]] twice daily or [[metoprolol succinate]] once daily for 2-3 days<br />
::❑ Titate to 200 mg daily, OR<br />
:❑ [[Carvedilol]]<br />
::❑ Begin with 6.25 mg twice daily<br />
::❑ Titrate to 25 mg twice daily<br />
❑ [[Calcium channel blockers]] are used as anti-ischemic or antihypertensive drugs and also in [[atrial fibrillation]] when [[beta blockers]] are contraindicated <br><br />
<span style="font-size:85%;color:red">Contraindicated in heart failure and left ventricular dysfunction</span> <br><br />
❑ [[ACE]] inhibitors and [[ARBs]] may also be considered in selected patients (no enough information)<ref name="www.ncbi.nlm.nih.gov">{{Cite web | last = | first = | title = Therapeutic effects of captopril on ischemia and ... [Am Heart J. 1994] - PubMed - NCBI | url = http://www.ncbi.nlm.nih.gov/pubmed?term=8273728 | publisher = | date = | accessdate = }}</ref><br />
<br><br />
<span style="font-size:85%;color:red">Contraindicated in hypotension, renal failure and hyperkalemia</span> <br><br />
❑ [[Atorvastatin]] 80 mg daily<br />
----<br />
'''Administer ONE of the following antiplatelet therapy for a duration of:'''<br />
: '''Up to 12 months in medically treated with no stenting (I-B)'''<br />
: '''Up to 12 months in BMS (I-B)'''<br />
: '''At least 12 months in DES (I-B)'''<br />
❑ [[Clopidogrel]] 75 mg daily, OR <br><br />
❑ [[Ticagrelor]] 90 mg twice a day, OR <br><br />
❑ [[Prasugrel]] 10 mg daily '''only for patients who underwent PCI'''<br><br />
<br><br />
<br />
<span style="font-size:85%;color:red">Consider earlier discontinuation in case bleeding risk exceeds benefit of the antiplatelet therapy (I-C).</span> <br><br />
----<br />
'''Assess the patient for ischemia:'''<br><br />
❑ Perform non invasive testing before discharge for the evaluation of ischemia among patients who did not undergo [[coronary angiography]] and in whom [[coronary angiography]] is not warranted due to the absence of high risk features ([[ACC AHA guidelines classification scheme|Class I, level of evidence B]]) <br><br />
❑ Assess the [[LVEF]] ([[ACC AHA guidelines classification scheme|Class I, level of evidence C]])<br />
</div>}}<br />
{{familytree/end}}<br />
<br />
<br />
<span style="font-size:85%"> '''Abbreviations:''' '''ACE:''' [[angiotensin converting enzyme]]; '''ARB:''' [[angiotensin receptor blocker]];</span><br />
<br />
{{Family tree/start}}<br />
{{familytree | A01 | | A01= <div style="float: left; text-align: left; width: 30em; padding:1em;"> ❑ Prepare a list of all the home medications and educate the patient about compliance<br />
:❑ [[Aspirin]] 81-325 mg (indefinitely) <br />
:❑ [[Antiplatelet drug|Antiplatelet therapy]]<br />
:❑ [[Beta blockers]]<br />
:❑ [[ACE inhibitors]] or [[ARB]] (only in selected patients <ref name="ACE">{{Cite web | last = | first = | title = Therapeutic effects of captopril on ischemia and ... [Am Heart J. 1994] - PubMed - NCBI | url = http://www.ncbi.nlm.nih.gov/pubmed?term=8273728 | publisher = | date = | accessdate = }}</ref><br />
<br />
:❑ [[Atorvastatin]] 80 mg daily<br />
❑ Encourage lifestyle modification <br><br />
:❑ [[Smoking]] cessation<br />
:❑ Physical activity<br />
:❑ Dietary changes<br />
❑ Ensure the initiation of the management of comorbidities<br />
:❑ [[Obesity]]<br />
:❑ [[Dyslipidemia]]<br />
:❑ [[Hypertension]]<br />
:❑ [[Diabetes]]<br />
:❑ [[Heart failure]]<br />
❑ Educate the patient about the early recognition of symptoms of [[acute coronary syndrome]]<br />
❑ Educate the patient about the use of [[nitroglycerin]] 0.4 mg, sublingually, up to 3 doses every 5 minutes </div> }}<br />
{{Family tree/end}}<br />
<br />
==Do's==<br />
* Administer a loading dose followed by a maintenance dose of [[clopidogrel]], [[ticagrelor]] or [[prasugrel]] (if [[PCI]] is planned) as initial treatment instead of [[aspirin]] among patients with gastrointestinal intolerance or hypersensitivity reaction to [[aspirin]].<br />
<br />
* Administer sublingual [[nitroglycerin]] in patients with ischemic [[chest pain]]; however, administer IV [[nitroglycerin]] among patients with persistent [[chest pain]] after three sublingual [[nitroglycerin]].<ref name="pmid6402912">{{cite journal| author=Kaplan K, Davison R, Parker M, Przybylek J, Teagarden JR, Lesch M| title=Intravenous nitroglycerin for the treatment of angina at rest unresponsive to standard nitrate therapy. | journal=Am J Cardiol | year= 1983 | volume= 51 | issue= 5 | pages= 694-8 | pmid=6402912 | doi= | pmc= | url=http://www.ncbi.nlm.nih.gov/entrez/eutils/elink.fcgi?dbfrom=pubmed&tool=sumsearch.org/cite&retmode=ref&cmd=prlinks&id=6402912 }} </ref><br />
<br />
*Discontinue [[NSAID]] drugs immediately. <ref name="pmid21224324">{{cite journal| author=Trelle S, Reichenbach S, Wandel S, Hildebrand P, Tschannen B, Villiger PM et al.| title=Cardiovascular safety of non-steroidal anti-inflammatory drugs: network meta-analysis. | journal=BMJ | year= 2011 | volume= 342 | issue= | pages= c7086 | pmid=21224324 | doi=10.1136/bmj.c7086 | pmc=PMC3019238 | url=http://www.ncbi.nlm.nih.gov/entrez/eutils/elink.fcgi?dbfrom=pubmed&tool=sumsearch.org/cite&retmode=ref&cmd=prlinks&id=21224324 }} [http://www.ncbi.nlm.nih.gov/entrez/eutils/elink.fcgi?dbfrom=pubmed&tool=sumsearch.org/cite&retmode=ref&cmd=prlinks&id=21460398 Review in: Evid Based Med. 2011 Oct;16(5):142-3] </ref> <ref name="pmid23726390">{{cite journal| author=Coxib and traditional NSAID Trialists' (CNT) Collaboration. Bhala N, Emberson J, Merhi A, Abramson S, Arber N et al.| title=Vascular and upper gastrointestinal effects of non-steroidal anti-inflammatory drugs: meta-analyses of individual participant data from randomised trials. | journal=Lancet | year= 2013 | volume= 382 | issue= 9894 | pages= 769-79 | pmid=23726390 | doi=10.1016/S0140-6736(13)60900-9 | pmc=PMC3778977 | url=http://www.ncbi.nlm.nih.gov/entrez/eutils/elink.fcgi?dbfrom=pubmed&tool=sumsearch.org/cite&retmode=ref&cmd=prlinks&id=23726390 }} [http://www.ncbi.nlm.nih.gov/entrez/eutils/elink.fcgi?dbfrom=pubmed&tool=sumsearch.org/cite&retmode=ref&cmd=prlinks&id=24126661 Review in: Ann Intern Med. 2013 Oct 15;159(8):JC12] </ref><br />
<br />
* If fondaparinux is chosen to be administered ad the anticoagulant therapy during PCI, co-administer another antocoagulant with factor IIa activity such as UFH.<br />
<br />
==Don'ts==<br />
* Do not administer IV [[GP IIb/IIIa inhibitors]] to patients with low risk of ischemic events or at high risk of [[bleeding]] and who are already on [[aspirin]] and P2Y12 receptor inhibitors therapy.<br />
<br />
* Do not administer [[prasugrel]] among patients with prior history of [[strokes]] or [[TIAs]].<br />
<br />
* Do not administer IV [[beta-blockers]] among hemodynamically unstable patients.<br />
<br />
* Do not administer a complete dose of [[prasugrel]] among patients under 60kg (132lbs) due to high exposure to the active metabolite. They should receive half the dose of [[prasugrel]] although there is no evidence that half the dose is as effective as a complete dose.<br />
<br />
* Do not administer fibrinolytic therapy to patients with [[unstable angina]].<ref name="pmid7475596">{{cite journal| author=Anderson HV| title=Intravenous thrombolysis in refractory unstable angina pectoris. | journal=Lancet | year= 1995 | volume= 346 | issue= 8983 | pages= 1113-4 | pmid=7475596 | doi= | pmc= | url=http://www.ncbi.nlm.nih.gov/entrez/eutils/elink.fcgi?dbfrom=pubmed&tool=sumsearch.org/cite&retmode=ref&cmd=prlinks&id=7475596 }} </ref><br />
<br />
*Do not administer [[abciximab]] for patients not scheduled for [[PCI]]. <ref name="pmid22809746">{{cite journal| author=Jneid H, Anderson JL, Wright RS, Adams CD, Bridges CR, Casey DE et al.| title=2012 ACCF/AHA focused update of the guideline for the management of patients with unstable angina/non-ST-elevation myocardial infarction (updating the 2007 guideline and replacing the 2011 focused update): a report of the American College of Cardiology Foundation/American Heart Association Task Force on Practice Guidelines. | journal=J Am Coll Cardiol | year= 2012 | volume= 60 | issue= 7 | pages= 645-81 | pmid=22809746 | doi=10.1016/j.jacc.2012.06.004 | pmc= | url=http://www.ncbi.nlm.nih.gov/entrez/eutils/elink.fcgi?dbfrom=pubmed&tool=sumsearch.org/cite&retmode=ref&cmd=prlinks&id=22809746 }} </ref><br />
<br />
* Do not administer 2 P2Y12 receptor inhibitors, even in the presence of hypersensitivity or GI interoperability to aspirin.<br />
<br />
==References==<br />
{{reflist|2}}<br />
<br />
[[Category:Emergency medicine]]<br />
[[Category:Medicine]]<br />
[[Category:Resident survival guide]]<br />
[[Category:Cardiology]]<br />
<br />
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{{WikiDoc Sources}}<br />
</div></div>Rim Halabyhttps://www.wikidoc.org/index.php?title=Unstable_angina/_NSTEMI_resident_survival_guide&diff=1088082Unstable angina/ NSTEMI resident survival guide2015-04-15T20:55:22Z<p>Rim Halaby: /* FIRE: Focused Initial Rapid Evaluation */</p>
<hr />
<div><div style="width: 80%;"><br />
__NOTOC__<br />
{{CMG}}; {{AE}} {{ATS}}; {{Rim}}<br />
<br />
{| class="infobox" style="margin: 0 0 0 0; border: 0; float: right; width: 100px; background: #A8A8A8; position: fixed; top: 250px; right: 21px; border-radius: 0 0 10px 10px;" cellpadding="0" cellspacing="0";<br />
|-<br />
! style="padding: 0 5px; font-size: 85%; background: #A8A8A8" align=center| {{fontcolor|#2B3B44|Unstable angina/ NSTEMI Resident Survival Guide Microchapters}}<br />
|-<br />
! style="font-size: 80%; padding: 0 5px; background: #DCDCDC" align=left | [[Unstable angina/ NSTEMI resident survival guide#Overview|Overview]]<br />
|-<br />
! style="font-size: 80%; padding: 0 5px; background: #DCDCDC" align=left | [[Unstable angina/ NSTEMI resident survival guide#Causes|Causes]]<br />
|-<br />
! style="font-size: 80%; padding: 0 5px; background: #DCDCDC" align=left | [[Unstable angina/ NSTEMI resident survival guide#FIRE: Focused Initial Rapid Evaluation|FIRE]]<br />
|-<br />
! style="font-size: 80%; padding: 0 5px; background: #DCDCDC" align=left | [[Unstable angina/ NSTEMI resident survival guide#Complete Diagnostic Approach|Diagnosis]]<br />
|-<br />
! style="font-size: 80%; padding: 0 5px; background: #DCDCDC" align=left | [[Unstable angina/ NSTEMI resident survival guide#Treatment|Treatment]]<br />
: [[Unstable angina/ NSTEMI resident survival guide#Management Following Angiography|Management Following Angiography]]<br />
|-<br />
! style="font-size: 80%; padding: 0 5px; background: #DCDCDC" align=left | [[Unstable angina/ NSTEMI resident survival guide#Pre-Discharge Care|Pre-Discharge Care]]<br />
|-<br />
! style="font-size: 80%; padding: 0 5px; background: #DCDCDC" align=left | [[Unstable angina/ NSTEMI resident survival guide#Long Term Managemnet|Long Term Management]]<br />
|-<br />
! style="font-size: 80%; padding: 0 5px; background: #DCDCDC" align=left | [[Unstable angina/ NSTEMI resident survival guide#Do's|Do's]]<br />
|-<br />
! style="font-size: 80%; padding: 0 5px; background: #DCDCDC" align=left | [[Unstable angina/ NSTEMI resident survival guide#Don'ts|Don'ts]]<br />
|}<br />
<br />
==Overview==<br />
[[Unstable angina]] and [[non ST elevation myocardial infarction]] ([[NSTEMI]]) belong to two different ends of the spectrum of [[acute coronary syndrome]]. These conditions have a similar clinical presentation characterized by an acute onset of chest pain that starts on minimal exertion, rest or sleep, lasts at least 20 minutes (but usually less that half an hour) and, is not relieved by medications or rest. [[NSTEMI]] is differentiated from [[unstable angina]] by the presence of elevated cardiac biomarkers secondary to myocardial injury. [[Unstabel angina]] and [[NSTEMI]] might not be differentiated early following the occurrence of symptoms because [[cardiac biomarker]]s may require a few hours to rise.<br />
<br />
==Causes==<br />
<br />
===Life Threatening Causes===<br />
Life-threatening causes include conditions which may result in death or permanent disability within 24 hours if left untreated. [[Unstable angina]] and [[NSTEMI]] are life-threatening conditions and must be treated as such irrespective of the causes.<br />
<br />
===Common Causes===<br />
====Myocardial Infarction====<br />
* [[Atherosclerotic]] [[plaque rupture]] and subsequent [[coronary thrombus]] (most common cause)<br />
* [[Coronary artery spasm]]<br />
* [[Arrhythmia]]<br />
* [[MI|Post-myocardial infarction]]<br />
* [[PCI|Post-percutaneous coronary intervention]]<br />
** [[Abrupt closure]]<br />
** [[PCI complications: loss of side branch|Loss of side branch]]<br />
** [[Distal embolization]]<br />
** [[PCI complications: restenosis|Restenosis]]<br />
**[[Stent thrombosis]]<br />
* [[CABG|Post-coronary artery bypass graft]]<br />
** Graft closure<br />
** New lesion in the graft<br />
<br />
''For a complete list of causes, click [[Unstable angina pathophysiology|here]] for unstable angina and [[Non ST elevation myocardial infarction pathophysiology|here]] for NSTEMI.''<br />
<br />
==FIRE: Focused Initial Rapid Evaluation==<br />
A Focused Initial Rapid Evaluation (FIRE) should be performed to identify patients in need of immediate intervention based on the 2012 ACCF/AHA focused update of the guideline for the management of patients with unstable angina/non-ST-elevation myocardial infarction.<ref name="pmid22809746">{{cite journal| author=Jneid H, Anderson JL, Wright RS, Adams CD, Bridges CR, Casey DE et al.| title=2012 ACCF/AHA focused update of the guideline for the management of patients with unstable angina/non-ST-elevation myocardial infarction (updating the 2007 guideline and replacing the 2011 focused update): a report of the American College of Cardiology Foundation/American Heart Association Task Force on Practice Guidelines. | journal=J Am Coll Cardiol | year= 2012 | volume= 60 | issue= 7 | pages= 645-81 | pmid=22809746 | doi=10.1016/j.jacc.2012.06.004 | pmc= | url=http://www.ncbi.nlm.nih.gov/entrez/eutils/elink.fcgi?dbfrom=pubmed&tool=sumsearch.org/cite&retmode=ref&cmd=prlinks&id=22809746 }} </ref> An invasive strategy is defined as diagnostic angiography with the intention of revascularization.<br />
<br />
<span style="font-size:85%">Boxes in the red color signify that an urgent management is needed.</span><br />
{{Family tree/start}}<br />
{{familytree |boxstyle=background: #FA8072; color: #F8F8FF; | | | | A00 | | A00=<div style="float: left; text-align: left; width: 17em; padding:1em;"> '''Identify cardinal findings of unstable angina/ NSTEMI :''' <br><br />
❑ '''[[Chest pain|<span style="color:white;"> Chest pain</span>]] or [[chest discomfort|<span style="color:white;">chest discomfort</span>]]''' <br><br />
:❑ Sudden onset<br />
:❑ Sensation of heaviness, tightness, pressure, or squeezing<br />
:❑ Duration> 20 minutes (but usually less than half an hour) <br><br />
:❑ Radiation to the left arm, jaw, neck, right arm, back or [[epigastrium|<span style="color:white;">epigastrium</span>]]<br />
:❑ No relief with medications<br><br />
:❑ No relief with rest <br><br />
:❑ Worse with time <br><br />
:❑ Worse with exertion<br><br />
:❑ Associated symptoms of [[palpitations|<span style="color:white;">palpitations</span>]], [[nausea|<span style="color:white;">nausea</span>]], [[vomiting|<span style="color:white;">vomiting</span>]], [[sweating|<span style="color:white;">sweating</span>]], [[dyspnea|<span style="color:white;">dyspnea</span>]], and [[lightheadedness|<span style="color:white;">lightheadedness</span>]]<br><br />
❑ '''Characteristic [[ECG|<span style="color:white;">ECG</span>]] changes consistent with [[unstable angina|<span style="color:white;">unstable angina</span>]]/ [[NSTEMI|<span style="color:white;">NSTEMI</span>]] '''<br />
:❑ No changes <br><br />
:❑ Non specific ST / T wave changes <br> <br />
:❑ Flipped or inverted T waves <br><br />
:❑ ST depression (carries the poorest prognosis) <br><br />
❑ '''Increase in >99th percentile of upper limit of normal of [[troponin|<span style="color:white;">troponin</span>]] and / or [[CKMB|<span style="color:white;">CK MB</span>]]''', which is consistent with [[NSTEMI|<span style="color:white;">NSTEMI</span>]]</div>}}<br />
{{familytree |boxstyle=background: #FA8072; color: #F8F8FF; | | | | |!| | | }}<br />
{{familytree |boxstyle=background: #FA8072; color: #F8F8FF; | | | | G02 | G02= <div style="float: left; text-align: left; width: 17em; padding:1em;"> '''Rule out life threatening alternative diagnoses:'''<br><br />
❑ [[Aortic dissection|<span style="color:white;">Aortic dissection</span>]] <br> (suggestive findings: [[back pain|<span style="color:white;">back pain</span>]], [[interscapular pain|<span style="color:white;">interscapular pain</span>]], [[aortic regurgitation|<span style="color:white;">aortic regurgitation</span>]], [[pulsus paradoxus|<span style="color:white;">pulsus paradoxus</span>]], [[blood pressure|<span style="color:white;">blood pressure</span>]] discrepancy between the arms) <br><br />
❑ [[Pulmonary embolism|<span style="color:white;">Pulmonary embolism</span>]] <br> (suggestive findings: acute onset of [[dyspnea|<span style="color:white;">dyspnea</span>]], [[tachypnea|<span style="color:white;">tachypnea</span>]], [[hemoptysis|<span style="color:white;">hemoptysis</span>]], previous [[DVT|<span style="color:white;">DVT</span>]]) <br><br />
❑ [[Cardiac tamponade|<span style="color:white;">Cardiac tamponade</span>]] <br> (suggestive findings: [[hypotension|<span style="color:white;">hypotension</span>]], [[jugular venous distention|<span style="color:white;">jugular venous distention</span>]], [[muffled heart sounds|<span style="color:white;">muffled heart sounds</span>]], [[pulsus paradoxus|<span style="color:white;">pulsus paradoxus</span>]])<br><br />
❑ [[Tension pneumothorax|<span style="color:white;">Tension pneumothorax</span>]] <br> (suggestive findings: sudden [[dyspnea|<span style="color:white;">dyspnea</span>]], [[tachycardia|<span style="color:white;">tachycardia</span>]], [[trauma|<span style="color:white;">chest trauma</span>]], unilateral absence of [[breath sounds|<span style="color:white;">breath sound</span>]])<br><br />
❑ [[Esophageal rupture|<span style="color:white;">Esophageal rupture</span>]] <br> (suggestive findings: [[vomiting|<span style="color:white;">vomiting</span>]], [[subcutaneous emphysema|<span style="color:white;">subcutaneous emphysema</span>]])</div>}}<br />
{{familytree |boxstyle=background: #FA8072; color: #F8F8FF; | | | | |!| | | }}<br />
{{familytree |boxstyle=background: #FA8072; color: #F8F8FF; | | | | A01 | | | | | A01= <div style="float: left; text-align: left; width: 17em; padding:1em;">'''Begin initial treatment:'''<br> <br />
❑ Administer 162 to 325 mg of non enteric [[aspirin|<span style="color:white;">aspirin</span>]],orally, crushed or chewed (I-A)<br />
:''Among patients with either GI intolerance or hypersensitivity to aspirin, administer a loading dose (75 mg) followed by maintenance dose of clopidogrel (I-B)''<br />
❑ Administer 2-4 L/min [[oxygen|<span style="color:white;">oxygen</span>]] via nasal cannula when saturation <90% (I-C)<br />
:''Caution in [[COPD|<span style="color:white;">COPD</span>]] patients: maintain an oxygen saturation between 88% and 92%.''<br />
❑ Administer [[nitroglycerin|<span style="color:white;">nitroglycerin</span>]]<br />
:❑ Administer sublingual nitroglycerin (0.3 to 0.4 mg, every 5 minutes for a total of 3 doses) then assess for further need to IV nitroglycerin (I-C)<br />
:❑ Administer IV nitroglyerin in case of persistent chest pain despite PO nitroglycerin, heart failure, or hypertenion (I-B): 10 mcg/min, increase by 10 mcg/min every 3 to 5 minutes until symptom relief; in case no response at 20 mcg/min, can increase by 10 mcg/min and then by 20 mcg/min<br />
<span style="font-size:85%;">Contraindicated in suspected [[RVMI|<span style="color:white;">right ventricular MI</span>]], recent use of [[phosphodiesterase inhibitors|<span style="color:white;">phosphodiesterase inhibitors</span>]], decreased [[blood pressure|<span style="color:white;">blood pressure</span>]] 30 mmHg below baseline</span> <br><br />
❑ Administer [[beta-blockers|<span style="color:white;">beta-blockers</span>]] (unless contraindicated) and titrate to the [[heart rate|<span style="color:white;">heart rate</span>]] and [[blood pressure|<span style="color:white;">blood pressure</span>]] (I-A)<br><br />
: ''PO in general, IV if patient has hypertension or ongoing pain''<br />
: ''Beta blocker is contraindicated in heart failure and high risk of cardiogenic shock.''<br />
:❑ [[Metoprolol|<span style="color:white;">Metoprolol</span>]]:<br />
:PO: 25 to 50 mg every 6 hours<br />
:IV: 5 mg every 5 min, up to 3 doses, then 25 to 50 mg orally every 6 hours<br />
:❑ [[Carvedilol|<span style="color:white;">Carvedilol</span>]] IV, 25 mg, two times a day<br />
<span style="font-size:85%;">Contraindicated in [[heart failure|<span style="color:white;">heart failure</span>]], bradycardia, hypotension (SBP<90 mmHg), [[AV block |<span style="color:white;">second or third degree AV block</span>]], [[reactive airway disease|<span style="color:white;">reactive airway disease</span>]], high risk of [[cardiogenic shock|<span style="color:white;">cardiogenic shock</span>]] and low [[cardiac output|<span style="color:white;">cardiac output</span>]] state</span> <br><br />
❑ Administer IV [[morphine|<span style="color:white;">morphine</span>]] if persistent symptoms (IIb-B) or [[pulmonary edema|<span style="color:white;">pulmonary edema</span>]]<br />
:❑ Initial dose 4-8 mg<br />
:❑ 2-8 mg every 5 to 15 minutes, as needed <br><br />
❑ Administer 80 mg [[atorvastatin|<span style="color:white;">atorvastatin</span>]] (I-A)<br><br />
❑ Monitor with a 12-lead [[ECG|<span style="color:white;">ECG</span>]] all the time<br />
</div>}}<br />
{{familytree |boxstyle=background: #FA8072; color: #F8F8FF; | | | | |!| | | }}<br />
{{familytree |boxstyle=background: #FA8072; color: #F8F8FF; | | | | G01 | G01= <div style="float: left; text-align: left; width: 17em; padding:1em;"> {{fontcolor|#000000|'''TRIAGE FOR IMMEDIATE INTERVENTION'''}} <br>'''Does the patient have ANY of the following indications that require immediate angiography and revascularization ?'''<br />
❑ Hemodynamic instability or [[cardiogenic shock|<span style="color:white;">cardiogenic shock</span>]], '''OR''' <br><br />
❑ Severe left ventricular dysfunction or [[heart failure|<span style="color:white;">heart failure</span>]], '''OR''' <br><br />
❑ Recurrent or persistent rest angina despite intensive medical therapy, '''OR''' <br><br />
❑ New or worsening [[mitral regurgitation|<span style="color:white;">mitral regurgitation</span>]] or new [[VSD|<span style="color:white;">VSD</span>]], '''OR''' <br><br />
❑ Sustained [[VT|<span style="color:white;">VT</span>]] or [[VF|<span style="color:white;">VF</span>]], '''OR''' <br><br />
❑ Prior [[PCI|<span style="color:white;">PCI</span>]] within past 6 months or [[CABG|<span style="color:white;">CABG</span>]] <br> </div> }}<br />
{{familytree |boxstyle=background: #FA8072; color: #F8F8FF; | |,|-|-|^|-|-|.| | }}<br />
{{familytree |boxstyle=background: #FA8072; color: #F8F8FF; | C01 | | | | C02 | | | C01=<div style="float: left; text-align: center; width: 17em; padding:1em;">'''YES''' </div>| C02= <div style="float: left; text-align: center; width: 17em; padding:1em;">'''NO''' </div> }}<br />
{{familytree |boxstyle=background: #FA8072; color: #F8F8FF; | |!| | | | | |!| | | | }}<br />
{{familytree |boxstyle=background: #FA8072; color: #F8F8FF; | |!| | | | | C03 | | | C03=<div style="float: left; text-align: left; width: 17em; padding:1em;">Does the patient have no ECG changes '''AND''' no rise in cardiac biomarkers > 99th percentile of ULN?</div>}}<br />
{{familytree |boxstyle=background: #FA8072; color: #F8F8FF; | |!| | | |,|-|^|-|.| | }}<br />
{{familytree |boxstyle=background: #FA8072; color: #F8F8FF; | |!| | | C04 | | C05 | C04= <div style="float: left; text-align: left; width: 17em; padding:1em;">Yes. The patient has no ECG changes AND no rise in cardiac biomarkers > 99th percentile of ULN. </div>| C05= <div style="float: left; text-align: left; width: 17em; padding:1em;">No. The patient has either positive ECG changes, OR rise in cardiac biomarkers, OR both. </div>}}<br />
{{familytree |boxstyle=background: #FA8072; color: #F8F8FF; | |!| | | |!| | | |!| | }} <br />
{{familytree |boxstyle=background: #FA8072; color: #F8F8FF; | |!| | | C06 | | |!| | C06= <div style="float: left; text-align: left; width: 17em; padding:1em;">Repeat ECG and biomarkers within next 3 hours and 6 hours <br><br> '''Does the patient still have no ECG changes '''AND''' no rise in cardiac biomarkers?'''</div>}} <br />
{{familytree |boxstyle=background: #FA8072; color: #F8F8FF; | |!| |,|^|-|-|.| |!| }}<br />
{{familytree |boxstyle=background: #FA8072; color: #F8F8FF; | |!| C07 | | C08 |!| C07= <div style="float: left; text-align: left; width: 17em; padding:1em;">Yes. The patient has no ECG changes AND no rise in cardiac biomarkers.</div>| C08= <div style="float: left; text-align: left; width: 17em; padding:1em;">No. The patient has either positive ECG changes, OR rise in cardiac biomarkers, OR both.</div>}}<br />
{{familytree |boxstyle=background: #FA8072; color: #F8F8FF; | |!| |!| | | |!| |!| }}<br />
{{familytree |boxstyle=background: #FA8072; color: #F8F8FF; | |!|C09 | | | C10 | | | C09= <div style="float: left; text-align: left; width: 17em; padding:1em;">[[Chest pain resident survival guide#Complete Diagnostic Approach|Proceed to complete diagnostic approach of chest pain to rule out differential diagnoses]]</div>| C10=<div style="float: left; text-align: left; width: 17em; padding:1em;">{{fontcolor|#000000|''' TRIAGE FOR INITIAL CONSERVATIVE OR INVASIVE THERAPY'''}} <br>'''Calculate the risk of future adverse clinical outcomes:'''<br><br />
❑ [[TIMI risk score|<span style="color:white;">Thrombolysis in Myocardial Infarction (TIMI) risk score</span>]], '''OR'''<br />
❑ [[GRACE score|<span style="color:white;">GRACE score</span>]] </div>}}<br />
{{familytree |boxstyle=background: #FA8072; color: #F8F8FF; | |!| | | |,|-|-|^|.| | }}<br />
{{familytree |boxstyle=background: #FA8072; color: #F8F8FF; | |!| | | C11 | | C12 | C11= '''Intermediate or high risk''' | C12= '''Low risk'''}}<br />
{{familytree |boxstyle=background: #FA8072; color: #F8F8FF; | |!| | | |!| | | |!| | }}<br />
{{familytree |boxstyle=background: #FA8072; color: #F8F8FF; | D01 | | D02 | | D03 | |D01=<div style="float: left; text-align: center; width: 17em; padding:1em;"> '''INITIAL INVASIVE THERAPY (IMMEDIATELY)'''<br></div><br />
| D02= <div style="float: left; text-align: center; width: 17em; padding:1em;">'''INITIAL INVASIVE THERAPY (4 to 48 hours)''' </div>| D03= <div style="float: left; text-align: center; width: 17em; padding:1em;"> '''INITIAL CONSERVATIVE THERAPY ''' </div>}}<br />
{{familytree |boxstyle=background: #FA8072; color: #F8F8FF; | | |!| |!| | | | |!| | }}<br />
{{familytree |boxstyle=background: #FA8072; color: #F8F8FF; | | | E02 | | | | E03 | |E02=<div style="float: left; text-align: left; width: 17em; padding:1em;">'''Initiate ONE of the following anticoagulant therapy (I-A)'''<br> <br />
❑ Enoxaparin (I-A)<br><br />
:❑ SC 1 mg/kg every 12 hours if CrCL≥ 30 mL/min<br />
:❑ SC 1 mg/kg every 12 hours if CrCL< 30 mL/min<br />
:❑ Initial IV 30 mg loading dose in selected patients<br />
'''OR''' <br><br />
❑ IV [[UFH|<span style="color:white;">Unfractionated heparin</span>]] (and adjust dose for apTT) for 48 hours or until PCI is perfomed (I-B)<br><br />
:❑ Initial loading dose 60 IU/kg (max 40,000 IU) <br><br />
:❑ Initial infusion 12 IU/kg/h (max 10,000 IU)<br>'''OR''' <br><br />
❑ [[Bivalirudin|<span style="color:white;">Bivalirudin</span>]] (I-B)<br />
::❑ Loading dose 0.1-mg/kg IV bolus, then 0.25–mg/kg/h infusion<br />
<br>'''OR''' <br><br />
❑ Fondaparinux , SC 2.5 mg daily (I-B)<br />
<br><br>'''PLUS'''<br><br><br />
'''Administer ONE of the following antiplatelet agents (before OR at the time of PCI) (I-A)'''<br><br />
❑ Loading dose of [[P2Y12|<span style="color:white;">P2Y12</span>]] receptor inhibitors <br><br />
:❑ [[Clopidogrel|<span style="color:white;">Clopidogrel</span>]] (I-B if before PCI, I-A if at time of PCI)<br />
::Loading dose: 300 mg or 600 mg<br />
:: Maintenance dose: 75 mg OD<br />
<br>'''OR''' <br><br />
:❑ [[Ticagrelor|<span style="color:white;">Ticagrelor</span>]] (I-B)<br />
::Loading dose: 180 mg<br />
:: Maintenance dose: 90 mg BID<br />
<br>'''OR''' <br><br />
:❑ Prasugrel ONLY AT THE TIME OF PCI, AND NOT PRE-PCI (I-B)<br><br />
::Loading dose: 60 mg<br />
:: Maintenance dose: 10 mg OD<br />
<span style="font-size:85%;">Prasugrel is contraindicated in case of prior history of strokes or TIAs, active pathological bleeding, age ≥75 years, when urgent coronary artery bypass graft surgery (CABG) is likely, body weight <60 kg, propensity to bleed, concomitant use of medications that increase the risk of bleeding</span><br><br><br />
'''Consider adding IV [[GP IIb/IIIa|<span style="color:white;">GP IIb/IIIa</span>]] inhibitors in case of high risk patients (IIb-B)'''<br><br />
❑ [[Eptifibatide|<span style="color:white;">Eptifibatide</span>]]<br><br />
:❑ Loading dose 180 mcg/kg IV bolus followed by another bolus after 10 minutes<br><br />
:❑ Maintenance dose 2 mcg/kg/min<br>'''OR''' <br><br />
❑ [[Tirofiban|<span style="color:white;">Tirofiban</span>]] <br><br />
:❑ Loading dose 25 mcg/kg<br><br />
:❑ Maintenance dose 0.15 mcg/kg/min </div><br />
|E03=<div style="float: left; text-align: left; width: 17em; padding:1em;">'''Initiate ONE of the following anticoagulant therapy (I-A)'''<br><br />
❑ Enoxaparin (I-A)<br>'''OR''' <br><br />
❑ UFH (I-A)<br>'''OR''' <br><br />
❑ Fondaparinux (I-B)<br>'''OR''' <br><br />
:''Enoxaparin or fondaparinux preferred over UFH (II-B)''<br />
<br><br> '''PLUS'''<br><br><br />
'''Administer ONE of the following antiplatelet agents (I-B):'''<br><br />
❑ [[P2Y12]] receptor inhibitors <br><br />
:❑ [[Clopidogrel]]<br><br />
::❑ Loading dose (300 mg or 600 mg)<br><br />
::❑ Maintenance dose (75 mg)<br>'''OR''' <br><br />
:❑ [[Ticagrelor]]<br><br />
::❑ Loading dose (180 mg)<br><br />
::❑ Maintenance dose (90 mg twice daily)<br>'''OR''' <br><br />
</div>}}<br />
{{familytree |boxstyle=background: #FA8072; color: #F8F8FF; | | | |!| | | | | |!| | }}<br />
{{familytree |boxstyle=background: #FA8072; color: #F8F8FF; | | | |!| | | | | F01 | |F01=<div style="float: left; text-align: left; width: 17em; padding:1em;">{{fontcolor|#000000|'''TRIAGE FOR NEED OF INVASIVE THERAPY'''}} <br>'''Does the patient experience ANY of the following?''' <br><br />
❑ Recurrence of symptoms, OR<br><br />
❑ [[Heart failure|<span style="color:white;">Heart failure</span>]], OR<br><br />
❑ Serious [[arrhythmia|<span style="color:white;">arrhythmia</span>]], OR<br><br />
❑ Subsequent ischemia</div>}}<br />
{{familytree |boxstyle=background: #FA8072; color: #F8F8FF; | | | |!| |,|-|-|-|^|.| }}<br />
{{familytree |boxstyle=background: #FA8072; color: #F8F8FF; | | | |!| G01 | | G02 | G01= YES| G02= NO}}<br />
{{familytree |boxstyle=background: #FA8072; color: #F8F8FF; | | | |!| |!| | | |!| }}<br />
{{familytree |boxstyle=background: #FA8072; color: #F8F8FF; | | | |!| H01 | | H02 | H01= <div style="float: left; text-align: left; width: 17em; padding:1em;"> '''PROCEED TO INVASIVE THERAPY (I-A)''' <br><br />
'''Administer ONE of the following antiplatelet agents if not already administered (I-A):'''<br><br />
:''The antiplatelet should be administered upstream (I-C)''<br />
❑ [[P2Y12]] receptor inhibitors <br><br />
:❑ [[Clopidogrel]] (I-B)<br><br />
::❑ Loading dose (300 mg or 600 mg)<br><br />
::❑ Maintenance dose (75 mg)<br>'''OR''' <br><br />
:❑ [[Ticagrelor]] (I-B)<br><br />
::❑ Loading dose (180 mg)<br><br />
::❑ Maintenance dose (90 mg twice daily)<br>'''OR''' <br><br />
❑ IV [[GP IIb/IIIa]] inhibitors (I-A)<br><br />
:❑ [[Eptifibatide]]<br><br />
::❑ Loading dose 180 mcg/kg IV bolus followed by another bolus after 10 minutes<br><br />
::❑ Maintenance dose 2 mcg/kg/min<br>'''OR''' <br><br />
:❑ [[Tirofiban]] <br><br />
::❑ Loading dose 25 mcg/kg<br><br />
::❑ Maintenance dose 0.15 mcg/kg/min<br></div><br />
| H02= <div style="float: left; text-align: left; width: 17em; padding:1em;">{{fontcolor|#000000|'''TRIAGE PATIENTS BY RISK ON STRESS TEST'''}} <br>❑ Perform a [[stress test]] (I-B) </div>}}<br />
{{familytree |boxstyle=background: #FA8072; color: #F8F8FF; | | | |!|!| |,|-|-|^|.|}}<br />
{{familytree |boxstyle=background: #FA8072; color: #F8F8FF; | | | |!|!| I01 | | I02 | I01= <div style="float: left; text-align: left; width: 17em; padding:1em;">'''High risk on stress test''' </div>| I02= <div style="float: left; text-align: left; width: 17em; padding:1em;">'''Low risk on stress test OR did not undergo stress test''' </div>}}<br />
{{familytree |boxstyle=background: #FA8072; color: #F8F8FF; | | | |!|!| |!| | | |!| | }}<br />
{{familytree |boxstyle=background: #FA8072; color: #F8F8FF; | | | |!|!| J01 | | |!| | J01= <div style="float: left; text-align: left; width: 17em; padding:1em;"> '''INVASIVE THERAPY''' <br>❑ Perform diagnostic [[angiography]] (I-A) </div>}}<br />
{{familytree |boxstyle=background: #FA8072; color: #F8F8FF; | | | |!|!|!| | | | K01 | K01= <div style="float: left; text-align: left; width: 17em; padding:1em;"> ❑ Continue [[aspirin]] for life (I-A)<br> ❑ Continue [[P2Y12]] receptor inhibitors up to 12 months (I-B)<br><br />
:❑ [[Clopidogrel]] (75 mg once a day)<br>'''OR''' <br><br />
:❑ [[Ticagrelor]] (90 mg twice a day)<br><br />
❑ Discontinue [[GP IIb/IIIa]] inhibitors if administered earlier (I-A)<br><br />
❑ Continue [[antithrombotic]] therapy:<br><br />
:❑ [[UFH]] for 48 hours (I-A)<br>'''OR''' <br><br />
:❑ [[Enoxaparin]] for duration of hospitalization (up to 8 days) (I-A)<br>'''OR''' <br><br />
:❑ [[Fondaparinux]] for duration of hospitalization (up to 8 days) (I-B)<br />
❑ Measure LVEF (I-B)</div>}}<br />
{{familytree |boxstyle=background: #FA8072; color: #F8F8FF; | | | |!|!|!| | | | | |}}<br />
{{familytree |boxstyle=background: #FA8072; color: #F8F8FF; | | | | C01 | | | | | | | | C01= <div style="float: left; text-align: left; width: 17em; padding:1em;">{{fontcolor|#000000|'''TRIAGE FOR SUBSEQUENT THERAPY PLAN FOLLOWING ANGIOGRAPHY'''}} <br> Does the [[angiography]] show coronary vessel obstruction ?</div> }}<br />
{{familytree |boxstyle=background: #FA8072; color: #F8F8FF; | | |,|-|^|-|-|.| | | | | }}<br />
{{familytree |boxstyle=background: #FA8072; color: #F8F8FF; | | D01 | | | | D02 | | | | D01= '''No'''| D02= '''Yes'''}}<br />
{{familytree |boxstyle=background: #FA8072; color: #F8F8FF; | | |!| | | |,|-|^|-|-|-|-|-|.| | | }}<br />
{{familytree |boxstyle=background: #FA8072; color: #F8F8FF; | | |!| | | E01 | | E02 | | E03 | | E01=<div style="float: left; text-align: left; width: 17em; padding:1em;">❑ 1 or 2 vessel disease <br> ''[[CABG]] or medical therapy might also be considered'' </div>|E02=<div style="float: left; text-align: left; width: 17em; padding:1em;">❑ Left main coronary artery disease <br>❑ 3 vessel disease <br>❑ 2 vessel disease with proximal left anterior descending artery affection <br>❑ [[Left ventricular dysfunction]] <br> ❑Patient treated from [[diabetes]]</div>| E03= }}<br />
{{familytree |boxstyle=background: #FA8072; color: #F8F8FF; | | |!| | | |!| | | |!| | | |!| | |}}<br />
{{familytree |boxstyle=background: #FA8072; color: #F8F8FF; | | L03 | | L01 | | L02 | | L03 | | L01= '''[[PCI]]''' <br> <br />
| L02= '''[[CABG]]''' <BR><br />
| L03= '''Medical treatment'''}}<br />
{{familytree |boxstyle=background: #FA8072; color: #F8F8FF; | | |!| | | |!| | | |!| | | |!| | | }}<br />
{{familytree |boxstyle=background: #FA8072; color: #F8F8FF; | | M01 | | M02 | | M03 | | M04 | | M01= <div style="float: left; text-align: left; width: 17em; padding:1em;"><br />
❑ Administer aspirin indefinitely <br><br />
❑ Administer additional antiplatelet therapy ''at the discretion of the physician'' (I-C)<br><br />
❑ Administer anticoagulant therapy ''at the discretion of the physician'' (I-C)</div><br />
|M02= <div style="float: left; text-align: left; width: 17em; padding:1em;"><br />
❑ Administer [[aspirin]] for life (I-B)<br><br />
❑ Initiate/continue [[P2Y12]] receptor inhibitor:<br><br />
:❑ [[Clopidogrel]] (I-B)<br>'''OR''' <br><br />
:❑ [[Ticagrelor]] (I-B)<br>'''OR''' <br><br />
:❑ [[Prasugrel]] (I-B)<br>'''OR''' <br><br />
❑ Initiate/continue [[GPI]] (if not treated with bivalirudin at the time of PCI):<br><br />
: High risk patients without adequate clopidogrel pre-treatment (I-A)<br />
: High risk patients with adequate clopidogrel pre-treatment (I-B)<br />
❑ Initiate/Continue anticoagulant therapy:<br />
:❑ Enoxaparin (I-A)<br />
:❑ UFH (I-B)<br />
:❑ Bivalirudin (I-B)<br />
:❑ Fondaparinux (not as a sole agent)</div><br />
| M03=<div style="float: left; text-align: left; width: 17em; padding:1em;"><br />
❑ Continue [[aspirin]] (I-B)<br><br />
❑ Discontinue IV [[GP IIb/IIIa]] inhibitors (I-B):<br><br />
:❑ Discontinue eptifibatide/tirofiban if started before angiography (2 to 4 hours prior to CABG)<br><br />
:❑ Discontinue abciximab if started before angiography (≥ 12 hours prior to CABG)<br><br />
❑ Manage the P2Y12 receptor inhibitor therapy as follows:<br />
''If CABG can be delayed'':<br><br />
:❑ Discontinue clopidogrel if started before angiography (5 days prior to CABG)<br><br />
:❑ Discontinue ticagrelor if started before angiography (5 days prior to CABG)<br><br />
:❑ Discontinue prasugrel if started before angiography (7 days prior to CABG)<br><br />
''If CABG is urgent'':<br><br />
:❑ Discontinue clopidogrel if started before angiography (up to 24 hours prior to CABG)<br><br />
:❑ Discontinue ticagrelor if started before angiography (up to 24 hours prior to CABG)<br><br />
❑ Manage the [[anticoagulation]] therapy <br><br />
:❑ Continue [[UFH]] (I-B)<br />
:❑ Discontinue [[enoxaparin]] if started before angiography (12-24 hours prior to CABG) and dose with UFH (I-B)<br><br />
:❑ Discontinue [[fondaparinux]] if started before angiography (24 hours prior to CABG) and dose with UFH (I-B)<br><br />
:❑ Discontinue [[bivalirudin]] if started before angiography (3 hours prior to CABG) and dose with UFH (I-B)</div><br />
|M04= <div style="float: left; text-align: left; width: 17em; padding:1em;"> ❑ Continue [[aspirin]] (I-A)<br><br />
❑ Administer a loading dose of [[P2Y12]] receptor inhibitors ''if not given before angiography'' (I-B)<br />
:❑ [[Clopidogrel]] (300 mg or 600 mg)<br>'''OR''' <br><br />
:❑ [[Prasugrel]] (60 mg) <br><br />
❑ Discontinue IV [[GP IIb/IIIa]] inhibitors if started before angiography (I-B)<br><br />
❑ Manage [[antithrombotic]] therapy:<br />
:❑ Continue IV [[UFH]] for at least 48 hours or until discharge if started before angiography (I-A)<br><br />
:❑ Continue [[enoxaparin]] for entire hospital stay, up to 8 days if started before angiography (I-A)<br><br />
:❑ Continue [[fondaparinux]] for entire hospital stay, up to 8 days if started before angiography (I-B)<br><br />
:❑ Discontinue [[bivalirudin]] or continue at 0.25 mg/kg/hour for up to 72 hours (I-B)</div> }}<br />
{{familytree/end}}<br />
<br />
==Complete Diagnostic Approach==<br />
A complete diagnostic approach should be carried out after a focused initial rapid evaluation is conducted and following initiation of any urgent intervention.<ref name="pmid22809746">{{cite journal| author=Jneid H, Anderson JL, Wright RS, Adams CD, Bridges CR, Casey DE et al.| title=2012 ACCF/AHA focused update of the guideline for the management of patients with unstable angina/non-ST-elevation myocardial infarction (updating the 2007 guideline and replacing the 2011 focused update): a report of the American College of Cardiology Foundation/American Heart Association Task Force on Practice Guidelines. | journal=J Am Coll Cardiol | year= 2012 | volume= 60 | issue= 7 | pages= 645-81 | pmid=22809746 | doi=10.1016/j.jacc.2012.06.004 | pmc= | url=http://www.ncbi.nlm.nih.gov/entrez/eutils/elink.fcgi?dbfrom=pubmed&tool=sumsearch.org/cite&retmode=ref&cmd=prlinks&id=22809746 }} </ref><br />
<br />
<span style="font-size:85%"> '''Abbreviations:''' '''CABG:''' [[coronary artery bypass graft]]; '''ECG:''' [[electrocardiogram]]; '''LAD:''' [[LAD|left anterior descending]]; '''LBBB:''' [[left bundle branch block]]; '''MI:''' [[myocardial infarction]]; '''PCI:''' [[percutaneous coronary intervention]]; '''S3:''' [[S3|third heart sound]]; '''S4:''' [[S4|fourth heart sound]]; '''VSD:''' [[ventricular septal defect]] </span><br />
<br />
{{Family tree/start}}<br />
{{familytree | A01 | | A01=<div style="float: left; text-align: left; width: 28em; padding:1em;"> '''Characterize the symptoms:''' <br><br />
❑ [[Chest pain]] or [[chest discomfort]] <br><br />
:❑ Sudden onset<br />
:❑ Sensation of heaviness, tightness, pressure, or squeezing<br />
:❑ Duration> 20 minutes <br><br />
:❑ Radiation to the left arm, jaw, neck, right arm, back or [[epigastrium]]<br />
:❑ No relief with rest <br><br />
:❑ Worse with time <br><br />
:❑ Worse with exertion<br><br />
❑ [[Dyspnea]] <br><br />
❑ [[Weakness]] <br><br />
❑ [[Palpitations]] <br><br />
❑ [[Nausea]] <br><br />
❑ [[Vomiting]] <br><br />
❑ [[Sweating]] <br><br />
❑ [[Loss of consciousness]]<br><br />
❑ [[Fatigue]]<br />
</div>}}<br />
{{familytree | |!| | |}}<br />
{{familytree | B01 | | B01=<div style="float: left; text-align: left; width: 35em; padding:1em;"> '''Obtain a detailed history:''' <br><br />
❑ Age <br><br />
❑ Baseline [[blood pressure]] <br><br />
❑ Previous episodes of [[chest pain]] <br><br />
❑ Previous [[PCI]] or [[CABG]] <br><br />
❑ Cardiac risk factors<br><br />
:❑ [[Hypertension]] <br><br />
:❑ [[Diabetes]] <br><br />
:❑ [[Hypercholesterolemia]] <br><br />
:❑ [[Smoking]] <br><br />
:❑ [[Obesity]] <br><br />
❑ List of medications <br><br />
❑ Family history of premature [[coronary artery disease]]<br />
----<br />
'''Identify possible triggers:'''<br><br />
❑ Physical exertion <br><br />
❑ Air pollution or fine particulate matter <br><br />
❑ Antecedant infection <br><br />
❑ Heavy meal <br><br />
❑ [[Cocaine]] <br><br />
❑ [[Marijuana]]</div>}}<br />
{{familytree | |!| | | }}<br />
{{familytree | C01 | | C01=<div style="float: left; text-align: left; width: 35em; padding:1em;">'''Examine the patient:''' <br><br />
<br />
'''Vital signs''' <br><br />
❑ [[Blood pressure]] <br><br />
:❑ [[Blood pressure]] lower than baseline, suggestive of:<br />
:❑ Discrepancy between arms (suggestive of [[aortic dissection]])<br />
:❑ Narrow [[pulse pressure]] (suggestive of [[heart failure]])<br />
<br />
❑ [[Heart rate]] <br><br />
:❑ [[Tachycardia]] (suggestive of [[heart failure]])<br />
:❑ [[Bradycardia]] (suggestive of [[heart block]] or [[bradyarrhythmias]])<br />
<br />
'''Pulses''' <br><br />
❑ [[Femoral artery|Femoral pulse]] (if a patient is to undergo [[PCI]])<br><br />
:❑ Strength<br />
:❑ [[Bruits]]<br />
<br />
'''Skin''' <br><br />
❑ [[Xanthelasma]] (suggestive of [[dyslipidemia]]) <br><br />
❑ [[Xanthoma]] (suggestive of [[dyslipidemia]]) <br><br />
❑ [[Edema]] (suggestive of [[heart failure]])<br><br />
❑ [[Cyanosis|Cyanotic]] and cold skin, lips, nail bed (suggestive of [[cardiogenic shock]]) <br><br />
<br />
'''Heart''' <br><br />
❑ [[Heart sounds]]<br><br />
:❑ [[S3]] (suggestive of [[heart failure]])<br />
:❑ [[S4]] (associated with conditions that increase the stiffness of the ventricle)<br />
❑ [[Murmurs]]<br />
:❑ [[Aortic regurgitation]]: early diastolic high-pitched sound best heard at the left sternal border (suggestive of [[aortic dissection]] with propagation to the aortic arch)<br />
❑ [[Friction rub|Pericardial friction rub]] (suggestive of [[pericarditis]])<br />
<br />
'''Lungs''' <br><br />
❑ [[Rales]] (suggestive of [[heart failure]]) <br><br />
</div>}}<br />
{{familytree | |!| | }}<br />
{{familytree | E01 | E01= <div style="float: left; width: 28em; text-align: left;">'''Order labs and tests:''' <br><br />
❑ [[EKG]] <br><br />
❑ Biomarkers <br><br />
:❑ Troponin I<br><br />
:❑ CK-MB <br><br />
❑ [[Echocardiography]]<br />
❑ [[Creatinine]] <br><br />
❑ [[Glucose]] <br><br />
❑ [[Hemoglobin]]<br><br />
❑ Multislice CT coronary imaging (rule out [[CAD]] as cause of pain in<br />
patients with low to intermediate likelihood of [[CAD]] and when [[troponin]] and [[ECG]] are<br />
inconclusive)<ref>{{Cite web | last = | first = | title = http://eurheartj.oxfordjournals.org/content/32/23/2999.full.pdf | url = http://eurheartj.oxfordjournals.org/content/32/23/2999.full.pdf | publisher = | date = | accessdate = }}</ref> <br><br />
❑ [[MRI]] (integrate imaging of function, perfusion and necrosis)<ref>{{Cite web | last = | first = | title = http://eurheartj.oxfordjournals.org/content/32/23/2999.full.pdf | url = http://eurheartj.oxfordjournals.org/content/32/23/2999.full.pdf | publisher = | date = | accessdate = }}</ref><br />
</div>}}<br />
{{Family tree/end}}<br />
<br />
==Pre-Discharge Care==<br />
<span style="font-size:85%"> '''Abbreviations:''' '''ACE:''' [[angiotensin converting enzyme]]; '''LVEF:''' [[left ventricular ejection fraction]]; '''PCI:''' [[percutaneous coronary intervention]]; '''PO:''' per os; '''VF:''' [[ventricular fibrillation]]; '''VT:''' [[ventricular tachycardia]] </span><br />
<br />
{{Family tree/start}}<br />
{{familytree | A01 | | |A01= <div style="float: left; text-align: left; width: 30em; padding:1em;">'''Administer the following medications in patients without contraindications:'''<br><br />
❑ [[Aspirin]] 81-325 mg (indefinitely) (I-A)<br><br />
:''Among patients with either GI intolerance or hypersensitivity to aspirin, administer a loading dose followed by maintenance dose of either clopidogrel 75 mg OD (I-B), OR prasugrel 10 mg OD (only in PCI patients) (I-C), OR ticagrelor 90 mg BID (I-C)'' <br><br />
❑ [[Beta blockers]] <br><br />
<span style="font-size:85%;color:red">Contraindicated in heart failure, prolonged or high degree AV block, reactive airway disease, high risk of cardiogenic shock and low cardiac output state</span> :❑ [[Metoprolol tartrate]]<br />
::❑ Begin with 25 to 50 mg PO every 6 to 12 hour<br />
::❑ Then, [[metoprolol tartrate]] twice daily or [[metoprolol succinate]] once daily for 2-3 days<br />
::❑ Titate to 200 mg daily, OR<br />
:❑ [[Carvedilol]]<br />
::❑ Begin with 6.25 mg twice daily<br />
::❑ Titrate to 25 mg twice daily<br />
❑ [[Calcium channel blockers]] are used as anti-ischemic or antihypertensive drugs and also in [[atrial fibrillation]] when [[beta blockers]] are contraindicated <br><br />
<span style="font-size:85%;color:red">Contraindicated in heart failure and left ventricular dysfunction</span> <br><br />
❑ [[ACE]] inhibitors and [[ARBs]] may also be considered in selected patients (no enough information)<ref name="www.ncbi.nlm.nih.gov">{{Cite web | last = | first = | title = Therapeutic effects of captopril on ischemia and ... [Am Heart J. 1994] - PubMed - NCBI | url = http://www.ncbi.nlm.nih.gov/pubmed?term=8273728 | publisher = | date = | accessdate = }}</ref><br />
<br><br />
<span style="font-size:85%;color:red">Contraindicated in hypotension, renal failure and hyperkalemia</span> <br><br />
❑ [[Atorvastatin]] 80 mg daily<br />
----<br />
'''Administer ONE of the following antiplatelet therapy for a duration of:'''<br />
: '''Up to 12 months in medically treated with no stenting (I-B)'''<br />
: '''Up to 12 months in BMS (I-B)'''<br />
: '''At least 12 months in DES (I-B)'''<br />
❑ [[Clopidogrel]] 75 mg daily, OR <br><br />
❑ [[Ticagrelor]] 90 mg twice a day, OR <br><br />
❑ [[Prasugrel]] 10 mg daily '''only for patients who underwent PCI'''<br><br />
<br><br />
<br />
<span style="font-size:85%;color:red">Consider earlier discontinuation in case bleeding risk exceeds benefit of the antiplatelet therapy (I-C).</span> <br><br />
----<br />
'''Assess the patient for ischemia:'''<br><br />
❑ Perform non invasive testing before discharge for the evaluation of ischemia among patients who did not undergo [[coronary angiography]] and in whom [[coronary angiography]] is not warranted due to the absence of high risk features ([[ACC AHA guidelines classification scheme|Class I, level of evidence B]]) <br><br />
❑ Assess the [[LVEF]] ([[ACC AHA guidelines classification scheme|Class I, level of evidence C]])<br />
</div>}}<br />
{{familytree/end}}<br />
<br />
<br />
<span style="font-size:85%"> '''Abbreviations:''' '''ACE:''' [[angiotensin converting enzyme]]; '''ARB:''' [[angiotensin receptor blocker]];</span><br />
<br />
{{Family tree/start}}<br />
{{familytree | A01 | | A01= <div style="float: left; text-align: left; width: 30em; padding:1em;"> ❑ Prepare a list of all the home medications and educate the patient about compliance<br />
:❑ [[Aspirin]] 81-325 mg (indefinitely) <br />
:❑ [[Antiplatelet drug|Antiplatelet therapy]]<br />
:❑ [[Beta blockers]]<br />
:❑ [[ACE inhibitors]] or [[ARB]] (only in selected patients <ref name="ACE">{{Cite web | last = | first = | title = Therapeutic effects of captopril on ischemia and ... [Am Heart J. 1994] - PubMed - NCBI | url = http://www.ncbi.nlm.nih.gov/pubmed?term=8273728 | publisher = | date = | accessdate = }}</ref><br />
<br />
:❑ [[Atorvastatin]] 80 mg daily<br />
❑ Encourage lifestyle modification <br><br />
:❑ [[Smoking]] cessation<br />
:❑ Physical activity<br />
:❑ Dietary changes<br />
❑ Ensure the initiation of the management of comorbidities<br />
:❑ [[Obesity]]<br />
:❑ [[Dyslipidemia]]<br />
:❑ [[Hypertension]]<br />
:❑ [[Diabetes]]<br />
:❑ [[Heart failure]]<br />
❑ Educate the patient about the early recognition of symptoms of [[acute coronary syndrome]]<br />
❑ Educate the patient about the use of [[nitroglycerin]] 0.4 mg, sublingually, up to 3 doses every 5 minutes </div> }}<br />
{{Family tree/end}}<br />
<br />
==Do's==<br />
* Administer a loading dose followed by a maintenance dose of [[clopidogrel]], [[ticagrelor]] or [[prasugrel]] (if [[PCI]] is planned) as initial treatment instead of [[aspirin]] among patients with gastrointestinal intolerance or hypersensitivity reaction to [[aspirin]].<br />
<br />
* Administer sublingual [[nitroglycerin]] in patients with ischemic [[chest pain]]; however, administer IV [[nitroglycerin]] among patients with persistent [[chest pain]] after three sublingual [[nitroglycerin]].<ref name="pmid6402912">{{cite journal| author=Kaplan K, Davison R, Parker M, Przybylek J, Teagarden JR, Lesch M| title=Intravenous nitroglycerin for the treatment of angina at rest unresponsive to standard nitrate therapy. | journal=Am J Cardiol | year= 1983 | volume= 51 | issue= 5 | pages= 694-8 | pmid=6402912 | doi= | pmc= | url=http://www.ncbi.nlm.nih.gov/entrez/eutils/elink.fcgi?dbfrom=pubmed&tool=sumsearch.org/cite&retmode=ref&cmd=prlinks&id=6402912 }} </ref><br />
<br />
*Discontinue [[NSAID]] drugs immediately. <ref name="pmid21224324">{{cite journal| author=Trelle S, Reichenbach S, Wandel S, Hildebrand P, Tschannen B, Villiger PM et al.| title=Cardiovascular safety of non-steroidal anti-inflammatory drugs: network meta-analysis. | journal=BMJ | year= 2011 | volume= 342 | issue= | pages= c7086 | pmid=21224324 | doi=10.1136/bmj.c7086 | pmc=PMC3019238 | url=http://www.ncbi.nlm.nih.gov/entrez/eutils/elink.fcgi?dbfrom=pubmed&tool=sumsearch.org/cite&retmode=ref&cmd=prlinks&id=21224324 }} [http://www.ncbi.nlm.nih.gov/entrez/eutils/elink.fcgi?dbfrom=pubmed&tool=sumsearch.org/cite&retmode=ref&cmd=prlinks&id=21460398 Review in: Evid Based Med. 2011 Oct;16(5):142-3] </ref> <ref name="pmid23726390">{{cite journal| author=Coxib and traditional NSAID Trialists' (CNT) Collaboration. Bhala N, Emberson J, Merhi A, Abramson S, Arber N et al.| title=Vascular and upper gastrointestinal effects of non-steroidal anti-inflammatory drugs: meta-analyses of individual participant data from randomised trials. | journal=Lancet | year= 2013 | volume= 382 | issue= 9894 | pages= 769-79 | pmid=23726390 | doi=10.1016/S0140-6736(13)60900-9 | pmc=PMC3778977 | url=http://www.ncbi.nlm.nih.gov/entrez/eutils/elink.fcgi?dbfrom=pubmed&tool=sumsearch.org/cite&retmode=ref&cmd=prlinks&id=23726390 }} [http://www.ncbi.nlm.nih.gov/entrez/eutils/elink.fcgi?dbfrom=pubmed&tool=sumsearch.org/cite&retmode=ref&cmd=prlinks&id=24126661 Review in: Ann Intern Med. 2013 Oct 15;159(8):JC12] </ref><br />
<br />
* If fondaparinux is chosen to be administered ad the anticoagulant therapy during PCI, co-administer another antocoagulant with factor IIa activity such as UFH.<br />
<br />
==Don'ts==<br />
* Do not administer IV [[GP IIb/IIIa inhibitors]] to patients with low risk of ischemic events or at high risk of [[bleeding]] and who are already on [[aspirin]] and P2Y12 receptor inhibitors therapy.<br />
<br />
* Do not administer [[prasugrel]] among patients with prior history of [[strokes]] or [[TIAs]].<br />
<br />
* Do not administer IV [[beta-blockers]] among hemodynamically unstable patients.<br />
<br />
* Do not administer a complete dose of [[prasugrel]] among patients under 60kg (132lbs) due to high exposure to the active metabolite. They should receive half the dose of [[prasugrel]] although there is no evidence that half the dose is as effective as a complete dose.<br />
<br />
* Do not administer fibrinolytic therapy to patients with [[unstable angina]].<ref name="pmid7475596">{{cite journal| author=Anderson HV| title=Intravenous thrombolysis in refractory unstable angina pectoris. | journal=Lancet | year= 1995 | volume= 346 | issue= 8983 | pages= 1113-4 | pmid=7475596 | doi= | pmc= | url=http://www.ncbi.nlm.nih.gov/entrez/eutils/elink.fcgi?dbfrom=pubmed&tool=sumsearch.org/cite&retmode=ref&cmd=prlinks&id=7475596 }} </ref><br />
<br />
*Do not administer [[abciximab]] for patients not scheduled for [[PCI]]. <ref name="pmid22809746">{{cite journal| author=Jneid H, Anderson JL, Wright RS, Adams CD, Bridges CR, Casey DE et al.| title=2012 ACCF/AHA focused update of the guideline for the management of patients with unstable angina/non-ST-elevation myocardial infarction (updating the 2007 guideline and replacing the 2011 focused update): a report of the American College of Cardiology Foundation/American Heart Association Task Force on Practice Guidelines. | journal=J Am Coll Cardiol | year= 2012 | volume= 60 | issue= 7 | pages= 645-81 | pmid=22809746 | doi=10.1016/j.jacc.2012.06.004 | pmc= | url=http://www.ncbi.nlm.nih.gov/entrez/eutils/elink.fcgi?dbfrom=pubmed&tool=sumsearch.org/cite&retmode=ref&cmd=prlinks&id=22809746 }} </ref><br />
<br />
* Do not administer 2 P2Y12 receptor inhibitors, even in the presence of hypersensitivity or GI interoperability to aspirin.<br />
<br />
==References==<br />
{{reflist|2}}<br />
<br />
[[Category:Emergency medicine]]<br />
[[Category:Medicine]]<br />
[[Category:Resident survival guide]]<br />
[[Category:Cardiology]]<br />
<br />
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{{WikiDoc Sources}}<br />
</div></div>Rim Halabyhttps://www.wikidoc.org/index.php?title=Unstable_angina/_NSTEMI_resident_survival_guide&diff=1088077Unstable angina/ NSTEMI resident survival guide2015-04-15T20:40:49Z<p>Rim Halaby: /* FIRE: Focused Initial Rapid Evaluation */</p>
<hr />
<div><div style="width: 80%;"><br />
__NOTOC__<br />
{{CMG}}; {{AE}} {{ATS}}; {{Rim}}<br />
<br />
{| class="infobox" style="margin: 0 0 0 0; border: 0; float: right; width: 100px; background: #A8A8A8; position: fixed; top: 250px; right: 21px; border-radius: 0 0 10px 10px;" cellpadding="0" cellspacing="0";<br />
|-<br />
! style="padding: 0 5px; font-size: 85%; background: #A8A8A8" align=center| {{fontcolor|#2B3B44|Unstable angina/ NSTEMI Resident Survival Guide Microchapters}}<br />
|-<br />
! style="font-size: 80%; padding: 0 5px; background: #DCDCDC" align=left | [[Unstable angina/ NSTEMI resident survival guide#Overview|Overview]]<br />
|-<br />
! style="font-size: 80%; padding: 0 5px; background: #DCDCDC" align=left | [[Unstable angina/ NSTEMI resident survival guide#Causes|Causes]]<br />
|-<br />
! style="font-size: 80%; padding: 0 5px; background: #DCDCDC" align=left | [[Unstable angina/ NSTEMI resident survival guide#FIRE: Focused Initial Rapid Evaluation|FIRE]]<br />
|-<br />
! style="font-size: 80%; padding: 0 5px; background: #DCDCDC" align=left | [[Unstable angina/ NSTEMI resident survival guide#Complete Diagnostic Approach|Diagnosis]]<br />
|-<br />
! style="font-size: 80%; padding: 0 5px; background: #DCDCDC" align=left | [[Unstable angina/ NSTEMI resident survival guide#Treatment|Treatment]]<br />
: [[Unstable angina/ NSTEMI resident survival guide#Management Following Angiography|Management Following Angiography]]<br />
|-<br />
! style="font-size: 80%; padding: 0 5px; background: #DCDCDC" align=left | [[Unstable angina/ NSTEMI resident survival guide#Pre-Discharge Care|Pre-Discharge Care]]<br />
|-<br />
! style="font-size: 80%; padding: 0 5px; background: #DCDCDC" align=left | [[Unstable angina/ NSTEMI resident survival guide#Long Term Managemnet|Long Term Management]]<br />
|-<br />
! style="font-size: 80%; padding: 0 5px; background: #DCDCDC" align=left | [[Unstable angina/ NSTEMI resident survival guide#Do's|Do's]]<br />
|-<br />
! style="font-size: 80%; padding: 0 5px; background: #DCDCDC" align=left | [[Unstable angina/ NSTEMI resident survival guide#Don'ts|Don'ts]]<br />
|}<br />
<br />
==Overview==<br />
[[Unstable angina]] and [[non ST elevation myocardial infarction]] ([[NSTEMI]]) belong to two different ends of the spectrum of [[acute coronary syndrome]]. These conditions have a similar clinical presentation characterized by an acute onset of chest pain that starts on minimal exertion, rest or sleep, lasts at least 20 minutes (but usually less that half an hour) and, is not relieved by medications or rest. [[NSTEMI]] is differentiated from [[unstable angina]] by the presence of elevated cardiac biomarkers secondary to myocardial injury. [[Unstabel angina]] and [[NSTEMI]] might not be differentiated early following the occurrence of symptoms because [[cardiac biomarker]]s may require a few hours to rise.<br />
<br />
==Causes==<br />
<br />
===Life Threatening Causes===<br />
Life-threatening causes include conditions which may result in death or permanent disability within 24 hours if left untreated. [[Unstable angina]] and [[NSTEMI]] are life-threatening conditions and must be treated as such irrespective of the causes.<br />
<br />
===Common Causes===<br />
====Myocardial Infarction====<br />
* [[Atherosclerotic]] [[plaque rupture]] and subsequent [[coronary thrombus]] (most common cause)<br />
* [[Coronary artery spasm]]<br />
* [[Arrhythmia]]<br />
* [[MI|Post-myocardial infarction]]<br />
* [[PCI|Post-percutaneous coronary intervention]]<br />
** [[Abrupt closure]]<br />
** [[PCI complications: loss of side branch|Loss of side branch]]<br />
** [[Distal embolization]]<br />
** [[PCI complications: restenosis|Restenosis]]<br />
**[[Stent thrombosis]]<br />
* [[CABG|Post-coronary artery bypass graft]]<br />
** Graft closure<br />
** New lesion in the graft<br />
<br />
''For a complete list of causes, click [[Unstable angina pathophysiology|here]] for unstable angina and [[Non ST elevation myocardial infarction pathophysiology|here]] for NSTEMI.''<br />
<br />
==FIRE: Focused Initial Rapid Evaluation==<br />
A Focused Initial Rapid Evaluation (FIRE) should be performed to identify patients in need of immediate intervention based on the 2012 ACCF/AHA focused update of the guideline for the management of patients with unstable angina/non-ST-elevation myocardial infarction.<ref name="pmid22809746">{{cite journal| author=Jneid H, Anderson JL, Wright RS, Adams CD, Bridges CR, Casey DE et al.| title=2012 ACCF/AHA focused update of the guideline for the management of patients with unstable angina/non-ST-elevation myocardial infarction (updating the 2007 guideline and replacing the 2011 focused update): a report of the American College of Cardiology Foundation/American Heart Association Task Force on Practice Guidelines. | journal=J Am Coll Cardiol | year= 2012 | volume= 60 | issue= 7 | pages= 645-81 | pmid=22809746 | doi=10.1016/j.jacc.2012.06.004 | pmc= | url=http://www.ncbi.nlm.nih.gov/entrez/eutils/elink.fcgi?dbfrom=pubmed&tool=sumsearch.org/cite&retmode=ref&cmd=prlinks&id=22809746 }} </ref> An invasive strategy is defined as diagnostic angiography with the intention of revascularization.<br />
<br />
<span style="font-size:85%">Boxes in the red color signify that an urgent management is needed.</span><br />
{{Family tree/start}}<br />
{{familytree |boxstyle=background: #FA8072; color: #F8F8FF; | | | | A00 | | A00=<div style="float: left; text-align: left; width: 17em; padding:1em;"> '''Identify cardinal findings of unstable angina/ NSTEMI :''' <br><br />
❑ '''[[Chest pain|<span style="color:white;"> Chest pain</span>]] or [[chest discomfort|<span style="color:white;">chest discomfort</span>]]''' <br><br />
:❑ Sudden onset<br />
:❑ Sensation of heaviness, tightness, pressure, or squeezing<br />
:❑ Duration> 20 minutes (but usually less than half an hour) <br><br />
:❑ Radiation to the left arm, jaw, neck, right arm, back or [[epigastrium|<span style="color:white;">epigastrium</span>]]<br />
:❑ No relief with medications<br><br />
:❑ No relief with rest <br><br />
:❑ Worse with time <br><br />
:❑ Worse with exertion<br><br />
:❑ Associated symptoms of [[palpitations|<span style="color:white;">palpitations</span>]], [[nausea|<span style="color:white;">nausea</span>]], [[vomiting|<span style="color:white;">vomiting</span>]], [[sweating|<span style="color:white;">sweating</span>]], [[dyspnea|<span style="color:white;">dyspnea</span>]], and [[lightheadedness|<span style="color:white;">lightheadedness</span>]]<br><br />
❑ '''Characteristic [[ECG|<span style="color:white;">ECG</span>]] changes consistent with [[unstable angina|<span style="color:white;">unstable angina</span>]]/ [[NSTEMI|<span style="color:white;">NSTEMI</span>]] '''<br />
:❑ No changes <br><br />
:❑ Non specific ST / T wave changes <br> <br />
:❑ Flipped or inverted T waves <br><br />
:❑ ST depression (carries the poorest prognosis) <br><br />
❑ '''Increase in >99th percentile of upper limit of normal of [[troponin|<span style="color:white;">troponin</span>]] and / or [[CKMB|<span style="color:white;">CK MB</span>]]''', which is consistent with [[NSTEMI|<span style="color:white;">NSTEMI</span>]]</div>}}<br />
{{familytree |boxstyle=background: #FA8072; color: #F8F8FF; | | | | |!| | | }}<br />
{{familytree |boxstyle=background: #FA8072; color: #F8F8FF; | | | | G02 | G02= <div style="float: left; text-align: left; width: 17em; padding:1em;"> '''Rule out life threatening alternative diagnoses:'''<br><br />
❑ [[Aortic dissection|<span style="color:white;">Aortic dissection</span>]] <br> (suggestive findings: [[back pain|<span style="color:white;">back pain</span>]], [[interscapular pain|<span style="color:white;">interscapular pain</span>]], [[aortic regurgitation|<span style="color:white;">aortic regurgitation</span>]], [[pulsus paradoxus|<span style="color:white;">pulsus paradoxus</span>]], [[blood pressure|<span style="color:white;">blood pressure</span>]] discrepancy between the arms) <br><br />
❑ [[Pulmonary embolism|<span style="color:white;">Pulmonary embolism</span>]] <br> (suggestive findings: acute onset of [[dyspnea|<span style="color:white;">dyspnea</span>]], [[tachypnea|<span style="color:white;">tachypnea</span>]], [[hemoptysis|<span style="color:white;">hemoptysis</span>]], previous [[DVT|<span style="color:white;">DVT</span>]]) <br><br />
❑ [[Cardiac tamponade|<span style="color:white;">Cardiac tamponade</span>]] <br> (suggestive findings: [[hypotension|<span style="color:white;">hypotension</span>]], [[jugular venous distention|<span style="color:white;">jugular venous distention</span>]], [[muffled heart sounds|<span style="color:white;">muffled heart sounds</span>]], [[pulsus paradoxus|<span style="color:white;">pulsus paradoxus</span>]])<br><br />
❑ [[Tension pneumothorax|<span style="color:white;">Tension pneumothorax</span>]] <br> (suggestive findings: sudden [[dyspnea|<span style="color:white;">dyspnea</span>]], [[tachycardia|<span style="color:white;">tachycardia</span>]], [[trauma|<span style="color:white;">chest trauma</span>]], unilateral absence of [[breath sounds|<span style="color:white;">breath sound</span>]])<br><br />
❑ [[Esophageal rupture|<span style="color:white;">Esophageal rupture</span>]] <br> (suggestive findings: [[vomiting|<span style="color:white;">vomiting</span>]], [[subcutaneous emphysema|<span style="color:white;">subcutaneous emphysema</span>]])</div>}}<br />
{{familytree |boxstyle=background: #FA8072; color: #F8F8FF; | | | | |!| | | }}<br />
{{familytree |boxstyle=background: #FA8072; color: #F8F8FF; | | | | A01 | | | | | A01= <div style="float: left; text-align: left; width: 17em; padding:1em;">'''Begin initial treatment:'''<br> <br />
❑ Administer 162 to 325 mg of non enteric [[aspirin|<span style="color:white;">aspirin</span>]],orally, crushed or chewed (I-A)<br />
:''Among patients with either GI intolerance or hypersensitivity to aspirin, administer a loading dose (75 mg) followed by maintenance dose of clopidogrel (I-B)''<br />
❑ Administer 2-4 L/min [[oxygen|<span style="color:white;">oxygen</span>]] via nasal cannula when saturation <90% (I-C)<br />
:''Caution in [[COPD|<span style="color:white;">COPD</span>]] patients: maintain an oxygen saturation between 88% and 92%.''<br />
❑ Administer [[nitroglycerin|<span style="color:white;">nitroglycerin</span>]]<br />
:❑ Administer sublingual nitroglycerin (0.3 to 0.4 mg, every 5 minutes for a total of 3 doses) then assess for further need to IV nitroglycerin (I-C)<br />
:❑ Administer IV nitroglyerin in case of persistent chest pain despite PO nitroglycerin, heart failure, or hypertenion (I-B): 10 mcg/min, increase by 10 mcg/min every 3 to 5 minutes until symptom relief; in case no response at 20 mcg/min, can increase by 10 mcg/min and then by 20 mcg/min<br />
<span style="font-size:85%;">Contraindicated in suspected [[RVMI|<span style="color:white;">right ventricular MI</span>]], recent use of [[phosphodiesterase inhibitors|<span style="color:white;">phosphodiesterase inhibitors</span>]], decreased [[blood pressure|<span style="color:white;">blood pressure</span>]] 30 mmHg below baseline</span> <br><br />
❑ Administer [[beta-blockers|<span style="color:white;">beta-blockers</span>]] (unless contraindicated) and titrate to the [[heart rate|<span style="color:white;">heart rate</span>]] and [[blood pressure|<span style="color:white;">blood pressure</span>]] (I-A)<br><br />
: ''PO in general, IV if patient has hypertension or ongoing pain''<br />
: ''Beta blocker is contraindicated in heart failure and high risk of cardiogenic shock.''<br />
:❑ [[Metoprolol|<span style="color:white;">Metoprolol</span>]]:<br />
:PO: 25 to 50 mg every 6 hours<br />
:IV: 5 mg every 5 min, up to 3 doses, then 25 to 50 mg orally every 6 hours<br />
:❑ [[Carvedilol|<span style="color:white;">Carvedilol</span>]] IV, 25 mg, two times a day<br />
<span style="font-size:85%;">Contraindicated in [[heart failure|<span style="color:white;">heart failure</span>]], bradycardia, hypotension (SBP<90 mmHg), [[AV block |<span style="color:white;">second or third degree AV block</span>]], [[reactive airway disease|<span style="color:white;">reactive airway disease</span>]], high risk of [[cardiogenic shock|<span style="color:white;">cardiogenic shock</span>]] and low [[cardiac output|<span style="color:white;">cardiac output</span>]] state</span> <br><br />
❑ Administer IV [[morphine|<span style="color:white;">morphine</span>]] if persistent symptoms (IIb-B) or [[pulmonary edema|<span style="color:white;">pulmonary edema</span>]]<br />
:❑ Initial dose 4-8 mg<br />
:❑ 2-8 mg every 5 to 15 minutes, as needed <br><br />
❑ Administer 80 mg [[atorvastatin|<span style="color:white;">atorvastatin</span>]] (I-A)<br><br />
❑ Monitor with a 12-lead [[ECG|<span style="color:white;">ECG</span>]] all the time<br />
</div>}}<br />
{{familytree |boxstyle=background: #FA8072; color: #F8F8FF; | | | | |!| | | }}<br />
{{familytree |boxstyle=background: #FA8072; color: #F8F8FF; | | | | G01 | G01= <div style="float: left; text-align: left; width: 17em; padding:1em;"> {{fontcolor|#000000|'''TRIAGE FOR IMMEDIATE INTERVENTION'''}} <br>'''Does the patient have ANY of the following indications that require immediate angiography and revascularization ?'''<br />
❑ Hemodynamic instability or [[cardiogenic shock|<span style="color:white;">cardiogenic shock</span>]], '''OR''' <br><br />
❑ Severe left ventricular dysfunction or [[heart failure|<span style="color:white;">heart failure</span>]], '''OR''' <br><br />
❑ Recurrent or persistent rest angina despite intensive medical therapy, '''OR''' <br><br />
❑ New or worsening [[mitral regurgitation|<span style="color:white;">mitral regurgitation</span>]] or new [[VSD|<span style="color:white;">VSD</span>]], '''OR''' <br><br />
❑ Sustained [[VT|<span style="color:white;">VT</span>]] or [[VF|<span style="color:white;">VF</span>]], '''OR''' <br><br />
❑ Prior [[PCI|<span style="color:white;">PCI</span>]] within past 6 months or [[CABG|<span style="color:white;">CABG</span>]] <br> </div> }}<br />
{{familytree |boxstyle=background: #FA8072; color: #F8F8FF; | |,|-|-|^|-|-|.| | }}<br />
{{familytree |boxstyle=background: #FA8072; color: #F8F8FF; | C01 | | | | C02 | | | C01=<div style="float: left; text-align: center; width: 17em; padding:1em;">'''YES''' </div>| C02= <div style="float: left; text-align: center; width: 17em; padding:1em;">'''NO''' </div> }}<br />
{{familytree |boxstyle=background: #FA8072; color: #F8F8FF; | |!| | | | | |!| | | | }}<br />
{{familytree |boxstyle=background: #FA8072; color: #F8F8FF; | |!| | | | | C03 | | | C03=<div style="float: left; text-align: left; width: 17em; padding:1em;">Does the patient have no ECG changes '''AND''' no rise in cardiac biomarkers > 99th percentile of ULN?</div>}}<br />
{{familytree |boxstyle=background: #FA8072; color: #F8F8FF; | |!| | | |,|-|^|-|.| | }}<br />
{{familytree |boxstyle=background: #FA8072; color: #F8F8FF; | |!| | | C04 | | C05 | C04= <div style="float: left; text-align: left; width: 17em; padding:1em;">Yes. The patient has no ECG changes AND no rise in cardiac biomarkers > 99th percentile of ULN. </div>| C05= <div style="float: left; text-align: left; width: 17em; padding:1em;">No. The patient has either positive ECG changes, OR rise in cardiac biomarkers, OR both. </div>}}<br />
{{familytree |boxstyle=background: #FA8072; color: #F8F8FF; | |!| | | |!| | | |!| | }} <br />
{{familytree |boxstyle=background: #FA8072; color: #F8F8FF; | |!| | | C06 | | |!| | C06= <div style="float: left; text-align: left; width: 17em; padding:1em;">Repeat ECG and biomarkers within next 3 hours and 6 hours <br><br> '''Does the patient still have no ECG changes '''AND''' no rise in cardiac biomarkers?'''</div>}} <br />
{{familytree |boxstyle=background: #FA8072; color: #F8F8FF; | |!| |,|^|-|-|.| |!| }}<br />
{{familytree |boxstyle=background: #FA8072; color: #F8F8FF; | |!| C07 | | C08 |!| C07= <div style="float: left; text-align: left; width: 17em; padding:1em;">Yes. The patient has no ECG changes AND no rise in cardiac biomarkers.</div>| C08= <div style="float: left; text-align: left; width: 17em; padding:1em;">No. The patient has either positive ECG changes, OR rise in cardiac biomarkers, OR both.</div>}}<br />
{{familytree |boxstyle=background: #FA8072; color: #F8F8FF; | |!| |!| | | |!| |!| }}<br />
{{familytree |boxstyle=background: #FA8072; color: #F8F8FF; | |!|C09 | | | C10 | | | C09= <div style="float: left; text-align: left; width: 17em; padding:1em;">[[Chest pain resident survival guide#Complete Diagnostic Approach|Proceed to complete diagnostic approach of chest pain to rule out differential diagnoses]]</div>| C10=<div style="float: left; text-align: left; width: 17em; padding:1em;">{{fontcolor|#000000|''' TRIAGE FOR INITIAL CONSERVATIVE OR INVASIVE THERAPY'''}} <br>'''Calculate the risk of future adverse clinical outcomes:'''<br><br />
❑ [[TIMI risk score|<span style="color:white;">Thrombolysis in Myocardial Infarction (TIMI) risk score</span>]], '''OR'''<br />
❑ [[GRACE score|<span style="color:white;">GRACE score</span>]] </div>}}<br />
{{familytree |boxstyle=background: #FA8072; color: #F8F8FF; | |!| | | |,|-|-|^|.| | }}<br />
{{familytree |boxstyle=background: #FA8072; color: #F8F8FF; | |!| | | C11 | | C12 | C11= '''Intermediate or high risk''' | C12= '''Low risk'''}}<br />
{{familytree |boxstyle=background: #FA8072; color: #F8F8FF; | |!| | | |!| | | |!| | }}<br />
{{familytree |boxstyle=background: #FA8072; color: #F8F8FF; | D01 | | D02 | | D03 | |D01=<div style="float: left; text-align: center; width: 17em; padding:1em;"> '''INITIAL INVASIVE THERAPY (IMMEDIATELY)'''<br></div><br />
| D02= <div style="float: left; text-align: center; width: 17em; padding:1em;">'''INITIAL INVASIVE THERAPY (4 to 48 hours)''' </div>| D03= <div style="float: left; text-align: center; width: 17em; padding:1em;"> '''INITIAL CONSERVATIVE THERAPY ''' </div>}}<br />
{{familytree |boxstyle=background: #FA8072; color: #F8F8FF; | | |!| |!| | | | |!| | }}<br />
{{familytree |boxstyle=background: #FA8072; color: #F8F8FF; | | | E02 | | | | E03 | |E02=<div style="float: left; text-align: left; width: 17em; padding:1em;">'''Initiate ONE of the following anticoagulant therapy (I-A)'''<br> <br />
❑ Enoxaparin (I-A)<br><br />
:❑ SC 1 mg/kg every 12 hours if CrCL≥ 30 mL/min<br />
:❑ SC 1 mg/kg every 12 hours if CrCL< 30 mL/min<br />
:❑ Initial IV 30 mg loading dose in selected patients<br />
'''OR''' <br><br />
❑ IV [[UFH|<span style="color:white;">Unfractionated heparin</span>]] (and adjust dose for apTT) for 48 hours or until PCI is perfomed (I-B)<br><br />
:❑ Initial loading dose 60 IU/kg (max 40,000 IU) <br><br />
:❑ Initial infusion 12 IU/kg/h (max 10,000 IU)<br>'''OR''' <br><br />
❑ [[Bivalirudin|<span style="color:white;">Bivalirudin</span>]] (I-B)<br />
::❑ Loading dose 0.1-mg/kg IV bolus, then 0.25–mg/kg/h infusion<br />
<br>'''OR''' <br><br />
❑ Fondaparinux , SC 2.5 mg daily (I-B)<br />
<br><br>'''PLUS'''<br><br><br />
'''Administer ONE of the following antiplatelet agents (before OR at the time of PCI) (I-A)'''<br><br />
❑ Loading dose of [[P2Y12|<span style="color:white;">P2Y12</span>]] receptor inhibitors <br><br />
:❑ [[Clopidogrel|<span style="color:white;">Clopidogrel</span>]] (I-B if before PCI, I-A if at time of PCI)<br />
::Loading dose: 300 mg or 600 mg<br />
:: Maintenance dose: 75 mg OD<br />
<br>'''OR''' <br><br />
:❑ [[Ticagrelor|<span style="color:white;">Ticagrelor</span>]] (I-B)<br />
::Loading dose: 180 mg<br />
:: Maintenance dose: 90 mg BID<br />
<br>'''OR''' <br><br />
:❑ Prasugrel ONLY AT THE TIME OF PCI, AND NOT PRE-PCI (I-B)<br><br />
::Loading dose: 60 mg<br />
:: Maintenance dose: 10 mg OD<br />
<span style="font-size:85%;">Prasugrel is contraindicated in case of prior history of strokes or TIAs, active pathological bleeding, age ≥75 years, when urgent coronary artery bypass graft surgery (CABG) is likely, body weight <60 kg, propensity to bleed, concomitant use of medications that increase the risk of bleeding</span><br><br><br />
'''Consider adding IV [[GP IIb/IIIa|<span style="color:white;">GP IIb/IIIa</span>]] inhibitors in case of high risk patients (IIb-B)'''<br><br />
❑ [[Eptifibatide|<span style="color:white;">Eptifibatide</span>]]<br><br />
:❑ Loading dose 180 mcg/kg IV bolus followed by another bolus after 10 minutes<br><br />
:❑ Maintenance dose 2 mcg/kg/min<br>'''OR''' <br><br />
❑ [[Tirofiban|<span style="color:white;">Tirofiban</span>]] <br><br />
:❑ Loading dose 25 mcg/kg<br><br />
:❑ Maintenance dose 0.15 mcg/kg/min </div><br />
|E03=<div style="float: left; text-align: left; width: 17em; padding:1em;">'''Initiate ONE of the following anticoagulant therapy (I-A)'''<br><br />
❑ Enoxaparin (I-A)<br>'''OR''' <br><br />
❑ UFH (I-A)<br>'''OR''' <br><br />
❑ Fondaparinux (I-B)<br>'''OR''' <br><br />
:''Enoxaparin or fondaparinux preferred over UFH (II-B)''<br />
<br><br> '''PLUS'''<br><br><br />
'''Administer ONE of the following antiplatelet agents (I-B):'''<br><br />
❑ [[P2Y12]] receptor inhibitors <br><br />
:❑ [[Clopidogrel]]<br><br />
::❑ Loading dose (300 mg or 600 mg)<br><br />
::❑ Maintenance dose (75 mg)<br>'''OR''' <br><br />
:❑ [[Ticagrelor]]<br><br />
::❑ Loading dose (180 mg)<br><br />
::❑ Maintenance dose (90 mg twice daily)<br>'''OR''' <br><br />
</div>}}<br />
{{familytree |boxstyle=background: #FA8072; color: #F8F8FF; | | | |!| | | | | |!| | }}<br />
{{familytree |boxstyle=background: #FA8072; color: #F8F8FF; | | | |!| | | | | F01 | |F01=<div style="float: left; text-align: left; width: 17em; padding:1em;">{{fontcolor|#000000|'''TRIAGE FOR NEED OF INVASIVE THERAPY'''}} <br>'''Does the patient experience ANY of the following?''' <br><br />
❑ Recurrence of symptoms, OR<br><br />
❑ [[Heart failure|<span style="color:white;">Heart failure</span>]], OR<br><br />
❑ Serious [[arrhythmia|<span style="color:white;">arrhythmia</span>]], OR<br><br />
❑ Subsequent ischemia</div>}}<br />
{{familytree |boxstyle=background: #FA8072; color: #F8F8FF; | | | |!| |,|-|-|-|^|.| }}<br />
{{familytree |boxstyle=background: #FA8072; color: #F8F8FF; | | | |!| G01 | | G02 | G01= YES| G02= NO}}<br />
{{familytree |boxstyle=background: #FA8072; color: #F8F8FF; | | | |!| |!| | | |!| }}<br />
{{familytree |boxstyle=background: #FA8072; color: #F8F8FF; | | | |!| H01 | | H02 | H01= <div style="float: left; text-align: left; width: 17em; padding:1em;"> '''PROCEED TO INVASIVE THERAPY (I-A)''' <br><br />
'''Administer ONE of the following antiplatelet agents if not already administered (I-A):'''<br><br />
:''The antiplatelet should be administered upstream (I-C)''<br />
❑ [[P2Y12]] receptor inhibitors <br><br />
:❑ [[Clopidogrel]] (I-B)<br><br />
::❑ Loading dose (300 mg or 600 mg)<br><br />
::❑ Maintenance dose (75 mg)<br>'''OR''' <br><br />
:❑ [[Ticagrelor]] (I-B)<br><br />
::❑ Loading dose (180 mg)<br><br />
::❑ Maintenance dose (90 mg twice daily)<br>'''OR''' <br><br />
❑ IV [[GP IIb/IIIa]] inhibitors (I-A)<br><br />
:❑ [[Eptifibatide]]<br><br />
::❑ Loading dose 180 mcg/kg IV bolus followed by another bolus after 10 minutes<br><br />
::❑ Maintenance dose 2 mcg/kg/min<br>'''OR''' <br><br />
:❑ [[Tirofiban]] <br><br />
::❑ Loading dose 25 mcg/kg<br><br />
::❑ Maintenance dose 0.15 mcg/kg/min<br></div><br />
| H02= <div style="float: left; text-align: left; width: 17em; padding:1em;">{{fontcolor|#000000|'''TRIAGE PATIENTS BY RISK ON STRESS TEST'''}} <br>❑ Perform a [[stress test]] (I-B) </div>}}<br />
{{familytree |boxstyle=background: #FA8072; color: #F8F8FF; | | | |!|!| |,|-|-|^|.|}}<br />
{{familytree |boxstyle=background: #FA8072; color: #F8F8FF; | | | |!|!| I01 | | I02 | I01= <div style="float: left; text-align: left; width: 17em; padding:1em;">'''High risk on stress test''' </div>| I02= <div style="float: left; text-align: left; width: 17em; padding:1em;">'''Low risk on stress test OR did not undergo stress test''' </div>}}<br />
{{familytree |boxstyle=background: #FA8072; color: #F8F8FF; | | | |!|!| |!| | | |!| | }}<br />
{{familytree |boxstyle=background: #FA8072; color: #F8F8FF; | | | |!|!| J01 | | |!| | J01= <div style="float: left; text-align: left; width: 17em; padding:1em;"> '''INVASIVE THERAPY''' <br>❑ Perform diagnostic [[angiography]] (I-A) </div>}}<br />
{{familytree |boxstyle=background: #FA8072; color: #F8F8FF; | | | |!|!|!| | | | K01 | K01= <div style="float: left; text-align: left; width: 17em; padding:1em;"> ❑ Continue [[aspirin]] for life (I-A)<br> ❑ Continue [[P2Y12]] receptor inhibitors up to 12 months (I-B)<br><br />
:❑ [[Clopidogrel]] (75 mg once a day)<br>'''OR''' <br><br />
:❑ [[Ticagrelor]] (90 mg twice a day)<br><br />
❑ Discontinue [[GP IIb/IIIa]] inhibitors if administered earlier (I-A)<br><br />
❑ Continue [[antithrombotic]] therapy:<br><br />
:❑ [[UFH]] for 48 hours (I-A)<br>'''OR''' <br><br />
:❑ [[Enoxaparin]] for duration of hospitalization (up to 8 days) (I-A)<br>'''OR''' <br><br />
:❑ [[Fondaparinux]] for duration of hospitalization (up to 8 days) (I-B)<br />
❑ Measure LVEF (I-B)</div>}}<br />
{{familytree |boxstyle=background: #FA8072; color: #F8F8FF; | | | |!|!|!| | | | | |}}<br />
{{familytree |boxstyle=background: #FA8072; color: #F8F8FF; | | | | C01 | | | | | | | | C01= <div style="float: left; text-align: left; width: 17em; padding:1em;">{{fontcolor|#000000|'''TRIAGE FOR SUBSEQUENT THERAPY PLAN FOLLOWING ANGIOGRAPHY'''}} <br> Does the [[angiography]] show coronary vessel obstruction ?</div> }}<br />
{{familytree |boxstyle=background: #FA8072; color: #F8F8FF; | | |,|-|^|-|-|.| | | | | }}<br />
{{familytree |boxstyle=background: #FA8072; color: #F8F8FF; | | D01 | | | | D02 | | | | D01= '''No'''| D02= '''Yes'''}}<br />
{{familytree |boxstyle=background: #FA8072; color: #F8F8FF; | | |!| | | |,|-|^|-|-|-|-|-|.| | | }}<br />
{{familytree |boxstyle=background: #FA8072; color: #F8F8FF; | | |!| | | E01 | | E02 | | E03 | | E01=<div style="float: left; text-align: left; width: 17em; padding:1em;">❑ 1 or 2 vessel disease <br> ''[[CABG]] or medical therapy might also be considered'' </div>|E02=<div style="float: left; text-align: left; width: 17em; padding:1em;">❑ Left main coronary artery disease <br>❑ 3 vessel disease <br>❑ 2 vessel disease with proximal left anterior descending artery affection <br>❑ [[Left ventricular dysfunction]] <br> ❑Patient treated from [[diabetes]]</div>| E03= }}<br />
{{familytree |boxstyle=background: #FA8072; color: #F8F8FF; | | |!| | | |!| | | |!| | | |!| | |}}<br />
{{familytree |boxstyle=background: #FA8072; color: #F8F8FF; | | L03 | | L01 | | L02 | | L03 | | L01= '''[[PCI]]''' <br> <br />
| L02= '''[[CABG]]''' <BR><br />
| L03= '''Medical treatment'''}}<br />
{{familytree |boxstyle=background: #FA8072; color: #F8F8FF; | | |!| | | |!| | | |!| | | |!| | | }}<br />
{{familytree |boxstyle=background: #FA8072; color: #F8F8FF; | | M01 | | M02 | | M03 | | M04 | | M01= <div style="float: left; text-align: left; width: 17em; padding:1em;"><br />
❑ Administer aspirin indefinitely <br><br />
❑ Administer additional antiplatelet therapy ''at the discretion of the physician'' (I-C)<br><br />
❑ Administer anticoagulant therapy ''at the discretion of the physician'' (I-C)</div><br />
|M02= <div style="float: left; text-align: left; width: 17em; padding:1em;"> ❑ Administer [[aspirin]] for life <br><br />
❑ Administer a loading dose of [[P2Y12]] receptor inhibitor (if not initially started)<br><br />
:❑ [[Clopidogrel]] 300 mg or 600 mg<br>'''OR''' <br><br />
:❑ [[Ticagrelor]] 180 mg<br>'''OR''' <br><br />
:❑ [[Prasugrel]] 60 mg<br>'''OR''' <br><br />
❑ Discontinue anticoagulant therapy following PCI in uncomplicated cases (I-B)</div><br />
| M03=<div style="float: left; text-align: left; width: 17em; padding:1em;"><br />
❑ Continue [[aspirin]] (I-A)<br><br />
❑ Discontinue IV [[GP IIb/IIIa]] inhibitors (4 hours before CABG) (I-B)<br><br />
❑ Manage the P2Y12 receptor inhibitor therapy as follows ''if CABG can be delayed'' (depending on whether benefits of CABG outweigh the risk of bleeding) (I-B):<br><br />
:❑ Discontinue clopidogrel if started before angiography (5 days prior to CABG) (I-B)<br><br />
:❑ Discontinue ticagrelor if started before angiography (5 days prior to CABG) (I-C)<br><br />
:❑ Discontinue prasugrel if started before angiography (7 days prior to CABG) (I-C)<br><br />
❑ Manage the [[anticoagulation]] therapy <br><br />
:❑ Continue [[UFH]] (I-B)<br />
:❑ Discontinue [[enoxaparin]] if started before angiography (12-24 hours prior to CABG) and dose with UFH (I-B)<br><br />
:❑ Discontinue [[fondaparinux]] if started before angiography (24 hours prior to CABG) and dose with UFH (I-B)<br><br />
:❑ Discontinue [[bivalirudin]] if started before angiography (3 hours prior to CABG) and dose with UFH (I-B)</div><br />
|M04= <div style="float: left; text-align: left; width: 17em; padding:1em;"> ❑ Continue [[aspirin]] (I-A)<br><br />
❑ Administer a loading dose of [[P2Y12]] receptor inhibitors ''if not given before angiography'' (I-B)<br />
:❑ [[Clopidogrel]] (300 mg or 600 mg)<br>'''OR''' <br><br />
:❑ [[Prasugrel]] (60 mg) <br><br />
❑ Discontinue IV [[GP IIb/IIIa]] inhibitors if started before angiography (I-B)<br><br />
❑ Manage [[antithrombotic]] therapy:<br />
:❑ Continue IV [[UFH]] for at least 48 hours or until discharge if started before angiography (I-A)<br><br />
:❑ Continue [[enoxaparin]] for entire hospital stay, up to 8 days if started before angiography (I-A)<br><br />
:❑ Continue [[fondaparinux]] for entire hospital stay, up to 8 days if started before angiography (I-B)<br><br />
:❑ Discontinue [[bivalirudin]] or continue at 0.25 mg/kg/hour for up to 72 hours (I-B)</div> }}<br />
{{familytree/end}}<br />
<br />
==Complete Diagnostic Approach==<br />
A complete diagnostic approach should be carried out after a focused initial rapid evaluation is conducted and following initiation of any urgent intervention.<ref name="pmid22809746">{{cite journal| author=Jneid H, Anderson JL, Wright RS, Adams CD, Bridges CR, Casey DE et al.| title=2012 ACCF/AHA focused update of the guideline for the management of patients with unstable angina/non-ST-elevation myocardial infarction (updating the 2007 guideline and replacing the 2011 focused update): a report of the American College of Cardiology Foundation/American Heart Association Task Force on Practice Guidelines. | journal=J Am Coll Cardiol | year= 2012 | volume= 60 | issue= 7 | pages= 645-81 | pmid=22809746 | doi=10.1016/j.jacc.2012.06.004 | pmc= | url=http://www.ncbi.nlm.nih.gov/entrez/eutils/elink.fcgi?dbfrom=pubmed&tool=sumsearch.org/cite&retmode=ref&cmd=prlinks&id=22809746 }} </ref><br />
<br />
<span style="font-size:85%"> '''Abbreviations:''' '''CABG:''' [[coronary artery bypass graft]]; '''ECG:''' [[electrocardiogram]]; '''LAD:''' [[LAD|left anterior descending]]; '''LBBB:''' [[left bundle branch block]]; '''MI:''' [[myocardial infarction]]; '''PCI:''' [[percutaneous coronary intervention]]; '''S3:''' [[S3|third heart sound]]; '''S4:''' [[S4|fourth heart sound]]; '''VSD:''' [[ventricular septal defect]] </span><br />
<br />
{{Family tree/start}}<br />
{{familytree | A01 | | A01=<div style="float: left; text-align: left; width: 28em; padding:1em;"> '''Characterize the symptoms:''' <br><br />
❑ [[Chest pain]] or [[chest discomfort]] <br><br />
:❑ Sudden onset<br />
:❑ Sensation of heaviness, tightness, pressure, or squeezing<br />
:❑ Duration> 20 minutes <br><br />
:❑ Radiation to the left arm, jaw, neck, right arm, back or [[epigastrium]]<br />
:❑ No relief with rest <br><br />
:❑ Worse with time <br><br />
:❑ Worse with exertion<br><br />
❑ [[Dyspnea]] <br><br />
❑ [[Weakness]] <br><br />
❑ [[Palpitations]] <br><br />
❑ [[Nausea]] <br><br />
❑ [[Vomiting]] <br><br />
❑ [[Sweating]] <br><br />
❑ [[Loss of consciousness]]<br><br />
❑ [[Fatigue]]<br />
</div>}}<br />
{{familytree | |!| | |}}<br />
{{familytree | B01 | | B01=<div style="float: left; text-align: left; width: 35em; padding:1em;"> '''Obtain a detailed history:''' <br><br />
❑ Age <br><br />
❑ Baseline [[blood pressure]] <br><br />
❑ Previous episodes of [[chest pain]] <br><br />
❑ Previous [[PCI]] or [[CABG]] <br><br />
❑ Cardiac risk factors<br><br />
:❑ [[Hypertension]] <br><br />
:❑ [[Diabetes]] <br><br />
:❑ [[Hypercholesterolemia]] <br><br />
:❑ [[Smoking]] <br><br />
:❑ [[Obesity]] <br><br />
❑ List of medications <br><br />
❑ Family history of premature [[coronary artery disease]]<br />
----<br />
'''Identify possible triggers:'''<br><br />
❑ Physical exertion <br><br />
❑ Air pollution or fine particulate matter <br><br />
❑ Antecedant infection <br><br />
❑ Heavy meal <br><br />
❑ [[Cocaine]] <br><br />
❑ [[Marijuana]]</div>}}<br />
{{familytree | |!| | | }}<br />
{{familytree | C01 | | C01=<div style="float: left; text-align: left; width: 35em; padding:1em;">'''Examine the patient:''' <br><br />
<br />
'''Vital signs''' <br><br />
❑ [[Blood pressure]] <br><br />
:❑ [[Blood pressure]] lower than baseline, suggestive of:<br />
:❑ Discrepancy between arms (suggestive of [[aortic dissection]])<br />
:❑ Narrow [[pulse pressure]] (suggestive of [[heart failure]])<br />
<br />
❑ [[Heart rate]] <br><br />
:❑ [[Tachycardia]] (suggestive of [[heart failure]])<br />
:❑ [[Bradycardia]] (suggestive of [[heart block]] or [[bradyarrhythmias]])<br />
<br />
'''Pulses''' <br><br />
❑ [[Femoral artery|Femoral pulse]] (if a patient is to undergo [[PCI]])<br><br />
:❑ Strength<br />
:❑ [[Bruits]]<br />
<br />
'''Skin''' <br><br />
❑ [[Xanthelasma]] (suggestive of [[dyslipidemia]]) <br><br />
❑ [[Xanthoma]] (suggestive of [[dyslipidemia]]) <br><br />
❑ [[Edema]] (suggestive of [[heart failure]])<br><br />
❑ [[Cyanosis|Cyanotic]] and cold skin, lips, nail bed (suggestive of [[cardiogenic shock]]) <br><br />
<br />
'''Heart''' <br><br />
❑ [[Heart sounds]]<br><br />
:❑ [[S3]] (suggestive of [[heart failure]])<br />
:❑ [[S4]] (associated with conditions that increase the stiffness of the ventricle)<br />
❑ [[Murmurs]]<br />
:❑ [[Aortic regurgitation]]: early diastolic high-pitched sound best heard at the left sternal border (suggestive of [[aortic dissection]] with propagation to the aortic arch)<br />
❑ [[Friction rub|Pericardial friction rub]] (suggestive of [[pericarditis]])<br />
<br />
'''Lungs''' <br><br />
❑ [[Rales]] (suggestive of [[heart failure]]) <br><br />
</div>}}<br />
{{familytree | |!| | }}<br />
{{familytree | E01 | E01= <div style="float: left; width: 28em; text-align: left;">'''Order labs and tests:''' <br><br />
❑ [[EKG]] <br><br />
❑ Biomarkers <br><br />
:❑ Troponin I<br><br />
:❑ CK-MB <br><br />
❑ [[Echocardiography]]<br />
❑ [[Creatinine]] <br><br />
❑ [[Glucose]] <br><br />
❑ [[Hemoglobin]]<br><br />
❑ Multislice CT coronary imaging (rule out [[CAD]] as cause of pain in<br />
patients with low to intermediate likelihood of [[CAD]] and when [[troponin]] and [[ECG]] are<br />
inconclusive)<ref>{{Cite web | last = | first = | title = http://eurheartj.oxfordjournals.org/content/32/23/2999.full.pdf | url = http://eurheartj.oxfordjournals.org/content/32/23/2999.full.pdf | publisher = | date = | accessdate = }}</ref> <br><br />
❑ [[MRI]] (integrate imaging of function, perfusion and necrosis)<ref>{{Cite web | last = | first = | title = http://eurheartj.oxfordjournals.org/content/32/23/2999.full.pdf | url = http://eurheartj.oxfordjournals.org/content/32/23/2999.full.pdf | publisher = | date = | accessdate = }}</ref><br />
</div>}}<br />
{{Family tree/end}}<br />
<br />
==Pre-Discharge Care==<br />
<span style="font-size:85%"> '''Abbreviations:''' '''ACE:''' [[angiotensin converting enzyme]]; '''LVEF:''' [[left ventricular ejection fraction]]; '''PCI:''' [[percutaneous coronary intervention]]; '''PO:''' per os; '''VF:''' [[ventricular fibrillation]]; '''VT:''' [[ventricular tachycardia]] </span><br />
<br />
{{Family tree/start}}<br />
{{familytree | A01 | | |A01= <div style="float: left; text-align: left; width: 30em; padding:1em;">'''Administer the following medications in patients without contraindications:'''<br><br />
❑ [[Aspirin]] 81-325 mg (indefinitely) (I-A)<br><br />
:''Among patients with either GI intolerance or hypersensitivity to aspirin, administer a loading dose followed by maintenance dose of either clopidogrel 75 mg OD (I-B), OR prasugrel 10 mg OD (only in PCI patients) (I-C), OR ticagrelor 90 mg BID (I-C)'' <br><br />
❑ [[Beta blockers]] <br><br />
<span style="font-size:85%;color:red">Contraindicated in heart failure, prolonged or high degree AV block, reactive airway disease, high risk of cardiogenic shock and low cardiac output state</span> :❑ [[Metoprolol tartrate]]<br />
::❑ Begin with 25 to 50 mg PO every 6 to 12 hour<br />
::❑ Then, [[metoprolol tartrate]] twice daily or [[metoprolol succinate]] once daily for 2-3 days<br />
::❑ Titate to 200 mg daily, OR<br />
:❑ [[Carvedilol]]<br />
::❑ Begin with 6.25 mg twice daily<br />
::❑ Titrate to 25 mg twice daily<br />
❑ [[Calcium channel blockers]] are used as anti-ischemic or antihypertensive drugs and also in [[atrial fibrillation]] when [[beta blockers]] are contraindicated <br><br />
<span style="font-size:85%;color:red">Contraindicated in heart failure and left ventricular dysfunction</span> <br><br />
❑ [[ACE]] inhibitors and [[ARBs]] may also be considered in selected patients (no enough information)<ref name="www.ncbi.nlm.nih.gov">{{Cite web | last = | first = | title = Therapeutic effects of captopril on ischemia and ... [Am Heart J. 1994] - PubMed - NCBI | url = http://www.ncbi.nlm.nih.gov/pubmed?term=8273728 | publisher = | date = | accessdate = }}</ref><br />
<br><br />
<span style="font-size:85%;color:red">Contraindicated in hypotension, renal failure and hyperkalemia</span> <br><br />
❑ [[Atorvastatin]] 80 mg daily<br />
----<br />
'''Administer ONE of the following antiplatelet therapy for a duration of:'''<br />
: '''Up to 12 months in medically treated with no stenting (I-B)'''<br />
: '''Up to 12 months in BMS (I-B)'''<br />
: '''At least 12 months in DES (I-B)'''<br />
❑ [[Clopidogrel]] 75 mg daily, OR <br><br />
❑ [[Ticagrelor]] 90 mg twice a day, OR <br><br />
❑ [[Prasugrel]] 10 mg daily '''only for patients who underwent PCI'''<br><br />
<br><br />
<br />
<span style="font-size:85%;color:red">Consider earlier discontinuation in case bleeding risk exceeds benefit of the antiplatelet therapy (I-C).</span> <br><br />
----<br />
'''Assess the patient for ischemia:'''<br><br />
❑ Perform non invasive testing before discharge for the evaluation of ischemia among patients who did not undergo [[coronary angiography]] and in whom [[coronary angiography]] is not warranted due to the absence of high risk features ([[ACC AHA guidelines classification scheme|Class I, level of evidence B]]) <br><br />
❑ Assess the [[LVEF]] ([[ACC AHA guidelines classification scheme|Class I, level of evidence C]])<br />
</div>}}<br />
{{familytree/end}}<br />
<br />
<br />
<span style="font-size:85%"> '''Abbreviations:''' '''ACE:''' [[angiotensin converting enzyme]]; '''ARB:''' [[angiotensin receptor blocker]];</span><br />
<br />
{{Family tree/start}}<br />
{{familytree | A01 | | A01= <div style="float: left; text-align: left; width: 30em; padding:1em;"> ❑ Prepare a list of all the home medications and educate the patient about compliance<br />
:❑ [[Aspirin]] 81-325 mg (indefinitely) <br />
:❑ [[Antiplatelet drug|Antiplatelet therapy]]<br />
:❑ [[Beta blockers]]<br />
:❑ [[ACE inhibitors]] or [[ARB]] (only in selected patients <ref name="ACE">{{Cite web | last = | first = | title = Therapeutic effects of captopril on ischemia and ... [Am Heart J. 1994] - PubMed - NCBI | url = http://www.ncbi.nlm.nih.gov/pubmed?term=8273728 | publisher = | date = | accessdate = }}</ref><br />
<br />
:❑ [[Atorvastatin]] 80 mg daily<br />
❑ Encourage lifestyle modification <br><br />
:❑ [[Smoking]] cessation<br />
:❑ Physical activity<br />
:❑ Dietary changes<br />
❑ Ensure the initiation of the management of comorbidities<br />
:❑ [[Obesity]]<br />
:❑ [[Dyslipidemia]]<br />
:❑ [[Hypertension]]<br />
:❑ [[Diabetes]]<br />
:❑ [[Heart failure]]<br />
❑ Educate the patient about the early recognition of symptoms of [[acute coronary syndrome]]<br />
❑ Educate the patient about the use of [[nitroglycerin]] 0.4 mg, sublingually, up to 3 doses every 5 minutes </div> }}<br />
{{Family tree/end}}<br />
<br />
==Do's==<br />
* Administer a loading dose followed by a maintenance dose of [[clopidogrel]], [[ticagrelor]] or [[prasugrel]] (if [[PCI]] is planned) as initial treatment instead of [[aspirin]] among patients with gastrointestinal intolerance or hypersensitivity reaction to [[aspirin]].<br />
<br />
* Administer sublingual [[nitroglycerin]] in patients with ischemic [[chest pain]]; however, administer IV [[nitroglycerin]] among patients with persistent [[chest pain]] after three sublingual [[nitroglycerin]].<ref name="pmid6402912">{{cite journal| author=Kaplan K, Davison R, Parker M, Przybylek J, Teagarden JR, Lesch M| title=Intravenous nitroglycerin for the treatment of angina at rest unresponsive to standard nitrate therapy. | journal=Am J Cardiol | year= 1983 | volume= 51 | issue= 5 | pages= 694-8 | pmid=6402912 | doi= | pmc= | url=http://www.ncbi.nlm.nih.gov/entrez/eutils/elink.fcgi?dbfrom=pubmed&tool=sumsearch.org/cite&retmode=ref&cmd=prlinks&id=6402912 }} </ref><br />
<br />
*Discontinue [[NSAID]] drugs immediately. <ref name="pmid21224324">{{cite journal| author=Trelle S, Reichenbach S, Wandel S, Hildebrand P, Tschannen B, Villiger PM et al.| title=Cardiovascular safety of non-steroidal anti-inflammatory drugs: network meta-analysis. | journal=BMJ | year= 2011 | volume= 342 | issue= | pages= c7086 | pmid=21224324 | doi=10.1136/bmj.c7086 | pmc=PMC3019238 | url=http://www.ncbi.nlm.nih.gov/entrez/eutils/elink.fcgi?dbfrom=pubmed&tool=sumsearch.org/cite&retmode=ref&cmd=prlinks&id=21224324 }} [http://www.ncbi.nlm.nih.gov/entrez/eutils/elink.fcgi?dbfrom=pubmed&tool=sumsearch.org/cite&retmode=ref&cmd=prlinks&id=21460398 Review in: Evid Based Med. 2011 Oct;16(5):142-3] </ref> <ref name="pmid23726390">{{cite journal| author=Coxib and traditional NSAID Trialists' (CNT) Collaboration. Bhala N, Emberson J, Merhi A, Abramson S, Arber N et al.| title=Vascular and upper gastrointestinal effects of non-steroidal anti-inflammatory drugs: meta-analyses of individual participant data from randomised trials. | journal=Lancet | year= 2013 | volume= 382 | issue= 9894 | pages= 769-79 | pmid=23726390 | doi=10.1016/S0140-6736(13)60900-9 | pmc=PMC3778977 | url=http://www.ncbi.nlm.nih.gov/entrez/eutils/elink.fcgi?dbfrom=pubmed&tool=sumsearch.org/cite&retmode=ref&cmd=prlinks&id=23726390 }} [http://www.ncbi.nlm.nih.gov/entrez/eutils/elink.fcgi?dbfrom=pubmed&tool=sumsearch.org/cite&retmode=ref&cmd=prlinks&id=24126661 Review in: Ann Intern Med. 2013 Oct 15;159(8):JC12] </ref><br />
<br />
* If fondaparinux is chosen to be administered ad the anticoagulant therapy during PCI, co-administer another antocoagulant with factor IIa activity such as UFH.<br />
<br />
==Don'ts==<br />
* Do not administer IV [[GP IIb/IIIa inhibitors]] to patients with low risk of ischemic events or at high risk of [[bleeding]] and who are already on [[aspirin]] and P2Y12 receptor inhibitors therapy.<br />
<br />
* Do not administer [[prasugrel]] among patients with prior history of [[strokes]] or [[TIAs]].<br />
<br />
* Do not administer IV [[beta-blockers]] among hemodynamically unstable patients.<br />
<br />
* Do not administer a complete dose of [[prasugrel]] among patients under 60kg (132lbs) due to high exposure to the active metabolite. They should receive half the dose of [[prasugrel]] although there is no evidence that half the dose is as effective as a complete dose.<br />
<br />
* Do not administer fibrinolytic therapy to patients with [[unstable angina]].<ref name="pmid7475596">{{cite journal| author=Anderson HV| title=Intravenous thrombolysis in refractory unstable angina pectoris. | journal=Lancet | year= 1995 | volume= 346 | issue= 8983 | pages= 1113-4 | pmid=7475596 | doi= | pmc= | url=http://www.ncbi.nlm.nih.gov/entrez/eutils/elink.fcgi?dbfrom=pubmed&tool=sumsearch.org/cite&retmode=ref&cmd=prlinks&id=7475596 }} </ref><br />
<br />
*Do not administer [[abciximab]] for patients not scheduled for [[PCI]]. <ref name="pmid22809746">{{cite journal| author=Jneid H, Anderson JL, Wright RS, Adams CD, Bridges CR, Casey DE et al.| title=2012 ACCF/AHA focused update of the guideline for the management of patients with unstable angina/non-ST-elevation myocardial infarction (updating the 2007 guideline and replacing the 2011 focused update): a report of the American College of Cardiology Foundation/American Heart Association Task Force on Practice Guidelines. | journal=J Am Coll Cardiol | year= 2012 | volume= 60 | issue= 7 | pages= 645-81 | pmid=22809746 | doi=10.1016/j.jacc.2012.06.004 | pmc= | url=http://www.ncbi.nlm.nih.gov/entrez/eutils/elink.fcgi?dbfrom=pubmed&tool=sumsearch.org/cite&retmode=ref&cmd=prlinks&id=22809746 }} </ref><br />
<br />
* Do not administer 2 P2Y12 receptor inhibitors, even in the presence of hypersensitivity or GI interoperability to aspirin.<br />
<br />
==References==<br />
{{reflist|2}}<br />
<br />
[[Category:Emergency medicine]]<br />
[[Category:Medicine]]<br />
[[Category:Resident survival guide]]<br />
[[Category:Cardiology]]<br />
<br />
{{WikiDoc Help Menu}}<br />
{{WikiDoc Sources}}<br />
</div></div>Rim Halabyhttps://www.wikidoc.org/index.php?title=Unstable_angina/_NSTEMI_resident_survival_guide&diff=1088076Unstable angina/ NSTEMI resident survival guide2015-04-15T20:37:14Z<p>Rim Halaby: /* FIRE: Focused Initial Rapid Evaluation */</p>
<hr />
<div><div style="width: 80%;"><br />
__NOTOC__<br />
{{CMG}}; {{AE}} {{ATS}}; {{Rim}}<br />
<br />
{| class="infobox" style="margin: 0 0 0 0; border: 0; float: right; width: 100px; background: #A8A8A8; position: fixed; top: 250px; right: 21px; border-radius: 0 0 10px 10px;" cellpadding="0" cellspacing="0";<br />
|-<br />
! style="padding: 0 5px; font-size: 85%; background: #A8A8A8" align=center| {{fontcolor|#2B3B44|Unstable angina/ NSTEMI Resident Survival Guide Microchapters}}<br />
|-<br />
! style="font-size: 80%; padding: 0 5px; background: #DCDCDC" align=left | [[Unstable angina/ NSTEMI resident survival guide#Overview|Overview]]<br />
|-<br />
! style="font-size: 80%; padding: 0 5px; background: #DCDCDC" align=left | [[Unstable angina/ NSTEMI resident survival guide#Causes|Causes]]<br />
|-<br />
! style="font-size: 80%; padding: 0 5px; background: #DCDCDC" align=left | [[Unstable angina/ NSTEMI resident survival guide#FIRE: Focused Initial Rapid Evaluation|FIRE]]<br />
|-<br />
! style="font-size: 80%; padding: 0 5px; background: #DCDCDC" align=left | [[Unstable angina/ NSTEMI resident survival guide#Complete Diagnostic Approach|Diagnosis]]<br />
|-<br />
! style="font-size: 80%; padding: 0 5px; background: #DCDCDC" align=left | [[Unstable angina/ NSTEMI resident survival guide#Treatment|Treatment]]<br />
: [[Unstable angina/ NSTEMI resident survival guide#Management Following Angiography|Management Following Angiography]]<br />
|-<br />
! style="font-size: 80%; padding: 0 5px; background: #DCDCDC" align=left | [[Unstable angina/ NSTEMI resident survival guide#Pre-Discharge Care|Pre-Discharge Care]]<br />
|-<br />
! style="font-size: 80%; padding: 0 5px; background: #DCDCDC" align=left | [[Unstable angina/ NSTEMI resident survival guide#Long Term Managemnet|Long Term Management]]<br />
|-<br />
! style="font-size: 80%; padding: 0 5px; background: #DCDCDC" align=left | [[Unstable angina/ NSTEMI resident survival guide#Do's|Do's]]<br />
|-<br />
! style="font-size: 80%; padding: 0 5px; background: #DCDCDC" align=left | [[Unstable angina/ NSTEMI resident survival guide#Don'ts|Don'ts]]<br />
|}<br />
<br />
==Overview==<br />
[[Unstable angina]] and [[non ST elevation myocardial infarction]] ([[NSTEMI]]) belong to two different ends of the spectrum of [[acute coronary syndrome]]. These conditions have a similar clinical presentation characterized by an acute onset of chest pain that starts on minimal exertion, rest or sleep, lasts at least 20 minutes (but usually less that half an hour) and, is not relieved by medications or rest. [[NSTEMI]] is differentiated from [[unstable angina]] by the presence of elevated cardiac biomarkers secondary to myocardial injury. [[Unstabel angina]] and [[NSTEMI]] might not be differentiated early following the occurrence of symptoms because [[cardiac biomarker]]s may require a few hours to rise.<br />
<br />
==Causes==<br />
<br />
===Life Threatening Causes===<br />
Life-threatening causes include conditions which may result in death or permanent disability within 24 hours if left untreated. [[Unstable angina]] and [[NSTEMI]] are life-threatening conditions and must be treated as such irrespective of the causes.<br />
<br />
===Common Causes===<br />
====Myocardial Infarction====<br />
* [[Atherosclerotic]] [[plaque rupture]] and subsequent [[coronary thrombus]] (most common cause)<br />
* [[Coronary artery spasm]]<br />
* [[Arrhythmia]]<br />
* [[MI|Post-myocardial infarction]]<br />
* [[PCI|Post-percutaneous coronary intervention]]<br />
** [[Abrupt closure]]<br />
** [[PCI complications: loss of side branch|Loss of side branch]]<br />
** [[Distal embolization]]<br />
** [[PCI complications: restenosis|Restenosis]]<br />
**[[Stent thrombosis]]<br />
* [[CABG|Post-coronary artery bypass graft]]<br />
** Graft closure<br />
** New lesion in the graft<br />
<br />
''For a complete list of causes, click [[Unstable angina pathophysiology|here]] for unstable angina and [[Non ST elevation myocardial infarction pathophysiology|here]] for NSTEMI.''<br />
<br />
==FIRE: Focused Initial Rapid Evaluation==<br />
A Focused Initial Rapid Evaluation (FIRE) should be performed to identify patients in need of immediate intervention based on the 2012 ACCF/AHA focused update of the guideline for the management of patients with unstable angina/non-ST-elevation myocardial infarction.<ref name="pmid22809746">{{cite journal| author=Jneid H, Anderson JL, Wright RS, Adams CD, Bridges CR, Casey DE et al.| title=2012 ACCF/AHA focused update of the guideline for the management of patients with unstable angina/non-ST-elevation myocardial infarction (updating the 2007 guideline and replacing the 2011 focused update): a report of the American College of Cardiology Foundation/American Heart Association Task Force on Practice Guidelines. | journal=J Am Coll Cardiol | year= 2012 | volume= 60 | issue= 7 | pages= 645-81 | pmid=22809746 | doi=10.1016/j.jacc.2012.06.004 | pmc= | url=http://www.ncbi.nlm.nih.gov/entrez/eutils/elink.fcgi?dbfrom=pubmed&tool=sumsearch.org/cite&retmode=ref&cmd=prlinks&id=22809746 }} </ref> An invasive strategy is defined as diagnostic angiography with the intention of revascularization.<br />
<br />
<span style="font-size:85%">Boxes in the red color signify that an urgent management is needed.</span><br />
{{Family tree/start}}<br />
{{familytree |boxstyle=background: #FA8072; color: #F8F8FF; | | | | A00 | | A00=<div style="float: left; text-align: left; width: 17em; padding:1em;"> '''Identify cardinal findings of unstable angina/ NSTEMI :''' <br><br />
❑ '''[[Chest pain|<span style="color:white;"> Chest pain</span>]] or [[chest discomfort|<span style="color:white;">chest discomfort</span>]]''' <br><br />
:❑ Sudden onset<br />
:❑ Sensation of heaviness, tightness, pressure, or squeezing<br />
:❑ Duration> 20 minutes (but usually less than half an hour) <br><br />
:❑ Radiation to the left arm, jaw, neck, right arm, back or [[epigastrium|<span style="color:white;">epigastrium</span>]]<br />
:❑ No relief with medications<br><br />
:❑ No relief with rest <br><br />
:❑ Worse with time <br><br />
:❑ Worse with exertion<br><br />
:❑ Associated symptoms of [[palpitations|<span style="color:white;">palpitations</span>]], [[nausea|<span style="color:white;">nausea</span>]], [[vomiting|<span style="color:white;">vomiting</span>]], [[sweating|<span style="color:white;">sweating</span>]], [[dyspnea|<span style="color:white;">dyspnea</span>]], and [[lightheadedness|<span style="color:white;">lightheadedness</span>]]<br><br />
❑ '''Characteristic [[ECG|<span style="color:white;">ECG</span>]] changes consistent with [[unstable angina|<span style="color:white;">unstable angina</span>]]/ [[NSTEMI|<span style="color:white;">NSTEMI</span>]] '''<br />
:❑ No changes <br><br />
:❑ Non specific ST / T wave changes <br> <br />
:❑ Flipped or inverted T waves <br><br />
:❑ ST depression (carries the poorest prognosis) <br><br />
❑ '''Increase in >99th percentile of upper limit of normal of [[troponin|<span style="color:white;">troponin</span>]] and / or [[CKMB|<span style="color:white;">CK MB</span>]]''', which is consistent with [[NSTEMI|<span style="color:white;">NSTEMI</span>]]</div>}}<br />
{{familytree |boxstyle=background: #FA8072; color: #F8F8FF; | | | | |!| | | }}<br />
{{familytree |boxstyle=background: #FA8072; color: #F8F8FF; | | | | G02 | G02= <div style="float: left; text-align: left; width: 17em; padding:1em;"> '''Rule out life threatening alternative diagnoses:'''<br><br />
❑ [[Aortic dissection|<span style="color:white;">Aortic dissection</span>]] <br> (suggestive findings: [[back pain|<span style="color:white;">back pain</span>]], [[interscapular pain|<span style="color:white;">interscapular pain</span>]], [[aortic regurgitation|<span style="color:white;">aortic regurgitation</span>]], [[pulsus paradoxus|<span style="color:white;">pulsus paradoxus</span>]], [[blood pressure|<span style="color:white;">blood pressure</span>]] discrepancy between the arms) <br><br />
❑ [[Pulmonary embolism|<span style="color:white;">Pulmonary embolism</span>]] <br> (suggestive findings: acute onset of [[dyspnea|<span style="color:white;">dyspnea</span>]], [[tachypnea|<span style="color:white;">tachypnea</span>]], [[hemoptysis|<span style="color:white;">hemoptysis</span>]], previous [[DVT|<span style="color:white;">DVT</span>]]) <br><br />
❑ [[Cardiac tamponade|<span style="color:white;">Cardiac tamponade</span>]] <br> (suggestive findings: [[hypotension|<span style="color:white;">hypotension</span>]], [[jugular venous distention|<span style="color:white;">jugular venous distention</span>]], [[muffled heart sounds|<span style="color:white;">muffled heart sounds</span>]], [[pulsus paradoxus|<span style="color:white;">pulsus paradoxus</span>]])<br><br />
❑ [[Tension pneumothorax|<span style="color:white;">Tension pneumothorax</span>]] <br> (suggestive findings: sudden [[dyspnea|<span style="color:white;">dyspnea</span>]], [[tachycardia|<span style="color:white;">tachycardia</span>]], [[trauma|<span style="color:white;">chest trauma</span>]], unilateral absence of [[breath sounds|<span style="color:white;">breath sound</span>]])<br><br />
❑ [[Esophageal rupture|<span style="color:white;">Esophageal rupture</span>]] <br> (suggestive findings: [[vomiting|<span style="color:white;">vomiting</span>]], [[subcutaneous emphysema|<span style="color:white;">subcutaneous emphysema</span>]])</div>}}<br />
{{familytree |boxstyle=background: #FA8072; color: #F8F8FF; | | | | |!| | | }}<br />
{{familytree |boxstyle=background: #FA8072; color: #F8F8FF; | | | | A01 | | | | | A01= <div style="float: left; text-align: left; width: 17em; padding:1em;">'''Begin initial treatment:'''<br> <br />
❑ Administer 162 to 325 mg of non enteric [[aspirin|<span style="color:white;">aspirin</span>]],orally, crushed or chewed (I-A)<br />
:''Among patients with either GI intolerance or hypersensitivity to aspirin, administer a loading dose (75 mg) followed by maintenance dose of clopidogrel (I-B)''<br />
❑ Administer 2-4 L/min [[oxygen|<span style="color:white;">oxygen</span>]] via nasal cannula when saturation <90% (I-C)<br />
:''Caution in [[COPD|<span style="color:white;">COPD</span>]] patients: maintain an oxygen saturation between 88% and 92%.''<br />
❑ Administer [[nitroglycerin|<span style="color:white;">nitroglycerin</span>]]<br />
:❑ Administer sublingual nitroglycerin (0.3 to 0.4 mg, every 5 minutes for a total of 3 doses) then assess for further need to IV nitroglycerin (I-C)<br />
:❑ Administer IV nitroglyerin in case of persistent chest pain despite PO nitroglycerin, heart failure, or hypertenion (I-B): 10 mcg/min, increase by 10 mcg/min every 3 to 5 minutes until symptom relief; in case no response at 20 mcg/min, can increase by 10 mcg/min and then by 20 mcg/min<br />
<span style="font-size:85%;">Contraindicated in suspected [[RVMI|<span style="color:white;">right ventricular MI</span>]], recent use of [[phosphodiesterase inhibitors|<span style="color:white;">phosphodiesterase inhibitors</span>]], decreased [[blood pressure|<span style="color:white;">blood pressure</span>]] 30 mmHg below baseline</span> <br><br />
❑ Administer [[beta-blockers|<span style="color:white;">beta-blockers</span>]] (unless contraindicated) and titrate to the [[heart rate|<span style="color:white;">heart rate</span>]] and [[blood pressure|<span style="color:white;">blood pressure</span>]] (I-A)<br><br />
: ''PO in general, IV if patient has hypertension or ongoing pain''<br />
: ''Beta blocker is contraindicated in heart failure and high risk of cardiogenic shock.''<br />
:❑ [[Metoprolol|<span style="color:white;">Metoprolol</span>]]:<br />
:PO: 25 to 50 mg every 6 hours<br />
:IV: 5 mg every 5 min, up to 3 doses, then 25 to 50 mg orally every 6 hours<br />
:❑ [[Carvedilol|<span style="color:white;">Carvedilol</span>]] IV, 25 mg, two times a day<br />
<span style="font-size:85%;">Contraindicated in [[heart failure|<span style="color:white;">heart failure</span>]], bradycardia, hypotension (SBP<90 mmHg), [[AV block |<span style="color:white;">second or third degree AV block</span>]], [[reactive airway disease|<span style="color:white;">reactive airway disease</span>]], high risk of [[cardiogenic shock|<span style="color:white;">cardiogenic shock</span>]] and low [[cardiac output|<span style="color:white;">cardiac output</span>]] state</span> <br><br />
❑ Administer IV [[morphine|<span style="color:white;">morphine</span>]] if persistent symptoms (IIb-B) or [[pulmonary edema|<span style="color:white;">pulmonary edema</span>]]<br />
:❑ Initial dose 4-8 mg<br />
:❑ 2-8 mg every 5 to 15 minutes, as needed <br><br />
❑ Administer 80 mg [[atorvastatin|<span style="color:white;">atorvastatin</span>]] (I-A)<br><br />
❑ Monitor with a 12-lead [[ECG|<span style="color:white;">ECG</span>]] all the time<br />
</div>}}<br />
{{familytree |boxstyle=background: #FA8072; color: #F8F8FF; | | | | |!| | | }}<br />
{{familytree |boxstyle=background: #FA8072; color: #F8F8FF; | | | | G01 | G01= <div style="float: left; text-align: left; width: 17em; padding:1em;"> {{fontcolor|#000000|'''TRIAGE FOR IMMEDIATE INTERVENTION'''}} <br>'''Does the patient have ANY of the following indications that require immediate angiography and revascularization ?'''<br />
❑ Hemodynamic instability or [[cardiogenic shock|<span style="color:white;">cardiogenic shock</span>]], '''OR''' <br><br />
❑ Severe left ventricular dysfunction or [[heart failure|<span style="color:white;">heart failure</span>]], '''OR''' <br><br />
❑ Recurrent or persistent rest angina despite intensive medical therapy, '''OR''' <br><br />
❑ New or worsening [[mitral regurgitation|<span style="color:white;">mitral regurgitation</span>]] or new [[VSD|<span style="color:white;">VSD</span>]], '''OR''' <br><br />
❑ Sustained [[VT|<span style="color:white;">VT</span>]] or [[VF|<span style="color:white;">VF</span>]], '''OR''' <br><br />
❑ Prior [[PCI|<span style="color:white;">PCI</span>]] within past 6 months or [[CABG|<span style="color:white;">CABG</span>]] <br> </div> }}<br />
{{familytree |boxstyle=background: #FA8072; color: #F8F8FF; | |,|-|-|^|-|-|.| | }}<br />
{{familytree |boxstyle=background: #FA8072; color: #F8F8FF; | C01 | | | | C02 | | | C01=<div style="float: left; text-align: center; width: 17em; padding:1em;">'''YES''' </div>| C02= <div style="float: left; text-align: center; width: 17em; padding:1em;">'''NO''' </div> }}<br />
{{familytree |boxstyle=background: #FA8072; color: #F8F8FF; | |!| | | | | |!| | | | }}<br />
{{familytree |boxstyle=background: #FA8072; color: #F8F8FF; | |!| | | | | C03 | | | C03=<div style="float: left; text-align: left; width: 17em; padding:1em;">Does the patient have no ECG changes '''AND''' no rise in cardiac biomarkers > 99th percentile of ULN?</div>}}<br />
{{familytree |boxstyle=background: #FA8072; color: #F8F8FF; | |!| | | |,|-|^|-|.| | }}<br />
{{familytree |boxstyle=background: #FA8072; color: #F8F8FF; | |!| | | C04 | | C05 | C04= <div style="float: left; text-align: left; width: 17em; padding:1em;">Yes. The patient has no ECG changes AND no rise in cardiac biomarkers > 99th percentile of ULN. </div>| C05= <div style="float: left; text-align: left; width: 17em; padding:1em;">No. The patient has either positive ECG changes, OR rise in cardiac biomarkers, OR both. </div>}}<br />
{{familytree |boxstyle=background: #FA8072; color: #F8F8FF; | |!| | | |!| | | |!| | }} <br />
{{familytree |boxstyle=background: #FA8072; color: #F8F8FF; | |!| | | C06 | | |!| | C06= <div style="float: left; text-align: left; width: 17em; padding:1em;">Repeat ECG and biomarkers within next 3 hours and 6 hours <br><br> '''Does the patient still have no ECG changes '''AND''' no rise in cardiac biomarkers?'''</div>}} <br />
{{familytree |boxstyle=background: #FA8072; color: #F8F8FF; | |!| |,|^|-|-|.| |!| }}<br />
{{familytree |boxstyle=background: #FA8072; color: #F8F8FF; | |!| C07 | | C08 |!| C07= <div style="float: left; text-align: left; width: 17em; padding:1em;">Yes. The patient has no ECG changes AND no rise in cardiac biomarkers.</div>| C08= <div style="float: left; text-align: left; width: 17em; padding:1em;">No. The patient has either positive ECG changes, OR rise in cardiac biomarkers, OR both.</div>}}<br />
{{familytree |boxstyle=background: #FA8072; color: #F8F8FF; | |!| |!| | | |!| |!| }}<br />
{{familytree |boxstyle=background: #FA8072; color: #F8F8FF; | |!|C09 | | | C10 | | | C09= <div style="float: left; text-align: left; width: 17em; padding:1em;">[[Chest pain resident survival guide#Complete Diagnostic Approach|Proceed to complete diagnostic approach of chest pain to rule out differential diagnoses]]</div>| C10=<div style="float: left; text-align: left; width: 17em; padding:1em;">{{fontcolor|#000000|''' TRIAGE FOR INITIAL CONSERVATIVE OR INVASIVE THERAPY'''}} <br>'''Calculate the risk of future adverse clinical outcomes:'''<br><br />
❑ [[TIMI risk score|<span style="color:white;">Thrombolysis in Myocardial Infarction (TIMI) risk score</span>]], '''OR'''<br />
❑ [[GRACE score|<span style="color:white;">GRACE score</span>]] </div>}}<br />
{{familytree |boxstyle=background: #FA8072; color: #F8F8FF; | |!| | | |,|-|-|^|.| | }}<br />
{{familytree |boxstyle=background: #FA8072; color: #F8F8FF; | |!| | | C11 | | C12 | C11= '''Intermediate or high risk''' | C12= '''Low risk'''}}<br />
{{familytree |boxstyle=background: #FA8072; color: #F8F8FF; | |!| | | |!| | | |!| | }}<br />
{{familytree |boxstyle=background: #FA8072; color: #F8F8FF; | D01 | | D02 | | D03 | |D01=<div style="float: left; text-align: center; width: 17em; padding:1em;"> '''INITIAL INVASIVE THERAPY (IMMEDIATELY)'''<br></div><br />
| D02= <div style="float: left; text-align: center; width: 17em; padding:1em;">'''INITIAL INVASIVE THERAPY (4 to 48 hours)''' </div>| D03= <div style="float: left; text-align: center; width: 17em; padding:1em;"> '''INITIAL CONSERVATIVE THERAPY ''' </div>}}<br />
{{familytree |boxstyle=background: #FA8072; color: #F8F8FF; | | |!| |!| | | | |!| | }}<br />
{{familytree |boxstyle=background: #FA8072; color: #F8F8FF; | | | E02 | | | | E03 | |E02=<div style="float: left; text-align: left; width: 17em; padding:1em;">'''Initiate ONE of the following anticoagulant therapy (I-A)'''<br> <br />
❑ Enoxaparin (I-A)<br><br />
:❑ SC 1 mg/kg every 12 hours if CrCL≥ 30 mL/min<br />
:❑ SC 1 mg/kg every 12 hours if CrCL< 30 mL/min<br />
:❑ Initial IV 30 mg loading dose in selected patients<br />
'''OR''' <br><br />
❑ IV [[UFH|<span style="color:white;">Unfractionated heparin</span>]] (and adjust dose for apTT) for 48 hours or until PCI is perfomed (I-B)<br><br />
:❑ Initial loading dose 60 IU/kg (max 40,000 IU) <br><br />
:❑ Initial infusion 12 IU/kg/h (max 10,000 IU)<br>'''OR''' <br><br />
❑ [[Bivalirudin|<span style="color:white;">Bivalirudin</span>]] (I-B)<br />
::❑ Loading dose 0.1-mg/kg IV bolus, then 0.25–mg/kg/h infusion<br />
<br>'''OR''' <br><br />
❑ Fondaparinux , SC 2.5 mg daily (I-B)<br />
<br><br>'''PLUS'''<br><br><br />
'''Administer ONE of the following antiplatelet agents (before OR at the time of PCI) (I-A)'''<br><br />
❑ Loading dose of [[P2Y12|<span style="color:white;">P2Y12</span>]] receptor inhibitors <br><br />
:❑ [[Clopidogrel|<span style="color:white;">Clopidogrel</span>]] (I-B if before PCI, I-A if at time of PCI)<br />
::Loading dose: 300 mg or 600 mg<br />
:: Maintenance dose: 75 mg OD<br />
<br>'''OR''' <br><br />
:❑ [[Ticagrelor|<span style="color:white;">Ticagrelor</span>]] (I-B)<br />
::Loading dose: 180 mg<br />
:: Maintenance dose: 90 mg BID<br />
<br>'''OR''' <br><br />
:❑ Prasugrel ONLY AT THE TIME OF PCI, AND NOT PRE-PCI (I-B)<br><br />
::Loading dose: 60 mg<br />
:: Maintenance dose: 10 mg OD<br />
<span style="font-size:85%;">Prasugrel is contraindicated in case of prior history of strokes or TIAs, active pathological bleeding, age ≥75 years, when urgent coronary artery bypass graft surgery (CABG) is likely, body weight <60 kg, propensity to bleed, concomitant use of medications that increase the risk of bleeding</span><br>'''OR''' <br><br />
❑ IV [[GP IIb/IIIa|<span style="color:white;">GP IIb/IIIa</span>]] inhibitors (IIb-B)<br><br />
:❑ [[Eptifibatide|<span style="color:white;">Eptifibatide</span>]]<br><br />
::❑ Loading dose 180 mcg/kg IV bolus followed by another bolus after 10 minutes<br><br />
::❑ Maintenance dose 2 mcg/kg/min<br>'''OR''' <br><br />
:❑ [[Tirofiban|<span style="color:white;">Tirofiban</span>]] <br><br />
::❑ Loading dose 25 mcg/kg<br><br />
::❑ Maintenance dose 0.15 mcg/kg/min </div><br />
|E03=<div style="float: left; text-align: left; width: 17em; padding:1em;">'''Initiate ONE of the following anticoagulant therapy (I-A)'''<br><br />
❑ Enoxaparin (I-A)<br>'''OR''' <br><br />
❑ UFH (I-A)<br>'''OR''' <br><br />
❑ Fondaparinux (I-B)<br>'''OR''' <br><br />
:''Enoxaparin or fondaparinux preferred over UFH (II-B)''<br />
<br><br> '''PLUS'''<br><br><br />
'''Administer ONE of the following antiplatelet agents (I-B):'''<br><br />
❑ [[P2Y12]] receptor inhibitors <br><br />
:❑ [[Clopidogrel]]<br><br />
::❑ Loading dose (300 mg or 600 mg)<br><br />
::❑ Maintenance dose (75 mg)<br>'''OR''' <br><br />
:❑ [[Ticagrelor]]<br><br />
::❑ Loading dose (180 mg)<br><br />
::❑ Maintenance dose (90 mg twice daily)<br>'''OR''' <br><br />
</div>}}<br />
{{familytree |boxstyle=background: #FA8072; color: #F8F8FF; | | | |!| | | | | |!| | }}<br />
{{familytree |boxstyle=background: #FA8072; color: #F8F8FF; | | | |!| | | | | F01 | |F01=<div style="float: left; text-align: left; width: 17em; padding:1em;">{{fontcolor|#000000|'''TRIAGE FOR NEED OF INVASIVE THERAPY'''}} <br>'''Does the patient experience ANY of the following?''' <br><br />
❑ Recurrence of symptoms, OR<br><br />
❑ [[Heart failure|<span style="color:white;">Heart failure</span>]], OR<br><br />
❑ Serious [[arrhythmia|<span style="color:white;">arrhythmia</span>]], OR<br><br />
❑ Subsequent ischemia</div>}}<br />
{{familytree |boxstyle=background: #FA8072; color: #F8F8FF; | | | |!| |,|-|-|-|^|.| }}<br />
{{familytree |boxstyle=background: #FA8072; color: #F8F8FF; | | | |!| G01 | | G02 | G01= YES| G02= NO}}<br />
{{familytree |boxstyle=background: #FA8072; color: #F8F8FF; | | | |!| |!| | | |!| }}<br />
{{familytree |boxstyle=background: #FA8072; color: #F8F8FF; | | | |!| H01 | | H02 | H01= <div style="float: left; text-align: left; width: 17em; padding:1em;"> '''PROCEED TO INVASIVE THERAPY (I-A)''' <br><br />
'''Administer ONE of the following antiplatelet agents if not already administered (I-A):'''<br><br />
:''The antiplatelet should be administered upstream (I-C)''<br />
❑ [[P2Y12]] receptor inhibitors <br><br />
:❑ [[Clopidogrel]] (I-B)<br><br />
::❑ Loading dose (300 mg or 600 mg)<br><br />
::❑ Maintenance dose (75 mg)<br>'''OR''' <br><br />
:❑ [[Ticagrelor]] (I-B)<br><br />
::❑ Loading dose (180 mg)<br><br />
::❑ Maintenance dose (90 mg twice daily)<br>'''OR''' <br><br />
❑ IV [[GP IIb/IIIa]] inhibitors (I-A)<br><br />
:❑ [[Eptifibatide]]<br><br />
::❑ Loading dose 180 mcg/kg IV bolus followed by another bolus after 10 minutes<br><br />
::❑ Maintenance dose 2 mcg/kg/min<br>'''OR''' <br><br />
:❑ [[Tirofiban]] <br><br />
::❑ Loading dose 25 mcg/kg<br><br />
::❑ Maintenance dose 0.15 mcg/kg/min<br></div><br />
| H02= <div style="float: left; text-align: left; width: 17em; padding:1em;">{{fontcolor|#000000|'''TRIAGE PATIENTS BY RISK ON STRESS TEST'''}} <br>❑ Perform a [[stress test]] (I-B) </div>}}<br />
{{familytree |boxstyle=background: #FA8072; color: #F8F8FF; | | | |!|!| |,|-|-|^|.|}}<br />
{{familytree |boxstyle=background: #FA8072; color: #F8F8FF; | | | |!|!| I01 | | I02 | I01= <div style="float: left; text-align: left; width: 17em; padding:1em;">'''High risk on stress test''' </div>| I02= <div style="float: left; text-align: left; width: 17em; padding:1em;">'''Low risk on stress test OR did not undergo stress test''' </div>}}<br />
{{familytree |boxstyle=background: #FA8072; color: #F8F8FF; | | | |!|!| |!| | | |!| | }}<br />
{{familytree |boxstyle=background: #FA8072; color: #F8F8FF; | | | |!|!| J01 | | |!| | J01= <div style="float: left; text-align: left; width: 17em; padding:1em;"> '''INVASIVE THERAPY''' <br>❑ Perform diagnostic [[angiography]] (I-A) </div>}}<br />
{{familytree |boxstyle=background: #FA8072; color: #F8F8FF; | | | |!|!|!| | | | K01 | K01= <div style="float: left; text-align: left; width: 17em; padding:1em;"> ❑ Continue [[aspirin]] for life (I-A)<br> ❑ Continue [[P2Y12]] receptor inhibitors up to 12 months (I-B)<br><br />
:❑ [[Clopidogrel]] (75 mg once a day)<br>'''OR''' <br><br />
:❑ [[Ticagrelor]] (90 mg twice a day)<br><br />
❑ Discontinue [[GP IIb/IIIa]] inhibitors if administered earlier (I-A)<br><br />
❑ Continue [[antithrombotic]] therapy:<br><br />
:❑ [[UFH]] for 48 hours (I-A)<br>'''OR''' <br><br />
:❑ [[Enoxaparin]] for duration of hospitalization (up to 8 days) (I-A)<br>'''OR''' <br><br />
:❑ [[Fondaparinux]] for duration of hospitalization (up to 8 days) (I-B)<br />
❑ Measure LVEF (I-B)</div>}}<br />
{{familytree |boxstyle=background: #FA8072; color: #F8F8FF; | | | |!|!|!| | | | | |}}<br />
{{familytree |boxstyle=background: #FA8072; color: #F8F8FF; | | | | C01 | | | | | | | | C01= <div style="float: left; text-align: left; width: 17em; padding:1em;">{{fontcolor|#000000|'''TRIAGE FOR SUBSEQUENT THERAPY PLAN FOLLOWING ANGIOGRAPHY'''}} <br> Does the [[angiography]] show coronary vessel obstruction ?</div> }}<br />
{{familytree |boxstyle=background: #FA8072; color: #F8F8FF; | | |,|-|^|-|-|.| | | | | }}<br />
{{familytree |boxstyle=background: #FA8072; color: #F8F8FF; | | D01 | | | | D02 | | | | D01= '''No'''| D02= '''Yes'''}}<br />
{{familytree |boxstyle=background: #FA8072; color: #F8F8FF; | | |!| | | |,|-|^|-|-|-|-|-|.| | | }}<br />
{{familytree |boxstyle=background: #FA8072; color: #F8F8FF; | | |!| | | E01 | | E02 | | E03 | | E01=<div style="float: left; text-align: left; width: 17em; padding:1em;">❑ 1 or 2 vessel disease <br> ''[[CABG]] or medical therapy might also be considered'' </div>|E02=<div style="float: left; text-align: left; width: 17em; padding:1em;">❑ Left main coronary artery disease <br>❑ 3 vessel disease <br>❑ 2 vessel disease with proximal left anterior descending artery affection <br>❑ [[Left ventricular dysfunction]] <br> ❑Patient treated from [[diabetes]]</div>| E03= }}<br />
{{familytree |boxstyle=background: #FA8072; color: #F8F8FF; | | |!| | | |!| | | |!| | | |!| | |}}<br />
{{familytree |boxstyle=background: #FA8072; color: #F8F8FF; | | L03 | | L01 | | L02 | | L03 | | L01= '''[[PCI]]''' <br> <br />
| L02= '''[[CABG]]''' <BR><br />
| L03= '''Medical treatment'''}}<br />
{{familytree |boxstyle=background: #FA8072; color: #F8F8FF; | | |!| | | |!| | | |!| | | |!| | | }}<br />
{{familytree |boxstyle=background: #FA8072; color: #F8F8FF; | | M01 | | M02 | | M03 | | M04 | | M01= <div style="float: left; text-align: left; width: 17em; padding:1em;"><br />
❑ Administer aspirin indefinitely <br><br />
❑ Administer additional antiplatelet therapy ''at the discretion of the physician'' (I-C)<br><br />
❑ Administer anticoagulant therapy ''at the discretion of the physician'' (I-C)</div><br />
|M02= <div style="float: left; text-align: left; width: 17em; padding:1em;"> ❑ Administer [[aspirin]] for life <br><br />
❑ Administer a loading dose of [[P2Y12]] receptor inhibitor (if not initially started)<br><br />
:❑ [[Clopidogrel]] 300 mg or 600 mg<br>'''OR''' <br><br />
:❑ [[Ticagrelor]] 180 mg<br>'''OR''' <br><br />
:❑ [[Prasugrel]] 60 mg<br>'''OR''' <br><br />
❑ Discontinue anticoagulant therapy following PCI in uncomplicated cases (I-B)</div><br />
| M03=<div style="float: left; text-align: left; width: 17em; padding:1em;"><br />
❑ Continue [[aspirin]] (I-A)<br><br />
❑ Discontinue IV [[GP IIb/IIIa]] inhibitors (4 hours before CABG) (I-B)<br><br />
❑ Manage the P2Y12 receptor inhibitor therapy as follows ''if CABG can be delayed'' (depending on whether benefits of CABG outweigh the risk of bleeding) (I-B):<br><br />
:❑ Discontinue clopidogrel if started before angiography (5 days prior to CABG) (I-B)<br><br />
:❑ Discontinue ticagrelor if started before angiography (5 days prior to CABG) (I-C)<br><br />
:❑ Discontinue prasugrel if started before angiography (7 days prior to CABG) (I-C)<br><br />
❑ Manage the [[anticoagulation]] therapy <br><br />
:❑ Continue [[UFH]] (I-B)<br />
:❑ Discontinue [[enoxaparin]] if started before angiography (12-24 hours prior to CABG) and dose with UFH (I-B)<br><br />
:❑ Discontinue [[fondaparinux]] if started before angiography (24 hours prior to CABG) and dose with UFH (I-B)<br><br />
:❑ Discontinue [[bivalirudin]] if started before angiography (3 hours prior to CABG) and dose with UFH (I-B)</div><br />
|M04= <div style="float: left; text-align: left; width: 17em; padding:1em;"> ❑ Continue [[aspirin]] (I-A)<br><br />
❑ Administer a loading dose of [[P2Y12]] receptor inhibitors ''if not given before angiography'' (I-B)<br />
:❑ [[Clopidogrel]] (300 mg or 600 mg)<br>'''OR''' <br><br />
:❑ [[Prasugrel]] (60 mg) <br><br />
❑ Discontinue IV [[GP IIb/IIIa]] inhibitors if started before angiography (I-B)<br><br />
❑ Manage [[antithrombotic]] therapy:<br />
:❑ Continue IV [[UFH]] for at least 48 hours or until discharge if started before angiography (I-A)<br><br />
:❑ Continue [[enoxaparin]] for entire hospital stay, up to 8 days if started before angiography (I-A)<br><br />
:❑ Continue [[fondaparinux]] for entire hospital stay, up to 8 days if started before angiography (I-B)<br><br />
:❑ Discontinue [[bivalirudin]] or continue at 0.25 mg/kg/hour for up to 72 hours (I-B)</div> }}<br />
{{familytree/end}}<br />
<br />
==Complete Diagnostic Approach==<br />
A complete diagnostic approach should be carried out after a focused initial rapid evaluation is conducted and following initiation of any urgent intervention.<ref name="pmid22809746">{{cite journal| author=Jneid H, Anderson JL, Wright RS, Adams CD, Bridges CR, Casey DE et al.| title=2012 ACCF/AHA focused update of the guideline for the management of patients with unstable angina/non-ST-elevation myocardial infarction (updating the 2007 guideline and replacing the 2011 focused update): a report of the American College of Cardiology Foundation/American Heart Association Task Force on Practice Guidelines. | journal=J Am Coll Cardiol | year= 2012 | volume= 60 | issue= 7 | pages= 645-81 | pmid=22809746 | doi=10.1016/j.jacc.2012.06.004 | pmc= | url=http://www.ncbi.nlm.nih.gov/entrez/eutils/elink.fcgi?dbfrom=pubmed&tool=sumsearch.org/cite&retmode=ref&cmd=prlinks&id=22809746 }} </ref><br />
<br />
<span style="font-size:85%"> '''Abbreviations:''' '''CABG:''' [[coronary artery bypass graft]]; '''ECG:''' [[electrocardiogram]]; '''LAD:''' [[LAD|left anterior descending]]; '''LBBB:''' [[left bundle branch block]]; '''MI:''' [[myocardial infarction]]; '''PCI:''' [[percutaneous coronary intervention]]; '''S3:''' [[S3|third heart sound]]; '''S4:''' [[S4|fourth heart sound]]; '''VSD:''' [[ventricular septal defect]] </span><br />
<br />
{{Family tree/start}}<br />
{{familytree | A01 | | A01=<div style="float: left; text-align: left; width: 28em; padding:1em;"> '''Characterize the symptoms:''' <br><br />
❑ [[Chest pain]] or [[chest discomfort]] <br><br />
:❑ Sudden onset<br />
:❑ Sensation of heaviness, tightness, pressure, or squeezing<br />
:❑ Duration> 20 minutes <br><br />
:❑ Radiation to the left arm, jaw, neck, right arm, back or [[epigastrium]]<br />
:❑ No relief with rest <br><br />
:❑ Worse with time <br><br />
:❑ Worse with exertion<br><br />
❑ [[Dyspnea]] <br><br />
❑ [[Weakness]] <br><br />
❑ [[Palpitations]] <br><br />
❑ [[Nausea]] <br><br />
❑ [[Vomiting]] <br><br />
❑ [[Sweating]] <br><br />
❑ [[Loss of consciousness]]<br><br />
❑ [[Fatigue]]<br />
</div>}}<br />
{{familytree | |!| | |}}<br />
{{familytree | B01 | | B01=<div style="float: left; text-align: left; width: 35em; padding:1em;"> '''Obtain a detailed history:''' <br><br />
❑ Age <br><br />
❑ Baseline [[blood pressure]] <br><br />
❑ Previous episodes of [[chest pain]] <br><br />
❑ Previous [[PCI]] or [[CABG]] <br><br />
❑ Cardiac risk factors<br><br />
:❑ [[Hypertension]] <br><br />
:❑ [[Diabetes]] <br><br />
:❑ [[Hypercholesterolemia]] <br><br />
:❑ [[Smoking]] <br><br />
:❑ [[Obesity]] <br><br />
❑ List of medications <br><br />
❑ Family history of premature [[coronary artery disease]]<br />
----<br />
'''Identify possible triggers:'''<br><br />
❑ Physical exertion <br><br />
❑ Air pollution or fine particulate matter <br><br />
❑ Antecedant infection <br><br />
❑ Heavy meal <br><br />
❑ [[Cocaine]] <br><br />
❑ [[Marijuana]]</div>}}<br />
{{familytree | |!| | | }}<br />
{{familytree | C01 | | C01=<div style="float: left; text-align: left; width: 35em; padding:1em;">'''Examine the patient:''' <br><br />
<br />
'''Vital signs''' <br><br />
❑ [[Blood pressure]] <br><br />
:❑ [[Blood pressure]] lower than baseline, suggestive of:<br />
:❑ Discrepancy between arms (suggestive of [[aortic dissection]])<br />
:❑ Narrow [[pulse pressure]] (suggestive of [[heart failure]])<br />
<br />
❑ [[Heart rate]] <br><br />
:❑ [[Tachycardia]] (suggestive of [[heart failure]])<br />
:❑ [[Bradycardia]] (suggestive of [[heart block]] or [[bradyarrhythmias]])<br />
<br />
'''Pulses''' <br><br />
❑ [[Femoral artery|Femoral pulse]] (if a patient is to undergo [[PCI]])<br><br />
:❑ Strength<br />
:❑ [[Bruits]]<br />
<br />
'''Skin''' <br><br />
❑ [[Xanthelasma]] (suggestive of [[dyslipidemia]]) <br><br />
❑ [[Xanthoma]] (suggestive of [[dyslipidemia]]) <br><br />
❑ [[Edema]] (suggestive of [[heart failure]])<br><br />
❑ [[Cyanosis|Cyanotic]] and cold skin, lips, nail bed (suggestive of [[cardiogenic shock]]) <br><br />
<br />
'''Heart''' <br><br />
❑ [[Heart sounds]]<br><br />
:❑ [[S3]] (suggestive of [[heart failure]])<br />
:❑ [[S4]] (associated with conditions that increase the stiffness of the ventricle)<br />
❑ [[Murmurs]]<br />
:❑ [[Aortic regurgitation]]: early diastolic high-pitched sound best heard at the left sternal border (suggestive of [[aortic dissection]] with propagation to the aortic arch)<br />
❑ [[Friction rub|Pericardial friction rub]] (suggestive of [[pericarditis]])<br />
<br />
'''Lungs''' <br><br />
❑ [[Rales]] (suggestive of [[heart failure]]) <br><br />
</div>}}<br />
{{familytree | |!| | }}<br />
{{familytree | E01 | E01= <div style="float: left; width: 28em; text-align: left;">'''Order labs and tests:''' <br><br />
❑ [[EKG]] <br><br />
❑ Biomarkers <br><br />
:❑ Troponin I<br><br />
:❑ CK-MB <br><br />
❑ [[Echocardiography]]<br />
❑ [[Creatinine]] <br><br />
❑ [[Glucose]] <br><br />
❑ [[Hemoglobin]]<br><br />
❑ Multislice CT coronary imaging (rule out [[CAD]] as cause of pain in<br />
patients with low to intermediate likelihood of [[CAD]] and when [[troponin]] and [[ECG]] are<br />
inconclusive)<ref>{{Cite web | last = | first = | title = http://eurheartj.oxfordjournals.org/content/32/23/2999.full.pdf | url = http://eurheartj.oxfordjournals.org/content/32/23/2999.full.pdf | publisher = | date = | accessdate = }}</ref> <br><br />
❑ [[MRI]] (integrate imaging of function, perfusion and necrosis)<ref>{{Cite web | last = | first = | title = http://eurheartj.oxfordjournals.org/content/32/23/2999.full.pdf | url = http://eurheartj.oxfordjournals.org/content/32/23/2999.full.pdf | publisher = | date = | accessdate = }}</ref><br />
</div>}}<br />
{{Family tree/end}}<br />
<br />
==Pre-Discharge Care==<br />
<span style="font-size:85%"> '''Abbreviations:''' '''ACE:''' [[angiotensin converting enzyme]]; '''LVEF:''' [[left ventricular ejection fraction]]; '''PCI:''' [[percutaneous coronary intervention]]; '''PO:''' per os; '''VF:''' [[ventricular fibrillation]]; '''VT:''' [[ventricular tachycardia]] </span><br />
<br />
{{Family tree/start}}<br />
{{familytree | A01 | | |A01= <div style="float: left; text-align: left; width: 30em; padding:1em;">'''Administer the following medications in patients without contraindications:'''<br><br />
❑ [[Aspirin]] 81-325 mg (indefinitely) (I-A)<br><br />
:''Among patients with either GI intolerance or hypersensitivity to aspirin, administer a loading dose followed by maintenance dose of either clopidogrel 75 mg OD (I-B), OR prasugrel 10 mg OD (only in PCI patients) (I-C), OR ticagrelor 90 mg BID (I-C)'' <br><br />
❑ [[Beta blockers]] <br><br />
<span style="font-size:85%;color:red">Contraindicated in heart failure, prolonged or high degree AV block, reactive airway disease, high risk of cardiogenic shock and low cardiac output state</span> :❑ [[Metoprolol tartrate]]<br />
::❑ Begin with 25 to 50 mg PO every 6 to 12 hour<br />
::❑ Then, [[metoprolol tartrate]] twice daily or [[metoprolol succinate]] once daily for 2-3 days<br />
::❑ Titate to 200 mg daily, OR<br />
:❑ [[Carvedilol]]<br />
::❑ Begin with 6.25 mg twice daily<br />
::❑ Titrate to 25 mg twice daily<br />
❑ [[Calcium channel blockers]] are used as anti-ischemic or antihypertensive drugs and also in [[atrial fibrillation]] when [[beta blockers]] are contraindicated <br><br />
<span style="font-size:85%;color:red">Contraindicated in heart failure and left ventricular dysfunction</span> <br><br />
❑ [[ACE]] inhibitors and [[ARBs]] may also be considered in selected patients (no enough information)<ref name="www.ncbi.nlm.nih.gov">{{Cite web | last = | first = | title = Therapeutic effects of captopril on ischemia and ... [Am Heart J. 1994] - PubMed - NCBI | url = http://www.ncbi.nlm.nih.gov/pubmed?term=8273728 | publisher = | date = | accessdate = }}</ref><br />
<br><br />
<span style="font-size:85%;color:red">Contraindicated in hypotension, renal failure and hyperkalemia</span> <br><br />
❑ [[Atorvastatin]] 80 mg daily<br />
----<br />
'''Administer ONE of the following antiplatelet therapy for a duration of:'''<br />
: '''Up to 12 months in medically treated with no stenting (I-B)'''<br />
: '''Up to 12 months in BMS (I-B)'''<br />
: '''At least 12 months in DES (I-B)'''<br />
❑ [[Clopidogrel]] 75 mg daily, OR <br><br />
❑ [[Ticagrelor]] 90 mg twice a day, OR <br><br />
❑ [[Prasugrel]] 10 mg daily '''only for patients who underwent PCI'''<br><br />
<br><br />
<br />
<span style="font-size:85%;color:red">Consider earlier discontinuation in case bleeding risk exceeds benefit of the antiplatelet therapy (I-C).</span> <br><br />
----<br />
'''Assess the patient for ischemia:'''<br><br />
❑ Perform non invasive testing before discharge for the evaluation of ischemia among patients who did not undergo [[coronary angiography]] and in whom [[coronary angiography]] is not warranted due to the absence of high risk features ([[ACC AHA guidelines classification scheme|Class I, level of evidence B]]) <br><br />
❑ Assess the [[LVEF]] ([[ACC AHA guidelines classification scheme|Class I, level of evidence C]])<br />
</div>}}<br />
{{familytree/end}}<br />
<br />
<br />
<span style="font-size:85%"> '''Abbreviations:''' '''ACE:''' [[angiotensin converting enzyme]]; '''ARB:''' [[angiotensin receptor blocker]];</span><br />
<br />
{{Family tree/start}}<br />
{{familytree | A01 | | A01= <div style="float: left; text-align: left; width: 30em; padding:1em;"> ❑ Prepare a list of all the home medications and educate the patient about compliance<br />
:❑ [[Aspirin]] 81-325 mg (indefinitely) <br />
:❑ [[Antiplatelet drug|Antiplatelet therapy]]<br />
:❑ [[Beta blockers]]<br />
:❑ [[ACE inhibitors]] or [[ARB]] (only in selected patients <ref name="ACE">{{Cite web | last = | first = | title = Therapeutic effects of captopril on ischemia and ... [Am Heart J. 1994] - PubMed - NCBI | url = http://www.ncbi.nlm.nih.gov/pubmed?term=8273728 | publisher = | date = | accessdate = }}</ref><br />
<br />
:❑ [[Atorvastatin]] 80 mg daily<br />
❑ Encourage lifestyle modification <br><br />
:❑ [[Smoking]] cessation<br />
:❑ Physical activity<br />
:❑ Dietary changes<br />
❑ Ensure the initiation of the management of comorbidities<br />
:❑ [[Obesity]]<br />
:❑ [[Dyslipidemia]]<br />
:❑ [[Hypertension]]<br />
:❑ [[Diabetes]]<br />
:❑ [[Heart failure]]<br />
❑ Educate the patient about the early recognition of symptoms of [[acute coronary syndrome]]<br />
❑ Educate the patient about the use of [[nitroglycerin]] 0.4 mg, sublingually, up to 3 doses every 5 minutes </div> }}<br />
{{Family tree/end}}<br />
<br />
==Do's==<br />
* Administer a loading dose followed by a maintenance dose of [[clopidogrel]], [[ticagrelor]] or [[prasugrel]] (if [[PCI]] is planned) as initial treatment instead of [[aspirin]] among patients with gastrointestinal intolerance or hypersensitivity reaction to [[aspirin]].<br />
<br />
* Administer sublingual [[nitroglycerin]] in patients with ischemic [[chest pain]]; however, administer IV [[nitroglycerin]] among patients with persistent [[chest pain]] after three sublingual [[nitroglycerin]].<ref name="pmid6402912">{{cite journal| author=Kaplan K, Davison R, Parker M, Przybylek J, Teagarden JR, Lesch M| title=Intravenous nitroglycerin for the treatment of angina at rest unresponsive to standard nitrate therapy. | journal=Am J Cardiol | year= 1983 | volume= 51 | issue= 5 | pages= 694-8 | pmid=6402912 | doi= | pmc= | url=http://www.ncbi.nlm.nih.gov/entrez/eutils/elink.fcgi?dbfrom=pubmed&tool=sumsearch.org/cite&retmode=ref&cmd=prlinks&id=6402912 }} </ref><br />
<br />
*Discontinue [[NSAID]] drugs immediately. <ref name="pmid21224324">{{cite journal| author=Trelle S, Reichenbach S, Wandel S, Hildebrand P, Tschannen B, Villiger PM et al.| title=Cardiovascular safety of non-steroidal anti-inflammatory drugs: network meta-analysis. | journal=BMJ | year= 2011 | volume= 342 | issue= | pages= c7086 | pmid=21224324 | doi=10.1136/bmj.c7086 | pmc=PMC3019238 | url=http://www.ncbi.nlm.nih.gov/entrez/eutils/elink.fcgi?dbfrom=pubmed&tool=sumsearch.org/cite&retmode=ref&cmd=prlinks&id=21224324 }} [http://www.ncbi.nlm.nih.gov/entrez/eutils/elink.fcgi?dbfrom=pubmed&tool=sumsearch.org/cite&retmode=ref&cmd=prlinks&id=21460398 Review in: Evid Based Med. 2011 Oct;16(5):142-3] </ref> <ref name="pmid23726390">{{cite journal| author=Coxib and traditional NSAID Trialists' (CNT) Collaboration. Bhala N, Emberson J, Merhi A, Abramson S, Arber N et al.| title=Vascular and upper gastrointestinal effects of non-steroidal anti-inflammatory drugs: meta-analyses of individual participant data from randomised trials. | journal=Lancet | year= 2013 | volume= 382 | issue= 9894 | pages= 769-79 | pmid=23726390 | doi=10.1016/S0140-6736(13)60900-9 | pmc=PMC3778977 | url=http://www.ncbi.nlm.nih.gov/entrez/eutils/elink.fcgi?dbfrom=pubmed&tool=sumsearch.org/cite&retmode=ref&cmd=prlinks&id=23726390 }} [http://www.ncbi.nlm.nih.gov/entrez/eutils/elink.fcgi?dbfrom=pubmed&tool=sumsearch.org/cite&retmode=ref&cmd=prlinks&id=24126661 Review in: Ann Intern Med. 2013 Oct 15;159(8):JC12] </ref><br />
<br />
* If fondaparinux is chosen to be administered ad the anticoagulant therapy during PCI, co-administer another antocoagulant with factor IIa activity such as UFH.<br />
<br />
==Don'ts==<br />
* Do not administer IV [[GP IIb/IIIa inhibitors]] to patients with low risk of ischemic events or at high risk of [[bleeding]] and who are already on [[aspirin]] and P2Y12 receptor inhibitors therapy.<br />
<br />
* Do not administer [[prasugrel]] among patients with prior history of [[strokes]] or [[TIAs]].<br />
<br />
* Do not administer IV [[beta-blockers]] among hemodynamically unstable patients.<br />
<br />
* Do not administer a complete dose of [[prasugrel]] among patients under 60kg (132lbs) due to high exposure to the active metabolite. They should receive half the dose of [[prasugrel]] although there is no evidence that half the dose is as effective as a complete dose.<br />
<br />
* Do not administer fibrinolytic therapy to patients with [[unstable angina]].<ref name="pmid7475596">{{cite journal| author=Anderson HV| title=Intravenous thrombolysis in refractory unstable angina pectoris. | journal=Lancet | year= 1995 | volume= 346 | issue= 8983 | pages= 1113-4 | pmid=7475596 | doi= | pmc= | url=http://www.ncbi.nlm.nih.gov/entrez/eutils/elink.fcgi?dbfrom=pubmed&tool=sumsearch.org/cite&retmode=ref&cmd=prlinks&id=7475596 }} </ref><br />
<br />
*Do not administer [[abciximab]] for patients not scheduled for [[PCI]]. <ref name="pmid22809746">{{cite journal| author=Jneid H, Anderson JL, Wright RS, Adams CD, Bridges CR, Casey DE et al.| title=2012 ACCF/AHA focused update of the guideline for the management of patients with unstable angina/non-ST-elevation myocardial infarction (updating the 2007 guideline and replacing the 2011 focused update): a report of the American College of Cardiology Foundation/American Heart Association Task Force on Practice Guidelines. | journal=J Am Coll Cardiol | year= 2012 | volume= 60 | issue= 7 | pages= 645-81 | pmid=22809746 | doi=10.1016/j.jacc.2012.06.004 | pmc= | url=http://www.ncbi.nlm.nih.gov/entrez/eutils/elink.fcgi?dbfrom=pubmed&tool=sumsearch.org/cite&retmode=ref&cmd=prlinks&id=22809746 }} </ref><br />
<br />
* Do not administer 2 P2Y12 receptor inhibitors, even in the presence of hypersensitivity or GI interoperability to aspirin.<br />
<br />
==References==<br />
{{reflist|2}}<br />
<br />
[[Category:Emergency medicine]]<br />
[[Category:Medicine]]<br />
[[Category:Resident survival guide]]<br />
[[Category:Cardiology]]<br />
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</div></div>Rim Halaby