ST elevation myocardial infarction aspirin therapy: Difference between revisions
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Prostaglandins are local [[hormone]]s produced in the body and have diverse effects in the body, including the transmission of pain information to the brain, modulation of the [[hypothalamus|hypothalamic]] thermostat, and inflammation. Thromboxanes are responsible for the aggregation of [[platelet]]s that form [[clot|blood clots]]. Heart attacks are primarily caused by blood clots, and low doses of aspirin are seen as an effective medical intervention for acute [[myocardial infarction]]. The major side-effect of this is that because the ability of blood to clot is reduced, excessive bleeding may result from the use of aspirin. | Prostaglandins are local [[hormone]]s produced in the body and have diverse effects in the body, including the transmission of pain information to the brain, modulation of the [[hypothalamus|hypothalamic]] thermostat, and inflammation. Thromboxanes are responsible for the aggregation of [[platelet]]s that form [[clot|blood clots]]. Heart attacks are primarily caused by blood clots, and low doses of aspirin are seen as an effective medical intervention for acute [[myocardial infarction]]. The major side-effect of this is that because the ability of blood to clot is reduced, excessive bleeding may result from the use of aspirin. | ||
===COX-1 and COX-2 inhibition=== | |||
There are at least two different types of cyclooxygenase: COX-1 and COX-2. Aspirin irreversibly inhibits COX-1 and modifies the enzymatic activity of COX-2. Normally COX-2 produces prostanoids, most of which are pro-inflammatory. Aspirin-modified COX-2 produces lipoxins, most of which are anti-inflammatory. Newer NSAID drugs called [[COX-2 selective inhibitor]]s have been developed that inhibit only COX-2, with the intent to reduce the incidence of gastrointestinal side-effects.<ref name="cox3article" /> | |||
However, several of the new [[COX-2 selective inhibitor]]s, such as [[Vioxx]], have been withdrawn recently, after evidence emerged that COX-2 inhibitors increase the risk of heart attack. It is proposed that endothelial cells lining the microvasculature in the body express COX-2, and, by selectively inhibiting COX-2, prostaglandins (specifically PGI2; prostacyclin) are downregulated with respect to thromboxane levels, as COX-1 in platelets is unaffected. Thus, the protective anti-coagulative effect of [[PGI2]] is decreased, increasing the risk of thrombus and associated heart attacks and other circulatory problems. Since platelets have no DNA, they are unable to synthesize new COX once aspirin has irreversibly inhibited the enzyme, an important difference with reversible inhibitors. | |||
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Editor-In-Chief: C. Michael Gibson, M.S., M.D. [1]
Associate Editor-In-Chief: Cafer Zorkun, M.D., Ph.D. [2]
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Overview
Antiplatelet therapy with aspirin is a mainstay of pharmacotherapy in STEMI. In the International Study of Infarct Survival 2 (ISIS 2), aspirin reduced mortality in STEMI as much as streptokinase (by approximately 25%) when compared to the administration of neither agent. [1] Full doses of non-enteric coated aspirin should be administered as soon as possible to patients with STEMI if there are no contraindications (history of aspirin allergy or anaphylaxis to aspirin). Aspirin should be administered irrespective of the reperfusion strategy selected (either primary PCI or fibrinolytic administration).
Clinical trials supporting the administration of aspirin in STEMI
ISIS 2 was a landmark trial which randomized a total of 17,187 patients from 417 hospitals who presented within 24 hours (median 5 h) of STEMI symptom onset to one of 4 strategies:
- Streptokinase (1.5 million units) administered via the intravenous route over 1 hour or
- Aspirin (enteric coated at a dose of 160 mg/day) for one month or
- Both streptokinase and aspirin treatments or
- Neither treatemnt
Both streptokinase alone and aspirin alone were associated with a similar significant reduction in 5 week cardiovascular mortality:
- 9.2% (791/8592) incidence of cardiovascular deaths among streptokinase versus 12.0% (1029/8595) among placebo infusion patients (odds reduction: 25% +/- 4; p < 0.00001)
- 9.4% (804/8587) incidence of cardiovascular deaths among aspirin versus 11.8% (1016/8600) among placebo tablet patients (odds reduction: 23% +/- 4; p < 0.00001)
The combination of streptokinase and aspirin was associated with a significant reduction in cardiovascular mortality when compared to the administration of either agent alone (p < 0.0001). Furthermore, the effect of SK and ASA appeared to be additive as the mortality was only 8.0% (343/4292) among patients treated with both SK and ASA vs 13.2% (568/4300) among those treated with neither agent (42% +/- 5 relative risk reduction; 95% confidence limits 34% to 50%).
Streptokinase was associated with an increased risk of bleeding requiring transfusion (0.5% versus 0.2%) and intracranial hemmorhage (ICH) (0.1% versus 0.0%). Streptokinase was, however, assocaited with fewer non-ICH strokes (0.6% versus 0.8%).
Aspirin was associated with a significant reduction in nonfatal reinfarction (1.0% versus 2.0%) as well as nonfatal stroke (0.3% versus 0.6%). In contrast to streptokinase, aspirin was not associated with a significant increase in intracranial hemorrhage or bleeding requiring transfusion. Furthermore, while streptokinase alone was associated with an increased risk of reinfarction. The addition of aspirin to streptokinase eliminated of this increased risk of reinfarction associated with streptokinase administration.
History
Medicines containing derivatives of salicylic acid, structurally similar to aspirin, have been in medical use since ancient times. Salicylate-rich willow bark extract became recognized for its specific effects on fever, pain and inflammation in the mid-eighteenth century. By the nineteenth century pharmacists were experimenting with and prescribing a variety of chemicals related to salicylic acid, the active component of willow extract.
A French chemist, Charles Frederic Gerhardt, was the first to prepare acetylsalicylic acid in 1853 (patented under the name aspirin on March 6, 1899 [2]). In the course of his work on the synthesis and properties of various acid anhydrides, he mixed acetyl chloride with a sodium salt of salicylic acid (sodium salicylate). A vigorous reaction ensued, and the resulting melt soon solidified.[3] Since no structural theory existed at that time, Gerhardt called the compound he obtained "salicylic-acetic anhydride" (wasserfreie Salicylsäure-Essigsäure). This preparation of aspirin ("salicylic-acetic anhydride") was one of the many reactions Gerhardt conducted for his paper on anhydrides, but he did not pursue it further.
Six years later, in 1859, von Gilm obtained analytically pure acetylsalicylic acid (which he called "acetylierte Salicylsäure", acetylated salicylic acid) by a reaction of salicylic acid and acetyl chloride.[4] In 1869 Schröder, Prinzhorn and Kraut repeated both Gerhardt's (from sodium salicylate) and von Gilm's (from salicylic acid) syntheses and concluded that both reactions gave the same compound—acetylsalicylic acid. They were first to assign to it the correct structure with the acetyl group connected to the phenolic oxygen.[5]
In 1897, scientists at the drug and dye firm Bayer began investigating acetylsalicylic acid as a less-irritating replacement for standard common salicylate medicines. By 1899, Bayer had dubbed this drug Aspirin and was selling it around the world.[6]The name Aspirin is derived from A = Acetyl and "Spirsäure" = an old (German) name for salicylic acid.[7] Aspirin's popularity grew over the first half of the twentieth century, spurred by its effectiveness in the wake of the Spanish flu pandemic of 1918, and aspirin's profitability led to fierce competition and the proliferation of aspirin brands and products, especially after the American patent held by Bayer expired in 1917.[8][9]
Aspirin's popularity declined after the market releases of paracetamol (acetaminophen) in 1956 and ibuprofen in 1969.[10] In the 1960s and 1970s, John Vane and others discovered the basic mechanism of aspirin's effects, while clinical trials and other studies from the 1960s to the 1980s established aspirin's efficacy as an anti-clotting agent that reduces the risk of clotting diseases.[11] Aspirin sales revived considerably in the last decades of the twentieth century, and remain strong in the twenty-first, thanks to widespread use as a preventive treatment for heart attacks and strokes.[12]
Mechanism(s) of Benefit
Suppression of prostaglandins and thromboxanes
Aspirin's ability to suppress the production of prostaglandins and thromboxanes is due to its irreversible inactivation of the cyclooxygenase (COX) enzyme. Cyclooxygenase is required for prostaglandin and thromboxane synthesis. Aspirin acts as an acetylating agent where an acetyl group is covalently attached to a serine residue in the active site of the COX enzyme. This makes aspirin different from other NSAIDs (such as diclofenac and ibuprofen), which are reversible inhibitors.
Low-dose, long-term aspirin use irreversibly blocks the formation of thromboxane A2 in platelets, producing an inhibitory effect on platelet aggregation. This anticoagulant property makes aspirin useful for reducing the incidence of heart attacks.[13] 40 mg of aspirin a day is able to inhibit a large proportion of maximum thromboxane A2 release provoked acutely, with the prostaglandin I2 synthesis being little affected; however, higher doses of aspirin are required to attain further inhibition.[14]
Prostaglandins are local hormones produced in the body and have diverse effects in the body, including the transmission of pain information to the brain, modulation of the hypothalamic thermostat, and inflammation. Thromboxanes are responsible for the aggregation of platelets that form blood clots. Heart attacks are primarily caused by blood clots, and low doses of aspirin are seen as an effective medical intervention for acute myocardial infarction. The major side-effect of this is that because the ability of blood to clot is reduced, excessive bleeding may result from the use of aspirin.
COX-1 and COX-2 inhibition
There are at least two different types of cyclooxygenase: COX-1 and COX-2. Aspirin irreversibly inhibits COX-1 and modifies the enzymatic activity of COX-2. Normally COX-2 produces prostanoids, most of which are pro-inflammatory. Aspirin-modified COX-2 produces lipoxins, most of which are anti-inflammatory. Newer NSAID drugs called COX-2 selective inhibitors have been developed that inhibit only COX-2, with the intent to reduce the incidence of gastrointestinal side-effects.[15]
However, several of the new COX-2 selective inhibitors, such as Vioxx, have been withdrawn recently, after evidence emerged that COX-2 inhibitors increase the risk of heart attack. It is proposed that endothelial cells lining the microvasculature in the body express COX-2, and, by selectively inhibiting COX-2, prostaglandins (specifically PGI2; prostacyclin) are downregulated with respect to thromboxane levels, as COX-1 in platelets is unaffected. Thus, the protective anti-coagulative effect of PGI2 is decreased, increasing the risk of thrombus and associated heart attacks and other circulatory problems. Since platelets have no DNA, they are unable to synthesize new COX once aspirin has irreversibly inhibited the enzyme, an important difference with reversible inhibitors.
Dosing
If not given prior to hospital admission, Aspirin should be administered to all patients at a dose of 162 to 325 mg to chew and swallow, unless there is a compelling contraindication (e.g., history of anaphylactic reaction). Aspirin is generally administered orally and is rapidly absorbed in the stomach and upper intestine. Enteric coating may delay the absorption, and it is for this reason that not enteric coated aspirin is often administered in the setting of ST elevation MI. It should also be noted that aspirin can also be administered via the intravenous route.[16]
Efficacy and safety of low dose (162 mg) aspirin versus high dose (325 mg) aspirin in STEMI patients
Large, prospective, randomized trials randomizing STEMI patients to either low vs high doses of aspirin in STEMI are lacking. The 30 day mortality and bleeding risks associated with the administration of 162 mg versus 325 mg aspirin among patients with STEMI treated with thrombolytic therapy has been compared in a non-randomized retrospective analysis. [17][18] Data for the analysis was drawn from a total of 48,422 patients with acute ST segment elevation myocardial infarction in the GUSTO I and GUSTO III trials (Global Utilization of Streptokinase and Tissue Plasminogen Activator for Occluded Coronary Arteries). 24.4% of patients (n=11 828) were treated in a non-randomized fashio with an initial aspirin dose of 325 mg, and 75.6% (n=36 594) were treated with 162 mg. 24-hour mortality did not differ between the two doses: 2.9% for those receiving an initial aspirin dose of 325 mg versus 2.8% (P=0.894) for those receiving an initial aspirin dose 162 mg. 7 and 30 day mortality rates were 5.2% versus 4.9% (P=0.118) and 7.1% versus 6.5% (P=0.017) among patients receiving the 325 versus 162 mg aspirin respectively. After multivariate adjustment for imbalances in baseline characteristics, the initial aspirin dose was not associated with 24-hour (odds ratio [OR], 1.01; 95% CI, 0.82 to 1.25), 7-day (OR, 1.00; 95% CI, 0.87 to 1.17), or 30-day (OR, 0.99; 95% CI, 0.87 to 1.12) mortality rates. No significant difference was noted for reinfarction or the composite of death or reinfarction between the two aspirin dose groups. In-hospital moderate/severe bleeding occurred in 9.3% of those treated with 325 mg versus 12.2% among those receiving 162 mg (P<0.001). However, after adjustment for imbalances in baseline characteristics, an initial dose of 325 mg was associated with a significant increase in moderate/severe bleeding (OR, 1.14; 95% CI, 1.05 to 1.24; P=0.003) compared to an initial does of 162 mg.
This non-randomized data from trials conducted many years ago with a substantial use of streptokinase demonstrates that the initial dose of 162 mg aspirin may be as effective as and perhaps safer than 325 mg for the acute treatment of ST elevation myocardial infarction. These findings require confirmation in large randomized trials before a firm recommendation can be made regarding the optimal initial dose of aspirin in STEMI patients.
Side Effects and Contraindications
The use of aspirin is contraindicated in those with a hypersensitivity to salicylate.
Aspirin suppositories (300 mg) can be used safely and are the recommended route of administration for patients with severe nausea and vomiting or known upper-gastrointestinal disorders.
In patients with true aspirin allergy (hives, nasal polyps, bronchospasm, or anaphylaxis), clopidogrel or ticlopidine may be substituted.[19]
Guidelines (DO NOT EDIT)
Class I
- For all post Percutaneous Coronary Interventions (PCI) stented STEMI patients without aspirin resistance, allergy, or increased risk of bleeding, aspirin 162 mg to 325 mg daily should be given for at least 1 month after bare metal stent (BMS) implantation, 3 months after Sirolimus eluting stent implantation (SES), and 6 months after Paclitaxel eluting stent implantation (PES), after which long term aspirin use should be continued indefinitely at a dose of 75 mg to 162 mg daily. Class I (Level of Evidence: B)[20]
Class IIa
- In patients for whom the physician is concerned about risk of bleeding lower-dose 75 mg to 162 mg of aspirin is reasonable during the initial period after stent implantation. Class IIa (Level of Evidence: C)[20]
References
- ↑ "Randomized trial of intravenous streptokinase, oral aspirin, both, or neither among 17,187 cases of suspected acute myocardial infarction: ISIS-2.ISIS-2 (Second International Study of Infarct Survival) Collaborative Group". J. Am. Coll. Cardiol. 12 (6 Suppl A): 3A–13A. 1988. PMID 2903874. Unknown parameter
|month=ignored (help) - ↑ "1899". Wonders of Aspirin. BAYER. Retrieved March 3, 2009.
- ↑ Template:De icon Gerhardt C (1853). "Untersuchungen über die wasserfreien organischen Säuren". Annalen der Chemie und Pharmacie. 87: 149–179. doi:10.1002/jlac.18530870107.
- ↑ Template:De icon von Gilm H (1859). "Acetylderivate der Phloretin- und Salicylsäure". Annalen der Chemie und Pharmacie. 112 (2): 180–185. doi:10.1002/jlac.18591120207.
- ↑ Template:De icon Schröder, Prinzhorn, Kraut K (1869). "Uber Salicylverbindungen". Annalen der Chemie und Pharmacie. 150 (1): 1–20. doi:10.1002/jlac.18691500102.
- ↑ Jeffreys, Diarmuid (August 11, 2005). Aspirin: The Remarkable Story of a Wonder Drug. Bloomsbury USA. p. 73. ISBN 1582346003.
- ↑ Ueber Aspirin. Pflügers Archiv : European journal of physiology, Volume: 84, Issue: 11-12 (March 1, 1901), pp: 527-546.
- ↑ Jeffreys, Aspirin, pp. 136–142 and 151-152
- ↑ http://www.history.com/this-day-in-history.do?action=VideoArticle&id=52415
- ↑ Jeffreys, Aspirin, pp. 212–217
- ↑ Jeffreys, Aspirin, pp. 226–231
- ↑ Jeffreys, Aspirin, pp. 267–269
- ↑ "Aspirin in Heart Attack and Stroke Prevention". American Heart Association. Retrieved 2008-05-08.
- ↑ Tohgi, H (1992). "Effects of low-to-high doses of aspirin on platelet aggregability and metabolites of thromboxane A2 and prostacyclin". Stroke. Vol 23: 1400–1403. PMID 1412574. Unknown parameter
|coauthors=ignored (help) - ↑
- ↑ Berger JS, Stebbins A, Granger CB; et al. (2008). "Initial aspirin dose and outcome among ST-elevation myocardial infarction patients treated with fibrinolytic therapy". Circulation. 117 (2): 192–9. doi:10.1161/CIRCULATIONAHA.107.729558. PMID 18086929. Unknown parameter
|month=ignored (help) - ↑ Alberts MJ, Bergman DL, Molner E, Jovanovic BD, Ushiwata I, Teruya J (2004). "Antiplatelet effect of aspirin in patients with cerebrovascular disease". Stroke. 35 (1): 175–8. doi:10.1161/01.STR.0000106763.46123.F6. PMID 14671242. Unknown parameter
|month=ignored (help) - ↑ Serebruany VL, Steinhubl SR, Berger PB; et al. (2005). "Analysis of risk of bleeding complications after different doses of aspirin in 192,036 patients enrolled in 31 randomized controlled trials". Am. J. Cardiol. 95 (10): 1218–22. doi:10.1016/j.amjcard.2005.01.049. PMID 15877994. Unknown parameter
|month=ignored (help) - ↑ Pirmohamed M, James S, Meakin S; et al. (2004). "Adverse drug reactions as cause of admission to hospital: prospective analysis of 18 820 patients". BMJ. 329 (7456): 15–9. doi:10.1136/bmj.329.7456.15. PMC 443443. PMID 15231615. Unknown parameter
|month=ignored (help) - ↑ 20.0 20.1 Antman EM, Hand M, Armstrong PW; et al. (2008). "2007 Focused Update of the ACC/AHA 2004 Guidelines for the Management of Patients With ST-Elevation Myocardial Infarction: a report of the American College of Cardiology/American Heart Association Task Force on Practice Guidelines: developed in collaboration With the Canadian Cardiovascular Society endorsed by the American Academy of Family Physicians: 2007 Writing Group to Review New Evidence and Update the ACC/AHA 2004 Guidelines for the Management of Patients With ST-Elevation Myocardial Infarction, Writing on Behalf of the 2004 Writing Committee". Circulation. 117 (2): 296–329. doi:10.1161/CIRCULATIONAHA.107.188209. PMID 18071078. Unknown parameter
|month=ignored (help)