Unstable angina non ST elevation myocardial infarction anticoagulant therapy
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Editor-In-Chief: C. Michael Gibson, M.S., M.D. [1]
Associate Editor-in-Chief: Smita Kohli, M.D.; Varun Kumar, M.B.B.S.; Lakshmi Gopalakrishnan, M.B.B.S.
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Overview
Anticoagulation, traditionally with unfractionated heparin (UFH), is a cornerstone of therapy for patients with Unstable angina/NSTEMI. Some of the agents available in this category include:
- unfractionated heparin,
- low molecular weight heparin,
- Direct Thrombin Inhibitors (e.g.,bivalirudin)
- Factor Xa Inhibitors (e.g.,fondaparinux), and
- warfarin.
These agents are also sometimes referred to as antithrombins, although, it should be noted that they often inhibit one or more proteins in the coagulation cascade before thrombin.
Unfractionated Heparin(UFH)
Mechanism of action:
- Unfractionated heparin exerts its anticoagulant effect by potentiating the action of circulating antithrombin, a proteolytic enzyme that inactivates factor IIa (thrombin), factor IXa, and factor Xa.
- It prevents thrombus propagation but does not lyse existing thrombi.
Clinical trial data:
- A meta-analysis showed that in aspirin-treated patients with acute coronary syndrome without ST elevation, short-term unfractionated heparin or LMWH halves the risk of myocardial infarction or death[1].
Dosing:
- This is a short acting drug with an anticoagulation half life of 1.5hrs. Hence, frequent monitoring of the anticoagulant response using activated partial thromboplastin time (APTT) is recommended with titrations made according to a standardized nomogram aiming for an APTT range between 1.5 to 2 times control or 50 to 70 seconds .
Adverse effects:
- bleeding(specially with elevated APTT)
- heparin induced thrombocytopenia
Low Molecular Weight Heparin(LMWH)
Mechanism of benefit:
- LMWH combine factor IIa and factor Xa inhibition and thus inhibit both the action and generation of thrombin.
- It has a number of advantages over UFH such as its greater anti-factor Xa activity inhibits thrombin generation more effectively, lower rate of thrombocytopenia, high bioavailabiltiy, more consistent anticoagulant effect and no requirement of intensive lab monitoring.
Clinical trial data:
- Results from TIMI 11B study[2] showed superiority of LMWH over UFH for reducing a composite of death and serious cardiac ischemic events during the acute management of Unstable angina/NQMI patients without causing a significant increase in the rate of major hemorrhage.
- Results from SYNERGY trial[3] revealed noninferiority of LMWH over UFH for the treatment of high-risk patients with non-ST-segment elevation ACS. However, both trials did show increased risk of major bleeding with LMWH.
- A prospective analysis of the A to Z trial[4] showed that enoxaparin provided significant benefit over UFH in patients managed conservatively (who are typically on heparin/LMWH for at least 48 hours) but not in those with early invasive approach(who are taken to the catheterization laboratory within 48 hours and have their heparin discontinued thereafter).
Disadvantages of LMWH:
- LMWH are more affected by renal dysfunction than UFH, and the dose should be reduced in patients with a creatinine clearance <30 mL/min.
- Also, in the event of bleeding, the anticoagulant effect of UFH can be reversed more effectively with protamine.
Direct Thrombin Inhibitors
Hirudin which is the prototype of this class of drugs has been studied in multiple trials with mixed results. Other drugs in this class include bivalirudin, argatroban, efegatran and inogatran. Bivalirudin is a synthetic analog of hirudin that binds reversibly to thrombin and inhibits clot-bound thrombin.
Indications:
- Hirudin (lepirudin) is presently indicated by the US Food and Drug Administration only for anticoagulation in patients with heparin-induced thrombocytopenia and for the prophylaxis of deep vein thrombosis in patients undergoing hip replacement surgery.
- Argatroban is another direct thrombin inhibitor that is approved for the management of patients with heparin-induced thrombocytopenia.
Clinical trial data:
- The relative benefits of hirudin versus UFH in ACS patients was evaluated in the 12,142 patient in GUSTO-IIb trial[5]. A reduction in risk for nonfatal MI was seen without increased risk of major bleeding.
- TIMI 9B study failed to show any difference in outcomes in Hirudin verus heparin treated patients getting TPA.
- The Acute Catheterization and Urgent Intervention Triage Strategy (ACUITY) trial[6] randomized 13,819 patients with Unstable angina/NSTEMI to one of three treatments: UFH, or enoxaparin plus a GP IIb/IIIa inhibitor, or bivalirudin plus a GP IIb/IIIa inhibitor, or bivalirudin alone. Patients were managed with an early invasive strategy and the primary endpoint was the composite of death, myocardial infarction, unplanned revascularization for ischemia, and major bleeding at 30 days. No differences were observed in the direct comparison of the anticoagulants i.e., between bivalirudin plus GP IIb/IIIa inhibitor and UFH/enoxaparin plus a GP IIb/IIIa inhibitor or bivalirudin alone. But for the bivalirudin alone group, when compared with the group receiving UFH/enoxaparin plus a GP IIb/IIIa inhibitor, there was decrease risk for bleeding.
Disadvantage of Direct Thrombin Inhibitors:
- Direct thrombin inhibitors lack a protamine-binding domain, hence it is not possible to reverse the effect with protamine. In the event of bleeding,discontinuation of their administration and, if needed, transfusion of coagulation factors (e.g., fresh frozen plasma)is required.
- In ACS, the monovalent direct thrombin inhibitors(including argatroban) are ineffective anti-thrombotic agents compared with UFH, and thus, argatroban should generally not be used in management of ACS.
Factor Xa Inhibitors
Fondaparinux is the prototype in this class of drug which is an indirect Xa inhibitor that requires antithrombin for its action.
Clinical trial data:
- The OASIS 5 and 6 trials[7] evaluated the use of fondaparinux in ACS and compared it with a heparin-based strategy. Results showed that compared to heparin based strategy, fondaparinux reduced mortality, ischemic events, and major bleeding across the full spectrum of acute coronary syndromes and was associated with a more favorable net clinical outcome in patients undergoing either an invasive or a conservative management strategy.
- The OASIS-5 trial[8] specifically compared fondaparinux, administered at a relatively low dose, 2.5 mg subcutaneously, once daily with standard-dose enoxaparin in 20,078 patients with high-risk UA/NSTEMI. The rates of death, MI, or refractory ischemia throughout the first 9 days were similar with fondaparinux and enoxaparin. Of note, however, the rate of major bleeding was almost 50 percent lower in the fondaparinux arm. By 30 days, mortality was significantly lower in the fondaparinux arm. However, in the subset of patients undergoing PCI, fondaparinux was associated with more than a threefold increased risk of catheter-related thrombi.
Disadvantage of Factor Xa Inhibitors:
- fondaparinux lacks a protamine-binding domain, hence it is not possible to reverse the effect with protamine. In the event of bleeding,discontinuation of their administration and, if needed, transfusion of coagulation factors (e.g., fresh-frozen plasma)is required.
Long Term Anticoagulation
Warfarin is the typical drug used for long term anticoagulation. However, its role, if any, in patients with UA/NSTEMI has not been clearly defined.
Clinical trial data:
- ASPECT 2 trial[9] showed that in patients recently admitted with ACS, treatment with high-intensity oral anticoagulants or aspirin with medium-intensity oral anticoagulants was more effective than aspirin alone in reduction of subsequent cardiovascular events and death. However, similar benefit is seen with clopidogrel plus aspirin over aspirin alone, the lack of need for monitoring of the INR, and the frequent use of PCI and stenting in the patient population in whom the need for clopidogrel is well established, the clinical use of aspirin plus warfarin is limited. Among patients without a coronary stent but with another indication for warfarin, such as chronic atrial fibrillation, mechanical valve or severe left ventricular dysfunction who are at high risk of systemic embolization, the combination of aspirin plus warfarin would be preferable as the long-term antithrombotic strategy.
ACC / AHA Guidelines for Anticoagulation Therapy (DO NOT EDIT) [10]
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See Also
Sources
- The ACC/AHA 2007 Guidelines for the Management of Patients With Unstable Angina/Non-ST-Elevation Myocardial Infarction [10]
References
- ↑ Eikelboom JW, Anand SS, Malmberg K, Weitz JI, Ginsberg JS, Yusuf S (2000). "Unfractionated heparin and low-molecular-weight heparin in acute coronary syndrome without ST elevation: a meta-analysis". Lancet. 355 (9219): 1936–42. doi:10.1016/S0140-6736(00)02324-2. PMID 10859038. Retrieved 2011-04-11. Unknown parameter
|month=ignored (help) - ↑ Antman EM, McCabe CH, Gurfinkel EP, Turpie AG, Bernink PJ, Salein D, Bayes De Luna A, Fox K, Lablanche JM, Radley D, Premmereur J, Braunwald E (1999). "Enoxaparin prevents death and cardiac ischemic events in unstable angina/non-Q-wave myocardial infarction. Results of the thrombolysis in myocardial infarction (TIMI) 11B trial". Circulation. 100 (15): 1593–601. PMID 10517729. Retrieved 2011-04-11. Unknown parameter
|month=ignored (help) - ↑ Ferguson JJ, Califf RM, Antman EM, Cohen M, Grines CL, Goodman S, Kereiakes DJ, Langer A, Mahaffey KW, Nessel CC, Armstrong PW, Avezum A, Aylward P, Becker RC, Biasucci L, Borzak S, Col J, Frey MJ, Fry E, Gulba DC, Guneri S, Gurfinkel E, Harrington R, Hochman JS, Kleiman NS, Leon MB, Lopez-Sendon JL, Pepine CJ, Ruzyllo W, Steinhubl SR, Teirstein PS, Toro-Figueroa L, White H (2004). "Enoxaparin vs unfractionated heparin in high-risk patients with non-ST-segment elevation acute coronary syndromes managed with an intended early invasive strategy: primary results of the SYNERGY randomized trial". JAMA : the Journal of the American Medical Association. 292 (1): 45–54. doi:10.1001/jama.292.1.45. PMID 15238590. Retrieved 2011-04-11. Unknown parameter
|month=ignored (help) - ↑ de Lemos JA, Blazing MA, Wiviott SD, Brady WE, White HD, Fox KA, Palmisano J, Ramsey KE, Bilheimer DW, Lewis EF, Pfeffer M, Califf RM, Braunwald E (2004). "Enoxaparin versus unfractionated heparin in patients treated with tirofiban, aspirin and an early conservative initial management strategy: results from the A phase of the A-to-Z trial". European Heart Journal. 25 (19): 1688–94. doi:10.1016/j.ehj.2004.06.028. PMID 15451146. Retrieved 2011-04-11. Unknown parameter
|month=ignored (help) - ↑ "A comparison of recombinant hirudin with heparin for the treatment of acute coronary syndromes. The Global Use of Strategies to Open Occluded Coronary Arteries (GUSTO) IIb investigators". The New England Journal of Medicine. 335 (11): 775–82. 1996. doi:10.1056/NEJM199609123351103. PMID 8778585. Retrieved 2011-04-11. Unknown parameter
|month=ignored (help) - ↑ Stone GW, McLaurin BT, Cox DA, Bertrand ME, Lincoff AM, Moses JW, White HD, Pocock SJ, Ware JH, Feit F, Colombo A, Aylward PE, Cequier AR, Darius H, Desmet W, Ebrahimi R, Hamon M, Rasmussen LH, Rupprecht HJ, Hoekstra J, Mehran R, Ohman EM (2006). "Bivalirudin for patients with acute coronary syndromes". The New England Journal of Medicine. 355 (21): 2203–16. doi:10.1056/NEJMoa062437. PMID 17124018. Retrieved 2011-04-11. Unknown parameter
|month=ignored (help) - ↑ Mehta SR, Boden WE, Eikelboom JW, Flather M, Steg PG, Avezum A, Afzal R, Piegas LS, Faxon DP, Widimsky P, Budaj A, Chrolavicius S, Rupprecht HJ, Jolly S, Granger CB, Fox KA, Bassand JP, Yusuf S (2008). "Antithrombotic therapy with fondaparinux in relation to interventional management strategy in patients with ST- and non-ST-segment elevation acute coronary syndromes: an individual patient-level combined analysis of the Fifth and Sixth Organization to Assess Strategies in Ischemic Syndromes (OASIS 5 and 6) randomized trials". Circulation. 118 (20): 2038–46. doi:10.1161/CIRCULATIONAHA.108.789479. PMID 18955665. Retrieved 2011-04-11. Unknown parameter
|month=ignored (help) - ↑ Mehta SR, Granger CB, Eikelboom JW, Bassand JP, Wallentin L, Faxon DP, Peters RJ, Budaj A, Afzal R, Chrolavicius S, Fox KA, Yusuf S (2007). "Efficacy and safety of fondaparinux versus enoxaparin in patients with acute coronary syndromes undergoing percutaneous coronary intervention: results from the OASIS-5 trial". Journal of the American College of Cardiology. 50 (18): 1742–51. doi:10.1016/j.jacc.2007.07.042. PMID 17964037. Retrieved 2011-04-11. Unknown parameter
|month=ignored (help) - ↑ van Es RF, Jonker JJ, Verheugt FW, Deckers JW, Grobbee DE (2002). "Aspirin and coumadin after acute coronary syndromes (the ASPECT-2 study): a randomised controlled trial". Lancet. 360 (9327): 109–13. doi:10.1016/S0140-6736(02)09409-6. PMID 12126819. Unknown parameter
|month=ignored (help) - ↑ 10.0 10.1 Anderson JL, Adams CD, Antman EM, Bridges CR, Califf RM, Casey DE, Chavey WE, Fesmire FM, Hochman JS, Levin TN, Lincoff AM, Peterson ED, Theroux P, Wenger NK, Wright RS, Smith SC, Jacobs AK, Adams CD, Anderson JL, Antman EM, Halperin JL, Hunt SA, Krumholz HM, Kushner FG, Lytle BW, Nishimura R, Ornato JP, Page RL, Riegel B (2007). "ACC/AHA 2007 guidelines for the management of patients with unstable angina/non-ST-Elevation myocardial infarction: a report of the American College of Cardiology/American Heart Association Task Force on Practice Guidelines (Writing Committee to Revise the 2002 Guidelines for the Management of Patients With Unstable Angina/Non-ST-Elevation Myocardial Infarction) developed in collaboration with the American College of Emergency Physicians, the Society for Cardiovascular Angiography and Interventions, and the Society of Thoracic Surgeons endorsed by the American Association of Cardiovascular and Pulmonary Rehabilitation and the Society for Academic Emergency Medicine". Journal of the American College of Cardiology. 50 (7): e1–e157. doi:10.1016/j.jacc.2007.02.013. PMID 17692738. Retrieved 2011-04-11. Unknown parameter
|month=ignored (help)