Anticoagulant therapy in non-ST elevation acute coronary syndromes
- Michael Simons, MD
Michael Simons, MD
- Robert W Berliner Professor of Medicine
- Yale University School of Medicine
- Donald Cutlip, MD
Donald Cutlip, MD
- Section Editor — Interventional Cardiology
- Professor of Medicine
- Harvard Medical School
- Beth Israel Deaconess Medical Center
- A Michael Lincoff, MD
A Michael Lincoff, MD
- Director, Center for Clinical Research
- Professor of Medicine
- Cleveland Clinic Lerner College of Medicine of Case Western Reserve University
- Section Editors
- Christopher P Cannon, MD
Christopher P Cannon, MD
- Section Editor — Coronary Heart Disease
- Professor of Medicine
- Harvard Medical School
- Freek Verheugt, MD, FACC, FESC
Freek Verheugt, MD, FACC, FESC
- Section Editor — Coronary Heart Disease
- Onze Lieve Vrouwe Gasthuis, Netherlands
Rupture of an atherosclerotic plaque is the usual initiating event in an acute coronary syndrome (ACS). Persistent thrombotic occlusion at the site of plaque rupture results in acute myocardial infarction. (See "The role of the vulnerable plaque in acute coronary syndromes".)
Thrombin activity at the site of plaque rupture may result in delayed or incomplete reperfusion of occluded vessels and contributes to reocclusion. Thrombin is a central mediator of clot formation through its activation of platelets, conversion of fibrinogen to fibrin, and activation of factor XIII, leading to fibrin cross-linking and clot stabilization. Anticoagulants, including heparins, direct thrombin inhibitors, and fondaparinux interfere with the activity of thrombin. (See "Overview of hemostasis".)
This topic will review the evidence that supports the use of parenteral anticoagulant therapy in all patients with an acute non-ST elevation ACS (NSTEACS), which includes both unstable angina and acute non-ST elevation myocardial infarction, and will provide recommendations for its use according to whether the patient receives reperfusion with percutaneous coronary intervention or no reperfusion therapy. Information regarding anticoagulant agents in ST elevation myocardial infarction and the role of antiplatelet therapy in NSTEACS is found elsewhere. (See "Anticoagulant therapy in acute ST elevation myocardial infarction" and "Antiplatelet agents in acute non-ST elevation acute coronary syndromes".)
CLASSIFICATION OF ANTICOAGULANT AGENTS
There are three classes of anticoagulants that have been evaluated in the management of acute coronary syndromes:
●The heparins, including unfractionated heparin (UFH) and the low molecular weight heparins (LMWH), are indirect thrombin inhibitors that complex with antithrombin (AT, formerly known as AT III) and convert AT from a slow to a rapid inactivator of thrombin, factor Xa, and to a lesser extent, factors XIIa, XIa, and IXa. (See "Overview of hemostasis" and "Heparin and LMW heparin: Dosing and adverse effects".)
There are a number of intrinsic limitations to UFH therapy in patients with acute MI. The most important is that the heparin-antithrombin (AT, formerly called antithrombin III) complex cannot bind or inactivate thrombin bound within a clot . Such clot-bound thrombin acts as an important thrombogenic stimulus at a site of coronary thrombosis, particularly after clot disruption by fibrinolytic agents . An additional concern with the administration of UFH has been heparin-induced thrombocytopenia (HIT). The risk is much lower but not absent with LMWH than with UFH and is not seen with the direct thrombin inhibitors or fondaparinux. (See "Anticoagulant therapy in acute ST elevation myocardial infarction", section on 'Classification of anticoagulant agents'.)
LMWH inactivates factor Xa, like UFH, but has a lesser effect on thrombin (figure 1). As a result, LMWH do not prolong the aPTT in a predictable fashion. They have a number of advantages over UFH, including a more predictable anticoagulant effect and a reduced likelihood of inducing immune-mediated thrombocytopenia.
- Weitz JI, Hudoba M, Massel D, et al. Clot-bound thrombin is protected from inhibition by heparin-antithrombin III but is susceptible to inactivation by antithrombin III-independent inhibitors. J Clin Invest 1990; 86:385.
- Weitz JI, Leslie B, Hudoba M. Thrombin binds to soluble fibrin degradation products where it is protected from inhibition by heparin-antithrombin but susceptible to inactivation by antithrombin-independent inhibitors. Circulation 1998; 97:544.
- Lefkovits J, Topol EJ. Direct thrombin inhibitors in cardiovascular medicine. Circulation 1994; 90:1522.
- Bittl JA, Strony J, Brinker JA, et al. Treatment with bivalirudin (Hirulog) as compared with heparin during coronary angioplasty for unstable or postinfarction angina. Hirulog Angioplasty Study Investigators. N Engl J Med 1995; 333:764.
- Eikelboom JW, Anand SS, Malmberg K, et al. Unfractionated heparin and low-molecular-weight heparin in acute coronary syndrome without ST elevation: a meta-analysis. Lancet 2000; 355:1936.
- Low-molecular-weight heparin during instability in coronary artery disease, Fragmin during Instability in Coronary Artery Disease (FRISC) study group. Lancet 1996; 347:561.
- Cohen M, Demers C, Gurfinkel EP, et al. A comparison of low-molecular-weight heparin with unfractionated heparin for unstable coronary artery disease. Efficacy and Safety of Subcutaneous Enoxaparin in Non-Q-Wave Coronary Events Study Group. N Engl J Med 1997; 337:447.
- Berkowitz SD, Stinnett S, Cohen M, et al. Prospective comparison of hemorrhagic complications after treatment with enoxaparin versus unfractionated heparin for unstable angina pectoris or non-ST-segment elevation acute myocardial infarction. Am J Cardiol 2001; 88:1230.
- Goodman SG, Cohen M, Bigonzi F, et al. Randomized trial of low molecular weight heparin (enoxaparin) versus unfractionated heparin for unstable coronary artery disease: one-year results of the ESSENCE Study. Efficacy and Safety of Subcutaneous Enoxaparin in Non-Q Wave Coronary Events. J Am Coll Cardiol 2000; 36:693.
- Antman EM, McCabe CH, Gurfinkel EP, et al. 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 1999; 100:1593.
- Morrow DA, Antman EM, Tanasijevic M, et al. Cardiac troponin I for stratification of early outcomes and the efficacy of enoxaparin in unstable angina: a TIMI-11B substudy. J Am Coll Cardiol 2000; 36:1812.
- Blazing MA, de Lemos JA, White HD, et al. Safety and efficacy of enoxaparin vs unfractionated heparin in patients with non-ST-segment elevation acute coronary syndromes who receive tirofiban and aspirin: a randomized controlled trial. JAMA 2004; 292:55.
- Ferguson JJ, Califf RM, Antman EM, et al. 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 2004; 292:45.
- Mahaffey KW, Cohen M, Garg J, et al. High-risk patients with acute coronary syndromes treated with low-molecular-weight or unfractionated heparin: outcomes at 6 months and 1 year in the SYNERGY trial. JAMA 2005; 294:2594.
- Silvain J, Beygui F, Barthélémy O, et al. Efficacy and safety of enoxaparin versus unfractionated heparin during percutaneous coronary intervention: systematic review and meta-analysis. BMJ 2012; 344:e553.
- Comparison of two treatment durations (6 days and 14 days) of a low molecular weight heparin with a 6-day treatment of unfractionated heparin in the initial management of unstable angina or non-Q wave myocardial infarction: FRAX.I.S. (FRAxiparine in Ischaemic Syndrome). Eur Heart J 1999; 20:1553.
- Michalis LK, Katsouras CS, Papamichael N, et al. Enoxaparin versus tinzaparin in non-ST-segment elevation acute coronary syndromes: the EVET trial. Am Heart J 2003; 146:304.
- Katsouras C, Michalis LK, Papamichael N, et al. Enoxaparin versus tinzaparin in non-ST-segment elevation acute coronary syndromes: results of the enoxaparin versus tinzaparin (EVET) trial at 6 months. Am Heart J 2005; 150:385.
- Klein W, Buchwald A, Hillis SE, et al. Comparison of low-molecular-weight heparin with unfractionated heparin acutely and with placebo for 6 weeks in the management of unstable coronary artery disease. Fragmin in unstable coronary artery disease study (FRIC). Circulation 1997; 96:61.
- Long-term low-molecular-mass heparin in unstable coronary-artery disease: FRISC II prospective randomised multicentre study. FRagmin and Fast Revascularisation during InStability in Coronary artery disease. Investigators. Lancet 1999; 354:701.
- Martel N, Lee J, Wells PS. Risk for heparin-induced thrombocytopenia with unfractionated and low-molecular-weight heparin thromboprophylaxis: a meta-analysis. Blood 2005; 106:2710.
- Direct Thrombin Inhibitor Trialists' Collaborative Group. Direct thrombin inhibitors in acute coronary syndromes: principal results of a meta-analysis based on individual patients' data. Lancet 2002; 359:294.
- Sinnaeve PR, Simes J, Yusuf S, et al. Direct thrombin inhibitors in acute coronary syndromes: effect in patients undergoing early percutaneous coronary intervention. Eur Heart J 2005; 26:2396.
- Fuchs J, Cannon CP. Hirulog in the treatment of unstable angina. Results of the Thrombin Inhibition in Myocardial Ischemia (TIMI) 7 trial. Circulation 1995; 92:727.
- Bittl JA, Chaitman BR, Feit F, et al. Bivalirudin versus heparin during coronary angioplasty for unstable or postinfarction angina: Final report reanalysis of the Bivalirudin Angioplasty Study. Am Heart J 2001; 142:952.
- Stone GW, McLaurin BT, Cox DA, et al. Bivalirudin for patients with acute coronary syndromes. N Engl J Med 2006; 355:2203.
- Stone GW, White HD, Ohman EM, et al. Bivalirudin in patients with acute coronary syndromes undergoing percutaneous coronary intervention: a subgroup analysis from the Acute Catheterization and Urgent Intervention Triage strategy (ACUITY) trial. Lancet 2007; 369:907.
- Lopes RD, Alexander KP, Manoukian SV, et al. Advanced age, antithrombotic strategy, and bleeding in non-ST-segment elevation acute coronary syndromes: results from the ACUITY (Acute Catheterization and Urgent Intervention Triage Strategy) trial. J Am Coll Cardiol 2009; 53:1021.
- Kastrati A, Neumann FJ, Schulz S, et al. Abciximab and heparin versus bivalirudin for non-ST-elevation myocardial infarction. N Engl J Med 2011; 365:1980.
- Valgimigli M, Frigoli E, Leonardi S, et al. Bivalirudin or Unfractionated Heparin in Acute Coronary Syndromes. N Engl J Med 2015; 373:997.
- White HD, Chew DP, Hoekstra JW, et al. Safety and efficacy of switching from either unfractionated heparin or enoxaparin to bivalirudin in patients with non-ST-segment elevation acute coronary syndromes managed with an invasive strategy: results from the ACUITY (Acute Catheterization and Urgent Intervention Triage strategY) trial. J Am Coll Cardiol 2008; 51:1734.
- Fifth Organization to Assess Strategies in Acute Ischemic Syndromes Investigators, Yusuf S, Mehta SR, et al. Comparison of fondaparinux and enoxaparin in acute coronary syndromes. N Engl J Med 2006; 354:1464.
- Fox KA, Bassand JP, Mehta SR, et al. Influence of renal function on the efficacy and safety of fondaparinux relative to enoxaparin in non ST-segment elevation acute coronary syndromes. Ann Intern Med 2007; 147:304.
- Mehta SR, Granger CB, Eikelboom JW, et al. Efficacy and safety of fondaparinux versus enoxaparin in patients with acute coronary syndromes undergoing percutaneous coronary intervention: results from the OASIS-5 trial. J Am Coll Cardiol 2007; 50:1742.
- Jolly SS, Faxon DP, Fox KA, et al. Efficacy and safety of fondaparinux versus enoxaparin in patients with acute coronary syndromes treated with glycoprotein IIb/IIIa inhibitors or thienopyridines: results from the OASIS 5 (Fifth Organization to Assess Strategies in Ischemic Syndromes) trial. J Am Coll Cardiol 2009; 54:468.
- FUTURA/OASIS-8 Trial Group, Steg PG, Jolly SS, et al. Low-dose vs standard-dose unfractionated heparin for percutaneous coronary intervention in acute coronary syndromes treated with fondaparinux: the FUTURA/OASIS-8 randomized trial. JAMA 2010; 304:1339.
- Steg PG, Mehta SR, Pollack CV Jr, et al. Anticoagulation with otamixaban and ischemic events in non-ST-segment elevation acute coronary syndromes: the TAO randomized clinical trial. JAMA 2013; 310:1145.
- Stone GW, Witzenbichler B, Guagliumi G, et al. Bivalirudin during primary PCI in acute myocardial infarction. N Engl J Med 2008; 358:2218.
- Lincoff AM, Bittl JA, Harrington RA, et al. Bivalirudin and provisional glycoprotein IIb/IIIa blockade compared with heparin and planned glycoprotein IIb/IIIa blockade during percutaneous coronary intervention: REPLACE-2 randomized trial. JAMA 2003; 289:853.
- Amsterdam EA, Wenger NK, Brindis RG, et al. 2014 AHA/ACC guideline for the management of patients with non-ST-elevation acute coronary syndromes: executive summary: a report of the American College of Cardiology/American Heart Association Task Force on Practice Guidelines. Circulation 2014; 130:2354.
- Roffi M, Patrono C, Collet JP, et al. 2015 ESC Guidelines for the management of acute coronary syndromes in patients presenting without persistent ST-segment elevation: Task Force for the Management of Acute Coronary Syndromes in Patients Presenting without Persistent ST-Segment Elevation of the European Society of Cardiology (ESC). Eur Heart J 2016; 37:267.
- CLASSIFICATION OF ANTICOAGULANT AGENTS
- ANTICOAGULANT VERSUS PLACEBO
- Enoxaparin versus UFH
- Other LMWHs
- - Nadroparin
- - Tinzaparin
- - Dalteparin
- Heparin-induced thrombocytopenia
- Heparins summary
- DIRECT THROMBIN INHIBITORS
- Direct thrombin inhibitors summary
- FACTOR XA INHIBITORS
- Factor Xa summary
- APPROACH TO ANTICOAGULATION
- ANTICOAGULANT REGIMENS
- RECOMMENDATIONS OF OTHERS
- SUMMARY AND RECOMMENDATIONS