Why We Do What We Do: The Evidence (or lack of) behind Anticoagulation in ACS – Dr. Alex Le

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Anticoagulation with Heparins in Acute Coronary Syndromes: Is it proven? If so, when is it indicated? – Alexander Le, MD

Acute coronary syndromes (ACS) are characterized by an occlusion of the coronary arteries.  An atherosclerotic plaque predisposes the vessel to tears in the intimal layer, which are misinterpreted by the body as bleeding leading to the formation of a thrombus.  This results in ischemia to the myocardium distal to the occlusion.  This phenomenon is further characterized as unstable angina, in the absence of elevated cardiac enzymes, or non-ST segment myocardial infarction (NSTEMI) or ST-segment elevation myocardial infarction (STEMI) if such enzymes are elevated, indicating infarction of the ischemic tissues.  Given the role of the coagulation cascade (specifically thrombin) in the pathophysiology of these conditions, anticoagulation with heparin is potentially a valuable treatment option.  It does, however, carry the potential risk of bleeding complications.10

This review will focus on the use of anticoagulation in unstable angina and NSTEMI after briefly discussing its use in STEMI patients.  The issue of anticoagulation in STEMI is shadowed by the condition’s amenability to immediate reperfusion therapy (percutaneous coronary intervention (PCI) and fibrinolysis), although its utility is somewhat controversial.5 While the use of unfractionated heparin (UFH) has been shown to have some benefit in improving reperfusion in the setting of fibrinolysis, there have not been statistically significant differences in mortality, recurrent MI or recurrent ischemia.2, 3, 11 Likewise, there have not been randomized trials demonstrating the effect of UFH in the setting of emergent PCI; however, it has been standard practice to administer it to patients in this setting and is recommended to support PCI in the latest 2013 ACCF/AHA STEMI guidelines.5, 12

Low molecular weight heparins (LMWH), specifically enoxaparin, have also been used with success in STEMI patients undergoing fibrinolysis.  When compared to UFH in these trials, LMWH was shown to be associated with reductions in mortality and short term recurrence of myocardial infarction (MI), albeit at the cost of increased major bleeding events.1, 8, 16 Again, this benefit was seen in comparison to UFH, as there were not placebo arms in these trials which did not receive any anticoagulation.  LMWH has not been well studied in the setting of primary PCI for STEMI, yet outcomes seem acceptable in patients treated with LMWH and fibrinolysis who subsequently required PCI – these patients were maintained on enoxaparin and did not experience increased rates of major bleeding compared to UFH.6, 8, 16

The use of anticoagulation for unstable angina and NSTEMI has been in practice for decades, and there have been multiple studies attempting to evaluate its efficacy.4 Early trials using heparin have tended to show trends toward efficacy but often failed to reach statistical significance with regard to the endpoints of death and recurrent MI.14, 15 A later meta analysis of six relevant studies titled “Adding heparin to aspirin reduces the incidence of myocardial infarction and death in patients with unstable angina” also approached but did not reach statistical significance in reduction of rates of death or MI, although it is frequently cited as evidence in support of heparin use in ACS.9, 13

The most high-powered study was a recent Cochrane Review published in 2009 which reviewed eight of these trials comparing the effects of anticoagulation with heparin to placebo.10 These randomized control trials included patients 18-72 years in age with presentations of ACS within 72 hours of the last episode of chest pain.  Classification as unstable angina required an episode of typical chest pain lasting at least ten minutes with “either historic, electrocardiographic, or angiographic evidence of underlying ischemic heart disease.”  To be classified as NSTEMI, chest pain along with EKG changes and significant elevation of cardiac enzymes (CK greater than double the upper normal limit or CK-MB greater than upper normal limit) was necessary.  Treatment was with UFH or LMWH (dalteparin or nadroparin), and aspirin was given concomitantly in all studies.10

Death was an outcome measured in six of the involved trials (>2400 patients) and was found to be slightly lower in the heparin group (0.7% versus 0.9%).  This was not, however, statistically significant.  MI was also a measured outcome in six trials (>2400 patients), and was significantly lower in the heparin group (1.9%, 24/1238) versus the placebo group (4.8%, 57/1188, RR = 0.40, 95% CI 0.25 to 0.63, P = 0.63).  The resulting number needed to treat with heparin to prevent one additional MI based on these numbers is 33.  Recurrent angina and need for revascularization procedures were observed outcomes in six trials as well, and no statistically significant difference was found in either – although there was a trend toward fewer revascularization procedures in the heparin group.10

As might be expected, the rates of both minor and major bleeding were greater in the heparin group.  Minor bleeding was significantly increased (8.0% or 79/989 in the heparin group versus only 0.5% or 5/942 in the control group, RR = 6.80, 95% CI 1.23 to 37.49).  While major bleeding rates were increased in the heparin group, they did not reach statistical significance (RR = 2.05, 95% CI 0.91 to 4.60).  There was not a statistical difference in rates of thrombocytopenia; however, the authors note that side effects were poorly reported in the included trials.10

To draw conclusions from the available evidence discussed above, there is not any proven mortality benefit from starting anticoagulation with heparin in ACS patients.  In unstable angina and NSTEMI patients, a significant reduction in subsequent myocardial infarction has been demonstrated when treated with heparin, despite a possible “rebound” effect after the discontinuation of anticoagulation.  On the other hand, there were also significantly more bleeding complications in the heparin group, although “major bleeding” was not significantly increased.  It is the author’s opinion that in light of the reduced rates of subsequent MI in the treatment groups, anticoagulation may be appropriate in certain patients with unstable angina and NSTEMI.  The decision should be made while taking into consideration the relatively strict criteria for unstable angina in the referenced studies (typical chest pain and EKG, angiographic, or historical evidence of underlying ischemic heart disease) and the significant risk of bleeding complications when anticoagulation is employed.



1. Assessment of the Safety and Efficacy of a New Thrombolytic Regimen (ASSENT)-3 Investigators. Efficacy and safety of tenecteplase in combination with enoxaparin, abciximab, or unfractionated heparin: the ASSENT-3 randomized trial in acute myocardial infarction. Lancet. 2001;358(9282):605-613.

2. CollinsR,MacMahonS,FlatherM,etal.Clinical effects of anticoagulant therapy in suspected acute myocardial infarction: systematic overview of randomized trials. BMJ. 1996;313(7058):652-659.

3. de Bono DP, Simoons ML, Tijssen J, et al. Effect of early intra- venous heparin on coronary patency, infarct size, and bleeding complications after alteplase thrombolysis: results of a rando- mised double blind European Cooperative Study Group trial. Br Heart J. 1992;67(2):122-128.

4. Dobesh PP, Trujillo TC. Anticoagulation in the management of non-ST-segment elevation acute coronary syndrome. J Pharm Pract. 2010;23(4).

5. Dobesh PP, Trujillo TC. Anticoagulation in the management of ST-segment elevation myocardial infarction. J Pharm Pract. 2010 Aug;23(4):335-43

6. Ferguson JJ, Califf RM, Antman EM, et al. Enoxaparin vs unfracionated 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(1):45-54.

7. FRISC Study Group. Low molecular weight heparin (Fragmin) during instability in coronary artery disease (FRISC). Lancet. 1996;347(9001):561-568.

8. Gibson CM, Murphy SA, Montalescot G, et al. Percutaneous coronary intervention in patients receiving enoxaparin or unfractionated heparin after fibrinolytic therapy for ST-segment elevation myocardial infarction in the ExTRACT-TIMI 25 trial. J Am Coll Cardiol. 2007;49(23):2238-2246.

9. Jneid H, Anderson JL, Wright RS, Adams CD, Bridges CR, Casey DE Jr., Ettinger SM, Fesmire FM, Ganiats TG, Lincoff AM, Peterson ED, Philippides GJ, Theroux P, Wenger NK, Zidar JP. 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. Circulation. 2012;126:875–910.

10. Magee K et al. Heparin versus placebo for acute coronary syndromes. Cochrane Database Syst Rev. 2008 Apr 16;(2):CD003462

11. Mahaffey KW, Granger CB, Collins R, et al. Overview of randomized trials of intravenous heparin in patients with acute myocardial infarction treated with thrombolytic therapy. Am J Cardiol. 1996;77(8):551-556

12. O’Gara PT, Kushner FG, Ascheim DD, Casey DE Jr., Chung MK, de Lemos JA, Ettinger SM, Fang JC, Fesmire FM, Franklin BA, Granger CB, Krumholz HM, Linderbaum JA, Morrow DA, Newby LK, Ornato JP, Ou N, Radford MJ, Tamis-Holland JE, Tommaso JE, Tracy CM, Woo YJ, Zhao DX; CF/AHA Task Force. 2013 ACCF/AHA guideline for the management of ST-elevation myocardial infarction: executive summary: a report of the American College of Cardiology Foundation/American Heart Association Task Force on Practice Guidelines. Circulation. 2013;127:529–555

13. Oler A, Whooley MA, Oler J, Grady D. Adding heparin to aspirin reduces the incidence of myocardial infarctionand death in patients with unstable angina. JAMA 1996;276:811-5.

14. Theroux P, H Ouimet, J McCans, Latour J.-G, Joly P, Levy G, et al. Aspirin, heparin, or both to treat acute unstable angina. New England Journal of Medicine 1988;319(17):1105-11.

15. Wallentin L. Risk of myocardial infarction and death during treatment with low-dose aspirin and intravenous heparin in men with unstable coronary artery disease. Lancet 1990;336(8719):830-7.

16. White HD, Braunwald E, Murphy SA, et al. Enoxaparin vs. unfractionated heparin with fibrinolysis for ST-elevation myocardial infarction in elderly and younger patients: results from ExTRACT-TIMI 25. Eur Heart J. 2007;28(9):1066-1071.



  • himynameisvince

    Well written! Thanks for the review. Having less time to keep up on EM literature, I find reading this blog, and especially this review, so pertinent to staying current. I’m pleasantly surprised by the quality of writing and research from busy, working residents. Keep it up!

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