Cochrane for Clinicians
Putting Evidence into Practice
Heparins for Unstable Angina and Non-ST Segment Elevation Myocardial Infarction
Am Fam Physician. 2009 Apr 1;79(7):560-562.
A 62-year-old man presents to the emergency department with substernal chest pain and associated dyspnea. Changes on electrocardiography (ECG) are noted, and his first set of cardiac enzymes are mildly elevated. The medical team wonders if the patient should receive heparin in addition to aspirin.
Do heparins (i.e., low-molecular-weight heparin [LMWH] and unfractionated heparin [UFH]) benefit patients with unstable angina and non-ST segment elevation myocardial infarction (NSTEMI)?
Compared with standard therapy with aspirin, the use of heparin does not reduce mortality, the need for revascularization, and recurrent angina. Heparin does reduce the occurrence of myocardial infarction (MI; number needed to treat [NNT] = 33), defined as “typical chest pain associated with the appearance of new significant ECG changes and the subsequent elevation of serum cardiac enzymes beyond levels drawn at enrollment.”1 Heparin use increases the incidence of minor bleeding (number needed to harm [NNH] = 17).1
Background: Acute coronary syndrome represents a spectrum of disease that includes unstable angina and non-ST segment elevation myocardial infarction (NSTEMI). Despite treatment with aspirin, beta blockers, and nitroglycerin, unstable angina or NSTEMI are still associated with significant morbidity and mortality. Although emerging evidence suggests that low-molecular-weight heparin (LMWH) is more effective compared with unfractionated heparin (UFH), there are limited data to support the role of heparins as a drug class in the treatment of acute coronary syndrome.
Objectives: To determine the effect of heparins (UFH and LMWH) compared with placebo for the treatment of patients with acute coronary syndrome.
Search Strategy: The authors searched the Cochrane Central Register of Controlled Trials on The Cochrane Library (Issue 4, 2002), Medline (1966 to May 2002), EMBASE (1980 to May 2002), and CINAHL (1982 to May 2002). Authors of included studies and pharmaceutical industry representatives were contacted to determine if unpublished studies that met the inclusion criteria were available.
Selection Criteria: Randomized controlled trials of parenteral UFH or LMWH versus placebo in persons with acute coronary syndrome (unstable angina or NSTEMI).
Data Collection and Analysis: Two reviewers independently assessed quality of studies. Data were extracted independently by two reviewers. Study authors were contacted to verify and clarify missing data.
Main Results: Eight studies (3,318 participants) were included in this review. We found no evidence for difference in overall mortality between the groups treated with heparin and placebo (relative risk [RR] = 0.84; 95% confidence interval [CI], 0.36 to 1.98). Heparins reduced the occurrence of myocardial infarction (RR = 0.40; 95% CI, 0.25 to 0.63; number needed to treat = 33), and increased the incidence of minor bleeds (RR = 6.80; 95% CI, 1.23 to 37.49; number needed to harm = 17).
Authors' Conclusions: Compared with placebo, patients treated with heparins had similar risks of mortality, revascularization, recurrent angina, major bleeding, and thrombocytopenia. However, those treated with heparins had a decreased risk of myocardial infarction and a higher incidence of minor bleeding.
These summaries have been derived from Cochrane reviews published in the Cochrane Database of Systematic Reviews in the Cochrane Library. Their content has, as far as possible, been checked with the authors of the original reviews, but the summaries should not be regarded as an official product of the Cochrane Collaboration; minor editing changes have been made to the text (http://www.cochrane.org).
Age-adjusted rates of death from heart disease have been in steady decline since 1979.2 Despite this, more than 1.5 million persons in the United States were hospitalized in 2004 for acute coronary syndrome.3 The management of acute coronary syndrome is constantly evolving to optimize treatments with anti-ischemic, antiplatelet, and antithrombotic agents. Considerable attention has been given to the use of anticoagulants in conservative and invasive management of unstable angina or NSTEMI. The literature regarding heparin use for acute coronary syndrome is confusing1,4,5 and, to date, heparins have not been shown to improve mortality in acute coronary syndrome management.
A 2003 Cochrane review of seven trials with 11,092 patients found that LMWH used in place of UFH for the treatment of acute coronary syndrome was associated with a decreased risk of new MI (NNT = 125), revascularization (NNT = 50), and thrombocytopenia (NNT = 125).5 The 2007 guidelines from the American College of Cardiology (ACC) and American Heart Association (AHA) support enoxaparin (Lovenox) or fondaparinux (Arixtra) instead of UFH for patients in whom conservative, noninvasive strategies are selected.4 In the studies cited in the guidelines, groups treated with LMWH, as opposed to UFH, had a modest absolute risk reduction of 4 percent or less in several composite end points (various combinations of death, MI, angina, or revascularization at 1 to 45 days).4 In contrast, the large SYNERGY (Superior Yield of the New strategy of Enoxaparin, Revascularization and Glycoprotein IIb/IIIa inhibitors) trial of 9,978 patients showed that enoxaparin was not any more or less effective than UFH in high-risk patients undergoing early invasive management.6
Despite the incremental superiority of LMWH in the conservative management of acute coronary syndrome, the authors of this Cochrane review assessed the clinical benefits of heparins as a class in the early treatment of acute coronary syndrome. They included eight randomized controlled trials with 3,118 patients; about one half of the patients received LMWH, and the other half received UFH. Patients started UFH or LMWH within 72 hours of presentation and continued for two to seven days. The outcomes were measured for five to eight days in four of the studies, and at three months in the other four studies. The authors found a significant decrease in MI within the LMWH and UFH groups (NNT = 33), despite an increased incidence of minor bleeds (NNH = 17). No significant differences were noted in the rate of death, recurrent angina, and need for revascularization. When looking at the LMWH subgroup versus placebo, absolute risk of recurrent angina and revascularization was reduced by 1 to 3 percent.1
With the increasing use of percutaneous coronary intervention, bleeding complications from anticoagulation remain a concern. In cardiac catheterization facilities, the Cochrane authors found that intravenous UFH may be safer than LMWH because of its shorter half-life and easy reversability.1 However, the STEEPLE (Safety and Efficacy of Enoxaparin in Percutaneous Coronary Intervention Patients) trial looked at 3,528 patients undergoing nonemergent percutaneous coronary intervention and showed that a single intravenous bolus of enoxaparin at 0.5 mg per kg before percutaneous coronary intervention was associated with less bleeding and four times better target anticoagulation than UFH.7
According to the ACC and AHA guidelines,4 enoxaparin can be given as a loading dose of 30 mg intravenously and 1 mg per kg subcutaneously every 12 hours (every 24 hours for renal impairment) during the initial medical management of acute coronary syndrome. If percutaneous coronary intervention is planned and eight hours have elapsed since the last subcutaneous dose, a 0.3 mg per kg intravenous bolus can be given. If no prior doses were given by the time of percutaneous coronary intervention, a 0.5 to 0.75 mg per kg intravenous bolus can be administered. In low-risk patients with acute coronary syndrome who do not undergo invasive management, it is recommended to continue enoxaparin for the duration of hospitalization (up to eight days). If coronary artery bypass grafting is planned within 24 hours, enoxaparin is discouraged because of less reversibility.4
With the ever-expanding medical cocktails used in patients with acute coronary syndrome (e.g., clopidogrel [Plavix], beta blockers, glycoprotein IIb/IIIa inhibitors), a clean comparison of one anticoagulant agent versus another remains difficult. Future investigations will need to clarify the optimal start time and duration of anticoagulation therapy. For now, enoxaparin remains the preferred option for conservative management of unstable angina or NSTEMI, and is as equally effective as UFH in early invasive strategies. Its ease of use, more predictable pharmacokinetics, and lower incidence of thrombocytopenia make it an attractive agent. For more information, the TIMI (Thrombosis in Myocardial Infarction) Study Group Web site (http://www.timi.org) can be used for risk stratification of patients with unstable angina or NSTEMI, and the 2007 ACC and AHA guidelines can help guide therapy.4
1. Magee KD, Campbell SG, Moher D, Rowe BH. Heparin versus placebo for acute coronary syndromes. Cochrane Database Syst Rev. 2008;2:CD003462.
2. Heron MP, Hoyert DL, Xu J, Scott C, Tejada-Vera B. Deaths: preliminary data for 2006. Natl Vital Stat Rep. 2008;56(16):1–52.
3. Thom T, Haase N, Rosamond W, et al. Heart disease and stroke statistics—2006 update: a report from the American Heart Association Statistics Committee and Stroke Statistics Subcommittee [published corrections appear in Circulation. 2006;113(14):e696, and Circulation. 2006;114(23):e630]. Circulation. 2006;113(6):e85–151.
4. Anderson JL, Adams CD, Antman EM, et al. 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 [published correction appears in J Am Coll Cardiol. 2008;51(9):974]. J Am Coll Cardiol. 2007;50(7):e1–e157.
5. Magee KD, Sevcik W, Moher D, Rowe BH. Low molecular weight heparins versus unfractionated heparin for acute coronary syndromes. Cochrane Database Syst Rev. 2003;1:CD002132.
6. 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(1):45–54.
7. Montalescot G, White HD, Gallo R, et al. Enoxaparin versus unfractionated heparin in elective percutaneous coronary intervention. N Engl J Med. 2006;355(10):1006–1017.
The Cochrane Abstract is a summary of a review from the Cochrane Library. It is accompanied by an interpretation that will help clinicians put evidence into practice. Drs. Hitzeman and Rafii present a clinical scenario and question based on the Cochrane Abstract, followed by an evidence-based answer and a critique of the review. The practice recommendations in this activity are available at http://www.cochrane.org/reviews/en/ab003462.html.
The series coordinator for AFP is Clarissa Kripke, MD, Department of Family and Community Medicine, University of California, San Francisco.
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