Current issues of ACP Journal Club are published in Annals of Internal Medicine


Therapeutics

Review: Low-molecular-weight heparin is more effective than unfractionated heparin for preventing reinfarction in STEMI

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ACP J Club. 2006 Jul-Aug;145:9. doi:10.7326/ACPJC-2006-145-1-009


Clinical Impact Ratings

Emergency Med: 7 stars

Hospitalists: 6 stars

Cardiology: 5 stars


Source Citation

Eikelboom JW, Quinlan DJ, Mehta SR, et al. Unfractionated and low-molecular-weight heparin as adjuncts to thrombolysis in aspirin-treated patients with ST-elevation acute myocardial infarction: a meta-analysis of the randomized trials. Circulation. 2005;112:3855-67. Epub 2005 Dec 12. [PubMed ID: 16344381]


Abstract

Question

In thrombolytic- and aspirin-treated patients with ST-elevation acute myocardial infarction (STEMI), is low-molecular-weight heparin (LMWH) more effective than unfractionated heparin (UFH)?

Methods

Data sources: MEDLINE and EMBASE/Excerpta Medica (1966 to February 2005), Cochrane Library (issue 1, 2005), conference abstracts from major international cardiology meetings, and bibliographies of relevant studies.

Study selection and assessment: Randomized controlled trials (RCTs) that compared intravenous UFH or subcutaneous LMWH with placebo or no heparin, or compared UFH with LMWH, in thrombolytic- and aspirin-treated patients with STEMI. Studies evaluating subcutaneous UFH were excluded. 14 RCTs (n = 25 280) met the selection criteria. LMWH was compared with UFH (6 RCTs, n = 7098) and placebo (4 RCTs, n = 16 943). UFH was compared with no heparin (4 RCTs, n = 1239). Quality assessment was based on concealment, blinding, and follow-up.

Outcomes: Mortality, MI, stroke, and bleeding at 7 and 30 days.

Main results

LMWH led to a lower incidence of MI and a higher incidence of minor bleeding than UFH (Table). LMWH and UFH groups did not differ for mortality, stroke, and major bleeding. Compared with placebo, the LMWH group had a lower incidence of MI and death, but a higher incidence of major and minor bleeding (Table). LMWH and placebo groups did not differ for stroke. Patients who received UFH had a higher incidence of minor bleeding than the no-heparin group (Table). UFH and no-heparin groups did not differ for mortality, MI, stroke, or major bleeding.

Conclusions

In thrombolytic- and aspirin-treated patients with ST-elevation acute myocardial infarction, low-molecular-weight heparin is more effective than unfractionated heparin or placebo for preventing reinfarction. Low-molecular-weight heparin is better than placebo for reducing mortality.

Source of funding: No external funding.

For correspondence: Dr. D.J. Quinlan, King's College Hospital, Denmark Hill, London, England, UK. E-mail dan.quinlan@consultoberon.com.


Table. Low-molecular-weight heparin (LMWH) vs unfractionated heparin (UFH) or placebo (plac), and UFH vs no heparin in ST-elevation myocardial infarction (MI) at 7 and 30 days*

Outcomes Number of trials (n) Comparisons Follow-up Weighted event rates RRR (95% CI) NNT (CI)
Mortality 3 (16 842) LMWH vs plac 7 d 7.9% vs 8.7% 9.2% (1.0 to 19) 125 (62 to 1258)
3 (16 167) 30 d 9.7% vs 11% 13% (4.5 to 20) 72 (45 to 202)
MI 6 (7093) LMWH vs UFH 7 d 3.0% vs 5.2% 42% (26 to 54) 47 (36 to 75)
5 (5454) 30 d 3.7% vs 5.6% 35% (15 to 49) 52 (37 to 118)
3 (16 842) LMWH vs plac 7 d 1.6% vs 2.2% 28% (10 to 41) 165 (110 to 464)
3 (16 167) 30 d 2.1% vs 2.7% 24% (6.8 to 37) 158 (100 to 543)
RRI (CI) NNH (CI)
Major bleeding 3 (16 842) LMWH vs plac 7 d 1.1% vs 0.4% 168% (82 to 294) 149 (85 to 304)
Minor bleeding 4 (6393) LMWH vs UFH 7 d 23% vs 19% 20% (9.5 to 32) 26 (17 to 55)
2 (1272) LMWH vs plac 7 d 15% vs 5.2% 190% (100 to 308) 11 (7 to 20)
3 (1022) UFH vs no heparin 7 d 20% vs 13% 58% (19 to 106) 14 (8 to 43)

*Abbreviations defined in Glossary; weighted event rates, RRR, RRI, NNT, NNH, and CI calculated from odds ratios in article.


Commentary

The role of adjunctive antithrombic therapy after fibrinolytic therapy in patients with STEMI has been debated for years. In the review by Eikelboom and colleagues, 4 small trials of intravenous UFH compared with no heparin were underpowered to show benefit. The addition of 4 trials that compared LMWH with placebo, particularly the CREATE trial (1), provides support for adjunctive antithrombic therapy and LMWH may be preferred in this setting.

The challenge of declaring LMWH as the superior antithrombic over UFH, bivalirudin, or fondaparinux is confounded by drug, dose, treatment duration, other adjunctive interventions, and study design. Previous studies in acute coronary syndromes showed benefit for enoxaparin, but not nadroparin or dalteparin, when compared with UFH. The dose of UFH has varied across trials. The ExTRACT-TIMI 25 trial (2) used 3 different doses of enoxaparin adjusted for age and renal function. It is important to note that UFH was given for only 2 days in ExTRACT-TIMI 25 (2) and OASIS-6 (3), while enoxaparin was given for 7 days and fondaparinux for 8 days. Therefore, a longer treatment strategy may be more important than the type of antithrombic. Also, definitions for MI and bleeding vary across trials—there is no accepted standard for comparison—so the net clinical benefit is difficult to define.

There is also a “new playing field.” Clopidogrel decreases MI in patients treated with lytics and aspirin (4), an accomplishment also claimed for the early invasive strategy with revascularization of the infarct artery. Thus, the number of preventable events with improved antithrombic therapy may be less now than in the trials of this review.

The recently published ExTRACT-TIMI 25 trial (2) reinforces the conclusions of this meta-analysis, showing that enoxaparin was superior to UFH in reducing reinfarction and death but increased minor and major bleeding. However, the major benefit of LMWH over intravenous UFH may be more practical than pharmacological: ease of administration, reliable anticoagulation without the need for therapeutic monitoring, and extended treatment duration.

Eric R. Bates, MD
University of Michigan
Ann Arbor, Michigan, USA


References

1. Yusuf S, Mehta SR, Xie C, et al. Effects of reviparin, a low-molecular-weight heparin, on mortality, reinfarction, and strokes in patients with acute myocardial infarction presenting with ST-segment elevation. JAMA. 2005;293:427-35. [PubMed ID: 15671427]

2. Antman EM, Morrow DA, McCabe CH, et al. Enoxaparin versus unfractionated heparin with fibrinolysis for ST-elevation myocardial infarction. N Engl J Med. 2006;354. [PubMed ID: 16537665]

3. The OASIS-6 Trial Group. Effects of fondaparinux on mortality and reinfarction in patients with acute ST-segment elevation myocardial infarction: The OASIS-6 randomized trial. JAMA 2006;295:1519-30. [PubMed ID: 16537725]

4. Sabatine MS, Cannon CP, Gibson CM, et al. Addition of clopidogrel to aspirin and fibrinolytic therapy for myocardial infarction with ST-segment elevation. N Engl J Med. 2005;352:1179-89. [PubMed ID: 15758000]