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CLINICAL RESEARCH: FOCUS ISSUE: SUBSTUDIES FROM EX: TRACT-TIMI 25

Efficacy and Safety of Enoxaparin Versus Unfractionated Heparin in Patients With ST-Segment Elevation Myocardial Infarction Also Treated With Clopidogrel

Marc S. Sabatine, MD, MPH, FACC^_*,1, David A. Morrow, MD, MPH, FACC^_*,2, Anthony Dalby, MD, Mathias Pfisterer, MD, Tibor Duris, MD, Jose Lopez-Sendon, MD, FACC^||,3, Sabina A. Murphy, MPH^_*, Runlin Gao, MD, FACC^¶, Elliott M. Antman, MD, FACC^_*,4,_*, Eugene Braunwald, MD, MACC^_*,4 for the ExTRACT-TIMI 25 Investigators

^_* Thrombolysis In Myocardial Infarction (TIMI) Study Group, Cardiovascular Division, Brigham and Women’s Hospital and Department of Medicine, Harvard Medical School, Boston, Massachusetts
South African Cardiology Clinical Trials Group, Milpark Hospital, Johannesburg, South Africa
Kantonsspital, Basel, Switzerland
FNsP, Nove Zamky, Slovakia
^|| Hospital Universitario La Paz, Madrid, Spain
^¶ Fu Wai Hospital, Beijing, China.

Manuscript received September 7, 2006; revised manuscript received December 21, 2006, accepted January 2, 2007.

^_* Reprint requests and correspondence: Dr. Elliott M. Antman, TIMI Study Group, 350 Longwood Avenue, Boston, Massachusetts 02115. (Email: eantman{at}rics.bwh.harvard.edu).

Objectives: The purpose of this study was to determine the efficacy and safety of enoxaparin (ENOX) versus unfractionated heparin (UFH) in patients with ST-segment elevation myocardial infarction (STEMI) receiving fibrinolytic therapy with and without clopidogrel.

Background: The efficacy and safety of ENOX and clopidogrel given together in STEMI remains to be defined.

Methods: We compared the rates of major adverse cardiovascular events (MACE) as well as the rates of bleeding in medically managed patients randomized to ENOX versus UFH in the ExTRACT-TIMI 25 (Enoxaparin and Thrombolysis Reperfusion for Acute Myocardial Infarction Treatment–Thrombolysis In Myocardial Infarction 25) trial, stratified by concomitant clopidogrel use.

Results: Enoxaparin significantly reduced the rate of the composite of death, recurrent myocardial infarction, myocardial ischemia, or stroke, compared with UFH, both in patients (n = 2,173) treated with clopidogrel (10.8% vs. 13.9%, adjusted odds ratio [OR_adj] 0.70, p = 0.013) and in patients (n = 12,918) not treated with clopidogrel (13.3% vs. 15.3%, OR_adj 0.85, p = 0.003) with no evidence of heterogeneity (p_interaction = 0.21). The excess risk of TIMI major bleeding with ENOX versus UFH was numerically but not statistically significantly higher in patients treated with clopidogrel (2.7% vs. 1.0%) versus those who were not (2.1% vs. 1.2%) (p_interaction = 0.61). Net clinical benefit (MACE and major bleeding) favored treatment with ENOX over UFH, either with concomitant clopidogrel (absolute risk reduction 2.4%, 95% confidence interval [CI] –0.5% to 5.3%) or without (absolute risk reduction 1.7%, 95% CI 0.5% to 3.0%) (p_interaction = 0.61).

Conclusions: In patients with STEMI receiving fibrinolytic therapy, the net benefit of ENOX is similar in patients who are and are not treated with clopidogrel. The totality of trial data suggest that the combination of a fibrinolytic, aspirin, clopidogrel, and ENOX offers an attractive pharmacologic reperfusion strategy in STEMI.

Abbreviations and Acronyms   ENOX = enoxaparin   ICH = intracranial hemorrhage   LMWH = low-molecular-weight heparin   MACE = major adverse cardiovascular event   MI = myocardial infarction   PCI = percutaneous coronary intervention   STEMI = ST-segment elevation myocardial infarction   UFH = unfractionated heparin

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