In patients with ST-segment elevation myocardial infarction managed with fibrinolytics, is enoxaparin as safe and effective as UFH in patients treated with clopidogrel?

In patients with ST-segment elevation myocardial infarction (STEMI) who receive fibrinolytic therapy, enoxaparin reduces short-term ischemic events more than unfractionated heparin (UFH), with or without concomitant clopidogrel treatment. Clopidogrel use does not seem to further increase excess bleeding associated with enoxaparin. As the authors note, for every 1000 patients already taking clopidogrel who are treated with enoxaparin rather than UFH, 31 fewer would die or have a nonfatal major adverse clinical event (MACE) at the cost of 10 more patients having a nonfatal major bleed. For patients not receiving clopidogrel, 21 fewer patients would die or have a nonfatal MACE with 4 more patients having a nonfatal major bleed. (LOE = 1b)

Sabatine MS, Morrow DA, Dalby A, et al, for the ExTRACT-TIMI 25 Investigators. Efficacy and safety of enoxaparin versus unfractionated heparin in patients with ST-segment elevation myocardial infarction also treated with clopidogrel. J Am Coll Cardiol 2007;49:2256-2263.  [PMID:17560290]

Randomized controlled trial (double-blinded)

Industry

Concealed

Inpatient (any location) with outpatient follow-up

This was one of several preplanned analyses of the ExTRACT-TIMI 25 trial, an international randomized double-blind double-dummy study that compared enoxaparin with UFH as adjunctive therapy for fibrinolysis among patients with acute STEMI. This study analyzed the impact of combining enoxaparin with clopidogrel in patients who did not undergo percutaneous intervention. Clopidogrel was administered at the discretion of the treating physician. The trial was analyzed by intention to treat for the efficacy analysis, but safety analyses were performed on the as-treated population. Of patients who did not undergo percutaneous intervention, 14.4% of patients were treated with clopidogrel. The rate of the composite of death, myocardial infarction, myocardial ischemia, or stroke was reduced with enoxaparin compared with UFH, both in patients treated with clopidogrel [number needed to treat (NNT) = 32; 17 - 270], and in those who did not receive clopidogrel (NNT= 48; 32 - 116). Major bleeding was increased with enoxaparin compared with UFH (with clopdiogrel: number needed to treat to harm [NNTH] = 60; 35 - 186; and without clopidogrel: NNTH = 116; 76 - 137). However, among patients treated with enoxaparin, bleeding was not increased by clopidogrel use. The overall net clinical benefit through 30 days on death, myocardial infarction, myocardial ischemia, stroke, or major bleeding favored enoxaparin in patients not treated with clopidogrel (NNT = 57; 34 - 194), but did not quite reach statistical significance in patients who received clopidogrel (adjusted risk ratio = 1.7%; -0.5% to 5.3%). The main limitation of this study is that clopidogrel use was not randomized. In addition, enoxaparin was administered for a longer duration than was UFH, which could contribute to both the reduction in ischemic events and the increase in bleeds. As patients with kidney disease were excluded, the safety of combined clopidogrel and enoxaparin in patients with renal disease is not addressed by this study.