Safety and efficacy of enoxaparin vs unfractionated heparin in patients with non-ST-segment elevation acute coronary syndromes who receive tirofiban and aspirin: A randomized controlled trial

Michael A. Blazing, James A de Lemos, Harvey D. White, Keith A A Fox, Freek W A Verheugt, Diego Ardissino, Peter M. DiBattiste, Joanne Palmisano, David W. Bilheimer, Steven M. Snapinn, Karen E. Ramsey, Laura H. Gardner, Vic Hasselblad, Marc A. Pfeffer, Eldrin F. Lewis, Eugene Braunwald, Robert M. Califf

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219 Scopus citations

Abstract

Context: Enoxaparin or the combination of glycoprotein IIb/IIIa inhibitor tirofiban with unfractionated heparin independently have shown superior efficacy over unfractionated heparin alone in patients with non-ST-elevation acute coronary syndromes (ACS). It is not clear if combining enoxaparin with glycoprotein IIb/IIIa inhibitors is as safe or as effective as the current standard combination of unfractionated heparin with glycoprotein IIb/IIIa inhibitors. Objective: To assess efficacy and safety of the combination of enoxaparin and tirofiban compared with unfractionated heparin and tirofiban in patients with non-ST-elevation ACS. Design, Setting, and Participants: A prospective, international, open-label, randomized, noninferiority trial of 1 mg/kg of enoxaparin every 12 hours (n=2026) compared with weight-adjusted intravenous unfractionated heparin (n=1961) in patients with non-ST-elevation ACS receiving tirofiban and aspirin. Phase A of the A to Z trial was conducted between December 1999 and May 2002. Main Outcome Measures: Death, recurrent myocardial infarction, or refractory ischemia at 7 days in the intent-to-treat population with boundaries set for superiority and noninferiority. Safety based on measures of bleeding using the Thrombolysis in Myocardial Infarction (TIMI) classification system. Results: A total of 169 (8.4%) of 2018 patients randomized to enoxaparin experienced death, myocardial infarction, or refractory ischemia at 7 days compared with 184 (9.4%) of 1952 patients randomized to unfractionated heparin (hazard ratio [HR], 0.88; 95% confidence interval [CI], 0.71-1.08). This met the prespecified criterion for non-inferiority. All components of the composite primary and secondary end points favored enoxaparin except death, which occurred in only 1% of patients (23 for enoxaparin and 17 for unfractionated heparin). Rates for any TIMI grade bleeding were low (3.0% for enoxaparin and 2.2% for unfractionated heparin; P=.13). Using a worst-case approach that combined 2 independent bleeding evaluations, use of enoxaparin was associated with 1 additional TIMI major bleeding episode for each 200 patients treated. Conclusions: In patients receiving tirofiban and aspirin, enoxaparin is a suitable alternative to unfractionated heparin for treatment of non-ST-elevation ACS. The 12% relative and 1% absolute reductions in the primary end point in favor of enoxaparin met criterion for noninferiority and are consistent with prior trials performed without the use of glycoprotein IIb/IIIa inhibitors.

Original languageEnglish (US)
Pages (from-to)55-64
Number of pages10
JournalJournal of the American Medical Association
Volume292
Issue number1
DOIs
StatePublished - Jul 1 2004

ASJC Scopus subject areas

  • Medicine(all)

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    Blazing, M. A., de Lemos, J. A., White, H. D., Fox, K. A. A., Verheugt, F. W. A., Ardissino, D., DiBattiste, P. M., Palmisano, J., Bilheimer, D. W., Snapinn, S. M., Ramsey, K. E., Gardner, L. H., Hasselblad, V., Pfeffer, M. A., Lewis, E. F., Braunwald, E., & Califf, R. M. (2004). Safety and efficacy of enoxaparin vs unfractionated heparin in patients with non-ST-segment elevation acute coronary syndromes who receive tirofiban and aspirin: A randomized controlled trial. Journal of the American Medical Association, 292(1), 55-64. https://doi.org/10.1001/jama.292.1.55