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A Randomized Controlled Trial

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

JAMA. 2004;292:55-64.

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 noninferiority. 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.

Author Affiliations: Duke Clinical Research Institute, Durham, NC (Drs Blazing, Hasselblad, and Califf and Ms Gardner); Donald W. Reynolds Cardiovascular Clinical Research Center, University of Texas Southwestern Medical Center, Dallas (Dr de Lemos); Department of Cardiology, Green Lane Hospital, Auckland, New Zealand (Dr White); Department of Cardiology Research, University of Edinburgh, Edinburgh, Scotland (Dr Fox); Department of Interventional Cardiology, University Medical Center, Nijmegen, the Netherlands (Dr Verheugt); Division of Cardiology, Ospedale Maggiore, Parma, Italy (Dr Ardissino); Merck & Company, Whitehouse Station, NJ (Drs DiBattiste, Palmisano, Bilheimer, and Snapinn and Ms Ramsey); and Department of Medicine, Harvard Medical School, Brigham and Women's Hospital, Boston, Mass (Drs Pfeffer, Lewis, and Braunwald).

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