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A Systematic Overview

John L. Petersen, MD; Kenneth W. Mahaffey, MD; Vic Hasselblad, PhD; Elliott M. Antman, MD; Marc Cohen, MD; Shaun G. Goodman, MD; Anatoly Langer, MD; Michael A. Blazing, MD; Anne Le-Moigne-Amrani, MS; James A. de Lemos, MD; Christopher C. Nessel, MD; Robert A. Harrington, MD; James J. Ferguson, MD; Eugene Braunwald, MD; Robert M. Califf, MD

JAMA. 2004;292:89-96.

Context  Antithrombin therapy has become a guidelines-recommended standard of care in the treatment of acute coronary syndromes (ACS), but recent trials comparing use of enoxaparin and unfractionated heparin in ACS have yielded less robust efficacy and safety results than have earlier trials of these antithrombin therapies.

Objective  To systematically evaluate the end points of all-cause death and nonfatal myocardial infarction (MI), transfusion, and major bleeding observed in the 6 randomized controlled trials comparing enoxaparin and unfractionated heparin in treatment of ACS.

Data Sources  The primary data sets for ESSENCE, A to Z, and SYNERGY were available at the Duke Clinical Research Institute. Baseline characteristics and event frequencies for TIMI 11B, ACUTE II, and INTERACT were provided by the principal investigator of each study.

Study Selection  All 6 randomized controlled trials comparing enoxaparin and unfractionated heparin in non–ST-segment elevation ACS were selected for analysis.

Data Extraction  Efficacy and safety end points were extracted from the overall trial populations and the subpopulation receiving no antithrombin therapy prior to randomization.

Data Synthesis  Systematic evaluation of the outcomes for 21 946 patients was performed using a random-effects empirical Bayes model. No significant difference was found in death at 30 days for enoxaparin vs unfractionated heparin (3.0% vs 3.0%; odds ratio [OR], 1.00; 95% confidence interval [CI], 0.85-1.17). A statistically significant reduction in the combined end point of death or nonfatal MI at 30 days was observed for enoxaparin vs unfractionated heparin in the overall trial populations (10.1% vs 11.0%; OR, 0.91; 95% CI, 0.83-0.99; number needed to treat, 107). A statistically significant reduction in the combined end point of death or MI at 30 days was also observed for enoxaparin in the populations receiving no prerandomization antithrombin therapy (8.0% vs 9.4%; OR, 0.81; 95% CI, 0.70-0.94; number needed to treat, 72). No significant difference was found in blood transfusion (OR, 1.01; 95% CI, 0.89-1.14) or major bleeding (OR, 1.04; 95% CI, 0.83-1.30) at 7 days after randomization in the overall safety population or in the population of patients receiving no prerandomization antithrombin therapy.

Conclusion  In a systematic overview of approximately 22 000 patients across the spectrum of ACS, enoxaparin is more effective than unfractionated heparin in preventing the combined end point of death or MI.

Author Affiliations: Duke Clinical Research Institute, Durham, NC (Drs Petersen, Mahaffey, Hasselblad, Blazing, Harrington, and Califf); Cardiovascular Division, Department of Medicine, Brigham and Women's Hospital, Boston, Mass (Drs Antman and Braunwald); Division of Cardiology, Newark Beth Israel Medical Center, Newark, NJ (Dr Cohen); Canadian Heart Research Centre and Terrence Donnelly Heart Centre, Division of Cardiology, St Michael's Hospital, University of Toronto, Toronto, Ontario (Drs Goodman and Langer); Division of Cardiology, University of Texas, Southwestern, Dallas (Dr de Lemos); Aventis Inc, Bridgewater, NJ (Dr Nessel, Ms Le-Moigne-Amrani); and St Luke's-Episcopal Hospital, Texas Heart Institute, Houston (Dr Ferguson).

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