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FOCUS ISSUE: CARDIAC INTERVENTION: INTERVENTION IN ACUTE CORONARY SYNDROME

A Subgroup Analysis of the Impact of Prerandomization Antithrombin Therapy on Outcomes in the SYNERGY Trial

Enoxaparin Versus Unfractionated Heparin in Non–ST-Segment Elevation Acute Coronary Syndromes

Marc Cohen, MD, FACC^_*,_*, Kenneth W. Mahaffey, MD, FACC, Karen Pieper, MS, Charles V. Pollack, Jr, MD, Elliott M. Antman, MD, FACC, James Hoekstra, MD^||, Shaun G. Goodman, MD, FACC^¶, Anatoly Langer, MD, FACC^¶, Jacques J. Col, MD^#, Harvey D. White, MD^_**, Robert M. Califf, MD, FACC, James J. Ferguson, MD, FACC on behalf of the SYNERGY Trial Investigators

^_* HEART Hospital of New Jersey, Newark Beth Israel Medical Center, Newark, New Jersey
Duke Clinical Research Institute, Durham, North Carolina
^|| Wake Forest University Health Sciences, Winston-Salem, North Carolina
Pennsylvania Hospital, University of Pennsylvania School of Medicine, Philadelphia, Pennsylvania
Brigham and Women’s Hospital, Boston, Massachusetts
^¶ Canadian Heart Research Centre and Terrence Donnelly Heart Center, St. Michael’s Hospital, University of Toronto, Toronto, Ontario, Canada
^# Clinique Universitaire St. Luc, Brussels, Belgium
^_** Green Lane Hospital, Auckland, New Zealand
Texas Heart Institute, St. Luke’s-Episcopal Hospital, Houston, Texas.

Manuscript received September 1, 2005; revised manuscript received May 5, 2006, accepted May 16, 2006.

^_* Reprint requests and correspondence: Dr. Marc Cohen, Cardiac Cath Lab Administration, Newark Beth Israel Medical Center, 201 Lyons Avenue, Newark, New Jersey 07112. (Email: marcohen{at}SBHCS.com).

OBJECTIVES: The purpose of this study was to compare the effect of receiving pretreatment with antithrombin before randomization as well as overall efficacy and safety of enoxaparin versus unfractionated heparin (UFH) in the SYNERGY (Superior Yield of the New Strategy of Enoxaparin, Revascularization, and Glycoprotein IIb/IIIa Inhibitors) trial.

BACKGROUND: The SYNERGY trial results demonstrated noninferiority in outcomes with enoxaparin compared with UFH. Randomized treatment was independent of prerandomization treatment.

METHODS: Analyses were first performed on the 4 prerandomization subgroups: patients who received no antithrombin therapy and those who were treated with enoxaparin or UFH or both. Then, we focused on the subgroup of patients who received no pretreatment or were pretreated with and randomized to the same drug. Of the 9,978 patients, 2,440 did not receive prerandomization therapy and 6,138 received consistent therapy through randomization. The primary end point was the composite of death and nonfatal myocardial infarction (MI) at 30 days.

RESULTS: After adjustment for differences among the subgroups, no significant difference in the association between the 4 pretreatment groups and death or MI remained (p = 0.171). The randomized treatment effect on 30-day death or MI tended to vary with pretreatment (p = 0.055 for interaction test after adjustment). Patients who received consistent therapy with enoxaparin had significantly less death or MI than patients randomized to UFH (adjusted p = 0.041) with a trend toward increased bleeding.

CONCLUSIONS: Treatment with antithrombin therapy before randomization had potential impact on comparison of study drug effects. After adjustment for differences in baseline characteristics between subgroups, consistent therapy with enoxaparin might be superior to UFH in reducing death or nonfatal MI, with a modest excess in bleeding.

Abbreviations and Acronyms   aPTT = activated partial thromboplastin time   CABG = coronary artery bypass graft   GP = glycoprotein   GUSTO = Global Utilization of Strategies to Open Occluded Arteries trial   MI = myocardial infarction   NSTE ACS = non–ST-segment elevation acute coronary syndromes   PCI = percutaneous coronary intervention   SYNERGY = Superior Yield of the New Strategy of Enoxaparin, Revascularization, and Glycoprotein IIb/IIIa Inhibitors trial   TIMI = Thrombolysis In Myocardial Infarction   UFH = unfractionated heparin

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