One-Year Mortality for Bivalirudin vs Heparins Plus Optional Glycoprotein IIb/IIIa Inhibitor Treatment Started in the Ambulance for ST-Segment Elevation Myocardial Infarction: A Secondary Analysis of the EUROMAX Randomized Clinical Trial

Abstract

Importance: Uncertainty exists regarding potential survival benefits of bivalirudin compared with heparin with routine or optional use of glycoprotein IIb/IIIa inhibitors (GPIs) in patients with ST-segment elevation myocardial infarction (STEMI). Few data are available regarding long-term mortality in the context of contemporary practice with frequent use of radial access and novel platelet adenosine diphosphate P2Y12 receptor inhibitors.

Objective: To assess the effect of bivalirudin monotherapy compared with unfractionated or low-molecular-weight heparin plus optional GPIs on 1-year mortality.

Design, setting, and participants: This international, randomized, open-label clinical trial (EUROMAX [European Ambulance Acute Coronary Syndrome Angiography]) included 2198 patients with STEMI undergoing transport for primary percutaneous coronary intervention from March 10, 2010, through June 20, 2013, and followed up for 1 year. Patients were randomized (1:1) in ambulance to bivalirudin monotherapy vs unfractionated or low-molecular-weight heparin plus optional GPIs (control group). Analysis was based on intention to treat.

Main outcomes and measures: The primary outcome of this prespecified analysis was 1-year mortality. All deaths were adjudicated as cardiac or noncardiac by an independent, blinded clinical events committee. One-year mortality was assessed and examined across multiple prespecified subgroups.

Results: Of the 2198 patients enrolled (1675 men [76.2%] and 523 women [23.8%]; median [interquartile range] age, 62 [52-72] years), complete 1-year follow-up data were available for 2164 (98.5%). All-cause 1-year mortality occurred in 118 patients (5.4%). The number of all-cause deaths was the same for both treatment groups (59 deaths; relative risk [RR], 1.02; 95% CI, 0.72-1.45; P = .92). No differences were noted in the rates of 1-year cardiac death (44 [4.0%] for the bivalirudin group vs 48 [4.3%] for the control group; RR, 0.93; 95% CI, 0.63-1.39; P = .74) or noncardiac death (15 [1.4%] for the bivalirudin group vs 11 [1.0%] for the control group; RR, 1.39; 95% CI, 0.64-3.01; P = .40). Results were consistent across the prespecified patient subgroups. The rate of deaths occurring from 30 days to 1 year was also similar (27 [2.5%] in the bivalirudin group vs 25 [2.3%] in the control group; RR, 1.10; 95% CI, 0.64-1.88; P = .73).

Conclusions and relevance: In patients with STEMI who were being transported for primary percutaneous coronary intervention, treatment with bivalirudin or with heparin with optional use of GPI resulted in similar 1-year mortality. The reduced composite end point of death and/or major bleeding at 30 days in the bivalirudin arm of the EUROMAX trial did not translate into reduced cardiovascular or all-cause death at 1 year.

Trial registration: clinicaltrials.gov Identifier: NCT01087723.

Conflict of interest statement

Conflict of Interest Disclosures: All authors have completed and submitted the ICMJE Form for Disclosure of Potential Conflicts of Interest. Dr van’t Hof reports grants, personal fees, and nonfinancial support from AstraZeneca; grants from Medtronic; grants from Daiichi Sankyo; and personal fees from Iroko Cardio. Dr ten Berg reports research grants from AstraZeneca and ZonMw and fees from AstraZeneca, Boehringer Ingelheim, The Medicines Company, Merck, Bayer, and Daiichi Sankyo. Dr Zeymer reports speaker fees from AstraZeneca, Bayer Healthcare, Boehringer Ingelheim, Bristol-Myers Squibb, Daiichi Sankyo, Eli Lilly, MSD, Pfizer, The Medicines Company, Novartis, and Sanofi. Drs Bernstein, Anthopoulos, and Deliargyris report being full-time employees of The Medicines Company. Dr Steg reports personal fees from The Medicines Company during the conduct of the study; personal fees from Amarin, AstraZeneca, Bayer, Boehringer Ingelheim, Bristol-Myers Squibb, Daiichi Sankyo, GlaxoSmithKline, Eli Lilly, Merck Sharpe & Dohme, Novartis, Pfizer, Roche, Medtronic, Janssen, CSL Behring, and Regeneron; grants and personal fees from Sanofi and Servier; and personal fees and nonfinancial support from The Medicines Company outside the submitted work. No other disclosures were reported.

Figures

Figure 1.. Kaplan-Meier Survival Curves

Analysis shows deaths to 1 year (365 days). The control group received unfractionated or low-molecular-weight heparin plus optional glycoprotein IIb/IIIa inhibitors. P values are calculated using the log-rank test.

Figure 2.. Subgroup Analyses of 1-Year Mortality Outcome

The control group received unfractionated or low-molecular-weight heparin plus optional glycoprotein IIb/IIIa inhibitors. LAD indicates left anterior descending; P2Y12, platelet adenosine diphosphate P2Y12 receptor; and RR, relative risk. aClass I, no clinical signs of heart failure; class II, rales or crackles in the lungs, a third heart sound, and an elevated jugular venous pressure; class III, frank acute pulmonary edema; and class IV, cardiogenic shock or hypotension and evidence of peripheral vasoconstriction.