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Thrombin-Receptor Antagonist Vorapaxar in Acute Coronary Syndromes
Study Questions:
Does the addition of vorapaxar, a platelet thrombin-receptor antagonist, to the treatment of acute non–ST-segment elevation myocardial infarction (NSTEMI) reduce cardiovascular ischemic event rates or improve outcomes without safety concerns?
Methods:
The TRACER (Thrombin Receptor Antagonist for Clinical Event Reduction in Acute Coronary Syndrome) trial investigators reported the results of a double-blind, placebo-controlled, multinational study comparing the effect of vorapaxar (40 mg loading dose, followed by 2.5 mg daily, orally) with placebo in patients who were over age 55, or had a history of coronary artery disease or peripheral artery disease, presenting with NSTE acute coronary syndrome (ACS), defined by symptoms with either cardiac enzyme elevation or dynamic ST-segment changes. The primary endpoint was a composite of death from cardiovascular causes, MI, stroke, rehospitalization for recurrent ischemia, or urgent revascularization.
Results:
Follow-up of 12,944 randomized patients was terminated early after safety review. Median follow-up was 502 days (interquartile range, 349-667). The primary endpoint Kaplan-Meier 2-year rate was 18.5% versus 19.9% in the vorapaxar and placebo groups, respectively (hazard ratio [HR], 0.92; 95% confidence interval [CI], 0.85-1.01; p = 0.07). Secondary endpoint of composite of death from cardiovascular cause, MI, or stroke had a rate of 14.7% versus 16.4% in the vorapaxar and placebo groups, respectively (HR, 0.89; 95% CI, 0.81-0.98; p = 0.02). Moderate and severe bleeding rates in the vorapaxar and placebo groups were 7.2% and 5.2%, respectively (HR, 1.35; 95% CI, 1.16-1.58; p < 0.001), and the intracranial hemorrhage rates were 1.1% and 0.2%, respectively (HR, 3.39; 95% CI, 1.78-6.45; p < 0.001).
Conclusions:
The authors concluded that in patients with ACS, the addition of vorapaxar to standard therapy did not significantly reduce the primary composite endpoint, but significantly increased the risk of major bleeding, including intracranial hemorrhage.
Perspective:
This very large and rigorously conducted multinational study of a thrombin-receptor antagonist in NSTE ACS was stopped early due to safety concerns, specifically a roughly 35% increase in moderate and severe bleeding, as well as a more than threefold increase in intracranial hemorrhage rate. There was no significant difference in the primary endpoint. Although there was a significant reduction in the key secondary endpoint (death from cardiovascular disease, MI, or stroke), superiority could not be declared technically, as the primary endpoint had not been decreased significantly. The effect on the primary endpoint of the early termination of this study is unknown. These data will warrant further analysis, and another thrombin-receptor antagonist study is ongoing, but the data suggest that we may be reaching the limit of multi-modal antiplatelet therapy to provide further efficacy improvement without conferring further bleeding risk.
Keywords: Stroke, Acute Coronary Syndrome, Myocardial Infarction, Coronary Artery Disease, Coronary Disease, Receptors, Thrombin, Pyridines, Blood Platelets, Peripheral Arterial Disease, Receptor, PAR-1, Intracranial Hemorrhages, Lactones, Cardiovascular Diseases, Confidence Intervals
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