The reduction in risk of death and ischemic events achieved by the use of dual antiplatelet therapy (aspirin and a thienopyridine) for secondary prevention after acute coronary syndromes (ACS) is not without a risk of bleeding. The delicate balance between the risk of bleeding and the benefit of cardiovascular events reduction has always been an evolving area for research.
Recently Merck announced what was thought to be a huge leap in the era of antiplatelet therapy; vorapaxar, a novel protease-activated receptor 1 (PAR-1) antagonist that blocks thrombin-induced platelet activation and therefore inhibits platelets. In two phase 2 trials, vorapaxar was found to decrease ischemic events without increasing the risk of bleeding.1,2 Unfortunately, the results of these trials were not replicated in a larger phase 3 trial. The Thrombin Receptor Antagonist for Clinical Event Reduction in Acute Coronary Syndrome (TRACER) trial was stopped prematurely in January, 2011 rather than continue as planned until June, 2011. The decision was made by the data and safety monitoring board after an interim analysis showed no difference in the primary endpoint and a significant increase in bleeding risk with vorapaxar compared to placebo.3
TRACER was a multinational, randomized, double-blind, placebo-controlled trial aimed to determine the safety and efficacy of adding vorapaxar to standard therapy (aspirin and a thienopyridine) in patients with ACS without ST-segment elevation. Total of 12,944 patients 6,471 in the placebo arm and 6,473 in the vorapaxar arm were enrolled. Vorapaxar was given as a loading dose of 40 mg followed by a daily maintenance of 2.5 mg for a median 386 days.
The composite primary end point, defined as death from cardiovascular causes, myocardial infarction, stroke, recurrent ischemia with rehospitalization, or urgent coronary revascularization, occurred in 1,031 (18.5%) and 1,102 (19.9%) patients in the vorapaxar and placebo group, respectively (hazard ratio [HR] 0.92; 95% confidence interval [CI], 0.85 to 1.01; P = 0.07).
Vorapaxar increased the rate of the Global Use of Strategies to Open Occluded Coronary Arteries (GUSTO) moderate or severe bleeding as compared to placebo (7.2% vs. 5.2%; HR, 1.35; 95% CI, 1.16 to 1.58; P<0.001). The rate of clinically significant Thrombolysis in Myocardial Infarction (TIMI) bleeding was also significantly increased in vorapaxar group (20.2% vs. 14.6%; HR, 1.43; 95% CI, 1.31 to 1.57; P<0.001). Moreover, intracranial hemorrhage was more than 3 times higher with vorapaxar compared to placebo (1.1% vs. 0.2%; HR, 3.39; 95% CI, 1.78 to 6.45; P<0.001). Number needed to harm was 52, 18, and 111 for GUSTO bleeding, TIMI bleeding and intracranial hemorrhage, respectively.
TRACER is the worst case scenario for an antiplatelet when added to dual antiplatelet therapy for ACS. With no significant reduction in ischemic event rate and increase in bleeding risk, TRACER will probably pull the plug on the development of vorapaxar for this indication.
1. Becker RC, Moliterno DJ, Jennings LK, et al. Safety and tolerability of SCH 530348 in patients undergoing non-urgent percutaneous coronary intervention: a randomised, double-blind, placebo-controlled phase II study. Lancet 2009;373:919-28.
2. Goto S, Yamaguchi T, Ikeda Y, et al. Safety and exploratory efficacy of the novel thrombin receptor (PAR-1) antagonist SCH530348 for non–ST-segment elevation acute coronary syndrome. J Atheroscler Thromb 2010;17:156-64.
3. Tricoci P, Huang Z, Held C, et al. Thrombin-Receptor Antagonist Vorapaxar in Acute Coronary ...