Use of thienopyridine prior to presentation with non-ST-segment elevation acute coronary syndrome and association with safety and efficacy of vorapaxar: insights from the TRACER trial

Background: Vorapaxar is effective in the prevention of secondary atherothrombotic events, although the efficacy/safety balance appears less favorable in the treatment of patients with non-ST-segment elevation (NSTE) acute coronary syndrome (ACS). We hypothesized that patients with NSTE ACS already receiving thienopyridine prior to the ACS event may show differential efficacy/safety effects with vorapaxar vs. placebo added to their standard care. Methods: We studied 12,944 patients from the Thrombin Receptor Antagonist for Clinical Event Reduction in Acute Coronary Syndrome (TRACER) trial with respect to thienopyridine use before admission for the index NSTE ACS event. The primary endpoint was a composite of cardiovascular death, myocardial infarction, stroke, rehospitalization for ischemia, and urgent revascularization. The key secondary endpoint was a composite of cardiovascular death, myocardial infarction, and stroke. Safety endpoints were bleeding complications. Results: Only 1513 patients (11.7%) were receiving thienopyridine before admission for the index NSTE ACS event. In these patients, Global Use of Strategies to Open Occluded Coronary Arteries (GUSTO) moderate/severe bleeding occurred in 5.7% treated with vorapaxar and 5.3% treated with a placebo (hazards ratio (HR) 1.10, 95% confidence interval (CI) 0.70–1.71); in thienopyridine-naïve patients, the rates were 5.7% and 4.1%, respectively (HR 1.32, 95% CI 1.11–1.57; P_int=0.45). GUSTO severe bleeding in the prior thienopyridine group occurred in 0.5% of patients treated with vorapaxar and 1.3% of patients treated with placebo (HR 0.34, 95% CI 0.09–1.30); in thienopyridine-naïve patients, the rates were 2.0% and 1.0%, respectively (HR 1.89, 95% CI 1.36–2.62; P_int=0.01). No interaction was observed between vorapaxar efficacy and prior thienopyridine use on the primary (adjusted P_int=0.53) or key secondary endpoints (P_int=0.61). Conclusions: TRACER was largely conducted in thienopyridine-naïve patients with unknown tolerance to multiple antiplatelet treatments. Patients receiving thienopyridine before the index event may have had an attenuated increase in bleeding when adding vorapaxar, whereas concomitantly adding vorapaxar and thienopyridine in naïve patients may have uncovered a latent susceptibility to bleeding.