3111Genetic variability in PAR4 platelet response in relation to bleeding and ischemic outcomes: a genetic substudy of the TRACER trial

Abstract

Background: Protease‐activated receptors (PARs) 1 and 4 play a key role in thrombin activation of platelets. PAR1 antagonism with vorapaxar reduces arterial thrombosis and ischemic events with an increased risk of bleeding. Genetic variation in platelet response to thrombin may affect bleeding risk and thrombotic events and may influence the safety and efficacy of PAR antagonism. We have demonstrated that the Thr120 variant of the common single nucleotide polymorphism (SNP) rs773902 in the PAR4 gene is associated with higher PAR4‐ mediated platelet aggregation in humans compared to the Ala120 variant. In this analysis of the TRACER trial, a randomized study comparing vorapaxar vs. placebo in patients with non‐ST‐segment elevation acute coronary syndromes (NSTE ACS), we investigated the relationship between the rs773902 SNP with major bleeding, ischemic events, safety, and efficacy of vorapaxar. Methods: A total of 6146 TRACER subjects were genotyped for rs773902. Patients were grouped according to alleles G (Ala120) and A (Thr120) pairs. The main outcome of the analysis was GUSTO moderate or severe bleeding at 2 years. Ischemic outcomes of interest were cardiovascular death, myocardial infarction, and stroke. Results: As expected for patients largely of European ancestry, 3884 (63%) patients were G/G homozygous, 1995 (32%) were G/A heterozygous, and 267 (4%) were A/A homozygous. There was a lower rate of GUSTO moderate/severe bleeding in patients with the Thr120 variant (p=0.053; Figure). The difference was driven by a lower rate in the smaller homozygous group (recessive model, HR 0.13 [0.02‐0.92] p=0.042). No significant differences were observed in the ischemic outcomes. There was a trend toward reduced excess in bleeding with vorapaxar in patients with the Thr120 variant, but interaction was not significant (p=0.178). Conclusions: In an NSTE ACS cohort, we observed a signal of lower major bleeding rates with the Thr120 PAR4 variant associated with enhanced PAR4 mediated platelet aggregation, which was mostly attributed to the A/A homozygous group. The increase in bleeding with vorapaxar seemed attenuated with the Thr120 variant, but we could not demonstrate an interaction. These findings need to be further explored in larger cohorts and different populations, including those of African descent where the A allele frequency is ∼65%.