Polygenic Risk Score for the Efficacy of Clopidogrel in Patients With Minor Stroke or Transient Ischemic Attack: A Post Hoc Analysis of the CHANCE Trial

Abstract

Background: Dual antiplatelet therapy (DAPT) with clopidogrel and aspirin is recommended for secondary prevention in patients with a minor stroke or transient ischemic attack. However, the effectiveness of DAPT can be significantly influenced by genetic variations. This study aimed to estimate the impact of multiple single-nucleotide polymorphisms across various genes on DAPT efficacy using polygenic risk score (PRS).

Methods: In this post hoc analysis, we included 2905 patients from the CHANCE trial (Clopidogrel in High-Risk Patients With Acute Nondisabling Cerebrovascular Events), which enrolled a total of 5170 patients in China between October 2009 and July 2012. The primary outcome was new stroke within 90 days. Sixteen single-nucleotide polymorphisms across 7 genes involved in clopidogrel metabolism were selected for PRS development. PRS were calculated by summing single-nucleotide polymorphisms from each individual. The Cox proportional-hazards regression model was utilized to estimate the hazard ratio (HR) and 95% CIs of PRS. The predictive value of PRS was estimated by C statistic and compared with a previously validated model.

Results: The elevated PRSs were associated with an increased risk of new stroke within 90 days (P_trend=0.01). The efficacy of DAPT versus aspirin alone in preventing 1-year composite vascular events was significantly different between patients with low (adjusted HR, 0.47 [95% CI, 0.31-0.71]) and high PRSs (adjusted HR, 0.84 [95% CI, 0.60-1.18]; P_interaction=0.03). In patients receiving DAPT, higher PRSs were associated with increased risk of new stroke and composite vascular events at 90 days (adjusted HR per SD increase was 1.51 [95% CI, 1.15-1.99]) and at 1 year (adjusted HR per SD increase was 1.34 [95% CI, 1.08-1.67]). The C statistic for predicting 90-day new stroke using the PRS developed in this study was 0.57 (95% CI, 0.52-0.62), compared with 0.52 (95% CI, 0.48-0.55) for the ABCD-GENE score.

Conclusions: Using PRS integrating multiple genes may enhance the precision of secondary prevention strategies for patients with minor stroke or transient ischemic attack in the short and long term.

Registration: URL: https://www.clinicaltrials.gov; Unique identifier: NCT00979589.

Keywords: aspirin; clopidogrel; platelet aggregation inhibitors; polymorphism, single nucleotide; stroke.