Polygenic risk, aspirin, and primary prevention of coronary artery disease

Aims Recent aspirin primary prevention trials failed to identify a net benefit of aspirin for preventing cardiovascular disease vs. the harms of bleeding. This study aimed to investigate whether a high-risk subgroup, individuals with elevated genetic predisposition to coronary artery disease ( CAD) , might derive more benefit than harm with aspirin, compared to those with lower genetic risk. Methods and results We performed genetic risk stratification of the Aspirin in Reducing Events in the Elderly (ASPREE) randomized controlled trial using a CAD polygenic risk score (GPSMult). For 12 031 genotyped participants ( 5974 aspirin, 6057 placebo) overall, we stratified them by GPS Mult quintiles ( q1-5) , then examined risk of CAD ( composite of myocardial infarction and coronary heart disease death) and bleeding events using Cox models. During a median 4.6 years of follow-up with randomization to 100 mg/day aspirin vs. placebo, 234 ( 1.9%) participants had CAD and 373 ( 3.1%) had bleeding events. In the overall cohort, aspirin resulted in higher bleeding risk [adjusted Hazard ratio (aHR) = 1.30 ( 1.06-1.61) , P = 0.01] but no significant CAD reduction [aHR = 0.84 ( 0.64-1.09) , P = 0.19]. However, among the highest quintile of polygenic risk ( q5, top 20% of the GPS(Mult) distribution) , there was a 47% reduction in risk of CAD events with aspirin [aHR = 0.53 ( 0.31-0.90) , P = 0.02] without increased bleeding risk [aHR = 1.05 ( 0.60-1.82) , P = 0.88]. Interaction between the GPS(Mult) and aspirin was significant for CAD ( q5 vs. q1, P = 0.02) but not bleeding ( P = 0.80) . Conclusion The balance between net benefit and harm on aspirin in the primary prevention setting shifts favourably in individuals with an elevated genetic predisposition.