Polygenic risk, aspirin, and primary prevention of coronary artery disease
Year: 2024
Type: article
Abstract: 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 GPSMult 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 GPSMult 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 GPSMult 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.
Language: English
Subfield: Cardiology and Cardiovascular Medicine
Field: Medicine
Domain: Health Sciences
Open Access status: hybrid
Estimated APC paid: $4,311
Funders: Commonwealth Scientific and Industrial Research Organisation, Monash University, Menzies Institute for Medical Research, National Institutes of Health, Medical Research Council, National Health and Medical Research Council, National Institute on Aging, National Heart, Lung, and Blood Institute, National Human Genome Research Institute, National Cancer Institute
Awards: G13697443, G1449261147, G1740950978, G313601605, G486581700, G608921188, ASPREE Completion Project, G6485832292, G713793082, G7210608478, G8586009266, G8718603654, ASPirin in Reducing Events in the Elderly (ASPREE), G9000020190, G9000088779, G9000156609, G9000275757, Whole genome sequences in ethnically diverse individuals to comprehensively characterize the genetic mechanisms of dyslipidemias, Enabling improved applicability and transferability of polygenic scores across populations, Aspirin for Primary Prevention of Cardiovascular Disease in Patients with Elevated Lipoprotein(a), Advancing the clinical actionability of polygenic scores for coronary artery disease
OpenAlex ID: W4403755523