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Randomized Controlled Trial
. 2025 Feb 8;11(1):84-91.
doi: 10.1093/ehjcvp/pvae085.

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

Chenglong Yu  1 , Pradeep Natarajan  2   3   4 , Aniruddh P Patel  2   3   4   5 , Harpreet S Bhatia  6 , Amit V Khera  7   8   9 , Johannes T Neumann  1   10   11 , Sotirios Tsimikas  6 , Rory Wolfe  1 , Stephen J Nicholls  1   12 , Christopher M Reid  1   13 , Sophia Zoungas  1 , Andrew M Tonkin  1 , John J McNeil  1 , Paul Lacaze  1
Affiliations
Randomized Controlled Trial

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

Chenglong Yu et al. Eur Heart J Cardiovasc Pharmacother. .

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.

Keywords: Aspirin; Coronary artery disease; Genetic risk stratification; Polygenic risk score; Randomized controlled trial.

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Conflict of interest statement

A.M.T. has received research support from Bayer for materials in ASPREE, and honoraria for Advisory Board participation or lectures from Amgen, AstraZeneca, Boehringer-Ingelheim, and Pfizer. S.J.N. has received research support from AstraZeneca, Amgen, Anthera, CSL Behring, Cerenis, Eli Lilly, Esperion, Resverlogix, Novartis, InfraReDx, and Sanofi-Regeneron and is a consultant for Amgen, Akcea, AstraZeneca, Boehringer Ingelheim, CSL Behring, Eli Lilly, Esperion, Kowa, Merck, Takeda, Pfizer, Sanofi-Regeneron, and Novo Nordisk. P.N. reports research grants from Allelica, Amgen, Apple, Boston Scientific, Genentech/Roche, and Novartis, personal fees from Allelica, Apple, AstraZeneca, Blackstone Life Sciences, Creative Education Concepts, CRISPR Therapeutics, Eli Lilly & Co, Esperion Therapeutics, Foresite Capital, Foresite Labs, Genentech/Roche, GV, HeartFlow, Magnet Biomedicine, Merck, Novartis, Novo Nordisk, TenSixteen Bio, and Tourmaline Bio, equity in Bolt, Candela, Mercury, MyOme, Parameter Health, Preciseli, and TenSixteen Bio, and spousal employment at Vertex Pharmaceuticals, all unrelated to the present work. Bayer AG provided low-dose aspirin and placebo tablets for the clinical trial but had no other relationship with the work. S.Z. reports previous payments to institution (Monash University) from AstraZeneca, Boehringer Ingelheim, CSL Seqirus, Eli Lilly Australia, Moderna, MSD Australia, Sanofi and Novo Nordisk for participation in advisory and educational meetings. S.Z. is a Board Director of the Australian Clinical Trials Alliance and the Victorian Institute of Forensic Medicine, and has no declaration of interest specific to the research reported in this paper. H.S.B. is a consultant/advisor for Kaneka, Novartis, Arrowhead and Abbott, all unrelated to the present work. No other conflicts were reported.

Figures

Figure 1
Figure 1
Study flow chart indicating the selection of the final dataset. The ASPirin in Reducing Events in the Elderly (ASPREE) trial enrolled N = 19 114 individuals aged ≥70 years (≥65 years for US minorities), with no prior history of cardiovascular disease events.
Figure 2
Figure 2
Association of aspirin treatment and incident CAD (a) and major haemorrhage (b) events, stratified by polygenic risk.
Figure 3
Figure 3
Effect of aspirin on CAD and bleeding events in the ASPREE trial after genetic stratification. Among 12 031 genotyped participants of European descent enrolled into the ASPirin Reducing Events in Elderly (ASPREE) trial, we used Cox proportional hazards regression to model relationships between GPSMult and aspirin allocation with incidence of coronary artery disease (CAD) events and clinically significant bleeding (haemorrhage) events, adjusting for covariates. We tested for interaction between aspirin allocation and high vs. low GPSMult quintile (q5).
Figure 4
Figure 4
Cumulative incidence of coronary artery disease (CAD) events in the ASPREE trial stratified by CAD polygenic risk.
See this image and copyright information in PMC

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