Yu Chenglong, Natarajan Pradeep, Patel Aniruddh P, Bhatia Harpreet S, Khera Amit V, Neumann Johannes T, Tsimikas Sotirios, Wolfe Rory, Nicholls Stephen J, Reid Christopher M, Zoungas Sophia, Tonkin Andrew M, McNeil John J, Lacaze Paul
Sc hool of Public Health and Preventive Medicine, Monash University, 553 St Kilda Road, Melbourne, VIC 3004, Australia.
Program in Medical and Population Genetics, Broad Institute of Harvard and MIT, Cambridge, MA 02142, USA.
Eur Heart J Cardiovasc Pharmacother. 2025 Feb 8;11(1):84-91. doi: 10.1093/ehjcvp/pvae085.
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.
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).
The balance between net benefit and harm on aspirin in the primary prevention setting shifts favourably in individuals with an elevated genetic predisposition.
近期的阿司匹林一级预防试验未能确定阿司匹林在预防心血管疾病方面的净获益与出血危害之间的关系。本研究旨在调查一个高危亚组，即冠状动脉疾病（CAD）遗传易感性升高的个体，与遗传风险较低的个体相比，服用阿司匹林是否利大于弊。
我们使用CAD多基因风险评分（GPSMult）对老年人阿司匹林减少事件（ASPREE）随机对照试验进行遗传风险分层。对于总共12031名基因分型参与者（5974名服用阿司匹林，6057名服用安慰剂），我们根据GPSMult五分位数（q1 - 5）对他们进行分层，然后使用Cox模型检查CAD风险（心肌梗死和冠心病死亡的综合）和出血事件。在随机分配接受100毫克/天阿司匹林与安慰剂治疗的中位4.6年随访期间，234名（1.9%）参与者发生CAD，373名（3.1%）参与者发生出血事件。在整个队列中，阿司匹林导致出血风险更高[调整后风险比（aHR）= 1.30（1.06 - 1.61），P = 0.01]，但CAD没有显著降低[aHR = 0.84（0.64 - 1.09），P = 0.19]。然而，在多基因风险最高的五分位数（q5，GPSMult分布的前20%）中，服用阿司匹林使CAD事件风险降低了47%[aHR = 0.53（0.31 - 0.90），P = 0.02]，且出血风险没有增加[aHR = 1.05（0.60 - 1.82），P = 0.88]。GPSMult与阿司匹林之间的相互作用对CAD有显著意义（q⑤与q①相比，P = 0.02），但对出血无显著意义（P = 0.80）。
在一级预防中，对于遗传易感性升高的个体，阿司匹林的净获益与危害之间的平衡向有利方向转变。
