Clopidogrel versus aspirin for secondary prevention of coronary artery disease: a systematic review and individual patient data meta-analysis

Background: Aspirin monotherapy is recommended indefinitely for patients with established coronary artery disease (CAD). The aim of this individual patient level meta-analysis was to provide a comprehensive evaluation of the comparative efficacy and safety of clopidogrel versus aspirin monotherapy in patients with established CAD, most of whom had undergone percutaneous coronary intervention or had acute coronary syndrome. Methods: We conducted a systematic search in PubMed, Scopus, Web of Science, and Embase to identify randomised trials published from database inception to April 12, 2025, comparing clopidogrel monotherapy with aspirin monotherapy in patients with established CAD who had discontinued or never started dual antiplatelet therapy. Randomised trials featuring an initial phase of dual antiplatelet therapy were eligible for inclusion in this individual patient data meta-analysis. In the main analysis, we used semi-parametric shared log-normal frailty models (one-stage analysis), including a random intercept to account for differences in the baseline hazard across trials, and a random slope to account for between-trial differences in treatment effects. The primary efficacy endpoint was a composite of cardiovascular death, myocardial infarction, or stroke (major adverse cardiovascular or cerebrovascular events [MACCE]); the primary safety endpoint was major bleeding. This study is registered with PROSPERO (CRD42025645594). Findings: Seven randomised trials including 28 982 patients (14 507 assigned to clopidogrel; 14 475 assigned to aspirin) with a median follow-up of 2·3 years (IQR 1·1–4·0) were eligible and included. At 5·5 years, MACCE was less common in patients assigned to clopidogrel than in patients assigned to aspirin (929 events [2·61 per 100 patient-years] vs 1062 events [2·99 per 100 patient-years]; hazard ratio 0·86 [95% CI 0·77–0·96]; p=0·0082). Mortality and major bleeding (256 events [0·71 per 100 patient-years] with clopidogrel vs 279 events [0·77 per 100 patient-years] with aspirin; 0·94 [0·74–1·21]; p=0·64) did not differ. Interpretation: These findings add to the evidence that clopidogrel monotherapy is superior to aspirin monotherapy for MACCE prevention with no increase in the risk of bleeding, and support the preferential use of clopidogrel over aspirin for secondary prevention in patients with established CAD. Funding: Cardiocentro Ticino Institute, Ente Ospedaliero Cantonale, Switzerland.