Increased cardiovascular mortality with single antiplatelet therapy in anticoagulation-treated chronic coronary syndrome patients: meta-analysis of randomized trials

INTRODUCTION The optimal antithrombotic regimen for chronic coronary artery disease (CAD) requiring long-term anticoagulation remains uncertain. OBJECTIVES We aimed to determine the effects of oral anticoagulation (OAC) monotherapy in comparison with OAC plus single antiplatelet therapy (OAC+SAPT) on cardiovascular mortality in chronic CAD. The secondary objective was to assess the effects of both antithrombotic approaches on major bleeding, nonfatal ischemic events, and all-cause death. PATIENTS AND METHODS We searched PubMed, Embase, and Cochrane CENTRAL (up to August 2025) for randomized trials comparing OAC alone vs OAC+SAPT in chronic CAD. Fixed-effects models were used when heterogeneity was low (I² <50%); otherwise, random-effects models were applied. Prespecified sensitivity analyses included a Bayesian meta-analysis and trial sequential analysis (TSA). The primary outcome was cardiovascular death; secondary outcomes were all-cause death, major bleeding, nonfatal myocardial infarction, and ischemic stroke. RESULTS Five trials (AFIRE, AQUATIC, EPIC-CAD, OAC-ALONE, and PRAEDO AF; n = 4964; follow-up range, 12–30 mo) met the eligibility criteria. Cardiovascular death occurred in 2.7% of the patients on OAC alone vs 3.8% on OAC+SAPT (hazard ratio [HR], 0.69; 95% CI, 0.5–0.96; P = 0.02). The Bayesian analysis confirmed the result (HR, 0.75; 95% credible interval, 0.61–0.93). TSA crossed the efficacy boundary, supporting firm evidence for cardiovascular mortality reduction with OAC alone. All-cause mortality was numerically, but not significantly, lower on OAC alone (4.9% vs 6.7%; HR, 0.79; 95% CI, 0.5–1.24; P = 0.3). Major bleeding was reduced on OAC alone (3.3% vs 6.4%; HR, 0.51; 95% CI, 0.39–0.66; P <0.001). Myocardial infarction and ischemic stroke incidence did not differ significantly in the treatment arms. CONCLUSIONS In chronic CAD requiring anticoagulation, OAC monotherapy vs OAC+SAPT reduced cardiovascular mortality and major bleeding without an excess in nonfatal thrombotic events, generally supporting OAC alone as the preferred long-term strategy in this patient population.