AbstractAimsSafety and efficacy of antithrombotic regimens in patients with atrial fibrillation (AF) undergoing percutaneous coronary intervention (PCI) may differ based on clinical presentation. We sought to compare double vs. triple antithrombotic therapy (DAT vs. TAT) in AF patients with or without acute coronary syndrome (ACS) undergoing PCI.Methods and resultsA systematic review and meta-analysis was performed using PubMed to search for non-vitamin K antagonist oral anticoagulant (NOAC)-based randomized clinical trials. Data on subgroups of ACS or elective PCI were obtained by published reports or trial investigators. A total of 10 193 patients from four NOAC trials were analysed, of whom 5675 presenting with ACS (DAT = 3063 vs. TAT = 2612) and 4518 with stable coronary artery disease (SCAD; DAT = 2421 vs. TAT = 2097). The primary safety endpoint of ISTH major bleeding or clinically relevant non-major bleeding was reduced with DAT compared with TAT in both ACS (12.2% vs. 19.4%; RR 0.63, 95% CI 0.56–0.71; P < 0.0001; I2 = 0%) and SCAD (14.6% vs. 22.0%; RR 0.68, 95% CI 0.55–0.85; P = 0.0008; I2 = 66%), without interaction (P-int = 0.54). Findings were consistent for secondary bleeding endpoints, including intra-cranial haemorrhage. In both subgroups, there was no difference between DAT and TAT for all-cause death, major adverse cardiovascular events, or stroke. Myocardial infarction and stent thrombosis were numerically higher with DAT vs. TAT consistently in ACS and SCAD (P-int = 0.60 and 0.86, respectively). Findings were confirmed by multiple sensitivity analyses, including a separate analysis on dabigatran regimens and a restriction to PCI population.ConclusionsDAT, compared with TAT, is associated with lower bleeding risks, including intra-cranial haemorrhage, and a small non-significant excess of cardiac ischaemic events in both patients with or without ACS.