BackgroundFor patients anticoagulated with direct oral anticoagulants (DOAC) or warfarin and on aspirin (ASA) for non-valvular atrial fibrillation (AF) and/or venous thromboembolism (VTE), it is unclear if bleeding outcomes differ. ObjectiveTo assess bleeding rates for ASA with DOACs versus warfarin and one another. Patients/MethodsRegistry-based cohort study of patients followed by a six-center quality improvement collaborative in Michigan using data from 2009-2022. The study includes adults on aspirin with warfarin or DOACs for AF and/or VTE without a recent myocardial infarction or heart valve replacement. ResultsAfter propensity matching by anticoagulant class, we compared two groups of 1,467 patients followed for a median of 18.0 months. Any bleeding and non-major bleeding were increased with DOACs+ASA compared to warfarin+ASA (32.2 versus 27.8 and 27.1 versus 22.9 events/100 patient years, relative risks [RR] 1.1 and 1.2, 95% confidence intervals [CI] 1.1-1.2 and 1.1-1.3). After matching by drug, patients on apixaban+ASA versus warfarin+ASA had more bleeding (31.2 versus 27.8 events/100 patient years, RR 1.1, 95% CI 1.0-1.2), and non-major bleeding, but less major bleeding (3.8 versus 4.7 events/100 patient years, RR 0.8, 95% CI 0.6-1.0), and emergency room visits for bleeding. Patients on rivaroxaban+ASA versus warfarin+ASA had more bleeding (39.3 versus 26.3 events/100 patient years, RR 1.5, 95% CI 1.3-1.6), non-major bleeding, and thrombosis. Patients on apixaban+ASA versus rivaroxaban+ASA had significantly less bleeding (22.5 versus 39.3/100 patient years, RR 0.6, 95% CI 0.5-0.7), non-major bleeding, major bleeding (2.1 versus 5.5 events/100 patient years, RR 0.4, 95% CI 0.2-0.6), emergency room visits for bleeding, and thrombotic events. ConclusionPatients on DOAC+ASA without a recent myocardial infarction or heart valve replacement had more non-major bleeding but otherwise similar outcomes compared to warfarin+ASA. Patients treated with rivaroxaban+ASA experienced more adverse clinical events compared to warfarin+ASA or apixaban+ASA.