BACKGROUND: Prior analyses of trials comparing direct oral anticoagulants (DOACs) to warfarin in atrial fibrillation (AF) have not routinely incorporated patient preferences, despite substantial variation in how patients value the trade-off between outcomes such as stroke and bleeding. By applying patient-centered approaches, we aimed to provide intuitive metrics to inform shared decision-making, particularly for frail older adults for whom DOAC benefit remains controversial. METHODS: Individual-level data from 58,634 participants in four randomized controlled trials (RCTs) comparing DOACs to warfarin (A Collaboration Between Multiple Institutions to Better Investigate Non-Vitamin K Antagonist Oral Anticoagulant Use in Atrial Fibrillation; COMBINE-AF) were analyzed using two patient-centered methods. Seven clinical outcomes (death, disabling stroke, major bleeding, moderate-severity stroke, systemic embolism, clinically relevant non-major bleeding, and minor stroke) were weighted based on a prior 1028-patient preference study with all values scaled relative to death. For the weighted composite endpoint (WCE), a survival-based approach incorporated weights of initial and recurrent events to estimate event-free survival. For win statistics, outcomes were hierarchically ranked for pairwise comparisons. The primary estimand was the 2-year difference in weighted death-equivalent events per 100 patients for the WCE. The win ratio was a secondary estimand. A prespecified subgroup analysis was conducted in frail, older patients. RESULTS: In the overall cohort, compared to warfarin, DOACs were associated with a more favorable outcome (WCE: 11.74 vs. 12.85 events per 100 patients; difference, -1.11 [95% confidence interval (CI): -1.61 to -0.61]; P<0.001; win ratio 1.11 [95% CI: 1.07 to 1.15]). In the prespecified subgroup of 5913 frail participants, the difference in the WCE was +0.50 events [95% CI: -1.39 to 2.40]) with a win ratio of 0.99 [95% CI: 0.90 to 1.08]) in individuals treated with DOAC versus warfarin. CONCLUSIONS: In individuals with atrial fibrillation pooled from four RCTs, DOACs were associated with a favorable net clinical benefit compared to warfarin when evaluated using a patient-weighted composite clinical outcome. (Funded by a Fellows Supplemental Funding grant from the Duke Clinical Research Institute's Executive Director Pathway Committee.).