Comparative Safety and Efficacy of Oral Anticoagulants in Patients With Atrial Fibrillation and Prior Ischemic Stroke: A Systematic Review and Network Meta-Analysis of Randomized-Controlled Clinical Trials.

BACKGROUND: Patients with atrial fibrillation (AF) and prior ischemic stroke represent a high-risk population facing competing risks of recurrent thromboembolism and hemorrhagic complications. Although direct oral anticoagulants (DOACs) are recommended over vitamin K antagonists for stroke prevention in AF, no randomized controlled clinical trial has directly compared individual DOACs to each other in this population. METHODS: We conducted a systematic review and frequentist random-effects network meta-analysis of randomized-controlled clinical trials enrolling patients with AF and prior ischemic stroke or transient ischemic attack. MEDLINE, Scopus, and ClinicalTrials.gov were searched from inception until May 2026. The primary outcome was any stroke. Secondary outcomes included ischemic stroke, hemorrhagic stroke, major bleeding, intracranial hemorrhage (ICH), cardiovascular mortality, and all-cause mortality. Treatment effects were expressed as risk ratios (RR) with 95% CIs. RESULTS: The evidence network comprised 6 trials (18 395 patients) in a star-shaped structure. Each DOAC was informed by a single warfarin-controlled trial, and 2 trials used aspirin as the comparator. All between-DOAC comparisons were indirect. In the network meta-analysis, compared with warfarin, apixaban was the only agent to significantly reduce both any stroke (RR, 0.72 [95% CI, 0.53-0.97]) and major bleeding (RR, 0.73 [95% CI, 0.54-0.99]). Dabigatran, apixaban, and edoxaban each significantly reduced hemorrhagic stroke and ICH versus warfarin, whereas rivaroxaban did not reach significance for any bleeding outcome. Edoxaban was the only agent associated with significantly lower cardiovascular (RR, 0.79 [95% CI, 0.65-0.97]) and all-cause mortality (RR, 0.84 [95% CI, 0.72-0.99]). Based on indirect comparisons only, no differences between individual DOACs were observed. CONCLUSIONS: In patients with AF and prior ischemic stroke, individual DOACs reduced intracranial and systemic bleeding relative to warfarin, although not uniformly across agents. Apixaban alone significantly reduced both any stroke and major bleeding versus warfarin, but differences between individual DOACs could not be established given the small number of trials. REGISTRATION: URL: https://www.crd.york.ac.uk/PROSPERO/; Unique identifier: CRD420261404062.