In this multicenter, registry-based cohort study of 1,006 patients with atrial fibrillation who experienced ischemic stroke despite ongoing DOAC therapy, switching to another oral anticoagulant was not associated with a clinically meaningful short-term benefit compared with continuing the same DOAC. At 90 days, rates of recurrent ischemic stroke and moderate to severe bleeding were similar between groups, meeting noninferiority criteria for most outcomes, although noninferiority was not demonstrated for mortality endpoints. Overall, findings suggest routine switching after breakthrough stroke does not improve short-term outcomes.