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BACKGROUND AND OBJECTIVES Ischemic stroke despite direct oral anticoagulant (DOAC) is increasingly common and portends high risk of subsequent ischemic stroke. Efficacy and safety of antithrombotic regimens following the condition are unclear. We aimed to compare the outcomes of patients with ischemic stroke despite DOAC with and without an alternative antithrombotic regimen, and determine the risk factors of recurrent ischemic stroke while on anticoagulation. METHODS In a population-based, propensity-score weighted, retrospective cohort study, we compared the clinical outcomes of DOAC-to-warfarin switch, DOAC-to-DOAC switch (DOACswitch) or addition of antiplatelet agents, with unchanged DOAC regimen (DOACsame) among non-valvular atrial fibrillation (NVAF) patients who developed the first ischemic stroke despite DOAC from 1st January 2015 to 31st December 2020 in Hong Kong. Primary outcome was recurrent ischemic stroke. Secondary outcomes were intracranial hemorrhage, acute coronary syndrome and death. We performed competing risk regression analyses to compare the clinical endpoints, and determined the predictors of recurrent ischemic stroke in an unweighted multivariable logistic regression model. RESULTS During the 6-year study period, among 45,946 AF patients on DOAC as stroke prophylaxis, 2,908 patients developed ischemic stroke despite DOAC. 2,337 NVAF patients were included in the final analyses. Compared to DOACsame, warfarin (aHR 1.96, 95%CI 1.27-3.02, p=0.002) and DOACswitch (aHR 1.62, 95%CI 1.25-2.11, p-value <0.001) were associated with increased risk of recurrent ischemic stroke. In DOACsame group, adjunctive antiplatelet agent was not associated with reduced risk of recurrent ischemic stroke. Diabetes mellitus, concurrent cytochrome P450/P-glycoprotein (CYP/P-gp) modulators and large artery atherosclerotic disease (LAD) were predictors of recurrent ischemic stroke. DISCUSSION In NVAF patients with ischemic stroke despite DOAC, the increased risk of recurrent ischemic stroke with switching to warfarin called for caution against such practice, while the increased ischemic stroke with DOAC-to-DOAC switch demands further studies. Adjunctive antiplatelet agent did not appear to reduce ischemic stroke relapse. As diabetes mellitus, use of CYP/P-gp modulators and LAD were predictors of recurrent ischemic stroke, further investigations should evaluate if strict glycemic control, DOAC level monitoring and routine screening for carotid and intracranial atherosclerosis may reduce ischemic stroke recurrence in these patients. CLASSIFICATION OF EVIDENCE This study provides Class II evidence that in patients with non-valvular atrial fibrillation suffering an ischemic stroke while being treated with a DOAC, continuing treatment with that DOAC is more effective at preventing recurrent ischemic stroke than switching to a different DOAC or to warfarin.