Anticoagulation Strategies Following Breakthrough Ischemic Stroke While on Direct Anticoagulants: A Meta-Analysis

Background and ObjectivesThe management of anticoagulation after ischemic stroke while on direct oral anticoagulants (DOACs) is controversial. We performed an aggregate-data meta-analysis to compare anticoagulation strategies against each other to define the effect of switch to warfarin, switch to another DOAC, change in dosage, and add-on antiplatelet for the prevention of recurrent stroke, intracranial hemorrhage (ICH), any stroke, and mortality.MethodsThe study protocol was deposited with PROSPERO (CRD42025639057). We systematically searched MEDLINE, Scopus, and the Cochrane Library - all studies reporting on anticoagulation strategies after a stroke while on DOAC up to January 31, 2025. We included randomized controlled clinical studies and cohort studies with sample size ≥50 that (1) enrolled adult patients who experienced ischemic stroke while on DOACs, (2) assessed modifications to anticoagulation therapy, and (3) reported on at least one of the outcomes. Main outcome was recurrent ischemic stroke; secondary outcomes were ICH, all-cause mortality, and any stroke. We pooled estimates by random-effects modelling, reporting risk ratio (RR) with 95% CIs comparing anticoagulation strategies against each other.ResultsWe retrieved 2,171 results, with 8 observational studies reaching quantitative synthesis (n = 14,307 patients, mean age = 75 years, 48% female). Switching to warfarin was associated with a higher risk of ischemic stroke compared with keeping the same DOAC (RR 1.80, 95% CI 1.42-2.29, I2 = 0%, nstudies = 5) or changing DOAC dosage (RR 1.72, 95% CI 1.20-2.45, I2 = 0%, nstudies = 4). Switching to warfarin was also associated with higher ICH rates compared with keeping the same DOAC (RR 2.90, 95% CI 2.01-4.18, I2 = 0%, nstudies = 5) and DOAC-to-DOAC switch (RR 3.25, 95% CI 2.13-4.96, I2 = 0%; nstudies = 5). Keeping the same DOAC and switching to another DOAC, independently from mechanism, had similar rates of primary and secondary outcomes.DiscussionOur meta-analysis indicates that switching to warfarin after a stroke while on DOAC seems less effective and safe in stroke recurrence prevention, ICH, and mortality compared with DOAC-based strategies.