Does breakthrough stroke on DOACs worsen functional outcomes and increase recurrence compared to newly discovered atrial fibrillation in patients with acute ischemic stroke?
Ischemic stroke occurring despite DOAC therapy for atrial fibrillation is a high-risk phenotype associated with worse functional outcomes, higher mortality, and increased recurrence compared to stroke in newly discovered atrial fibrillation.
Abstract Background and aims Despite anticoagulation with direct oral anticoagulants (DOACs), some atrial fibrillation (AF) patients still experience ischemic stroke. Understanding whether breakthrough stroke (BS) represents therapeutic failure or identifies higher-risk phenotypes is essential for optimizing secondary prevention. We compared outcomes between breakthrough stroke patients on DOACs versus newly discovered AF patients. Methods Retrospective cohort study using Vall d'Hebron University Hospital stroke registry (2020-2025). Patients with acute ischemic stroke and AF were classified as breakthrough stroke (known AF on DOACs) or newly discovered AF. Propensity score matching (1:1) adjusted for age, sex, pre-stroke modified Rankin Scale, baseline NIHSS, and reperfusion therapies. Primary outcomes: 90-day mRS shift and functional independence (mRS 0-2). Secondary outcomes: mortality and 1-year recurrence using Fine-Gray competing risk regression. Results Among 9,000 stroke admissions, 778 had AF-related stroke. After matching, 229 pairs were analyzed. Breakthrough stroke patients showed significantly worse mRS distribution (common OR 1.72; 95% CI 1.24-2.39; p=0.001) and lower functional independence (39.7% vs 54.1%; RR 0.73; 95% CI 0.60-0.90; p0.001). Breakthrough patients had higher 90-day mortality (7.9% vs 3.1%; RR 3.60; 95% CI 1.36-9.53; p=0.011) and five-fold increased 1-year recurrence risk (HR 3.59; 95% CI 1.19-10.86; p=0.024). All primary outcomes survived multiple testing corrections. Conclusions Breakthrough stroke patients on DOACs have significantly worse functional outcomes, higher mortality, and increased recurrence compared to newly discovered AF patients. These findings identify breakthrough stroke as a high-risk phenotype requiring intensified secondary prevention strategies. Conflict of interest Giulio Fiore: Nothing to disclose, Marta Olive: Nothing to disclose, Federica Rizzo: Nothing to disclose, Claudia Patricia Meza Burgos: Nothing to disclose, David Rodriguez-Luna: Nothing to disclose, Noelia Rodriguez-Villatoro: Nothing to disclose, Alvaro Garcia-Tornel: Nothing to disclose, Adriano Bonura: Nothing to disclose, Marián Muchada: Nothing to disclose, Carlos A. Molina: Nothing to disclose, Marta Rubiera: Nothing to disclose, Jorge Pagola: Nothing to disclose Figure 1 - belongs to Results Table 1 - belongs to Conclusions
Fiore et al. (2026) studied this question.