Early versus late starting of direct oral anticoagulants after breakthrough ischemic stroke: A target trial analysis from the ASPERA-R study

Background and purpose: Randomized trials support early initiation of direct oral anticoagulants (DOACs) after atrial fibrillation (AF)–related ischemic stroke, but patients with breakthrough ischemic stroke occurring despite ongoing anticoagulation have been largely under-represented. We evaluated the effectiveness and safety of early versus delayed DOAC initiation after breakthrough ischemic stroke. Methods: We performed a target trial emulation comparing early versus delayed DOAC initiation in patients with breakthrough ischemic stroke. Treatment strategies were prespecified using severity-adapted timing thresholds based on baseline National Institutes of Health Stroke Scale (NIHSS) scores. The study population was drawn from the retrospective arm of the international, multicenter Advancing Knowledge in Ischemic Stroke Patients on Oral Anticoagulant (ASPERA) study and included patients with AF who experienced an ischemic stroke while receiving continuous anticoagulation. To emulate random assignment and avoid immortal time bias, a cloning–censoring–weighting approach with inverse probability weighting was applied. Primary outcomes were 90-day new ischemic events and moderate-to-severe bleeding. Risk ratios (RRs), absolute risk differences (RDs), and hazard ratios (HRs) were estimated using weighted regression and Cox models. Results: Among 833 patients (median age = 81 years), 336 were assigned to early and 497 to delayed DOAC initiation. At 90 days, early initiation was associated with a lower risk of new ischemic events (RR = 0.44, 95% CI = 0.21–0.90; RD = −3.64%, 95% CI = −6.40 to −0.87; HR = 0.43, 95% CI = 0.21–0.91). Moderate-to-severe bleeding occurred less frequently with early initiation (RR = 0.10, 95% CI = 0.01–0.76). Early initiation was also associated with lower 90-day all-cause and vascular mortality. A Net Early Benefit Score integrating ischemic and bleeding risks was positive across all NIHSS strata. Conclusion: In patients with breakthrough ischemic stroke, early severity-adapted DOAC initiation was associated with lower risks of recurrent ischemic events and mortality at 90 days without an increase in major bleeding. These findings support early anticoagulation initiation in this high-risk population.