ABSTRACT NUMBER: ESOC2026A456 EARLY VERSUS LATE STARTING OF DIRECT ORAL ANTICOAGULANTS AFTER BREAKTHROUGH ISCHEMIC STROKE: A TARGET TRIAL ANALYSIS FROM THE ASPERA-R STUDY

Abstract Background and aims Randomized trials support early initiation of direct oral anticoagulants (DOACs) after atrial fibrillation (AF)–related ischemic stroke. However, patients with breakthrough ischemic stroke occurring despite ongoing anticoagulation have been largely under-represented. We evaluated the comparative effectiveness and safety of early versus delayed DOAC resumption after breakthrough stroke. Methods We conducted a target-trial emulation comparing early versus delayed DOAC resumption after breakthrough stroke. Treatment strategies were prespecified using severity-adapted timing rules based on baseline NIHSS scores. To emulate random treatment assignment and address 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 We included 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 (3.0% vs 6.6%; 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 was less frequent with early initiation. Early initiation was associated with lower all-cause and vascular mortality. Net Early Benefit Score integrating ischemic and bleeding risks was positive across all NIHSS strata. Conclusions In patients with breakthrough ischemic stroke, early DOAC initiation was associated with reduced recurrent ischemic events and mortality at 90 days without increased bleeding. These findings support early anticoagulation initiation in this population pending randomized trials. Conflict of interest NOTHING TO DISCLOSE