Optimal Delay Time to Initiate Anticoagulation After Ischemic Stroke in Atrial Fibrillation: A Pragmatic, Response-Adaptive Randomized Clinical Trial

Abstract

Importance: Clinical practice guidelines recommend initiation of anticoagulation within 2 weeks after stroke with atrial fibrillation. It is unknown whether there is an optimal starting day within the 14-day period that balances the risks of recurrent embolic events against serious hemorrhagic events.

Objective: To determine if there is an optimal delay time to initiate treatment with a direct oral anticoagulant after atrial fibrillation-related stroke that minimizes the risk of a composite outcome of ischemic or hemorrhagic events.

Design, setting, and participants: This phase 2, pragmatic, response-adaptive randomized clinical trial was conducted between June 2017 and June 2023 at acute care hospitals in Texas and included patients who had a mild to moderate ischemic stroke (minimum lesion diameter of 1.5 cm) with atrial fibrillation and were prescribed a direct oral anticoagulant within 2 weeks from stroke onset.

Intervention: Within 3 to 4 days after atrial fibrillation-associated ischemic stroke, patients were randomized to a group for treatment start date (group 1 was day 3 or 4 after stoke onset; group 2 was day 6; group 3 was day 10; and group 4 was day 14) with a direct oral anticoagulant for secondary stroke prevention.

Main outcomes and measures: The composite primary outcome was an ischemic (stroke or systemic embolism) or hemorrhagic (symptomatic intracranial hemorrhage or major systemic hemorrhage) event observed within 30 days from the index stroke time of onset. Posterior probabilities were used to estimate which timing groups were optimal for treatment initiation and were recalculated at predefined intervals. The randomization allocations were adjusted to favor the groups with higher probabilities.

Results: The trial enrolled and randomized 200 patients (50% were female; the median age was 75 years [IQR, 65-81 years]; 17.5% were Asian, Black, or >1 race; 16.5% were Hispanic; the median National Institutes of Health Stroke Scale score was 6.5 [IQR, 4-14]; and the median lesion diameter was 3.1 cm [IQR, 2.0-4.4 cm]). No ischemic events were observed for group 1, 3 events were observed for group 2, 2 events were observed for group 3, and 2 events were observed for group 4. One hemorrhagic event was observed for group 1, 1 event was observed for group 2, 1 event was observed for group 3, and 0 events were observed for group 4. Group 1 had a posterior probability of 0.41 for being the optimal day for treatment initiation and it was 0.26 for group 2, 0.17 for group 3, and 0.15 for group 4. The use of response-adaptive randomization was feasible and favored groups with earlier initiation times for use of a direct oral anticoagulant.

Conclusions and relevance: A clearly superior day to initiate use of a direct oral anticoagulant for secondary stroke prevention in patients with atrial fibrillation was not identified, but the evidence suggests that initiating use of a direct oral anticoagulant earlier is better than at later times within the first 2 weeks after stroke onset.

Trial registration: ClinicalTrials.gov Identifier: NCT03021928.