Background/Aims: Guidelines suggest initiating anticoagulation after cardioembolic stroke within 4-14 days from the index event. Data supporting this suggestion did not account for important factors such as infarct burden or early hemorrhagic transformation.

Methods: We pooled data from stroke registries of 8 comprehensive stroke centers across the United States. We included consecutive patients admitted with an acute cardioembolic stroke in the setting of atrial fibrillation. The primary predictor was timing of initiating anticoagulation (0-3 days, 4-14 days, or >14 days) and the primary outcome was the composite endpoint of recurrent stroke/TIA/systemic embolism, symptomatic intracerebral hemorrhage (sICH), or major extracranial hemorrhage (ECH) within 90 days.

Results: We enrolled 2090 patients from 8 comprehensive centers in the United States, 1325 met the inclusion criteria (362 were excluded due to non-composite endpoint related death within 90 days, 145 lost to follow up, and 258 were not started on oral anticoagulation or the timing was not reported). Anticoagulation (875 DOAC, 404 Warfarin) was initiated in 0-3 days in 49.7%, 4-14 days in 40.4%, and >14 days in 9.9%. The combined endpoint occurred in 10.7% (142) (98 ischemic events, 21 sICH, and 30 ECH) and did not differ between the three groups: 0-3 days (11.9%), 4-14 days (9.9%), >14 days (9.9%), p=0.525. After adjusting for confounders (such as infarct volume, bridging, CHADS2-Vasc, cardiac thrombus, and hemorrhage on 24-hr imaging), oral anticoagulation timing in the 4-14 day period (vs. >14) was not associated with a reduction in ischemic events (adjusted OR 0.74, p=0.438) and oral anticoagulation timing 4-14 days (vs. 0-3) was not associated with a reduction in sICH (OR 1.28, p=0.638). Factors associated with sICH were bridging (OR 5.36, p=0.001) and hemorrhage on 24-hr imaging (OR 7.26, p<0.001) whereas for ischemic events were warfarin treatment (OR 1.66 95%, p = 0.030) and prior stroke (OR 1.81, p=0.013).

Conclusion: In this multicenter real world cohort, the recommended (4-14 days) timeframe to start oral anticoagulation was not associated with reduced ischemic and hemorrhagic outcomes. Randomized trials are required determine the optimal timing of anticoagulation initiation.