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Background: The risk of recurrent ischemia is high in the acute period after transient ischemic attack (TIA) and minor stroke. Therefore, event rates and treatment effects may vary in relation to time to loading dose (TLD) of antiplatelet treatment. We aimed to explore safety and efficacy of ticagrelor in relation to TLD from the onset of the index event.Methods: In the SOCRATES trial (NCT01994720), we randomized 13,199 patients with a non-cardioembolic, non-severe ischemic stroke or high-risk TIA to ticagrelor (180 mg loading dose on day 1, followed by 90 mg twice daily for days 2-90) or aspirin (300 mg on day 1, followed by 100 mg daily for days 2-90) within 24 hours of symptom onset. Ticagrelor was not found to be superior to aspirin in reducing the rate of the primary composite endpoint of stroke, myocardial infarction, or death at 90 days. Patients were categorized according to TLD as <12 h and ≥12h from index event for this pre-specified exploratory analysis. The primary endpoint was time to the occurrence of stroke, myocardial infarction, or death within 90 days. The first secondary endpoint was ischemic stroke, with major bleeding serving as the primary safety endpoint.Results: TLD was <12 h in 4,403 (33.4%) and ≥12 h in 8,723 (66.1%). Among TLD <12 h patients, the primary endpoint occurred in 147/2196 (6.7%) patients randomized to ticagrelor and in 184/2207 (8.3%) randomized to aspirin (HR 0.79; 95% CI 0.64-0.98, p=0.036); ischemic stroke was less frequent in those treated with ticagrelor (6.0% vs 7.5%, HR 0.79; 95% CI 0.63-0.99, p=0.041). Among patients with TLD ≥12 h, there were no differences in the treatment groups for the primary endpoint (6.7 vs 7.0%) or for ischemic stroke (5.8% vs 6.2%). There were no significant treatment-by-TLD interactions. Major bleeding was comparable in TLD <12 h patients (0.5% vs 0.7%, p=0.25) and TLD ≥12 h (0.5% vs 0.5%, p=0.95) on ticagrelor and aspirin, respectively.Conclusion: In this pre-specified exploratory analysis, ticagrelor showed a greater treatment effect over aspirin in patients with TLD <12 h, although the interaction terms for treatment by TLD were not significant. Event rates for primary and secondary endpoints tended to be higher in patients randomized <12 h. Major bleeding was unrelated to TLD.