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Abstract Background and aims We aimed to compare the effectiveness of ticagrelor vs. clopidogrel or prasugrel on recurrence of acute coronary syndromes (ACS) in real-life conditions, as requested by regulatory authorities at the time of marketing. Methods We performed a cohort study in SNDS, the French national healthcare database. All patients with a hospital admission for ACS in 2013 were followed one year. Patients on ticagrelor, clopidogrel or prasugrel were matched 1:1 using age, gender, index ACS type, and high-dimensional propensity scores (hdPS). Outcomes were ACS, stroke, all-cause death, and major bleeding, compared within matched groups using Cox proportional hazards models analysis during treatment. Results 54,048 ACS were hospitalized in 2013. At discharge, 19,796 were dispensed clopidogrel, 8242 prasugrel, and 13,916 ticagrelor. Per group, 9224 ticagrelor vs. clopidogrel, 6752 ticagrelor vs. prasugrel, and 4676 prasugrel vs. clopidogrel patients were matched. Compared to clopidogrel, ticagrelor was associated with a lower hazard ratio of death 0.73 [0.59–0.90] and composite criterion (0.88, 95% CI [0.79–0.99] but not ACS 0.92 [0.80–1.06], stroke (0.96 [017-5.53]) or major bleeding (1.02 [0.82–1.26]). Prasugrel was not different from ticagrelor or clopidogrel for any outcome, in matched patients. Conclusions Ticagrelor in real-life conditions in matched populations was associated with a lower risk of all-cause death than clopidogrel, and a lower risk of composite outcome, as in the main pivotal clinical trial. Ticagrelor and prasugrel were not different, nor were prasugrel and clopidogrel. Graphical abstract Image 1 Highlights • In real-life, clopidogrel was used in older patients compared with ticagrelor or prasugrel. • Prasugrel was used mostly after percutaneous intervention. • There were fewer deaths in ticagrelor users than in matched clopidogrel users. • There was no difference between ticagrelor and matched prasugrel users, or between clopidogrel and matched prasugrel users. [ABSTRACT FROM AUTHOR]