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Background: We aimed to compare the clinical outcomes of clopidogrel, prasugrel, and ticagrelor in clinical practice using the National Cardiovascular Database ACTION Registry ® . Treatment guidelines for patients with acute coronary syndrome (ACS) undergoing percutaneous coronary intervention recommend dual antiplatelet therapy (DAPT) for 12 months. Few clinical trials have compared the safety and efficacy of clopidogrel with that of newer antiplatelet therapies., Methods: A retrospective study of patients hospitalized for ACS at Cleveland Clinic Akron General was conducted. Data elements included detailed medical history and clinical outcomes during hospital stay. The primary outcome was a composite of major clinical events (cardiogenic shock, atrial fibrillation, ventricular fibrillation, ventricular tachycardia, heart failure, bleeding, and mechanical ventilation). The independent variable was the type of DAPT. Statistical analyses were performed using Chi-square and Mann-Whitney U tests. A post-hoc analysis was performed to compare between the antiplatelet drugs head-to-head., Results: Subjects (n = 1,388) admitted between January 2011 and March 2016 with ACS and treated with clopidogrel, prasugrel, or ticagrelor were included in the study. Mean age was 65 ± 14 years and 46% had ST-segment elevation myocardial infarction. Prasugrel administration within 24 h was associated with a lower incidence of the composite outcome (P = 0.049), bleeding (P = 0.028), and heart failure (P = 0.002)., Conclusion: There was a significant difference between the type of antiplatelet drug and clinical outcomes in ACS patients who were treated with DAPT. Observations from current study may provide important information for prescribers in clinical decision-making.