title: Efficacy and safety of intensive antiplatelet therapy with prasugrel from TRITON-TIMI 38 in a core clinical cohort defined by worldwide regulatory agencies.
abstract: TRITON-TIMI 38 showed that in patients with acute coronary syndrome undergoing percutaneous coronary intervention prasugrel decreased ischemic events compared to standard clopidogrel, but with more bleeding. The United States Food and Drug Administration and the European Medicines Agency approved prasugrel but provided contraindications in patients with previous stroke or transient ischemic attack and recommended limited use or reduced dose in patients ≥75 years old and weighing <60 kg. This defined 3 clinically relevant groups of patients for use of prasugrel at the studied dose regimen: group I (core clinical cohort), group II (noncore cohort), and group III (contraindicated). We assessed clinical outcomes of patients within these cohorts in the TRITON-TIMI 38 trial. Survival analysis methods were used to compare outcomes by treatment assignment (prasugrel vs clopidogrel) and by cohort (groups I and II or III). Patients in group I (n = 10,804, 79%) treated with prasugrel had a clinically significant and robust decrease in the primary end point of cardiovascular death, myocardial infarction, or stroke (8.3 vs 11.0%, hazard ratio [HR] 0.74, 95% confidence interval 0.66 to 0.84, p <0.0001), whereas patients in group II (n = 2149, 16%) had limited efficacy (15.3% vs 16.3%, HR 0.94, 0.76 to 1.18, p = 0.61, p for interaction = 0.07). For Thrombolysis In Myocardial Infarction major bleeding not related to coronary artery bypass grafting, there were tendencies to higher rates with prasugrel in group I (1.9% vs 1.5%, HR 1.24, 0.91 to 1.69, p = 0.17) and group II (4.1% vs 3.4%, HR 1.23, 0.77 to 1.97, p = 0.40); however, the absolute difference was greater for group II. The net clinical outcome (all-cause death/myocardial infarction/stroke/Thrombolysis In Myocardial Infarction major bleeding) in group I patients was highly favorable (10.2% vs 12.5%, HR 0.80, 0.71 to 0.89, p <0.0001) and neutral in group II (19.5% vs 19.7%, HR 0.98, 0.81 to 1.20, p for interaction = 0.07). Patients in group III (n = 518, 4%) did poorly with regard to efficacy and safety. In TRITON-TIMI 38 patients without previous stroke, <75 years old, and weighing >60 kg had substantial decreases in ischemic events with prasugrel compared to clopidogrel. Although relative bleeding excess exists in this population, absolute rates and differences in bleeding were attenuated. In conclusion, these data indicate that use of prasugrel in a core clinical cohort that has been defined by regulatory action will maximize the benefit of prasugrel and limit the risk of adverse outcomes.
authors.affiliation: The TIMI Study Group, Cardiovascular Division, Department of Medicine, Brigham and Women's Hospital, Harvard Medical School, Boston, Massachusetts, USA. swiviott@partners.org
authors.forename: Stephen D
authors.initials: SD
authors.lastname: Wiviott
authors.forename: Nihar
authors.initials: N
authors.lastname: Desai
authors.forename: Sabina A
authors.initials: SA
authors.lastname: Murphy
authors.forename: Guiseppe
authors.initials: G
authors.lastname: Musumeci
authors.forename: Michael
authors.initials: M
authors.lastname: Ragosta
authors.forename: Elliott M
authors.initials: EM
authors.lastname: Antman
authors.forename: Eugene
authors.initials: E
authors.lastname: Braunwald
mesh_terms: D054058:Acute Coronary Syndrome / Q000097:blood / Q000150:complications / Q000188:drug therapy*; D000368:Aged; D002545:Brain Ischemia / Q000150:complications / Q000453:epidemiology / Q000517:prevention & control; D004305:Dose-Response Relationship, Drug; D005260:Female; D005500:Follow-Up Studies; D006801:Humans; D015994:Incidence; D007558:Italy / Q000453:epidemiology; D008297:Male; D009203:Myocardial Infarction / Q000453:epidemiology / Q000209:etiology / Q000517:prevention & control; D010879:Piperazines / Q000008:administration & dosage / Q000627:therapeutic use*; D010974:Platelet Aggregation / Q000187:drug effects*; D000068799:Prasugrel Hydrochloride; D058921:Purinergic P2Y Receptor Antagonists / Q000008:administration & dosage / Q000627:therapeutic use; D013876:Thiophenes / Q000008:administration & dosage / Q000627:therapeutic use*; D016896:Treatment Outcome; D014481:United States / Q000453:epidemiology
chemical_list: D010879:Piperazines; D058921:Purinergic P2Y Receptor Antagonists; D013876:Thiophenes; D000068799:Prasugrel Hydrochloride