n engl j med 357;20 www.nejm.org november 15, 20072001The new england journal of medicineestablished in 1812 november 15, 2007 vol. 357 no. 20Prasugrel versus Clopidogrel in Patients with Acute Coronary SyndromesStephen D. Wiviott, M.D., Eugene Braunwald, M.D., Carolyn H. McCabe, B.S., Gilles Montalescot, M.D., Ph.D., Witold Ruzyllo, M.D., Shmuel Gottlieb, M.D., Franz-Joseph Neumann, M.D., Diego Ardissino, M.D., Stefano De Servi, M.D., Sabina A. Murphy, M.P.H., Jeffrey Riesmeyer, M.D., Govinda Weerakkody, Ph.D., C. Michael Gibson, M.D., and Elliott M. Antman, M.D., for the TRITON–TIMI 38 Investigators*A b s t r ac tFrom Brigham and Women’s Hospital and Harvard Medical School, Boston (S.D.W., E.B., C.H.M., S.A.M., C.M.G., E.M.A.); Institut de Cardiologie and INSERM Unit 856, Pitié–Salpêtrière University Hospital, Paris (G.M.); Instytut Kardiologii, Warsaw, Poland (W.R.); Bikur Cholim Hospital, Jerusalem, Israel (S.G.); Herz-Zentrum Bad Krozingen, Bad Krozingen, Germany (F.-J.N.); Azienda Ospedaliero–Universi-taria di Parma, Parma, Italy (D.A.); Azien-da Ospedaliera Civile di Legano, Legano, Italy (S.D.S.); and Eli Lilly Research Labo-ratories, Indianapolis (J.R., G.W.). Address reprint requests to Dr. Antman at the Car-diovascular Division, Brigham and Wom-en’s Hospital, TIMI Study Group, 350 Longwood Ave., 1st Fl., Boston, MA 02115, or at [email protected].*The members of the Steering and Oper-ations Committees of the Trial to Assess Improvement in Therapeutic Outcomes by Optimizing Platelet Inhibition with Prasugrel–Thrombolysis in Myocardial Infarction (TRITON–TIMI) 38 are listed in the Appendix. The TRITON–TIMI 38 Investigators are listed in the Supple-mentary Appendix, available with the full text of this article at www.nejm.org.This article (10.1056/NEJMoa0706482) was published at www.nejm.org on Novem-ber 4, 2007.N Engl J Med 2007;357:2001-15.Copyright © 2007 Massachusetts Medical Society.BackgroundDual-antiplatelet therapy with aspirin and a thienopyridine is a cornerstone of treat-ment to prevent thrombotic complications of acute coronary syndromes and percu-taneous coronary intervention. MethodsTo compare prasugrel, a new thienopyridine, with clopidogrel, we randomly assigned 13,608 patients with moderate-to-high-risk acute coronary syndromes with sched-uled percutaneous coronary intervention to receive prasugrel (a 60-mg loading dose and a 10-mg daily maintenance dose) or clopidogrel (a 300-mg loading dose and a 75-mg daily maintenance dose), for 6 to 15 months. The primary efficacy end point was death from cardiovascular causes, nonfatal myocardial infarction, or nonfatal stroke. The key safety end point was major bleeding.ResultsThe primary efficacy end point occurred in 12.1% of patients receiving clopidogrel and 9.9% of patients receiving prasugrel (hazard ratio for prasugrel vs. clopidogrel, 0.81; 95% confidence interval [CI], 0.73 to 0.90; P<0.001). We also found significant reductions in the prasugrel group in the rates of myocardial infarction (9.7% for clopidogrel vs. 7.4% for prasugrel; P<0.001), urgent target-vessel revascularization (3.7% vs. 2.5%; P<0.001), and stent thrombosis (2.4% vs. 1.1%; P<0.001). Major bleed-ing was observed in 2.4% of patients receiving prasugrel and in 1.8% of patients receiving clopidogrel (hazard ratio, 1.32; 95% CI, 1.03 to 1.68; P = 0.03). Also great-er in the prasugrel group was the rate of life-threatening bleeding (1.4% vs. 0.9%; P = 0.01), including nonfatal bleeding (1.1% vs. 0.9%; hazard ratio, 1.25; P = 0.23) and fatal bleeding (0.4% vs. 0.1%; P = 0.002).ConclusionsIn patients with acute coronary syndromes with scheduled percutaneous coronary intervention, prasugrel therapy was associated with significantly reduced rates of ischemic events, including stent thrombosis, but with an increased risk of major bleeding, including fatal bleeding. Overall mortality did not differ significantly between treatment groups. (ClinicalTrials.gov number, NCT00097591.)Copyright © 2007 Massachusetts Medical Society. All rights reserved. Downloaded from www.nejm.org at LANE MEDICAL LIBRARY on November 8, 2007 .T h e n e w e n g l a n d j o u r n a l o f m e d i c i n en engl j med 357;20 www.nejm.org november 15, 20072002The short-term and long-term ben-efits of dual-antiplatelet therapy with aspi-rin and clopidogrel have been established for patients with acute coronary syndromes1-3 and those undergoing percutaneous coronary interven-tion (PCI).4,5 Despite these benefits, many patients continue to have recurrent atherothrombotic events while receiving standard dual antiplatelet therapy.1 In addition, important limitations of clopidogrel remain, such as only a modest antiplatelet effect, with substantial interpatient variability 6,7 and a de-layed onset of action.5 Small clinical studies have suggested that patients with a reduced pharma-cologic response to clopidogrel may be at increased risk for adverse clinical events, including myocar-dial infarction and coronary-stent thrombosis.8-11Prasugrel — a novel thienopyridine — is a pro-drug that, like clopidogrel, requires conversion to an active metabolite before binding to the plate-let P2Y12 receptor to confer antiplatelet activity.12 At the currently studied doses, prasugrel inhibits adenosine diphosphate–induced platelet aggrega-tion more rapidly, more consistently, and to a greater extent than do standard and higher doses of clopidogrel in healthy volunteers13 and in pa-tients with coronary artery disease,14,15 including those undergoing PCI.16 Phase 2 testing of prasu-grel, as compared with clopidogrel, in patients undergoing elective or urgent PCI showed a trend toward fewer ischemic events, with an acceptable safety profile.17 Thus, we designed the Trial to As-sess Improvement in Therapeutic Outcomes by Optimizing Platelet Inhibition with Prasugrel–Thrombolysis in Myocardial Infarction (TRITON–TIMI) 38, a phase 3 trial involving patients with acute coronary syndromes with scheduled PCI, comparing a regimen of prasugrel with the stan-dard-dose regimen of clopidogrel approved by the Food and Drug Administration.18 Although our trial was designed to compare regimens of prasu-grel and clopidogrel, it also tests the hypothesis that the use of an agent producing a higher level of inhibition of adenosine diphosphate–induced platelet aggregation and a less-variable response than