Published Online
on December 3, 2007

A more recent version of this article appeared on December 18, 2007

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Submitted on September 14, 2007
Accepted on October 17, 2007

Prasugrel Compared With High Loading- and Maintenance-Dose Clopidogrel in Patients With Planned Percutaneous Coronary Intervention. The Prasugrel in Comparison to Clopidogrel for Inhibition of Platelet Activation and Aggregation–Thrombolysis in Myocardial Infarction 44 Trial

Stephen D. Wiviott MD^*, Dietmar Trenk PhD, Andrew L. Frelinger PhD, Michelle O'Donoghue MD, Franz-Josef Neumann MD, Alan D. Michelson MD, Dominick J. Angiolillo MD, PhD, Hanoch Hod MD, Gilles Montalescot MD, PhD, Debra L. Miller RN, RCIS, Joseph A. Jakubowski PhD, Richard Cairns MSc, Sabina A. Murphy MPH, Carolyn H. McCabe BS, Elliott M. Antman MD, Eugene Braunwald MD, for the PRINCIPLE-TIMI 44 Investigators

From the TIMI Study Group, Cardiovascular Division, Brigham and Women's Hospital, Boston, Mass (S.D.W., S.A.M., C.H.M., E.M.A., E.B.); Cardiovascular Division, Massachusetts General Hospital, Boston (M.O.); Herz-Zentrum Bad Krozingen, Bad Krozingen, Germany (D.T., F.-J.N.); Center for Platelet Function Studies, Departments of Pediatrics, Medicine and Pathology, University of Massachusetts Medical School, Worcester (A.L.F., A.D.M.); University of Florida, College of Medicine, Jacksonville (D.J.A.); The Heart Institute, Sheba Medical Center, Tel Hashomer, Sackler Faculty of Medicine, Tel Aviv, Israel (H.H.); Institut de Cardiologie and INSERM Unit 856, Petie-Salpetriere University Hospital, Paris, France (G.M.); Lilly Research Laboratories, Eli Lilly and Co, Indianapolis, Ind (D.L.M., J.A.J.); and Nottingham Clinical Research Ltd, Nottingham, UK (R.C.).

^* To whom correspondence should be addressed. E-mail: swiviott{at}partners.org.

Background—The increasing use of higher-than-approved doses of clopidogrel in clinical practice is based in part on the desire for greater levels of inhibition of platelet aggregation (IPA). Prasugrel is a new thienopyridine that is more potent than standard-dose clopidogrel in healthy subjects and patients with stable coronary artery disease. The relative antiplatelet effects of prasugrel versus high-dose clopidogrel in percutaneous coronary intervention patients are unknown.

Methods and Results—Prasugrel in Comparison to Clopidogrel for Inhibition of Platelet Activation and Aggregation–Thrombolysis in Myocardial Infarction 44 (PRINCIPLE-TIMI 44) was a randomized, double-blind, 2-phase crossover study of prasugrel compared with high-dose clopidogrel in patients undergoing cardiac catheterization for planned percutaneous coronary intervention. The primary end point of the loading-dose phase (prasugrel 60 mg versus clopidogrel 600 mg) was IPA with 20 µmol/L ADP at 6 hours. Patients with percutaneous coronary intervention entered the maintenance-dose phase, a 28-day crossover comparison of prasugrel 10 mg/d versus clopidogrel 150 mg/d with a primary end point of IPA after 14 days of either drug. In this study, 201 subjects were randomized. IPA at 6 hours was significantly higher in subjects receiving prasugrel (mean±SD, 74.8±13.0%) compared with clopidogrel (31.8±21.1%; P<0.0001). During the maintenance-dose phase, IPA with 20 µmol/L ADP was higher in subjects receiving prasugrel (61.3±17.8%) compared with clopidogrel (46.1±21.3%; P<0.0001). Results were consistent across all key secondary end points; significant differences emerged by 30 minutes and persisted across all time points.

Conclusions—Among patients undergoing cardiac catheterization with planned percutaneous coronary intervention, loading with 60 mg prasugrel resulted in greater platelet inhibition than a 600-mg clopidogrel loading dose. Maintenance therapy with prasugrel 10 mg/d resulted in a greater antiplatelet effect than 150 mg/d clopidogrel.

Key words: anticoagulants • antiplatelet agents • coronary disease • platelets • thrombosis

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