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(Circulation. 2008;118:1626-1636.)
© 2008 American Heart Association, Inc.

Coronary Heart Disease

Greater Clinical Benefit of More Intensive Oral Antiplatelet Therapy With Prasugrel in Patients With Diabetes Mellitus in the Trial to Assess Improvement in Therapeutic Outcomes by Optimizing Platelet Inhibition With Prasugrel–Thrombolysis in Myocardial Infarction 38

Stephen D. Wiviott, MD; Eugene Braunwald, MD; Dominick J. Angiolillo, MD, PhD; Simha Meisel, MD; Anthony J. Dalby, MD; Freek W.A. Verheugt, MD; Shaun G. Goodman, MD; Ramon Corbalan, MD; Drew A. Purdy, MD; Sabina A. Murphy, MPH; Carolyn H. McCabe, BS; Elliott M. Antman, MD, for the TRITON-TIMI 38 Investigators

From the TIMI Study Group, Cardiovascular Division, Department of Medicine, Brigham and Women’s Hospital and Harvard Medical School, Boston, Mass (S.D.W., E.B., S.A.M. C.H.M., E.M.A.); University of Florida College of Medicine, Jacksonville (D.J.A.); Hillel Yaffe Medical Center, Hadera, Israel (S.M.); St Michael’s Hospital, University of Toronto, and Canadian Heart Research Center, Toronto, Ontario, Canada (S.G.G.); Millpark Hospital, Johannesburg, South Africa (A.J.D.); Department of Cardiology, University Hospital Nijmegen, Nijmegen, the Netherlands (F.W.A.V.); Department of Cardiology, Catholic University School of Medicine, Santiago, Chile (R.C.); and Black Hills Cardiovascular Research Group, Black Hills, SD (D.A.P.).

Reprint requests to Dr S.D. Wiviott, TIMI Study Group, Cardiovascular Division, Brigham and Women’s Hospital, 75 Francis St, Boston, MA 02115. E-mail swiviott{at}partners.org

Received May 7, 2008; accepted August 7, 2008.

Background— Patients with diabetes mellitus (DM) are at high risk for recurrent cardiovascular events after acute coronary syndromes, in part because of increased platelet reactivity. The Trial to Assess Improvement in Therapeutic Outcomes by Optimizing Platelet Inhibition With Prasugrel–Thrombolysis in Myocardial Infarction 38 (TRITON-TIMI 38) showed an overall reduction in ischemic events with more intensive antiplatelet therapy with prasugrel than with clopidogrel but with more bleeding. We compared prasugrel with clopidogrel among subjects with DM in TRITON-TIMI 38.

Methods and Results— We classified 13 608 subjects on the basis of preexisting history of DM and further according to insulin use. Prespecified analyses of the primary (cardiovascular death, nonfatal myocardial infarction, or nonfatal stroke) and key secondary end points, including net clinical benefit (death, nonfatal myocardial infarction, nonfatal stroke, and nonfatal TIMI major bleeding) were compared by use of the log-rank test. We found that 3146 subjects had a preexisting history of DM, including 776 receiving insulin. The primary end point was reduced significantly with prasugrel among subjects without DM (9.2% versus 10.6%; hazard ratio [HR], 0.86; P=0.02) and with DM (12.2% versus 17.0%; HR, 0.70; P<0.001, P_interaction=0.09). A benefit for prasugrel was observed among DM subjects on insulin (14.3% versus 22.2%; HR, 0.63; P=0.009) and those not on insulin (11.5% versus 15.3%; HR, 0.74; P=0.009). Myocardial infarction was reduced with prasugrel by 18% among subjects without DM (7.2% versus 8.7%; HR, 0.82; P=0.006) and by 40% among subjects with DM (8.2% versus 13.2%; HR, 0.60; P<0.001, P_interaction=0.02). Although TIMI major hemorrhage was increased among subjects without DM on prasugrel (1.6% versus 2.4%; HR, 1.43; P=0.02), the rates were similar among subjects with DM for clopidogrel and prasugrel (2.6% versus 2.5%; HR, 1.06; P=0.81, P_interaction=0.29). Net clinical benefit with prasugrel was greater for subjects with DM (14.6% versus 19.2%; HR, 0.74; P=0.001) than for subjects without DM (11.5% versus 12.3%; HR, 0.92; P=0.16, P_interaction=0.05).

Conclusions— Subjects with DM tended to have a greater reduction in ischemic events without an observed increase in TIMI major bleeding and therefore a greater net treatment benefit with prasugrel compared with clopidogrel. These data demonstrate that the more intensive oral antiplatelet therapy provided with prasugrel is of particular benefit to patients with DM.

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