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Original Article
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Volume 354:1706-1717 April 20, 2006 Number 16
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Clopidogrel and Aspirin versus Aspirin Alone for the Prevention of Atherothrombotic Events
Deepak L. Bhatt, M.D., Keith A.A. Fox, M.B., Ch.B., Werner Hacke, M.D., Peter B. Berger, M.D., Henry R. Black, M.D., William E. Boden, M.D., Patrice Cacoub, M.D., Eric A. Cohen, M.D., Mark A. Creager, M.D., J. Donald Easton, M.D., Marcus D. Flather, M.D., Steven M. Haffner, M.D., Christian W. Hamm, M.D., Graeme J. Hankey, M.D., S. Claiborne Johnston, M.D., Koon-Hou Mak, M.D., Jean-Louis Mas, M.D., Gilles Montalescot, M.D., Ph.D., Thomas A. Pearson, M.D., P. Gabriel Steg, M.D., Steven R. Steinhubl, M.D., Michael A. Weber, M.D., Danielle M. Brennan, M.S., Liz Fabry-Ribaudo, M.S.N., R.N., Joan Booth, R.N., Eric J. Topol, M.D., for the CHARISMA Investigators

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ABSTRACT

Background Dual antiplatelet therapy with clopidogrel plus low-dose aspirin has not been studied in a broad population of patients at high risk for atherothrombotic events.

Methods We randomly assigned 15,603 patients with either clinically evident cardiovascular disease or multiple risk factors to receive clopidogrel (75 mg per day) plus low-dose aspirin (75 to 162 mg per day) or placebo plus low-dose aspirin and followed them for a median of 28 months. The primary efficacy end point was a composite of myocardial infarction, stroke, or death from cardiovascular causes.

Results The rate of the primary efficacy end point was 6.8 percent with clopidogrel plus aspirin and 7.3 percent with placebo plus aspirin (relative risk, 0.93; 95 percent confidence interval, 0.83 to 1.05; P=0.22). The respective rate of the principal secondary efficacy end point, which included hospitalizations for ischemic events, was 16.7 percent and 17.9 percent (relative risk, 0.92; 95 percent confidence interval, 0.86 to 0.995; P=0.04), and the rate of severe bleeding was 1.7 percent and 1.3 percent (relative risk, 1.25; 95 percent confidence interval, 0.97 to 1.61 percent; P=0.09). The rate of the primary end point among patients with multiple risk factors was 6.6 percent with clopidogrel and 5.5 percent with placebo (relative risk, 1.2; 95 percent confidence interval, 0.91 to 1.59; P=0.20) and the rate of death from cardiovascular causes also was higher with clopidogrel (3.9 percent vs. 2.2 percent, P=0.01). In the subgroup with clinically evident atherothrombosis, the rate was 6.9 percent with clopidogrel and 7.9 percent with placebo (relative risk, 0.88; 95 percent confidence interval, 0.77 to 0.998; P=0.046).

Conclusions In this trial, there was a suggestion of benefit with clopidogrel treatment in patients with symptomatic atherothrombosis and a suggestion of harm in patients with multiple risk factors. Overall, clopidogrel plus aspirin was not significantly more effective than aspirin alone in reducing the rate of myocardial infarction, stroke, or death from cardiovascular causes. (ClinicalTrials.gov number, NCT00050817 [ClinicalTrials.gov] .)


Source Information

From Cleveland Clinic, Cleveland (D.L.B., D.M.B., L.F.-R., J.B.); University and Royal Infirmary of Edinburgh, Edinburgh(K.A.A.F.); University of Heidelberg, Heidelberg, Germany (W.H.); Duke University, Durham, N.C. (P.B.B.); Rush Medical College, Chicago (H.R.B.); Hartford Hospital, Hartford, Conn. (W.E.B.); Hôpital Pitié-Salpêtrière (P.C.), Sainte-Anne Hospital (J.-L.M.), Institut de Cardiologie–CHU Pitié-Salpêtrière (G.M.), and Hopital Bichat (P.G.S.) — all in Paris; Sunnybrook and Women's College Health Science Centre, Toronto (E.A.C.); Brigham and Women's Hospital and Harvard Medical School, Boston (M.A.C.); Rhode Island Hospital and Brown University, Providence (J.D.E.); Royal Brompton Hospital, London (M.D.F.); University of Texas Health Science Center at San Antonio, San Antonio (S.M.H.); Kerckhoff-Klinik Center, Bad Nauheim, Germany (C.W.H.); Royal Perth Hospital and School of Medicine and Pharmacology, University of Western Australia, Perth (G.J.H.); University of California, San Francisco, San Francisco (S.C.J.); Gleneagles Medical Centre, Singapore (K.-H.M.); University of Rochester School of Medicine, Rochester, N.Y. (T.A.P.); University of Kentucky, Lexington (S.R.S.); SUNY Downstate Medical Center, Brooklyn, N.Y. (M.A.W.); and Case Western Reserve University, Cleveland (E.J.T.).

This article was published at www.nejm.org on March 12, 2006.

Address reprint requests to Dr. Topol at the Department of Genetics, Case Western Reserve University, BRB 724, 10900 Euclid Ave., Cleveland, OH 44106-4955, or at eric.topol{at}case.edu.

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