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EXPEDITED REVIEW

Patients With Prior Myocardial Infarction, Stroke, or Symptomatic Peripheral Arterial Disease in the CHARISMA Trial

Deepak L. Bhatt, MD, FACC^_*,_*, Marcus D. Flather, MD, Werner Hacke, MD, Peter B. Berger, MD, FACC, Henry R. Black, MD^||, William E. Boden, MD, FACC^¶, Patrice Cacoub, MD^#, Eric A. Cohen, MD^_**, Mark A. Creager, MD, FACC, J. Donald Easton, MD, Christian W. Hamm, MD, FACC, Graeme J. Hankey, MD^||||, S. Claiborne Johnston, MD, PhD^¶¶, Koon-Hou Mak, MD, FACC^##, Jean-Louis Mas, MD^_***, Gilles Montalescot, MD, PhD, Thomas A. Pearson, MD, FACC, P. Gabriel Steg, MD, FACC, Steven R. Steinhubl, MD, FACC^||||||, Michael A. Weber, MD, FACC^¶¶¶, Liz Fabry-Ribaudo, MSN, RN^_*, Tingfei Hu, MS^_*, Eric J. Topol, MD, FACC^###, Keith A.A. Fox, MBChB^_**** for the CHARISMA Investigators

^_* Department of Cardiovascular Medicine, Cleveland Clinic, Cleveland, Ohio
Clinical Trials and Evaluation Unit, Royal Brompton Hospital, London, United Kingdom
Department of Neurology, University of Heidelberg, Heidelberg, Germany
Geisinger Center for Health Research, Danville, Pennsylvania
^|| New York University School of Medicine, New York, New York
^¶ Division of Cardiology, Kaleida Healthcare, Buffalo, New York
^# Department of Internal Medicine, Hopital Pitie-Salpetriere, Paris, France
^_** Division of Cardiology, Sunnybrook and Women’s College Health Science Centre, Toronto, Canada
Division of Cardiovascular Medicine, Brigham and Women’s Hospital and Harvard Medical School, Boston, Massachusetts
Department of Neurology, Rhode Island Hospital and Brown University, Providence, Rhode Island
Department of Cardiology, Kerckhoff-Klinik Center, Bad Nauheim, Germany
^|||| Department of Neurology, Royal Perth Hospital and School of Medicine and Pharmacology, The University of Western Australia, Perth, Australia
^¶¶ Department of Neurology, University of California San Francisco, San Francisco, California
^## Gleneagles Medical Centre, Singapore
^_*** Department of Neurology and Stroke Unit, Sainte-Anne Hospital, Paris, France
Institut de Cardiologie — Centre Hospitalier Universitaire Pitié-Salpêtrière, Paris, France
Department of Community & Preventive Medicine, University of Rochester School of Medicine, Rochester, New York
Service de Cardiologie, Hôpital Bichat, Paris, France
^|||||| Division of Cardiology, University of Kentucky, Lexington, Kentucky
^¶¶¶ SUNY Downstate Medical Center College of Medicine, Brooklyn, New York
^### Case Western Reserve University, Cleveland, Ohio
^_**** University and Royal Infirmary of Edinburgh, Edinburgh, United Kingdom.

Manuscript received December 4, 2006; revised manuscript received March 16, 2007, accepted March 20, 2007.

^_* Reprint requests and correspondence: Dr. Deepak L. Bhatt, Associate Director, Cardiovascular Coordinating Center, Staff, Cardiac, Peripheral, and Carotid Intervention, Department of Cardiovascular Medicine, Cleveland Clinic, 9500 Euclid Avenue, Desk F25, Cleveland, Ohio 44195. (Email: bhattd{at}ccf.org).

Objectives: The purpose of this study was to determine the possible benefit of dual antiplatelet therapy in patients with prior myocardial infarction (MI), ischemic stroke, or symptomatic peripheral arterial disease (PAD).

Background: Dual antiplatelet therapy with clopidogrel plus aspirin has been validated in the settings of acute coronary syndromes and coronary stenting. The value of this combination was recently evaluated in the CHARISMA (Clopidogrel for High Atherothrombotic Risk and Ischemic Stabilization, Management, and Avoidance) trial, where no statistically significant benefit was found in the overall broad population of stable patients studied.

Methods: We identified the subgroup in the CHARISMA trial who were enrolled with documented prior MI, ischemic stroke, or symptomatic PAD.

Results: A total of 9,478 patients met the inclusion criteria for this analysis. The median duration of follow-up was 27.6 months. The rate of cardiovascular death, MI, or stroke was significantly lower in the clopidogrel plus aspirin arm than in the placebo plus aspirin arm: 7.3% versus 8.8% (hazard ratio [HR] 0.83, 95% confidence interval [CI] 0.72 to 0.96, p = 0.01). Additionally, hospitalizations for ischemia were significantly decreased, 11.4% versus 13.2% (HR 0.86, 95% CI 0.76 to 0.96, p = 0.008). There was no significant difference in the rate of severe bleeding: 1.7% versus 1.5% (HR 1.12, 95% CI 0.81 to 1.53, p = 0.50); moderate bleeding was significantly increased: 2.0% versus 1.3% (HR 1.60, 95% CI 1.16 to 2.20, p = 0.004).

Conclusions: In this analysis of the CHARISMA trial, the large number of patients with documented prior MI, ischemic stroke, or symptomatic PAD appeared to derive significant benefit from dual antiplatelet therapy with clopidogrel plus aspirin. Such patients may benefit from intensification of antithrombotic therapy beyond aspirin alone, a concept that future trials will need to validate. (Clopidogrel for High Atherothrombotic Risk and Ischemic Stabilization, Management, and Avoidance [CHARISMA]; http://clinicaltrials.gov/ct/show/NCT00050817?order=1; NCT00050817 [ClinicalTrials.gov] )

Abbreviations and Acronyms   CI = confidence interval   HR = hazard ratio   MI = myocardial infarction   PAD = peripheral arterial disease

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