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CLINICAL RESEARCH: CLINICAL TRIALS

Lack of Evidence of a Clopidogrel–Statin Interaction in the CHARISMA Trial

Jacqueline Saw, MD^_*, Danielle M. Brennan, MS, Steven R. Steinhubl, MD, Deepak L. Bhatt, MD, Koon-Hou Mak, MD, Keith Fox, MB, ChB^||, Eric J. Topol, MD^#,_* CHARISMA Investigators

^_* Division of Cardiology, Vancouver General Hospital, University of British Columbia, Vancouver, British Columbia, Canada
Department of Cardiovascular Medicine, Cleveland Clinic, Cleveland, Ohio
Department of Cardiovascular Medicine, University of Kentucky, Lexington, Kentucky
Gleneagles Medical Center, Singapore
^|| University and Royal Infirmary of Edinburgh, Edinburgh, Scotland, United Kingdom
^# Department of Cardiovascular Diseases, Scripps Clinic, La Jolla, California.

Manuscript received November 7, 2006; revised manuscript received January 19, 2007, accepted January 22, 2007.

^_* Reprint requests and correspondence: Dr. Eric J. Topol, Director, Scripps Translational Science Institute, Chief Academic Officer, Scripps Health, Professor of Translational Genomics, The Scripps Research Institute, Scripps Clinic, Division of Cardiovascular Diseases, 10666 North Torey Pines Road, Mail Drop SW206, La Jolla, California 92037. (Email: etopol{at}scripps.edu).

Objectives: The purpose of this study was to evaluate the potential impact of clopidogrel and statin interaction in a randomized, placebo-controlled trial with long-term follow-up.

Background: There are conflicting data regarding whether statins predominantly metabolized by CYP3A4 reduce the metabolism of clopidogrel to its active metabolite and diminish its clinical efficacy.

Methods: The CHARISMA trial was a randomized trial comparing long-term 75 mg/day clopidogrel versus placebo in patients with cardiovascular disease or multiple risk factors on aspirin. The primary end point was a composite of myocardial infarction, stroke, or cardiovascular death at median follow-up of 28 months. We performed a secondary analysis evaluating the interaction of clopidogrel versus placebo with statin administration, categorizing baseline statin use to those predominantly CYP3A4 metabolized (atorvastatin, lovastatin, simvastatin; CYP3A4-MET) or others (pravastatin, fluvastatin; non–CYP3A4-MET).

Results: Of 15,603 patients enrolled, 10,078 received a statin at baseline (8,245 CYP3A4-MET, 1,748 non–CYP3A4-MET) and 5,496 did not. For the overall population, the primary end point was 6.8% with clopidogrel and 7.3% with placebo (hazard ratio [HR] 0.93; p = 0.22). This was similar among patients on CYP3A4-MET (5.9% clopidogrel, 6.6% placebo, HR 0.89; p = 0.18) or non–CYP3A4-MET statin (5.7% clopidogrel, 7.2% placebo, HR 0.78; p = 0.19). There was no interaction between statin types and randomized treatment (p = 0.69). Patients on atorvastatin (n = 4,127) (5.7% clopidogrel, 7.1% placebo, HR 0.80; p = 0.06) or pravastatin (n = 1,440) (5.1% clopidogrel, 7.0% placebo, HR 0.72; p = 0.13) had similar event rates.

Conclusions: Despite theoretic concerns and ex vivo testing suggesting a potential negative interaction with concomitant clopidogrel and CYP3A4-MET statin administration, there was no evidence of an interaction clinically in a large placebo-controlled trial with long-term follow-up.

Abbreviations and Acronyms   CI = confidence interval   CYP3A4-MET = cytochrome P450 3A4-metabolized statin   HR = hazard ratio   MI = myocardial infarction   OR = odds ratio

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