Jacqueline Saw, MD*, Danielle Brennan, Jacqueline Saw, MD*, Danielle Brennan, MS MS † , Steven Steinhubl, MD , Steven Steinhubl, MD ‡ , Deepak L. , Deepak L. Bhatt, MD Bhatt, MD † , Koon-Hou Mak, MD , Koon-Hou Mak, MD § , Keith , Keith Fox, MB Fox, MB ^ ^ , and Eric J. Topol, MD , and Eric J. Topol, MD # for the CHARISMA Investigators for the CHARISMA Investigators *Vancouver, *Vancouver, British Columbia, Canada; Columbia, Canada; † Cleveland, Ohio; Cleveland, Ohio; ‡ Lexington, Kentucky; Lexington, Kentucky; § Singapore; Singapore; ^ Edinburgh, Scotland, United Edinburgh, Scotland, United Kingdom; and Kingdom; and # La Jolla, California La Jolla, California Lack of Evidence of a Lack of Evidence of a Clopidogrel – Statin Interaction Clopidogrel – Statin Interaction in the CHARISMA Trial in the CHARISMA Trial J Am Coll Cardiol 2007;50:291-5
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Jacqueline Saw, MD*, Danielle Brennan, MSJacqueline Saw, MD*, Danielle Brennan, MS††, Steven , Steven Steinhubl, MDSteinhubl, MD‡‡, Deepak L. Bhatt, MD, Deepak L. Bhatt, MD††, Koon-Hou , Koon-Hou Mak, MDMak, MD§§, Keith Fox, MB, Keith Fox, MB^̂, and Eric J. Topol, MD, and Eric J. Topol, MD##
for the CHARISMA Investigatorsfor the CHARISMA Investigators
*Vancouver, *Vancouver, British Columbia, Canada; Columbia, Canada; ††Cleveland, Ohio; Cleveland, Ohio; ‡‡Lexington, Kentucky; Lexington, Kentucky; §§Singapore; Singapore; ^̂Edinburgh, Scotland, United Kingdom; and Edinburgh, Scotland, United Kingdom; and ##La Jolla, CaliforniaLa Jolla, California
Lack of Evidence of a Clopidogrel – Lack of Evidence of a Clopidogrel – Statin Interaction in the CHARISMA TrialStatin Interaction in the CHARISMA Trial
• To evaluate the potential impact of long-To evaluate the potential impact of long-term concomitant administration of term concomitant administration of clopidogrel and statins in the CHARISMA clopidogrel and statins in the CHARISMA study on long-term clinical event-ratesstudy on long-term clinical event-rates
• We performed a secondary analysis evaluating We performed a secondary analysis evaluating the differential treatment effect (interaction) of the differential treatment effect (interaction) of clopidogrel versus placebo according to the clopidogrel versus placebo according to the type of statin administered:type of statin administered:
• CYP3A4-MET versus Non-CYP3A4-METCYP3A4-MET versus Non-CYP3A4-MET
• Atorvastatin versus pravastatinAtorvastatin versus pravastatin
• Analyses of the entire CHARISMA cohort, Analyses of the entire CHARISMA cohort, symptomatic cohort, & asymptomatic cohortsymptomatic cohort, & asymptomatic cohort
• Statin administration was non-randomizedStatin administration was non-randomized
• Recorded at baseline and each follow-up visitRecorded at baseline and each follow-up visit
• Our analysis was based upon baseline statin Our analysis was based upon baseline statin administered administered —— 2 major groups:2 major groups:
• CYP3A4-METCYP3A4-MET: Statins predominantly metabolized by : Statins predominantly metabolized by CYP3A4 (atorvastatin, lovastatin, simvastatin)CYP3A4 (atorvastatin, lovastatin, simvastatin)
• Non-CYP3A4-METNon-CYP3A4-MET: Statins not predominantly : Statins not predominantly metabolized by CYP3A4 (pravastatin, fluvastatin)metabolized by CYP3A4 (pravastatin, fluvastatin)
• Chi-square to compare baseline variablesChi-square to compare baseline variables
• Cox proportional-hazards model to estimate the HR and Cox proportional-hazards model to estimate the HR and 95% CI for the primary efficacy endpoint95% CI for the primary efficacy endpoint
• Logistic regression model to compute OR and 95% CI Logistic regression model to compute OR and 95% CI for the primary safety endpointfor the primary safety endpoint
• Interactions tested with Cox proportional-hazards Interactions tested with Cox proportional-hazards model, incorporating terms for randomized treatment model, incorporating terms for randomized treatment and treatment-by-statin, to assess if treatment effect and treatment-by-statin, to assess if treatment effect differed for CYP3A4-MET vs. non-CYP3A4-MET, and differed for CYP3A4-MET vs. non-CYP3A4-MET, and atorvastatin vs. pravastatinatorvastatin vs. pravastatin
• SAS software (8.2, SAS Institute, Cary, NC).SAS software (8.2, SAS Institute, Cary, NC).
interaction of the type of statin used (CYP3A4-MET vs. Non-CYP3A4-MET) and the randomized treatment (clopidogrel vs. placebo) remained insignificant: p=0.18
Likewise, the interaction of atorvastatin versus pravastatin and randomized treatment was not significant: p=0.25
• Despite theoretical concerns and Despite theoretical concerns and ex vivoex vivo testing testing suggesting a potential negative interaction with suggesting a potential negative interaction with concomitant clopidogrel and CYP3A4-MET concomitant clopidogrel and CYP3A4-MET statin administration, there was no evidence of statin administration, there was no evidence of an interaction clinically in a large placebo-an interaction clinically in a large placebo-controlled trial with long-term follow-upcontrolled trial with long-term follow-up
• Our study is concordant with other clinical Our study is concordant with other clinical analyses, suggesting that clinicians need not analyses, suggesting that clinicians need not choose statins on the basis of CYP3A4-choose statins on the basis of CYP3A4-metabolism, even when long-term clopidogrel metabolism, even when long-term clopidogrel co-administration is requiredco-administration is required
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