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Lack of Evidence of a Clopidogrel – Statin Interaction in the CHARISMA Trial. J Am Coll Cardiol 2007;50:291-5.

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lack of evidence of a clopidogrel statin interaction in the charisma trial

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

J Am Coll Cardiol 2007;50:291-5

Jacqueline Saw, MD*, Danielle Brennan, MS†, Steven Steinhubl, MD‡, Deepak L. Bhatt, MD†, Koon-Hou Mak, MD§, Keith Fox, MB^, and Eric J. Topol, MD#for the CHARISMA Investigators

*Vancouver, British Columbia, Canada; †Cleveland, Ohio; ‡Lexington, Kentucky; §Singapore; ^Edinburgh, Scotland, United Kingdom; and #La Jolla, California

study objective
Study Objective
  • To evaluate the potential impact of long-term concomitant administration of clopidogrel and statins in the CHARISMA study on long-term clinical event-rates
charisma trial design
CHARISMA Trial Design

Median 28 months

Bhatt DL, et al. N Eng J Med 2006;354:1-12.

methods 1
Methods (1)
  • We performed a secondary analysis evaluating the differential treatment effect (interaction) of clopidogrel versus placebo according to the type of statin administered:
    • CYP3A4-MET versus Non-CYP3A4-MET
    • Atorvastatin versus pravastatin
  • Analyses of the entire CHARISMA cohort, symptomatic cohort, & asymptomatic cohort
methods 2
Methods (2)
  • Statin administration was non-randomized
  • Recorded at baseline and each follow-up visit
  • Our analysis was based upon baseline statin administered —2 major groups:
    • CYP3A4-MET: Statins predominantly metabolized by CYP3A4 (atorvastatin, lovastatin, simvastatin)
    • Non-CYP3A4-MET: Statins not predominantly metabolized by CYP3A4 (pravastatin, fluvastatin)
statistical analyses
Statistical Analyses
  • Intention-to-treat population, 2-sided tests, 5% α
  • Chi-square to compare baseline variables
  • Cox proportional-hazards model to estimate the HR and 95% CI for the primary efficacy endpoint
  • Logistic regression model to compute OR and 95% CI for the primary safety endpoint
  • Interactions tested with Cox proportional-hazards model, incorporating terms for randomized treatment and treatment-by-statin, to assess if treatment effect differed for CYP3A4-MET vs. non-CYP3A4-MET, and atorvastatin vs. pravastatin
  • SAS software (8.2, SAS Institute, Cary, NC).
primary efficacy endpoint

HR 1.02p=0.87

HR 0.93p=0.23

HR 0.78p=0.19

HR 0.80p=0.06

HR 0.72p=0.13

HR 0.87p=0.08

HR 0.89p=0.18

Primary Efficacy Endpoint
interaction cyp3a4 met
Interaction: CYP3A4-MET

The interaction of the type of statin (CYP3A4-MET vs. non-CYP3A4-MET) and randomized treatment was not significant.

p=0.69

interaction atorvastatin pravastatin
Interaction: Atorvastatin/Pravastatin

The interaction of atorvastatin versus pravastatin and randomized treatment was not significant.

p=0.54

symptomatic patients
Symptomatic Patients

In the symptomatic subgroup, the 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

gusto major bleeding

OR 1.29p=0.20

OR 1.24p=0.11

OR 1.19p=0.33

OR 1.19p=0.39

OR 1.14p=0.76

OR 0.87p=0.61

OR 1.04p=0.93

GUSTO Major Bleeding
limitations
Limitations
  • Retrospective post hoc analysis
  • Statin administration not randomized
  • Statin dose not recorded
  • Analysis based upon baseline statin use
  • Platelet aggregation or activation not assessed
conclusions
Conclusions
  • Despite theoretical 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
  • Our study is concordant with other clinical analyses, suggesting that clinicians need not choose statins on the basis of CYP3A4-metabolism, even when long-term clopidogrel co-administration is required