1. 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, Columbia, Canada; † Cleveland, Ohio; ‡ Lexington, Kentucky; § Singapore; ^Edinburgh, Scotland, United Kingdom; and # La Jolla, California *Vancouver, British Columbia, Canada; † Cleveland, Ohio; ‡ Lexington, Kentucky; § Singapore; ^Edinburgh, Scotland, United Kingdom; and # La Jolla, California Lack of Evidence of a Clopidogrel – Statin Interaction in the CHARISMA Trial J Am Coll Cardiol 2007;50:291-5

2. Copyright ©2007 American College of Cardiology Foundation. Restrictions may apply. Saw, J. et al. J Am Coll Cardiol 2007;50:291-5 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-ratesTo evaluate the potential impact of long- term concomitant administration of clopidogrel and statins in the CHARISMA study on long-term clinical event-rates

3. Copyright ©2007 American College of Cardiology Foundation. Restrictions may apply. Saw, J. et al. J Am Coll Cardiol 2007;50:291-5 CHARISMA Trial Design Median 28 months Bhatt DL, et al. N Eng J Med 2006;354:1-12.

4. Copyright ©2007 American College of Cardiology Foundation. Restrictions may apply. Saw, J. et al. J Am Coll Cardiol 2007;50:291-5 Methods (1) We performed a secondary analysis evaluating the differential treatment effect (interaction) of clopidogrel versus placebo according to the type of statin administered: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-METCYP3A4-MET versus Non-CYP3A4-MET Atorvastatin versus pravastatinAtorvastatin versus pravastatin Analyses of the entire CHARISMA cohort, symptomatic cohort, & asymptomatic cohortAnalyses of the entire CHARISMA cohort, symptomatic cohort, & asymptomatic cohort

5. Copyright ©2007 American College of Cardiology Foundation. Restrictions may apply. Saw, J. et al. J Am Coll Cardiol 2007;50:291-5 Methods (2) 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 administered — 2 major groups:Our analysis was based upon baseline statin administered — 2 major groups: CYP3A4-MET: Statins predominantly metabolized by CYP3A4 (atorvastatin, lovastatin, simvastatin)CYP3A4-MET: Statins predominantly metabolized by CYP3A4 (atorvastatin, lovastatin, simvastatin) Non-CYP3A4-MET: Statins not predominantly metabolized by CYP3A4 (pravastatin, fluvastatin)Non-CYP3A4-MET: Statins not predominantly metabolized by CYP3A4 (pravastatin, fluvastatin)

6. Copyright ©2007 American College of Cardiology Foundation. Restrictions may apply. Saw, J. et al. J Am Coll Cardiol 2007;50:291-5 Statistical Analyses Intention-to-treat population, 2-sided tests, 5% αIntention-to-treat population, 2-sided tests, 5% α Chi-square to compare baseline variablesChi-square to compare baseline variables Cox proportional-hazards model to estimate the HR and 95% CI for the primary efficacy endpointCox 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 endpointLogistic 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. pravastatinInteractions 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).SAS software (8.2, SAS Institute, Cary, NC).

7. Copyright ©2007 American College of Cardiology Foundation. Restrictions may apply. Saw, J. et al. J Am Coll Cardiol 2007;50:291-5 Baseline Characteristics CYP3A4-MET(N=8,245)Non-CYP3A4-MET(N=1,748) P value Age 63.9 ± 9.4 64.4 ± 9.4 0.048 Body mass index 29.0 ± 5.2 28.5 ± 5.1 <0.001 Female 2278 (27.6%) 478 (27.3%) 0.810 Diabetes mellitus 3418 (41.5%) 702 (40.2%) 0.318 Active smoker 871 (10.6%) 171 (9.8%) 0.332 Hypertension 6098 (74.0%) 1254 (71.7%) 0.056 Hyperlipidemia 7488 (90.8%) 1544 (88.3%) 0.001 History of MI 3615 (43.8%) 754 (43.1%) 0.584 History of stroke 1545 (18.7%) 376 (21.5%) 0.008 History of CHF 553 (6.7%) 99 (5.7%) 0.109 Prior CABG 2173 (26.4%) 373 (21.3%) <0.001 Prior CEA 521 (6.3%) 86 (4.9%) 0.026 PAD 1844 (22.4%) 330 (18.9%) 0.001

8. Copyright ©2007 American College of Cardiology Foundation. Restrictions may apply. Saw, J. et al. J Am Coll Cardiol 2007;50:291-5 Primary Efficacy Endpoint HR 0.93 p=0.23 HR 1.02 p=0.87 HR 0.87 p=0.08 HR 0.89 p=0.18 HR 0.78 p=0.19 HR 0.80 p=0.06 HR 0.72 p=0.13

9. Copyright ©2007 American College of Cardiology Foundation. Restrictions may apply. Saw, J. et al. J Am Coll Cardiol 2007;50:291-5 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

10. Copyright ©2007 American College of Cardiology Foundation. Restrictions may apply. Saw, J. et al. J Am Coll Cardiol 2007;50:291-5 Interaction: Atorvastatin/Pravastatin The interaction of atorvastatin versus pravastatin and randomized treatment was not significant. p=0.54

11. Copyright ©2007 American College of Cardiology Foundation. Restrictions may apply. Saw, J. et al. J Am Coll Cardiol 2007;50:291-5 Statins Versus No Statins p<0.001

12. Copyright ©2007 American College of Cardiology Foundation. Restrictions may apply. Saw, J. et al. J Am Coll Cardiol 2007;50:291-5 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

13. Copyright ©2007 American College of Cardiology Foundation. Restrictions may apply. Saw, J. et al. J Am Coll Cardiol 2007;50:291-5 GUSTO Major Bleeding OR 1.24 p=0.11 OR 1.29 p=0.20 OR 1.19 p=0.33 OR 1.19 p=0.39 OR 1.14 p=0.76 OR 0.87 p=0.61 OR 1.04 p=0.93

14. Copyright ©2007 American College of Cardiology Foundation. Restrictions may apply. Saw, J. et al. J Am Coll Cardiol 2007;50:291-5 Limitations Retrospective post hoc analysisRetrospective post hoc analysis Statin administration not randomizedStatin administration not randomized Statin dose not recordedStatin dose not recorded Analysis based upon baseline statin useAnalysis based upon baseline statin use Platelet aggregation or activation not assessedPlatelet aggregation or activation not assessed

15. Copyright ©2007 American College of Cardiology Foundation. Restrictions may apply. Saw, J. et al. J Am Coll Cardiol 2007;50:291-5 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-upDespite 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 requiredOur 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