Abstract 3287: Lack of Evidence of a Clopidogrel-Statin Interaction in the CHARISMA Trial
Background: Conflicting data exist regarding whether statins predominantly metabolized by cytochrome P450 3A4 (CYP3A4) reduce the metabolism of clopidogrel to its active metabolite and therefore diminish its clinical efficacy. We evaluated the clinical impact of this potential interaction with concomitant long-term clopidogrel and statin administration.
Methods: CHARISMA was a double-blind, placebo-controlled, randomized trial comparing long-term clopidogrel 75mg/d versus placebo in patients with cardiovascular disease or multiple risk factors. All patients received low-dose aspirin. The primary endpoint was a composite of myocardial infarction, stroke, or cardiovascular death at a median of 28 months follow-up. We performed a secondary analysis evaluating the clinical efficacy of concomitant clopidogrel and statin administration, categorizing baseline statin use to those predominantly metabolized by CYP3A4 (atorvastatin, lovastatin, simvastatin) [CYP3A4-MET], or others (pravastatin, fluvastatin) [non-CYP3A4-MET]. Results: Of 15,603 patients enrolled, 10,078 received a statin (8,245 CYP3A4-MET and 1,748 non-CYP3A4-MET), and 5,496 did not receive a statin. For the overall study population, the primary endpoint occurred in 6.8% of patients with clopidogrel and 7.3% with placebo (relative risk 0.93, 95% confidence interval 0.83 to 1.05, p=0.22). This was similar among patients on CYP3A4-MET (6.7% clopidogrel, 7.3% placebo, RR 0.89, p=0.18) or non-CYP3A4-MET statins (6.7% clopidogrel, 8.1% placebo, RR 0.78, p=0.19). Likewise, patients on atorvastatin (6.4% clopidogrel, 8.1% placebo, RR 0.80, p=0.06) or pravastatin (6.0% clopidogrel, 8.0% placebo, RR 0.72, p=0.13) had similar event-rates. Severe or moderate bleeding event-rates were also similar, irrespective of statin administration.
Conclusions: Despite theoretical concerns and ex vivo testing suggesting a potential negative interaction with concomitant clopidogrel and CYP3A4-MET statin administration, there is no evidence of an interaction clinically in a large, placebo-controlled trial with long term follow-up.