Clopidogrel-Atorvastatin Interaction

Abstract

Clopidogrel is a pro-drug, which must be converted to its active form to exert its antiplatelet effect. This conversion appears to occur via the cytochrome P4503A4 isoenzyme. 1 Several statins are substrates for CYP3A4, whereas others are not.As a result, some investigators have proposed that the coadministration of statins that are CYP3A4 substrates with clopidogrel may competitively inhibit the metabolic activation of clopidogrel in the liver in a dose-related manner. 2,3 We read with interest the paper by Saw et al 4 evaluating the interaction between statins and clopidogrel from the Clopidogrel for the Reduction of Events During Observation (CREDO) trial. Although similar event rates at 1 year comparing atorvastatin and pravastatin were reported, there appears to be a trend toward improved outcomes with pravastatin. In addition, event rates from day 29 to 1 year appear to be significantly higher with atorvastatin compared with pravastatin. This post hoc evaluation unfortunately was not adequately powered to assess event rates in the pravastatin group. Given these data and the in vivo data published by Lau et al 2 and more recently by Neubauer et al, 3 the potential for a significant interaction between clopidogrel and statins that are CYP3A4 substrates cannot be discounted. Because of limitations with post hoc and observational study evaluations of drug interactions, well-designed clinical trials are needed to specifically evaluate this interaction. Ryan A. Hobbs, RPh ResponseA recent ex vivo study suggesting attenuation of clopidogrel's antiplatelet effectiveness by atorvastatin roused widespread concerns in the medical community. 1 Our post-hoc analysis of the Clopidogrel for the Reduction of Events During Observation (CREDO) trial specifically addressed whether this potential adverse laboratory interaction translates to adverse clinical effects after percutaneous coronary interventions (PCI) with concomitant clopidogrel and statin administration. 2 Hobbs et al raised an important limitation of our study. Because our analysis was retrospective, it was limited by the intended enrollment numbers to address the primary CREDO analysis comparing bolus/ long-term clopidogrel to placebo. Thus, our analysis was underpowered for the groups of patients who received a non-CYP3A4-metabolized statin (nϭ158) or pravastatin (nϭ142). The 1-year death, myocardial infarction, or stroke event rate was 6.5% with atorvastatin and 4.6% with pravastatin (Pϭ0.62). The relative risk reduction of 1-year events for clopidogrel compared with placebo was 49.8% when atorvastatin was coadministered and 63.3% when pravastatin was coadministered. The Breslow-Day test was performed to compare the odds ratio (OR) of 1-year event rates in the atorvastatin (ORϭ0.49) and pravastatin (ORϭ0.34) arms, which showed no difference (Pϭ0.634). Despite these comparisons, we could not exclude that the lack of difference was due to a beta error; in short, our study could not exclude a small benefit with the use of pravastatin compared with atorvastatin....