Existence of a clinically relevant interaction between clopidogrel and HMG-CoA reductase inhibitors? Re-evaluating the evidence

Abstract

Clopidogrel is an inactive prodrug, which requires activation by the cytochrome P450 3A4 system in order to exert its antiplatelet action. Some statins (atorvastatin, lovastatin and simvastatin) also requires metabolism by the cytochrome P450 3A4 system. From a theoretical point of view, a clinical relevant interaction may exist between clopidogrel and cytochrome P450 3A4 metabolized statins. Nine studies have investigated the existence of this potential interaction. Seven studies have used results based on platelet function as surrogate endpoints and two studies have dealt with objective clinical events including mortality, acute myocardial infarction and stroke. However the studies have yielded conflicting results. This controversy is primarily caused by substantial differences in study design and methods used for assessment of the antiaggregatory effect of clopidogrel. Most studies have included too few patients, and there appears to be no consensus regarding the definition of and optimal way of measuring the platelet inhibitory effect of clopidogrel. Therefore an adequately powered prospective study, ensuring elimination of identified possible confounders and with the use of a well-defined surrogate ex vivo parameter should be performed.