Thienopyridines and Statins: Assessing a Potential Drug-Drug Interaction

H.      Neubauer; A.      Mugge

Abstract

Clopidogrel and statins are frequently administered in patients with ischemic heart disease or other atherothrombotic manifestations and are effective in the prevention of cardiovascular disease. The thienopyridine clopidogrel is a pro-drug metabolised in the liver via the cytochrome P450 (CYP) 3A4 system to the active compound which inhibits the P2Y12 ADP platelet receptor. The assumption exists that the effect of clopidogrel in inhibiting platelet aggregation is attenuated by co-administration of lipophilic statins such as atorvastatin or simvastatin which are metabolised by the CYP3A4 system to inactive substrates. Assessing a possible drug-drug interaction ex-vivo, inconclusive studies have been published: In an aggregometer study, a strong and dose-dependent interference between atorvastatin and the inhibitory effect of clopidogrel on platelet function was observed. Another study, measuring the effect of clopidogrel by flow cytometry, found a significant attenuation of the clopidogrel effect by lipophilic statins, predominantly in the loading phase. In contrast a recent study, which used 600mg clopidogrel for loading, found no significant interference between various statins and clopidogrel on ADP-induced platelet aggregation and in addition another study revealed no attenuation of the clopidogrel effect despite statin co-medication after 5 weeks. Additionally, retrospective analysis of clinical studies (CREDO-study) or registries (MITRA-PLUS) revealed no significant influence of different statins on the clinical outcome in patients treated with clopidogrel. However, these clinical studies showed a trend towards a diminishing effect of clopidogrel on those treated with cytochrome CYP3A4 metabolised statins. Even more important seems to be the considerable variability in the response of the antiplatelet effect of clopidogrel. A certain percentage of patients apparently do not respond adequately to clopidogrel treatment. This effect of clopidogrel resistance seems to be more important as the potential interference between CYP3A4 metabolized statins and clopidogrel. Finally, up until now sufficient evidence has not been gained to prefer hydrophil statins on patients receiving clopidogrel co-medication or when to discontinue the use of statins in clopidogrel treatment. Prospective studies are necessary in order to evaluate the magnitude of clopidogrel resistance and the impact of clopidogrel co-medication as well as to redefine antithrombotic therapy for this subgroup.

Keywords: Clopidogrel, statin, cytochrome P450, interaction, aggregometer, flow cytometry, thienopyridine

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