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 P2Y(12)
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 600 mg
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.