title: 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.
authors.affiliation: Department of Cardiology, Odense University Hospital, Odense, Denmark. tina.poulsen@ouh.fyns-amt.dk
authors.forename: Tina Svenstrup
authors.initials: TS
authors.lastname: Poulsen
authors.forename: Pernille
authors.initials: P
authors.lastname: Vinholt
authors.forename: Hans
authors.initials: H
authors.lastname: Mickley
authors.forename: Lars
authors.initials: L
authors.lastname: Korsholm
authors.forename: Søren Risom
authors.initials: SR
authors.lastname: Kristensen
authors.forename: Per
authors.initials: P
authors.lastname: Damkier
mesh_terms: D000069059:Atorvastatin; D000077144:Clopidogrel; D051544:Cytochrome P-450 CYP3A; D003577:Cytochrome P-450 Enzyme System / Q000378:metabolism; D004347:Drug Interactions; D006538:Heptanoic Acids / Q000378:metabolism / Q000494:pharmacology / Q000627:therapeutic use; D006801:Humans; D019161:Hydroxymethylglutaryl-CoA Reductase Inhibitors / Q000378:metabolism / Q000494:pharmacology / Q000627:therapeutic use*; D015201:Meta-Analysis as Topic; D015337:Multicenter Studies as Topic; D011355:Prodrugs / Q000378:metabolism / Q000494:pharmacology / Q000627:therapeutic use; D011758:Pyrroles / Q000378:metabolism / Q000494:pharmacology / Q000627:therapeutic use; D013988:Ticlopidine / Q000031:analogs & derivatives* / Q000378:metabolism / Q000494:pharmacology / Q000627:therapeutic use
chemical_list: D006538:Heptanoic Acids; D019161:Hydroxymethylglutaryl-CoA Reductase Inhibitors; D011355:Prodrugs; D011758:Pyrroles; D003577:Cytochrome P-450 Enzyme System; D000069059:Atorvastatin; D000077144:Clopidogrel; C104464:CYP3A protein, human; D051544:Cytochrome P-450 CYP3A; D013988:Ticlopidine