title: Impact of cytochrome P450 3A4-metabolized statins on the antiplatelet effect of a 600-mg loading dose clopidogrel and on clinical outcome in patients undergoing elective coronary stent placement.
abstract: Early studies suggested interactions between statins and clopidogrel. Based on the outcome and platelet data, there is now huge evidence of no interactions between statins and 75 to 300 mg clopidogrel; however, data with 600-mg loading are lacking. In a pre-specified analysis of the EXCELSIOR cohort, we investigated the interaction between statins, especially cytochrome P4503A4-metabolized atorvastatin and simvastatin, and the antiplatelet effects of a 600-mg loading dose of clopidogrel. We analyzed 1,395 patients scheduled for coronary angiography (CA). Patients received clopidogrel 600 mg at least two hours before CA and 75 mg daily thereafter in case of percutaneous coronary intervention (PCI). Statin medication on admission was continued unaltered until discharge. Platelet function was assessed by optical aggregometry and flow cytometry of adenosine diphosphate (ADP)-stimulated surface expression of CD62P, CD63 and PAC-1 before clopidogrel and immediately before CA. Residual platelet aggregation (RPA) after addition of ADP 5 muM was similar irrespective of statin treatment at baseline (p = 0.968). RPA at CA was 46.2 +/- 16.8% in patients without statin (n = 682), 45.5 +/- 17.0% in patients with atorvastatin (n = 255), 45.8 +/- 16.3% with simvastatin (n = 335), 47.3 +/- 14.9% with fluvastatin (n = 42) and 45.9 +/- 16.2% with pravastatin (n = 81; p = 0.962). Consistent results were obtained by flow cytometry. In patients with PCI (n = 553), the one-year incidence of death, myocardial infarction and target lesion reintervention did not differ between cohorts stratified according to statin co-medication (p = 0.645). Thus, peri-interventional atorvastatin and simvastatin had no effect on the antiplatelet activity of a loading dose of clopidogrel 600 mg and did not affect clinical outcome after PCI.
authors.affiliation: Herz-Zentrum Bad Krozingen, Suedring 15, 79189 Bad Krozingen, Germany. Dietmar.Trenk@herzzentrum.de
authors.forename: Dietmar
authors.initials: D
authors.lastname: Trenk
authors.forename: Willibald
authors.initials: W
authors.lastname: Hochholzer
authors.forename: Devine
authors.initials: D
authors.lastname: Frundi
authors.forename: Christian
authors.initials: C
authors.lastname: Stratz
authors.forename: Christian M
authors.initials: CM
authors.lastname: Valina
authors.forename: Hans-Peter
authors.initials: HP
authors.lastname: Bestehorn
authors.forename: Heinz Joachim
authors.initials: HJ
authors.lastname: Büttner
authors.forename: Franz-Josef
authors.initials: FJ
authors.lastname: Neumann
mesh_terms: D000244:Adenosine Diphosphate / Q000378:metabolism; D000368:Aged; D015906:Angioplasty, Balloon, Coronary / Q000009:adverse effects / Q000295:instrumentation*; D000069059:Atorvastatin; D001792:Blood Platelets / Q000187:drug effects* / Q000378:metabolism; D002318:Cardiovascular Diseases / Q000209:etiology / Q000401:mortality / Q000517:prevention & control; D000077144:Clopidogrel; D015331:Cohort Studies; D003327:Coronary Disease / Q000097:blood / Q000188:drug therapy / Q000378:metabolism / Q000401:mortality / Q000628:therapy*; D051544:Cytochrome P-450 CYP3A; D003577:Cytochrome P-450 Enzyme System / Q000378:metabolism*; D004305:Dose-Response Relationship, Drug; D004347:Drug Interactions; D005260:Female; D005434:Flow Cytometry; D006538:Heptanoic Acids / Q000008:administration & dosage; D006801:Humans; D019161:Hydroxymethylglutaryl-CoA Reductase Inhibitors / Q000008:administration & dosage* / Q000378:metabolism; D053208:Kaplan-Meier Estimate; D008297:Male; D008875:Middle Aged; D010974:Platelet Aggregation / Q000187:drug effects; D010975:Platelet Aggregation Inhibitors / Q000008:administration & dosage*; D010979:Platelet Function Tests / Q000379:methods; D011758:Pyrroles / Q000008:administration & dosage; D019821:Simvastatin / Q000008:administration & dosage; D015607:Stents; D013988:Ticlopidine / Q000008:administration & dosage / Q000031:analogs & derivatives*; D013997:Time Factors; D016896:Treatment Outcome
chemical_list: D006538:Heptanoic Acids; D019161:Hydroxymethylglutaryl-CoA Reductase Inhibitors; D010975:Platelet Aggregation Inhibitors; D011758:Pyrroles; D000244:Adenosine Diphosphate; D003577:Cytochrome P-450 Enzyme System; D000069059:Atorvastatin; D000077144:Clopidogrel; D019821:Simvastatin; D051544:Cytochrome P-450 CYP3A; C510163:CYP3A4 protein, human; D013988:Ticlopidine