title: Interaction of clopidogrel and statins in secondary prevention after cerebral ischaemia - a randomized, double-blind, double-dummy crossover study.
abstract: OBJECTIVE
  Variability in responsiveness to clopidogrel is a clinical problem in secondary prevention after cerebral ischaemia which has been suggested to be linked to competitive metabolization of clopidogrel and cytochrome P450 (CYP) 3A4-oxidated statins such as simvastatin. We assessed the hypothesis that simvastatin, in contrast to CYP 2C9-metabolized fluvastatin, reduces clopidogrel-mediated platelet inhibition.
  
  
  METHODS
  We performed a randomized, double-blind, double-dummy, two period crossover study in 13 patients with cerebral ischaemia (8F, 5 M), aged 64.1 ± 8.0 years (mean ± SD). After a 14 day period in which all patients received 75 mg clopidogrel day(-1) , patients additionally received either 20 mg simvastatin day(-1) or 80 mg fluvastatin day(-1) for 14 days. Regimens were crossed over after a 14 day wash-out period and switched regimens were continued for another 14 days. Platelet aggregation, clopidogrel active metabolite (CAM) plasma concentrations and routine laboratory parameters including prothrombin time (PT) Quick percent value were assessed at baseline and following each treatment phase.
  
  
  RESULTS
  Clopidogrel reduced platelet aggregation in all patients as expected. Platelet aggregation and CAM plasma concentrations were unaltered when simvastatin or fluvastatin was added to clopidogrel. Simvastatin decreased PT Quick percent value (decrease from 109 ± 10.5% to 103 ± 11%, P < 0.05) when combined with clopidogrel but there was no such change following treatment with fluvastatin and clopidogrel.
  
  
  CONCLUSIONS
  Our data indicate that treatment with CYP 3A4-metabolized simvastatin does not jeopardize clopidogrel-mediated inhibition of platelet aggregation. After co-administration of simvastatin and clopidogrel we observed a decrease in the PT Quick percent value which could be due to simvastatin-induced reduction of activity of prothrombin fragment 1 + 2.
authors.affiliation: Department of Neurology, Dresden University of Technology, Dresden, Germany.
authors.forename: Timo
authors.initials: T
authors.lastname: Siepmann
authors.forename: Denise
authors.initials: D
authors.lastname: Heinke
authors.forename: Jessica
authors.initials: J
authors.lastname: Kepplinger
authors.forename: Kristian
authors.initials: K
authors.lastname: Barlinn
authors.forename: Siegmund
authors.initials: S
authors.lastname: Gehrisch
authors.forename: Xina
authors.initials: X
authors.lastname: Grählert
authors.forename: Uta
authors.initials: U
authors.lastname: Schwanebeck
authors.forename: Heinz
authors.initials: H
authors.lastname: Reichmann
authors.forename: Volker
authors.initials: V
authors.lastname: Puetz
authors.forename: Ulf
authors.initials: U
authors.lastname: Bodechtel
authors.forename: Georg
authors.initials: G
authors.lastname: Gahn
mesh_terms: D000368:Aged; D002545:Brain Ischemia / Q000097:blood / Q000378:metabolism / Q000517:prevention & control*; D000077144:Clopidogrel; D018592:Cross-Over Studies; D051544:Cytochrome P-450 CYP3A / Q000378:metabolism; D004311:Double-Blind Method; D004347:Drug Interactions; D004359:Drug Therapy, Combination; D005229:Fatty Acids, Monounsaturated / Q000008:administration & dosage / Q000493:pharmacokinetics / Q000627:therapeutic use; D005260:Female; D000077340:Fluvastatin; D006801:Humans; D019161:Hydroxymethylglutaryl-CoA Reductase Inhibitors / Q000008:administration & dosage / Q000493:pharmacokinetics* / Q000627:therapeutic use; D007211:Indoles / Q000008:administration & dosage / Q000493:pharmacokinetics / Q000627:therapeutic use; D008297:Male; D008875:Middle Aged; D010975:Platelet Aggregation Inhibitors / Q000008:administration & dosage / Q000493:pharmacokinetics* / Q000627:therapeutic use; D055502:Secondary Prevention / Q000379:methods*; D019821:Simvastatin / Q000008:administration & dosage / Q000493:pharmacokinetics / Q000627:therapeutic use; D013379:Substrate Specificity; D013988:Ticlopidine / Q000008:administration & dosage / Q000031:analogs & derivatives* / Q000493:pharmacokinetics / Q000627:therapeutic use
chemical_list: D005229:Fatty Acids, Monounsaturated; D019161:Hydroxymethylglutaryl-CoA Reductase Inhibitors; D007211:Indoles; D010975:Platelet Aggregation Inhibitors; D000077340:Fluvastatin; D000077144:Clopidogrel; D019821:Simvastatin; D051544:Cytochrome P-450 CYP3A; C510163:CYP3A4 protein, human; D013988:Ticlopidine
keywords: CYP 3A4; clopidogrel; fluvastatin; platelet aggregation; simvastatin