title: Epidemiology of CYP3A4-mediated clopidogrel drug-drug interactions and their clinical consequences.
abstract: OBJECTIVE
  Clopidogrel is a prodrug that needs to be activated to inhibit platelet aggregation. The objective of this study was to evaluate the prevalence and clinical consequences of potential drug-drug interactions of clopidogrel with drugs affecting CYP3A4 activity.
  
  
  METHODS
  Co-administrations of clopidogrel together with well-established CYP3A4 inhibitors, CYP3A4 inducers, and atorvastatin were investigated in a population-based pharmacoepidemiological study utilizing data from the national healthcare registers and in more detail from a university hospital register in Finland. The main outcome measures were all-cause mortality and mortality and morbidity related to thrombosis or bleeding.
  
  
  RESULTS
  In the nationwide analysis, 6.1%, 1.0%, and 20.8% of the clopidogrel-treated patients were exposed to concomitant use of CYP3A4 inhibitors, CYP3A4 inducers, and atorvastatin, respectively. In the survival analysis, the adjusted hazard ratio for overall mortality was 2.29 (P < 0.001) for CYP3A4 inducer users and 0.74 (P = 0.003) for atorvastatin users compared with controls (patients receiving clopidogrel without interacting medication). CYP3A4 inhibitor use seemed to prevent from thrombosis: HR 0.67, P < 0.001. The hospitalizations due to bleedings were rarer in atorvastatin and CYP3A4 inhibitor groups compared with controls. Thrombosis complications leading to hospitalizations were more often seen in the atorvastatin group than in the control group.
  
  
  CONCLUSIONS
  No uniform untoward effect of concomitant CYP3A4 inhibitor use on the clinical efficacy of clopidogrel was found. In patients receiving concomitant atorvastatin and clopidogrel, the antithrombotic effect of clopidogrel was moderately attenuated, but the combination significantly reduced the overall mortality. CYP3A4 inhibitors and atorvastatin may reduce bleedings in clopidogrel users.
authors.affiliation: Department of Pharmacology, Drug Development and Therapeutics, University of Turku, Turku, Finland; Clinical Pharmacology Unit, Turku University Hospital, Turku, Finland.
authors.forename: Tuire
authors.initials: T
authors.lastname: Tirkkonen
authors.forename: Pekka
authors.initials: P
authors.lastname: Heikkilä
authors.forename: Tero
authors.initials: T
authors.lastname: Vahlberg
authors.forename: Risto
authors.initials: R
authors.lastname: Huupponen
authors.forename: Kari
authors.initials: K
authors.lastname: Laine
mesh_terms: D000368:Aged; D000069059:Atorvastatin; D000077144:Clopidogrel; D051544:Cytochrome P-450 CYP3A / Q000502:physiology*; D065692:Cytochrome P-450 CYP3A Inhibitors; D004347:Drug Interactions; D005260:Female; D006538:Heptanoic Acids / Q000494:pharmacology*; D006801:Humans; D019161:Hydroxymethylglutaryl-CoA Reductase Inhibitors / Q000494:pharmacology*; D008297:Male; D008875:Middle Aged; D010975:Platelet Aggregation Inhibitors / Q000494:pharmacology*; D011758:Pyrroles / Q000494:pharmacology*; D013988:Ticlopidine / Q000031:analogs & derivatives* / Q000494:pharmacology
chemical_list: D065692:Cytochrome P-450 CYP3A Inhibitors; D006538:Heptanoic Acids; D019161:Hydroxymethylglutaryl-CoA Reductase Inhibitors; D010975:Platelet Aggregation Inhibitors; D011758:Pyrroles; D000069059:Atorvastatin; D000077144:Clopidogrel; D051544:Cytochrome P-450 CYP3A; C510163:CYP3A4 protein, human; D013988:Ticlopidine
keywords: Atorvastatin; CYP3A4; Clopidogrel; Drug-drug interaction