title: Concomitant use of clopidogrel and statins and risk of major adverse cardiovascular events following coronary stent implantation.
abstract: BACKGROUND
  • The CYP3A4 inhibition by lipophilic statins may attenuate the effectiveness of clopidogrel. • No studies have measured drug exposure in a time-varying manner that detects discontinuation and restart of clopidogrel and statin therapy, allowing clinical quantification of the interaction effect.
  
  
  CONCLUSIONS
  • Clopidogrel and CYP3A4-metabolizing statin use were each associated with a substantially reduced rate of major adverse cardiovascular events within 12 months after coronary stent implantation. • Although we observed an interaction between use of clopidogrel and statins, statin use vs. non-use was not associated with an increased rate of major adverse cardiovascular events in patients using clopidogrel after coronary stent implantation.
  
  
  OBJECTIVE
  To examine whether CYP3A4-metabolizing statin use modified the association between clopidogrel use and major adverse cardiovascular events (MACE) after coronary stent implantation, using time-varying drug exposure ascertainment.
  
  
  METHODS
  We conducted this population-based cohort study in Western Denmark (population: 3 million) using medical databases. We identified all 13 001 patients with coronary stent implantation between 2002 and 2005 and their comorbidities. During 12 months of follow-up, we tracked the use of clopidogrel and CYP3A4-metabolizing statins and the rate of MACE. We used Cox regression to compute hazard ratios (HRs) controlling for potential confounders.
  
  
  RESULTS
  The rate of MACE per 1000 person years was 104 for concomitant clopidogrel and statin use, 130 for clopidogrel without statin use, 108 for statin without clopidogrel use and 446 for no use of either drug. The adjusted HR comparing clopidogrel use with non-use was 0.68 (95% confidence interval (CI) 0.58, 0.79) among statin users and 0.34 (95% CI 0.29, 0.40) among statin non-users, yielding an interaction effect (i.e. relative rate increase) of 1.97 (95% CI 1.59, 2.44). The adjusted HR for MACE comparing statin use with non-use was 0.97 (95% CI 0.83, 1.13) among clopidogrel users and 0.49 (95% CI 0.42, 0.57) among clopidogrel non-users.
  
  
  CONCLUSIONS
  Clopidogrel and CYP3A4-metabolizing statin use were each associated with a substantially reduced rate of MACE within 12 months after coronary stent implantation. Although we observed an interaction between use of clopidogrel and statins, statin use vs. non-use was not associated with an increased rate of MACE in patients using clopidogrel after coronary stent implantation.
authors.affiliation: Department of Clinical Epidemiology, Aarhus University Hospital, Aarhus Department of Cardiology, Aarhus, Denmark. morten.schmidt@dce.au.dk
authors.forename: Morten
authors.initials: M
authors.lastname: Schmidt
authors.forename: Martin B
authors.initials: MB
authors.lastname: Johansen
authors.forename: Michael
authors.initials: M
authors.lastname: Maeng
authors.forename: Anne
authors.initials: A
authors.lastname: Kaltoft
authors.forename: Lisette O
authors.initials: LO
authors.lastname: Jensen
authors.forename: Hans-Henrik
authors.initials: HH
authors.lastname: Tilsted
authors.forename: Hans E
authors.initials: HE
authors.lastname: Bøtker
authors.forename: John A
authors.initials: JA
authors.lastname: Baron
authors.forename: Henrik Toft
authors.initials: HT
authors.lastname: Sørensen
mesh_terms: D000328:Adult; D000368:Aged; D000369:Aged, 80 and over; D002318:Cardiovascular Diseases / Q000453:epidemiology* / Q000517:prevention & control*; D000077144:Clopidogrel; D015331:Cohort Studies; D051544:Cytochrome P-450 CYP3A; D065692:Cytochrome P-450 CYP3A Inhibitors; D003718:Denmark; D004347:Drug Interactions; D005260:Female; D006801:Humans; D019161:Hydroxymethylglutaryl-CoA Reductase Inhibitors / Q000009:adverse effects / Q000627:therapeutic use*; D008297:Male; D008875:Middle Aged; D010975:Platelet Aggregation Inhibitors / Q000009:adverse effects / Q000627:therapeutic use*; D012044:Regression Analysis; D012307:Risk Factors; D015607:Stents; D013988:Ticlopidine / Q000009:adverse effects / Q000031:analogs & derivatives* / Q000627:therapeutic use; D013997:Time Factors
chemical_list: D065692:Cytochrome P-450 CYP3A Inhibitors; D019161:Hydroxymethylglutaryl-CoA Reductase Inhibitors; D010975:Platelet Aggregation Inhibitors; D000077144:Clopidogrel; D051544:Cytochrome P-450 CYP3A; C510163:CYP3A4 protein, human; D013988:Ticlopidine