title: Impact of proton pump inhibitor therapy on the efficacy of clopidogrel in the CAPRIE and CREDO trials.
abstract: BACKGROUND
  Proton pump inhibitors (PPIs) may interfere with the metabolic activation of clopidogrel via inhibition of cytochrome P450 2C19, but the clinical implications remain unclear.
  
  
  RESULTS
  The impact of PPI use on the 1-year primary end point (ischemic stroke, myocardial infarction [MI], or vascular death) in the Clopidogrel versus Aspirin in Patients at Risk of Ischemic Events (CAPRIE) trial and the 28-day (all-cause death, MI, or urgent target vessel revascularization) and 1-year (all-cause death, MI, or stroke) primary end points in the Clopidogrel for Reduction of Events During Observation (CREDO) trial were examined. Clopidogrel appeared to elevate risk for the primary end point in CAPRIE among PPI users (estimated hazard ratio [EHR] 2.66, 95% CI 0.94 to 7.50) while lowering it for non-PPI users (EHR 0.90, 95% CI 0.83 to 0.99, interaction P=0.047). Moreover, PPI use was associated with worse outcomes in patients receiving clopidogrel (EHR 2.39, 95% CI 1.74 to 3.28) but not aspirin (EHR 1.04, 95% CI 0.70 to 1.57, interaction P=0.001). Clopidogrel did not significantly alter risk for the 1-year primary end point in CREDO among PPI users (EHR 0.82, 95% CI 0.48 to 1.40) while lowering it for non-PPI users (EHR 0.71, 95% CI 0.52 to 0.98, interaction P=0.682). Also, PPI use was associated with worse outcomes in both patients receiving clopidogrel (EHR 1.67, 95% CI 1.06 to 2.64) and those receiving placebo (EHR 1.56, 95% CI 1.06 to 2.30, interaction P=0.811).
  
  
  CONCLUSIONS
  In CREDO, the efficacy of clopidogrel was not significantly affected by PPI use. However, in CAPRIE, clopidogrel was beneficial to non-PPI users while apparently harmful to PPI users. Whether this negative interaction is clinically important for patients receiving clopidogrel without aspirin needs further study.
authors.affiliation: University of Virginia Health System, Charlottesville, VA 22908-0674, USA. spdunn@virginia.edu
authors.forename: Steven P
authors.initials: SP
authors.lastname: Dunn
authors.forename: Steven R
authors.initials: SR
authors.lastname: Steinhubl
authors.forename: Deborah
authors.initials: D
authors.lastname: Bauer
authors.forename: Richard J
authors.initials: RJ
authors.lastname: Charnigo
authors.forename: Peter B
authors.initials: PB
authors.lastname: Berger
authors.forename: Eric J
authors.initials: EJ
authors.lastname: Topol
mesh_terms: D000368:Aged; D001189:Aryl Hydrocarbon Hydroxylases / Q000037:antagonists & inhibitors* / Q000378:metabolism; D002545:Brain Ischemia / Q000401:mortality / Q000517:prevention & control; D016009:Chi-Square Distribution; D000077144:Clopidogrel; D065731:Cytochrome P-450 CYP2C19; D004347:Drug Interactions; D004791:Enzyme Inhibitors / Q000009:adverse effects / Q000627:therapeutic use*; D005260:Female; D006801:Humans; D008297:Male; D008875:Middle Aged; D009203:Myocardial Infarction / Q000401:mortality / Q000517:prevention & control; D062645:Percutaneous Coronary Intervention / Q000009:adverse effects / Q000401:mortality; D010975:Platelet Aggregation Inhibitors / Q000009:adverse effects / Q000378:metabolism / Q000627:therapeutic use*; D016016:Proportional Hazards Models; D054328:Proton Pump Inhibitors / Q000009:adverse effects / Q000627:therapeutic use*; D016032:Randomized Controlled Trials as Topic; D012189:Retrospective Studies; D018570:Risk Assessment; D012307:Risk Factors; D020521:Stroke / Q000401:mortality / Q000517:prevention & control; D013988:Ticlopidine / Q000009:adverse effects / Q000031:analogs & derivatives* / Q000378:metabolism / Q000627:therapeutic use; D016896:Treatment Outcome
chemical_list: D004791:Enzyme Inhibitors; D010975:Platelet Aggregation Inhibitors; D054328:Proton Pump Inhibitors; D000077144:Clopidogrel; D001189:Aryl Hydrocarbon Hydroxylases; C045793:CYP2C19 protein, human; D065731:Cytochrome P-450 CYP2C19; D013988:Ticlopidine