title: Pharmacodynamic effect and clinical efficacy of clopidogrel and prasugrel with or without a proton-pump inhibitor: an analysis of two randomised trials.
abstract: BACKGROUND
  Proton-pump inhibitors (PPIs) are often prescribed in combination with thienopyridines. Conflicting data exist as to whether PPIs diminish the efficacy of clopidogrel. We assessed the association between PPI use, measures of platelet function, and clinical outcomes for patients treated with clopidogrel or prasugrel.
  
  
  METHODS
  In the PRINCIPLE-TIMI 44 trial, the primary outcome was inhibition of platelet aggregation at 6 h assessed by light-transmission aggregometry. In the TRITON-TIMI 38 trial, the primary endpoint was the composite of cardiovascular death, myocardial infarction, or stroke. In both studies, PPI use was at physician's discretion. We used a multivariable Cox model with propensity score to assess the association of PPI use with clinical outcomes.
  
  
  RESULTS
  In the PRINCIPLE-TIMI 44 trial, 201 patients undergoing elective percutaneous coronary intervention were randomly assigned to prasugrel (n=102) or high-dose clopidogrel (n=99). Mean inhibition of platelet aggregation was significantly lower for patients on a PPI than for those not on a PPI at 6 h after a 600 mg clopidogrel loading dose (23.2+/-19.5% vs 35.2+/-20.9%, p=0.02), whereas a more modest difference was seen with and without a PPI after a 60 mg loading dose of prasugrel (69.6+/-13.5% vs 76.7+/-12.4%, p=0.054). In the TRITON-TIMI 38 trial, 13,608 patients with an acute coronary syndrome were randomly assigned to prasugrel (n=6813) or clopidogrel (n=6795). In this study, 33% (n=4529) of patients were on a PPI at randomisation. No association existed between PPI use and risk of the primary endpoint for patients treated with clopidogrel (adjusted hazard ratio [HR] 0.94, 95% CI 0.80-1.11) or prasugrel (1.00, 0.84-1.20).
  
  
  CONCLUSIONS
  The current findings do not support the need to avoid concomitant use of PPIs, when clinically indicated, in patients receiving clopidogrel or prasugrel.
  
  
  BACKGROUND
  Daiichi Sankyo Company Limited and Eli Lilly and Company sponsored the trials. This analysis had no funding.
authors.affiliation: Brigham and Women's Hospital, Boston, MA, USA. Electronic address: modonoghue@partners.org.
authors.forename: Michelle L
authors.initials: ML
authors.lastname: O'Donoghue
authors.affiliation: Brigham and Women's Hospital, Boston, MA, USA.
authors.forename: Eugene
authors.initials: E
authors.lastname: Braunwald
authors.affiliation: Brigham and Women's Hospital, Boston, MA, USA.
authors.forename: Elliott M
authors.initials: EM
authors.lastname: Antman
authors.affiliation: Brigham and Women's Hospital, Boston, MA, USA.
authors.forename: Sabina A
authors.initials: SA
authors.lastname: Murphy
authors.affiliation: University of Michigan, Ann Arbor, MI, USA.
authors.forename: Eric R
authors.initials: ER
authors.lastname: Bates
authors.affiliation: Edith Wolfson Medical Center, Tel-Aviv University, Holon, Israel.
authors.forename: Yoseph
authors.initials: Y
authors.lastname: Rozenman
authors.affiliation: Children's Hospital, Boston, MA, USA.
authors.forename: Alan D
authors.initials: AD
authors.lastname: Michelson
authors.affiliation: Medisch Centrum Alkmaar, Alkmaar, Netherlands.
authors.forename: Raymond W
authors.initials: RW
authors.lastname: Hautvast
authors.affiliation: Northeast Cardiology Associates, Bangor, ME, USA.
authors.forename: Peter N
authors.initials: PN
authors.lastname: Ver Lee
authors.affiliation: Eli Lilly Research Laboratories, Indianapolis, IN, USA.
authors.forename: Sandra L
authors.initials: SL
authors.lastname: Close
authors.affiliation: Eli Lilly Research Laboratories, Indianapolis, IN, USA.
authors.forename: Lei
authors.initials: L
authors.lastname: Shen
authors.affiliation: Brigham and Women's Hospital, Boston, MA, USA.
authors.forename: Jessica L
authors.initials: JL
authors.lastname: Mega
authors.affiliation: Brigham and Women's Hospital, Boston, MA, USA.
authors.forename: Marc S
authors.initials: MS
authors.lastname: Sabatine
authors.affiliation: Brigham and Women's Hospital, Boston, MA, USA.
authors.forename: Stephen D
authors.initials: SD
authors.lastname: Wiviott
mesh_terms: D054058:Acute Coronary Syndrome / Q000188:drug therapy; D000368:Aged; D002318:Cardiovascular Diseases / Q000453:epidemiology / Q000517:prevention & control; D000077144:Clopidogrel; D004347:Drug Interactions; D004359:Drug Therapy, Combination; D005260:Female; D006801:Humans; D053208:Kaplan-Meier Estimate; D016015:Logistic Models; D008297:Male; D008875:Middle Aged; D015999:Multivariate Analysis; D010879:Piperazines / Q000009:adverse effects / Q000627:therapeutic use*; D010974:Platelet Aggregation / Q000187:drug effects; D010975:Platelet Aggregation Inhibitors / Q000009:adverse effects / Q000627:therapeutic use*; D000068799:Prasugrel Hydrochloride; D016016:Proportional Hazards Models; D054328:Proton Pump Inhibitors / Q000009:adverse effects / Q000627:therapeutic use*; D011725:Pyridines / Q000009:adverse effects / Q000627:therapeutic use; D016032:Randomized Controlled Trials as Topic; D012307:Risk Factors; D013876:Thiophenes / Q000009:adverse effects / Q000627:therapeutic use*; D013988:Ticlopidine / Q000009:adverse effects / Q000031:analogs & derivatives* / Q000627:therapeutic use; D016896:Treatment Outcome
chemical_list: D010879:Piperazines; D010975:Platelet Aggregation Inhibitors; D054328:Proton Pump Inhibitors; D011725:Pyridines; D013876:Thiophenes; C446540:thienopyridine; D000077144:Clopidogrel; D000068799:Prasugrel Hydrochloride; D013988:Ticlopidine