title: Doubling the dose of clopidogrel restores the loss of antiplatelet effect induced by esomeprazole.
abstract: BACKGROUND
  Concerns have been raised about the potential adverse interaction between clopidogrel and PPIs. We studied the impact of esomeprazole and ranitidine on the antiplatelet action of clopidogrel and aspirin and sought to determine whether doubling the dose of clopidogrel could restore its efficacy.
  
  
  METHODS
  In a randomized prospective crossover study, we tested platelet reactivity to aspirin and clopidogrel (75 and 150 mg) with and without esomeprazole or ranitidine using the VerifyNow system (Accumetrics Inc, San Diego, CA, USA) in 4 stages, each lasting 7 days: T1, 160 mg aspirin and 75 mg clopidogrel; T2 : 160 mg aspirin+75 mg clopidogrel+20 mg esomeprazole, T3 : 160 mg aspirin+150 mg clopidogrel+20 mg esomeprazole and T4 : 160 mg aspirin+75 mg clopidogrel+150 mg ranitidine. Results are expressed in P2Y12 Reaction Units (PRU%) and Aspirin Reaction Units (ARU).
  
  
  RESULTS
  In 21 patients with stable coronary artery disease, esomeprazole reduced the effect of clopidogrel with a 38.6%±24 loss in PRU% (p<0.001) (absolute mean difference -16.7 PRU% [-21;-12.5]), increasing 8-fold the prevalence of low responders to clopidogrel (defined as patients with PRU% below 20%). Doubling clopidogrel dosage to 150 mg restored the basal response. Ranitidine did not modify the antiplatelet effect of clopidogrel.
  
  
  CONCLUSIONS
  Our study demonstrates a strong negative clopidogrel/esomeprazole interaction, compensated by increasing the dose of clopidogrel to 150 mg or replacing esomeprazole with ranitidine. That could offer a simple solution to the PPI-induced clopidogrel resistance.
authors.affiliation: Cardiology Department, Pasteur Hospital, CHU de Nice, Nice, France. pamela.moceri@free.fr
authors.forename: Pamela
authors.initials: P
authors.lastname: Moceri
authors.forename: Denis
authors.initials: D
authors.lastname: Doyen
authors.forename: Pierre
authors.initials: P
authors.lastname: Cerboni
authors.forename: Emile
authors.initials: E
authors.lastname: Ferrari
mesh_terms: D000368:Aged; D000897:Anti-Ulcer Agents; D001241:Aspirin / Q000008:administration & dosage; D000077144:Clopidogrel; D018592:Cross-Over Studies; D004305:Dose-Response Relationship, Drug; D004334:Drug Administration Schedule; D004347:Drug Interactions; D004359:Drug Therapy, Combination; D064098:Esomeprazole / Q000008:administration & dosage* / Q000494:pharmacology; D005260:Female; D006801:Humans; D008297:Male; D008875:Middle Aged; D010975:Platelet Aggregation Inhibitors; D010979:Platelet Function Tests; D011899:Ranitidine / Q000008:administration & dosage; D013988:Ticlopidine / Q000008:administration & dosage / Q000031:analogs & derivatives* / Q000494:pharmacology
chemical_list: D000897:Anti-Ulcer Agents; D010975:Platelet Aggregation Inhibitors; D011899:Ranitidine; D000077144:Clopidogrel; D064098:Esomeprazole; D013988:Ticlopidine; D001241:Aspirin