title: The potential drug-drug interaction between proton pump inhibitors and warfarin.
abstract: BACKGROUND
  Proton pump inhibitors (PPIs) have been suggested to increase the effect of warfarin, and clinical guidelines recommend careful monitoring of international normalized ratio (INR) when initiating PPI among warfarin users. However, this drug-drug interaction is sparsely investigated in a clinical setting. The aim was to assess whether initiation of PPI treatment among users of warfarin leads to increased INR values.
  
  
  METHODS
  The study was an observational self-controlled study from 1998 to 2012 leveraging data on INR measurements on patients treated with warfarin from primary care and outpatient clinics and their use of prescription drugs. Data were analyzed in 2015. We assessed INR, warfarin dose, and dose/INR ratio before and after initiating PPI treatment using the paired student's t-test.
  
  
  RESULTS
  We identified 305 warfarin users initiating treatment with PPIs. The median age was 71 years (interquartile range 63-78 years), and 64% were men. The mean INR in the 70 days prior to PPI initiation was 2.6 (95%CI 2.5-2.8) and 2.6 (95%CI 2.5-2.7) in the period 1-3 weeks after PPI initiation (p = 0.67). Further, neither mean warfarin dose nor the dose/INR ratios were significantly different before and after PPI initiation. Sensitivity analyses revealed no differences among individual PPIs.
  
  
  CONCLUSIONS
  We found no evidence of a clinically meaningful drug-drug interaction between PPIs and warfarin in a Northern European patient population of unselected patients from an everyday outpatient and primary care clinical setting. Thus, we do not support the recommendation to "cautiously monitor" users of warfarin initiating PPI treatment.
authors.affiliation: Department of Clinical Chemistry and Pharmacology, Odense University Hospital, Odense, Denmark.
authors.forename: Daniel Pilsgaard
authors.identifier: http://orcid.org/0000-0003-1303-6195
authors.initials: DP
authors.lastname: Henriksen
authors.affiliation: Clinical Pharmacology, Department of Public Health, University of Southern Denmark, Odense, Denmark.
authors.forename: Tore Bjerregaard
authors.initials: TB
authors.lastname: Stage
authors.affiliation: Department of Clinical Chemistry and Pharmacology, Odense University Hospital, Odense, Denmark.|Clinical Pharmacology, Department of Public Health, University of Southern Denmark, Odense, Denmark.
authors.forename: Morten Rix
authors.initials: MR
authors.lastname: Hansen
authors.affiliation: Clinical Pharmacology, Department of Public Health, University of Southern Denmark, Odense, Denmark.
authors.forename: Lotte
authors.initials: L
authors.lastname: Rasmussen
authors.affiliation: Department of Clinical Chemistry and Pharmacology, Odense University Hospital, Odense, Denmark.|Clinical Pharmacology, Department of Public Health, University of Southern Denmark, Odense, Denmark.
authors.forename: Per
authors.initials: P
authors.lastname: Damkier
authors.affiliation: Clinical Pharmacology, Department of Public Health, University of Southern Denmark, Odense, Denmark.
authors.forename: Anton
authors.initials: A
authors.lastname: Pottegård
mesh_terms: D000368:Aged; D000925:Anticoagulants / Q000009:adverse effects*; D003718:Denmark / Q000453:epidemiology; D004347:Drug Interactions; D064420:Drug-Related Side Effects and Adverse Reactions / Q000453:epidemiology* / Q000209:etiology; D005260:Female; D006801:Humans; D019934:International Normalized Ratio; D008297:Male; D008875:Middle Aged; D010818:Practice Patterns, Physicians'; D054328:Proton Pump Inhibitors / Q000009:adverse effects*; D014859:Warfarin / Q000009:adverse effects*
chemical_list: D000925:Anticoagulants; D054328:Proton Pump Inhibitors; D014859:Warfarin
keywords: adverse drug reactions; drug interactions; pharmacoepidemiology; proton pump inhibitors; vitamin K antagonists