title: Comparative risk of gastrointestinal bleeding with dabigatran, rivaroxaban, and warfarin: population based cohort study.
abstract: OBJECTIVE
  To determine the real world risk of gastrointestinal bleeding associated with the use of the novel oral anticoagulants dabigatran and rivaroxaban compared with warfarin.
  
  
  METHODS
  Retrospective, propensity matched cohort study.
  
  
  METHODS
  Optum Labs Data Warehouse, a large database including administrative claims data on privately insured and Medicare Advantage enrollees.
  
  
  METHODS
  New users of dabigatran, rivaroxaban, and warfarin from 1 November 2010 to 30 September 2013.
  
  
  METHODS
  Incidence rates (events/100 patient years) and propensity score matched Cox proportional hazards models were used to estimate rates of total gastrointestinal bleeds, upper gastrointestinal bleeds, and lower gastrointestinal bleeds for the novel oral anticoagulants compared with warfarin in patients with and without atrial fibrillation. Heterogeneity of treatment effect related to age was examined using a marginal effects model.
  
  
  RESULTS
  The incidence of gastrointestinal bleeding associated with dabigatran was 2.29 (95% confidence interval 1.88 to 2.79) per 100 patient years and that associated with warfarin was 2.87 (2.41 to 3.41) per 100 patient years in patients with atrial fibrillation. In non-atrial fibrillation patients, the incidence of gastrointestinal bleeding was 4.10 (2.47 to 6.80) per 100 patient years with dabigatran and 3.71 (2.16 to 6.40) per 100 patient years with warfarin. With rivaroxaban, 2.84 (2.30 to 3.52) gastrointestinal bleeding events per 100 patient years occurred in atrial fibrillation patients (warfarin 3.06 (2.49 to 3.77)/100 patient years) and 1.66 (1.23 to 2.24) per 100 patient years in non-atrial fibrillation patients (warfarin 1.57 (1.25 to 1.99)/100 patient years). In propensity score matched models, the risk of gastrointestinal bleeding with novel oral anticoagulants was similar to that with warfarin in atrial fibrillation patients (dabigatran v warfarin, hazard ratio 0.79 (0.61 to 1.03); rivaroxaban v warfarin, 0.93 (0.69 to 1.25)) and in non-AF patients (dabigatran v warfarin, hazard ratio 1.14 (0.54 to 2.39); rivaroxaban v warfarin, 0.89 (0.60 to 1.32)). The risk of gastrointestinal bleeding increased after age 65, such that by age 76 the risk exceeded that with warfarin among atrial fibrillation patients taking dabigatran (hazard ratio 2.49 (1.61 to 3.83)) and patients with and without atrial fibrillation taking rivaroxaban (2.91 (1.65 to 4.81) and 4.58 (2.40 to 8.72), respectively).
  
  
  CONCLUSIONS
  The risk of gastrointestinal bleeding related to novel oral anticoagulants was similar to that for warfarin. Caution should be used when prescribing novel oral anticoagulants to older people, particularly those over 75 years of age.
authors.affiliation: Division of Gastroenterology and Hepatology, Department of Medicine, Mayo Clinic, 13400 East Shea Boulevard, Scottsdale, AZ, 85259, USA Division of Health Care Policy and Research, Department of Health Services Research, Mayo Clinic, Rochester, MN, USA Mayo Clinic Robert D and Patricia E Kern Center for the Science of Health Care Delivery, Rochester, MN, USA abraham.neena@mayo.edu.
authors.forename: Neena S
authors.initials: NS
authors.lastname: Abraham
authors.affiliation: Division of General Internal Medicine, Johns Hopkins School of Medicine, Baltimore, MD, USA Department of Epidemiology, Johns Hopkins Bloomberg School of Public Health and Center for Drug Safety and Effectiveness, Baltimore, MD, USA.
authors.forename: Sonal
authors.initials: S
authors.lastname: Singh
authors.affiliation: Division of General Internal Medicine, Johns Hopkins School of Medicine, Baltimore, MD, USA Department of Epidemiology, Johns Hopkins Bloomberg School of Public Health and Center for Drug Safety and Effectiveness, Baltimore, MD, USA.
authors.forename: G Caleb
authors.initials: GC
authors.lastname: Alexander
authors.affiliation: Mayo Clinic Robert D and Patricia E Kern Center for the Science of Health Care Delivery, Rochester, MN, USA.
authors.forename: Herbert
authors.initials: H
authors.lastname: Heien
authors.affiliation: Mayo Clinic Robert D and Patricia E Kern Center for the Science of Health Care Delivery, Rochester, MN, USA.
authors.forename: Lindsey R
authors.initials: LR
authors.lastname: Haas
authors.affiliation: Optum Labs, Cambridge, MA, USA.
authors.forename: William
authors.initials: W
authors.lastname: Crown
authors.affiliation: Division of Health Care Policy and Research, Department of Health Services Research, Mayo Clinic, Rochester, MN, USA Mayo Clinic Robert D and Patricia E Kern Center for the Science of Health Care Delivery, Rochester, MN, USA.
authors.forename: Nilay D
authors.initials: ND
authors.lastname: Shah
mesh_terms: D000368:Aged; D000369:Aged, 80 and over; D000925:Anticoagulants / Q000008:administration & dosage* / Q000009:adverse effects; D001281:Atrial Fibrillation / Q000188:drug therapy*; D001562:Benzimidazoles / Q000008:administration & dosage* / Q000009:adverse effects; D015331:Cohort Studies; D000069604:Dabigatran; D005260:Female; D006471:Gastrointestinal Hemorrhage / Q000139:chemically induced* / Q000517:prevention & control; D006801:Humans; D015994:Incidence; D008297:Male; D008484:Medicaid / Q000706:statistics & numerical data; D008875:Middle Aged; D009025:Morpholines / Q000008:administration & dosage* / Q000009:adverse effects; D018579:Patient Selection; D010818:Practice Patterns, Physicians'; D016016:Proportional Hazards Models; D012189:Retrospective Studies; D012307:Risk Factors; D000069552:Rivaroxaban; D013876:Thiophenes / Q000008:administration & dosage* / Q000009:adverse effects; D014481:United States / Q000453:epidemiology; D014859:Warfarin / Q000008:administration & dosage* / Q000009:adverse effects; D015091:beta-Alanine / Q000008:administration & dosage / Q000009:adverse effects / Q000031:analogs & derivatives*
chemical_list: D000925:Anticoagulants; D001562:Benzimidazoles; D009025:Morpholines; D013876:Thiophenes; D015091:beta-Alanine; D014859:Warfarin; D000069552:Rivaroxaban; D000069604:Dabigatran