title: Gastrointestinal bleeding and intracranial hemorrhage in concomitant users of warfarin and antihyperlipidemics.
abstract: BACKGROUND
  Drug interactions, particularly those involving warfarin, are a major clinical and public health problem. Minimizing serious bleeding caused by anticoagulants is a recent major focus of the United States (US) Department of Health and Human Services. This study quantified the risk of gastrointestinal bleeding (GIB) and intracranial hemorrhage (ICH) among concomitant users of warfarin and individual antihyperlipidemics.
  
  
  METHODS
  The authors conducted a high-dimensional propensity score-adjusted cohort study of new concomitant users of warfarin and an antihyperlipidemic, among US Medicaid beneficiaries from five states during 1999-2011. Exposure was defined by concomitant use of warfarin plus one of eight antihyperlipidemics. The primary outcome measure was a composite of GIB/ICH within the first 30days of concomitant use. As a secondary outcome measure, GIB/ICH was examined within the first 180days of concomitant use.
  
  
  RESULTS
  Among 236,691 persons newly-exposed to warfarin and an antihyperlipidemic, the crude incidence of GIB/ICH was 13.2 (95% confidence interval 12.7 to 13.8) per 100person-years. Users were predominantly older, female, and Caucasian. Adjusted hazard ratios (aHRs) for warfarin and individual statins were consistent with no association. Warfarin+gemfibrozil was associated with an 80% increased risk of GIB/ICH within the first month of concomitant use (aHR=1.8, 1.4 to 2.4). Warfarin+fenofibrate was associated with a similar increased risk (aHR=1.8, 1.2 to 2.7), yet with an onset during the second month of concomitant use.
  
  
  CONCLUSIONS
  Among warfarin-treated persons, the use of fibrates-but not statins-increases the risk of hospital presentation for GIB/ICH.
authors.affiliation: Center for Clinical Epidemiology and Biostatistics, Department of Biostatistics and Epidemiology, Perelman School of Medicine at the University of Pennsylvania, Philadelphia, PA, USA; Center for Pharmacoepidemiology Research and Training, Department of Biostatistics and Epidemiology, Perelman School of Medicine at the University of Pennsylvania, Philadelphia, PA, USA. Electronic address: celeonar@mail.med.upenn.edu.
authors.forename: Charles E
authors.initials: CE
authors.lastname: Leonard
authors.affiliation: Center for Clinical Epidemiology and Biostatistics, Department of Biostatistics and Epidemiology, Perelman School of Medicine at the University of Pennsylvania, Philadelphia, PA, USA. Electronic address: cbrensin@mail.med.upenn.edu.
authors.forename: Colleen M
authors.initials: CM
authors.lastname: Brensinger
authors.affiliation: Center for Clinical Epidemiology and Biostatistics, Department of Biostatistics and Epidemiology, Perelman School of Medicine at the University of Pennsylvania, Philadelphia, PA, USA; Center for Pharmacoepidemiology Research and Training, Department of Biostatistics and Epidemiology, Perelman School of Medicine at the University of Pennsylvania, Philadelphia, PA, USA; Department of Psychiatry, Perelman School of Medicine at the University of Pennsylvania, Philadelphia, PA, USA. Electronic address: warren@upenn.edu.
authors.forename: Warren B
authors.initials: WB
authors.lastname: Bilker
authors.affiliation: Center for Clinical Epidemiology and Biostatistics, Department of Biostatistics and Epidemiology, Perelman School of Medicine at the University of Pennsylvania, Philadelphia, PA, USA; Center for Pharmacoepidemiology Research and Training, Department of Biostatistics and Epidemiology, Perelman School of Medicine at the University of Pennsylvania, Philadelphia, PA, USA; Department of Medicine, Division of Cardiovascular Medicine, Perelman School of Medicine at the University of Pennsylvania, Philadelphia, PA, USA. Electronic address: stevek@mail.med.upenn.edu.
authors.forename: Stephen E
authors.initials: SE
authors.lastname: Kimmel
authors.affiliation: Center for Clinical Epidemiology and Biostatistics, Department of Biostatistics and Epidemiology, Perelman School of Medicine at the University of Pennsylvania, Philadelphia, PA, USA; Center for Pharmacoepidemiology Research and Training, Department of Biostatistics and Epidemiology, Perelman School of Medicine at the University of Pennsylvania, Philadelphia, PA, USA. Electronic address: hanxu1@mail.med.upenn.edu.
authors.forename: Xu
authors.initials: X
authors.lastname: Han
authors.affiliation: Center for Clinical Epidemiology and Biostatistics, Department of Biostatistics and Epidemiology, Perelman School of Medicine at the University of Pennsylvania, Philadelphia, PA, USA; Center for Pharmacoepidemiology Research and Training, Department of Biostatistics and Epidemiology, Perelman School of Medicine at the University of Pennsylvania, Philadelphia, PA, USA. Electronic address: ynam@mail.med.upenn.edu.
authors.forename: Young Hee
authors.initials: YH
authors.lastname: Nam
authors.affiliation: Division of Pharmacoepidemiology and Pharmacoeconomics, Department of Medicine, Brigham and Women's Hospital and Harvard Medical School, Boston, MA, USA. Electronic address: jgagne1@partners.org.
authors.forename: Joshua J
authors.initials: JJ
authors.lastname: Gagne
authors.affiliation: Center for Clinical Epidemiology and Biostatistics, Department of Biostatistics and Epidemiology, Perelman School of Medicine at the University of Pennsylvania, Philadelphia, PA, USA; Center for Pharmacoepidemiology Research and Training, Department of Biostatistics and Epidemiology, Perelman School of Medicine at the University of Pennsylvania, Philadelphia, PA, USA. Electronic address: mmanga@mail.med.upenn.edu.
authors.forename: Margaret J
authors.initials: MJ
authors.lastname: Mangaali
authors.affiliation: Center for Clinical Epidemiology and Biostatistics, Department of Biostatistics and Epidemiology, Perelman School of Medicine at the University of Pennsylvania, Philadelphia, PA, USA; Center for Pharmacoepidemiology Research and Training, Department of Biostatistics and Epidemiology, Perelman School of Medicine at the University of Pennsylvania, Philadelphia, PA, USA; Department of Systems Pharmacology and Translational Therapeutics, Perelman School of Medicine at the University of Pennsylvania, Philadelphia, PA, USA. Electronic address: hennessy@upenn.edu.
authors.forename: Sean
authors.initials: S
authors.lastname: Hennessy
mesh_terms: D000368:Aged; D000925:Anticoagulants / Q000627:therapeutic use*; D015331:Cohort Studies; D004359:Drug Therapy, Combination; D005260:Female; D006471:Gastrointestinal Hemorrhage / Q000453:epidemiology*; D006801:Humans; D000960:Hypolipidemic Agents / Q000627:therapeutic use*; D015994:Incidence; D007342:Insurance Benefits; D020300:Intracranial Hemorrhages / Q000453:epidemiology*; D008297:Male; D006278:Medicare; D008875:Middle Aged; D057216:Propensity Score; D014481:United States; D014859:Warfarin / Q000627:therapeutic use*
chemical_list: D000925:Anticoagulants; D000960:Hypolipidemic Agents; D014859:Warfarin
keywords: Cohort studies; Drug interactions; Hemorrhage; Medicaid; Pharmacoepidemiology; Warfarin