title: Bleeding events following concurrent use of warfarin and oseltamivir by Medicare beneficiaries.
abstract: BACKGROUND
  During the 2009 H1N1 influenza pandemic, the UK Medicines and Healthcare Products Regulatory Agency received case reports suggesting a potentiation of warfarin anticoagulation by the antiviral drug oseltamivir. We evaluated this putative interaction using Medicare data.
  
  
  OBJECTIVE
  To determine the frequency of bleeding following addition of oseltamivir or comparator drugs among Medicare beneficiaries taking warfarin.
  
  
  METHODS
  This was a retrospective cohort evaluation using Medicare nationwide data. Cohort members were Medicare Parts A, B, and D beneficiaries from June 30, 2006 to October 31, 2010 receiving warfarin for at least 1 month prior to a concomitant drug of interest (oseltamivir, ampicillin, trimethoprim-sulfamethoxazole (TMP-SMX), and angiotensin-converting enzyme (ACE) inhibitors). Bleeding within 14 days of new prescriptions for oseltamivir or comparators was identified using inpatient or emergency department ICD-9 (International Classification of Diseases, ninth revision) discharge diagnosis codes for gastrointestinal hemorrhage, epistaxis, hematuria, and intracranial bleeding. Patients with bleeding within 30 days preceding the prescription concomitant to warfarin were excluded.
  
  
  RESULTS
  With concomitant ACE inhibitors as reference, adjusted odds ratios (ORs) for any bleeding events within 14 days were 1.47 (95% confidence interval [CI] = 1.08-1.88), 1.24 (95% CI = 0.97-1.57), and 2.74 (95% CI = 2.53-3.03), for warfarin plus ampicillin, oseltamivir, and TMP-SMX, respectively. In a sensitivity analysis, adjusted ORs over a 7-day period were 1.89 (95% CI = 1.29-2.59), 1.47 (95% CI = 1.06-2.02), and 3.07 (95% CI = 2.76-3.49) for warfarin plus ampicillin, oseltamivir, and TMP-SMX, respectively.
  
  
  CONCLUSIONS
  Bleeding with oseltamivir plus warfarin was not significantly increased over a 14-day observation period; a sensitivity analysis showed a statistically significant increase over a 7-day period; in contrast, the data consistently showed the known tendency of TMP-SMX to potentiate the effects of warfarin. The results should be interpreted with the limitations of this approach in mind, including the inability to control for unmeasured confounders.
authors.affiliation: Center for Drug Evaluation and Research, U.S. Food and Drug Administration, Silver Spring, MD, USA.
authors.forename: Andrew D
authors.initials: AD
authors.lastname: Mosholder
authors.forename: Judith A
authors.initials: JA
authors.lastname: Racoosin
authors.forename: Stephanie
authors.initials: S
authors.lastname: Young
authors.forename: Michael
authors.initials: M
authors.lastname: Wernecke
authors.forename: Azadeh
authors.initials: A
authors.lastname: Shoaibi
authors.forename: Thomas E
authors.initials: TE
authors.lastname: MaCurdy
authors.forename: Christopher
authors.initials: C
authors.lastname: Worrall
authors.forename: Jeffrey A
authors.initials: JA
authors.lastname: Kelman
mesh_terms: D000368:Aged; D000369:Aged, 80 and over; D000925:Anticoagulants / Q000008:administration & dosage / Q000009:adverse effects* / Q000627:therapeutic use; D000998:Antiviral Agents / Q000008:administration & dosage / Q000009:adverse effects* / Q000627:therapeutic use; D015331:Cohort Studies; D004347:Drug Interactions; D005260:Female; D006470:Hemorrhage / Q000139:chemically induced* / Q000175:diagnosis / Q000453:epidemiology; D006801:Humans; D007251:Influenza, Human / Q000097:blood / Q000150:complications / Q000188:drug therapy* / Q000453:epidemiology; D038801:International Classification of Diseases; D016015:Logistic Models; D008297:Male; D006278:Medicare; D008875:Middle Aged; D015999:Multivariate Analysis; D053139:Oseltamivir / Q000008:administration & dosage / Q000009:adverse effects* / Q000627:therapeutic use; D058873:Pandemics; D012189:Retrospective Studies; D014481:United States; D014859:Warfarin / Q000008:administration & dosage / Q000009:adverse effects* / Q000627:therapeutic use
chemical_list: D000925:Anticoagulants; D000998:Antiviral Agents; D053139:Oseltamivir; D014859:Warfarin
keywords: bleeding; drug–drug interaction; influenza; oseltamivir; warfarin