title: Hemorrhagic and thrombotic events associated with generic substitution of warfarin in patients with atrial fibrillation: a retrospective analysis.
abstract: BACKGROUND
  Substitution of generic warfarin for imprint warfarin (Coumadin; DuPont/Bristol-Myers Squibb) has been a controversial issue due to bioavailability and bioequivalence concerns.
  
  
  OBJECTIVE
  To assess the risk of thrombotic and hemorrhagic events following substitution of warfarin formulations in patients with atrial fibrillation (AF).
  
  
  METHODS
  Historical cohort analysis was performed using a commercial insurance claims database. Adults with a diagnosis of AF between January 2003 and December 2007, with 16 or more months of continuous eligibility, a warfarin prescription within 30 days after index AF diagnosis, and at least 3 warfarin prescription fills during the follow-up period were included. Individuals with AF diagnosis or warfarin prescription during the pre-index period were excluded. Cox proportional hazard regression models controlling for sex and baseline comorbidities (Charlson comorbidity index, CCI) were used to evaluate the risks of thrombotic and hemorrhagic events following warfarin formulation switches.
  
  
  RESULTS
  Of 37,756 subjects included in the analysis (mean age 70.96 years, 42.3% females), 12,996 (34.4%) switched warfarin formulations, 20,292 (53.7%) used only 1 generic product, and 4468 (11.8%) used only Coumadin during follow-up. Compared with continued use of Coumadin, switching from that product to the generic formulation was associated with a significantly higher risk of thrombotic events (HR = 1.81; 95% CI 1.42 to 2.31). Similar findings were observed for switching from generic warfarin to Coumadin (HR = 1.76; 95% CI 1.35 to 2.30), and from 1 generic to another generic product (HR = 1.89; 95% CI 1.57 to 2.29). Similarly, switching from Coumadin to generic warfarin (HR = 1.51; 95% CI 1.17 to 1.93), generic warfarin to Coumadin (HR = 1.60; 95% CI 1.23 to 2.1), and from 1 generic to another generic product (HR = 1.74; 95% CI 1.45 to 2.11) were associated with significantly higher risk of hemorrhage than remaining on Coumadin.
  
  
  CONCLUSIONS
  Switching warfarin formulations exposed patients with AF to a higher risk of bleeding events compared to remaining on a single product. Maintaining patients on a product with consistent bioavailability may optimize the risk-benefit balance of anticoagulation therapy.
authors.affiliation: Department of Pharmacotherapy, University of Utah, Salt Lake City, UT, USA.
authors.forename: Sameer R
authors.initials: SR
authors.lastname: Ghate
authors.forename: Joseph E
authors.initials: JE
authors.lastname: Biskupiak
authors.forename: Xiangyang
authors.initials: X
authors.lastname: Ye
authors.forename: Michael
authors.initials: M
authors.lastname: Hagan
authors.forename: Winghan Jacqueline
authors.initials: WJ
authors.lastname: Kwong
authors.forename: Eben S
authors.initials: ES
authors.lastname: Fox
authors.forename: Diana I
authors.initials: DI
authors.lastname: Brixner
mesh_terms: D000368:Aged; D000925:Anticoagulants / Q000008:administration & dosage / Q000009:adverse effects* / Q000493:pharmacokinetics; D001281:Atrial Fibrillation / Q000188:drug therapy; D001682:Biological Availability; D016208:Databases, Factual; D016568:Drugs, Generic / Q000008:administration & dosage / Q000009:adverse effects / Q000493:pharmacokinetics; D005260:Female; D005500:Follow-Up Studies; D006470:Hemorrhage / Q000139:chemically induced*; D006801:Humans; D008297:Male; D008875:Middle Aged; D016016:Proportional Hazards Models; D012189:Retrospective Studies; D012306:Risk; D013810:Therapeutic Equivalency; D013927:Thrombosis / Q000139:chemically induced*; D014859:Warfarin / Q000008:administration & dosage / Q000009:adverse effects* / Q000493:pharmacokinetics
chemical_list: D000925:Anticoagulants; D016568:Drugs, Generic; D014859:Warfarin