title: Use of pharmacogenetic and clinical factors to predict the therapeutic dose of warfarin.
abstract: Initiation of warfarin therapy using trial-and-error dosing is problematic. Our goal was to develop and validate a pharmacogenetic algorithm. In the derivation cohort of 1,015 participants, the independent predictors of therapeutic dose were: VKORC1 polymorphism -1639/3673 G>A (-28% per allele), body surface area (BSA) (+11% per 0.25 m(2)), CYP2C9(*)3 (-33% per allele), CYP2C9(*)2 (-19% per allele), age (-7% per decade), target international normalized ratio (INR) (+11% per 0.5 unit increase), amiodarone use (-22%), smoker status (+10%), race (-9%), and current thrombosis (+7%). This pharmacogenetic equation explained 53-54% of the variability in the warfarin dose in the derivation and validation (N= 292) cohorts. For comparison, a clinical equation explained only 17-22% of the dose variability (P < 0.001). In the validation cohort, we prospectively used the pharmacogenetic-dosing algorithm in patients initiating warfarin therapy, two of whom had a major hemorrhage. To facilitate use of these pharmacogenetic and clinical algorithms, we developed a nonprofit website, http://www.WarfarinDosing.org.
authors.affiliation: Department of Internal Medicine, Washington University School of Medicine, St. Louis, Missouri, USA. bgage@im.wustl.edu
authors.forename: B F
authors.initials: BF
authors.lastname: Gage
authors.forename: C
authors.initials: C
authors.lastname: Eby
authors.forename: J A
authors.initials: JA
authors.lastname: Johnson
authors.forename: E
authors.initials: E
authors.lastname: Deych
authors.forename: M J
authors.initials: MJ
authors.lastname: Rieder
authors.forename: P M
authors.initials: PM
authors.lastname: Ridker
authors.forename: P E
authors.initials: PE
authors.lastname: Milligan
authors.forename: G
authors.initials: G
authors.lastname: Grice
authors.forename: P
authors.initials: P
authors.lastname: Lenzini
authors.forename: A E
authors.initials: AE
authors.lastname: Rettie
authors.forename: C L
authors.initials: CL
authors.lastname: Aquilante
authors.forename: L
authors.initials: L
authors.lastname: Grosso
authors.forename: S
authors.initials: S
authors.lastname: Marsh
authors.forename: T
authors.initials: T
authors.lastname: Langaee
authors.forename: L E
authors.initials: LE
authors.lastname: Farnett
authors.forename: D
authors.initials: D
authors.lastname: Voora
authors.forename: D L
authors.initials: DL
authors.lastname: Veenstra
authors.forename: R J
authors.initials: RJ
authors.lastname: Glynn
authors.forename: A
authors.initials: A
authors.lastname: Barrett
authors.forename: H L
authors.initials: HL
authors.lastname: McLeod
mesh_terms: D000368:Aged; D000465:Algorithms; D000925:Anticoagulants / Q000008:administration & dosage* / Q000009:adverse effects / Q000378:metabolism; D001189:Aryl Hydrocarbon Hydroxylases / Q000235:genetics*; D015331:Cohort Studies; D065729:Cytochrome P-450 CYP2C9; D004305:Dose-Response Relationship, Drug; D005260:Female; D006470:Hemorrhage / Q000139:chemically induced; D006801:Humans; D008297:Male; D008875:Middle Aged; D006899:Mixed Function Oxygenases / Q000235:genetics*; D010597:Pharmacogenetics; D011110:Polymorphism, Genetic; D011237:Predictive Value of Tests; D064417:Vitamin K Epoxide Reductases; D014859:Warfarin / Q000008:administration & dosage* / Q000009:adverse effects / Q000378:metabolism
chemical_list: D000925:Anticoagulants; D014859:Warfarin; D006899:Mixed Function Oxygenases; C450260:CYP2C9 protein, human; D065729:Cytochrome P-450 CYP2C9; D001189:Aryl Hydrocarbon Hydroxylases; C578523:VKORC1 protein, human; D064417:Vitamin K Epoxide Reductases