title: Prospective dosing of warfarin based on cytochrome P-450 2C9 genotype.
abstract: Cytochrome P-450 2C9 (CYP2C9) polymorphisms (CYP2C9*2 and CYP2C9*3) reduce the clearance of warfarin, increase the risk of bleeding, and prolong the time to stable dosing. Whether prospective use of a retrospectively developed algorithm that incorporates CYP2C9 genotype and nongenetic factors can ameliorate the propensity to bleeding and delay in achieving a stable warfarin dose is unknown. We initiated warfarin therapy in 48 orthopedic patients tailored to the following variables: CYP2C9 genotype, age, weight, height, gender, race, and use of simvastatin or amiodarone. By using pharmacogenetics-based dosing, patients with a CYP2C9 variant achieved a stable, therapeutic warfarin dose without excessive delay. However compared to those without a CYP2C9 variant, patients with a variant continued to be at increased risk (hazard ratio 3.6, 95% confidence interval 1.4-9.5, p = 0.01) for an adverse outcome (principally INR > 4), despite pharmacogenetics-based dosing. There was a linear relationship (R(2) = 0.42, p < 0.001) between the pharmacogenetics-predicted warfarin doses and the warfarin maintenance doses, prospectively validating the dosing algorithm. Prospective, perioperative pharmacogenetics-based dosing of warfarin is feasible; however, further evaluation in a randomized, controlled study is recommended.
authors.affiliation: Department of Medicine, Washington University School of Medicine, St. Louis, MO 63110, USA.
authors.forename: Deepak
authors.initials: D
authors.lastname: Voora
authors.forename: Charles
authors.initials: C
authors.lastname: Eby
authors.forename: Mark W
authors.initials: MW
authors.lastname: Linder
authors.forename: Paul E
authors.initials: PE
authors.lastname: Milligan
authors.forename: Bonny L
authors.initials: BL
authors.lastname: Bukaveckas
authors.forename: Howard L
authors.initials: HL
authors.lastname: McLeod
authors.forename: William
authors.initials: W
authors.lastname: Maloney
authors.forename: John
authors.initials: J
authors.lastname: Clohisy
authors.forename: R Steven
authors.initials: RS
authors.lastname: Burnett
authors.forename: Leonard
authors.initials: L
authors.lastname: Grosso
authors.forename: Susan K
authors.initials: SK
authors.lastname: Gatchel
authors.forename: Brian F
authors.initials: BF
authors.lastname: Gage
mesh_terms: D000328:Adult; D000368:Aged; D000465:Algorithms; D019643:Arthroplasty, Replacement / Q000009:adverse effects; D001189:Aryl Hydrocarbon Hydroxylases / Q000235:genetics*; D065729:Cytochrome P-450 CYP2C9; D005260:Female; D014644:Genetic Variation; D005838:Genotype; D006470:Hemorrhage / Q000139:chemically induced; D006801:Humans; D019934:International Normalized Ratio; D008297:Male; D008875:Middle Aged; D019990:Perioperative Care; D010597:Pharmacogenetics / Q000379:methods*; D011237:Predictive Value of Tests; D011446:Prospective Studies; D013997:Time Factors; D014859:Warfarin / Q000008:administration & dosage* / Q000493:pharmacokinetics
chemical_list: D014859:Warfarin; C450260:CYP2C9 protein, human; D065729:Cytochrome P-450 CYP2C9; D001189:Aryl Hydrocarbon Hydroxylases