Prospective dosing of warfarin based on cytochrome P-450 2C9 genotype.
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.
Voora
Deepak
D
Department of Medicine, Washington University School of Medicine, St. Louis, MO 63110, USA.
Eby
Charles
C
Linder
Mark W
MW
Milligan
Paul E
PE
Bukaveckas
Bonny L
BL
McLeod
Howard L
HL
Maloney
William
W
Clohisy
John
J
Burnett
R Steven
RS
Grosso
Leonard
L
Gatchel
Susan K
SK
Gage
Brian F
BF
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
D014859:Warfarin; C450260:CYP2C9 protein, human; D065729:Cytochrome P-450 CYP2C9; D001189:Aryl Hydrocarbon Hydroxylases