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Deepak Voora, Charles Eby, Mark W. Linder, Paul E. Milligan, Bonny L. Bukaveckas, Howard L. McLeod, William Maloney, John Clohisy, R. Steven Burnett, Leonard Grosso, Susan K. Gatchel, Brian F. Gage
Prospective dosing of warfarin based on cytochrome P-450 2C9 genotype
Cytochrome P-450 2C9 (CYP2C9) polymorphisms (CYP2C92 and CYP2C93) 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 1.49.5, p = 0.01) for an adverse outcome (principally INR > 4), despite pharmacogenetics-based dosing. There was a linear relationship (R2 = 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.
Thrombosis and Haemostasis, Schattauer
Print ISSN: 0340-6245
Volume: 93, 04/2005
Pages: 700 - 705