Summary

Cytochrome P-450 2C9 (CYP2C9) polymorphisms (CYP2C9*2and CYP2C9*3) reduce the clearance of warfarin, increase therisk of bleeding, and prolong the time to stable dosing.Whetherprospective use of a retrospectively developed algorithm thatincorporates CYP2C9 genotype and nongenetic factors canameliorate the propensity to bleeding and delay in achieving astable warfarin dose is unknown.We initiated warfarin therapyin 48 orthopedic patients tailored to the following variables:CYP2C9 genotype, age, weight, height, gender, race, and use ofsimvastatin or amiodarone. By using pharmacogenetics-baseddosing, patients with a CYP2C9 variant achieved a stable, thera- peutic warfarin dose without excessive delay. However comparedto those without a CYP2C9 variant, patients with a variantcontinued to be at increased risk (hazard ratio 3.6, 95% confidenceinterval 1.4–9.5, p = 0.01) for an adverse outcome (principallyINR > 4), despite pharmacogenetics-based dosing.Therewas a linear relationship (R2 = 0.42,p < 0.001) between the pharmacogenetics-predicted warfarin doses and the warfarin maintenancedoses, prospectively validating the dosing algorithm.Prospective, perioperative pharmacogenetics-based dosing ofwarfarin is feasible; however, further evaluation in a randomized,controlled study is recommended.