Pharmacogenetic dose adjustments in orthopedic patients beginning warfarin therapy

Excerpt

Warfarin sodium (Coumadin™ and others) is commonly prescribed for the prophylaxis and treatment of venous thromboembolism. Dosing algorithms have not been widely adopted because they often only apply after three warfarin doses, they require a fixed initial warfarin dose (e.g., 5 or 10 mg) and/or because they are not tailored to genetic and clinical factors that influence the International Normalized Ratio (INR). We thus sought to develop a pharmacogenetics dosing algorithm that predicted the therapeutic warfarin dose from factors available after the initial 4 days of therapy. We collected a blood sample for genotyping, clinical variables, current medications, and pre- and post-operative laboratory values from 98 patients undergoing primary or revision total hip or knee replacement. We genotyped for polymorphisms in the cytochrome P450 (CYP) 2C9 and vitamin K epoxide reductase (VKORC1) genes. We used stepwise regression to model the logarithm of the therapeutic dose after four warfarin doses. Most of the variability in therapeutic dose could be explained after 4 days of therapy (R ² = 82.5%) by genetic and clinical factors. INR response after four warfarin doses (INR4) inversely correlated with therapeutic dose (P < 0.001). Intra-operative blood loss transiently, but significantly elevated the post-operative INR values. Other significant (P < 0.02) predictors of therapeutic warfarin dose were the first three doses (+8.6% for the 1st and +15.8% for the average of the 2nd and the 3rd, per 1 mg), CYP2C9*3 and CYP2C9*2 genotype (−32.0% and −12.2%, respectively, per allele), smoking status (+22% in current smokers), and a history of liver disease (−37%). In summary, we developed an algorithm to estimate the therapeutic warfarin dose based on pharmacogenetic and clinical factors (including INR value) available after 4 days of warfarin therapy. We have posted the algorithm to http://​www.​WarfarinDosing.​org. …