Pharmacogentic factors affecting INR control during warfarin initiation

Excerpt

Background Empiric warfarin-dosing algorithms start with a standard dose followed by modifications based on the INR until achieving the target range. Age, ethnicity, and allelelic variations in CYP2C9 and VKORC1 genes can significantly change the warfarin dose needed to maintain therapeutic anticoagulation. However, if an empiric dosing algorithm can compensate for genetic factors that affect therapeutic warfarin dose, then genetic testing for these variants is unnecessary. Methods We thus measured the effect of CYP2C9 and VKORC1 genotype on the performance of the warfarin-dosing algorithm used in 508 eligible subjects in the Prevention of Recurrent Venous Thromboembolism (PREVENT) trial. Prior to randomization to receive warfarin or placebo, eligible patients participated in a 28-day open-label run-in phase designed to ensure that all participants could have their dose of warfarin titrated to a stable INR level between 1.5 and 2.0. Patients were started with 3 mg of warfarin and subsequently had 4 or 5 follow up visits (3–7 days apart) to evaluate the INR and titrate warfarin dose. Results Using linear interpolation, we computed the time above and below the target INR range (1.5–2.0) for 7–28 days. Most of the patients (87%) were white and all had a history of venous thromboembolism. MANOVA (multivariate analysis of variance) indicated a significant association between the VKORC1 and CYP2C9 genotype with percent of INR values above and below the target INR (1.5–2.0) on days 7–28 of warfarin. Further, a stepwise regression was performed to determine which of the genetic and demographic variables were associated with % time spent above and below the target INR. Independent predictors of time above were CYP2C9*3 allele and VKORC1 haplotype, while for time below were wild type CYP2C9 allele, younger age, and VKORC1 haplotype group B. Conclusions CYP2C9 and VKORC1 genotype correlated strongly with the INR values on days 7–28 of warfarin therapy, suggesting that pharmacogenetic-testing may be useful even if results are not available when warfarin is initiated. CYP2C9*3 appears useful not only for estimating the initial warfarin dose, but also for identifying patients at risk for elevated INRs during induction. …