Application of a pharmacogenetic-based warfarin dosing algorithm derived from British patients to predict dose in Swedish patients

Abstract

To cite this article: Hatch E, Wynne H, Avery P, Wadelius M, Kamali F. Application of a pharmacogenetic-based warfarin dosing algorithm derived from British patients to predict dose in Swedish patients. J Thromb Haemost 2008; 6: 1038-40.The anticoagulation response to warfarin is influenced by a number of genetic and environmental factors. Two major genes affect warfarin dose requirements. The gene that encodes CYP2C9, the main enzyme responsible for S-warfarin metabolism, is highly polymorphic; two common allelic variants, CYP2C9 * 2 and CYP2C9 * 3, have been associated with low dose warfarin requirements and increased risk of bleeding [1]. Vitamin K epoxide reductase (VKOR) is the pharmacological target for warfarin. Polymorphisms in the VKOR complex subunit 1 (VKORC1) gene have been demonstrated to contribute to inter-individual differences in warfarin dose requirement, with (-1639) GG genotype patients requiring a significantly higher daily dose of warfarin than GA and AA genotypes to achieve the same target International Normalized Ratio (INR) [2].We recently demonstrated that the factors of patient age, height, and CYP2C9 and VKORC1 genotypes account for over half the variability in warfarin dose requirement in a cohort of British Caucasian patients [2]. A dosing algorithm was developed based on the regression model containing these factors. In the search for a wider applicability of the dosing algorithm, we set out to test its accuracy in predicting warfarin dose requirements in a cohort of Swedish Caucasian patients. We also examined the influence of concomitant use of drugs known to influence warfarin dose requirement on the accuracy of the predicted dose.Data were obtained on CYP2C9 and VKORC1 polymorphisms, and demographic information relating to an anonymized cohort of Swedish Caucasian patients, with a target INR of 2-3 and with stable maintenance warfarin dose, attending the anticoagulation clinic at Uppsala University Hospital, Uppsala, Sweden. The genotype information on this group of patients was available as part of an earlier study [3,4]. A patient was deemed as stable when his/her daily dose requirement had remained unchanged for at least the previous three visits to the clinic. Warfarin dose requirement for each patient was estimated using the published pharmacogenetic-based dosing algorithm [2].Statistical analysis of data was performed using Minitab 14 (Coventry, UK). Regression analysis between actual and estimated warfarin dose was assessed for the cohort as a whole and for those patients taking no interacting drugs. Concurrent drug use was input in the multiple regression analysis. A P value of <0.05 was considered as statistically significant. Data were analyzed from 88 patients (65 males) on stable warfarin doses aged 48-86 years, with a mean ± SD height of 175.7 ± 77 cm and weight of 81.9 ± 13.8 kg. Eight of the patients were smokers. The primary indication for anticoagulation was atrial fibrillation in 68 patients, pulmonary embolism/deep vein thrombosis in five patients and other t...

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Pharmacogenetic Impact of VKORC1 and CYP2C9 Allelic Variants on Warfarin Dose Requirements in a Hispanic Population Isolate

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