Pharmacogenetics and other factors in individualization of oral anti-vitamine k anti-coagulants

Abstract

The use of vitamin K antagonists (VKA) is challenging because of their narrow therapeutic index and a large interindividual variability. Pauci data were available regarding the relative contribution of pharmacogenetic and nongenetic factors to VKA response in specific populations (elderly, children, resistant patients). In 2 cohorts of elderly patients receiving warfarin (n = 300) or fluindione (n = 156), genetic factors were the main determinants of the maintenance dose, explaining ~20% of the variability versus ~10% for nongenetic factors. The variables significantly associated with the maintenance dose were VKORC1/CYP2C9/CYP4F2/EPHX1 and age for warfarin, and VKORC1/ABCB/CYP4F2, weight, and amiodarone intake for fluindione by multivariate analysis. During warfarin initiation, VKORC1 genotype had a strong predictive value for warfarin sensitivity. When building prediction models of the warfarin dose, VKORC1/CYP2C9 were the best predictors before initiation, whereas their contribution was negligible once INR value was available after starting warfarin using a standardized regimen. In the children cohort (n = 120), height and VKORC1/CYP2C9 were the main determinants of warfarin dose requirement, explaining 70% of the variability accounting for 48% and 20%, respectively. Among the 100 patients resistant referred to us for analysis, only 30 patients were carriers of VKORC1 mutations for which in vitro functional characterization was performed. Our results suggest the involvement of other genetic factors in VKA resistance. Pharmacogenetics will help the development of personalized medicine to improve safety and efficacy during VKA treatment. Whether genetic testing improves long-term anticoagulation control in patients receiving VKA and prone to instability remains to be determined. None declared.