Vitamin K antagonists in children with heart disease: height and VKORC1 genotype are the main determinants of the warfarin dose requirement

Blood. 2012 Jan 19;119(3):861-7. doi: 10.1182/blood-2011-07-365502. Epub 2011 Nov 30.

Abstract

Managing vitamin K antagonist (VKA) therapy is challenging in children because of a narrow therapeutic range and wide inter- and intra-individual variability in dose response. Only a few small studies have investigated the effect of nongenetic and genetic factors on the dose response to VKAs in children. In a cohort study including 118 children (median age 9 years; range, 3 months-18 years) mostly with cardiac disease, we evaluated by multivariate analysis the relative contribution of nongenetic factors and VKORC1/CYP2C9/CYP4F2 genotypes on warfarin (n = 83) or fluindione (n = 35) maintenance dose and the influence of these factors on the time spent within/above/below the range. The results showed that height, target international normalized ratio and VKORC1 and CYP2C9 genotypes were the main determinants of warfarin dose requirement, accounting for 48.1%, 4.4%, 18.2%, and 2.0% of variability, respectively, and explaining 69.7% of the variability. Our model predicted the warfarin dose within 7 mg/wk in 86.7% of patients. None of the covariates was associated with the time spent above or below the international normalized ratio range. Whether this model predicts accurately the effective maintenance dose is currently being investigated.

Publication types

  • Research Support, Non-U.S. Gov't

MeSH terms

  • Adolescent
  • Anticoagulants / administration & dosage*
  • Aryl Hydrocarbon Hydroxylases / genetics
  • Body Height / genetics*
  • Child
  • Child, Preschool
  • Cohort Studies
  • Cytochrome P-450 CYP2C9
  • Cytochrome P-450 Enzyme System / genetics
  • Cytochrome P450 Family 4
  • DNA / genetics
  • Dose-Response Relationship, Drug
  • Female
  • Genotype
  • Heart Diseases / drug therapy
  • Heart Diseases / genetics
  • Humans
  • Infant
  • International Normalized Ratio
  • Male
  • Mixed Function Oxygenases / genetics*
  • Models, Statistical
  • Polymerase Chain Reaction
  • Polymorphism, Genetic / genetics*
  • Vitamin K / antagonists & inhibitors*
  • Vitamin K Epoxide Reductases
  • Warfarin / administration & dosage*

Substances

  • Anticoagulants
  • Vitamin K
  • Warfarin
  • DNA
  • Cytochrome P-450 Enzyme System
  • Mixed Function Oxygenases
  • CYP2C9 protein, human
  • Cytochrome P-450 CYP2C9
  • Aryl Hydrocarbon Hydroxylases
  • Cytochrome P450 Family 4
  • CYP4F2 protein, human
  • VKORC1 protein, human
  • Vitamin K Epoxide Reductases