Ability of VKORC1 and CYP2C9 to predict therapeutic warfarin dose during the initial weeks of therapy

N. S. Ferder, C. S. Eby, E. Deych, J. K. HARRIS, P. M. Ridker, P. E. Milligan, S. Z. Goldhaber, C. R. King, T. Giri, H. L. Mcleod, R. J. Glynn, B. F. Gage

Research output: Contribution to journalArticlepeer-review

64 Scopus citations

Abstract

Background: CYP2C9 and VKORC1 genotypes predict therapeutic warfarin dose at initiation of therapy; however, the predictive ability of genetic information after a week or longer is unknown. Experts have hypothesized that genotype becomes irrelevant once international normalized ratio (INR) values are available because INR response reflects warfarin sensitivity. Methods: We genotyped the participants in the Prevention of Recurrent Venous Thromboembolism (PREVENT) trial, who had idiopathic venous thromboemboli and began low-intensity warfarin (therapeutic INR 1.5-2.0) using a standard dosing protocol. To develop pharmacogenetic models, we quantified the effect of genotypes, clinical factors, previous doses and INR on therapeutic warfarin dose in the 223 PREVENT participants who were randomized to warfarin and achieved stable therapeutic INRs. Results: A pharmacogenetic model using data from day 0 (before therapy initiation) explained 54% of the variability in therapeutic dose (R2). The R2 increased to 68% at day 7, 75% at day 14, and 77% at day 21, because of increasing contributions from prior doses and INR response. Although CYP2C9 and VKORC1 genotypes were significant independent predictors of therapeutic dose at each weekly interval, the magnitude of their predictive ability diminished over time: partial R2 of genotype was 43% at day 0, 12% at day 7, 4% at day 14, and 1% at day 21. Conclusion: Over the first weeks of warfarin therapy, INR and prior dose become increasingly predictive of therapeutic dose, and genotype becomes less relevant. However, at day 7, genotype remains clinically relevant, accounting for 12% of therapeutic dose variability.

Original languageEnglish
Pages (from-to)95-100
Number of pages6
JournalJournal of Thrombosis and Haemostasis
Volume8
Issue number1
DOIs
StatePublished - Jan 2010

Keywords

  • Cytochrome P450 2C9 gene
  • Pharmacogenetics
  • Vitamin K epoxide reductase complex 1
  • Warfarin

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