Indications for Warfarin Therapy Clinical Trial
Official title:
A Randomized Controlled Trial to Assess the Clinical Benefits of a Pharmacogenetics-Guided Dosing Regimen for Calculating Warfarin Maintenance Dose
Interethnic differences in warfarin dose requirements in the Asian population have been well described. Our previous studies showed that warfarin maintenance doses in our multi-ethnic population were closely related to patient demographics and genetic polymorphisms in cytochrome(CYP)P4502C9 and vitamin K epoxide reductase complex subunit 1(VKORC1). A retrospective regression model combining these predictors accounts for 57.8% of the variability in warfarin dose.
Hypothesis: We hypothesize that warfarin dose requirement could be more accurately predicted
using a simplified genotyping procedure requiring the identification of a single CYP2C9
allele and a single nucleotide polymorphism of VKORC1 to discern between the 2 major
haplotypes H1 and H7.
Aims: The aim is to compare the clinical benefits of genetics-guided dosing versus
traditional trial and error dosing with protocol guided-adjustments. Two secondary
objectives are (1) to prospectively evaluate a dosing algorithm built on demographics and
genetic predictors; (2) to assess the feasibility of a simplified test for CYP2C9*3 and
VKORC1 SNP in clinical practice.
Methodology: A randomized controlled trial targeted at accruing 100 patients with indication
for wafarin therapy. The endpoint for comparing genetics-guided dosing against traditional
dosing method at the anticoagulant clinic is the number of dosage titrations to achieve
targeted International Normalized Ratio (INR) at 1, 2 and 3 months of initializing warfarin.
Upon reaching steady-state, pharmacokinetics of warfarin R- and S-isomers will be assessed
for correlation with dose requirements based. An assay for easy identification of genetic
polymorphisms required in this dosing regimen in a clinic setting will also be validated.
Significance: This concerted, multi-disciplinary effort to bring pharmacogenetics-based
therapy from bench to bedside has the potential to reduce the efforts incurred with multiple
dose titrations of the most commonly prescribed oral anticoagulant. With the aid of
mathematical modeling, a simplified and more cost-effective genotyping method could be
implementation for the future treatment and prophylaxis of thromboembolic diseases.
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Allocation: Randomized, Endpoint Classification: Efficacy Study, Intervention Model: Parallel Assignment, Masking: Open Label, Primary Purpose: Treatment