Assessing the Clinical Benefits of a Pharmacogenetics-Guided Dosing Regiment for Calculating Warfarin Maintenance Dose

Study Overview
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Brief Summary
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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.

Detailed Description
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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.

Official Title
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A Randomized Controlled Trial to Assess the Clinical Benefits of a Pharmacogenetics-Guided Dosing Regimen for Calculating Warfarin Maintenance Dose

Conditions
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Indications for Warfarin Therapy

Intervention / Treatment
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* Drug: Warfarin Sodium


Participation Criteria
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Eligibility Criteria
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Inclusion Criteria: At least 18 years of age New indication for warfarin therapy No previous history of liver disease; transaminases must be less than 3 times upper limit of normal and bilirubin within normal range No previous history of malabsorption syndrome or chronic diarrheal conditions Written, informed consent Exclusion Criteria: Uncontrolled hypertension Peptic ulcer disease Any other medical conditions as deemed unfit for warfarin therapy based on clinical judgement of primary physician

Ages Eligible for Study
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Minimum Age: 18 Years

Sexes Eligible for Study
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All

Accepts Healthy Volunteers
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No

Study Plan
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How is the study designed?
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Design Details

Primary Purpose: Treatment
Allocation: Randomized
Intervention Model: Parallel Assignment
Masking: None (Open Label)


Arms and Interventions

| Participant Group/Arm | Intervention/Treatment |
| --- | --- |
| Experimental: Pharmacogenetics-guided dosing group<br>For patients randomized to the pharmacogenetics-guided dosing group, this 10mls of blood will be immediately sent for genotyping studies. Genotyping results will be available for pharmacogenetics-guided dosing within 3 working days, (ranging 3 to 5 days). During this period, if patients need to be initiated on anticoagulation, a low molecular weight heparin, Fraxiparine, will be given. Fraxiparine will be overlapped with warfarin for 2 to 3 days until target INR is achieved. Elective cases should have the pharmacogenetics-based warfarin dose available at the time of warfarin therapy. | Drug: Warfarin Sodium<br>* All predicted warfarin dose will be administered by rounding down to the nearest 0.5 mg. Warfarin (Marevan®) is available as 1mg (brown), 3 mg (blue) and 5 mg (pink) oral tablets from GlaxoSmithKline Pte. Ltd.<br>* Other names: Warfarin (Marevan®);|
| Experimental: Traditional dosing group<br>For patients randomized to the traditional dosing regime, the blood will be stored and genotyped retrospectively at the end of the study. Overlapping of warfarin with Fraxiparine or heparin till target INR is achieved is allowed for this group as per normal clinical practice. All warfarin dosage adjustments based on INR results will be according to the current protocol used by the NUH Anticoagulant Clinic. | Drug: Warfarin Sodium<br>* All predicted warfarin dose will be administered by rounding down to the nearest 0.5 mg. Warfarin (Marevan®) is available as 1mg (brown), 3 mg (blue) and 5 mg (pink) oral tablets from GlaxoSmithKline Pte. Ltd.<br>* Other names: Warfarin (Marevan®);|

What is the study measuring?
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Primary Outcome Measures

| Outcome Measure | Measure Description | Time Frame |
| --- | --- | --- |
| No. of dosage titrations required to achieve targeted INR at 3 months of initializing warfarin. | 1. Number of dosage titrations/adjustments required to achieve targeted International Normalized Ratio (INR) at 3 months of initializing warfarin. The number of titrations refers to the number of times warfarin dosage was adjusted when INR was out of target range (>1.9 and ≤ 3.1) or in response to an adverse event or therapeutic failure. This endpoint will be compiled every 4 weeks, up to 3 months after the initialization of warfarin therapy | 3 months | 

Secondary Outcome Measures

| Outcome Measure | Measure Description | Time Frame |
| --- | --- | --- |
| pharmacokinetics of warfarin R- and S-enantiomers | Upon reaching steady-state, pharmacokinetics of warfarin R- and S-enantiomers will be determined for correlation with dose requirements and genotypes based on a single 5ml blood sample taken after achieving target INR without a change in dose for at least 3 months. Warfarin concentrations will be measured using a validated method through a high-performance liquid chromatography (HPLC) method modified from Henne et al. | 3 months |