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

National University Health System (NUHS)

Status and phase: Unknown; Phase 3

Conditions: Indications for Warfarin Therapy

Treatments: Drug: Warfarin Sodium

Study type: Interventional

Funder types: Other

Identifiers

NCT00700895

PG01/11/06

Details and patient eligibility

About

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.

Full description

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.

Enrollment: 320 estimated patients

Sex: All

Ages: 18+ years old

Volunteers: No Healthy Volunteers

Inclusion criteria

1. At least 18 years of age
2. New indication for warfarin therapy
3. No previous history of liver disease; transaminases must be less than 3 times upper limit of normal and bilirubin within normal range
4. No previous history of malabsorption syndrome or chronic diarrheal conditions
5. Written, informed consent

Exclusion criteria

1. Uncontrolled hypertension
2. Peptic ulcer disease
3. Any other medical conditions as deemed unfit for warfarin therapy based on clinical judgement of primary physician

Trial design

Primary purpose: Treatment

Allocation: Randomized

Interventional model: Parallel Assignment

Masking: None (Open label)

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320 participants in 2 patient groups

Pharmacogenetics-guided dosing group

Experimental group

Description:

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.

Treatment:

Drug: Warfarin Sodium

Traditional dosing group

Experimental group

Description:

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.

Treatment:

Drug: Warfarin Sodium