Genotype-Guided Warfarin Therapy Trial (WARFPGX)

May 5, 2016 updated by: University of North Carolina, Chapel Hill

Randomized Controlled Trial of Genotype-Guided Dosing of Warfarin Therapy

The purpose of the investigators' study is to determine the clinical utility of a warfarin-dosing algorithm that incorporates genetic information (VKORC1 and CYP2C9 alleles) for adult patients initiating warfarin therapy.

Study Overview

Status

Completed

Conditions

Intervention / Treatment

Detailed Description

Almost 20 million prescriptions are written for warfarin each year in the US and yet it is one of the most problematic drugs in the modern medical formulary. Warfarin has a narrow therapeutic window and the hemorrhagic or thrombotic implications of modest over- or under-dosing can be devastating. Warfarin is one of the leading causes of emergency department visits and hospitalizations due to adverse drug events worldwide. Adverse events from warfarin are more common during the initial months of treatment before the optimal dose is determined. Moreover, there is substantial individual variation in response to warfarin necessitating frequent monitoring and dosage adjustments. The monitoring and dosing of warfarin is so problematic that many primary care physicians have abdicated this role to specialized "warfarin clinics" which are devoted solely to following patients on this agent. Unfortunately, no good alternatives to warfarin exist for the common indications requiring chronic anticoagulation such as atrial fibrillation, deep vein thrombosis, pulmonary embolism, and artificial heart valves.

Pharmacogenomics offers substantial hope for improved care of patients taking warfarin. One group estimated that formally integrating genetic testing into routine warfarin therapy in the US could result in the avoidance of 85,000 serious bleeding events and 17,000 strokes annually with a cost savings of over $1 billion annually. Common single nucleotide polymorphisms (SNPs) in the gene encoding Vitamin K Epoxide Reductase (VKOR) substantially affect one's sensitivity to warfarin, mediating a doubling or halving of the dose required for optimal anticoagulation. Warfarin inhibits clotting by inhibiting the enzyme VKOR, and thus inhibiting vitamin K dependent clotting factors. A number of recent retrospective studies have shown that polymorphisms in the VKOR gene may account for 20-30% of the variance in warfarin dose seen in patients on stable, long-term warfarin therapy.

Another genetic determinant of variance in warfarin dose is the cytochrome p450 2C9 enzyme CYP2C9. It is almost wholly responsible for metabolism of the more active S-enantiomer of warfarin. The 2C9*2 and 2C9*3 polymorphisms in the CYP2C9 gene are associated with reduced warfarin metabolism, and a number of retrospective studies have shown that these polymorphisms may account for 10-15% of the variance in warfarin dosage in patients on stable, long-term warfarin therapy. In addition, the variant CYP2C9 alleles have been associated with longer times to stabilization of INR and a higher risk for bleeding events. These polymorphisms are seen in ~20-30% of the Caucasian population, but are rare in African Americans and Asians. Together, known VKOR and CYP2C9 variants may account for 40% of the variability in warfarin dosing.

By combining clinical information such as weight, height, and concomitant medications with VKOR and CYP2C9 genotypic information, several algorithms have been devised that calculate warfarin doses. These algorithms have been shown to accurately predict warfarin doses in retrospective studies of patients already on long-term stable warfarin doses. Some small, pilot studies in orthopedic patients suggest that prospective genetic-based dosing is feasible and may result in achieving stable doses sooner in patients with certain genetic variants. However, the prospective studies are small, pilot studies limited to orthopedic patients that did not include medical patients with common indications requiring chronic oral anticoagulation. They are also limited by study designs that include only historical controls. No RCTs have been reported in the literature and further evaluation is needed to determine the utility and cost-effectiveness of genetic-based algorithms. The NHLBI is planning a double-blind, randomized three-arm trial, but the trial will not begin enrolling subjects until 2008 at the earliest and data analysis and dissemination is planned to begin beyond 2011.

Study Type

Interventional

Enrollment (Actual)

109

Phase

  • Not Applicable

Contacts and Locations

This section provides the contact details for those conducting the study, and information on where this study is being conducted.

Study Locations

  • United States
    • North Carolina
      • Chapel Hill, North Carolina, United States, 27599
        • UNC Hospitals, UNC Anticoagulation Clinic at the Ambulatory Care Center (ACC), UNC Family Medicine Center Anti-coagulation Clinic

Participation Criteria

Researchers look for people who fit a certain description, called eligibility criteria. Some examples of these criteria are a person's general health condition or prior treatments.

Eligibility Criteria

Ages Eligible for Study

18 years and older (Adult, Older Adult)

Accepts Healthy Volunteers

No

Genders Eligible for Study

All

Description

Inclusion Criteria:

  • Adults ≥18 years old
  • Patients who are beginning warfarin for a variety of diseases or conditions that require long-term oral anticoagulation with target INR > 2.0 for at least 3 months
  • Subjects that will be following up in UNC anticoagulation clinics at the Ambulatory Care Center or the Family Medicine Center

Exclusion Criteria:

  • Patients who are unable to complete the study materials (questionnaires) with or without assistance (for example, those with dementia)
  • Non-English speaking patients
  • Patients who are being started on anticoagulation intended to last < 3 months or whose target INR is < 2.0
  • Patients who have a history of treatment with warfarin and a known dose requirement will be excluded (as they should be restarted on the previous dose)
  • Pregnant women will be excluded because warfarin is a teratogen and pregnant women should not take the medication
  • Patients will also be excluded if their treating physician does not agree to use the recommended INR dose or feels that the patient should not be enrolled in the study

Study Plan

This section provides details of the study plan, including how the study is designed and what the study is measuring.

How is the study designed?

Design Details

  • Primary Purpose: Treatment
  • Allocation: Randomized
  • Interventional Model: Parallel Assignment
  • Masking: Double

Arms and Interventions

Participant Group / Arm
Intervention / Treatment
Experimental: Genotype-guided warfarin dosing
A dosing algorithm including clinical factors and genotype information (VKORC1 and CYP2C9) will be used to determine initial warfarin doses.
Other: Genotype-guided dose determination
Patients in both arms will be treated with warfarin. Those in the experimental group will have initial doses determined using an algorithm (from www.warfarindosing.org) incorporating genetic and clinical factors. Those in the control group will have doses determined using the same algorithm, but without including the genetic factors.
Active Comparator: Non-genotype guided warfarin dosing
Initial warfarin dosing will be determined using the same algorithm as in the experimental group, but only including the clinical factors and not including the genotype information
Other: Non-genotype guided warfarin dosing
Those in the control group will have doses determined using the same algorithm, but without including the genetic factors.

What is the study measuring?

Primary Outcome Measures

Outcome Measure
Time Frame
Time in therapeutic range (TTR)
Time Frame: 3 months
3 months
Number of anticoagulation visits
Time Frame: 3 months
3 months

Secondary Outcome Measures

Outcome Measure
Time Frame
All-cause mortality
Time Frame: 3 months
3 months
Proportion of INRs > 4
Time Frame: 3 months
3 months
Major bleeding events
Time Frame: 3 months
3 months
Minor bleeding events
Time Frame: 3 months
3 months
Thromboembolic complications
Time Frame: 3 months
3 months
Time to therapeutic dose
Time Frame: 3 months
3 months
Emergency department visits
Time Frame: 3 months
3 months
Hospitalizations
Time Frame: 3 months
3 months
Costs and cost-effectiveness
Time Frame: 3 months
3 months

Collaborators and Investigators

This is where you will find people and organizations involved with this study.

Sponsor

University of North Carolina, Chapel Hill

Collaborators

UNC Institute for Pharmacogenomics and Individualized Therapy

Investigators

  • Principal Investigator: Daniel E Jonas, MD, MPH, UNC Institute for Pharmacogenomics and Individualized Therapy

Publications and helpful links

The person responsible for entering information about the study voluntarily provides these publications. These may be about anything related to the study.

General Publications

Study record dates

These dates track the progress of study record and summary results submissions to ClinicalTrials.gov. Study records and reported results are reviewed by the National Library of Medicine (NLM) to make sure they meet specific quality control standards before being posted on the public website.

Study Major Dates

Study Start

August 1, 2008

Primary Completion (Actual)

January 1, 2012

Study Completion (Actual)

January 1, 2012

Study Registration Dates

First Submitted

April 6, 2009

First Submitted That Met QC Criteria

May 18, 2009

First Posted (Estimate)

May 19, 2009

Study Record Updates

Last Update Posted (Estimate)

May 6, 2016

Last Update Submitted That Met QC Criteria

May 5, 2016

Last Verified

October 1, 2013

More Information

Terms related to this study

Keywords

Additional Relevant MeSH Terms

Other Study ID Numbers

  • 07-1644

This information was retrieved directly from the website clinicaltrials.gov without any changes. If you have any requests to change, remove or update your study details, please contact register@clinicaltrials.gov. As soon as a change is implemented on clinicaltrials.gov, this will be updated automatically on our website as well.

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