Working… Menu
Help guide our efforts to modernize
Send us your comments by March 14, 2020.

Genotype-Guided Warfarin Therapy Trial (WARFPGX)

The safety and scientific validity of this study is the responsibility of the study sponsor and investigators. Listing a study does not mean it has been evaluated by the U.S. Federal Government. Read our disclaimer for details. Identifier: NCT00904293
Recruitment Status : Completed
First Posted : May 19, 2009
Last Update Posted : May 6, 2016
UNC Institute for Pharmacogenomics and Individualized Therapy
Information provided by (Responsible Party):
University of North Carolina, Chapel Hill

Brief Summary:
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.

Condition or disease Intervention/treatment Phase
Atrial Fibrillation Deep Vein Thrombosis Pulmonary Embolism Artificial Heart Valve Other: Genotype-guided dose determination Other: Non-genotype guided warfarin dosing Not Applicable

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.

Layout table for study information
Study Type : Interventional  (Clinical Trial)
Actual Enrollment : 109 participants
Allocation: Randomized
Intervention Model: Parallel Assignment
Masking: Double (Participant, Care Provider)
Primary Purpose: Treatment
Official Title: Randomized Controlled Trial of Genotype-Guided Dosing of Warfarin Therapy
Study Start Date : August 2008
Actual Primary Completion Date : January 2012
Actual Study Completion Date : January 2012

Resource links provided by the National Library of Medicine

MedlinePlus related topics: Blood Thinners

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 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.

Primary Outcome Measures :
  1. Time in therapeutic range (TTR) [ Time Frame: 3 months ]
  2. Number of anticoagulation visits [ Time Frame: 3 months ]

Secondary Outcome Measures :
  1. Proportion of INRs > 4 [ Time Frame: 3 months ]
  2. Major bleeding events [ Time Frame: 3 months ]
  3. Minor bleeding events [ Time Frame: 3 months ]
  4. Thromboembolic complications [ Time Frame: 3 months ]
  5. All-cause mortality [ Time Frame: 3 months ]
  6. Time to therapeutic dose [ Time Frame: 3 months ]
  7. Emergency department visits [ Time Frame: 3 months ]
  8. Hospitalizations [ Time Frame: 3 months ]
  9. Costs and cost-effectiveness [ Time Frame: 3 months ]

Information from the National Library of Medicine

Choosing to participate in a study is an important personal decision. Talk with your doctor and family members or friends about deciding to join a study. To learn more about this study, you or your doctor may contact the study research staff using the contacts provided below. For general information, Learn About Clinical Studies.

Layout table for eligibility information
Ages Eligible for Study:   18 Years and older   (Adult, Older Adult)
Sexes Eligible for Study:   All
Accepts Healthy Volunteers:   No

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

Information from the National Library of Medicine

To learn more about this study, you or your doctor may contact the study research staff using the contact information provided by the sponsor.

Please refer to this study by its identifier (NCT number): NCT00904293

Layout table for location information
United States, North Carolina
UNC Hospitals, UNC Anticoagulation Clinic at the Ambulatory Care Center (ACC), UNC Family Medicine Center Anti-coagulation Clinic
Chapel Hill, North Carolina, United States, 27599
Sponsors and Collaborators
University of North Carolina, Chapel Hill
UNC Institute for Pharmacogenomics and Individualized Therapy
Layout table for investigator information
Principal Investigator: Daniel E Jonas, MD, MPH UNC Institute for Pharmacogenomics and Individualized Therapy

Additional Information:
McWilliam A, Lutter R, Nardinelli C. Jointcenter; AEI-Brookings Joint Center For Regulatory Studies. Working Paper 06-23, November 2006
Millican, E., et al. Blood, Epub ahead of print, Mar 26, 2007

Publications automatically indexed to this study by Identifier (NCT Number):
Layout table for additonal information
Responsible Party: University of North Carolina, Chapel Hill Identifier: NCT00904293    
Other Study ID Numbers: 07-1644
First Posted: May 19, 2009    Key Record Dates
Last Update Posted: May 6, 2016
Last Verified: October 2013
Keywords provided by University of North Carolina, Chapel Hill:
genotype-guided therapy
Additional relevant MeSH terms:
Layout table for MeSH terms
Pulmonary Embolism
Atrial Fibrillation
Venous Thrombosis
Arrhythmias, Cardiac
Heart Diseases
Cardiovascular Diseases
Pathologic Processes
Embolism and Thrombosis
Vascular Diseases
Lung Diseases
Respiratory Tract Diseases