Genotype-Guided Warfarin Therapy Trial (WARFPGX)

This study has been completed.
Sponsor:
Collaborator:
UNC Institute for Pharmacogenomics and Individualized Therapy
Information provided by (Responsible Party):
University of North Carolina, Chapel Hill
ClinicalTrials.gov Identifier:
NCT00904293
First received: April 6, 2009
Last updated: October 10, 2013
Last verified: October 2013

April 6, 2009
October 10, 2013
August 2008
January 2012   (final data collection date for primary outcome measure)
  • Time in therapeutic range (TTR) [ Time Frame: 3 months ] [ Designated as safety issue: No ]
  • Number of anticoagulation visits [ Time Frame: 3 months ] [ Designated as safety issue: No ]
To determine the utility of a warfarin-dosing algorithm that incorporates genetic information for adult patients initiating warfarin therapy. [ Time Frame: 3 months ] [ Designated as safety issue: No ]
Complete list of historical versions of study NCT00904293 on ClinicalTrials.gov Archive Site
  • Proportion of INRs > 4 [ Time Frame: 3 months ] [ Designated as safety issue: Yes ]
  • Major bleeding events [ Time Frame: 3 months ] [ Designated as safety issue: Yes ]
  • Minor bleeding events [ Time Frame: 3 months ] [ Designated as safety issue: Yes ]
  • Thromboembolic complications [ Time Frame: 3 months ] [ Designated as safety issue: Yes ]
  • All-cause mortality [ Time Frame: 3 months ] [ Designated as safety issue: Yes ]
  • Time to therapeutic dose [ Time Frame: 3 months ] [ Designated as safety issue: No ]
  • Emergency department visits [ Time Frame: 3 months ] [ Designated as safety issue: Yes ]
  • Hospitalizations [ Time Frame: 3 months ] [ Designated as safety issue: Yes ]
  • Costs and cost-effectiveness [ Time Frame: 3 months ] [ Designated as safety issue: No ]
If this study finds using this algorithm useful, we will implement a warfarin response testing (genotyping of VKOR and CYP2C9 alleles) service at UNC. [ Time Frame: 12-24 months ] [ Designated as safety issue: No ]
Not Provided
Not Provided
 
Genotype-Guided Warfarin Therapy Trial
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.

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.

Interventional
Not Provided
Allocation: Randomized
Endpoint Classification: Efficacy Study
Intervention Model: Parallel Assignment
Masking: Double Blind (Subject, Caregiver)
Primary Purpose: Treatment
  • Atrial Fibrillation
  • Deep Vein Thrombosis
  • Pulmonary Embolism
  • Artificial Heart Valve
  • 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.
  • 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.
  • 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.
    Intervention: Other: Genotype-guided dose determination
  • 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
    Intervention: Other: Non-genotype guided warfarin dosing
Jonas DE, Evans JP, McLeod HL, Brode S, Lange LA, Young ML, Shilliday BB, Bardsley MM, Swinton-Jenkins NJ, Weck KE. Impact of genotype-guided dosing on anticoagulation visits for adults starting warfarin: a randomized controlled trial. Pharmacogenomics. 2013 Oct;14(13):1593-603. doi: 10.2217/pgs.13.145.

*   Includes publications given by the data provider as well as publications identified by ClinicalTrials.gov Identifier (NCT Number) in Medline.
 
Completed
109
January 2012
January 2012   (final data collection date for primary outcome measure)

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
Both
18 Years and older
No
Contact information is only displayed when the study is recruiting subjects
United States
 
NCT00904293
07-1644
No
University of North Carolina, Chapel Hill
University of North Carolina, Chapel Hill
UNC Institute for Pharmacogenomics and Individualized Therapy
Principal Investigator: Daniel E Jonas, MD, MPH UNC Institute for Pharmacogenomics and Individualized Therapy
University of North Carolina, Chapel Hill
October 2013

ICMJE     Data element required by the International Committee of Medical Journal Editors and the World Health Organization ICTRP