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Genetics Informatics Trial (GIFT) of Warfarin to Prevent DVT (GIFT)

This study has been completed.
Sponsor:
Collaborators:
National Heart, Lung, and Blood Institute (NHLBI)
Hospital for Special Surgery, New York
Intermountain Health Care, Inc.
University of Utah
Rush University Medical Center
University of Texas Southwestern Medical Center
Information provided by (Responsible Party):
Washington University School of Medicine
ClinicalTrials.gov Identifier:
NCT01006733
First received: October 30, 2009
Last updated: December 28, 2016
Last verified: December 2016
  Purpose
Blood clots contribute to the death of at least 100,000 Americans each year. Because many of these deaths occur suddenly where treatment is impossible, the best treatment is prevention. With this grant, researchers in Missouri, New York, Utah, Illinois, and Texas are developing strategies to improve the safety and effectiveness of clot prevention by customizing a popular blood thinner (warfarin) to each person's genetic and clinical profile. They hypothesize that the use of genetics to guide warfarin therapy will reduce the risk of venous thromboembolism (VTE) postoperatively. They further hypothesize that using a target international normalized ratio (INR) of 1.8 is non-inferior to using a target INR of 2.5 in VTE prevention.

Condition Intervention Phase
Thromboembolism
Genetic: Pharmacogenetic
Drug: Target INR 1.8
Phase 3

Study Type: Interventional
Study Design: Allocation: Randomized
Intervention Model: Factorial Assignment
Masking: Double Blind (Subject, Caregiver, Investigator, Outcomes Assessor)
Primary Purpose: Prevention
Official Title: Genetics Informatics Trial (GIFT) of Warfarin to Prevent Deep Venous Thrombosis (DVT)

Resource links provided by NLM:


Further study details as provided by Washington University School of Medicine:

Primary Outcome Measures:
  • For Aim 1: The composite outcome of: non-fatal venous thromboembolism (VTE), non-fatal major hemorrhage, INR>=4.0, and death. [ Time Frame: 30-days, except that VTE may be detected up to day 60 ]
  • For Aim 2: The composite outcome of: non-fatal venous thromboembolism (VTE) and death. [ Time Frame: 30-days for death; 60 days for VTE ]

Secondary Outcome Measures:
  • Percent Time in Therapeutic INR Range [ Time Frame: 4-28 days ]
    We also we report INR Variability using the method of Lind et al. (2012 Thrombosis research).

  • Composite Outcomes [ Time Frame: 30 days for death; 60 days for VTE, major bleed, INR >=4.0. ]
    We will compare the two arms in Aim 2 using the same composite outcome from Aim 1: VTE, major hemorrhage, death, or INR >= 4.0.

  • Ranked Outcomes [ Time Frame: 4-28 days for PTTR (INR variability); 30 days for death; 60 days for VTE. ]

    Outcomes will be ranked using the following tiers in hierarchical order, from worst to best: (1) death; (2) PE; (3) Major bleed; (4) symptomatic DVT; (5) INR >= 4 with minor bleed; (6) asymptomatic DVT; (7) INR >= 4 (w/out major/minor bleed); (8) PTTR.

    Events that happen earliest receive the lowest (worst) score. For PTTR, lower time in the target INR range is worse. This approach, similar to that used in the RELAX trial (Redfield et al. 2013) weighs outcomes according to their clinical relevance. Ranks will be compared using a standard non-parametric test (Mann-Whitney 1947) to determine if one arm improves outcomes.


  • Time to first laboratory event (INR > 1.5 + Target INR) [ Time Frame: Maximum of 90 days; median time to last INR is 28 days ]

Enrollment: 1598
Study Start Date: March 2011
Study Completion Date: November 2016
Primary Completion Date: October 2016 (Final data collection date for primary outcome measure)
Arms Assigned Interventions
Experimental: Target INR 1.8 and Pharmacogenetic
The target International Normalized Ratio (INR) is 1.8. Warfarin initiation is via Pharmacogenetic dosing.
Genetic: Pharmacogenetic
The pharmacogenetic arm estimates therapeutic warfarin dose using cytochrome P 450 2C9 (CYP2C9), vitamin K epoxide reductase complex subunit 1 (VKORC1), and cytochrome P 450 4F2 (CYP4F2) genotype and clinical information. The clinical arm estimates warfarin dose from clinical information alone.
Drug: Target INR 1.8
We will randomize patients to a target International Normalized Ratio (INR) of 2.5 or 1.8.
Experimental: Target INR 2.5 and Pharmacogenetic
The target INR is 2.5. Warfarin initiation is via Pharmacogenetic dosing.
Genetic: Pharmacogenetic
The pharmacogenetic arm estimates therapeutic warfarin dose using cytochrome P 450 2C9 (CYP2C9), vitamin K epoxide reductase complex subunit 1 (VKORC1), and cytochrome P 450 4F2 (CYP4F2) genotype and clinical information. The clinical arm estimates warfarin dose from clinical information alone.
Experimental: Target INR 1.8 and Clinical
The target INR is 1.8. Warfarin initiation is via clinical dosing.
Drug: Target INR 1.8
We will randomize patients to a target International Normalized Ratio (INR) of 2.5 or 1.8.
No Intervention: Target INR 2.5 and Clinical
The target INR is 2.5. Warfarin initiation is via clinical dosing.

  Show Detailed Description

  Eligibility

Ages Eligible for Study:   65 Years and older   (Adult, Senior)
Sexes Eligible for Study:   All
Accepts Healthy Volunteers:   Yes
Criteria

Inclusion Criteria:

  • 65 years of age or older
  • must anticipate taking warfarin for at least 4 weeks for VTE prophylaxis after hip or knee arthroplasty
  • must be able to give written, informed consent
  • must have venous access
  • must not be institutionalized, incarcerated at the time of enrollment (nursing home okay)
  • must have life expectancy > 6 months
  • must have plans to have regular INR monitoring
  • willing/able to follow-up in 3-7 weeks with a Doppler Ultrasound

Exclusion Criteria:

  • Baseline INR > 1.35
  • knowledge of CYP2C9, VKORC1, or CYP4F2 genotype
  • knowledge of warfarin dose requirements from prior warfarin therapy
  • absolute contraindication or allergy to warfarin therapy (e.g. pregnancy)
  • receiving or planning to receive any anticoagulant besides warfarin (if low molecular weight heparin (LMWH) or subcutaneous heparin is deemed necessary by the clinician after enrollment, such patients will be allowed to remain in the study)
  • unlikely to be compliant (e.g. due to history of non-compliance, or alcoholism)
  • known thrombophilia, bleeding disorder, or history of serious bleed in the past 2 years (unless caused by trauma)
  • personal history of venous thromboembolism
  Contacts and Locations
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, see Learn About Clinical Studies.

Please refer to this study by its ClinicalTrials.gov identifier: NCT01006733

Locations
United States, Illinois
Rush University Medical Center
Chicago, Illinois, United States, 60612
United States, Missouri
Washington University in St. Louis, School of Medicine
St. Louis, Missouri, United States, 63110
United States, New York
Hospital for Special Surgery, Weill-Cornell
NY, New York, United States, 10021
United States, Texas
University of Texas Southwestern
Dallas, Texas, United States, 75390-8870
United States, Utah
University of Utah
Salt Lake City, Utah, United States, 84132
Intermountain Medical Center
Salt Lake City, Utah, United States, 84157
Sponsors and Collaborators
Washington University School of Medicine
National Heart, Lung, and Blood Institute (NHLBI)
Hospital for Special Surgery, New York
Intermountain Health Care, Inc.
University of Utah
Rush University Medical Center
University of Texas Southwestern Medical Center
Investigators
Principal Investigator: Brian F Gage, MD, MSc Washington University School of Medicine
  More Information

Additional Information:
Publications:

Responsible Party: Washington University School of Medicine
ClinicalTrials.gov Identifier: NCT01006733     History of Changes
Other Study ID Numbers: HL097036-01  R01HL097036 
Study First Received: October 30, 2009
Last Updated: December 28, 2016
Individual Participant Data  
Plan to Share IPD: Yes
Plan Description: GIFT plans to share anonymous IPD with other researchers via BioLINCC in March 2018.

Keywords provided by Washington University School of Medicine:
pharmacogenetics
arthroplasty
VKORC1
thromboembolism
warfarin

Additional relevant MeSH terms:
Thromboembolism
Embolism and Thrombosis
Vascular Diseases
Cardiovascular Diseases
Warfarin
Anticoagulants

ClinicalTrials.gov processed this record on February 24, 2017