Genetics Informatics Trial (GIFT) of Warfarin to Prevent DVT

NCT01006733 | Completed Phase 3 DMC

• 2 other identifiers: HL097036-01R01HL097036
• Study Type: interventional
• Target: 1,598
• Locations: 1 country
• Sites: 6

Brief Summary

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.

Conditions

Thromboembolism

Keywords

pharmacogenetics; arthroplasty; VKORC1; thromboembolism; warfarin

Outcome Measures

Primary Outcomes (2)

• For Aim 1: The composite outcome of: non-fatal venous thromboembolism (VTE), non-fatal major hemorrhage, INR>=4.0, and death.

  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.

  30-days for death; 60 days for VTE

Secondary Outcomes (4)

• Percent Time in Therapeutic INR Range

  4-28 days

• Composite Outcomes

  30 days for death; 60 days for VTE, major bleed, INR >=4.0.

• Ranked Outcomes

  4-28 days for PTTR (INR variability); 30 days for death; 60 days for VTE.

• Time to first laboratory event (INR > 1.5 + Target INR)

  Maximum of 90 days; median time to last INR is 28 days

Study Arms (4)

Target INR 1.8 and Pharmacogenetic

EXPERIMENTAL

The target International Normalized Ratio (INR) is 1.8. Warfarin initiation is via Pharmacogenetic dosing.

Genetic: Pharmacogenetic; Drug: Target INR 1.8

Target INR 2.5 and Pharmacogenetic

EXPERIMENTAL

The target INR is 2.5. Warfarin initiation is via Pharmacogenetic dosing.

Genetic: Pharmacogenetic

Target INR 1.8 and Clinical

EXPERIMENTAL

The target INR is 1.8. Warfarin initiation is via clinical dosing.

Drug: Target INR 1.8

Target INR 2.5 and Clinical

NO INTERVENTION

The target INR is 2.5. Warfarin initiation is via clinical dosing.

Interventions

Pharmacogenetic GENETIC

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.

Target INR 1.8 and Pharmacogenetic; Target INR 2.5 and Pharmacogenetic

Target INR 1.8 DRUG

We will randomize patients to a target International Normalized Ratio (INR) of 2.5 or 1.8.

Target INR 1.8 and Clinical; Target INR 1.8 and Pharmacogenetic

Eligibility Criteria

• Age: 65 Years+
• Sex: all
• Healthy Volunteers: Yes
• Age Groups: Older Adult (65+)

You may qualify if:

• 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

You may not qualify if:

• 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

Sponsors & Collaborators

• Washington University School of Medicine: lead
• National Heart, Lung, and Blood Institute (NHLBI): collaborator
• Hospital for Special Surgery, New York: collaborator
• Intermountain Health Care, Inc.: collaborator
• University of Utah: collaborator
• Rush University Medical Center: collaborator
• University of Texas Southwestern Medical Center: collaborator

Study Sites (6)

Rush University Medical Center

Chicago, Illinois, 60612, United States

Location

Washington University in St. Louis, School of Medicine

St Louis, Missouri, 63110, United States

Location

Hospital for Special Surgery, Weill-Cornell

New York, New York, 10021, United States

Location

University of Texas Southwestern

Dallas, Texas, 75390-8870, United States

Location

University of Utah

Salt Lake City, Utah, 84132, United States

Location

Intermountain Medical Center

Salt Lake City, Utah, 84157, United States

Location

Related Publications (12)

• Lenzini P, Wadelius M, Kimmel S, Anderson JL, Jorgensen AL, Pirmohamed M, Caldwell MD, Limdi N, Burmester JK, Dowd MB, Angchaisuksiri P, Bass AR, Chen J, Eriksson N, Rane A, Lindh JD, Carlquist JF, Horne BD, Grice G, Milligan PE, Eby C, Shin J, Kim H, Kurnik D, Stein CM, McMillin G, Pendleton RC, Berg RL, Deloukas P, Gage BF. Integration of genetic, clinical, and INR data to refine warfarin dosing. Clin Pharmacol Ther. 2010 May;87(5):572-8. doi: 10.1038/clpt.2010.13. Epub 2010 Apr 7.

  PMID: 20375999 BACKGROUND

• Ferder NS, Eby CS, Deych E, Harris JK, Ridker PM, Milligan PE, Goldhaber SZ, King CR, Giri T, McLeod HL, Glynn RJ, Gage BF. Ability of VKORC1 and CYP2C9 to predict therapeutic warfarin dose during the initial weeks of therapy. J Thromb Haemost. 2010 Jan;8(1):95-100. doi: 10.1111/j.1538-7836.2009.03677.x. Epub 2009 Oct 30.

  PMID: 19874474 BACKGROUND

• King CR, Deych E, Milligan P, Eby C, Lenzini P, Grice G, Porche-Sorbet RM, Ridker PM, Gage BF. Gamma-glutamyl carboxylase and its influence on warfarin dose. Thromb Haemost. 2010 Oct;104(4):750-4. doi: 10.1160/TH09-11-0763. Epub 2010 Aug 5.

  PMID: 20694283 BACKGROUND

• Finkelman BS, Gage BF, Johnson JA, Brensinger CM, Kimmel SE. Genetic warfarin dosing: tables versus algorithms. J Am Coll Cardiol. 2011 Feb 1;57(5):612-8. doi: 10.1016/j.jacc.2010.08.643.

  PMID: 21272753 BACKGROUND

• Johnson JA, Gong L, Whirl-Carrillo M, Gage BF, Scott SA, Stein CM, Anderson JL, Kimmel SE, Lee MT, Pirmohamed M, Wadelius M, Klein TE, Altman RB; Clinical Pharmacogenetics Implementation Consortium. Clinical Pharmacogenetics Implementation Consortium Guidelines for CYP2C9 and VKORC1 genotypes and warfarin dosing. Clin Pharmacol Ther. 2011 Oct;90(4):625-9. doi: 10.1038/clpt.2011.185. Epub 2011 Sep 7.

  PMID: 21900891 BACKGROUND

• Horne BD, Lenzini PA, Wadelius M, Jorgensen AL, Kimmel SE, Ridker PM, Eriksson N, Anderson JL, Pirmohamed M, Limdi NA, Pendleton RC, McMillin GA, Burmester JK, Kurnik D, Stein CM, Caldwell MD, Eby CS, Rane A, Lindh JD, Shin JG, Kim HS, Angchaisuksiri P, Glynn RJ, Kronquist KE, Carlquist JF, Grice GR, Barrack RL, Li J, Gage BF. Pharmacogenetic warfarin dose refinements remain significantly influenced by genetic factors after one week of therapy. Thromb Haemost. 2012 Feb;107(2):232-40. doi: 10.1160/TH11-06-0388. Epub 2011 Dec 21.

  PMID: 22186998 BACKGROUND

• Do EJ, Lenzini P, Eby CS, Bass AR, McMillin GA, Stevens SM, Woller SC, Pendleton RC, Anderson JL, Proctor P, Nunley RM, Davila-Roman V, Gage BF. Genetics informatics trial (GIFT) of warfarin to prevent deep vein thrombosis (DVT): rationale and study design. Pharmacogenomics J. 2012 Oct;12(5):417-24. doi: 10.1038/tpj.2011.18. Epub 2011 May 24.

  PMID: 21606949 BACKGROUND

• Kawai VK, Cunningham A, Vear SI, Van Driest SL, Oginni A, Xu H, Jiang M, Li C, Denny JC, Shaffer C, Bowton E, Gage BF, Ray WA, Roden DM, Stein CM. Genotype and risk of major bleeding during warfarin treatment. Pharmacogenomics. 2014 Dec;15(16):1973-83. doi: 10.2217/pgs.14.153.

  PMID: 25521356 BACKGROUND

• Bass AR, Rodriguez T, Hyun G, Santiago FG, Kim JI, Woller SC, Gage BF. Myocardial ischaemia after hip and knee arthroplasty: incidence and risk factors. Int Orthop. 2015 Oct;39(10):2011-6. doi: 10.1007/s00264-015-2853-0. Epub 2015 Jul 9.

  PMID: 26156715 BACKGROUND

• Hyun G, Li J, Bass AR, Mohapatra A, Woller SC, Lin H, Eby C, McMillin GA, Gage BF. Use of signals and systems engineering to improve the safety of warfarin initiation. J Thromb Thrombolysis. 2016 Nov;42(4):529-33. doi: 10.1007/s11239-016-1402-z.

  PMID: 27443162 BACKGROUND

• Gage BF, Bass AR, Lin H, Woller SC, Stevens SM, Al-Hammadi N, Anderson JL, Li J, Rodriguez T Jr, Miller JP, McMillin GA, Pendleton RC, Jaffer AK, King CR, Whipple B, Porche-Sorbet R, Napoli L, Merritt K, Thompson AM, Hyun G, Hollomon W, Barrack RL, Nunley RM, Moskowitz G, Davila-Roman V, Eby CS. Effect of Low-Intensity vs Standard-Intensity Warfarin Prophylaxis on Venous Thromboembolism or Death Among Patients Undergoing Hip or Knee Arthroplasty: A Randomized Clinical Trial. JAMA. 2019 Sep 3;322(9):834-842. doi: 10.1001/jama.2019.12085.

  PMID: 31479138 DERIVED

• Gage BF, Bass AR, Lin H, Woller SC, Stevens SM, Al-Hammadi N, Li J, Rodriguez T Jr, Miller JP, McMillin GA, Pendleton RC, Jaffer AK, King CR, Whipple BD, Porche-Sorbet R, Napoli L, Merritt K, Thompson AM, Hyun G, Anderson JL, Hollomon W, Barrack RL, Nunley RM, Moskowitz G, Davila-Roman V, Eby CS. Effect of Genotype-Guided Warfarin Dosing on Clinical Events and Anticoagulation Control Among Patients Undergoing Hip or Knee Arthroplasty: The GIFT Randomized Clinical Trial. JAMA. 2017 Sep 26;318(12):1115-1124. doi: 10.1001/jama.2017.11469.

  PMID: 28973620 DERIVED

Related Links

• pharmacogenetic and clinical warfarin dosing algorithms for trial

MeSH Terms

Conditions

Thromboembolism; Vitamin K-Dependent Clotting Factors, Combined Deficiency Of, Type 2

Interventions

Pharmacogenomic Testing

Condition Hierarchy (Ancestors)

Embolism and Thrombosis; Vascular Diseases; Cardiovascular Diseases

Intervention Hierarchy (Ancestors)

Genetic Testing; Clinical Laboratory Techniques; Diagnostic Techniques and Procedures; Diagnosis; Investigative Techniques; Genetic Techniques; Genetic Services; Health Services; Health Care Facilities Workforce and Services; Diagnostic Services; Preventive Health Services

Study Officials

• Brian F Gage, MD, MSc

  Washington University School of Medicine

  PRINCIPAL INVESTIGATOR

Study Design

• Study Type: interventional
• Phase: phase 3
• Allocation: RANDOMIZED
• Masking: QUADRUPLE
• Who Masked: PARTICIPANT, CARE PROVIDER, INVESTIGATOR, OUTCOMES ASSESSOR
• Purpose: PREVENTION
• Intervention Model: FACTORIAL
• Sponsor Type: OTHER
• Responsible Party: SPONSOR

Study Record Dates

• First Submitted: October 30, 2009
• First Posted: November 3, 2009
• Study Start: March 1, 2011
• Primary Completion: October 1, 2016
• Study Completion: November 1, 2016
• Last Updated: December 29, 2016

Record last verified: 2016-12

Data Sharing

• IPD Sharing: Will share

Locations

US (6)