On September 15, 2008, acting Surgeon General, Steven Galson, MD MPH, noted that venous thromboembolic events (VTE) contribute to the death of at least 100,000 Americans each year. Because many of these deaths occur suddenly, the best management is prevention. In this randomized, controlled trial, Washington University researchers will test strategies to improve the safety and effectiveness of VTE prevention by using a non-profit web application (www.WarfarinDosing.org) to tailor the dose of warfarin to each person's pharmacogenetic and/or clinical profile. They also propose to test the recommendation of the American Academy of Orthopedic Surgeons (AAOS) to use low levels of anticoagulation (i.e., a target International Normalized Ratio (INR) <2.0) for VTE prevention in orthopedic patients. Thus, the overall objective of the Genetics-InFormatics Trial (GIFT) of Warfarin to Prevent DVT is to elucidate novel strategies to improve the safety and effectiveness of warfarin therapy. Washington University researchers propose a randomized controlled trial of 1500 patients having total hip or knee replacement surgery at Barnes-Jewish Hospital. By studying this high- risk population and screening for asymptomatic deep venous thrombosis by Doppler ultrasound post-operatively, the proposed trial will be appropriately powered to elucidate two novel strategies to prevent VTE. The researchers will use a 2 x 2 factorial design to randomize patients to: (1) pharmacogenetic vs. clinical dosing of warfarin;and (2) to a target INR of 2.5 vs. <2.0. The proposal has two specific aims:
Aim 1 : To determine how pharmacogenetic-based warfarin therapy affects risk of non-fatal VTE, non-fatal major hemorrhage, and vascular death. Although the FDA has approved genetic testing for variants that affect warfarin dose, no prior (or planned) trial has been powered to determine whether this strategy affects outcomes.
Aim 2 : To determine whether warfarin therapy with a target INR of <2.0 is non-inferior to a target INR of 2.5 at preventing VTE in orthopedic patients. Although the American College of Chest Physician (ACCP) recommends a target INR of 2.5, the AAOS recommends <2.0 and these conflicting goals have never been compared in a trial of primary VTE prevention.

Public Health Relevance

On September 15, 2008, Acting Surgeon General Steven Galson, MD, MPH noted that blood clots (deep venous thrombosis and pulmonary embolism) 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. In this grant, Washington University researchers develop strategies to improve the safety and effectiveness of clot prevention by customizing blood thinners to each person's genetic and clinical profile.

Agency
National Institute of Health (NIH)
Institute
National Heart, Lung, and Blood Institute (NHLBI)
Type
Research Project (R01)
Project #
5R01HL097036-04
Application #
8288161
Study Section
Clinical and Integrative Cardiovascular Sciences Study Section (CICS)
Program Officer
Kindzelski, Andrei L
Project Start
2009-09-10
Project End
2014-03-31
Budget Start
2012-06-01
Budget End
2013-03-31
Support Year
4
Fiscal Year
2012
Total Cost
$736,139
Indirect Cost
$251,837
Name
Washington University
Department
Internal Medicine/Medicine
Type
Schools of Medicine
DUNS #
068552207
City
Saint Louis
State
MO
Country
United States
Zip Code
63130
Venker, Brett T; Ganti, Beejal R; Lin, Hannah et al. (2017) Safety and Efficacy of New Anticoagulants for the Prevention of Venous Thromboembolism After Hip and Knee Arthroplasty: A Meta-Analysis. J Arthroplasty 32:645-652
Johnson, J A; Caudle, K E; Gong, L et al. (2017) Clinical Pharmacogenetics Implementation Consortium (CPIC) Guideline for Pharmacogenetics-Guided Warfarin Dosing: 2017 Update. Clin Pharmacol Ther 102:397-404
Gage, Brian F; Bass, Anne R; Lin, Hannah et al. (2017) 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 318:1115-1124
Nassif, Michael E; LaRue, Shane J; Raymer, David S et al. (2016) Relationship Between Anticoagulation Intensity and Thrombotic or Bleeding Outcomes Among Outpatients With Continuous-Flow Left Ventricular Assist Devices. Circ Heart Fail 9:
French, Benjamin; Wang, Le; Gage, Brian F et al. (2016) A systematic analysis and comparison of warfarin initiation strategies. Pharmacogenet Genomics 26:445-52
Hyun, G; Li, J; Bass, A R et al. (2016) Use of signals and systems engineering to improve the safety of warfarin initiation. J Thromb Thrombolysis 42:529-33
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Wang, Tzu-Fei; Wong, Catherine A; Milligan, Paul E et al. (2014) Risk factors for inpatient venous thromboembolism despite thromboprophylaxis. Thromb Res 133:25-9
Wang, Tzu-Fei; Milligan, Paul E; Wong, Catherine A et al. (2014) Efficacy and safety of high-dose thromboprophylaxis in morbidly obese inpatients. Thromb Haemost 111:88-93
Kawai, Vivian K; Cunningham, Andrew; Vear, Susan I et al. (2014) Genotype and risk of major bleeding during warfarin treatment. Pharmacogenomics 15:1973-83

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