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.

National Institute of Health (NIH)
National Heart, Lung, and Blood Institute (NHLBI)
Research Project (R01)
Project #
Application #
Study Section
Clinical and Integrative Cardiovascular Sciences Study Section (CICS)
Program Officer
Kindzelski, Andrei L
Project Start
Project End
Budget Start
Budget End
Support Year
Fiscal Year
Total Cost
Indirect Cost
Washington University
Internal Medicine/Medicine
Schools of Medicine
Saint Louis
United States
Zip Code
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
Venker, Brett T; Ganti, Beejal R; Lin, Hannah et al. (2016) Safety and Efficacy of New Anticoagulants for the Prevention of Venous Thromboembolism After Hip and Knee Arthroplasty: A Meta-Analysis. J Arthroplasty :
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
Bass, Anne Ruth; Rodriguez, Tomás; Hyun, Gina et al. (2015) Myocardial ischaemia after hip and knee arthroplasty: incidence and risk factors. Int Orthop 39:2011-6
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
Eby, Charles (2012) Warfarin pharmacogenetics: does more accurate dosing benefit patients? Semin Thromb Hemost 38:661-6
Do, E J; Lenzini, P; Eby, C S et al. (2012) Genetics informatics trial (GIFT) of warfarin to prevent deep vein thrombosis (DVT): rationale and study design. Pharmacogenomics J 12:417-24

Showing the most recent 10 out of 18 publications