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)
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Clinical and Integrative Cardiovascular Sciences Study Section (CICS)
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Kindzelski, Andrei L
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Washington University
Internal Medicine/Medicine
Schools of Medicine
Saint Louis
United States
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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
Haas, David W; Kuritzkes, Daniel R; Ritchie, Marylyn D et al. (2011) Pharmacogenomics of HIV therapy: summary of a workshop sponsored by the National Institute of Allergy and Infectious Diseases. HIV Clin Trials 12:277-85
Finkelman, Brian S; Gage, Brian F; Johnson, Julie A et al. (2011) Genetic warfarin dosing: tables versus algorithms. J Am Coll Cardiol 57:612-8
Gage, Brian F (2011) Cost of dabigatran for atrial fibrillation. BMJ 343:d6980
Johnson, J A; Gong, L; Whirl-Carrillo, M et al. (2011) Clinical Pharmacogenetics Implementation Consortium Guidelines for CYP2C9 and VKORC1 genotypes and warfarin dosing. Clin Pharmacol Ther 90:625-9
Lenzini, P; Wadelius, M; Kimmel, S et al. (2010) Integration of genetic, clinical, and INR data to refine warfarin dosing. Clin Pharmacol Ther 87:572-8
King, Cristi R; Deych, Elena; Milligan, Paul et al. (2010) Gamma-glutamyl carboxylase and its influence on warfarin dose. Thromb Haemost 104:750-4
Ferder, N S; Eby, C S; Deych, E et al. (2010) Ability of VKORC1 and CYP2C9 to predict therapeutic warfarin dose during the initial weeks of therapy. J Thromb Haemost 8:95-100