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Genetics Informatics Trial of Warfarin to Prevent Deep Venous Thrombosis (DVT)

2014-08-27 03:18:14 | BioPortfolio

Summary

On September 15, 2008, Acting Surgeon General Steven Galson, MD, MPH noted that 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. In this grant, researchers in Missouri and Utah develop strategies to improve the safety and effectiveness of clot prevention by customizing blood thinners 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 < 2.0 is non-inferior to using a target INR of 2.5 in clot prevention.

Description

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. With this study we directly respond to Health and Human Services (HHS) priorities to advance the field of personalized medicine and to prevent venous thromboembolic disease. One year ago, the Honorable Mike Leavitt, Secretary of HHS, announced the Personalized Health Care Initiative and wrote that a key goal was, "… to use our personal genetic information to tailor treatments more effectively to each patient."(Leavitt, 2007) On September 15, 2008, the Acting Surgeon General (Dr. Steven K. Galson, MD, MPH) issued a Call to Action to reduce the number of cases of deep vein thrombosis and pulmonary embolism in the United States.(Galson, 2008) To facilitate the dosing strategies for the trial proposed herein and for the public at large, we have made publically available a non-profit, decision-support web application, www.WarfarinDosing.org.

Aim 1: To determine how pharmacogenetic-based warfarin therapy affects the safety and effectiveness of warfarin therapy. The intensity of anticoagulant therapy is measured by the International Normalized Ratio (INR). During initiation, the INR often falls outside the therapeutic range. INRs that are too low predispose patients to thromboembolism (Kearon, 2003) while supratherapeutic INR values increase risk of bleeding. (Hylek, 1994; Hylek, 2007) In August 2007, the FDA approved the label change of warfarin/Coumadin™ to recommend considering lower initial doses in patients known to have certain polymorphisms in genes affecting warfarin metabolism and sensitivity.(Wood, 2007) However, whether this strategy improves the safety and effectiveness of warfarin therapy in general is unknown. In particular, how this strategy affects subgroups with and without the genetic variants of interest is also unknown. To test the resulting joint hypothesis while preserving an Aim-wide Type I error rate of < 0.05 we will partition our expected error rate as described in the methods section below.

Primary Joint hypothesis: Pharmacogenetic therapy decreases the composite risk of a non-fatal VTE, non-fatal major hemorrhage, death, or INR>4.0 in all patients, and in the subgroup of patients whose pharmacogenetic and clinical predicted therapeutic maintenance doses differ by >1.0 mg/day. Based on our meta-analysis of prior trials (Hillman, 2005; Anderson, 2007; Caraco, 2008; Huang, 2009) (Sections B.3 and B.7 of grant proposal) and our pilot studies (Section C of grant proposal), we anticipate >99% power to simultaneously detect a reduction in the composite outcome, as measured by a chi-square test in both populations.

Aim 2: To determine whether warfarin therapy with a target INR of 1.8 is non-inferior to therapy with a target INR of 2.5 at preventing VTE or death in orthopedic patients. One randomized trial (PREVENT) found that a target INR value of 1.5-2.0 prevented 64% of VTE recurrence.(Ridker, 2003) Although that trial excluded orthopedic patients, such an approach has been endorsed by the American Academy of Orthopedic Surgeons (AAOS) and by many academic orthopedists (Table C.4). On page 15 of the latest AAOS guidelines (American Academy of Orthopaedic Surgeons, 2007) they offer the following recommendation for VTE prophylaxis around the time of joint replacement: "Warfarin, with an INR goal of ≤2.0, starting either the night before or the night after surgery, for 2-6 weeks." However, the AAOS grade the overall evidence for VTE prophylaxis in this population as low (level III) because no randomized trials have answered key clinical questions in this area—what is the optimal target INR value and whether pharmacogenetic therapy can improve clinical outcomes. The AAOS guidelines conflict with the American College of Chest Physician (ACCP) guidelines, (Geerts, 2004) which recommend, as one of their (Grade 1A) options (page 338S), using an "…adjusted-dose vitamin K antagonist (INR target, 2.5; range 2.0 to 3.0)." Because lower target INR values may reduce the risk of hemorrhage and simplify warfarin management (Ridker, 2003) we propose to test the following:

Hypothesis 2: For prevention of non-fatal VTE or death, a target INR of 1.8 will be non-inferior to a higher target INR (2.5). Using a non-inferiority margin of 10% (corresponding to a 1% absolute change in symptomatic VTE rate), we will have 80% power to detect the non-inferiority of a target INR of 1.8 in 1600 patients.

Study Design

Allocation: Randomized, Endpoint Classification: Safety/Efficacy Study, Intervention Model: Factorial Assignment, Masking: Double Blind (Subject, Caregiver, Investigator), Primary Purpose: Prevention

Conditions

Thromboembolism

Intervention

Pharmacogenetic Warfarin Initiation, Clinical Warfarin Initiation (non-pharmacogenetic)

Location

Washington University in St. Louis, School of Medicine
St. Louis
Missouri
United States
63110

Status

Not yet recruiting

Source

Washington University School of Medicine

Results (where available)

View Results

Links

Published on BioPortfolio: 2014-08-27T03:18:14-0400

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