Genetics Informatics Trial (GIFT) of Warfarin to Prevent DVT

Study Overview
=================
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.

Detailed 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 (VTE) disease. In 2007, 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.(1) Recently, President Obama and Francis Collins (Director of the NIH) have made precision medicine a national priority.(2) Previously, the Acting Surgeon General issued a Call to Action to reduce the number of cases of VTE in the United States.(3) To facilitate precision dosing strategies for VTE prevention, we have made publically available a non-profit, web application, www.WarfarinDosing.org. A public version of www.WarfarinDosing.org estimates warfarin doses for the initial 5 days of warfarin therapy. The version being evaluated in GIFT provides doses for the initial 11 days of warfarin therapy. 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 VTE while supratherapeutic INR values increase risk of bleeding.(4, 5) Previously, 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.(6) 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. Hypothesis 1: Pharmacogenetic therapy decreases the composite risk of a non-fatal VTE, non-fatal major hemorrhage, death, or INR ≥ 4.0 in all patients, and/or 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(7), we anticipate 80% power to simultaneously detect a 32% relative risk reduction in the composite outcome for Aim 1 (as measured by a chi-square test). In the clinical arm, based on preliminary data, we anticipate that the rate of the composite outcome will be 15.7% in the clinical arm and 10.7% in the pharmacogenetic arm. We obtained these estimates because they average a rate of 13.2%, which is the rate of the composite outcome for Aim 1 observed from the initial 775 GIFT participants. The power was calculated using a two-sided alpha of 0.05 for a test of proportions, a drop-out rate of 2%, and a partitioned (two-sided) alpha with 0.044 allocated to the whole population and 0.01 to the high-risk subgroup. Because of correlation between these two subgroups, using these alphas preserves an overall type 1 error rate of 0.05. 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.(8) Although that trial excluded orthopedic patients, such an approach has been endorsed by the American Academy of Orthopedic Surgeons (AAOS). On page 15 of the 2007 AAOS guidelines (9) 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). The AAOS guidelines conflict with the prior American College of Chest Physician (ACCP) guidelines,(10) which recommend, as one of their (Grade 1A) options (page 338 S), 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(8) 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 3% absolute risk reduction in non-fatal VTE or death and an estimated composite rate of 5.56% (based on preliminary GIFT data), we will have 83% power to detect the non-inferiority of a target INR of 1.8 in 1600 patients.

Official Title
-----------------
Genetics Informatics Trial (GIFT) of Warfarin to Prevent Deep Venous Thrombosis (DVT)

Conditions
-----------------
Thromboembolism

Intervention / Treatment
-----------------
* Genetic: Pharmacogenetic
* Drug: Target INR 1.8


Participation Criteria
=================
Eligibility Criteria
-----------------
Inclusion Criteria: 65 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 Exclusion Criteria: 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

Ages Eligible for Study
-----------------
Minimum Age: 65 Years

Sexes Eligible for Study
-----------------
All

Accepts Healthy Volunteers
-----------------
Accepts Healthy Volunteers

Study Plan
=================
How is the study designed?
-----------------

Design Details

Primary Purpose: Prevention
Allocation: Randomized
Intervention Model: Factorial Assignment
Masking: Quadruple


Arms and Interventions

| Participant Group/Arm | Intervention/Treatment |
| --- | --- |
| Experimental: Target INR 1.8 and Pharmacogenetic<br>The target International Normalized Ratio (INR) is 1.8. Warfarin initiation is via Pharmacogenetic dosing. | Genetic: Pharmacogenetic<br>* 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.<br>Drug: Target INR 1.8<br>* We will randomize patients to a target International Normalized Ratio (INR) of 2.5 or 1.8.<br>|
| Experimental: Target INR 2.5 and Pharmacogenetic<br>The target INR is 2.5. Warfarin initiation is via Pharmacogenetic dosing. | Genetic: Pharmacogenetic<br>* 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.<br>|
| Experimental: Target INR 1.8 and Clinical<br>The target INR is 1.8. Warfarin initiation is via clinical dosing. | Drug: Target INR 1.8<br>* We will randomize patients to a target International Normalized Ratio (INR) of 2.5 or 1.8.<br>|
| No Intervention: Target INR 2.5 and Clinical<br>The target INR is 2.5. Warfarin initiation is via clinical dosing. | |

What is the study measuring?
-----------------
Primary Outcome Measures

| Outcome Measure | Measure Description | Time Frame |
| --- | --- | --- |
| 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 Outcome Measures

| Outcome Measure | Measure Description | Time Frame |
| --- | --- | --- |
| Percent Time in Therapeutic INR Range | We also we report INR Variability using the method of Lind et al. (2012 Thrombosis research). | 4-28 days | 
| Composite Outcomes | We will compare the two arms in Aim 2 using the same composite outcome from Aim 1: VTE, major hemorrhage, death, or INR >= 4.0. | 30 days for death; 60 days for VTE, major bleed, INR >=4.0. | 
| Ranked Outcomes | Outcomes will be ranked using the following tiers in hierarchical order, from worst to best: (1) death; (2) PE; (3) Major bleed; (4) symptomatic DVT; (5) INR >= 4 with minor bleed; (6) asymptomatic DVT; (7) INR >= 4 (w/out major/minor bleed); (8) PTTR. Events that happen earliest receive the lowest (worst) score. For PTTR, lower time in the target INR range is worse. This approach, similar to that used in the RELAX trial (Redfield et al. 2013) weighs outcomes according to their clinical relevance. Ranks will be compared using a standard non-parametric test (Mann-Whitney 1947) to determine if one arm improves 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 | 

 Terms related to the study
=================
Keywords Provided by Centre Hospitalier Valida
-----------------
pharmacogenetics, arthroplasty, VKORC1, thromboembolism, warfarin