Genetics Informatics Trial (GIFT) of Warfarin to Prevent DVT

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.

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