| Purpose: |
|
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, Utah, and NY 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 1.8 is non-inferior
to using a target INR of 2.5 in clot prevention.
|
| Study Summary: |
|
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.
|
| Criteria: |
|
Inclusion Criteria:
- 65 years of age or older
- must anticipate taking warfarin for at least 4-6 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 4-6 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 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
- family or personal history of thromboembolism before age 50
|