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Genotype-guided warfarin dosing now a reality
An NIH study planned for this year will assess multiple outcomes related to warfarin safety and efficacy.
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Every year in the United States more than 2 million people are treated with warfarin.
While warfarin is the most commonly prescribed oral anticoagulant and is highly effective for treating and preventing thromboembolism and stroke, warfarin also ranks number one in total mentions of death for drugs causing adverse events. It is one of the top drugs associated with emergency room visits, and it is associated with an estimated 10% to 16% overall frequency of major bleeding complications.
Warfarin dosing is difficult primarily due to its narrow therapeutic index and significant inter-patient variability in response. Warfarin response depends not only on age, race, diet and concomitant medications, but also on an individual’s genetic makeup. Warfarin dosing is usually started with 5 mg to 10 mg with a target international normalized ratio of 2-3. Achieving that target can take weeks, which often extends hospital stays and can add significantly to the health care costs associated with anticoagulation. And, it has been estimated that patients are over-anticoagulated more than 30% of the time in the first month of warfarin therapy, putting them at increased risk for bleeding and associated morbidity and mortality.
Genetic considerations
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Cytochrome P450 isoenzyme 2C9 (CYP2C9) is the main enzyme responsible for metabolism and clearance of S-warfarin (the most potent enantiomer). Individuals with one of the common variants (CYP2C9*2 or CYP2C9*3) will have decreased enzyme activity, which results in reduced metabolism and slower clearance of S-warfarin. These patients are three to four times more likely to bleed. They take more time to reach stable doses and have at least a 15% lower maintenance dose requirement, or about 2 mg lower on average, than patients without gene variations. The CYP2C9 variants are more common in whites than blacks, and the frequency can be as high as 20%. Therefore, a large number of patients may benefit from clinical testing of these variants.
Warfarin’s main action is to inhibit vitamin K epoxide reductase (VKOR), a multiprotein enzyme that makes vitamin K available in a form necessary for synthesis of several downstream clotting factors. Inhibition of VKOR results in lower levels of vitamin K- dependent clotting factors and a reduced tendency to clot. Like variants of CYP2C9, individuals with genetic variations in the VKORC1 gene, such as -1639/3673, are more sensitive to the effects of warfarin. They have a reduced warfarin dose requirement and spend less time in the therapeutic range. Patients with variations in this gene may need at least a 20% reduction in warfarin dose. On average, this amounts to an average difference of about 3 mg for patients with different genotypes. VKORC1 variants have been estimated to occur in 14% to 37% of whites and blacks and in up to 89% of Asians.
Individuals with variation in both genes are at the highest risk for overanticoagulation and bleeding complications when exposed to conventional warfarin doses. Together, CYP2C9 and VKORC1 genotypes account for approximately 25% of the warfarin dose variability. When genotype information is combined with clinical information, such as smoking history, race and concomitant medications, upwards of 50% of the dosing variability can be explained.
In accordance with the FDA’s Critical Path Initiative (which seeks to utilize new scientific knowledge in drug development to enhance the health and well-being of all Americans), the FDA amended warfarin’s labeling in August 2007 to include a statement about the potential benefits of genetic information when dosing warfarin. This recommendation is based not only on many population-based observational studies but prospective studies as well, all of which suggests a strong correlation between genetic variability and warfarin dose. Two studies have now shown that adjusting warfarin dose at the beginning of therapy based on genotype information can reduce the need for dose adjustments and reduce the time to reach the target INR.
Practical issues
Genetic variability does not change warfarin volume of distribution or the half-life of the existing vitamin K dependent clotting factors, but understanding an individual’s genotype status is helpful to most efficiently determine the warfarin maintenance dose. Warfarin therapy should not be delayed if genotype data is not immediately available, and INR remains the gold standard for monitoring warfarin therapy. Many hospitals have genotyping capabilities and there are several CLIA-approved reference laboratories providing warfarin genotyping services. Testing can be accomplished with DNA isolated from either a blood sample (preferred) or from a cheek swab. Turnaround time varies from one to five days depending on which genotyping assay is used and how many genes are tested. Several CPT codes exist, and Medicare and other third party payers do reimburse for the cost of genotyping. Obtaining pre-approval from Medicare or insurance is recommended.
Once the genotype information is obtained, a dosing algorithm is used that incorporates genetic and other clinical factors to determine the optimal warfarin dose for the individual. A free website, warfarindosing.org, developed at the Barnes-Jewish Hospital at Washington University Medical Center and supported by the National Institutes of Health, utilizes a validated dosing algorithm to arrive at a warfarin dose estimate based on inputted genotype and clinical factors. Once an initial dose determination is estimated by the algorithm, subsequent INR values can be input for further dose refinement.
A large NIH study is planned this year that will incorporate genotype testing for warfarin dosing and assess multiple outcomes related to warfarin safety and efficacy. Until the results of this study and other studies are known, use of CYP2C9 and VKORC1 genotype to guide warfarin dosing will remain an FDA recommendation and not a requirement. However, this genotype-guided approach is a way to improve dose estimates in a more standardized, efficient way, which may ultimately avoid suboptimal dosing and reduce the risk of bleeding.
For more information:
- Rhonda Cooper-DeHoff, Pharm D, MS, FAHA, is Assistant Director of Clinical Programs and Research Assistant Professor in the Division of Cardiology at University of Florida College of Medicine, Gainesville. She is a member of the Cardiovascular Pharmacology Section of the Cardiology Today Editorial Board.
- Michael Pacanowski, PharmD, MPH is a Fellow in Cardiovascular Pharmacogenomics at the University of Florida College of Pharmacy, Center for Pharmacogenomics, Gainesville.
- Visit the free warfarin dosing website developed at Barnes-Jewish Hospital: www.warfarindosing.org.