Warfarin Institute of America
DEDICATED TO YOUR HEALTH SINCE 2000
State-of-the-Art Review
Warfarin and Genetic Dosing
by
Mandy J. Hemmert, Stephanie E.Cho, Charli J. Strebig,
Pharm D. Candidates University of Colorado School of Pharmacy
BACKGROUND
Mandy J. Hemmert
Warfarin(Coumadin®) is an anticoagulant medication used for prophylaxis and treatment of deep vein thrombosis, pulmonary embolisms and other thromboembolic disorders.1 Warfarin has the potential to interact with many other medications and some foods and often times, can be difficult to manage. Therefore, frequent monitoring of prothrombin time (PT) and/or international normalized ratio (INR) must be done. This is done through a simple blood test either by a finger prick or by a blood draw. If done by a finger prick, the test only takes several minutes to complete the entire process and results are available immediately. The main adverse effect of warfarin is bleeding. The risk of bleeding depends on patient specific variables and the intensity of anticoagulation. On the other hand, if patients aren’t anticoagulated enough, they run the risk of clotting. With its narrow therapeutic index, warfarin management can be very tedious. Patients who do not take warfarin usually have an INR of 1 or less. Patients who take warfarin usually have a goal INR between 2 and 3, but sometimes can be as high as 3.5. It has recently been proposed that genetic testing be completed in patients before they start taking warfarin to possibly prevent over or under anticoagulation and to improve the safety and efficacy of warfarin use.
Warfarin acts by interfering with hepatic synthesis of the following vitamin K-dependent factors; II, VII, IX, X.1 Warfarin is metabolized by the CYP2C9 enzyme and testing for variations in CYP2C9 could determine if a patient needs a higher or lower dose of warfarin due to altered metabolism. Currently there are two tests, CYP2C9 and VKORC1, that may show variations with the potential to affect warfarin dosing.2 The variant alleles of the CYP2C9 gene are CYP2C9*2 and CYP2C9*3 and if present, reduce the rate of warfarin metabolism, ultimately requiring a lower dose.3 Vitamin-K epoxide reductase complex 1 (VKORC1) is the target enzyme for warfarin and determines the drug’s site of action. VKORC1 variations lead to decreased levels of the vitamin-K dependent clotting factors.3 The VKORC1 variant may determine a patient’s sensitivity to warfarin and help determine appropriate dosing. Patients with a variation of VKORC1 most likely will require lower doses of warfarin due to increased sensitivity to the medication.3 The VKORC1 variant is generally high in Asians and low in African Americans. The CYP2C9 and VKORC1 together are thought to account for about 35-40% of warfarin dosing variability, with the remaining percentage being attributed to diet, exercise, weight, race, smoking status, other medical conditions and other medications.3
Several companies, including Clinical Data, Kimball Genetics and Genelex, are offering genetic testing for warfarin dosing. The price for both the CYP2C9 and VKORC1 tests ranges from $500 to $600. Although CMS and AMA recently suggested codes for billing and reimbursement for pharmacogenetic diagnostics.4
©2007 Mandy Hemmert
WARFARIN PHARMACOGENETICS RESEARCH
Stephanie E. Cho
With the completion of the human genome project and further understanding of the genetic framework of humans, pharmacogenetics, the study of genetic variation that gives rise to differing response to medications, has become a hugely expanding field. 2 Pharmacogenetic-guided warfarin dosing is currently an area of interest because we now understand genetic factors that differentiate people’s responses to warfarin and because warfarin is associated with several risks. The focus of pharmacogenetic research with warfarin is shifting from conceptual genetic and laboratory based data into actually incorporating genetic-based dosing into clinical practice with patients.
Current research topics include examining the occurrence of different CYP2C9 and VKORC1 genotypes and their effects on warfarin dosing, effectiveness, and safety, as well as comparing the outcomes of conventional warfarin dosing to warfarin dosing based on genetics. Several early warfarin genetic studies took DNA from patients already stabilized on warfarin and examined the trends of patient maintenance warfarin doses and their genotype. A study by Higashi and colleagues found that patients with variant CYP2CP genotypes (who are more sensitive to warfarin) had a higher risk of bleeding and it also took longer for them to reach their stable dosing compared to non-variant patients.5 A study by Reider and colleagues looked at 186 patients stabilized on warfarin and found that the average maintenance warfarin doses of the patients coincided with their VKORC1 genotype.6 Patients on average who were maintained on lower doses expressed warfarin-sensitive VKORC1 variant genes. Carlquist and colleagues estimated that carrying a CYP2C9 variant resulted in reduction of warfarin dose by 18-72% and carrying a VKORC1 variant reduced doses by 65% compared to non-variant genotypes.7
Studies are now examining the efficacy and applicability of pharmacogenetic-based dosing of warfarin into clinical practice. More head to head studies are emerging where warfarin pharmacogenetic-based dosing is directly compared to standard warfarin dosing. Hillman and colleagues performed a pilot study examining genetic-guided warfarin dosing in 38 patients. They found that patients in the genetic-guided dosing group experienced more accurate dosing.8
Caraco and colleagues expanded on this comparison of standard dosing versus genetic-guided and found that genetic guided (with CYP2C9 genotyping) resulted in reaching therapeutic INR and stable anticoagulation sooner and with fewer incidences of bleeds. It was concluded in this study that genetic-based dosing resulted in safer and more efficient patient outcomes.9 However, there is also conflicting data to these results. Although a study by Dr. Jeffrey Anderson and colleagues found that the genetic-guided resulted in more accurate doses and need for fewer and smaller dosing changes versus standard, they found that genetic dosing did not result in fewer INR’s out of therapeutic range, which was the study’s main goal. The current body of research in genetics and warfarin, though promising, is still inconclusive. More research is needed to determine the effectiveness, safety, and applicability of genetic warfarin dosing.
© Stephanie Cho
Implications of Warfarin and Genetic Dosing
Charli J. Strebig
The world of medicine has vastly increased its knowledge of the factors that contribute to patient-warfarin variability. It is now accepted that there is a distinct relationship between genetic variations in CYP2C9 and VKORC genotypes and the warfarin dose required to therapeutically treat patients.10-11 Despite our current knowledge of pharmacogenomics and clinical factors that effect warfarin therapy, the source of more than 40% of the variability remains unclear.10 Additional genetic factors, such as genes that encode vitamin-K dependent clotting factors or multidrug resistance genes, may be responsible for the observed variability. Unfortunately, there is limited information on these genetic variants and their effect on warfarin dosing is still unclear.
However, information from genetic testing for the CYP2C9 and VKORC genotypes variants could still help optimize drug efficacy while minimizing adverse drug reactions.10 Several clinic trials have been conducted which have proposed dosing algorithms which integrate genetics into warfarin dosing. It is thought that the algorithms that incorporate genetic, demographic and clinical factors to estimate warfarin dosage could potentially minimize the risk of overdose during warfarin induction and improve the quality of warfarin dose management.10-11 An FDA advisory panel stated that genetic testing of warfarin could reduce adverse events and improve achievement of stable INR.12 The evidence that supports the relationship of certain genotypes (CYP2C9 and VKORC1) and warfarin dosing may warrant a re-labeling of warfarin to include genetic test information.12 It is believed by many scientists and health care professionals that the use of this testing will dramatically improve warfarin efficacy and safety and reduce the occurrence of adverse outcomes.12
A cost-benefit analysis of pre-prescription genotyping during warfarin treatment is still needed to determine the overall benefit of performing such genetic tests. Some feel it may not be cost effective to genotype a large population of patients to identify the small minority that may be at a markedly higher risk of adverse effects.10 On the other hand, even a small reduction in the risk of major bleeding during warfarin therapy induction could make genotyping of patients cost-effective.10 However, these benefits are still to be determined. Although the discovery of certain genotypes and their influence on warfarin therapy is very substantial, it may not be the most optimal method for managing patients.
The use of genetic information in the treatment and management of patients offers many potential clinical benefits, but may also provide many challenges. A warfarin-dosing regimen using clinical data and pharmacogenomic information could benefit many patients, however, further studies are still required before this type of testing will be incorporated into routine practice.1 Future research will also be needed to assess patient preferences and willingness to pay for these genetic tests.13 The balance between the benefits of using of genetic testing to determine warfarin dose and costs to use such technology also needs to be assessed in regards to providers, industry, insurers and government as well.13 The use of genetic testing is likely to have a positive impact on patients using warfarin therapy. However, like all new technologies, further investigation is needed to fully understand what the overall result may be.
©2007 Charli Strebig
References:
1. Lacy CF, Armstrong LL, Goldman MP, Lance LL. Drug Information Handbook, 16th ed. Hudson, Ohio, Lexi-Comp, Inc.; 2007: 1143-7.
2. Anderson JL, Horne BD, Stevens SM, Grove AS, Barton S, Nicholas ZP, et al. Randomized Trial of Genotype-Guided Versus Standard Warfarin Dosing in Patients Initiating Oral Anticoagulation. Journal of the American Heart Association 2007; 116: 1-8.
3. Warfarin Sensitivity DNA Test. Genetics and Health Web site. Available at: http://www.geneticsandhealth.com. Accessed November 15, 2007.
4. Warfarin (Coumadin) and DNA. Health and DNA Web site. Available at http://www.healthanddna.com/warfarin.html. Accessed November 15, 2007.
5. Higashi MK, Veenstra DL, Kondo LM, Wittkowsky AK, Srinouanprachanh SL, Farin FM, Rettie AE. Association between CYP2C9 genetic variants and anticoagulation-related outcomes during warfarin therapy. JAMA 2002; 287(13): 1690-1698.
6. Reider MJ, Reiner AP, Gage BF, Nickerson DA, Eby CS, McLeod HL, Blough DK, Thummel KE, Veenstra DL, Rettie AE. Effect of VKORC1 haplotypes on transcriptional regulation and warfarin dose. NEJM 2005;352:2285-2293.
7. Carlquist JF, Horne BD, Mublestein JB, Lappe DL, Whiting BM, Koleck MJ, Clarke JI, James BC and Anderson JL. Genotypes of the cytochrome p450 CYP2C9 and the vitamin K epoxide reductase complex subunit 1 conjointly determine stable warfarin dose: a prospective study. J Thromb Throbolysis 2006; 22:191-197.
8. Hillman MA, Wilke RA, Yale SH, Vidaillet HJ, Caldwell MD, Blurich I, Berg RL, Schmelzer J, Burmester JK. A prospective, randomized pilot trial of model-based warfarin dose initiation using CYP2C9 genotype and clinical data. Clinical Medicine and Research 2005; 3(3): 137-145.
9. Caraco Y, Blotnick S, Muszkat M. CYP2C9 genotype-guided warfarin prescribing enhances the efficacy and safety of anticoagulation: a prospective randomized controlled study. Clinical Pharmacology and Therapeutics. September 12, 2007. DOI:10.1038/sj.clpt.6100316. Available at: http://www.nature.com/clpt/journal.
10. Yin T, Miyata T. Warfarin dose and the pharmacogenomics of CYP2C9 and VKORC – Rationale and perspectives. Thrombosis Research 2007; 120: 1-10.
11. Lippi G, Salvagno GL, Guidi GC. Genetic Analysis to prevent warfarin complications. CMAJ August 2007; 177(4): 377.
12. Warfarin (Coumadin) and DNA. Health and DNA Web site. Available at http://www.healthanddna.com/warfarin.html. Accessed November 19, 2007.
13. Phillips KA, Veenstra DL, Ramsey SD, Van Bebber SL, Sakowski J. Genetic Testing and Pharmacogenomics: Issues for Determining the Impact to Healthcare and Delivery Costs. American Journal of Managed Care July 2004; 10(7): 425-432.
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Last updated December 2, 2007