Genetic Testing for Warfarin Dose
DESCRIPTION
Warfarin is administered for preventing and treating thromboembolic events in high risk individuals. Warfarin dosing can be a challenging process, due to the narrow therapeutic window, variable response to dosing, and bleeding events. Individuals are typically initiated on a starting dose and monitored frequently with dose adjustments until a stable International Normalized Ratio (INR) value (a standardized indicator of clotting time) between 2 and 3 is achieved. Factors influencing a stable dose include body mass index, age, interacting drugs, and indication for therapy. In addition, genetic variants of cytochrome p450 2C9 (CYP2C9) and vitamin K epoxide reductase subunit C1 (VKORC1) genes together account for a substantial proportion of inter-individual variability. Using the results of CYP2C9 and VKORC1genetic testing to predict a warfarin starting dose that approximates the individual patient’s likely maintenance dose allegedly benefits individuals by decreasing the risk of serious bleeding events and the time to stable INR.
In September 2007, the U.S. Food and Drug Administration (FDA) approved a new genetic test (e.g., Nanosphere Verigene Warfarin Metabolism Nucleic Acid Test) to help assess warfarin sensitivity.
POLICY
Genetic testing to determine cytochrome p450 2C9 (CYP2C9) and vitamin K epoxide reductase subunit C1 (VKORC1) genetic polymorphisms for the purpose of managing the administration and dosing of warfarin, including use in guiding the initial warfarin dose to decrease time to stable the International Normalized Ratio (INR) and reduce the risk of serious bleeding is considered investigational.
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ADDITIONAL INFORMATION
According to the FDA web site: Healthcare professionals are not required to conduct CYP2C9 and VKORC1 testing before initiating warfarin therapy, nor should genetic testing delay the start of warfarin therapy. Genetic testing is not appropriate for individuals already on Warfarin. Genetic testing does not replace International Normalized Ratio (INR) monitoring. Based on available evidence, not all individuals with one or more genetic variants in CYP2C9 or VKORC1 will have a serious bleeding event, nor will all individuals without gene variants avoid a bleeding episode. The current literature does not validate any improved efficacy, treatment management or health outcomes with the use of genetic testing for determining warfarin dosage.
SOURCES
Anderson, J., Horne, B., Stevens, S., Grove, A., Barton, S., Nicholas, Z. et al. (2007). Randomized trialof genotype-guided versus standard warfarin dosing in patients initiating oral anticoagulation. Circulation, 116 (22), 2563-70. (Level 2 Evidence - Independent)
BlueCross BlueShield Association. Medical Policy Reference Manual. (12:2010). Genetic testing for warfarin dose (2.04.48). Retrieved August 17, 2011 from BlueWeb. (43 articles and/or guidelines reviewed)
Caldwell, M., Awad, T., Johnson, J., Gage, B., Falkowski, M., Gardina, P., et al. (2008). CYP4F2 genetic variant alters required warfarin dose. Blood, 111 (8), 4106 - 4112. (Level 4 Evidence - Industry Sponsored)
ECRI Institute. Health Technology Information Service. Emerging Technology. Evidence Report. (2010, April). Pharmacogenetic testing to determine warfarin dose. Retrieved August 24, 2011 from ECRI Institute. (70 articles and/or guidelines reviewed)
French, B., Joo, J., Geller, N., Kimmel, S., Rosenberg, Y., Anderson, J., et al. (2010). Statistical design of personalized medicine interventions: The Clarification of Optimal Anticoagulation through Genetics (COAG) trial Trials, 11 (108), 1 - 9.
Hillman, M. A., Wilke, R. A., Yale, S. H., Vidaillet, H. J., Caldwell, M. D., Glurich, I., et al. (2005). A prospective, randomized pilot trial of model-based warfarin dose initiation using CYP2C9 genotype and clinical data. Clinical Medicine & Research, 3 (3), 137-145. (Level 1 Evidence - Independent)
International Warfarin Pharmacogenetics Consortium, Klein, T., Altman, R., Eriksson, N., Gage, B., Kimmel, S., Lee, M., et al. (2009). Estimation of the warfarin dose with clinical and pharmacogenetic data. New England Journal of Medicine, 360 (8), 753 - 764. (Level 4 Evidence - Independent)
Kangelaris, K., Bent, S., Nussbaum, R., Garcia, D., & Tice, J. (2009). Genetic testing before anticoagulation? A systematic review of pharmacogenetic dosing of warfarin. Journal of General Internal Medicine, 24 (5), 656 - 664. (Level 1 Evidence - Independent)
Lee, S. Y., Nam, M. H., Kim, J. S., & Kim, J. W. (2007). A case report of a patient carrying CYP2C9*3/4 genotype with extremely low warfarin dose requirement. Journal of Korean Medical Science, 22 (3), 557-559. (Level 5 Evidence)
Lyon, E., McMillin, G., & Melis, R. (2008). Pharmacogenetic testing for warfarin sensitivity. Clinics in Laboratory Medicine, 28 (4), 525 - 537. (Level 5 Evidence)
Sconce, E. A., Khan, T. I., Wynne, H. A., Avery, P., Monkhouse, L., King, B. P., et al. (2005). The impact of CYP2C9 and VKORC1 genetic polymorphism and patient characteristics upon warfarin dose requirements: Proposal for a new dosing regimen. Blood, 106 (7), 2329 - 2333. (Level 4 Evidence - Independent)
Takeuchi, F., McGinnis, R., Bourgeois S., Barnes, C., Eriksson, n., Soranzo, N., et all. (2009). A genome-wide association study confirms VKORC1, CYP2C9, and CYP4F2 as principal genetic determinants of warfarin dose. PLoS Genetics, 5 (3), e 1000433. (Level 5 evidence - Independent)
Technology Evaluation Center. (2004, December). Special report: Genotyping for cytochrome P450 polymorphisms to determine drug-metabolizer status (Vol. 19, No. 9). Chicago: BlueCross BlueShield Association. (67 articles and/or guidelines reviewed)
U. S. Food and Drug Administration. (2007, September). Center for Devices and Radiological Health. 510(k) Premarket Notification Database. K070804. Retrieved November 20, 2007 from http://www.accessdata.fda.gov/scripts/cdrh/cfdocs/cfPMN/pmn.cfm?ID=24413.
Wadelius, M., Sorlin, K., Wallerman, O., Karlsson, J., Yue, Q. Y., Magnusson, P. K., et al. (2004). Warfarin sensitivity related to CYP2C9, CYP3A5, ABCB1 (MDR1) and other factors. The Pharmacogenomics Journal, 4 (1), 40 - 48. (Level 4 Evidence - Independent)
ORIGINAL EFFECTIVE DATE: 4/11/2008
MOST RECENT REVIEW DATE: 10/13/2011
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