Genetic Testing for Warfarin Dose
Does Not Apply to Commercial Genetic Testing Program effective 6/1/2018
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 dose include body mass index, age, interacting drugs, and indications for therapy. Algorithms have been developed that incorporate genetic variations and other significant clinical factors to predict the best starting dose. It has been proposed that using the results of CYP2C9 and VKORC1 genetic testing to predict a warfarin starting dose can benefit individuals by decreasing the risk of serious bleeding events and the time to achieve a stable INR. Recent genome-wide association studies have also identified that a single nucleotide variant (SNV) in the CYP4F2 gene has been reported to account for a small proportion of the variability in stable dose. The CYP4F2 gene encodes a protein involved in vitamin K oxidation.
Several tests to help assess warfarin sensitivity by determining the presence or absence of the relevant CYP2C9, VKORC1, and CYP4F2 variants have been cleared by the U.S. Food and Drug Administration (FDA) for marketing. Similar tests also may be available as laboratory-developed services; laboratory-developed tests must meet the general regulatory standards of the Clinical Laboratory Improvement Amendments. These include Verigene® Warfarin Metabolism Nucleic Acid Test (Nanosphere); Infiniti® 2C9-VKORC1 Multiplex Assay for Warfarin (AutoGenomics); eQ-PRC™ LC Warfarin Genotyping Kit (Trimgen Corp.); eSensor® Warfarin Sensitivity Test (GenMark Dx.); Rapid Genotyping Assay (ParagonDx.).
POLICY
Genetic testing of cytochrome p450 2C9 (CYP2C9), vitamin K epoxide reductase subunit C1 (VKORC1), and CYP4F2 genetic polymorphisms to determine warfarin dosage and decrease time to a stable International Normalized Ratio (INR) is considered investigational.
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ADDITIONAL INFORMATION
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 or health outcomes with the use of genetic testing for determining warfarin dosage.
SOURCES
American College of Medical Genetics (ACMG). (2008). Pharmacogenetic testing of CYP2C9 and VKORC1 alleles for warfarin. Retrieved September 25, 2017 from http://www.acmg.net/docs/Pharmacogenetics_Alleles_for_Warfarin.pdf.
BlueCross BlueShield Association. Evidence Positioning System. (7:2023). Genotype-guided warfarin dosing (2.04.48). Retrieved April 30, 2024 from www.bcbsaoca.com/eps/. (88 articles and/or guidelines reviewed)
Canadian Pharmacogenomics Network for Drug Safety. (2015). Clinical practice recommendations on genetic testing of CYP2C9 and VKORC1 variants in Warfarin therapy. Retrieved February 24, 2023 from https://www.cpnds.ubc.ca/publications.
Centers for Medicare & Medicaid Services. CMS.gov. (2009) NCD for pharmacogenomics testing for warfarin response (90.1). Retrieved January 4, 2016 from http://www.cms.gov.
Clinical Pharmacogenetics Implementation Consortium (CPIC). (2017). Clinical Pharmacogenetics Implementation Consortium (CPIC) guideline for pharmacogenetics-guided warfarin dosing: 2017 update. Retrieved September 4, 2019 from https://cpicpgx.org.
Jorgensen, A.L., Prince, C., Fitzgerald, G., Hanson, A., Downing, J., Reynolds, J., et al. (2019). Implementation of genotype-guided dosing of warfarin with point-of-care genetic testing in three UK clinics: a matched cohort study. BMC Medicine, 17 (1), 76. (Level 4 evidence)
Pengo, V., Zambon, C., Fogar, P., Padoan, A., Nante, G., Pelloso, M., et al. (2015). A randomized trial of pharmacogenetic warfarin dosing in naïve patients with non-valvular atrial fibrillation. PLoS ONE, 10 (12), e0145318. Doi:10.1371/journal. (Level 2 evidence)
Sridharan, K., & Sivaramakrishnan, G. (2021). A network meta-analysis of CYP2C9, CYP2C9 with VKORC1 and CYP2C9 with VKORC1 and CYP4F2 genotype-based warfarin dosing strategies compared to traditional. Journal of Clinical Pharmacy and Therapeutics, 46 (3), 640–648. Abstract retrieved February 24, 2023 from PubMed database.
Tang, W., Shi, Q., Ding, F., Yu, M., Hua, J., & Wang, Y. (2017). Impact of VKORC1 gene polymorphisms on warfarin maintenance dosage: a novel systematic review and meta-analysis of 53 studies. International Journal of Clinical Pharmacology and Therapeutics, 55 (4), 304-321. Abstract retrieved September 25, 2017 from PubMed database.
Wang, X., Tang, B., Zhou, M., Liu, L., Feng, X., Wang, X., & Qiu, K. (2022). Efficacy and safety of genotype-guided warfarin dosing versus non-genotype-guided warfarin dosing strategies: A systematic review and meta-analysis of 27 randomized controlled trials. Thrombosis Research, 210, 42–52. Abstract retrieved February 24, 2023 from PubMed database.
Zhang, J., Tian, L, Huang, J., Huang, S., Chai, T., & Shen, J. (2017). Cytochrome P450 2C9 gene polymorphism and warfarin maintenance dosage in pediatric patients: a systematic review and meta-analysis. Cardiovascular Therapeutics, 35 (1), 26-32. (Level 2 evidence)
ORIGINAL EFFECTIVE DATE: 4/11/2008
MOST RECENT REVIEW DATE: 6/13/2024
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