Genetic Testing for Warfarin Dose
Does Not Apply to Commercial Genetic Testing Program effective 6/1/2018
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.
The following are examples or trade names of genetic tests:
Test Name (Manufacturer)
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.)
Genetic testing to determine cytochrome p450 2C9 (CYP2C9), vitamin K epoxide reductase subunit C1 (VKORC1), and CYP4F2 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 a stable International Normalized Ratio (INR) and reduce the risk of serious bleeding, is considered investigational.
Any specific products referenced in this policy are just examples and are intended for illustrative purposes only. It is not intended to be a recommendation of one product over another, and is not intended to represent a complete listing of all products available. These examples are contained in the parenthetical e.g. statement.
We develop Medical Policies to provide guidance to Members and Providers. This Medical Policy relates only to the services or supplies described in it. The existence of a Medical Policy is not an authorization, certification, explanation of benefits or a contract for the service (or supply) that is referenced in the Medical Policy. For a determination of the benefits that a Member is entitled to receive under his or her health plan, the Member's health plan must be reviewed. If there is a conflict between the Medical Policy and a health plan, the express terms of the health plan will govern.
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.
American College of Chest Physicians. (2016). Antithrombotic therapy for VTE Disease, CHEST guideline and expert panel report, 10th ed. Retrieved August 27, 2018 from www.journal.publications.chestnet.org.
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. Medical Policy Reference Manual. (6:2017). Genetic testing for warfarin dose (2.04.48). Retrieved September 25, 2017 from BlueWeb. (85 articles and/or guidelines reviewed)
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.
Lin, G., Yi, L., Zhang, K., Sun, Y., Wang, L., Zhang, R., et al. (2015). Improvements in CYP2C9 genotyping accuracy are needed: a report of the first proficiency testing for warfarin-related CYP2C0 and VKORC1 genotyping in China. Journal of Cardiovascular Pharmacology, 66 (2), 129-134. Abstract retrieved January 5, 2016 from PubMed database.
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)
Shahin, M. H., & Johnson, J. A. (May 2013). Clopidogrel and warfarin pharmacogenetic tests: what is the evidence for use in clinical practice? Current Opinion in Cardiology, 28 (3), 305-314. (Level 5 evidence)
Shaw, K., Amstutz, U., Kim, R., Lesko, L., Turgeon, J., Michaud, V., et al. (2015). Clinical practice recommendations on genetic testing of CYP2C9 and VKORC1 variants in Warfarin therapy. Therapeutic Drug Monitoring, 37 (4), 428-436. Abstract retrieved January 5, 2016 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.
U. S. Food and Drug Administration. (2007, September). Center for Devices and Radiological Health. 510(k) Premarket Notification Database. (Verigene®) K070804. Retrieved November 20, 2007 from http://www.accessdata.fda.gov.
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. Abstract retrieved September 25, 2017 from PubMed database.
ORIGINAL EFFECTIVE DATE: 4/11/2008
MOST RECENT REVIEW DATE: 11/8/2018
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