Genetic Testing for Warfarin Dose

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.

IMPORTANT REMINDERS

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 or government program (e.g., TennCare), the express terms of the health plan or government program will govern.

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

ID_BA

Policies included in the Medical Policy Manual are not intended to certify coverage availability. They are medical determinations about a particular technology, service, drug, etc. While a policy or technology may be medically necessary, it could be excluded in a member's benefit plan. Please check with the appropriate claims department to determine if the service in question is a covered service under a particular benefit plan. Use of the Medical Policy Manual is not intended to replace independent medical judgment for treatment of individuals. The content on this Web site is not intended to be a substitute for professional medical advice in any way. Always seek the advice of your physician or other qualified health care provider if you have questions regarding a medical condition or treatment.

This document has been classified as public information.