Genotype-Guided Warfarin Dosing

POLICY NUMBER

A.2.04.48

DESCRIPTION

Using information about an individual’s genotype may help in guiding warfarin dosing and could reduce the time to dose stabilization and selection of an appropriate maintenance dose that might avoid the consequences of too much or too little anticoagulation.

Warfarin

Warfarin is administered to prevent and treat thromboembolic events in high-risk patients; warfarin dosing is a challenging process, due to the narrow therapeutic window, variable response to dosing, numerous drug interactions, and serious bleeding events in 5% or more of patients (depending on definition). Patients are typically given a starting dose of 2 mg to 5 mg and frequently monitored with dose adjustments until a stable international normalized ratio (INR) value (a standardized indicator of clotting time) between 2 and 3 is achieved (depending on indication). During this adjustment period, a patient is at high-risk for bleeding. Stable or maintenance warfarin dose varies among patients by more than an order of magnitude. Factors influencing stable dose include body mass index, age, interacting drugs, and indication for therapy.

Enzyme Variant Impact on Warfarin Metabolism

Warfarin, which is primarily metabolized in the liver by the cytochrome P450 2C9 (CYP2C9) enzyme, exerts an anticoagulant effect by inhibiting the protein vitamin K epoxide reductase complex, subunit 1 (VKORC1). Three single-nucleotide variants, two in the CYP2C9 gene and one in the VKORC1 gene play key roles in determining the effect of warfarin therapy on coagulation. CYP2C9*1 metabolizes warfarin normally, CYP2C9*2 reduces warfarin metabolism by 30%, and CYP2C9*3 reduces warfarin metabolism by 90%. Because warfarin given to patients with *2 or *3 variants will be metabolized less efficiently, the drug will remain in circulation longer, so lower warfarin doses will be needed to achieve anticoagulation. CYP2C9 and VKORC1 genetic variants account for approximately 55% of the variability in warfarin maintenance dose. Genome-wide association studies have also identified that a single nucleotide variant 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). Studies have predicted that CYP4F2 variants explain 2% to 7% of the variability in warfarin dose in models, including other genetic and nongenetic factors.

Using the results of CYP2C9 and VKORC1 genetic testing to predict a warfarin starting dose that approximates a likely maintenance dose may benefit patients by decreasing the risk of serious bleeding events and the time to stable international normalized ratio. Algorithms have incorporated not only genetic variation but also other significant patient characteristics and clinical factors to predict the best starting dose. Studies have compared the ability of different algorithms to predict a stable warfarin dose accurately. Currently, there does not appear to be a consensus for a single algorithm.

Several studies have examined associations between CYP2C9 and VKORC1 variants and warfarin dosing requirements in children.

There are different frequencies of variants related to warfarin pharmacokinetics across different races and ethnicities. Many of the original studies identifying associations between genes and prediction of warfarin dosing as well as studies developing algorithms were derived from cohorts composed largely of people of European descent. Evidence has suggested these algorithms do not perform as well in other ethnic groups. For example, CYP2C9*2 and CYP2C9*3 are not as useful in predicting warfarin dosing in Black individuals, but other important variants have been identified such as CYP2C9*5, *6, *8, and *11. Studies have also identified new genetic variants and/or evaluated clinical genetic algorithms for warfarin dose in Black, Puerto Rican, Thai, Egyptian, Chinese, Japanese, Arabic, Turkish, African, Russian, and Scandinavian populations.

Several tests to help assess warfarin sensitivity, by determining the presence or absence of the relevant CYP2CP,VKORC1, and CYP4F2 variants, have been cleared by the U.S. Food and Drug Administration (FDA) for marketing (see the table below). Similar tests also may be available as laboratory-developed services; laboratory-developed tests must meet the general regulatory standards of the Clinical Laboratory ImprovementAmendments.The tests are not identical regarding the specific variants and number of variants detected. Generally,such tests are not intended as stand-alone tools to determine optimum drug dosage, but should be used with clinical evaluation and other tools, including the international normalized ratio, to predict the initial dose that best approximates the maintenance dose for patients.

FDA-Cleared Warfarin Tests

^{CYP2C9: cytochrome P450 2C9 enzyme; FDA: Food and Drug Administration; VKORC1: vitamin K epoxide reductase complex, subunit 1.a} eSensor Warfarin Plus Test offers testing for CYP2C9*2, *3, *5, *6, *11, *14, *15, and *16, VKORC1 1639G>A, and CYP4F2.^b Langley et al (2009) reported a turnaround time of 1.5 hours for the ParagonDx SmartCycler, which may be a precursor assay.^c The expanded Infiniti CYP450 2C9 assay offers testing for CYP2C9*2, *3, *4, *5, *6, and *11,VKORC1 1639G>A, and 6 other VKORC variants.

In 2007, the FDA approved updated labeling for warfarinto include information on testing for gene variants that may help “personalize” the starting dose for each patient and reduce the number of serious bleeding events. The label was updated again in 2010. With each update, manufacturers of warfarin were directed to add similar information to their product labels. The 2010 update added information on guiding initial dose by genotyping results for CYP2C9 and VKORC1, providing a table of genotypes and suggested initial dose ranges for each. However, suggested starting doses are also provided when genotyping information is unavailable, indicating that genetic testing is not required. Furthermore, the FDA did not include information on genetic variation in the label’s black box warning regarding bleeding risk.

POLICY

Genotyping to determine cytochrome P450 2C9 (CYP2C9), P450 4F2 (CYP4F2), and vitamin K epoxide reductase subunit C1 (VKORC1) genetic variants is considered investigational for the purpose of managing the administration and dosing of warfarin, including use in guiding the initial warfarin dose to decrease time to stable international normalized ratio and to reduce the risk of serious bleeding.

POLICY EXCEPTIONS

Federal Employee Program (FEP) may dictate that all FDA-approved devices, drugs or biologics may not be considered investigational and thus these items may be assessed only on the basis of their medical necessity.

POLICY GUIDELINES

The coverage guidelines outlined in the Medical Policy Manual should not be used in lieu of the Member’s specific benefit plan language.

Investigative is defined as the use of any treatment procedure, facility, equipment, drug, device, or supply not yet recognized as a generally accepted standard of good medical practice for the treatment of the condition being treated and; therefore, is not considered medically necessary. For the definition of Investigative, “generally accepted standards of medical practice” means standards that are based on credible scientific evidence published in peer-reviewed medical literature generally recognized by the relevant medical community, and physician specialty society recommendations, and the views of medical practitioners practicing in relevant clinical areas and any other relevant factors. In order for equipment, devices, drugs or supplies [i.e, technologies], to be considered not investigative, the technology must have final approval from the appropriate governmental bodies, and scientific evidence must permit conclusions concerning the effect of the technology on health outcomes, and the technology must improve the net health outcome, and the technology must be as beneficial as any established alternative and the improvement must be attainable outside the testing/investigational setting.

POLICY HISTORY

1/20/2009: Policy added.

5/13/2010: Policy description section revised to include language about test kits cleared for marketing by the FDA; FEP verbiage added to the Policy Exceptions section; Investigative language added to the Policy Guidelines section; and Code Reference section was updated to add HCPCS Code G9413 to the Non-Covered Codes Table.

02/23/2011: Policy reviewed; no changes.

01/18/2012: Policy reviewed; no changes.

01/10/2013: Added CPT codes 81227 and 81355 to the Code Reference section.

03/10/2014: Policy reviewed; no changes.

01/21/2015: Policy description updated regarding product labeling information. Policy statement unchanged. Removed deleted CPT codes 88384, 88385, and 88386 from the Code Reference section.

07/30/2015: Code Reference section updated for ICD-10.

12/31/2015: Investigative definition updated in policy guidelines section. Code Reference section updated to revise the code description for CPT code 81355 with an effective date of 01/01/2016.

01/15/2016: Policy description updated regarding laboratory-developed tests. Policy statement unchanged.

06/06/2016: Policy number A.2.04.48 added.

07/12/2017: Policy description updated regarding effects of warfarin therapy. Policy statement unchanged. Policy Guidelines updated regarding standard terminology for variant classification and to add genetic counseling information.

09/24/2018: Policy title changed from "Genetic Testing for Warfarin Dose" to "Genotype-Guided Warfarin Dosing." Policy description updated regarding warfarin tests and studies examining associations between CYP2C9 and VKORC1 variants. Policy statement updated to include genotyping to determine CYP4F2 as investigational. Policy Guidelines updated regarding genetic counseling. Code Reference section updated to add CPT code 0030U.

07/15/2019: Policy reviewed; no changes.

07/13/2020: Policy description updated regarding FDA-cleared warfarin tests. Policy statement unchanged. Policy Guidelines updated to remove genetics nomenclature and genetic counseling information.

08/26/2021: Policy description updated regarding populations with new genetic variants and/or evaluated clinical genetic algorithms for warfarin dose. Policy statement unchanged.

07/14/2022: Policy description updated to add section headings. Policy statement unchanged.

08/02/2023: Policy description updated. Policy statement unchanged.

07/23/2024: Policy description updated with minor changes. Policy statement unchanged.

08/21/2025: Policy reviewed; no changes.

SOURCE(S)

Blue Cross Blue Shield Association policy # 2.04.48

CODE REFERENCE

This may not be a comprehensive list of procedure codes applicable to this policy.

Investigational Codes

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