Notification Issue Date:

Policy Attachment

Attachment to Policy # MA06.008b


Policy #:MA06.008b

Description:Pharmacogenomic testing (CYP2C9 or VKORC1 alleles) for predicting warfarin response

Title:Pharmacogenetic Testing to Determine Drug Sensitivity

The Coding Table lists any CPT, ICD-9, ICD-10, and HCPCS billing codes related only to the specific policy in which they appear.

Title: Pharmacogenomic Testing (CYP2C9 or VKORC1 alleles) for Predicting Warfarin Response


Coverage is subject to the terms, conditions, and limitations of the member's Evidence of Coverage.

Genotyping for the purpose of managing the administration and dosage of warfarin may be a covered service when an individual is enrolled in a prospective, randomized, controlled clinical study when such study meets the standards listed under Nationally Covered Indications as indicated in Centers for Medicare and Medicaid Services (CMS) NCD 90.1. For complete information on Medicare Requirements for Coverage with Evidence Development (CED), please refer to the Centers for Medicare and Medicaid Services National Coverage Decision 90.1, "Pharmacogenomic Testing for Warfarin Response," available at this link:

Genotyping for the purpose of managing the administration and dosing of warfarin, including use in guiding the initial warfarin dose to decrease time to stable INR and reduce the risk of serious bleeding, outside of an approved CED study, is considered experimental/investigational and, therefore, not covered because the safety and/or efficacy cannot be established by review of the available published peer-reviewed literature.

Claims for genotyping for the purpose of managing the administration and dosage of warfarin should be submitted to the Medicare Advantage plan.

The individual's medical record must reflect the medical necessity for the care provided. These medical records may include, but are not limited to: records from the professional provider's office, hospital, nursing home, home health agencies, therapies, and test reports.

The Company may conduct reviews and audits of services to our members, regardless of the participation status of the provider. All documentation is to be available to the Company upon request. Failure to produce the requested information may result in a denial for the service.


This policy is consistent with Medicare's coverage determination. The Company's reimbursement methodology may differ from Medicare.


Determination of medical necessity requirements for genotyping for the purpose of managing the administration and dosage of warfarin will be through the local Medicare Administrative Contractor (MAC) when the service is part of an approved CED study.

Subject to the terms and conditions of the applicable Evidence of Coverage, genetic testing for management of warfarin (Coumadin®) dosing is not eligible for payment under the medical benefits of the Company's Medicare Advantage products outside of an approved CED study because the service is considered experimental/investigational and, therefore, not covered.


Genetic testing is a laboratory procedure and is historically not regulated by the US Food and Drug Administration (FDA). Clinical Laboratory Improvement Amendments (CLIA) establishes quality standards for all laboratory testing. However, recently, the FDA is reported to be involved in the evaluation of the service of genetic testing.


In individuals at risk for untoward cardiac events, warfarin (trade names: Coumadin®, Jantoven®, Marevan®) is prescribed specifically to prevent or treat thrombosis. It is difficult to achieve the optimal dose of this agent due to several factors: its narrow therapeutic window, variable response to dosing, and serious bleeding events in 5% or more of patients. In many instances, individuals beginning this treatment are given a starting dose of 2-5 mg, are frequently monitored, and receive dosage adjustments as needed until a stable International Normalized Ratio (INR) value (a standardized indicator of clotting time) between 2 and 3 is achieved. The individual is at high risk for bleeding until the INR has been stabilized.

Many factors can influence the ability to achieve a stable warfarin dose, including body mass index, age, interaction with food and drugs, the individual's nutritional state, and individual compliance. Additionally, variability is also influenced by genetic variants of Cytochrome p450 2C9 (CYP2C9) and vitamin K epoxide reductase subunit C1 (VKORC1) genes. Variability is also influenced, albeit to a lesser degree, by a single nucleotide polymorphism (SNP; change in a single base-pair in a DNA sequence) in the CYP4F2 gene.

Using the results of CYP2C9 and VKORC1 genetic testing to predict a warfarin starting dose that approximates the individual patient’s likely maintenance dose may benefit patients by decreasing the risk of serious bleeding events and the time to stable INR. Algorithms have also been developed that incorporate not only genetic variation but also other significant patient characteristics and clinical factors to predict the best starting dose. However, a review of the literature indicates that, although studies have been published using various algorithms (including CYP2C9 and VKORC1 information, patient characteristics, concurrently administered interacting drugs, and other variables), some algorithms specifically excluded patient populations that concurrently used drugs that interacted with warfarin.

Several steps are required in order to validate the individual's genotyping to improve pharmacologic treatment outcomes. In general, important steps in the validation process address the following:
  • Analytic validity: measures technical performance, ie, whether the test accurately and reproducibly detects the gene markers of interest.
  • Clinical validity: measures the strength of the associations between the selected genetic markers and dose, therapeutic efficacy, and/or adverse events.
  • Clinical utility: determines whether the use of genotyping for specific genetic markers to guide prescribing and/or dosing improves patient outcomes such as therapeutic effect, time to effective dose, and/or adverse event rate compared to standard treatment without genotyping.

A recent systematic review, commissioned by the American College of Medical Genetics, evaluated CYP2C9 and VKORC1 genetic testing prior to warfarin dosing and concluded the following:
  • Clinical validity: CYP2C9 and VKORC1 genotypes contribute significant and independent information to the stable warfarin dose and, compared to the most common combination, some individuals with other genotype combinations will need more than the usual dose, while others will require less.
  • Clinical utility: The purpose of genetic testing in this clinical scenario is to predict an individual’s likely stable warfarin dose by incorporating demographic, clinical, and genotype data (CYP2C9 and VKORC1), and to initiate warfarin at that predicted dose in order to limit high International Normalized Ratio (INR) values (over-anticoagulation) that are associated with an increased risk of serious bleeding events. No large study has yet shown this to be acceptable or effective. Based on limited clinical data, the number needed to treat in order to avoid one serious bleeding event is estimated to range from 48 to 385.

The American College of Chest Physicians Evidence-Based Clinical Practice Guidelines on Antithrombotic and Thrombolytic Therapy, 8th edition (2008, with re-review in 2009) published the following statement relative to initiation and maintenance dosing of warfarin: "At the present time, for patients beginning VKA (vitamin K antagonist) therapy, without evidence from randomized trials, we suggest against the use of pharmacogenetic-based initial dosing to individualize warfarin dosing."

While there is supporting evidence of a strong association between genetic variants and stable warfarin dose, and, to a lesser extent, between genetic variants and INR and bleeding outcomes, the clinical utility (clinical outcomes) is not currently established. Several large clinical trials, including some that are randomized, strive to address clinical utility. However, at this time, there does not appear to be consensus for one single algorithm that can be generalized for a diverse patient population and that has been validated by a large, prospective, representative cohort study.


Anderson JL, Horne BD, Stevens SM, et al. Randomized trial of genotype-guided versus standard warfarin dosing in patients initiating oral anticoagulation. Circulation. 2007;116(22):2563-70.

Blue Cross Blue Shield Association. Technology Evaluation Center 2004. TEC Special Report: Genotyping for Cytochrome P450 Polymorphisms to Determine Drug-Metabolizer Status.

Borgiani P, Ciccacci C, Forte V, et al. CYP4F2 genetic variant (rs2108622) significantly contributes to warfarin dosing variability in the Italian population. Pharmacogenomics. 2009;10(2):261-266.

Caldwell MD, Awad T, Johnson JA, et al. CYP4F2 genetic variant alters required warfarin dose. Blood. 2008;111(8):4106-4112.

Center for Medicare and Medicaid Services. National Coverage Analysis Decision Memo. Pharmacogenetic Testing for Warfarin Response. August 3, 2009. Available at: Accessed July 31, 2013.

Center for Medicare and Medicaid Services. National Coverage Determinations. Pharmacogenetic Testing for Warfarin Response (NCD 90.1) 08/03/2009. Available at: Accessed July 31, 2013.

D'Andrea G, D'Ambrosio RL, Di Perna P, et al. A polymorphism in the VKORC1 gene is associated with an interindividual variability in the dose-anticoagulant effect of warfarin. Blood. 2005;105(2):645-9.

Eckman MH, Rosand J, Greenberg SM, et al. Cost-effectiveness of using pharmacogenetic information in warfarin dosing for patients with nonvalvular atrial fibrillation. Ann Intern Med. 2009;150(2):73-83.

Gage BF, Eby C, Milligan PE, et al. Use of pharmacogenetics and clinical factors to predict the maintenance dose of warfarin. Thromb Haemost. 2004;91(1):87-94.

Gage BF, Eby C, Johnson JA, et al. Use of pharmacogenetic and clinical factors to predict the therapeutic dose of warfarin. Clin Pharmacol Ther. 2008;84(3):326-31.

Geisen C, Watzka M, Sittinger K, et al. VKORC1 haplotypes and their impact on the inter-individual and inter-ethnical variability of oral anticoagulation. Thromb Haemost. 2005;94(4):773-9.

Hatch E, Wynne H, Avery P, et al. Application of a pharmacogenetic-based warfarin dosing algorithm derived from British patients to predict dose in Swedish patients. J Thromb Haemost. 2008;6(6):1038-40.

Hillman MA, Wilke RA, Caldwell MD et al. Relative impact of covariates in prescribing warfarin according to CYP2C9 genotype. Pharmacogenetics. 2004;14(8):539-47.

Hillman MA, Wilke RA, Yale SH, et al. A prospective, randomized pilot trial of model-based warfarin dose initiation using CYP2C9 genotype and clinical data. Clin Med Res. 2005;3(3):137-45.

Hirsh J, Guyatt G, Albers GW, et al., American College of Chest Physicians. Antithrombotic and thrombolytic therapy: American College of Chest Physicians Evidence-Based Clinical Practice Guidelines (8th Edition). Chest. 2008;133(6 suppl):110S-112S.

The International Warfarin Pharmacogenetics Consortium. Estimation of the warfarin dose with clinical and pharmacogenetic data. N Engl J Med. 2009;360(8):753-64.

Jonas DE, McLeod HL. Genetic and clinical factors relating to warfarin dosing. Trends Pharmacol Sci. 2009;30(7):375-86.

Kangelaris KN, Bent S, Nussbaum RL, et al. Genetic testing before anticoagulation? A systematic review of pharmacogenetic dosing of warfarin. J Gen Intern Med. 2009;24(5):656-64.

King CR, Porche-Sorbet RM, Gage BF, et al. Performance of commercial platforms for rapid genotyping of polymorphisms affecting warfarin dose. Am J Clin Pathol. 2008;129(6):876-83.

Langley MR, Booker JK, Evans JP, et al. Validation of clinical testing for warfarin sensitivity: Comparison of CYP2C9-VKORC1 genotyping assays and warfarin-dosing algorithms. J Mol Diagn. 2009;11(3):216-225.

Leey JA, McCabe S, Koch JA, et al. Cost-effectiveness of genotype-guided warfarin therapy for anticoagulation in elderly patients with atrial fibrillation. Am J Geriatr Pharmacother. 2009;7(4):197-203.

Limdi NA, Wiener H, Goldstein JA, et al. Influence of CYP2C9 and VKORC1 on warfarin response during initiation of therapy. Blood Cells Mol Dis. 2009;43(1):119-28.

McClain MR, Palomaki GE, Piper M, et al. A rapid ACCE1 review of CYP2C9 and VKORC1 allele testing to inform warfarin dosing in adults at elevated risk for thrombotic events to avoid serious bleeding. Genet Med. 2008;10(2):89-98.

Meckley LM, Wittkowsky AK, Rieder MJ, et al. An analysis of the relative effects of VKORC1 and CYP2C9 variants on anticoagulation related outcomes in warfarin-treated patients. Thromb Haemost. 2008;100(2):229-39.

Millican E, Lenzini PA, Milligan PE, et al. Genetic-based dosing in orthopaedic patients beginning warfarin therapy. Blood. 2007;110(5):1511-5.

Patrick AR, Avorn J, Choudhry NK. Cost-effectiveness of genotype-guided warfarin dosing for patients with atrial fibrillation. Circ Cardiovasc Qual Outcomes. 2009;2(5):429-36.

Pautas E, Moreau C, Gouin-Thibault I, et al. Genetic factors (VKORC1, CYP2C9, EPHX1, and CYP4F2) are predictor variables for warfarin response in very elderly, frail inpatients. Clin Pharmacol Ther. 2009;87(1):57-64.

Rieder MJ, Reiner AP, Gage BF, et al. Effect of VKORC1 haplotypes on transcriptional regulation and warfarin dose. N Engl J Med. 2005;352(22):2285-93.

Rosove MH, Grody WW. Should we be applying warfarin pharmacogenetics to clinical practice? No, not now. Ann Intern Med. 2009;151(4):270-3.

Schelleman H, Chen J, Chen Z, et al. Dosing algorithms to predict warfarin maintenance dose in Caucasians and African Americans. Clin Pharmacol Ther. 2008;84(3):332-9.

Schwarz UI, Ritchie MD, Bradford Y, et al. Genetic determinants of response to warfarin during initial anticoagulation. N Engl J Med. 2008;358(10):999-1008.

Sconce EA, Khan TI, Wynne HA, et al. The impact of CYP2C9 and VKORC1 genetic polymorphism and patient characteristics upon warfarin dose requirements: proposal for a new dosing regimen. Blood. 2005;106(7):2329-33.

Takeuchi F, McGinnis R, Bourgeois S, et al. A genome-wide association study confirms VKORC1, CYP2C9, and CYP4F2 as principal genetic determinants of warfarin dose. PLoS Genet. 2009;5(3): e1000433.

Wadelius M, Chen LY, Downes K, et al. Common VKORC1 and GGCX polymorphisms associated with warfarin dose. Pharmacogenomics J. 2005;5(4):262-70.

Wadelius M, Chen LY, Eriksson N, et al. Association of warfarin dose with genes involved in its action and metabolism. Hum Genet. 2007;121(1):23-34.

Wadelius M, Chen LY, Lindh JD, et al. The largest prospective warfarin-treated cohort supports genetic forecasting. Blood. 2009;113(4):784-92.

Wadelius M, Sorlin K, Wallerman O, et al. Warfarin sensitivity related to CYP2C9, CYP3A5, ABCB1 (MDR1) and other factors. Pharmacogenomics J. 2004;4(1):40-8.

Wen MS, Lee M, Chen JJ, et al. Prospective study of warfarin dosage requirements based on CYP2C9 and VKORC1 genotypes. Clin Pharmacol Ther. 2008;84(1):83-9.

Wu AH, Wang P, Smith A, et al. Dosing algorithm for warfarin using CYP2C9 and VKORC1 genotyping from a multi-ethnic population: comparison with other equations. Pharmacogenomics. 2008;9(2):169-78.

Yuan HY, Chen JJ, Lee MT, et al. A novel functional VKORC1 promoter polymorphism is associated with inter-individual and inter-ethnic differences in warfarin sensitivity. Hum Mol Genet. 2005;14(13):1745-51.

Zhu Y, Shennan M, Reynolds KK, et al. Estimation of warfarin maintenance dose based on VKORC1 (-1639 G>A) and CYP2C9 genotypes. Clin Chem. 2007;53(7):1199-205.

Coding Table
Inclusion of a code in this table does not imply reimbursement. Eligibility, benefits, limitations, exclusions, precertification/referral requirements, provider contracts, and Company policies apply.

The codes listed below are updated on a regular basis, in accordance with nationally accepted coding guidelines. Therefore, this policy applies to any and all future applicable coding changes, revisions, or updates.

In order to ensure optimal reimbursement, all health care services, devices, and pharmaceuticals should be reported using the billing codes and modifiers that most accurately represent the services rendered, unless otherwise directed by the Company.

Code System
Code Number and Narrative
CPT81227, 81355
ICD DiagnosisN/A
HCPCS Level IIG9143 Warfarin responsiveness testing by genetic technique using any method, any number of specimen(s)

G0452 Molecular pathology procedure; physician interpretation and report
Revenue Codes N/A

Version Effective Date: 07/01/2016
Version Issued Date: 07/01/2016
Version Reissued Date: 10/10/2019

Connect with Us        

© 2017 Independence Blue Cross.
Independence Blue Cross is an independent licensee of the Blue Cross and Blue Shield Association, serving the health insurance needs of Philadelphia and southeastern Pennsylvania.