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Medical Policy: 02.01.33
Original Effective Date: October 2007
Reviewed: November 2011
Revised:
Benefit Application
Benefit determinations are based on the applicable contract language in effect at the time the
services were rendered. Exclusions, limitations or exceptions may apply. Benefits may vary
based on contract, and individual member benefits must be verified. Wellmark determines medical
necessity only if the benefit exists and no contract exclusions are applicable. This medical
policy may not apply to FEP. Benefits are determined by the Federal Employee Program.
This Medical Policy document describes the status of medical technology at the time the document
was developed. Since that time, new technology may have emerged or new medical literature may
have been published. This Medical Policy will be reviewed regularly and be updated as scientific
and medical literature becomes available.
Description:
Warfarin is indicated for the prevention and treatment of thromboembolic events in high risk individuals; warfarin dosing is a challenging process, due to the narrow therapeutic window, variable response to dosing, and serious bleeding events in 5% or more of patients. Patients are typically initiated on a starting dose of 2-5 mg and monitored frequently with dose adjustments until a stable International Normalized Ratio (INR) value between 2 and 3 is achieved. During this period of adjustment, a patient is at high risk for bleeding.
Final, stable warfarin dose varies among individuals; factors influencing stable dose include body mass index, age, interacting drugs, and indication for therapy. In addition, genetic variants of cytochrome p 450 2C9 (CYP2C9) and vitamin K epoxide reductase subunit C1 (VKORC1) genes together account for a substantial proportion of inter-individual variability.
Warfarin is metabolized by CYP2C9; genetic variants result in enzymes with decreased activity, increased serum warfarin concentration at standard doses, and a higher risk of serious bleeding.
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 factors to predict the best starting dose.
A systematic review, commissioned by the American College of Medical Genetics, evaluated CYP2C9 and VKORC1 genetic testing prior to warfarin dosing and concluded the following:
- Analytic validity: Nearly all available data for analytic validity refer to two variants in the CYP2C9 gene; fewer data are available for the variants on the VKORC1 gene. Based on these data, analytic sensitivity and specificity are likely near 100%. Depending on methodology, 1% to 10% of samples may experience repeated assay failures resulting in inconclusive test results.
- 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 would require less. Time to steady state warfarin levels varies by CYP2C9 genotype (3-5 days vs. 5-8 vs. 12-15 for the three most common genotypes). CYP2C9 positive predictive value (PPV) for serious bleeding events is estimated to be 7%; the negative predictive value (NPV) is 96%. Similar information for VKORC1 was not available.
- Clinical utility: The purpose of genetic testing in this clinical scenario is to predict an individuals likely stable warfarin dose by incorporating demographic, clinical, and genotype data (CYP2C9 and VKORC1), and initiate warfarin at that predicted dose as a way to limit high INR values that are associated with an increased risk of serious bleeding events. No large study has yet shown this to be acceptable or effective. Several randomized trials are underway to determine clinical utility. The number needed to treat to avoid one serious bleeding event is estimated to range from 48 to 385.
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Prior Approval:
Not applicable
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Policy:
Genetic testing to determine cytochrome p450 2C9 (CYP2C9) and vitamin K epoxide reductase subunit C1 (VKORC1) genetic polymorphisms is considered investigational.
While the evidence suggests a strong association between genetic variants and stable warfarin dose, and to a lesser extent, between genetic variants and INR and bleeding outcomes, the impact of this testing on clinical outcomes (clinical utility) is not currently established. The evidence is insufficient to inform conclusions concerning the impact of this testing on warfarin-related adverse events and hospitalizations, and the impact on quality of life.
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Procedure Codes and Billing Guidelines:
- To report provider services, use appropriate CPT* codes, Modifiers, Alpha Numeric (HCPCS level 2) codes, Revenue codes, and/or ICD-9-CM diagnostic codes.
- G9143 Warfarin responsiveness testing by genetic technique using any method, any number of specimen(s)
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Selected References:
- Wadelius M, Chen LY, Downes K et al. Common VKORC1 and GGCX polymorphism associated with warfarin dose. Pharmacogenomics J 2005; 5(4):262-70.
- 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.
- McClain MR, Palomaki GE, Piper M et al. A rapid ACCE 1 review of CYP2C9 and VKORC1 allele testing to inform warfarin dosing in adults at elevated risk for thrombotic events to avoid serious bleeding. Available at: http;//www.acmg.net.
- Millican E, Lensini PA, Milligan PE et al. Genetic-based dosing in orthopaedic patients beginning warfarin therapy. Blood 2007; 110(5):1511-5.
- 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.
- 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.
- Schwarz UI, Ritchie MD, Bradford Y et al. Genetic Determinants of Response to Warfarin during Initial Anticoagulation. N Engl J Med 2008; 358:999-1008.
- The International Warfarin Pharmacogenetics Consortium. Estimation of the Warfarin Dose with Clinical and Pharmacogenetic Data. N Engl J Med 2009; 360:753-64.
- 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; 150:73-83.
- Centers for Medicare and Medicaid Services. Decision Memo for Pharmacogenomic Testing for Warfarin Response (CAG-00400N). August 3, 2009. Available at: http://www.cms.gov/mcd/viewdecisionmemo.asp?id=224
- Epstein RS, Moyer TP, Aubert RE et al. Warfarin Genotyping Reduces Hospitalization rates. Results from the MM-WES (Medco-Mayo Warfarin Effectiveness Study). J Am Coll Cardiol 2010; 55:2804-12.
- Ferder NS, Eby CS, Deych E et al. Ability of VKORC1 and CYP2C9 to predict therapeutic warfarin dose during the initial weeks of therapy. J Thromb Haemost. 2010 Jan;8(1):95-100. Epub 2009 Oct 30.
- McMillin GA, Melis R, Wilson A et al. Gene-based warfarin dosing compared with standard of care practices in an orthopedic surgery population: a prospective, parallel cohort study. Ther Drug Monit. 2010 Jun;32(3):338-45.
- ECRI Institute. Plymouth Meeting (PA). April 2011. Emerging Technology Evidence Report. Pharmacogenetic testing to determine warfarin dose. Available at: www.ecri.org.
- Lefferts JA, Schwab MC, Dandamudi UB et al. Warfarin genotyping using three different platforms. Am J Transl Res. 2010 Jul 25;2(4):441-6.
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Policy History:
Date Reason Action
September 2010 Annual review Policy renewed
November 2011 Annual review Policy renewed
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Wellmark medical policies address the complex issue
of technology assessment of new and emerging treatments, devices,
drugs, etc. They are developed to
assist in administering plan benefits and constitute neither offers of
coverage nor medical advice. Wellmark medical policies contain only a
partial, general description of plan or program benefits and do not
constitute a contract. Wellmark does not provide health care services
and, therefore, cannot guarantee any results or outcomes.
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affiliates. Treating providers are solely responsible for medical
advice and treatment of members. Our medical policies may be updated
and therefore are subject to change without notice.
*Current Procedural Terminology © 2010 American Medical Association. All Rights Reserved.
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