Medical Policy: 02.01.33
Original Effective Date: October 2007
Reviewed: August 2015
Revised: September 2014
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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
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Genetic variants in CYP2C9 and VKORC1 genes result in individual differences in the ability to metabolize warfarin. It has been proposed that using information regarding an individual’s CYP2C9 and VKORC1 genotypes, as well as other characteristics, to determine a personalized starting dose, may reduce the time to a stable warfarin dose and avoid serious bleeding events.
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.
Stable or maintenance 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 meta-analysis of randomized trials found that dosing incorporating hepatic cytochrome P-450 2C9 (CYP2C9) or vitamin K epoxide reductase complex (VKORC1) genotype did not reduce rates of bleeding or thromboembolism, or improve time in the therapeutic range. The following trials illustrate the range of findings:
- A multicenter trial randomly assigned 455 patients with atrial fibrillation and venous thromboembolism to standard or genotype-guided initial warfarin dosing. The TTR during the first three months was 60.3 percent in the standard dosing group and 67.4 percent with the genotype-guided dosing (adjusted difference: 7 percent; 95% CI 3.3-10.6). The standard dosing group took longer to reach a therapeutic INR than the genotype-guided dosing group (median 29 versus 21 days). There were no major bleeding events and no differences in overall bleeding.
- The Clarification of Optimal Anticoagulation through Genetics (COAG) trial randomly assigned 1015 patients with stroke, venous thrombosis, or atrial arrhythmias to warfarin dosing based on clinical variables alone or clinical variables plus CYP2C9 and VKORC1 genotype during the first five days of therapy. During four weeks of therapy, the TTR was 45 percent for both groups. There was no difference in a composite endpoint that included INR > 4, major bleeding or thromboembolism.
- Data from the European Pharmacogenetics of AntiCoagulant Therapy (EUPACT) trials for dosing of phenprocoumon and acenocoumarol were pooled due to low accrual. Together 548 patients were randomly assigned to initial dosing using clinical variable alone or clinical variables plus CYP2C9 and VKORC1 genotype. During 10 weeks of therapy, the TTR was similar (60.2 and 61.6 percent for standard and genotype-based dosing, respectively), and there were no differences in bleeding or thromboembolic events.
Although the evidence supports a strong association between genetic variants and stable warfarin dose, and to a lesser extent, between genetic variants and International Normalized Ratio (INR) and bleeding outcomes, the evidence is not sufficient to conclude that testing for CYP2C9 and VKORC1 genetic variants improves health outcomes. Genetic testing may help predict the initial warfarin dose within the first week of warfarin treatment, but the evidence, including several meta-analyses of randomized controlled trials, does not provide consistent evidence for the conclusion that clinically relevant outcomes, such as bleeding rates or thromboembolism, are improved. Therefore, genotyping for variants to predict initial warfarin dose is considered investigational.
Practice Guidelines and Position Statement:
American College of Medical Genetics Policy Statement
Pharmacogenetic Testing of CYP2C9 and VKORC1 Alleles for Warfarin
The 2008 policy statement concluded: "There is insufficient evidence, at this time, to recommend for or against routine CYP2C9 and VKORC1 testing in warfarin-naive patients. Prospective clinical trials are needed that provide direct evidence of the benefits, disadvantages, and costs associated with this testing in the setting of initial warfarin dosing."
The 9th Edition of the American College of Chest Physicians Evidence Based Clinical Practice Guidelines on Antithrombotic Therapy and Prevention of Thrombosis, published in 2012, states: “ For patients initiating VKA (vitamin K antagonist) therapy, the expert panel recommends against the routine use of pharmacogenetic testing for guiding doses of VKA.” (Grade 1B)
See also medical policy for CYP450 Genotyping to Determine Drug Metabolizer Status 02.04.48
Genetic testing to determine cytochrome p450 2C9 (CYP2C9) and vitamin K epoxide reductase subunit C1 (VKORC1) genetic polymorphisms is considered investigational for the purpose of managing the administration and dosing of warfarin, including use in guiding initial warfarin dose to decrease time to stable INR and reduce the risk of serious bleeding.
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 evidence is not sufficient to conclude that testing for CYP2C9 and VKORC1 genetic variants improves health outcomes. Genetic testing may help predict the initial warfarin dose within first week of warfarin treatment, but the evidence does not support the conclusion that clinically relevant outcomes, such as bleeding rates or thromboembolism are improved. Therefore, genotyping for variants to predict initial warfarin dose is considered investigational.
Procedure Codes and Billing Guidelines:
- To report provider services, use appropriate CPT* codes, Modifiers, Alpha Numeric (HCPCS level 2) codes, Revenue codes, and/or diagnosis codes.
- G9143 Warfarin responsiveness testing by genetic technique using any method, any number of specimen(s)
- 81227 CYP2C9 (cytochrome P450, family 2, subfamily C, polypeptide 9) (eg, drug metabolism), gene analysis, common variants (eg, *2, *3, *5, *6)
- 81355 VKORC1 (vitamin K epoxide reductase complex, subunit 1) (eg, warfarin metabolism), gene analysis, common variant(s) (eg, -1639G>A, c.173+1000C>T)
- 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.
- 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.
- 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.
- 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.
- Anderson JL, Horne BD, Stevens SM et al. A randomized and clinical effectiveness trial comparing two pharmacogenetic algorithms and standard care for individualizing warfarin dosing (CoumaGen-II). Circulation. 2012 Apr 24; 125(16):1997-2005. Epub 2012 Mar 19.
- UpToDate. Overview of Pharmacogenomics. Kelan Tantisira, M.D., MPH, Scott T. Weiss, M.D., MS. January 18, 2013
- ECRI InstituteWhy Isn't Pharmacogenetic Testing Widespread for Anticoagulant Dosing? Published 9/1/2012. American College of Medical Genetics. ACMG Policy Statement: Pharmacogenetic Testing of CYP2C9 and VKORC1 Alleles for Warfarin. Issued 2008
- American College of Medical Genetics. ACMG Policy Statement: Pharmacogenetic Testing of CYP2C9 and VKORC1 Alleles for Warfarin. Issued 2008
- Evidence-Based Management of Anticoagulation Therapy: Antithrombotic Therapy and Prevention of Thrombosis, 9th ed: American College of Chest Physicians Evidence Based Clinical Practice Guidelines. Chest 1210 Feb;141(2 Suppl):e152S-84S.
- American College of Obstetricians and Gynecologists (ACOG), Committee Opinion, Number 488 May 2011. Pharmacogenetics. 2011:117:1240-1.
- Centers for Medicare and Medicaid Services. National Coverage Determination (NCD) for Pharmacogenomic Testing for Warfarin Response (90.1). www.cms.gov
- Gary Stack, M.D., PhD, Pathology Consultation on Warfarin Pharmacogenetic Testing. Am J Clin Pathol 2011:135:13-19
- UpToDate. Therapeutic use of Warfarin and Other Vitamin K Antagonists. Karen A. Valentine M.D.,PhD, Russell D. Hull, MBBS, MSc. Topic last updated July 27, 2015. www.uptodate.com
- UpToDate. Overview of Pharmacogenomics. Kelan Tantisira, M.D., MPH, Scott T. Weiss, M.D., MS. Topic last updated July 29, 2014. www.uptodate.com
- Pharmacological Reviews, Pharmacogenetics and Cardiovascular Disease-Implications for Personalized Medicine, Julie A. Johnson and Larisa H. Cavallari. Pharmacol Rev 65:987-1009 July 2013.
- MedScape. Pharmacogenetics: From Discovery to Patient. www.medscape.com/viewarticle/590270
- Magnani Giulia, American College of Cardiology, The Pharmacogenetics of Warfarin: Insights from COAG and EU-PACT, January 14, 2014. Also available at www.accc.org
Date Reason Action
September 2010 Annual review Policy renewed
November 2011 Annual review Policy renewed
November 2012 Annual review Policy renewed
October 2013 Annual review Policy revised
September 2014 Annual review Policy revised
August 2015 Annual review Policy renewed
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