Medical Policy: 02.01.33
Original Effective Date: October 2007
Reviewed: July 2016
Revised: July 2016
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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
and medical literature becomes available.
Genetic variants in CYP2C9 and VKORC1 genes may result in an individual's 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 (a standardized indicator of clotting time) 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. More recently, a single nucleotide polymorphism (change in a single base-pair in a DNA sequence) in the CYP4F2 gene has been reported to account for a small proportion of the variability in stable dose; CYP4F2 encodes a protein involved in vitamin K oxidation.
Using the results of CYP2C9 and VKORC1 (and possibly CYP4f2) 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.
Several studies have compared the ability of different algorithms to accurately predict stable warfarin dose. In general, there does not appear to be consensus for a single algorithm at this time. Rather, it may be necessary to select the algorithm best suited to the treatment population due to the differences. Also, several studies have included ethnically diverse populations, but it is unclear whether one or several algorithms are needed to address ethnicity. Accuracy of the algorithms appears to depend on the alleles tested; number of reduced function alleles present; use of interacting drugs; ethnicity; time of warfarin dosing after initiation; and maintenance dose eventually required (high or low). Evidence for the ability of pharmacogenomic algorithms to predict maintenance warfarin dose and to increase time in the therapeutic INR range comes from retrospective and cohort studies and is inconsistent. A single dosing algorithm readily generalizable to a diverse population and prospectively tested in a large, representative validation cohort has not been developed.
Several authors have examined associations between CYP2C9 and VKORC1 variants and warfarin dosing requirements in children. Findings are preliminary. Proposed dosing algorithms require evaluation in large, prospective, randomized trials in comparison with current standard-of-care approaches to determine net health benefit.
The evidence for genetic testing to determine warfarin dose in patients who have a warfarin treatment regimen includes randomized controlled trial (RCTs), systematic reviews of RCTs, and cohort studies. 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 (and possibly CYP4f2) 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, (e.g. bleeding rates, thromboembolism) are improved. The evidence is insufficient to determine the effects of the technology on health outcomes and 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 American College of Medical Genetics policy statement concluded: "There is insufficient evidence, at this time, to recommend for or against routine CYP2C9 and VKORC1 testing in warfarin-naive patients because no substantive prospective study has yet shown this intervention to be effective in reducing the incidence of high INR values, the time to stable INR, or the occurrence of serious bleeding events, while maintaining the ability of the drug to prevent thrombolytic events.”
American College of Chest Physicians
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 Related Medical Policies
- 02.04.48 CYP450 Genotyping to Determine Drug Metabolizer Status
- 02.04.54 Genetic Testing for Mental Health Conditions
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, including several meta-analyses of randomized controlled trials, does not provide consistent evidence for the conclusion that clinically relevant outcomes (e.g. bleeding rates, thromboembolism) are improved. The evidence is insufficient to determine the effects of the technology on health outcomes and 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 External Site(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 External SitePlymouth 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 Institute External SiteWhy 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. Genet Med 2008:138-140
- American College of Obstetricians and Gynecologists (ACOG), Committee Opinion, Number 488 May 2011. Pharmacogenetics. 2011:117:1240-1.
- Centers for Medicare and Medicaid Services External SiteNational Coverage Determination (NCD) for Pharmacogenomic Testing for Warfarin Response (90.1).
- Gary Stack, M.D., PhD, Pathology Consultation on Warfarin Pharmacogenetic Testing. Am J Clin Pathol 2011:135:13-19
- UpToDate External SiteTherapeutic 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.
- UpToDate External SiteOverview of Pharmacogenomics. Kelan Tantisira, M.D., MPH, Scott T. Weiss, M.D., MS. Topic last updated July 29, 2014.
- 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 External SitePharmacogenetics: From Discovery to Patient.
- Magnani Giulia, American College of Cardiology External SiteThe Pharmacogenetics of Warfarin: Insights from COAG and EU-PACT, January 14, 2014.
- Liang R, Wang C, Zhao H, et al. Influence of CYP4F2 genotype on warfarin dose requirement-a systematic review and meta-analysis. Thromb Res. Jul 2012;130(1):38-44. PMID 22192158
- Avery PJ, Jorgensen A, Hamberg AK, et al. A proposal for an individualized pharmacogenetics-based warfarin initiation dose regimen for patients commencing anticoagulation therapy. Clin Pharmacol Ther. Nov 2011;90(5):701-706. PMID 22012312
- 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. Jan 2010;8(1):95-100. PMID 19874474
- Moreau C, Pautas E, Gouin-Thibault I, et al. Predicting the warfarin maintenance dose in elderly inpatients at treatment initiation: accuracy of dosing algorithms incorporating or not VKORC1/CYP2C9 genotypes. J Thromb Haemost. Apr 2011;9(4):711-718. PMID 21255252
- Gong IY, Tirona RG, Schwarz UI, et al. Prospective evaluation of a pharmacogenetics-guided warfarin loading and maintenance dose regimen for initiation of therapy. Blood. Jul 1 2011. PMID 21725053
- Horne BD, Lenzini PA, Wadelius M, et al. Pharmacogenetic warfarin dose refinements remain significantly influenced by genetic factors after one week of therapy. Thromb Haemost. Feb 2012;107(2):232-240. PMID 22186998
- Perlstein TS, Goldhaber SZ, Nelson K, et al. The Creating an Optimal Warfarin Nomogram (CROWN) Study. Thromb Haemost. Jan 2012;107(1):59-68. PMID 22116191
- Hamberg AK, Wadelius M. Pharmacogenetics-based warfarin dosing in children. Pharmacogenomics. Feb 2014;15(3):361-374. PMID 24533715
- Hawcutt DB, Ghani AA, Sutton L, et al. Pharmacogenetics of warfarin in a paediatric population: time in therapeutic range, initial and stable dosing and adverse effects. Pharmacogenomics J. Jul 8 2014. PMID 25001883
- Vear SI, Ayers GD, Van Driest SL, et al. The impact of age and CYP2C9 and VKORC1 variants on stable warfarin dose in the paediatric population. Br J Haematol. Jun 2014;165(6):832-835. PMID 24601977
- Skov J, Bladbjerg EM, Leppin A, et al. The influence of VKORC1 and CYP2C9 gene sequence variants on the stability of maintenance phase warfarin treatment. Thromb Res. Feb 2013;131(2):125-129. PMID 23159229
- Stergiopoulos K, Brown DL. Genotype-guided vs clinical dosing of warfarin and its analogues: meta-analysis of randomized clinical trials. JAMA Intern Med. Aug 2014;174(8):1330-1338. PMID 24935087
- Franchini M, Mengoli C, Cruciani M, et al. Effects on bleeding complications of pharmacogenetic testing for initial dosing of vitamin K antagonists: a systematic review and meta-analysis. J Thromb Haemost. Sep 2014;12(9):1480-1487. PMID 25040440
- Goulding R, Dawes D, Price M, et al. Genotype-guided Drug Prescribing: A Systematic Review and Metaanalysis of Randomized Control Trials. Br J Clin Pharmacol. Jul 24 2014. PMID 25060532
- Liao Z, Feng S, Ling P, et al. Meta-analysis of randomized controlled trials reveals an improved clinical outcome of using genotype plus clinical algorithm for warfarin dosing. J Thromb Thrombolysis. Jun 25 2014. PMID 24962733
- Kimmel SE, French B, Kasner SE, et al. A pharmacogenetic versus a clinical algorithm for warfarin dosing. N Engl J Med. Dec 12 2013;369(24):2283-2293. PMID 24251361
- Pirmohamed M, Burnside G, Eriksson N, et al. A randomized trial of genotype-guided dosing of warfarin. N Engl J Med. Dec 12 2013;369(24):2294-2303. PMID 24251363
- Mega JL, Walker JR, Ruff CT, et al. Genetics and the clinical response to warfarin and edoxaban: findings from the randomised, double-blind ENGAGE AF-TIMI 48 trial. Lancet. Jun 6 2015;385(9984):2280-2287. PMID 25769357
- 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. Apr 24 2012;125(16):1997-2005. PMID 22431865
- Guyatt GH, Akl EA, Crowther M, et al. Executive summary: Antithrombotic Therapy and Prevention of Thrombosis, 9th ed: American College of Chest Physicians Evidence-Based Clinical Practice Guidelines. Chest. Feb 2012;141(2 Suppl):7S-47S.
- National Institute for Health External SiteGenetic Testing Doesn’t Improve Warfarin Dosing. December 9, 2013.
- Chong K, Vaux K. MedScape. Warfarin Dosing and VKORC1/CYP2C9 External SiteUpdated November 10, 2015.
- CMS External SiteNational Coverage Determination (NCD) for Pharmacogenetic Testing for Warfarin Response (90.1).
- Johnson JA, Gong L, Whirl-Carrillo M, et. al. Clinical Pharmacogenetics Implementation Consortium Guideliner CYP2C9 and VKORC1 Genetypes an Warfarin Dosing External Site2011 American Society for Clinical Pharmacology and Therapeutics.
- July 2016 - Annual Review, Policy Revised
- August2015 - Annual Review, Policy Renewed
- September 2014 - Annual Review, Policy Revised
- October 2013 - Annual Review, Policy Revised
- November 2012 - Annual Review, Policy Renewed
- November 2011 - Annual Review, Policy Renewed
- September 2010 - Annual Review, Policy Renewed
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*Current Procedural Terminology © 2012 American Medical Association. All Rights Reserved.