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Variants in CYP2C9 and VKORC1 genes result in differences in warfarin metabolization. Using information about an individual’s CYP2C9 and VKORC1 genotypes, as well as other known characteristics, to personalize starting dose may reduce the time to warfarin dose stabilization and avoid serious bleeding events.
Warfarin is administered for preventing and treating 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 (depending on definition). Patients are typically given 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 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. In addition, genetic variants of cytochrome p450 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 (SNP; 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 genetic testing to predict a warfarin starting dose that approximates a patient’s likely maintenance dose may benefit patients by decreasing the risk of serious bleeding events and the time to stable INR. Algorithms have been developed that incorporate not only genetic variation but also other significant patient characteristics and clinical factors to predict the best starting dose.
Several tests to help assess warfarin sensitivity by determining 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. Similar tests also may be available as laboratory-developed services; laboratory-developed tests must meet the general regulatory standards of the Clinical Laboratory Improvement Act. The tests are not all the same in terms of 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 along with clinical evaluation and other tools, including the INR, to predict the initial dose that best approximates the maintenance dose for patients.
On August 16, 2007, FDA approved updated labeling for Coumadin®, to include information on genetic 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 on January 22, 2010. With each update, manufacturers of warfarin (generic for Coumadin®) were directed to add similar information to their products’ labels. The 2010 update added information on personalizing initial dose according to genotyping results for CYP2C9 and VKORC1, providing a table of genotypes and suggested initial dose ranges for each. However, suggested starting doses also are provided for when genotyping information is unavailable, indicating that genetic testing is not required. Furthermore, FDA did not include information on genetic variation in the label’s black box warning regarding bleeding risk.
POLICYGenotyping 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 the initial warfarin dose to decrease time to stable INR and reduce the risk of serious bleeding.
POLICY EXCEPTIONSFederal 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 GUIDELINESInvestigative 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.
The coverage guidelines outlined in the Medical Policy Manual should not be used in lieu of the Member’s specific benefit plan language.
POLICY HISTORY1/20/2009: 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.
SOURCESBlue Cross Blue Shield Association policy # 2.04.48
CODE REFERENCEThis may not be a comprehensive list of procedure codes applicable to this policy.