Thursday, December 27, 2018

CPT G9143, 0030U - Genotype-Guided Warfarin Dosing

Code Description CPT

0030U Drug metabolism (warfarin drug response), targeted sequence analysis (ie, CYP2C9, CYP4F2, VKORC1, rs12777823) (new code effective 1/1/18)

G9143 Warfarin responsiveness testing by genetic technique using any method, any number of specimen(s)


Warfarin (Coumadin) is a blood thinner that works by reducing the blood’s ability to clot. It’s often prescribed to prevent blood clot formation in people who have conditions like atrial fibrillation. Finding the correct dose can be complicated. Too high a dose can cause bleeding. Too low a dose can result in blood clots being formed. Factors such as age, weight, use of other medications, and smoking go into the calculation of how much is prescribed. Once the drug is prescribed, the doctor then adjusts the dose based on blood tests. Two genes have been associated with how well the body processes warfarin. Genetic tests have been developed to look at these genes to try to determine warfarin dosing. These genetic tests are investigational (unproven). Medical studies do not show whether genetic testing to try to adjust warfarin doses leads to better health results. More studies are needed.

Test Investigational 

Testing of cytochrome p450 2C9 (CYP2C9), P450 4F2 (CYP4F2), and vitamin K epoxide reductase subunit C1 (VKORC1)

Coding Genotyping for CYP2C9, CYP4F2, and VKORC1 variants is considered investigational to manage the administration and dosing of warfarin, including: * Guiding the initial  warfarin dose  * Decreasing the time needed to achieve a stable international  normalized ratio (INR) * Reducing the risk of serious bleeding

Related Information 

Genetics Nomenclature Update

The Human Genome Variation Society nomenclature is used to report information on variants found in DNA and serves as an international standard in DNA diagnostics (see  Table 1). The Society’s nomenclature is recommended by the Human Variome Project, the HUman Genome Organization, and by the Human Genome Variation Society itself.  The American College of Medical Genetics and Genomics and the Association for Molecular Pathology standards and guidelines for interpretation of sequence variants  represent expert opinion from both organizations, in addition to the College of American Pathologists. These  recommendations primarily apply to genetic tests used in clinical laboratories, including genotyping, single genes, panels, exomes, and genomes. Table 2 shows the  recommended standard terminology*“pathogenic,” “likely pathogenic,” “uncertain significance,” “likely benign,” and “benign”*to describe variants identified that cause  Mendelian disorders.

Table 1. Nomenclature to Report on Variants Found in DNA
Previous  Updated  Definition

Mutation Disease-associated variant

Disease-associated change in the DNA sequence
Variant Change in the DNA sequence 
Familial variant Disease-associated variant identified in a proband for use in subsequent targeted genetic testing in first-degree relatives
Table 2. ACMG-AMP Standards and Guidelines for Variant Classification
Variant Classification Definition
Pathogenic Disease-causing change in the DNA sequence
Likely pathogenic Likely disease-causing change in the DNA sequence 
Variant of uncertain significance Change in DNA sequence with uncertain effects on disease
Likely benign Likely benign change in the DNA sequence
Benign Benign change in the DNA sequence
ACMG: American College of Medical Genetics and Genomics; AMP: Association for Molecular Pathology.

Genetic Counseling

Experts recommend formal genetic counseling for patients who are at risk for inherited disorders and who wish to undergo genetic testing. Interpreting the results of genetic tests and understanding risk factors can be difficult for some patients; genetic counseling helps individuals understand the impact of genetic testing, including the possible effects the test results could have on the individual or their family members. It should be noted that genetic counseling may alter the utilization of genetic testing substantially and may reduce inappropriate testing; further, genetic counseling should be performed by an individual with experience and expertise in genetic medicine and genetic testing methods.

Evidence Review 


Using information about an individual’s genotypes may help in guiding warfarin dosing and could reduce the time to dose stabilization and selection of an appropriate maintenance dose that might avoid the consequences of too much or too little anticoagulation.


Warfarin is administered to prevent and treat thromboembolic events in high-risk patients;   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 to 5 mg and are frequently monitored with dose adjustments until a stable international normalized ratio value (a standardized indicator of clotting time) between 2 and 3 is achieved. During this adjustment period, a patient is at high risk of 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. 

Warfarin, which is primarily metabolized in the liver by the CYP2C9 enzyme, exerts an anticoagulant effect by inhibiting the protein vitamin K epoxide reductase complex, subunit 1 (VKORC1). Three single nucleotide variants, two in the CYP2C9 gene and one in the VKORC1 gene play key roles in determining the effect of warfarin therapy on coagulation.

 CYP2C9*1 metabolizes warfarin normally, CYP2C9*2 reduces warfarin metabolism by 30%, and CYP2C9*3 reduces warfarin metabolism by 90%. Because warfarin given to patients with *2 or *3 variants will be metabolized less efficiently, the drug will remain in circulation longer, so lower warfarin doses will be needed to achieve anticoagulation. CYP2C9 and VKORC1 genetic variants account for approximately 55% of the variability in warfarin maintenance dose.

 Recent genome-wide association studies have also identified that a single nucleotide variant in the CYP4F2 gene has been reported to account for a small proportion of the variability in stable dose (the CYP4F2 gene encodes a protein involved in vitamin K oxidation).

Medicare National Coverage

In 2009, the Centers for Medicare and Medicaid Services published a national coverage determination on pharmacogenomic testing for warfarin response.

The Centers for Medicare & Medicaid Services stated that “the available evidence does not demonstrate that pharmacogenomic testing of CYP2C9 or VKORC1 alleles to predict warfarin responsiveness improves health outcomes in Medicare beneficiaries outside the context of CED, and is therefore not reasonable and necessary….” 
However, the Centers also “believes that the available evidence supports that coverage with evidence development (CED) …. is appropriate for pharmacogenomic testing of CYP2C9 or VKORC1 alleles to predict warfarin responsiveness by any method, and is therefore covered only when provided to Medicare beneficiaries who are candidates for anticoagulation therapy with warfarin who:
* Have not been previously tested for CYP2C9 or VKORC1 alleles; and

* Have received fewer than five days of warfarin in the anticoagulation regimen for which the testing is ordered; and
* Are enrolled in a prospective, randomized, controlled clinical study when that study meets described standards.”

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