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L.2.04.453
Heart Disease
Heart disease is the leading cause of death in the United States, accounting for approximately one-third of all deaths in people over age 35. The death rate is higher in men compared with women, and in blacks compared with whites, but lower in Hispanic populations compared with blacks and whites. The most common form of heart disease is ischemic heart disease, also known as coronary artery disease.
Angina is the first symptom of coronary artery disease in approximately 50% of patients. However, women and the elderly are more likely to present with atypical symptoms such as nausea, vomiting, gastric discomfort, or atypical chest pain, which makes diagnosis more challenging.
DiagnosisPatients with signs and symptoms of obstructive coronary artery disease may be evaluated with a variety of tests according to prior risk. Coronary angiography is the criterion standard for diagnosing obstructive coronary artery disease, but it is invasive and associated with a low but finite risk of harm. Coronary angiography has a relatively low yield. In a study of nearly 400,000 patients without known coronary artery disease undergoing elective coronary angiography, approximately 38% were positive for obstructive coronary artery disease (using the coronary artery disease definition, stenosis of 50% or more of the diameter of the left main coronary artery or stenosis of 70% or more of the diameter of a major epicardial or branch vessel that was more than 2.0 mm in diameter) and 41% if using the broader definition (stenosis of 50% or more in any coronary vessel). Thus, methods of improving patient risk prediction before invasive coronary angiography are needed.
In an initial proof-of-principle study of the Corus CAD score in patients referred for invasive coronary angiography, Wingrove and colleagues evaluated 27 cases (96% symptomatic) with and 14 controls without angiographically defined coronary artery disease for expression of genes that differed significantly between the 2 groups, selecting 50 genes. To that, authors added 56 genes selected from relevant literature reports and evaluated the expression of these 106 genes in an independent set of 63 cases and 32 controls, resulting in the selection of 14 genes that independently and significantly discriminated between groups in multivariable analysis. The significance of 11 of these 14 genes was replicated in a third set of 86 cases and 21 controls. Expression of the 14 genes was proportional to maximal coronary artery stenosis in the combined cohort of 215 patients.
Elashoff and colleagues described the final Corus CAD score development. Investigators conducted two successive case-control gene expression discovery studies using samples from independent cohorts. Cases were angiographically defined as 75% or greater maximum stenosis in one major vessel, or 50% or greater in two vessels, and controls defined as less than 25% stenosis in all major vessels. Of clinical factors, diabetes had the most significant effect on gene expression; in the first case-control study in symptomatic patients (CATHeterization GENetics; N=195), expression of 42 genes in nondiabetic patients and 12 genes in diabetic patients were found to (p<0.05) discriminate significantly between cases and controls with no overlap. As a result, the second case-control study, in a subset of 198 patients from the prospective Personalized Risk Evaluation and Diagnosis In the Coronary Tree study, and final development of the assay was limited to nondiabetic patients (62% symptomatic). The participants were 76% male and 89% white. Final variable selection comprised the expression of 20 coronary artery disease-associated genes, 3 normalization genes, and terms for age and sex. The majority of the selected genes were immune and inflammatory-related. All terms were incorporated into an algorithm that resulted in an obstructive coronary artery disease score ranging from 1 to 40.
CardioDX has closed operations and the Corus CAD test is no longer available.
Related medical policies are as follows:
Gene expression testing in the evaluation of patients with stable ischemic heart disease is considered investigationalfor all indications, including but not limited to prediction of coronary artery disease in stable, nondiabetic patients.
None
The coverage guidelines outlined in the Medical Policy Manual should not be used in lieu of the Member's specific benefit plan language.
Genetic Counseling
Genetic counseling is primarily aimed at patients who are at risk for inherited disorders, and experts recommend formal genetic counseling in most cases when genetic testing for an inherited condition is considered. The interpretation of the results of genetic tests and the understanding of risk factors can be very difficult and complex. Therefore, genetic counseling will assist individuals in understanding the possible benefits and harms of genetic testing, including the possible impact of the information on the individual’s family. Genetic counseling may alter the utilization of genetic testing substantially and may reduce inappropriate testing. Genetic counseling should be performed by an individual with experience and expertise in genetic medicine and genetic testing methods.
Investigative 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.
07/29/2011: Approved by Medical Policy Advisory Committee.
07/17/2012: Policy reviewed; no changes.
10/15/2013: Policy reviewed; no changes.
08/04/2014: Policy reviewed; description updated. Policy statement revised to add "for all indications, including but not limited to prediction of the likelihood of CAD in stable, nondiabetic patients" for clarification. It previously stated: Gene expression testing to predict coronary artery disease is considered investigational.
07/20/2015: Code Reference section updated for ICD-10.
11/02/2015: Policy description updated regarding tests. Policy statement unchanged. Investigative definition updated in policy guidelines section.
12/31/2015: Code Reference section updated to add new 2016 CPT code 81493.
06/06/2016: Policy number A.2.04.72 added.
03/08/2017: Policy title changed from "Gene Expression Testing to Predict Coronary Artery Disease" to "Gene Expression Testing in the Evaluation of Patients with Stable Ischemic Heart Disease." Policy description updated regarding studies on the Gene Expression Score test. Policy statement revised to change "coronary artery disease" to "patients with stable ischemic heart disease." Policy guidelines updated to add genetic counseling information.
04/05/2018: Policy description updated regarding heart disease in the U.S. and patient symptoms. Policy statements unchanged.
05/24/2018: Medical policy links updated in policy description.
04/05/2019: Policy reviewed; no changes.
04/20/2020: Policy description updated regarding tests. Policy statement unchanged.
03/28/2023: Policy reviewed. Policy statement unchanged. Medical policy number changed from "A.2.04.72" to "L.2.04.453."
04/30/2024: Policy reviewed; no changes.
07/31/2025: Policy reviewed; no changes.
Blue Cross Blue Shield Association policy # 2.04.72
Code Number | Description |
CPT-4 | |
81493 | Coronary artery disease, mRNA, gene expression profiling by real-time RT-PCT of 23 genes, utilizing whole peripheral blood, algorithm reported as a risk score |
84999 | Unlisted chemistry procedure |
HCPCS | |
ICD-10 Procedure | |
ICD-10 Diagnosis |
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