Biomarker Testing in Risk Assessment and Management of Cardiovascular Disease

POLICY NUMBER

A.2.04.65

DESCRIPTION

Numerous lipid and non-lipid biomarkers have been proposed as potential risk markers for cardiovascular disease (CVD). Biomarkers assessed in this policy include apolipoprotein B, apolipoprotein AI, apolipoprotein E, B-type natriuretic peptide, cystatin C, fibrinogen, high-density lipoprotein subclass, leptin, low-density lipoprotein subclass, lipoprotein(a), and lipoprotein-associated phospholipase A₂ (Lp-PLA₂). These biomarkers have been studied as alternatives or additions to standard lipid panels for risk stratification in cardiovascular disease or as treatment targets for lipid-lowering therapy. Cardiovascular risk panels refer to different combinations of cardiac markers that are intended to evaluate the risk of CVD. There are numerous commercially available risk panels that include different combinations of lipids, noncardiac biomarkers, measures of inflammation, metabolic parameters, and/or genetic markers. Risk panels report the results of multiple individual tests, as distinguished from quantitative risk scores that combine the results of multiple markers into a single score.

Cardiovascular Disease

Cardiovascular disease (CVD) remains the single largest cause of morbidity and mortality in the developed world. Mortality from CVD has accounted for 1 in 4 deaths in the United States, and there are numerous socio-economic factors that affect CVD mortality rates. Lower-income, race, age, and behavioral factors all have a significant impact on health outcome disparities associated with CVD.

As a result, accurate prediction of CVD risk is a component of medical care that has the potential to focus on and direct preventive and diagnostic activities. Current methods of risk prediction in use in general clinical care are not highly accurate and, as a result, there is a potential unmet need for improved risk prediction instruments.

Risk Assessment

Although treatment for elevated coronary disease risk with statins targets cholesterol levels, selection for treatment involves estimation of future coronary artery disease (CAD) risk using well-validated prediction models that use additional variables.

Components of CVD risk include family history, cigarette smoking, hypertension, and lifestyle factors such as diet and exercise. Also, numerous laboratory tests have been associated with CVD risk, most prominently lipids such as low-density lipoprotein (LDL) and high-density lipoprotein (HDL). These clinical and lipid factors are often combined into simple risk prediction instruments, such as the Framingham Risk Score. The Framingham Risk Score provides an estimate of the 10-year risk for developing cardiac disease and is currently used in clinical care to determine the aggressiveness of risk factor intervention, such as the decision to treat hyperlipidemia with statins.

Many additional biomarkers, genetic factors, and radiologic measures have been associated with an increased risk of CVD. Over 100 emerging risk factors have been proposed as useful for refining estimates of CVD risk. Some general categories of these potential risk factors are as follows:

• Lipid markers. In addition to LDL and HDL, other lipid markers may have predictive ability, including the apolipoproteins, lipoprotein (a) (Lp[a]), lipid subfractions, and/or other measures.

• Inflammatory markers. Many measures of inflammation have been linked to the likelihood of CVD. High-sensitivity C-reactive protein (hs-CRP) is an example of an inflammatory marker; others include fibrinogen, interleukins, and tumor necrosis factor.

• Metabolic syndrome biomarkers. Measures associated with metabolic syndromes, such as specific dyslipidemic profiles or serum insulin levels, have been associated with an increased risk of CVD.

• Genetic markers. A number of variants associated with increased thrombosis risk, such as the 5,10-methylene tetrahydrofolate reductase (MTHFR) variant or the prothrombin gene variants, have been associated with increased CVD risk. Also, numerous single nucleotide variants have been associated with CVD in large genome-wide studies.

Risk Panel Testing

CVD risk panels may contain measures from 1 or all of the previous categories and may include other measures not previously listed such as radiologic markers (carotid medial thickness, coronary artery calcium score). Some CVD risk panels are relatively limited, including a few markers in addition to standard lipids. Others include a wide variety of potential risk factors from a number of different categories, often including both genetic and nongenetic risk factors. Other panels are composed entirely of genetic markers.

Some examples of commercially available CVD risk panels are as follows:

• CV Health Plus Genomics™ Panel (Genova Diagnostics): apolipoprotein (apo) E; prothrombin; factor V Leiden; fibrinogen; HDL; HDL size; HDL particle number; homocysteine; LDL; LDL size; LDL particle number; Lp(a); lipoprotein-associated phospholipase A2 (Lp-PLA2); MTHFR gene; triglycerides; very-low-density lipoprotein (VLDL); VLDL size; vitamin D; hs-CRP.

• CV Health Plus™ Panel (Genova Diagnostics): fibrinogen; HDL; HDL size; HDL particle number; homocysteine; LDL; LDL size; LDL particle number; lipid panel; Lp(a); Lp-PLA2; triglycerides; VLDL; VLDL size; vitamin D; hs-CRP.

• CVD Inflammatory Profile (Cleveland HeartLab): hs-CRP, urinary microalbumin, myeloperoxidase, Lp-PLA2, F₂ isoprostanes.

• Applied Genetics Cardiac Panel: genetic variants associated with CAD: cytochrome p450 variants associated with the metabolism of clopidogrel, ticagrelor, warfarin, beta-blockers, rivaroxaban, prasugrel (2C19, 2C9/VKORC1, 2D6, 3A4/3A5), factor V Leiden, prothrombin gene, MTHFR gene, APOE gene.

• Genetiks Genetic Diagnosis and Research Center Cardiovascular Risk Panel: factor V Leiden, factor V R2, prothrombin gene, factor XIII, fibrinogen-455, plasminogen activator inhibitor-1, platelet glycoprotein (GP) IIIA variant human platelet antigen (HPA)-1 (PLA1/2), MTHFR gene, angiotensin-converting enzyme insertion/deletion, apo B, apo E.

In addition to panels that are specifically focused on CVD risk, a number of commercially available panels include markers associated with cardiovascular health, along with a range of other markers that have been associated with inflammation, thyroid disorders and other hormonal deficiencies, and other disorders. An example of these panels is:

• Advanced Health Panel (Thorne): total cholesterol, HDL, LDL, triglycerides, HDL ratios, non-HDL cholesterol, LDL particle number, small LDL, medium LDL, LDL pattern, LDL peak size, large HDL, apo A1, apo B, Lp(a), cortisol, hs-CRP, homocysteine, glucose, hemoglobin A1c, insulin, homeostatic model assessment for insulin resistance, free T4, free T3, thyroid-stimulating hormone, reverse T3, dehydroepiandrosterone sulfate, estradiol, follicle stimulating hormone, luteinizing hormone, sex hormone binding globulin, total testosterone, free testosterone, albumin, globulin, albumin/globulin ratio, alkaline phosphatase, alanine aminotransferase, aspartate aminotransferase, gamma-glutamyl transferase, total bilirubin, total serum protein, blood urea nitrogen, creatinine, blood urea nitrogen/creatinine ratio, estimated glomerular filtration rate form creatinine, estimated glomerular filtration rate from cystatin C, cystatin C, fibrinogen, platelet count, white cell count, absolute neutrophils, lymphocytes, absolute lymphocytes, monocytes, absolute monocytes, eosinophils, absolute eosinophils, basophils, absolute basophils, red blood cell count, hemoglobin, hematocrit, mean platelet volume, mean corpuscular hemoglobin, mean corpuscular hemoglobin concentration, mean corpuscular volume, red cell distribution width, folate, vitamin B12, vitamin D, red blood cell magnesium, calcium, carbon dioxide, chloride, potassium, sodium, ferritin, iron total iron binding capacity, omega-3 index, omega-6 to omega-3 ratio, arachidonic acid, eicosapentaenoic acid, eicosapentaenoic acid/arachidonic acid ratio, docosahexaenoic acid, free fatty acids.

Low-density Lipoproteins and Cardiovascular Disease

Low-density lipoproteins (LDLs) have been identified as the major atherogenic lipoproteins and have long been identified by the National Cholesterol Education Project as the primary target of cholesterol-lowering therapy. An LDL particle consists of a surface coat composed of phospholipids, free cholesterol, and apolipoproteins, surrounding an inner lipid core composed of cholesterol ester and triglycerides. Traditional lipid risk factors such as LDL cholesterol (LDL-C), while predictive on a population basis, are weaker markers of risk on an individual basis. Only a minority of subjects with elevated LDL and cholesterol levels will develop clinical disease, and up to 50% of cases of coronary artery disease (CAD) occur in subjects with "normal" levels of total cholesterol and LDL-C. Thus, there is considerable potential to improve the accuracy of current cardiovascular risk prediction models.

Other non-lipid markers have been identified as being associated with cardiovascular disease (CVD), including B-type natriuretic peptide, cystatin C, fibrinogen, and leptin. These biomarkers may have a predictive role in identifying cardiovascular disease risk or in targeting therapy. In the United States, social, biological, and environmental disparities exist in the prevalence, morbidity, and mortality rates that are associated with cardiovascular disease. Population subgroups that are most significantly adversely affected by such disparities included Black and Hispanic Americans, individuals with low socioeconomic status, and individuals who live in rural settings.

Lipid Markers

Apolipoprotein B

Apolipoprotein (Apo) B is the major protein moiety of all lipoproteins, except for high-density lipoprotein (HDL). The most abundant form of apo B, large B or B₁₀₀, constitutes the apo B found in LDL and very-low density LDL. Since LDL and very-low density LDL each contain 1 molecule of apo B, the measurement of apo B reflects the total number of these atherogenic particles, 90% of which are LDL. Since LDL particles can vary in size and in cholesterol content, for a given concentration of LDL-C, there can be a wide variety in size and numbers of LDL particles. Thus, it has been postulated that apo B is a better measure of the atherogenic potential of serum LDL than LDL concentration.

Apolipoprotein AI

High-density lipoprotein contains two associated apolipoproteins (i.e., apo AI and apo AII). High-density lipoprotein particles can also be classified by whether they contain apo AI only or whether they contain apo AI and apo AII. All lipoproteins contain apo AI, and some also contain apo AII. Because all HDL particles contain apo AI, this lipid marker can be used as an approximation for HDL number, similar to the way apo B has been proposed as an approximation of the LDL number.

Direct measurement of apo AI has been proposed as more accurate than the traditional use of HDL level in the evaluation of the cardioprotective, or “good,” cholesterol. In addition, the ratio of apo B/apo AI has been proposed as a superior measure of the ratio of proatherogenic (ie, “bad”) cholesterol to anti-atherogenic (ie, “good”) cholesterol.

Apolipoprotein E

Apolipoprotein E is the primary apolipoprotein found in very-low density LDLs and chylomicrons. Apolipoprotein E is the primary binding protein for LDL receptors in the liver and is thought to play an important role in lipid metabolism. The apolipoprotein E (APOE) gene is polymorphic, consisting of 3epsilon alleles (e2, e3, and e4) that code for 3 protein isoforms, known as E2, E3, and E4, which differ from one another by one amino acid. These molecules mediate lipid metabolism through their different interactions with the LDL receptors. The genotype of apo E alleles can be assessed by gene amplification techniques, or the APOE phenotype can be assessed by measuring plasma levels of apo E.

It has been proposed that various APOE genotypes are more atherogenic than others and that APOE measurement may provide information on the risk of coronary artery disease beyond traditional risk factor measurement. It has also been proposed that the APOE genotype may be useful in the selection of specific components of lipid-lowering therapy, such as drug selection. In the major lipid-lowering intervention trials, including trials of statin therapy, there is considerable variability in response to therapy that cannot be explained by factors such as compliance. The APOE genotype may be a factor that determines an individual’s degree of response to interventions such as statin therapy.

High-Density Lipoprotein Subclass

High-density lipoprotein particles exhibit considerable heterogeneity, and it has been proposed that various subclasses of HDL may have a greater role in protection from atherosclerosis. Particles of HDL can be characterized based on size or density and/or on the apolipoprotein composition. Using size or density, HDL can be classified into HDL₂, the larger, less dense particles that may have the greatest degree of cardioprotection, and HDL₃, which are smaller, denser particles.

An alternative to measuring the concentration of subclasses of HDL (eg, HDL₂ and HDL₃) is direct measurement of HDL particle size and/or number. Particle size can be measured by nuclear magnetic resonance spectroscopy or by gradient-gel electrophoresis. High-density lipoprotein particle numbers can be measured by nuclear magnetic resonance spectroscopy. Several commercial labs offer these measurements of HDL particle size and number. Measurement of apo AI has used HDL particle number as a surrogate, based on the premise that each HDL particle contains a single apo AI molecule.

Low-Density Lipoprotein Subclass

Two main subclass patterns of LDL, called A and B, have been described. In subclass pattern A, the particles have a diameter larger than 25 nm and are less dense, while in subclass pattern B, the particles have a diameter less than 25 nm and a higher density. Subclass pattern B is a common inherited disorder associated with a more atherogenic lipoprotein profile, also termed “atherogenic dyslipidemia.” In addition to small, dense LDL, this pattern includes elevated levels of triglycerides, elevated levels of apo B, and low levels of HDL. This lipid profile is commonly seen in type 2 diabetes and is a component of the “metabolic syndrome,” defined by the Third Report of the Expert Panel on Detection, Evaluation, and Treatment of High Blood Cholesterol in Adults (Adult Treatment Panel III) to also include high normal blood pressure, insulin resistance, increased levels of inflammatory markers such as C-reactive protein, and a prothrombotic state. The presence of the metabolic syndrome is considered by Adult Treatment Panel III to be a substantial risk-enhancing factor for coronary artery disease (CAD).

Low-density lipoprotein size has also been proposed as a potentially useful measure of treatment response. Lipid-lowering treatment decreases total LDL and may also induce a shift in the type of LDL, from smaller, dense particles to larger particles. It has been proposed that this shift in lipid profile may be beneficial in reducing the risk for CAD independent of the total LDL level. Also, some drugs may cause a greater shift in lipid profiles than others. Niacin and/or fibrates may cause a greater shift from small to large LDL size than statins. Therefore, measurement of LDL size may potentially play a role in drug selection or may be useful in deciding whether to use a combination of drugs rather than a statin alone.

In addition to the size of LDL particles, interest has been shown in assessing the concentration of LDL particles as a distinct cardiac risk factor. For example, the commonly performed test for LDL-C is not a direct measure of LDL, but, chosen for its convenience, measures the amount of cholesterol incorporated into LDL particles. Since LDL particles carry much of the cholesterol in the bloodstream, the concentration of cholesterol in LDL correlates reasonably well with the number of LDL particles when examined in large populations. However, for an individual patient, the LDL level may not reflect the number of particles due to varying levels of cholesterol in different sized particles. It is proposed that the discrepancy between the number of LDL particles and the serum level of LDL represents a significant source of unrecognized atherogenic risk. The size and number of particles are interrelated. For example, all LDL particles can invade the arterial wall and initiate atherosclerosis. However, small, dense particles are thought to be more atherogenic than larger particles. Therefore, for patients with elevated numbers of LDL particles, cardiac risk may be further enhanced when the particles are smaller versus larger.

Lipoprotein (a)

Lipoprotein (Lp) (a) is a lipid-rich particle similar to LDL. The major apolipoprotein associated with LDL is Apo B; in Lp(a), however, there is an additional apolipoprotein A covalently linked to apolipoprotein B. The apolipoprotein A molecule is structurally similar to plasminogen, suggesting that Lp(a) may contribute to the thrombotic and atherogenic basis of cardiovascular disease. Levels of Lp(a) are relatively stable in individuals over time, but vary up to 1,000-fold between individuals, presumably on a genetic basis. The similarity between Lp(a) and fibrinogen has stimulated intense interest in Lp(a) as a link between atherosclerosis and thrombosis. In addition, approximately 20% of patients with CAD have elevated Lp(a) levels. Therefore, it has been proposed that levels of Lp(a) may be an independent risk factor for CAD.

Non-Lipid Markers

B-type or Brain Natriuretic Peptide

Brain natriuretic peptide (BNP, also called B-type natriuretic peptide) is an amino acid polypeptide that is secreted primarily by the ventricles of the heart when pressure to the cardiac muscles increases or there is myocardial ischemia. Elevations in BNP levels reflect deterioration in cardiac loading levels and may predict adverse events. Brain natriuretic peptide has been studied as a biomarker for managing heart failure and predicting cardiovascular and heart failure risk.

Cystatin C

Cystatin C is a small serine protease inhibitor protein that is secreted from all functional cells in the body. It has primarily been used as a biomarker of kidney function. Cystatin C has also been studied to determine whether it may serve as a biomarker for predicting cardiovascular risk. Cystatin C is encoded by the CST3 gene.

Fibrinogen

Fibrinogen is a circulating clotting factor and precursor of fibrin. It is important in platelet aggregation and a determinant of blood viscosity. Fibrinogen levels have been shown to be associated with future risk of cardiovascular disease and all-cause mortality.

Leptin

Leptin is a protein secreted by fat cells that has been found to be elevated in heart disease. Leptin has been studied to determine if it has any relation to the development of cardiovascular disease.

Lipoprotein-associated Phospholipase A2

Lipoprotein-associated phospholipase A₂ (Lp-PLA₂), also known as platelet-activating factor acetylhydrolase, is an enzyme that hydrolyzes phospholipids and is primarily associated with LDLs. Accumulating evidence has suggested that Lp-PLA₂ is a biomarker of CAD and may have a proinflammatory role in the progression of atherosclerosis. Recognition that atherosclerosis represents, in part, an inflammatory process has created considerable interest in the measurement of pro-inflammatory factors as part of cardiovascular disease risk assessment.

Interest in Lp-PLA₂ as a possible causal risk factor for CAD has generated the development and testing of Lp-PLA2 inhibitors as a new class of drugs to reduce the risk of CAD. However, clinical trials of Lp-PLA₂ inhibitors have not shown significant reductions in CAD endpoints. Furthermore, assessment of Lp-PLA₂ levels has not been used in the selection or management of subjects in the clinical trials.

Multiple assay methods for cardiac risk marker components, such as lipid panels and other biochemical assays, have been cleared for marketing by the U.S. Food and Drug Administration (FDA) through the 510(k) process.

In December 2014, the PLAC® Test (diaDexus), a quantitative enzyme assay, was cleared for marketing by the U.S. Food and Drug Administration (FDA) through the 510(k) process for Lp-PLA₂ activity. It was considered substantially equivalent to a previous version of the PLAC® Test (diaDexus), which was cleared for marketing by the FDA in July 2003. FDA product code: NOE.

Clinical laboratories may develop and validate tests in-house and market them as a laboratory service; laboratory-developed tests (LDTs) must meet the general regulatory standards of the Clinical Laboratory Improvement Amendments (CLIA). Components of testing panels, lipid, and non-lipid biomarker tests are available under the auspices of the CLIA. Laboratories that offer LDTs must be licensed by the CLIA for high-complexity testing. To date, the U.S. Food and Drug Administration has chosen not to require any regulatory review of these tests.

POLICY

Measurement of nontraditional lipid and non-lipid biomarkers (i.e., apolipoprotein B, apolipoprotein AI, apolipoprotein E, LDL subclass, HDL subclass, lipoprotein[a], B-type natriuretic peptide, cystatin C, fibrinogen, leptin) is considered investigational as an adjunct to LDL cholesterol in the risk assessment and management of cardiovascular disease.

Measurement of lipoprotein-associated phospholipase A₂ is considered investigational.

Cardiovascular disease risk panels, consisting of multiple individual biomarkers intended to assess cardiac risk (other than simple lipid panels, see Policy Guidelines section), are considered investigational.

POLICY EXCEPTIONS

None

POLICY GUIDELINES

The coverage guidelines outlined in the Medical Policy Manual should not be used in lieu of the Member's specific benefit plan language.

A simple lipid panel is generally composed of the following lipid measures:

• Total cholesterol

• Low-density lipoprotein cholesterol

• High-density lipoprotein cholesterol

• Triglycerides

Certain calculated ratios (eg, total/high-density lipoprotein cholesterol) may also be reported as part of a simple lipid panel.

Other types of lipid testing (ie, apolipoproteins, lipid particle number or particle size, lipoprotein [a]) are not considered components of a simple lipid profile.

This policy does not address the use of panels of biomarkers in the diagnosis of acute myocardial infarction.

The following policies were incorporated into this policy: Measurement of Lipoprotein-Associated Phospholipase A2 in the Assessment of Cardiovascular Risk and Cardiovascular Risk Panels.

Genetic Counseling

Experts recommend formal genetic counseling for individuals 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 individuals; 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. 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. 

POLICY HISTORY

09/23/2011: New policy created to combine the following policies: 1) Apolipoprotein E Genotype or Phenotype in the Management of Cardiovascular Disease; 2) Lipoprotein(a) Enzyme Immunoassay in the Management of Cardiovascular Disease; 3) Apolipoprotein B in the Risk Assessment and Management of Cardiovascular Disease; 4) High-Density Lipoprotein Subclass Testing in the Diagnosis and Management of Cardiovascular Disease; 5) Measurement of Small Low-Density Lipoprotein (LDL) Particles and Concentration of LDL Particles in Cardiac Risk Assessment and Management. Policy statement remains the same.

09/25/2012: Policy reviewed; no changes.

12/13/2013: Added Biomarkers to policy title. Policy description updated regarding nonlipid risk factors. Added B-type natriuretic peptide, cystatin C, fibrinogen, leptin as investigational as adjunct to LDL cholesterol in the risk assessment and management of cardiovascular disease. Added the following policy statement: The use of panels that include lipid and non-lipid cardiovascular risk markers is considered not medically necessary.

11/11/2014: Policy reviewed; description updated regarding Apolipoprotein AI. Deleted the following policy statement: The use of panels that include lipid and non-lipid cardiovascular risk markers is considered not medically necessary.

07/31/2015: Code Reference section updated for ICD-10.

11/06/2015: Policy title changed from "Novel Lipid Risk Factors and Biomarkers in Risk Assessment and Management of Cardiovascular Disease" to "Novel Biomarkers in Risk Assessment and Management of Cardiovascular Disease." Policy description updated regarding tests. Policy statement unchanged. Investigative definition updated in policy guidelines section.

06/06/2016: Policy number A.2.04.65 added.

07/01/2016: Added CPT code 82610 to the Code Reference section.

12/30/2016: Code Reference section updated to revise code description for CPT code 83704.

01/19/2017: Policy description updated. Policy statement unchanged. Policy Guidelines updated to add genetic counseling information.

02/27/2018: Policy description updated. Policy statement unchanged. Policy Guidelines updated regarding genetic counseling.

06/21/2018: Code Reference section updated to add new CPT code 0052U, effective 07/01/2018.

12/18/2018: Code Reference section updated to add new CPT code 83722, effective 01/01/2019.

01/17/2019: Policy reviewed; no changes.

01/16/2020: Policy reviewed; no changes.

02/03/2021: Policy reviewed; no changes.

02/04/2022: Policy reviewed. Policy statement updated to change "risk factors" to "biomarkers."

01/26/2023: Policy description updated regarding disparities associated with cardiovascular disease. Policy statement unchanged. Policy Guidelines updated to change "patients" to "individuals."

03/31/2023: Code Reference section updated to add new CPT code 0377U, effective 04/01/2023.

09/25/2023: Code Reference section updated to add new CPT code 0415U, effective 10/01/2023.

02/15/2024: Policy title changed from "Novel Biomarkers in Risk Assessment and Management of Cardiovascular Disease" to "Biomarker Testing in Risk Assessment and Management of Cardiovascular Disease." Policy description updated regarding non-lipid markers. Policy statement unchanged.

06/01/2024: Policy updated to combine the Cardiovascular Risk Panels medical policy and the Measurement of Lipoprotein-Associated Phospholipase A2 in the Assessment of Cardiovascular Risk medical policy with this policy. First policy statement updated to change "novel" to "nontraditional." Code Reference section updated to add CPT codes 0019M, 0401U, 0439U, 0440U, 81599, and 83698.

02/10/2025: Policy description updated. Policy statements unchanged.

04/01/2025: Code Reference section updated to add new CPT code 0541U, effective 04/01/2025.

SOURCE(S)

Blue Cross Blue Shield Association policy # 2.04.65

CODE REFERENCE

This may not be a comprehensive list of procedure codes applicable to this policy.

Investigational Codes

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