Medical Policy: 02.04.04 
Original Effective Date: September 2002 
Reviewed: April 2016 
Revised: April 2016 


Benefit Application:

Benefit determinations are based on the applicable contract language in effect at the time the services were rendered. Exclusions, limitations or exceptions may apply. Benefits may vary based on contract, and individual member benefits must be verified. Wellmark determines medical necessity only if the benefit exists and no contract exclusions are applicable. This medical policy may not apply to FEP. Benefits are determined by the Federal Employee Program.

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.


Description:

Cardiovascular disease remains the single largest cause of morbidity and mortality. As a result, accurate prediction of cardiovascular risk is a component of medical care that has the potential to focus and direct preventative 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.

 

Non-traditional risk factors for coronary heart disease (CHD) are used increasingly to determine patient risk, in part because of an assumption that many patients with CHD lack traditional risk factors (e.g. cigarette smoking, diabetes, hyperlipidemia and hypertension). Numerous lipid and non-lipid biomarkers have been proposed as potential risk markers for cardiovascular disease.  

 

Novel Biomarkers in Risk Assessment and Management of Cardiovascular Disease

 

LDL Subspecies (Small and Large Particles)

A high serum cholesterol level is recognized as a major risk factor for coronary artery disease (CAD), also known as coronary heart disease (CHD).  Serum cholesterol is transported in low-density lipoprotein (LDL) particles, and these are considered the most atherogenic component of serum cholesterol.   The statin drugs (i.e., HMG CoA reductase inhibitors) mainly lower levels of LDL and clinical trials have shown that the use of these drugs has resulted in a significant reduction in new coronary events. 

 

However, LDL particles are not uniform in size or density, and two subclass patterns, (A and B), have been described.  The subclass pattern B is frequently associated with a more atherogenic lipoprotein profile (ALP).  LDL subclass pattern B consists of higher levels of triglyceride, apoprotein B (which indicates the number of LDL particles rather than their content), intermediate density lipoprotein (IDL), very low-density lipoprotein (VLDL) and a lower level of high-density lipoprotein (HDL).   An increased prevalence of small dense LDL particles has been noted in patients with CAD.

 

Therefore, measurement of LDL particle density or diameter has been proposed as a technique for further risk stratification in patients with elevated LDL levels, or for patients with normal LDL levels who have other high risk factors for CAD, or to predict response to a particular therapy.

 

2010 American College of Cardiology Foundation (ACCF)/American Heart Association (AHA) Guideline for Assessment of Cardiovascular Risk in Asymptomatic Adults: Recommendation for Assessment of Lipoprotein Concentrations, Other Lipoprotein Parameters, and Modified Lipids: “Measurement of lipid parameters, including lipoproteins, apolipoproteins, particle size, and density, beyond standard fasting lipid profile is not recommended for cardiovascular disease risk assessment in asymptomatic adults.”  

 

LDL Gradient Gel Electrophoresis

LDL particle diameter can be measured using nuclear magnetic resonance or ultracentrifugation while particle density can be measured by gradient gel electrophoresis (GGE).  GGE is the most commonly used lab technique.

 

LDL gradient gel electrophoresis (GGE) has been promoted as an important determinant of coronary heart disease (CHD) risk, and as a guide to drug and diet therapy in patients with established coronary artery disease (CAD). The measurement of LDL subclass patterns may be useful in elucidating possible atherogenic dyslipemia in patients who have no abnormalities in conventional measurement (total cholesterol, HDL, LDL and triglycerides). However, the therapeutic usefulness of discovering such subclass abnormalities has not been substantiated.

 

There is inadequate evidence that LDL subclassification by electrophoresis improves outcomes of patients with cardiovascular disease:

 

2010 American College of Cardiology Foundation (ACCF)/American Heart Association (AHA) Guideline for Assessment of Cardiovascular Risk in Asymptomatic Adults: Recommendation for Assessment of Lipoprotein Concentrations, Other Lipoprotein Parameters, and Modified Lipids: “Measurement of lipid parameters, including lipoproteins, apolipoproteins, particle size, and density, beyond standard fasting lipid profile is not recommended for cardiovascular disease risk assessment in asymptomatic adults.”  

  

An assessment by the National Academy of Clinical Biochemistry on Lipoprotein Subclasses and Particle Concentration (including measurement by gel electrophoresis) concluded: "Lipoprotein subclasses, especially the number or concentration of small, dense LDL particles, have been shown to be related to the development of initial CHD events, but the data analysis of existing studies are generally not adequate to show added benefit over standard risk assessment for primary prevention.” Furthermore, the recommendation does not support the testing “There is insufficient data that the measurement of lipoprotein subclasses over time is useful to evaluate the effects of treatment.” 

 

Measurement of LDL GGE has not been established as a clinically useful test at this time. It has not been proven useful in determining therapy for patients with CAD or dyslipemia.

 

Lipoprotein A Enzyme Immunoassay Lp(a)

The lipoprotein (a) (Lp(a)) enzyme immunoassay have been promoted as an important determinant of coronary heart disease (CHD) risk, and as a guide to drug and diet therapy in patients with established coronary artery disease (CAD).

 

Although there is evidence for an association of Lp(a) with cardiovascular disease, there is no data to suggest that more aggressive risk factor modification would improve patient oriented health outcomes. Furthermore, it is very difficult to modify Lp(a). 

  

2010 American College of Cardiology Foundation (ACCF)/American Heart Association (AHA) Guideline for Assessment of Cardiovascular Risk in Asymptomatic Adults: Recommendation for Assessment of Lipoprotein Concentrations, Other Lipoprotein Parameters, and Modified Lipids: “Measurement of lipid parameters, including lipoproteins, apolipoproteins, particle size, and density, beyond standard fasting lipid profile is not recommended for cardiovascular disease risk assessment in asymptomatic adults.”

    

An assessment by the National Academy of Clinical Biochemistry on Lipoprotein (a) and Cardiovascular Risk: “Lipoprotein (a) screening is not warranted for primary prevention and assessment of cardiovascular risk.”

 

High Density Lipoprotein (HDL) Subclass (Lipoprotein AI 9LpAI) and Lipoprotein AI/AII (LpA1/AII) and/or HDL3 and HDL2

HDL comprises several components and subfractions that also have been related to CHD risk. While HDL cholesterol is the risk indicator most often used, HDL sufractions (lipoprotein AI (LpAI) and lipoprotein Ai/AII (LPAI/AII) and/or HDL3 and HDL2) have also been used for risk prediction.

 

The National Cholesterol Education Program (NCEP) expert panel on: Detection, Evaluation, and Treatment of High Blood Cholesterol in Adults (Adult Treatment Panel III (ATPIII). ATPIII concluded “superiority over HDL cholesterol has not been demonostrated in large, prospective studies. Consequently ATPIII does not recommend the routine measurement of HDL subspecies in CHD risk assessment.”

 

2010 American College of Cardiology Foundation (ACCF)/American Heart Association (AHA) Guideline for Assessment of Cardiovascular Risk in Asymptomatic Adults: Recommendation for Assessment of Lipoprotein Concentrations, Other Lipoprotein Parameters, and Modified Lipids: “Measurement of lipid parameters, including lipoproteins, apolipoproteins, particle size, and density, beyond standard fasting lipid profile is not recommended for cardiovascular disease risk assessment in asymptomatic adults.”    

 

Apolipoprotein B (apo B)

Each LDL particle has one molecule of apo B per particle. Therefore, apo B concentration is an indirect measurement of the number of LDL particles, in contrast to LDL cholesterol, which is simply a measure of the cholesterol contained within the LDL. Because apo B is a marker for LDL particle number, the greater or higher the apo B level suggests an increased level of small, dense LDL particles which are thought to be especially atherogenic.

 

APO B testing has not been validated as a tool for risk assessment in the general population. A recent study found that measuring apo B and apo A-I, the main structural proteins of atherogenic and antiartherogenic lipoproteins and particles, adds little to existing measures of CAD risk assessment and discrimination in the general population. 

 

2010 American College of Cardiology Foundation (ACCF)/American Heart Association (AHA) Guideline for Assessment of Cardiovascular Risk in Asymptomatic Adults: Recommendation for Assessment of Lipoprotein Concentrations, Other Lipoprotein Parameters, and Modified Lipids: “Measurement of lipid parameters, including lipoproteins, apolipoproteins, particle size, and density, beyond standard fasting lipid profile is not recommended for cardiovascular disease risk assessment in asymptomatic adults.”  

 

Apolipoprotein A-I

Apolipoprotein AI (Apo AI) is the major protein constituent of HDL cholesterol. Although most guidelines recommend cardiovascular risk assessment based on LDL, measurement of APO I has not been established as a clinically useful test at this time. It has not been proven useful in determining therapy for patients with CAD or dyslipemia. 

  
2010 American College of Cardiology Foundation (ACCF)/American Heart Association (AHA) Guideline for Assessment of Cardiovascular Risk in Asymptomatic Adults: Recommendation for Assessment of Lipoprotein Concentrations, Other Lipoprotein Parameters, and Modified Lipids: “Measurement of lipid parameters, including lipoproteins, apolipoproteins, particle size, and density, beyond standard fasting lipid profile is not recommended for cardiovascular disease risk assessment in asymptomatic adults.”   

 
The National Cholesterol Education Program (NCEP) expert panel on: Detection, Evaluation, and Treatment of High Blood Cholesterol in Adults (Adult Treatment Panel III (ATPIII). ATPIII concluded: “Apolipoprotein A-I is carried in HDL, and it is usually low when HDL is reduced. A low apolipoprotein A-I thus is associated with increased risk of CHD, but not independently of low HDL. Whether it has independent predictive power beyond HDL cholesterol is uncertain. In any case, standardized methodology for estimating apolipoprotein A-I is not widely available. Its measurement thus is not recommended for routine risk assessment in ATP III.”

 

Apolipoprotein E

Apolipoprotein E (apo E) is the primary apolipoprotein found in VLDLs and chylomicrons. Apo E is the primary binding protein for LDL receptors in the liver and is thought to play an important role in lipid metabolism.


It has been proposed that various apo E genotypes are more atherogenic than others and that apo E measurement may provide information on risk of coronary artery disease (CAD) above traditional risk factor measurement. It has also been proposed that the apo E 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. Apo E genotype may be one factor that determines an individual’s degree of response to interventions such as statin therapy. However, the value of apo E testing in the diagnosis and management of CHD needs further evaluation.

 
2010 American College of Cardiology Foundation (ACCF)/American Heart Association (AHA) Guideline for Assessment of Cardiovascular Risk in Asymptomatic Adults: Recommendation for Assessment of Lipoprotein Concentrations, Other Lipoprotein Parameters, and Modified Lipids: “Measurement of lipid parameters, including lipoproteins, apolipoproteins, particle size, and density, beyond standard fasting lipid profile is not recommended for cardiovascular disease risk assessment in asymptomatic adults.”

 

Natriuretic Peptides (BNP and NT-proBNP)

BNP is an amino acid polypeptide that is secreted primarily by the ventricles of the heart when pressure to the cardiac muscles increase or there is myocardial ischemia. Elevations in BNP levels reflect deterioration in cardiac loading levels and may predict adverse events. BNP has been studied as a biomarker for managing heart failure and predicting cardiovascular and heart failure risk.

 
2010 American College of Cardiology Foundation (ACCF)/American Heart Association (AHA) Guideline for Assessment of Cardiovascular Risk in Asymptomatic Adults: Recommendation for Measurement of Natriuretic Peptides: “ Measurement of natriuretic peptides is not recommended for CHD risk assessment in asymptomatic adults.”

 

An assessment by the National Academy of Clinical Biochemistry on Natriuretic Peptides (BNP and NT-proBNP) and Cardiovascular Disease Risk: “Increased B-type natriuretic peptide (BNP) or N-terminal proBNP (NT-proBNP) concentrations are associated with increased mortality in the next 2 to 7 years in community based populations. However, the benefits of therapy based on these measurements are uncertain. Measurement in cardiovascular disease risk assessment in the primary prevention setting is unwarranted.” Furthermore, there recommendation is against measurement.

 

Cystatin C

Cystatin C is a small serine protease inhibitor protein that is secreted from all functional cells found through the body. It has primarily been used as a biomarker for kidney function. Cystatic 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.

 
None of the available evidence provides adequate data to establish that cystatin C improves outcomes when used in clinical care.


An assessment by the National Academy of Clinical Biochemistry on Biomarkers of Renal Function and Cardiovascular Disease Risk: “Properly designed studies focusing on the role of kidney disease markers (microalbumin, creatinine, estimated GCR, and cystatin C) should be conducted to characterize the utility of these markers in the global assessment of cardiovascular disease risk in the primary prevention setting.” 

 

Thrombogenic/Hemostatic Factors

Thrombosis plays a key role in acute coronary syndromes, including myocardial infarction. Both platelets and coagulation factors are involved in the thrombotic process. Although the precise hemostatic or prothrombotic mechanisms that predisopose to myocardial infarction have not been worked out, the evidence that aspirin and other antiplatelet therapy can reduce risk is compelling and suggests a role for platelet hyperaggregability. Another hemostatic factor associated with CHD risk is fibrinogen. A high fibrinogen level associates significantly with increased risk for coronary events, independent of cholesterol level; and conversely, a low fibrinogen level indicates a reduced risk, even in the presence of high total cholesterol levels. Other hemostatic factors that have been found to be associated with increased coronary risk include activated factor VII, plasminogen activator inhibitor-1 (PAI-1), tissue plasminogen activator (tPA), von Willebrand factor, factor V Leiden, protein C, and antithrombin III. Studies have shown that some of these prothrombotic factors are elevated as a component of the metabolic syndrome.

 
Fibrinogen is a circulating glycoprotein that acts at the final step in the coagulation response to vascular and tissue injury, and epidemiological data support an independent association between elevated levels of fibrinogen and cardiovascular morbidity and mortality. Further clinical trials are necessary before it can be determined whether fibrinogen has a casual role in atherothrombosis or is merely a marker of the degree of vascular damage taking place.  

 
The National Cholesterol Education Program (NCEP) expert panel on: Detection, Evaluation, and Treatment of High Blood Cholesterol in Adults (Adult Treatment Panel III (ATPIII). ATPIII concluded: “ATP III does not recommend measurement of prothrombotic factors as part of routine assessment of CHD risk. The strength of the association between these factors and CHD risk has not been defined. Clinical trials have not been carried out that target specific prothrombotic factors.”  

 

MTHFR

A number of mutations associated with increased thrombosis risk, such as MTHFR mutation, have been associated with increased cardiovascular risk. Evidence for the association of MTHFR with VTE is not definitive. Some studies have shown association, but others have not. In 2007 MEGA study, showed no association between the MTHFR mutation with recurrent VTE. A randomized controlled trial (RCT) reported no reduction in VTE associated with the treatment of hyperhomocysteinemia.


Published evidence on the utility of testing for MTHFR mutations in patients who have or are at risk for VTE is limited. Given the available evidence, and lack of clinical utility for serum homocysteine testing in general, it is unlikely that testing for MTHFR will improve outcomes. 

 

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 relationship with the development of cardiovascular disease.


None of the available evidence provides adequate data to establish that Leptin improves outcomes when used in clinical care. Therefore, given the uncertain impact on clinical outcomes this testing is considered investigational.        

 

Measurement of Long Chain Omega-3 Fatty Acids in Red Blood Cell Membranes

Higher palmitic and lower long chain omega-3 fatty acids (e..g alpha-linolenic, eicosapentaenoic and docosahexaenoic acids) in serum are correlated with higher incidence of CHD. It has been proposed that red blood cell (RBC) fatty acids composition, which is an index of long term intake of eicosapentaenoic plus docosahexaenoic acids, can be considered a new, modifiable, and clinically relevant risk factor for death from CHD.

 
However, there is lack of scientific evidence regarding how measurements of RBC omega-3 fatty acids composition would affect management of individuals at risk for or patients with CHD. Large randomized clinical trials are needed to ascertain the clinical value of RBC

 

Inflammatory Markers of Coronary Artery Disease Risk

Increasing recognition that atherosclerosis involves a chronic inflammatory process has brought greater attention to arterial “inflammation” as a risk factor for major coronary events.

 

Lipoprotein-Associated Phospholipase A2 (Lp-PLA2) and Secretory Phospholipase A2 (sPLA2-IIA):

Also known as platelet activating factor acetylhydrolase,  is an enzyme that hydrolyzes phospholipids and is primarily associated with low-density lipoproteins (LDLs). Accumulating evidence has suggested that Lp-PLA2  and secretory phospholilpase A2 (sPLA2-IIA) are biomarkers of coronary artery disease (CAD) and may have a pro-inflammatory role in the progression of atherosclerosis. 

 

There is a large body of literature evaluating lipoprotein-associated phospholipase A2 (Lp-PLA2) as a predictor of cardiovascular risk. These studies demonstrated that Lp-PLA2 is an independent predictor of cardiovascular disease but do not demonstrate that health outcomes are improved as a result of measuring Lp-PLA2. Improved risk prediction does not by itself result in improved health outcomes. To improve outcomes, clinicians must have the tools to incorporate emerging risk factors into existing risk prediction models, and these models should demonstrate improved classification into risk categories that will lead to more appropriate treatment. These tools are not currently available to the practicing clinician for Lp-PLA2. As a result, use of Lp-PLA2 for risk stratification for cardiovascular risk is considered investigational.

 

The National Cholesterol Education Program (NCEP) expert panel on: Detection, Evaluation, and Treatment of High Blood Cholesterol in Adults (Adult Treatment Panel III (ATPIII). ATPIII concluded: “ATP III does not recommend routine measurement of inflammatory markers for the purpose of modifying LDL-cholesterol goals in primary prevention.”

 

2010 American College of Cardiology Foundation (ACCF)/American Heart Association (AHA) Guideline for Assessment of Cardiovascular Risk in Asymptomatic Adults: “Lipoprotein-associated phospholipase A2 (Lp-PLA2) might be reasonable for cardiovascular risk assessment in intermediate risk asymptomatic adults.

 

Myeloperoxidase (MPO):

Higher levels of the leukocyte enzyme myeloperoxidase (MPO), which is secreted during acute inflammation and promotes oxidation of lipoproteins, are associated with the presence of coronary disease and may be predictive of acute coronary syndrome in patients with chest pain. Although elevated plasma MPO concentration may be associated with a more advance cardiovascular disease risk profile, plasma MPO does not predict mortality independent of other cardiovascular disease risk factors in patients with stable coronary artery disease. There is a lack of scientific evidence regarding how measurements of MPO would affect management of individuals at risk for or patients with CHD. Large randomized controlled studies are needed to ascertain the clinical value of MPO in the management of CHD.

 

Homocysteine Testing in the Screening, Diagnosis and Management of Cardiovascular Disease

Homocysteine (Hcy) is an amino acid that is found normally in the body. Studies suggest that high blood levels of this substance may increase a person’s change of developing heart disease, stroke, and reduced blood flow to the hands and feet. It is believed that high levels of Hcy may damage arteries, may make blood more likely to clot, and may make blood vessels less flexible. It is also suggested that treatment consisting of high doses of folic acid, vitamin B6 and B12 decreases a patient’s Hcy levels and therefore decreases their risk of CVD. However, published study results in the medical literature are conflicting and the usefulness of Hcy testing is reducing CVD risk and improving patient outcomes has not been demonstrated.   

 

2009 National Academy of Clinical Biochemistry, Laboratory Medicine Practice Guidelines, Emerging Biomarkers for Primary Prevention of Cardiovascular Disease and Stroke: The clinical application of Hcy measurement for risk assessment for primary prevention of CVD is uncertain. Hcy screening for primary prevention and assessment of CVD risk in healthy individuals is not warranted. 

 

2010 ACCF/AHA Guideline for Assessment of Cardiovascular Risk in Asymptomatic Adults: The guideline did not address measurement of homocysteine levels.  

 

2013 ACC/AHA Guideline on the Assessment of Cardiovascular Risk: The guideline did not address measurement of homocysteine levels.

 

Genomic Profiling to Assess Cardiovascular Risk

Susceptibility of coronary artery disease (CAD) is claimed to be 40% to 60% inherited, but until recently genetic risk factors predisposing to CAD have been elusive. It has been suggested that an improvement in CVD risk classification (adjusting intermediate risk of CVD into high or low risk categories) might lead to management changes (e.g. earlier initiation or higher rates of medical interventions, or targeted recommendations for behavioral change) that improve CVD outcomes.

 

The evaluation of Genomic Applications in Practice and Prevention Working Group (EWG) (2010) found insufficient evidence to recommend testing for the 9p21 genetic variant or 57 other variants in 28 genes to assess risk for cardiovascular disease (CVD) in the general population, specifically heart disease and stroke. The EWG found that the magnitude of net health benefit from use of any of these tests alone or in combination are negligible. The EWG discourages clinical use unless further evidence supports improved clinical outcomes. Based on the available evidence, the overall certainty of net health benefit is deemed low.  

 

2010 ACCF/AHA Guideline for Assessment of Cardiovascular Risk in Asymptomatic Adults: Genotype testing for CHD risk assessment in adults is not recommended.

 

Cardiovascular Risk Panels

Cardiovascular risk panels refer to different combinations of cardiac markers that are intended to evaluate risk of cardiovascular disease. 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 results of multiple markers into one score.

  

Some examples of commercially available Cardiovascular (CV) risk panels are as follows:

  • Health Diagnostics Cardiac Risk Panel: MTHFR gene analysis, common variants; vitamin D, 1, 25 dihydroxy; B-type natriuretic peptide (BNP); Lp-PLA2; myeloperoxidase; apolipoprotein; immune complex assay; lipoprotein, blood; electrophorectic separation and quanititation; very long chain fatty acids; total cholesterol; HDL; LDL; triglycerides; (high sensitivity CRP, hs-CRP); lipoprotein (a); insulin; total fibrinogen; apolipoprotein analysis; multiple SNPs associated with coronary artery disease (CAD).

  • Boston Heart Diagnostics: total cholesterol; triglyceride; HDL-C; APO A-1; Boston Heart Lab Mapy; LDL-C; Lp(a); Apo-B; sdLDL-C; Boston Heart Cholesterol Balance; hs-CRP; Lp-PLA2; MPO; Boston Heart Prediabetes Assessment; glucose; insulin; HbA1c; Boston Heart Statin Induced Myopathy (SLCO1B1) Genotype; Apo-E; Factor II/Factor V; NT-proBNP; vitamin D.

  • Genova Diagnostics CV Health Plus Genomics Panel: apo E; prothrombin; factor V leiden; fibrinogen; HDL; HDL size; HDL particle number; homocysteine; LDL; LDL size; LDL particle number; lipoprotein (a); Lp-PLA2: MTHFR gene; triglycerides; very low density lipoprotein (VLDL); VLDL size; vitamin D; hs-crp

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

  • Metametrix Cardiovascular Health Profile: homocysteine; C-reactive protein (hs-CRP); fibrinogen; red blood cell magnesium; coenzyme Q10; vitamin E; lipid peroxides; total testosterone; sex hormone binding globulin; free androgen index (calculation); insulin; ferritin; total cholesterol; HDL cholesterol; LDL cholesterol; triglycerides; lipoprotein (a).

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

  • Applied Genetics Cardiac Panel: genetic mutations associated with CAD; cytochrome p450 mutations associated with metabolism of clopidogrel, ticagrelor, warfarin,B-blockers, rivaroxaban, and prasurgrel (2C19, 2C9/VKORC1, 2D6, 3A4/3A5); factor V leiden;, prothrombin gene; MTHFR gene; apo-E gene.

  • Genetiks Genetic Diagnosis and Research Center Cardiovascular Risk Panel: factor V leiden; factor V R2; prothrombin gene; factor XIII; fibrinogen -455; PAI-1; GPIIIs (HPA-1); MTHFR; ACE I/D; apo B; apo E.

  • Quest Diagnostics 4myheart: lipoprotein subfractionation by ion mobility; Apo-B; Lp(a); homocysteine; Lp-PLA2; hs-CRP; fibrinogen; insulin; NT-proBNP; vitamin D; omega 3 and 6; 4q25-AF risk genotype test; 9p21 genotype; Apo-E genotype; CYP2C19 genotype; KIF6 genotype; LPA-aspirin genotype; LPA intron 25 genotype; apolipoprotein A1; hemoglobin A1c.

  • Singulex Cardiac Related Test Panels:

    • Cardiac Dysfunction panel: SMCTM cTmNI (high sensitivity troponin); NT-proBNP

    • Vascular Information and Dysfunction panel: SMCTM IL-6; SMCTM IL-7; SMCTM TNFa; SMCTM Endothelin; Lp-PLA2; hs-CRP; homocysteine; vitamin B12; folate

    • Dyslipidemia panel: cholesterol total; LDL-C (direct); APO B; sdLDL; HDL-C; APO A-1; HDL2b; triglycerids; Lp(a)  

    • Cardiometabolic: Parathyroid hormone; vitamin D; calcium;magnesium; leptin; adiponectin; ferritin; cortisol a.m.; testosterone; cystatin C; glucose; insulin; T4; T3; Free T4; Free T3; TSH; uric acid. 

Numerous cardiovascular (CV) panels are commercially available. These panels report results for multiple individual CV risk markers and have wide variability in the risk factors included in the panel. While the individual risk factors have in most cases been associated with increased risk of CV disease, it is not clear how the results of individual risk factors impact management changes, so it is also not certain how the panels will impact management decisions. Given the lack of evidence for clinical utility of any individual risk factor beyond simple lipid measures, it is unlikely that the use of CV risk panels improve outcome. As a result, the use of cardiac risk panels for predicting risk of cardiovascular disease is considered investigational.

 

In 2013, the American College of Cardiology (ACC) and the American Heart Association (AHA) issued guidelines on the assessment of cardiovascular risk. The guidelines do not recommend other novel cardiac risk factors or panels of cardiac risk factors.   


Prior Approval:

 

Not applicable


Policy:

 

Novel biomarkers in Risk Assessment and Management of Cardiovascular Disease

The measurement of novel lipid and nonlipid risk factors including but not limited to the following is considered investigational as an adjunct to LDL cholesterol in the risk assessment and management of cardiovascular disease:

  • Small low density lipoprotein (LDL) particles
  • LDL gradient gel electrophoresis
  • Lipoprotein remnants: intermediate density lipoprotein (IDL)
  • Lipoprotein (a) enzyme immunoassay
  • HDL subspecies (LpA1, LpAI/AII and/or HDL3 and HDL2)
  • Apolipoprotein B (apo B)
  • Apolipoprotein A-I (apo A-I)
  • Apolipoprotein E (apo E and apo E genotyping)
  • B-type natriuretic peptide (BNP) and N-terminal proBNP (NT-proBNP)
  • Cystatin C
  • Fibrinogen; (may also include thrombogenic or hemostatic factors including but not limited to Fibrinogen, Prothrombin coagulation factor II and Factor V Leiden)
  • Long chain omega-3 fatty acids composition in red blood cell
  • Leptin
  • Vitamin D (see also medical policy 02.04.46)
  • Homocysteine (see also medical policy 02.04.22)

Numerous non-traditional lipid measurements have been proposed for use in improving risk prediction for cardiovascular disease. In general, there is evidence that some of these markers may provide some incremental accuracy in risk prediction. However,  it has not been established that the incremental accuracy provides clinically important information beyond that of traditional lipid measures. Furthermore, no study has provided high-quality evidence that measurement of markers leads to changes in management that improve health outcomes.

 

Some markers, eg, apo B, have also been proposed as treatment targets for lipid lowering therapy. While some evidence supports that they may be accurate in predicting residual risk for patients on lipid lowering therapy, there is no high quality evidence that these markers lead to health outcome improvements when used in place of traditional lipid targets, such as LDL. Because of the deficiencies in the literature around these issues, the use of novel lipid and nonlipid risk markers remains investigational.

 

Measure of Inflammotory Markers in the Assessment of Cardiovascular Risk

The measurement of inflammatory makers including but not limited to lipoprotein-associated phospholipase A2 (Lp-PLA2), other hyman A2 phospholipase such as secretory phospholipase A2 (sPLA2-IIA) or plasma myeloperoxidase (MPO) in the assessment of cardiovascular risk has not been proven to improve health outcomes and is considered investigational.

 

Cardiovascular Risk Panels

Cardiovascular risk panels, consisting of multiple individual biomarkers intended to assess cardiac risk (other than simple lipid panels, see below note) are considered investigational

  

Numerous cardiovascular risk panels are commercially available. These panels report results for multiple cardiovascular risk markers and have wide variability in the risk factors included in the panel. While the individual risk factors have in most cases been associated with increased risk of cardiovascular disease, it is not clear how the results of individual risk factors impact management changes, so it is also not certain how the panels will impact management decisions. Given the lack of evidence for clinical utility of any individual risk factor beyond simple lipid measures, it is unlikely that the use of CV risk panels improves outcomes. As a result, the use of cardiac risk panels for predicting risk of cardiovascular disease is considered  investigational.

 

Note: A simple lipid panel generally includes the following lipid measures: total cholesterol, LDL cholesterol, HDL cholesterol and triglycerides)

 

Genotype Testing for Predicting Cardiovascular Risk

Genotype testing for predicting cardiovascular disease risk is considered investigational, including but not limited to the following: 

  • KIF6 genotype
  • 9p21 genotype
  • CYP2C19 genotype (see also medical policy 02.04.48)
  • 4q25-AF risk genotyping
  • LPA –Aspirin genotype
  • LPA intron 25 genotype
  • Apolipoprotein E genotyping
  • MTHFR (see also medical policy 02.04.46)

Based on review of the medical literature there is insufficient evidence to support that genotype testing alters the management or improves outcomes for prevention of cardiovascular heart disease and therefore, 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.
  • 81240 Prothrombin coagulation factor II
  • 81241 Factor V Leiden
  • 81225 CYP2C19
  • 81291 MTHFR
  • 81401 Molecular pathology procedure, Level 2 (eg, 2-10 SNPs, 1 methylated variant, or 1 somatic variant [typically using nonsequencing target variant analysis], or detection of a dynamic mutation disorder/triplet repeat)
  • 81479 Unlisted molecular pathology procedure (when utilized with a description of KIF6, 9p21, 4q25-AF, LPA-Aspirin, LPA-Intron 25)
  • 82172 Apolipoprotein, each
  • 82306 Vitamin D; 25 hydroxy, includes fraction(s), if performed
  • 82652 Vitamin D; 1,25 dihydroxy, includes fraction(s), if performed
  • 82397 Chemiluminescent assay (Leptin)
  • 82610 Cystatin C
  • 82664 Electrophoretic technique, not otherwise classified
  • 83090 Homocysteine
  • 83695 Lipoprotein (a) enzyme immunoassay
  • 83698 Lipoprotein-associated phospholipase A2 (Lp-PLA2)
  • 83700 Lipoprotein, blood; electrophoretic separation and quantitation
  • 83701 high resolution fractionation and quantitation of lipoprotein subclasses when performed (e.g., electrophoresis, ultracentrifugation)
  • 83704 quantitation of lipoprotein particle numbers and lipoprotein particle subclasses (e.g., by nuclear magnetic resonance spectroscopy)
  • 83876 Myeloperoxidase (MPO)
  • 83880 Natriuretic peptid
  • 85384 Fibrinogen activity
  • 85385 Fibrinogen antigen
  • 0111T Long chain omega-3 fatty acids in red blood cell (RBC) membranes
  • 0423T Secretory type II phospholipase A2 (sPLA2-IIA)


Selected References:

  • Esteva FJ, Sahin AA, Cristofanilli M et al. Prognostic role of a multigene reverse transcriptase-PCR assay in patients with Node-negative breast cancer not receiving adjuvant systemic therapy. Clin Cancer Res. 2005; 11(9):3315-3319.
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Policy History:

  • April 2016 - Annual Review, Policy Revised 
  • May 2015  - Annual Review, Policy Revised 
  • June 2014 - Annual Review, Policy Revised 
  • Augugst 2013 - Annual Review, Policy Revised 
  • September 2012  - Annual Review, Policy Renewed
  • September 2011 - Annual Review, Policy Renewed

Wellmark medical policies address the complex issue of technology assessment of new and emerging treatments, devices, drugs, etc.   They are developed to assist in administering plan benefits and constitute neither offers of coverage nor medical advice. Wellmark medical policies contain only a partial, general description of plan or program benefits and do not constitute a contract. Wellmark does not provide health care services and, therefore, cannot guarantee any results or outcomes. Participating providers are independent contractors in private practice and are neither employees nor agents of Wellmark or its affiliates. Treating providers are solely responsible for medical advice and treatment of members. Our medical policies may be updated and therefore are subject to change without notice.

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