Medical Policy: 02.04.04 

Original Effective Date: September 2002 

Reviewed: April 2017 

Revised: April 2017 

 

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 (CVD) risk testing is utilized to indicate the chances of having a coronary event.

 

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). The rationale for early detection is that detection during the subclinical stages of diseases might permit the reliable identification of individuals at increased risk of an adverse cardiac event and that appropriate therapy (e.g. lipid lowering) might improve the prognosis of those at high risk.  The most common tests to determine cardiac risk is a basic or standard lipid panel, however, numerous lipid and non-lipid biomarkers and genetic testing have been proposed as potential risk markers for cardiovascular disease risk assessment.  

 

Novel Biomarkers in Risk Assessment and Management of Cardiovascular Disease

Numerous lipid and non-lipid biomarkers have been proposed as potential risk markers for cardiovascular disease (CVD). These biomarkers have been studied as alternatives or additions to standard lipid panels for risk stratification in CVD or as treatment targets for lipid lowering therapy.

LDL Subclasses (Small and Large Particles)

LDL particles are not uniform in size or density, and two subclass patterns, (A and B), have been described. In subclass pattern A, particles have a diameter larger than 25 nm and are less dense, while in subclass pattern B, particles have a diameter less than 25 nm and a higher density. Subclass pattern B is a commonly 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.

 

LDL size has also been proposed as a potentially useful measure of treatment response. Lipid-lowering treatment decreases total LDL and may also include 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 risk for CAD independent of the total LDL level. Also, some drugs may cause a greater shift in lipid profile than others. 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. Because 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-C 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-C 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.

 

Measurement of LDL particle density 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. 

 

Based on review of the literature some studies have reported that LDL size is an independent risk factor for CAD, while others have reported that a shift in LDL size may be a useful marker of treatment response. However, the direct clinical application of measuring small, dense lipoprotein particles is unclear. To improve outcomes, clinicians must have tools to translate this information into clinical practice. Such tools for linking small, dense LDL to clinical decision making, both in risk assessment and treatment response, are currently not available. Published data are inadequate to determine how such measurements should guide treatment decisions and whether these treatment decisions result in beneficial patient outcomes.

 

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.”

 

2013 American College of Cardiology (ACC)/American Heart Association (AHA) Guideline on the Assessment of Cardiovascular Risk, the guideline does not address the measurement of LDL subclasses.   

 

The National Cholesterol Education Panel (NCEP) expert panel on: Detection, Evaluation and Treatment of High Blood Cholesterol in Adults (Adult Treatment Panel III (ATPIII)). “ATPIII does not recommend measurement of small LDL particles in routine practice, LDL cholesterol remains the primary target of treatment.”

  

 

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

Lipoprotein (a) (Lp(a)) is a lipid-rich particle similar to LDL. Apo B is the major apolipoprotein associated with LDL; in Lp(a), however, there is an additional apo A covalently linked to the apo B. The apo A molecule is structurally similar to plasminogen, suggesting that Lp(a) may contribute to the thrombotic and atherogenic basis of  CVD. Levels of Lp(a) are relatively stable in individuals over time but vary up to 1000-fold between individuals, presumably on a genetic basis. The similarity between Lp (a) and fibrinogen has stimulated an 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.   

 

Numerous prospective RCTs, cohort studies, and systematic reviews have evaluated lipoprotein (a) (Lp(a)) as a cardiovascular risk factor. The overall degree of risk associated with Lp(a) levels appears to be modest, and the degree of risk may be mediated by other factors such as LDL levels and/or hormonal status. There is considerable uncertainty regarding the clinical utility of measuring Lp(a), specifically how knowledge of Lp(a) levels can be used in clinical care of patients being evaluated for lipid disorders. There is limited evidence on the use of Lp(a) as a treatment target for patients with hyperlipidemia. The available evidence is insufficient related to impact on clinical outcomes.

  

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.”

 

2013 American College of Cardiology (ACC)/American Heart Association (AHA) Guideline on the Assessment of Cardiovascular Risk, the guideline does not address the measurement of Lipoprotein a (Lp(a)).

    

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

 

An alternative to measuring the concentration of subclasses of HDL is direct measurement of HDL particle size and/or number. Particle size can be measured by NMR spectroscopy or by gradient-gel electrophoresis. HDL particle numbers can be measured by NMR spectroscopy. Measurement of apo AI has used HDL particle number as a surrogate, based on the premise that each HDL particle contains 1 apo AI molecule. Based on review of the literature it is uncertain how NMR measured HDL particle number would be used to change clinical management beyond information provided by traditional lipid measures. 

 

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 demonstrated 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.”  

 

2013 American College of Cardiology (ACC)/American Heart Association (AHA) Guideline on the Assessment of Cardiovascular Risk, the guideline does not address the measurement of high density lipoprotein (HDL) subclasses.  

 

Apolipoprotein B (apo B)

Apolipoprotein B (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 B, constitutes the apo B found in LDL and very low density lipoproteins (VLDL). LDL and VLDL each contain 1 molecule of apo B, measurement of apo B reflects the total number of these atherogenic particles, 90% of which are LDL. 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. Therefore, apo B concentration is an indirect measurement of the number of LDL particles and it has been suggested that apo B is a better measure of the atherogenic potential of serum LDL than LDL concentration. 

 

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. 

 

Based on review of the literature the evidence has suggested that apo B provides independent information on risk assessment for CVD. Numerous large prospective cohort studies and case controlled studies have compared these measures, and most have concluded that apo B is a better predictor of risk than LDL-C. However, some meta-analyses have concluded that apo B is not a better predictor of cardiac risk than HDL or non-HDL combined with LDL. There is also greater uncertainty about the degree of improvement in risk prediction and whether the magnitude of improvement is clinically significant. While there have been attempts to incorporate apo B into multivariate risk prediction models, at present, apo B is not included in the models most commonly used in routine clinical care, such as Framingham risk model and the Prospective Cardiovascular Munster Study (PROCAM) Score.

 

Currently, it is not possible to conclude that the use of apo B levels will improve clinical outcomes in routine clinical care. Improved ability to predict risk and/or treatment response does not by itself result in better health outcomes. To improve outcomes, clinicians must have the tools to translate this information into clinical practice. No studies have demonstrated improved health outcomes by using apo B in place of LDL-C for risk assessment and/or treatment response. The most widely used risk assessment models (e.g. Framingham prediction model) and current treatment guidelines do not provide the tools necessary for clinicians to incorporate apo B measurements into routine assessment and management of hyperlipidemic patients. The lack of these tools creates difficulties in interpreting and applying the results of apo B and/or apo B/apo AI measurements to routine clinical care.

 

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.”

 

2013 American College of Cardiology (ACC)/American Heart Association (AHA) Guideline on the Assessment of Cardiovascular Risk states: “The contribution of Apo B, chronic kidney disease, albuminuria, and cardiorespiratory fitness to risk assessment for a first ASCVD event is uncertain at present.”  

 

The National Cholesterol Education Program (NCEP) expert panel on: Detection, Evaluation, and Treatment of High Blood Cholesterol in Adults (Adult Treatment Panel III (ATPIII). “Apo B is a potential marker for all atherogenic lipoproteins and has been proposed as an alternative to LDL cholesterol as a risk factor. Limited epidemiological and clinical trial evidence supports is superiority over LDL cholesterol in risk prediction. Nonetheless, the body of evidence in favor of apolipoprotein B has not been developed sufficiently to justify replacing LDL cholesterol, which itself is a powerful independent predictor of CHD.”

  

 

Apolipoprotein A-I

HDL contains 2 associated apolipoproteins (i.e. AI, AII). HDL 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 HLD level  in the evaluation of the cardioprotective, or “good” cholesterol. In addition the ration of apo B/apo AI has been proposed as a superior measure of the ratio of proatherogenic (i.e.“bad”) cholesteroal to anti-atherogenic (i.e “good”) cholesterol.

 

The current evidence has generally indicated that measurement of apo AI and the apo B/apo AI ratio are as good as or better than currently used lipid measures such as LDL and HDL. Some experts have argued that the apo B/apo AI ratio is superior to the LDL/HDL ratio as a predictor of cardiovascular risk and should supplement or replace traditional lipid measures as both a risk marker and a treatment target. However, based on the evidence in the literature there is uncertainty regarding the degree of improvement that these measures provide, the evidence suggests that any incremental improvement in predictive ability over traditional measures is likely to be small and of uncertain clinical significance.

 

To improve outcomes, clinicians must have the tools to translate this information into clinical practice. Such tools for linking apo AI to clinical decision making, both in risk assessment and treatment response, are currently not available. Apo AI has not been incorporated into quantitative risk assessment models or treatment guidelines that can be used in clinical practice. Practice guidelines continue to tie clinical decision making to conventional lipid measures such as TC (total cholesterol), LDL-C, and HDL-C. Therefore, it is not yet possible to conclude that these measures improve health outcomes or that they should be adopted in routine clinical care.

 

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.”  

 

2013 American College of Cardiology (ACC)/American Heart Assocation (AHA) Guideline on the Assessment of Cardiovascular Risk, the guideline does not address the measurement of Apolipoprotein A-I.

 

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.”

 

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.

 

The evidence has suggested that APOE genotype may be associated with lipid levels and CAD but is probably not useful in providing additional clinically relevant information beyond established risk factors. Apo E is considered a relatively poor predictor of CAD, especially compared with other established and emerging clinical variables, and does not explain a large of percentage of the variation in total cholesterol and LDL levels. Apo E has not been incorporated into standardized cardiac risk assessment models.

 

The evidence on response to treatment indicates that APOE genotype may be a predictor of response to statins and may allow clinicians to better gauge a patient’s chance of successful treatment, although not all studies have consistently reported this relation. At present, it is unclear how this type of information would change clinical management. Dietary modifications are a universal recommendation for those with elevated cholesterol or LDL levels, and statin drugs are the preferred agents for lipid lowing therapy. It is unlikely that a clinician will choose alternative therapies, even in the presence of an APOE phenotype that indicated diminished response.

 

None of the available evidence has provided adequate data to establish that APOE genotype or phenotype improves outcomes in clinical care.

 

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.”  This guideline also states: “genotype testing for CHD risk assessment in adults is not recommended.”   

 

2013 American College of Cardiology (ACC)/American Heart Assocation (AHA) Guideline on the Assessment of Cardiovascular Risk, the guideline does not address the measurement of Apolipoprotein A-I.

 

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.

 

BNP levels appear to be associated with cardiovascular risks. However, no evidence was identified in demonstrating that the use of BNP testing in clinical care improves net health outcomes.

 

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 in the body. It has primarily been used as a biomarker for 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.

 

None of the available evidence provides adequate data to establish that cystatin C improves net health 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.” 

 

2010 American College of Cardiology Foundation (ACCF)/American Heart Association (AHA) Guideline for Assessment of Cardiovascular Risk in Asymptomatic Adults, the guideline does not address the measurement of cystatin C.

2013 American College of Cardiology (ACC)/American Heart Association (AHA) Guideline for Assessment of Cardiovascular Risk, the guideline does not address the measurement of cystatin C.

 

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 clotting factor 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 to be associated with future risk of cardiovascular disease. The evidence regarding fibrinogen and cardiovascular risk is based on cohort studies which has not proven that the use of fibrinogen testing in clinical care improves outcomes.  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. 

2010 American College of Cardiology Foundation (ACCF)/American Heart Association (AHA) Guideline for Assessment of Cardiovascular Risk in Asymptomatic Adults, the guideline does not address the measurement of leptin. 

2013 American College of Cardiology (ACC)/American Heart Association (AHA) Guideline, the guideline does not address the measurement of leptin.      

 

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 omega-3 fatty acids composition in the management of CHD.

 

2010 American College of Cardiology Foundation (ACCF)/American Heart Association (AHA) Guideline for Assessment of Cardiovascular Risk in Asymptomatic Adults, the guideline does not address the measurement of long chain omega-3 fatty acids.

2013 American College of Cardiology (ACC)/American Heart Association (AHA) Guideline, the guideline does not address measurement of long chain omega-3 fatty acids.

 

Inflammatory Markers of Coronary Artery Disease Risk

Evidence has suggested that there may be certain biomarkers of CAD that may have a pro-inflammatory role in the progression of atherosclerosis.  Recognition that atherosclerosis represents, in part, an inflammatory process has created interest in measurement of pro-inflammatory factors as part of cardiovascular disease risk assessment.

 

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 improve treatment and health outcomes. These tools are not currently available to the practicing clinician for Lp-PLA2. Direct evidence for improved health outcomes with the use of Lp-PLA2 in clinical management is lacking and changes in patient management that would occur as a result of obtaining Lp-PLA2 levels in practice are not well defined. The evidence is insufficient to determine the effects of this testing on net health outcomes.

 

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.

 

2013 American College of Cardiology (ACC)/American Heart Association (AHA) Guideline on the Assessment of Cardiovascular Risk, the guideline does not address lipoprotein-associated phospholipase A2 (Lp-PLA2) testing.

 

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 CVD risk.

 

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 American College of Cardiology Foundation (ACCF)/American Heart Association (AHA) Guideline for Assessment of Cardiovascular Risk in Asymptomatic Adults: The guideline did not address measurement of homocysteine levels.  

 

2013 American College of Cardiology (ACC)/American Heart Association (AHA) Guideline on the Assessment of Cardiovascular Risk: The guideline does not address measurement of homocysteine levels.

 

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 does not recommend routine measurement of homocysteine as part of risk assessment to modify LDL cholesterol goal for primary prevention.”

 

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.

 

9p21 Genetic Variant

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. 

 

KIF6 Genotyping

Genetic testing to determine KIF6 (Trp719Arg) variant status is being evaluated as a prognostic test to predict risk of future cardiovascular events and/or as a pharmacogenetic test to predict response to statin therapy, particularly high risk patients. 

 

The evidence for use of KIF6 genotyping for individuals who are asymptomatic with risk of CVD is limited and it has not been determined whether knowledge of carrier status can be used to improve patient management decisions and improve net health outcomes. The evidence is insufficient to determine the effects of this  

 

LPA Genetic Variant

Patients with a positive test for the LPA genetic variant rs3798220 have a higher risk for thrombosis and therefore may derive greater benefit from the antithrombotic properties of aspirin. As a result, testing for the rs3798220 variant has been proposed as a method of stratifying benefit from aspirin treatment.

 

The LPA minor allele, rs3798220, is associated with higher levels of LPA and a higher risk of cardiovascular events. This allele is infrequent in the population and is associated with a modest increase in cardiovascular risk in the general population. Testing for this allele is commercially available, but performance characteristics are uncertain and standardization of testing has not been demonstrated. Several observational studies have reported that this genetic variant is an independent risk factor for cardiovascular disease, but some studies have not reported a significant association. It is unclear whether the information derived from genetic testing leads to changes in management. In particular, it cannot be determined from available evidence whether deviating from current guidelines on aspirin treatment based on LPA genetic testing improves outcomes. Therefore, the measurement of the LPA rs3798220 variant as a decision aid for aspirin treatment is considered investigational.

 

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

 

2013 American College of Cardiology (ACC)/American Heart Association (AHA) Guideline on the Assessment of Cardiovascular Risk, the guideline does not address genotyping for CHD risk assessment. 

 

Cardiovascular Risk Panels

Cardiovascular risk panels refer to different combinations of cardiac markers that are intended to evaluate risk of cardiovascular disease. There are several commercially available risk panels that include different combinations of lipids, non-cardiac 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.

  

Examples of commercially available Cardiovascular (CV) risk panels including but not limited to the following:

  • 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. 

The evidence for the use of cardiovascular (CV) risk panels in individuals who have risk factors for cardiovascular disease includes multiple cohort and case-control studies and systematic reviews of these studies. The available evidence indicates that many of the individual risk factors included in the cardiovascular risk panels are associated with increased risk of CV disease. However, it is not clear how the results of individual risk factors impact management changes, so it is uncertain 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 panels improves outcome. Studies that have evaluated the clinical validity of panels of multiple markers have not assessed management changes that would occur as a result of testing, or demonstrate improvements in outcomes. The evidence is insufficient to determine the effects of this testing on net health outcomes.

 

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 lipid or non-lipid biomarkers for cardiovascular disease risk assessment and/or management including but not limited to the following is considered investigational:

  • 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)
  • 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.  The evidence is insufficient to determine the effects on net health outcomes.

 

Measure of Inflammatory 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 is considered investigational.

 

Based on review of the medical literature the evidence is insufficient to support conclusions concerning net health outcomes and benefits associated with this testing. Additional well-designed clinical trials are necessary to establish the clinical utility of this testing for cardiovascular risk assessment.

 

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.

 

The evidence for the use of cardiovascular (CV) risk panels in individuals who have risk factors for cardiovascular disease includes multiple cohort and case-control studies and systematic reviews of these studies. The available evidence indicates that many of the individual risk factors included in the cardiovascular risk panels are associated with increased risk of CV disease. However, it is not clear how the results of individual risk factors impact management changes, so it is uncertain 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 panels improves outcome. Studies that have evaluated the clinical validity of panels of multiple markers have not assessed management changes that would occur as a result of testing, or demonstrate improvements in outcomes. The evidence is insufficient to determine the effects of this testing on net health outcomes.

 

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 and/or management 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 (APO 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 net health outcomes 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 Lipoprotein, blood; high resolution fractionation and quantitation of lipoprotein subclasses when performed (e.g., electrophoresis, ultracentrifugation)
  • 83704 Lipoprotein, blood; quantitation of lipoprotein particle number(s) (eg, by nuclear magnetic resonance spectroscopy), includes lipoprotein particle subclass(es), when performed
  • 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)


 

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Policy History:

  • April 2017 - Annual Review, Policy Revised 
  • 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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