LCD L36358: MolDX: Biomarkers in Cardiovascular Risk Assessment

Indications and Limitations

Under preventative services, Medicare Part B covers the basic lipid panel (total cholesterol, high density lipoprotein-cholesterol (HDL-C), triglycerides, and low density lipoprotein-cholesterol (LDL-C) for cardiovascular (CV) disease screening, every 5 years when ordered by a doctor.

NCD 190.23 covers lipid panel testing for symptomatic patients for evaluating atherosclerotic CV disease, to monitor the progress of patients on anti-lipid dietary management and pharmacologic therapy for various lipid disorders. Per NCD 190.23, “Routine screening and prophylactic testing for lipid disorders are not covered by Medicare. While lipid screening may be medically appropriate, Medicare by statue does not pay for it. Lipid testing in asymptomatic individuals is considered to be screening regardless of the presence of other risk factors such as family history, tobacco use, etc.”

This policy denies coverage for all CV risk assessment panels , except the basic lipid panel, for symptomatic (with signs and symptoms) patients with suspected or documented CV disease because panel testing is not specific to a given patient’s lipid abnormality or disease. The policy indicates the medical indication(s) based on published scientific articles and consensus guidelines for individual lipid biomarkers that may be covered to characterize a given lipid abnormality or disease, to determine a treatment plan or to assist with intensification of therapy. Each individual lipid biomarkers must be specifically ordered and the reason for the test order documented in the patient’s medical record. The policy denies coverage for all non-lipid biomarkers when used for CV risk assessment including but not limited to, biochemical, immunologic, and hematologic, and genetic biomarkers for CV risk assessment regardless of whether ordered in a panel or individually.

The following biomarkers, when they are included in a CV risk assessment panel, are non-covered:

• Lipoprotein subclasses;

• LDL particles;

• Intermediate density lipoproteins;

• High density lipoprotein AI9LpAI and AI/AII;

• Lipoprotein(a);

• Apolipoprotein B (Apo B), Apo A-I and Apo E;

• Lipoprotein-associated phospholipase A2 (Lp-PLA2)

• BNP

• Cystatin C

• Thrombogenic/hematologic actors

• Interleukin-6 (IL-6), tissue necrosis factor- a (TNF- a), plasminogen activator inhibitor-1 (PAI-1) and IL-6 promoter polymorphism

• Free fatty acids

• Visfatin, angiotensin-converting enzyme 1 (ACE2) and serum amyloid A

• Microalbumin

• Myeloperoxidase (MPO)

• Homocysteine and methylenetetrahydrofolate reductase (MTHFR) mutation testing

• Uric acid

• Vitamin D

• White blood cell count

• Long-chain omega-3 fatty acids in red blood cell membranes

• Gamma-glutamyltransferase (GGT)

• Genomic profiling including CardiaRisk angiotensin gene

• Leptin, ghrelin, adiponectin and adipokines including retinol binding protein 4 (RBP4) and resistin

• Inflammatory markers including VCAM-1, P-selectin (PSEL) and E-selectin (ESEL)

• Cardiovascular risk panels

Note #1: There is no Medicare benefit for screening CV risk assessment testing for asymptomatic (without signs or symptoms of disease) patients. Screening asymptomatic patients for cardiovascular risk is statutorily excluded by Medicare and will not be addressed in this policy.

Note #2: FDA approval/clearance means that a test/assay has analytical and clinical validity. The FDA does not review clinical utility (that the test/assay demonstrates improved patient outcomes). To meet Medicare’s “reasonable and necessary” criteria for coverage, a test/assay must have proven clinical utility.

Traditional vs Non-traditional CV Risk Assessment

During the last two decades the interest in CV biomarkers as early screening tools has risen dramatically, largely fueled by the recognition that traditional CV risk factors (diabetes, smoking, hypertension and hyperlipidemia) do not fully explain individual variation in CV risk, and by advances in genetic and molecular research. Risk assessment for determining the 10-year risk for developing coronary heart disease (CHD) is traditionally carried out using the Framingham risk score (http://www.nhlbi.nih.gov/guidelines/cholesterol/atp3xsum.pdf) or other classification that incorporates a lipid profile in the calculation.

Despite the Framingham risk-scoring tool, clinicians have sought non-traditional lipid and other biomarker measurements to predict CV events. The most promising biomarkers are the ones that closely correlate with the pathophysiological process of the disease. In general, there is evidence that some of these biomarkers may alter risk categorization (higher or lower) compared to traditional risk prediction, but it has not been established that changes in categorization provides clinically actionable information beyond that of traditional lipid measures. In addition, no study has provided high-quality evidence that measurement of non-traditional lipid and other biomarkers leads to changes in management that improve health outcomes.

To provide clinically useful knowledge, a biomarker should meet the following criteria:

• Adds clinical knowledge that improves patient outcomes (criteria for Medicare “reasonable and necessary”);

• Provides risk information that is independent of established predictors;

• Is easy to measure and interpret in the clinical setting; and

• Is accurate, reproducible and standardized.

High-sensitivity C-reactive protein (hs-CRP)

CRP is a protein produced in the liver during episodes of acute inflammation or infection. The hs-CRP test measures CRP that is in the normal range for healthy people, and is used to distinguish people with low normal levels from those with high normal levels. In recent years, prospective epidemiologic studies have demonstrated that inflammation is essential for CV disease pathogenesis and that high normal levels of hs-CRP correlate with an increased risk of CV events such as myocardial infarction (MI), stroke, sudden cardiac death and peripheral vascular disease (PVD) even when lipid levels are within acceptable ranges. The American Heart Association (AHA) and the US Centers for Disease Control and Prevent (CDC) recommend averaging two hs-CRP levels obtained two weeks apart. Based on hs-CRP test results, they recognize: low (3.0 mg/L) risk groups.

In 2009, the US Preventive Services Task Force (USPSTF) report on the use of non-traditional risk factors noted there is insufficient evidence to recommend the use of non-traditional risk factors to screen asymptomatic individuals with no history of CHD to prevent CHD events. The non-traditional risk factors in their recommendation included: hs-CRP, ankle-brachial index (ABI), leukocyte count, fasting blood glucose level, periodontal disease, carotid intima-media thickness, coronary artery calcification (CAC) score on electron beam computerized tomography (EBCT), homocysteine level, and lipoprotein(a) level. The USPSTF stated there is insufficient evidence to determine the percentage of intermediate-risk individuals who would be reclassified by screening with non-traditional risk factors, other than hs-CRP or ABI. For individuals re-classified as high-risk by hs-CRP or ABI, data are not available to determine whether they benefit from additional treatment. They note the potential harms resulting from re-classification including the use of medications without proven benefit and psychological effects. The USPSTF stated that clinicians should continue to use the Framingham model to assess CHD risk and guide risk-based preventive therapy.

While data from the Physicians’ Health Study and Framingham Heart Study have shown that hs-CRP measurements may result in reclassification of an individual’s risk compared to standard risk prediction models, meta-analysis including data from the second Northwick Park Heart Study (NPHS II) and the Edinburgh Artery Study concluded that the ability of hs-CRP to reclassify risk correctly was modest and inconsistent.

The Jupiter trial, a randomized, double-blind, placebo-controlled trial of the use of rosuvastatin vs placebo in the primary prevention of CVD in patients without diabetes with LDL-C

• Men >50 years of age, or women >60 years of age or older,

• LDL-C

• Patients not on lipid-lowering, hormone replacement, or immunosuppressant therapy,

• Patients without clinical CHD, diabetes, chronic kidney disease, severe inflammatory conditions, or contraindications to statins

For example, a patient may appear to have a low or low-moderate elevated risk of CV events based on traditional risk factor scoring with cholesterol levels, weight, level of exercise, smoking history, diabetes and hypertension. However, an elevated hs-CRP level would indicate that the cardiac risk may be substantially greater than traditional risk factors suggest, and that treatment might be considered. For patients who are already known to have high risk, according to current recommendations, hs-CRP levels will not add any substantially new information, since the patient should already be receiving all available therapy including statins to reduce the risk.

The ACCF/AHA recommended measurement of hs-CRP for CV risk assessment in asymptomatic intermediate-risk men 50 years of age or younger, or women 60 years of age or younger (Class IIb; LOE B). Since screening (asymptomatic patient) is statutorily excluded from coverage, hs-CRP testing for these individuals is not a Medicare benefit. They found no benefit for hs-CRP testing in asymptomatic high-risk adults or men and women below the ages stated above. (Class III; LOE B).

The Canadian Cardiovascular Society guidelines recommend hs-CRP testing in men older than 50 and women older than 60 years of age who are at intermediate risk (10-19%) according to their Framingham risk score and who do not otherwise qualify for lipid-lowering therapy. They also state that subjects who meet Jupiter criteria can be considered for treatment based on the results of that study.

In the National Academy of Clinical Biochemistry’s practice guidelines on emerging CV risk factors, only hs-CRP met the stated criteria as a biomarker for risk assessment in primary prevention. They recommended:

• If the 10-year predicted risk, after standard global risk assessment, is

The NACB also recommended that:

• Therapies based on hs-CRP should be based on a clinician’s clinical judgment because benefits of such treatment are uncertain;

• There is insufficient data that therapeutic monitoring using hs-CRP over time is useful to evaluate effects of treatment in primary prevention;

• The utility of hs-CRP levels to motivate patients to improve lifestyle behaviors has not been demonstrated;

• Evidence is inadequate to support concurrent measurement of other inflammatory markers in addition to hs-CRP for coronary risk assessment.

In 2012, the American Association of Clinical Endocrinologist gave a 2b recommendation for the use of hs-CRP to stratify borderline CV risk in patients with a standard risk assessment, or those with an LDL-C.

The AHA’s statement on non-traditional risk factors and biomarkers in CV disease in youth notes “There is currently no clinical role for measuring CRP routinely in children when assessing or considering therapy for CVD risk factors.” The AHA also state that it is not clear whether high hs-CRP levels during childhood and adolescence lead to an increased risk of CVD in adult life. While lifestyle changes have been shown to decrease hs-CRP in children, and statins reduce CRP in adults, the AHA indicates there is minimal information available on the effect of statins on hs-CRP in children and whether lowering hs-CRP in children mitigates preclinical disease or CVD in adulthood. Similarly, the National Heart, Blood and Lung Institute (NHBLI) guideline on CV risk in children and adolescents found insufficient evidence to recommend hs-CRP testing in these patient groups.

In summary, this contractor expects testing to be limited to the following criteria:

• Patient has intermediate CV risk (10-20% risk of CVD per 10 years using the Framingham point score); and

• Patient has LDL-C between 100-130 mg/dL; and

• Patient has two or more CHD major risk factors, including

• Age (Men> 50 years; Women >60 years

• Current cigarette smoking

• Family history of premature CHD (CHD in male first degree relative 140 mm Hg, or on anti-hypertensive medication

• Low HDL-C (

The use of hs-CRP testing to evaluate the effects of treatment or to motivate patients to improve lifestyle behaviors are not considered medically reasonable and necessary, and therefore not covered by Medicare.

Lipoprotein subclasses

Lipoprotein subclass determination based on density, electric charge and other physical chemistry aspect of particles such as nuclear magnetic resonance allow more specific characterization of the major subclasses (VLDL, LDL, IDL and HDL). Studies showed that small, dense LDL particles were highly associated with the occurrence of CVD and diabetes.

LDL Particles (LDL-P) (aka LDL or Lipoprotein Particles or Particle Number, LDL or Lipid Subfractionation, Lipid Phenotyping, Nuclear Magnetic Resonance or NMR Profile)

Small dense LDL with elevated triglyceride levels and low HDL-cholesterol levels constitute the “atherogenic lipoprotein phenotype” form of dyslipidemia that is a feature of type II diabetes and the metabolic syndrome. Measurement of LDL particle density has been proposed as a technique to 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.

Although great progress has been made in the development of refined lipoprotein assessment and such measurements have helped in understanding the atherosclerotic process, it is not known whether measurements beyond traditional lipids can identify CV risk subgroups and how treatment would differ based on subgroup classification. Furthermore, it is not known whether this additional information helps the health care provider to identify with greater precision and accuracy the person who will develop clinical or subclinical CVD.

The NACB does not recommend testing as there is insufficient data that measurement of lipoprotein subclasses can identify CV risk subgroups, how treatment would differ based on subgroup classification and whether, over time, measurement is useful to evaluate the effects of treatments. In addition, the 2010 ACCF/AHA guidelines for assessment of lipoprotein, other lipoprotein parameters and modified lipids state that “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.”

Unlike lipoprotein size or subclass measures, which seek to improve CV risk assessment beyond conventional lipid testing, LDL particle number tests (NMR LDL-P) and ApoB) are simply an alternate measure of LDL quantity. Current data supports the ability of LDL particle number to provide clinically actionable information beyond traditional lipid measures to adjudicate individual response to treatment and guide adjustment in therapy. In addition, recent data demonstrate that patients with established CHD, stroke, TIA, peripheral arterial or diabetes achieving NMR LDL-P Intermediate Density Lipoproteins (Remnant Proteins)

Intermediate density lipoproteins (IDLs) have a density that falls between LDLs and VLDLs, and may be referred to as remnant lipoproteins because they vary in size and contain varying proportion of triglycerides and cholesterol. Although there is abundant evidence the remnant lipoproteins are atherogenic, and a risk factor for CAD, there is no evidence how testing improves patient outcomes.

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

HDL cholesterol (HDL-C) is the risk indicator most often used in associated with CHD risk. HDL subfractions have been used for risk prediction. However, data is lacking how the subfractions aid in the diagnosis and management of CHD. Neither the NCEP nor ACCF/AHA guidelines recommend the routine measurement of HDL subspecies in CHD risk assessment.

Lipoprotein(a) (Lp(a))

Lp(a) is a modified form of LDL in which a large glycoprotein, apolipoprotein(a) is bound to apolipoprotein B. It promotes foam cell formation and the deposition of cholesterol in atherosclerotic plaques, and, because it is structurally similar to plasminogen, Lp(a) may contribute to clot formation. However, the complete role of lipoprotein(a) is not fully understood.

There is no standardized scale for measuring Lp(a) because there is no level that is considered “normal”. Because Lp(a) levels are controlled predominantly by genes, cholesterol-lowering drugs have little effect on lowering Lp(a) levels. Elevated Lp(a) is considered an independent risk factor for cardiovascular events, including myocardial infarction, stroke, CVD, vein graft restenosis, and retinal arterial occlusion and may be used to identify individuals who might benefit from more aggressive treatment of other risk factors. However, regardless of the association between Lp(a) and CV disease, there is no data to suggest that more aggressive risk factor modification improves patient health outcomes.

The NACB specifies that Lp(a) screening is not warranted for primary prevention and assessment of cardiovascular risk. They comment that Lp(a) measurement may be done at the physician’s discretion if the risk is intermediate (10%–20%) and uncertainty remains as to the use of preventive therapies such as statins or aspirin (Recommendation – IIb; LOE – C). They further note there is insufficient evidence to support therapeutic monitoring of Lp(a) concentrations for evaluating the effects of treatment.

Similarly, the 2010 ACCF/AHA guidelines conclude that apolipoproteins is not recommended for CV disease risk assessment in asymptomatic adults. UpToDate notes that Lp(a) is a modest, independent risk factor for CVD, especially MI, but notes there are no clinical trials that have adequately tested the hypothesis that Lp(a) reduction reduces the incidence of first or recurrent CVD events.

Lp(a) testing may be indicated in select patients, particularly intermediate risk patient, to assist physicians with the use of preventive therapies. Routine testing is not covered by Medicare.

Apolipoprotein B (Apo B), Apolipoprotein A-I (Apo AI), and Apolipoprotein E (Apo E)

Apo B is a constituent of LDL particles, and serves as an indirect measurement of the number of LDL particles. Consequently, elevated levels of Apo B suggest increased levels of small dense LDL particles that are thought to be atherogenic.

Apo AI is the major protein constituent of HDL-C. However, its measurement has not been established as a clinically useful test in determining clinical therapy for patients with CAD or dyslipidemia at the current time.

While Apo B and Apo A-I are thought to be the main structural proteins of atherogenic and anti-atherogenic lipoproteins and particles, testing for these compounds has not been validated as a tool for risk assessment. As such, the 2010 ACCF/AHA guidelines indicate that apolipoproteins testing is not recommended for CV risk assessment in asymptomatic adults. However, AACE recommends ApoB testing to assess residual risk in patients for CAD (even when LDL-C levels are controlled) in patients when the triglyceride concentration is >150 mg/dL or the HDL-C concentration is Medicare expects testing to be limited to assessment of residual risk in patients with CAD with triglyceride concentrations of >150 mg/dL or HDL-C of Apo E, the major constituent of VLDL and chylomicrons, acts as the primary binding protein for LDL receptors in the liver and is thought to play a role in lipid metabolism. Although some individuals hypothesize that Apo E genotypes may be useful in the selection of drug therapy, the value of Apo E testing in the diagnosis and management of CHD is insufficient and needs further evaluation.

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