In-vitro Testing for Cardiovascular Disease (CVD) and CVD Risk

Lab Management Guidelines V2.0.2021

In-vitro Testing for Cardiovascular Disease (CVD) and CVD Risk

MOL.CS.316.Xv2.0.2021

Introduction

In-vitro testing for cardiovascular disease (CVD) and CVD risk is addressed by this guideline.

Procedures Addressed

The inclusion of any procedure code in this table does not imply that the code is under management or requires prior authorization. Refer to the specific Health Plan's procedure code list for management requirements.

Procedure addressed by this guideline Procedure code

Apolipoprotein, each 82172

Cholesterol, serum or whole blood, total 82465

Creatinine kinase (CK), (CPK); MB fraction only

82553

C-reactive protein; high sensitivity (hsCRP)

86141

Cystatin C 82610

Galectin-3 82777

Glycosylated acute phase proteins (GlycA), nuclear magnetic resonance spectroscopy, quantitative

0024U

Growth stimulation expressed gene 2 (ST2, Interleukin 1 receptor like-1)

83006

Homocysteine 83090

Lipid panel 80061

Lipoprotein (a) 83695

Lipoprotein-associated phospholipase A2 (Lp-PLA2)

83698

Lipoprotein, blood; electrophoretic separation and quantitation

83700

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Procedure addressed by this guideline Procedure code

Lipoprotein, blood; high resolution fractionation and quantitation of lipoproteins including lipoprotein subclasses when performed (e.g., electrophoresis, ultracentrifugation)

83701

Lipoprotein, blood; quantitation of lipoprotein particle numbers and lipoprotein particle subclasses (e.g., by nuclear magnetic resonance spectroscopy), includes lipoprotein particle subclass(es) when performed

83704

Lipoprotein, blood, high resolution fractionation and quantitation of lipoproteins, including all five major lipoprotein classes and subclasses of HDL, LDL, and VLDL by vertical auto profile ultracentrifugation

0052U

Lipoprotein, direct measurement; high density cholesterol (HDL cholesterol)

83718

Lipoprotein, direct measurement; VLDL cholesterol

83719

Lipoprotein, direct measurement; LDL cholesterol

83721

Lipoprotein, direct measurement; small dense LDL cholesterol

83722

MI-HEART Ceramides, Plasma 0119U

Myeloperoxidase (MPO) 83876

Natriuretic peptide 83880

Secretory type II phospholipase A2 (sPLA2-IIA)

0423T

Thromboxane metabolite(s), including thromboxane if performed, urine

84431

Troponin, quantitative 84484

Triglycerides 84478

Unlisted chemistry procedure 84999


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What Is Cardiovascular Disease Definition

Atherosclerotic (or arteriosclerotic) cardiovascular disease (ASCVD) is the most common cause of death in the United States, accounting for 1 in 3 deaths.1

Atherosclerotic Cardiovascular Disease

There is general agreement that excess cholesterol, which is present in particular lipoprotein particles in the blood, is a necessary element in the developmental pathway of ASCVD. This has been expressed in recommendations from the National Lipid Association (NLA)2, in joint guidelines from the American Heart Association (AHA) and American College of Cardiology (ACC)3, in joint guidelines from the American Association of Clinical Endocrinology (AACE) and American College of Endocrinology (ACE)4, and in joint guidelines from the AHA and the American Stroke Association (ASA).5 For example, the NLA recommendations state:2

“An elevated level of cholesterol carried by circulating apolipoprotein (apo) B–containing lipoproteins (non–HDL-C and LDL-C, termed atherogenic cholesterol) is a root cause of atherosclerosis, the key underlying process contributing to most clinical ASCVD events.”* [*HDL=high density lipoprotein; LDL = low density lipoprotein; non-HDL-C= non-HDL Cholesterol; LDL-C=LDL Cholesterol]

Lipoproteins are particles that transport cholesterol and triglycerides to and from the tissues. They are defined as follows:6

“Cholesterol and triglycerides are insoluble in water and therefore these lipids must be transported in association with proteins. Lipoproteins are complex particles with a central core containing cholesterol esters and triglycerides surrounded by free cholesterol, phospholipids, and apolipoproteins, which facilitate lipoprotein formation and function. Plasma lipoproteins can be divided into seven classes based on size, lipid composition, and apolipoproteins (chylomicrons, chylomicron remnants, VLDL, IDL, LDL, HDL, and Lp (a)). Chylomicron remnants, VLDL, IDL, LDL, and Lp (a) are all pro-atherogenic while HDL is anti-atherogenic.”

Along with cholesterol, triglycerides are the other commonly occurring lipid in lipoproteins. Triglycerides are brought to tissues as a source of energy. Cholesterol is an important component of cell membranes and is used in the synthesis of a variety of compounds including steroid hormones and bile acids.

When diagnosing and monitoring ASCVD, lipoproteins are commonly classified as HDL-cholesterol (HDL-C) and non-HDL-C, which the NLA defines as:2

“Non–HDL-C (calculated as total-C – HDL-C) represents the sum of cholesterol carried by all potentially atherogenic, apo B-containing lipoprotein particles, including LDL, IDL, Lp (a), VLDL (including VLDL remnants), and chylomicron particles and remnants.”* [* Total-C=total cholesterol; IDL=intermediate density lipoproteins; Lp(a) = Lipoprotein a]


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ASCVD encompasses coronary heart disease (CHD, also known as coronary artery disease (CAD)), cerebrovascular disease and peripheral vascular disease.1,2 Coronary heart disease can present as stable or unstable angina, and myocardial infarction (MI). Cerebrovascular disease leads to transient ischemic attacks and non-hemorrhagic stroke. Peripheral vascular disease, which in the context of ASCVD is often synonymous with peripheral arterial disease, affects many organs with a proclivity to produce signs and symptoms of ischemia in the lower limbs, upper limbs and kidneys. ASCVD also includes aortic aneurysm if it is secondary to atherosclerosis.2

Guidelines and recommendations regarding ASCVD risk assessment often use the term “hard ASCVD event”, which most frequently refers to fatal or nonfatal MI, or fatal or non-fatal non-hemorrhagic stroke.3 ASCVD risk assessment, diagnosis, and treatment seek to reduce these adverse clinical outcomes. “Soft” events usually refer to angina, transient ischemic attacks, or symptoms associated with ASCVD-related peripheral vascular disease, such as claudication (ischemic pain in the lower limbs) or diminished renal function.

The major ASCVD risk factors have been summarized in the AACE/ACE guideline.4 According to the AACE/ACE, the major risk factors are:

advancing age

increased Total-C

increased Non-HDL-C

increased LDL-C

diabetes

hypertension

cigarette smoking

chronic kidney disease

family history of ASCVD

“Additional” risk factors include:4

obesity

family history of lipidemia

increased Apo B

increased LDL particle concentration

increased triglycerides

polycystic ovarian syndrome

Non-traditional risk factors include: 4

increased lipoprotein a (Lp(a))

increased clotting factors, such as fibrinogen


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increased high sensitivity CRP (hsCRP)

increased lipoprotein-associated phospholipase A2 (Lp-PLA2)

increased homocysteine

increased uric acid

reduced LDL particle size and increased LDL density

There are numerous other ASCVD risk factors—including certain medications (e.g., anabolic steroids, cyclosporine, amiodarone) as well as clinical conditions (e.g., pregnancy, hypothyroidism, HIV infection, autoimmune inflammatory disorders, and obstructive liver diseases) 4 that can also predispose individuals to ASCVD. These conditions can impact ASCVD through raising atherogenic cholesterol or by other mechanisms.2

National guidelines and recommendations are in strong agreement that risk calculators can be useful to assess ASCVD risk.2-5. Risk calculators use a small subset of the risk factors, strongly emphasizing the major risk factors described in the AACE/ACE guideline.4 Limitations of risk calculators include over- or under-estimation of risk, which is dependent on the population being tested.4

Risk calculators are not necessary in patients already known to be in any of the following high risk groups requiring treatment:2

ASCVD with the presence of hard or soft ASCVD events

Type 1 or 2 diabetes

advanced chronic renal disease

familial hypercholesterolemia or related genetic disorder

LDL-C > 190 mg/dL

Outside of these conditions, and related conditions that automatically place a patient in a high-risk category requiring treatment, risk calculators are useful for calculating the 10-year risk of hard ASCVD events. The USPSTF has summarized the use of risk calculators:1

“Risk factors can be combined in many ways to classify a person’s risk for a CVD event as low, intermediate, or high. Several calculators and models are available to quantify a person’s 10-year CVD event risk. The Framingham Risk Score (which estimates a person’s 10-year risk of coronary heart disease) was one of the first widely used risk assessment tools. Persons with a 10-year CVD event risk greater than 20% are generally considered at high risk, those with a 10-year risk less than 10% are considered at low risk, and those in the 10% to 20% range are considered at intermediate risk. The Pooled Cohort Equations (which estimate 10-year risk of myocardial infarction, death from coronary heart disease, or stroke) were introduced in 2013 and were developed using more contemporary and diverse cohort data, with the inclusion of race/ethnicity and diabetes. Persons with a 10-year CVD event risk less than 7.5% are considered at low risk, and those with a 10-


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year risk of 7.5% or greater are considered at high risk.”* [*Pooled cohort equations are described in the AHA/ACC guidelines3]

Besides the Framingham Risk calculator7, and Pooled Cohort equations3, there are a number of other risk calculators including the Reynold’s Risk Score8,9 and the MESA risk calculator.10

Opinions vary regarding which calculators are most predictive. The USPSTF1 prefers the pooled cohort equations described in the AHA/ACC guidelines:3

“Although in the United States both the Framingham Risk Score and the Pooled Cohort Equations are used in practice, the USPSTF recommends that clinicians use the Pooled Cohort Equations to assess CVD risk and to guide treatment decisions until further evidence shows additional benefit of adding other CVD risk factors.”1

The AACE/ACE does not express a strong preference for which risk assessment tool should be used:4

“The 10-year risk of a coronary event (high, intermediate, or low) should be determined by detailed assessment using one or more of the following tools:

o Framingham Risk Assessment Tool

o Multi-Ethnic Study of Atherosclerosis (MESA) 10-year ASCVD Risk with Coronary Artery Calcification Calculator

o Reynolds Risk score which includes high sensitivity CRP (hsCRP) and family history of premature ASCVD

o United Kingdom Prospective Diabetes Study (UKPDS) risk engine to calculate ASCVD risk in individuals with T2DM”* [*T2DM=Type 2 diabetes mellitus]

ASCVD risk assessment is just one tool to help clinicians identify patients more likely to benefit from lifestyle modifications – such as weight loss, smoking cessation, dietary change, or exercise – or pharmaceutical interventions, such as a statin.

In general, risk assessment and subsequent treatment decisions are individualized. Guidelines are often explicit regarding the need for personalized assessment. Thus, the AACE/ACC makes these recommendations:4

“Identify risk factors that enable personalized and optimal therapy for dyslipidemia”

“The frequency of lipid testing should be based on individual clinical circumstances and the clinician’s best judgment”

There is a difference between estimating primary risk in individuals who are asymptomatic without ASCVD versus those who are asymptomatic but have been diagnosed with ASCVD. Certain tests that have not been shown to be useful in primary risk estimation may be useful in following an individual patient who has known ASCVD.4


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Treatment with lifestyle modification and drugs are commonly recommended to the following patients according to the NLA recommendations:2

Those with clinical signs and symptoms of ASCVD, or a previous hard ASCVD event

Those with history of other conditions that nearly always produce high risk of an ASCVD event (e.g. Type 1 or 2 Diabetes, chronic kidney disease, familial hypercholesterolemia)

Those with only 0-1 major ASCVD risk factor but with a very high non-HDL cholesterol >190 mg/dL or LDL-C > 160 mg/dL

Heart Failure

Heart failure (HF) is defined as follows:11

“Heart failure (HF) is a clinical syndrome caused by structural and functional defects in myocardium resulting in impairment of ventricular filling or the ejection of blood. The most common cause for HF is reduced left ventricular myocardial function…Heart failure can be classified as predominantly left ventricular, right ventricular or biventricular based on the location of the deficit. Depending on the time of onset, HF is classified as acute or chronic. Clinically, it is typically classified into two major types based on the functional status of heart: heart failure with preserved ejection fraction (HFpEF) and heart failure with reduced ejection fraction (HFrEF).”

The most common cause of HF is ASCVD, which can cause either chronic ischemic damage to the heart, or acute ischemic damage through MI.12 HF can also be caused by anything that damages the heart including: 12

viruses

chronic alcohol use

toxins

chronic hypertension

hyperthyroidism

congenital diseases of the heart including the congenital cardiomyopathies and congenital arrhythmias

B-Natriuretic peptide is a foundational test in diagnosing and monitoring heart failure.12,13 Galectin-3 and ST2 are less frequently used as markers of HF and can play a secondary role in risk stratification of HF patients.12-16 Risk stratification, in turn, helps guide the selection of treatment.12


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Test Information

Introduction

Testing for cardiovascular disease includes traditional biomarkers, non-traditional biomarkers, and proprietary laboratory testing.

The traditional biomarkers for CVD risk assessment and management of ASCVD are Total-C, LDL-C, HDL-C, and triglycerides.2-4 These are most commonly measured using automated, FDA-approved chemistry assay platforms offered by the major in-vitro diagnostic manufacturers. The instrument platforms vary from large high throughput instruments for the commercial lab setting to smaller tabletop instruments and point-of-care devices suitable for smaller labs and the ambulatory setting.

Similarly, many of the other tests addressed in this policy are measured on the same or similar FDA-approved platforms. These include high sensitivity C-Reactive Protein (hsCRP), apolipoprotein A and B (ApoA, ApoB), Lp(a), B-Natriuretic Peptide (BNP), Galectin-3, ST2, homocysteine, Cystatin C, and troponin. These tests are not traditionally used for ASCVD assessment, with the exception of ApoA and ApoB which are employed as alternative biomarkers for risk stratification.2,4 The primary use of the remaining tests is in the evaluation of other clinical conditions. These uses are described in numerous lab test compendia .17,18 For example:

CRP is most commonly used as a nonspecific clinical marker of inflammation. Elevations of CRP are used to diagnose and monitor a large number of inflammatory states, especially in rheumatologic and infectious diseases.

As noted above, BNP peptide is a foundational test in diagnosing and monitoring HF. Elevation of BNP is associated with HF, and reduction in BNP is associated with improvements in clinical status.

Galectin-3 and ST2 are less frequently used markers for HF. Like BNP, elevations of these markers can indicate HF.

Homocysteine is an amino acid used in the diagnosis of homocystinuria, a genetic disease of methionine metabolism. Homocysteine is also used in the evaluation of vitamin B6, B12 and folate deficiencies. An increase in serum homocysteine is an early marker of these conditions.

Cystatin C is a less common marker of renal function. It can be used along with, or as a replacement for, creatinine, which is the primary indicator of kidney health. A decrease in Cystatin C is associated with deteriorating renal status and renal failure.

Troponin is the main test used to diagnose acute MI. Troponin levels follow a characteristic time course of elevation and recovery during the course of an infarction. It is the best marker of myocardial injury and subsequently has a variety of more subtle uses involving risk-stratifying patients with heart disease. Increases in troponin reflect myocardial damage.

The procedures in the table above representing measurements of other lipoprotein


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particles, such as VLDL, involve specialized chemistry techniques such as nuclear magnetic resonance spectroscopy, ultracentrifugation, and electrophoresis.

The remaining tests addressed in this policy have either rare indications or no proven clinical utility for any specific indication. These include thromboxane metabolites, long-chain (C20-22) omega-3 fatty acids in red blood cell (RBC) membranes, and myeloperoxidase. Most of them are performed using a variety of immunoassay formats such as microplate-based enzyme immunoassays or bead-based immunoassays. Many of these formats are highly automatable and could be scaled for high-volume testing.

Guidelines and Evidence

Introduction

There are a number of expert guidelines2,4,5,19,20, recommendations1,2,21, algorithms from academic practices18 and opinions from professional societies17 related to lipid metabolism, ASCVD risk assessment in both symptomatic and asymptomatic individuals, the diagnosis of ASCVD, and the further evaluation and management of patients diagnosed with ASCVD.

Traditional Tests for ASCVD

Traditional tests for ASCVD risk assessment, diagnosis and treatment

Test Name Procedure Code(s)

Cholesterol, serum or whole blood, total 82465

HDL cholesterol (Lipoprotein, direct measurement; high density cholesterol

83718

LDL cholesterol (Lipoprotein, direct measurement)

83721

Lipid panel 80061

Triglycerides 84478

US guidelines regarding ASCVD risk assessment in asymptomatic adults have been published jointly by the AHA and ACC.3,19 Subsequently, the National Lipid Association made recommendations designed to make the AHA/ACC guidelines more practical.2,20 The summaries of these key recommendations assert the following:

“... Serum cholesterol and its lipoprotein carriers (LDL, very low-density lipoprotein [VLDL], and HDL) are known to be related to ASCVD. LDL-C is the dominant form of atherogenic cholesterol. VLDL is the chief carrier of triglycerides, and VLDL cholesterol (VLDL-C) is also atherogenic. HDL-C is seemingly not atherogenic. Chylomicrons transport dietary fat; chylomicron atherogenicity is uncertain. The combination of LDL-C and VLDL-C is called non–HDL-C and is more atherogenic


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than either lipoprotein alone. The main protein embedded in LDL and VLDL is apolipoprotein B (apoB), and like non–HDL-C, apoB is a stronger indicator of atherogenicity than LDL-C alone.” 20

“The measurement and monitoring of atherogenic cholesterol levels remain an important part of a comprehensive ASCVD prevention strategy.”2

Each of these recent major US guidelines make recommendations regarding the frequency of risk assessment in asymptomatic individuals.2-4,19,20 The frequency of risk assessment in asymptomatic people without ASCVD is as follows from the AHA/ACC guideline:19

“Periodic assessment of risk factors (eg, at least every 4 to 6 years in younger adults 20 to 39 years of age) is important to guide discussions about intensity of lifestyle interventions, frequency of risk factor monitoring, treatment of nonlipid risk factors, and consideration of 30-year or lifetime risk estimation.”

The AACE/ACC guideline recommends the following for asymptomatic men aged 20-45 years and women 20-55 years:4

“Evaluate all adults 20 years of age or older for dyslipidemia every 5 years as part of a global risk assessment”

Similarly, the NLA makes the following recommendations for the frequency of ASCVD risk assessment in patients found to be at low risk of dyslipidemia and ASCVD.20

“After age 20 years, traditional risk factors should be assessed every 4 to 6 years.”

Due to concerns about the epidemic of obesity in children, the American Academy of Pediatrics (AAP) recommends children with no risk factors of ASCVD undergo dyslipidemia screening between 9 – 11 years.22

In patients with 1 or more risk factors for ASCVD, the frequency of risk assessment increases as risk factors accumulate.2,4,19 The specific frequency of assessment is individualized, depending on a patient’s specific clinical situation. For example, in older adults the following recommendation is made:

“Annually screen older adults with zero or one ASCVD risk factors for dyslipidemia. Patients with multiple ASCVD risk factors should undergo lipid assessment. The frequency of lipid testing in older adults should be based on individual clinical circumstances.” 4

And for those at high risk of ASCVD due to diabetes, the AACE/ACE guideline recommends the following:4,19

"Annually screen all adults with type 1 or type 2 diabetes for dyslipidemia."4

For children with the following risk factors of ASCVD, the National Lipid Association (NLA) has the following recommendations for cholesterol testing in individuals between 2 – 18 years:23


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“1) in whom one or both biological parents are known to have hypercholesterolemia or are receiving lipid-lowering medications; 2) who have a family history of premature ASCVD in an expanded first-degree pedigree in men <55 or women <65 years of age; and 3) whose family history is unknown (e.g., children who were adopted).”

The goal of treatment is to lower risk for events associated with ASCVD, such as MI, stroke, and CHD. The NLA recommends:2

“Reducing elevated levels of atherogenic cholesterol will lower ASCVD risk in proportion to the extent that atherogenic cholesterol is reduced. This benefit is presumed to result from atherogenic cholesterol lowering through multiple modalities, including lifestyle and drug therapies.”

For patients who are being treated for ASCVD and dyslipidemia, the primary target of therapy is lowering non-HDL-C. In practice this usually means following non-HDL-C, which is calculated by subtracting HDL-C from Total-C. Another common approach is to follow LDL-C, which makes up about 75% of non-HDL-C. Historically, lowering LDL-C was favored as the focus of therapy but there is a trend toward preferring non-HDL-C. Alternatively, Apo B, which is the predominant apolipoprotein on LDL particles and a major apolipoprotein on VLDL, can also be followed. See the Apolipoprotein section below for more details. The latest guidelines from the NLA, list the treatment goals for LDL-C, Non-HDL-C and ApoB:2,20

“In ASCVD with and without high risk features, lowering LDL-C by > 50% is recommended.” 20

The frequency of lipid testing during therapy monitoring is addressed by both the AACE/ACE4 and NLA Guidelines.2,20 The AACE/ACE guideline states:4

“Re-assess individuals’ lipid status 6 weeks after therapy initiation and again at 6-week intervals until the treatment goal is achieved…”

“While on stable lipid therapy, individuals should be tested at 6- to 12-month intervals…”

“While on stable lipid therapy, the specific interval of testing should depend on individual adherence to therapy and lipid profile consistency; if adherence is a concern or the lipid profile is unstable, the individual will probably benefit from more frequent assessment…”

“More frequent lipid status evaluation is recommended in situations such as deterioration of diabetes control, use of a new drug known to affect lipid levels, progression of atherothrombotic disease, considerable weight gain, unexpected adverse change in any lipid parameter, development of a new ASCVD risk factor, or convincing new clinical trial evidence or guidelines that suggest stricter lipid goals…”

The NLA guideline also notes that 6-12 month intervals for lipid testing are sufficient for monitoring stable patients:2


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“If goal levels of atherogenic cholesterol have been attained, responses to therapy should be monitored at intervals of 6 to 12 months.”

Triglycerides (TG) are not a component of the main ASCVD risk calculators, but they are useful and recommended as part of ASCVD risk assessment, diagnosis and management as well as for other clinical uses.4,19,20 TG levels are modifiable by lifestyle changes and pharmaceutical intervention. The guidelines state:

“TG levels should be part of routine lipid screening: moderate elevations (≥150 mg/dL) may identify individuals at risk for the insulin resistance syndrome and levels ≥200 mg/dL may identify individuals at substantially increased ASCVD risk…” 4

“The diagnosis [of metabolic syndrome, a risk factor for ASCVD] is made by the presence of any 3 of the following 5 risk factors: elevated waist circumference, elevated serum triglycerides, reduced HDL-C, elevated blood pressure, and elevated fasting glucose.” 20

Very high TG levels, over 500 mg/dL, are associated with certain genetic conditions and place the patient at high risk for pancreatitis and other adverse outcomes. It is particularly important to identify these individuals with TG testing and treat them accordingly.2

Non-traditional Tests for ASCVD

Non-traditional Tests for ASCVD Risk Assessment, Diagnosis and Management


Apolipoprotein, each 82172

C-reactive protein; high sensitivity (hsCRP)

86141

Cystatin C 82610

Galectin-3 82777


0024U

Growth stimulation expressed gene 2 (ST2, Interleukin 1 receptor like-1)

83006

Homocysteine 83090

Lipoprotein (a) 83695


83698


83700


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83701

Lipoprotein, blood; quantitation of lipoprotein particle numbers and lipoprotein particle subclasses, e.g., by nuclear magnetic resonance (NMR) spectroscopy, includes lipoprotein particle subclass(es) when performed

83704


0052U



Natriuretic peptide 83880


84431


Unlisted chemistry procedure 84999

VLDL cholesterol Lipoprotein, direct measurement

83719

The rationale for uncovering additional biomarkers to assess CVD risk has been described by the USPSTF:1

“Cardiovascular disease risk assessment in the United States has been generally based on the Framingham Risk Score and, more recently, the Pooled Cohort Equations. However, both have been documented to overestimate and underestimate risk in some persons. Therefore, identification of additional tests (for non-traditional risk factors) that could improve risk prediction, including the ABI, hsCRP level, and CAC score, is of interest.”* [*ABI=Ankle Brachial Index; CAC=Coronary Artery Calcification]

Hundreds of biomarkers have been studied in the quest to improve the risk prediction and management of ASCVD. Of these, national guidelines have endorsed infrequent uses for:1-5


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hsCRP

Apolipoprotein B (apo B)

Apolipoprotein A (apo A)

Lp(a)


In 2018 the USPSTF24 updated its earlier recommendations1 and removed hsCRP stating:

“There are insufficient adequately powered clinical trials evaluating the incremental effect of the ABI [Ankle Brachial Index], hsCRP level, or CAC [coronary artery calcium] score in risk assessment and initiation of preventive therapy.” 24

For this reason, hsCRP has been removed as a recommended risk marker for ASCVD.24

Current guidelines do not include recommendations of the following biomarkers for ASCVD risk assessment, diagnosis and/or management:1-5,19,20,24

VLDL

Cystatin C

Homocysteine

Galectin-3

ST2

Lipoprotein measurement by electrophoresis and/or ultracentrifugation

Lipoprotein particle counting (e.g. by NMR)

MI-HEART Ceramides

Myeloperoxidase

Natriuretic peptides

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

Thromboxane metabolites

The absence of these laboratory tests from all ASCVD guideline recommendations is significant. ASCVD is the most common serious clinical condition and cause of death in the US and is the most widely studied disease. The multiple guidelines noted here have performed an exhaustive literature search encompassing 50 years and including thousands of studies.

Some of these biomarkers – such as B-Natriuretic Peptide, Cystatin C, and homocysteine – have clear indications in other clinical conditions, but not in ASCVD (see discussion below).


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Expanded Lipid Panels

There are a variety of highly marketed, large panels that combine the traditional lipid markers (Total-C, HDL-C, LDL-C, and triglycerides) with additional measurements purporting to improve cardiovascular risk assessment. Examples include the Vertical Auto Profile (VAP)25, NMR lipoprotein particle counting (LipoScience, Inc.; Raleigh, NC), Lipoprotein Particle Profile (SpectraCell Laboratories, Inc.), and others. As noted above, the major guidelines for ASCVD risk assessment, diagnosis, and management do not include these tests in their recommendations.2-5,19,20,24

The American Society of Clinical Pathology (ASCP) has published a recommendation as part of the Choosing Wisely Campaign regarding the use of lipid panels that are expanded beyond Total Cholesterol, HDL, LDL, and triglycerides.21 The recommendation states:21

“Do not routinely order expanded lipid panels (particle sizing, nuclear magnetic resonance) as screening tests for cardiovascular disease….A variety of lipoprotein assays have been developed that subfractionate lipoprotein particles according to some of these properties such as size, density or charge. However, selection of these lipoprotein assays for improving assessment of risk of cardiovascular disease and guiding lipid-lowering therapies should be on an individualized basis for intermediate to high-risk patients only. They are not indicated for population based cardiovascular risk screening.”

Apolipoproteins

ApoB is occasionally useful in ASCVD risk assessment and management. It is sometimes used with Apo A, the main apolipoprotein on HDL particles, expressed as a ratio of Apo B:Apo A. The measurement of ApoB, or the ratio ApoB:ApoA, is not superior to non-HDL-C for ASCVD risk assessment, diagnosis or management and the NLA guidelines state there is no need to measure both non-HDL-C and apolipoproteins in patients being monitored for ASCVD:2

“Apo B is considered an optional, secondary target for treatment. Epidemiologic studies have generally shown that both apo B and non–HDL-C are better predictors of ASCVD risk than LDL-C. Because each potentially atherogenic lipoprotein particle contains a single molecule of apo B, the apo B concentration is a direct indicator of the number of circulating particles with atherogenic potential. Apo B and non–HDL-C share the advantage that neither requires fasting for accurate assessment. Non–HDL-C is favored over apo B by the NLA Expert Panel because it is universally available, requiring no additional expense compared with the standard lipid profile, and because apo B has not been consistently superior to non–HDL-C in predicting ASCVD event risk”

The AACE/ACE guidelines do provide a potential rationale for the use of apolipoproteins for individuals at risk for ASCVD, but not for asymptomatic individuals:4

“APOB and/or an APOB/APOA1 ratio calculation and evaluation may be useful in at-risk individuals (TG ≥150, HDL-C <40, prior ASCVD event, T2DM, and/or the


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insulin resistance syndrome [even at target LDL-C levels]) to assess residual risk and guide decision-making…”

“A high plasma apo B level (>130 mg/dL) combined with an LDL-C concentration less than 160 mg/dL, with or without hypertriglyceridemia, identifies hyperapobetalipoproteinemia, which is a cause of premature ASCVD.”

High Sensitivity C-Reactive Protein (hsCRP), Lipoprotein-Associated Phospholipase A2 (Lp-PLA2), and Lipoprotein (a) [Lp(a)]

The role of hsCRP in ASCVD risk assessment in asymptomatic individuals is secondary to Total-C and HDL-C. Debate exists concerning the role of hsCRP for risk assessment. While the USPSTF does not recommend its use,24 the AHA/ACC guideline states:3

“Evidence suggests that hsCRP may be helpful in predicting coronary events. Although studies suggest that hsCRP may be of limited value as a broadly applied screening tool, it may be helpful in stratifying cardiovascular risk in individuals with a standard risk assessment that is borderline or in those with an LDL-C level less than 130 mg/dL.”

The NLA recommendations describe the limited role of both Lp(a) and hsCRP in its three-step approach to risk assessment.2 Lp(a) and hsCRP are listed in step 3 which only applies to moderate risk patients where additional “risk refinement” is desired:

“…the presence of one or more of the following additional risk indicators may warrant moving the patient into a higher risk category based on clinical judgment…

o High-sensitivity C-reactive protein >2.0 mg/L….

o Lp (a) ≥50 mg/dL (protein) using an isoform insensitive Assay…”

The AHA/ASA guidelines for the primary prevention of stroke5 mention the use of hsCRP in the risk assessment for stroke and for informing the decision to initiate statin therapy. The recommendation regarding stroke risk includes a reference to Lp-PLA2 and appears to indicate the clinical utility of these markers in this situation has not been established:5

“Measurement of inflammatory markers such as hsCRP or lipoprotein-associated phospholipase A2 in patients without CVD may be considered to identify patients who may be at increased risk of stroke, although their usefulness in routine clinical practice is not well-established”

The recommendation regarding using hsCRP levels to guide statin therapy is similarly non-commital:5

“Treatment of patients with high-sensitivity C-reactive protein >2.0 mg/dL with a statin to decrease stroke risk might be considered”

The AHA/ASA guideline does not endorse the use of Lp (a) in stroke risk prediction:5


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“The clinical benefit of using lipoprotein(a) in stroke risk prediction is not well established”

Despite some guidelines on the use of hsCRP in CVD risk prediction there is a lack of clear consensus regarding the optimal clinical use of hsCRP. Specifically, the biology of hsCRP and its role in atherosclerosis remains elusive as does the epidemiological association of hsCRP with CVD. Most significantly, the quality of hsCRP as a biomarker of risk is often poor.26

Cystatin C

Cystatin C is a clinical biomarker of renal function used in conjunction with, or selectively in place of, creatinine. It has shown to be an independent predictor of ASCVD apart from traditional risk factors.27 The major guidelines for diagnosing and managing ASCVD do not include cystatin C in their recommendations regarding ASCVD risk assessment, diagnosis and management.2-5,19,20,24 In addition, a large Mendelian randomization analysis concluded the following regarding the lack of a causal relationship between low cystatin C and ASCVD:27

“Mendelian randomization analyses did not support a causal role of cystatin C in the etiology of CVD. As such, therapeutics targeted at lowering circulating cystatin C are unlikely to be effective in preventing CVD.”

The lack of a causal relationship between cystatin C levels and ASCVD, and the lack of inclusion of cystatin C in the detailed risk assessment framework already published in numerous guidelines, suggests cystatin C is not clinically useful in the diagnosis and management of ASCVD--apart from its well-known role in assessing kidney function.

Galectin-3, Soluble ST2

Galectin-3 is a beta-galactoside binding protein that is a marker of fibrosis in multiple organs.14 ST2 is in the interleukin 1 receptor family and it is released by cardiac myocytes when they are stretched.15 These are occasionally useful for heart failure (HF) prognostics, where they are used in addition to or in replacement of B-type natriuretic peptides.14-16 The ACC guideline on heart failure states:12

“Measurement of other clinically available tests such as biomarkers of myocardial injury or fibrosis may be considered for additive risk stratification in patients with acutely decompensated HF”

“Biomarkers of myocardial fibrosis, soluble ST2 and galectin-3 are not only predictive of hospitalization and death in patients with HF but also additive to natriuretic peptide levels in their prognostic value.”

Galectin-3 and ST2 are not included in the major guidelines for ASCVD risk assessment, diagnosis and management.2-5,19,20 Testing should be restricted to their use in heart failure.


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Homocysteine

Testing for the amino acid homocysteine is indicated in the evaluation and management of the genetic disease, homocystinuria, and in the evaluation of vitamin B12 and folate deficiency. Homocysteine is an independent predictor of ASCVD, apart from traditional risk factors.4

The AACE/ACE guideline does not recommend using homocysteine in ASCVD risk assessment. The guideline states:4

“Elevated homocysteine levels appear to be mediated by deficiencies in folic acid and vitamins B6 and B12…. Although treatment with these supplements lowers plasma homocysteine levels, research to date does not indicate that such therapy reduces ASCVD risk… Therefore, homocysteine measurement is not recommended as part of routine screening.”

“The routine measurement of homocysteine, uric acid, plasminogen activator inhibitor-1, or other inflammatory markers is not recommended because the benefit of doing so is not sufficiently proven.”

A similar conclusion was reached by another expert review, which stated:28

“Although treatment with [supplements] lowers plasma homocysteine levels, research to date does not indicate that such therapy reduces ASCVD risk. Therefore, homocysteine measurement is not recommended as part of routine screening.”

Myeloperoxidase

The use of myeloperoxidase as a clinical biomarker for ASCVD has been studied for more than 20 years. The latest review by Schindheim and colleagues concluded:29

“Epidemiological studies in a wide range of patient populations clearly indicate that MPO, in addition to traditional markers, is an important CVD risk marker, especially in patients with unstable CAD…. Before MPO can be used routinely in clinical practice for CVD risk stratification, however, a better understanding of and recommendations for pre-analytical and analytical procedures are important.”

Myeloperoxidase currently does not appear as a clinical test in the major compendia of clinical tests from the American Association for Clinical Chemistry17 and the Associated Regional and University Pathologists.18 The major guidelines for diagnosing and managing ASCVD do not include myeloperoxidase in their recommendations regarding specific tests for ASCVD risk assessment, diagnosis and/or management.2-5,19,20

Natriuretic Peptides

The ACC has offered the following description of natriuretic peptides, BNP or NT-ProBNP, in its guideline regarding the diagnosis and management of congestive heart failure:12


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“BNP or its amino-terminal cleavage equivalent (NT-proBNP) is derived from a common 108-amino acid precursor peptide (proBNP…) that is generated by cardiomyocytes in the context of numerous triggers, most notably myocardial stretch. Following several steps of processing, BNP and NT-proBNP are released from the cardiomyocyte, along with variable amounts of proBNP…, the latter of which is detected by all assays that measure either BNP or NT-proBNP.”

The major use of BNP and NT-proBNP is in the diagnosis and management of heart failure.12,13 The ACC guidelines regarding the use of BNP and NT-proBNP in the diagnosis and management of heart failure (HF) state:12

“In ambulatory patients with dyspnea, measurement of BNP or N-terminal pro-B-type natriuretic peptide (NT-proBNP) is useful to support clinical decision making regarding the diagnosis of HF, especially in the setting of clinical uncertainty…”

“Measurement of BNP or NT-proBNP is useful for establishing prognosis or disease severity in chronic HF”

“BP- or NT-proBNP guided HF therapy can be useful to achieve optimal dosing of GDMT in select clinically euvolemic patients followed in a well-structured HF disease management program” * [*GDMT= Guideline Determined Medical Therapy]

“Measurement of BNP or NT-proBNP is useful to support clinical judgment for the diagnosis of acutely decompensated HF, especially in the setting of uncertainty for the diagnosis...”

“Measurement of BNP or NT-proBNP and/or cardiac troponin is useful for establishing prognosis or disease severity in acutely decompensated HF…”

The major guidelines for diagnosing and managing ASCVD do not include BNP or NT-proBNP in their recommendations and analysis regarding specific tests for ASCVD risk assessment, diagnosis and/or management.2-5,19,20

Thromboxane B2

Thromboxanes are products of prostaglandin metabolism. Thromboxane B2 is a biomarker of platelet activation and has been studied as a biomarker of ASCVD.30

Thromboxanes currently do not appear as a clinical test in the major compendia of clinical tests from the American Association for Clinical Chemistry17 and the Associated Regional and University Pathologists.18 The major guidelines for diagnosing and managing ASCVD do not include thromboxanes in their recommendations and analysis regarding specific tests for ASCVD risk assessment, diagnosis and/or management.2-

5,19,20

Long-chain omega-3 Fatty Acids in Red Blood Cell Membranes

Long-chain omega-3 fatty acids are a popular nutritional supplement, taken under the auspices of improving heart health. The clinical outcomes associated with this supplement remain controversial.31


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In the absence of demonstrable improved clinical outcomes, the measurement of long-chain omega-3 fatty acids in RBC membranes is unlikely to be useful in the evaluation of cardiovascular disease.

Testing for long-chain omega-3 fatty acids is addressed in a NIH fact sheet on this supplement:32

“Currently, most clinicians do not assess omega-3 status, but it can be done by measuring individual omega-3s in plasma or serum phospholipids and expressing them as the percentage of total phospholipid fatty acids by weight [14-16]. Experts have not established normal ranges, but mean values for serum or plasma phospholipid EPA plus DHA among U.S. adults not taking omega-3 supplements are about 3%–4% [14-16]. Plasma and serum fatty acid values, however, can vary substantially based on an individual’s most recent meal, so they do not reflect long-term dietary consumption.”

“Some researchers propose that the relative intakes of omega-6s and omega-3s—the omega-6/omega-3 ratio—may have important implications for the pathogenesis of many chronic diseases, such as cardiovascular disease and cancer [8], but the optimal ratio—if any—has not been defined [10]. Others have concluded that such ratios are too non-specific and are insensitive to individual fatty acid levels.”

Long-chain omega-3 fatty acids in red blood cell membranes currently do not appear as a clinical test in the major compendia of clinical tests from the American Association for Clinical Chemistry17 and the Associated Regional and University Pathologists18. The major guidelines for diagnosing and managing ASCVD do not include long-chain omega-3 fatty acids in red blood cell membranes in their recommendations and analysis regarding specific tests for ASCVD risk assessment, diagnosis and/or management.2-5,19,20

Troponin

The main use of cardiac troponin (cTn) is as the primary laboratory test for suspected acute MI. This use, along with other less common clinical scenarios for troponin, are described in a guideline from an international task force representing the American College of Cardiology (ACC), the American Heart Association (AHA), the Joint European Society of Cardiology (ESC), and the World Heart Federation (WHF).33 This guideline emphasizes the clinical value of elevated troponin levels arise from their role in diagnosing acute MI:33

“The term acute myocardial infarction should be used when there is acute myocardial injury with clinical evidence of acute myocardial ischaemia and with detection of a rise and/or fall of cTn values with at least one value above the 99th percentile URL and at least one of the following:

o Symptoms of myocardial ischaemia;

o New ischaemic ECG changes;

o Development of pathological Q waves;


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o Imaging evidence of new loss of viable myocardium or new regional wall motion abnormality in a pattern consistent with an ischaemic aetiology

o Identification of a coronary thrombus by angiography or autopsy (not for type 2 or 3 MIs)”* [*URL = Upper Reference Limit]

The same guideline also states that troponin is part of the universal definition of any myocardial injury:33

“The term myocardial injury should be used when there is evidence of elevated cardiac troponin values (cTn) with at least one value above the 99th percentile upper reference limit (URL). The myocardial injury is considered acute if there is a rise and/or fall of cTn values.”

Myocardial injury can vary in severity from small and self-limiting to severe and life-threatening MI. Troponin can be useful for risk stratifying a variety of patients with myocardial injury.33 Myocardial injury has many different causes that can overlap, including:

ASCVD

Heart failure from any cause

Arrhythmias

Cardiotoxic drugs such as a variety chemotherapeutic agents;

Infections of the heart

Blunt injury to the heart

Injury caused by cardiac surgery

Shock

Conditions in other organs that can injure the heart such as pulmonary embolism or renal failure

The presence of elevated troponin is necessary to identify myocardial injury but it is not sufficient to make a specific diagnosis.33 However, troponin is useful for risk assessment in patients with ASCVD where myocardial injury is suspected or known to be present.

The major guidelines for diagnosing or managing ASCVD do not include troponin in their copious recommendations and analysis regarding ASCVD risk assessment and diagnosis.2-5,19

Criteria

Introduction

This policy addresses testing used for ASCVD risk stratification in individuals without cardiovascular disease. Comments are also included regarding their utility in other


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cardiovascular disorders. Genomic tests are addressed by separate policies and are not addressed here. These include, but are not limited to: Corus CAD; Other complex genomic tests designed to assess ASCVD risk, which may or may not be billed as Multianalyte Assays with Algorithmic Analyses (e.g., Cardio IQ Risk Panel with Score, PULS Cardiac Test); Pharmacogenomic testing for the metabolism of drugs used to treat ASCVD.

Traditional Biomarkers for ASCVD

Traditional Biomarkers for ASCVD risk assessment and ASCVD management

Test Name Procedure Code

Cholesterol, Serum or Whole Blood, total 82465

High-density Lipoprotein (HDL) Cholesterol Measurement

83718

Lipid panel 80061

Low-density Lipoprotein (LDL) Cholesterol Measurement

83721

Triglycerides 84478

Medical Necessity Requirements

Lipid panel, Cholesterol, HDL, LDL and triglycerides are indicated in the following circumstances:

o ASCVD risk assessment in all children, regardless of general health or the presence or absence of CVD risk factors, between 9 and 11 years of age, with repeat lipid screening every five years thereafter if normal.

o ASCVD risk assessment in children 2–18 years of age who have the following cardiovascular risk factors:

One or both biological parents are known to have hypercholesterolemia or are receiving lipid-lowering medications.

Have a family history of premature ASCVD in an expanded first-degree pedigree in men <55 or women <65 years of age.

Have an unknown family history of ASCVD (e.g., children who were adopted).

o ASCVD risk assessment in asymptomatic individuals > age 20 years who do not have ASCVD up to once every four years.

o ASCVD risk assessment in individuals who have one or more of the following ASCVD risk factors but who do not have ASCVD once per year:


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risk for familial hypercholesterolemia, or related inherited disorders predisposing to ASCVD

major ASCVD risk factors including any of the following:

diabetes

hypertension

cigarette smoking


minor or additional ASCVD risk factors such as:

obesity

pregnancy

hypothyroidism

HIV infection

autoimmune inflammatory disorders

obstructive liver disease

use of prescription drugs associated with cardiotoxicity (e.g. (anabolic steroids, cyclosporine, amiodarone)

o Diagnostic evaluation or monitoring up to six times per year in individuals with a history of at least one of the following:

stable or unstable angina

myocardial infarction

non-hemorrhagic stroke

transient ischemic attacks

aortic aneurysm

peripheral vascular disease effecting limbs, kidneys, skin or other organs

o Risk assessment, diagnostic evaluation, or monitoring of patients with a history of dyslipidemia including increased Total-C, increased Non-HDL-C; or increased LDL-C

Billing and Reimbursement

Claims submitted with a diagnosis code from Table: Codes Indicating ASCVD will be eligible for reimbursement of one unit of each traditional biomarker for ASCVD addressed in this section up to six times per 12-month period.

Claims submitted with a diagnosis code from Table: Codes Indicating Dyslipidemia will be eligible for reimbursement of one unit of each traditional biomarker for ASCVD addressed in this section up to six times per 12-month period.


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Claims submitted with a diagnosis code from Table: Codes Indicating ASCVD Risk Factors Without a Diagnosis will be eligible for reimbursement of one unit of each traditional biomarker for ASCVD addressed in this section up to one time per 12-month period.

All other claims will be eligible for reimbursement of one unit of each traditional biomarker for ASCVD addressed in this section up to one time per 48-month period.

Note that testing for traditional ASCVD biomarkers should only be performed when medically necessary. Any claim may be reviewed post-service to ensure only medically necessary tests are performed.

When all components of a lipid panel are performed (total cholesterol [CPT 82465], HDL cholesterol [CPT 83718], triglycerides [CPT 84478]) on the same date of service by the same billing provider, the lipid panel CPT code, 80061, must be billed instead of its individual components.

Non-traditional Biomarkers for ASCVD

Non-traditional tests for ASCVD risk assessment and management


Apolipoprotein A 82172

Apolipoprotein B 82172

Cystatin C 82610

Galectin-3 82777

Homocysteine 83090

hsCRP 86141

Lp(a) 83695

Lp-PLA2 83698

Natriuretic Peptide 83880

ST2 83006


hsCRP, Lp(a), Lp-PLA2

hsCRP (CPT 86141), Lp(a) (CPT 83695), Lp-PLA2 (CPT 83698)

Medical necessity requirement

hsCRP, Lp(a), and/or Lp-PLA2 are indicated for more accurate ASCVD risk stratification in individuals when their ASCVD risk assessment, using the lipid panel described above, shows the individual has intermediate ASCVD risk, and


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o ASCVD risk assessment is being performed in asymptomatic individuals > age 20 and who do not have ASCVD; allowable up to once every four years, or

o ASCVD risk assessment in individuals who have one or more of the following ASCVD risk factors but who do not have ASCVD; allowable once per year:

risk for familial hypercholesterolemia, or related inherited disorders predisposing to ASCVD

major ASCVD risk factors including any of the following:

diabetes

hypertension

cigarette smoking


minor or additional ASCVD risk factors such as:

obesity

pregnancy

hypothyroidism

HIV infection

autoimmune inflammatory disorders

obstructive liver disease

use of prescription drugs associated with cardiotoxicity (e.g. (anabolic steroids, cyclosporine, amiodarone)

hsCRP, Lp(a), and/or Lp-PLA2 are not indicated for individuals known to have ASCVD with the following clinical history:

o stable or unstable angina

o myocardial infarction

o non-hemorrhagic stroke

o transient ischemic attacks

o aortic aneurysm

o peripheral vascular disease affecting limbs, kidneys, skin or other organs

o dyslipidemia in the form of increased Total-C, increased Non-HDL-C; or increased LDL-C

Billing and reimbursement

Claims submitted with a diagnosis code from Table: Codes Indicating ASCVD will not be eligible for reimbursement of hsCRP, Lp(a), and/or Lp-PLA2 testing.


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Intermediate ASCVD risk is documented, AND

o Claims submitted with a diagnosis code from Table: Codes Indicating ASCVD Risk Factors Without a Diagnosis will be eligible for reimbursement of hsCRP, Lp(a), and/or Lp-PLA2 up to one time per 12-month period.

o Claims submitted with a diagnosis code from Table: Codes Indicating Dyslipidemia will be eligible for reimbursement of hsCRP, Lp(a), and/or Lp-PLA2 up to six times per 12-month period.

o All other claims will be eligible for reimbursement of hsCRP, Lp(a), and/or Lp-PLA2 up to one time per 48 month period.

Note that testing for hsCRP, Lp(a), and/or Lp-PLA2 should only be performed when medically necessary. Any claim may be reviewed post-service to ensure only medically necessary tests are reimbursed.

Apolipoprotein B, Apolipoprotein A

Apolipoprotein B (CPT 82172), Apolipoprotein A (CPT 82172)


Apo B or ApoB:ApoA ratio is indicated to monitor individuals being treated for either ASCVD or high ASCVD risk, and who are not being monitored by a lipid panel.

Apo B or ApoB:ApoA ratio is not indicated in screening for ASCVD in asymptomatic individuals.


Claims submitted with a diagnosis code from Table: Codes Indicating ASCVD, or Table: Codes Indicating Dyslipidemia, or Table: Codes Indicating ASCVD Risk Factors Without a Diagnosis will be eligible for reimbursement of ApoB or ApoB: ApoA ratio up to six times per 12-month period. All other claims without one of these diagnosis codes will not be eligible for reimbursement of Apo B or ApoB:ApoA ratio.

When testing is medically necessary, up to 2 units of CPT 82172 are reimbursable for the same date of service, but are not payable on the same date of service with either a lipid panel (CPT 80061) or non-HDL cholesterol (calculated using Total-C, CPT 82465, and HDL-C, CPT 83718).

Note that testing for Apo B or ApoB:ApoA ratio should only be performed when medically necessary. Any claim may be reviewed post-service to ensure only medically necessary tests are reimbursed.

Natriuretic Peptide

Natriuretic Peptide (CPT 83880)


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B-Natriuretic Peptide (CPT 83880) or N-Terminal B-Natriuretic peptide (also CPT 83880) is indicated in the evaluation and/or management of heart failure. The most common signs and symptoms of heart failure are:

o Dyspnea

o Exercise intolerance

o Fatigue

o Edema

o Rapid or irregular heart beat

o Productive cough or wheezing

BNP or NT-proBNP are not indicated in screening for ASCVD or ASCVD risk and are not coverable for indications other than assessment of heart failure.


Claims for B-Natriuretic Peptide or N-Terminal B-Natriuretic peptide submitted with an ICD code in the range I50.X will be eligible for reimbursement of one unit of CPT 83880 per date of service.

Claims for B-Natriuretic Peptide or N-Terminal B-Natriuretic peptide billed on the same date of service as any other ASCVD procedure code included in this policy will be subject to post-service medical necessity review.

Note that testing for B-Natriuretic Peptide or N-Terminal B-Natriuretic peptide should only be performed when medically necessary. Any claim may be reviewed post-service to ensure only medically necessary tests are reimbursed.

Galectin-3 and ST2

Galectin-3 (CPT 82777), ST2 (CPT 83006)


Galectin-3 and/or ST2 are indicated in individuals with heart failure when additional risk stratification is needed beyond what is provided by B-Natriuretic Peptide (CPT 83880) or N-Terminal B-Natriuretic peptide

Galectin-3 or ST2 are not indicated in screening for ASCVD or ASCVD risk and are not coverable for indications other than risk stratification in individuals with heart failure.


Claims for galectin-3 and/or ST2 submitted with an ICD code in the range I50.X will be eligible for reimbursement of one unit of CPT 82777 and/or CPT 83006 per date of service.


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Claims for galectin-3 and/or ST2 billed on the same date of service as any other ASCVD procedure code included in this policy will be subject to post-service medical necessity review.

Note that testing for galectin-3 and/or ST2 should only be performed when medically necessary. Any claim may be reviewed post-service to ensure only medically necessary tests are reimbursed.

Troponin

Troponin, quantitative (CPT 84484)


Troponin is indicated in the following circumstances:

o In the evaluation and/or management of acute myocardial infarction.

o In the evaluation and/or management of myocardial injury from any cause including but not limited to:

Infections of the heart

Heart failure from any cause

Cardiotoxic drugs

Cardiac surgery

Blunt force injury to the heart

Injury to other organs (e.g. pulmonary embolism, renal failure) that can affect the heart

Shock

Anemia

Arrhythmias

Troponin has no role in screening for ASCVD and is not coverable for indications other than assessment of myocardial injury.


Claims for troponin (CPT 84484) billed on the same date of service as any other ASCVD procedure code included in this policy will be subject to post-service medical necessity review.

Note that testing for troponin should only be performed when medically necessary. Any claim may be reviewed post-service to ensure only medically necessary tests are reimbursed.


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Cystatin C

Cystatin C (CPT 82610)


Cystatin C is indicated in the evaluation of renal failure when additional information is needed beyond what can be provided by creatinine testing. Signs and symptoms of renal failure include:

o Edema especially in the ankles, feet, and in the periorbital region

o Fatigue

o Loss of appetite

o Dry and itchy skin

o Confusion

o Muscle cramps

o Changes in urinary frequency

o Proteinuria

o Hematuria

Cystatin C is not indicated in screening for ASCVD or ASCVD risk and is not coverable for indications other than assessment of renal failure.


Claims for cystatin C submitted with an ICD code in the range N00.0-N29 will be eligible for reimbursement of one unit of CPT 82610 per date of service.

Claims for cystatin C billed on the same date of service as any other ASCVD procedure code included in this policy will be subject to post-service medical necessity review.

Note that testing for cystatin C should only be performed when medically necessary. Any claim may be reviewed post-service to ensure only medically necessary tests are reimbursed.

Homocysteine

Homocysteine (CPT 83090)


Homocysteine is indicated in the diagnosis and management of homocystinuria. Signs and symptoms of homocystinuria include:


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o A variety of thrombotic manifestations including deep venous thrombosis and sequela of deep venous thrombosis

o Joint and skeletal abnormalities including:

Osteoporosis

Abnormal shape of breastbone

Long arms

Long legs

Scoliosis

o Abnormalities of the eye including:

Dislocation of the lens

Nearsightedness

o Developmental problems and learning disabilities

Homocysteine is indicated in the diagnosis and management of Vitamin B12 or folate deficiency.

Homocysteine has no role in screening for ASCVD and is not coverable for indications other than diagnosis and management of homocystinuria, Vitamin B12 deficiency, or folate deficiency.


Claims for homocysteine submitted with an ICD code for homocystinuria (E72.11), vitamin B12 deficiency (D51.X) or folate deficiency (D52.X) will be eligible for reimbursement of up to two units of CPT 83090 per date of service.

Claims for homocysteine billed on the same date of service as any other ASCVD procedure code included in this policy will be subject to post-service medical necessity review.

Note that testing for homocysteine should only be performed when medically necessary. Any claim may be reviewed post-service to ensure only medically necessary tests are reimbursed.

Creatinine Kinase (CK), (CPK); MB Fraction Only

Creatinine kinase (CK), (CPK); MB fraction only (CK-MB) (CPT 82553)

CK-MB testing is considered obsolete. Please refer to Obsolete Testing Policy (MOL.CS.322.X).

Tests for ASCVD with No Coverable Indications

Tests for ASCVD risk assessment and management with no coverable indications


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0024U


83700


83701

Lipoprotein, blood; quantitation of lipoprotein particle numbers and lipoprotein particle subclasses (e.g., by nuclear magnetic resonance spectroscopy), includes lipoprotein particle subclass(es) when performed

83704


0052U

Lipoprotein, direct measurement; small dense LDL cholesterol

83722



Secretory type II phospholipase A2 (sPLA2-IIA)

0423T


84431

VLDL cholesterol Lipoprotein, direct measurement

83719


The medical necessity of the tests represented by the procedure codes in the table above have not been demonstrated. These procedure codes are considered investigational and experimental and are therefore not eligible for reimbursement for any clinical indication.


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In addition, the following proprietary tests for ASCVD risk assessment or management are specifically noted to be investigational and experimental based on the above coverage principles, regardless of the procedure codes used to bill them.

o CardioMetabolic Risk Assessment; SpectraCell Laboratories

o Boston Heart HDL Map; Boston Heart Diagnostics

o Boston Heart Fatty Acid Balance Test; Boston Heart Diagnostics

o Boston Heart Cholesterol Balance Test; Boston Heart Diagnostics

o Cardio IQ Lipid Subfractionation by Ion Mobility; Quest Diagnostics

o True Health Diagnostics: Comprehensive Cardiovascular Disease Testing

Diagnosis Codes

Diagnosis codes in this section may be used to support or refute medical necessity as described in the above guidelines.

Table: Codes Indicating ASCVD

Codes and descriptions

Code or Range Description

G45.X Transient cerebral ischemic attacks and related syndromes

G46.X Vascular syndromes of brain in cerebrovascular diseases

I20.X Angina pectoris

I21.X Acute myocardial infarction

I22.X Subsequent ST elevation (STEMI) and non-ST elevation (NSTEMI) myocardial infarction

I23.X Certain current complications following ST elevation (STEMI) and non-ST elevation (NSTEMI) myocardial infarction (within the 28 day period)

I24.X Other acute ischemic heart diseases

I25.X Chronic ischemic heart disease

I63.X Cerebral infarction

I65.X Occlusion and stenosis of precerebral arteries, not resulting in cerebral infarction


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I66.X Occlusion and stenosis of cerebral arteries, not resulting in cerebral infarction

I67.X Other cerebrovascular diseases

I68.X Cerebrovascular disorders in diseases classified elsewhere

I69.X Sequelae of cerebrovascular disease

I70.X – I79.X Atherosclerosis

R29.7X National Institutes of Health Stroke Scale (NIHSS) Score

Z86.73 Personal history of transient ischemic attack (TIA), and cerebral infarction without residual deficits

Z86.74 Personal history of sudden cardiac arrest

Z86.79 Personal history of other diseases of the circulatory system

Table: Codes Indicating Dyslipidemia



E78.X Disorders of lipoprotein metabolism and other lipidemias

Table: Codes Indicating ASCVD Risk Factors Without a Diagnosis



B20 Human immunodeficiency virus [HIV] disease

E03.X Other hypothyroidism

E08.X-E13.X Diabetes mellitus

E66.X Overweight and obesity

F17.X Nicotine dependence

I10.X-I16.X Hypertensive diseases

N18.X Chronic kidney disease (CKD)


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O00.X-O9A.X Pregnancy, childbirth and the puerperium

Z33.X Pregnant state

Z34.X Encounter for supervision of normal pregnancy

Z36.X Encounter for antenatal screening of mother

Z3A.X Weeks of gestation

Z82.4X Family history of ischemic heart disease and other diseases of the circulatory system

Z83.42 Family history of familial hypercholesterolemia

Z83.43X Family history of other disorder of lipoprotein metabolism and other lipidemias

References

Introduction

These references are cited in this guideline.

1. Curry SJ, Krist AH, Owens DK et al. Risk assessment for cardiovascular disease with nontraditional risk factors: US Preventive Services Task Force recommendation statement. JAMA. 2018;320(3):272-280.

2. Jacobson TA, Ito MK, Maki KC, et al. National Lipid Association recommendations for patient-centered management of dyslipidemia: part 1—full report. J Clin Lipidol. 2015;9(2):129-169.

3. Goff DC, Lloyd-Jones DM, Bennett G, et al. 2013 ACC/AHA Guideline on the Assessment of Cardiovascular Risk. A Report of the American College of Cardiology/American Heart Association Task Force on Practice Guidelines. Circulation. 2014 June; 29(25 Suppl 2):S49-S73.

4. Jellinger, PS, Handelsman Y, Rosenblit PD, et al. American Association of Clinical Endocrinologists and American College of Endocrinology Guidelines for Management of Dyslipidemia and Prevention of Cardiovascular Disease. Endocr Pract. 2017;23(Suppl 2):1-87.

5. Meschia JF, Bushnell C, Boden-Albala B, et al. Guidelines for the primary prevention of stroke. A statement for healthcare professionals from the American Heart Association/American Stroke Association. Stroke. 2014;45(12):1-10.


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6. Feingold KR, Grunfeld C. Introduction to Lipids and Lipoproteins. [Updated 2018 Feb 2]. In: Feingold KR, Anawalt B, Boyce A, et al., eds. Endotext [Internet]. South Dartmouth (MA): MDText.com, Inc.; 2000. Available at: https://www.ncbi.nlm.nih.gov/books/NBK305896/.

7. Framingham Heart Study, Primary Risk Functions. 2018. Boston University and the National Heart, Lung and Blood Institute (NHLBI).

8. Ridker PM, Buring JE, Rifai N, Cook NR. Development and validation of improved algorithms for the assessment of global cardiovascular risk in women: The Reynolds Risk Score. JAMA. 2007;297(6):611-619.

9. Reynold’s Risk Score. 2018. Available at: http://www.reynoldsriskscore.org/.

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In-vitro Testing for Cardiovascular Disease (CVD) and CVD Risk