CAR039 Comprehensive Lipid Profile Testing in the Evaluation of ...

COMPREHENSIVE LIPID PROFILE TESTING IN THE 

EVALUATION OF CARDIOVASCULAR DISEASE 

Protocol: CAR039 

Effective Date: May 7, 2012 

Table of Contents 

Page 

COMMERCIAL COVERAGE RATIONALE......................................................................................... 1 

MEDICARE & MEDICAID COVERAGE RATIONALE...................................................................... 2 

BACKGROUND ...................................................................................................................................... 4 

CLINICAL EVIDENCE........................................................................................................................... 5 

U.S. FOOD AND DRUG ADMINISTRATION (FDA)........................................................................ 11 

APPLICABLE CODES.......................................................................................................................... 12 

REFERENCES ....................................................................................................................................... 12 

PROTOCOL HISTORY/REVISION INFORMATION ........................................................................ 14 

INSTRUCTIONS FOR USE 

This protocol provides assistance in interpreting UnitedHealthcare benefit plans. When deciding 

coverage, the enrollee specific document must be referenced. The terms of an enrollee's document 

(e.g., Certificate of Coverage (COC) or Evidence of Coverage (EOC)) may differ greatly. In the event 

of a conflict, the enrollee's specific benefit document supersedes this protocol. All reviewers must first 

identify enrollee eligibility, any federal or state regulatory requirements and the plan benefit coverage 

prior to use of this Protocol. Other Protocols, Policies and Coverage Determination Guidelines may 

apply. UnitedHealthcare reserves the right, in its sole discretion, to modify its Protocols, Policies and 

Guidelines as necessary. This protocol is provided for informational purposes. It does not constitute 

medical advice. 

For consistency in this document, the acronyms of cardiovascular disease (CVD), coronary artery 

disease (CAD) and ischemic heart disease (IHD) used in various research references have been 

standardized to coronary heart disease (CHD) as used in the National Cholesterol Education Program 

(NCEP) recommendations. 

COMMERCIAL COVERAGE RATIONALE 

Standard lipoprotein analysis of measurement of total serum cholesterol, total triglyceride, high density 

lipoprotein cholesterol, and calculation of low-density lipoprotein cholesterol is medically necessary 

for prediction of risk for coronary artery disease. The VAP (Vertical Auto Profile) Test, an expanded 

lipid measurement panel that includes a direct measurement of LDL, is considered equivalent but not 

superior to standard lipoprotein analysis. 

Fractionated lipoprotein analysis, homocysteine testing, or lipoprotein subclass testing is not 

medically necessary for use as independent risk factors to identify persons at risk for coronary heart 

Comprehensive Lipid Profile Testing in the Evaluation of Cardiovascular Disease Page 1 of 14

disease due to inadequate clinical evidence of safety and/or efficacy in published peer-reviewed 

medical literature. 

Components of fractionated lipoprotein analysis may include: 

• LDL-C gradient gel electrophoresis (GGE) for low-density lipoprotein (LDL) subclasses 

• HDL-C GGE for HDL subclasses 

• lipoprotein(a) [Lp(a)] assay 

• apo A-I 

• apo B 

• apoE isoforms (E2, E3, E4) 

• total plasma homocysteine 

• lipoprotein-associated phospholipase A2 (Lp-PLA2) 

• non-HDL cholesterol 

• hs-CRP 

• Kinesin-like protein 6 (KIF6) 

• LDL particle number 

MEDICARE & MEDICAID COVERAGE RATIONALE 

Medicare has a National Coverage Determination (NCD) for Lipid Testing (190.23). Medicare does 

not have a Local Coverage Determination (LCD) for Nevada for Lipid Testing at this time. Accessed 

March 2012. The National Coverage Determination is as follows: 

Item/Service Description 

Lipoproteins are a class of heterogeneous particles of varying sizes and densities containing lipid and 

protein. These lipoproteins include cholesterol esters and free cholesterol, triglycerides, phosphor 

lipids and A, C, and E apoproteins. Total cholesterol comprises all the cholesterol found in various 

lipoproteins. 

Factors that affect blood cholesterol levels include age, sex, body weight, diet, alcohol and tobacco 

use, exercise, genetic factors, family history, medications, menopausal status, the use of hormone 

replacement therapy, and chronic disorders such as hypothyroidism, obstructive liver disease, 

pancreatic disease (including diabetes), and kidney disease. 

In many individuals, an elevated blood cholesterol level constitutes an increased risk of developing 

coronary artery disease. Blood levels of total cholesterol and various fractions of cholesterol, 

especially low density lipoprotein cholesterol (LDL-C) and high density lipoprotein cholesterol (HDL- 

C), are useful in assessing and monitoring treatment for that risk in patients with cardiovascular and 

related diseases. Blood levels of the above cholesterol components including triglyceride have been 

separated into desirable, borderline and high risk categories by the National Heart, Lung and Blood 

Institute in their report in 1993. These categories form a useful basis for evaluation and treatment of 

patients with hyperlipidemia. Therapy to reduce these risk parameters includes diet, exercise and 

medication, and fat weight loss, which is particularly powerful when combined with diet and exercise. 


Indications and Limitations of Coverage 

Indications 

The medical community recognizes lipid testing as appropriate for evaluating atherosclerotic 

cardiovascular disease. Conditions in which lipid testing may be indicated include: 

• Assessment of patients with atherosclerotic cardiovascular disease. 

• Evaluation of primary dyslipidemia. 

• Any form of atherosclerotic disease, or any disease leading to the formation of atherosclerotic 

disease. 

• Diagnostic evaluation of diseases associated with altered lipid metabolism, such as: nephrotic 

syndrome, pancreatitis, hepatic disease, and hypo and hyperthyroidism. 

• Secondary dyslipidemia, including diabetes mellitus, disorders of gastrointestinal absorption, 

chronic renal failure. 

• Signs or symptoms of dyslipidemias, such as skin lesions. 

• As follow-up to the initial screen for coronary heart disease (total cholesterol + HDL 

cholesterol) when total cholesterol is determined to be high (>240 mg/dL), or borderline-high 

(200-240 mg/dL) plus two or more coronary heart disease risk factors, or an HDL cholesterol, 

Limitations 

Lipid panel and hepatic panel testing may be used for patients with severe psoriasis which has not 

responded to conventional therapy and for which the retinoid etretinate has been prescribed and who 

have developed hyperlipidemia or hepatic toxicity. Specific examples include erythrodermia and 

generalized pustular type and psoriasis associated with arthritis. 

Routine screening and prophylactic testing for lipid disorder are not covered by Medicare. While lipid 

screening may be medically appropriate, Medicare by statute 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. 

Once a diagnosis is established, one or several specific tests are usually adequate for monitoring the 

course of the disease. Less specific diagnoses (for example, other chest pain) alone do not support 

medical necessity of these tests. 

When monitoring long term anti-lipid dietary or pharmacologic therapy and when following patients 

with borderline high total or LDL cholesterol levels, it is reasonable to perform the lipid panel 

annually. A lipid panel at a yearly interval will usually be adequate while measurement of the serum 

total cholesterol or a measured LDL should suffice for interim visits if the patient does not have 

hypertriglyceridemia. 

Any one component of the panel or a measured LDL may be medically necessary up to six times the 

first year for monitoring dietary or pharmacologic therapy. More frequent total cholesterol HDL 

cholesterol, LDL cholesterol and triglyceride testing may be indicated for marked elevations or for 

changes to anti-LIPID therapy due to inadequate initial patient response to dietary or pharmacologic 

therapy. The LDL cholesterol or total cholesterol may be measured three times yearly after treatment 

goals have been achieved. 

If no dietary or pharmacological therapy is advised, monitoring is not necessary. 

When evaluating non-specific chronic abnormalities of the liver (for example, elevations of 

transaminase, alkaline phosphatase, abnormal imaging studies, etc.), a lipid panel would generally not 

be indicated more than twice per year. 

For Medicare and Medicaid Determinations Related to States Outside of Nevada: 

Please review Local Coverage Determinations that apply to other states outside of Nevada. 

http://www.cms.hhs.gov/mcd/search 

Important Note: Please also review local carrier Web sites in addition to the Medicare Coverage 

database on the Centers for Medicare and Medicaid Services’ Website 

BACKGROUND 

Cardiovascular disease (defined as coronary artery disease (CAD), cerebrovascular disease (CVD), and 

peripheral vascular disease (PVD)) is a major cause of morbidity and mortality in the Western world. It 


is well known that CAD alone is the largest killer of American men and women, amounting to more 

than 500,000 deaths per year. The highest incidence of new CAD events is in persons >65 years of age 

and 85% of all deaths attributable to CAD occur in this population. Unfortunately, up to 1/3 of initial 

presentation of CAD is sudden death. This statistic underscores the importance of appropriate 

cholesterol testing and management, since cholesterol blood level predicts CAD risk. 

The National Cholesterol Education Program (NCEP) Adult Treatment Panel (ATP III) guidelines, 

released in 2001, focus on multiple risk factors and use the Framingham risk calculation to identify 

certain patients for more intense treatment. The ATP III guidelines are endorsed by the American 

College of Cardiology (ACC) and American Heart Association (AHA). 

By strict ATP III definition, risk factors include: 

1. Family history (primary male relative with CAD before age 55, female relative before age 65), 

2. Hypertension (blood pressure >140/90), 

3. Low HDL (45). 

In general, low cardiac risk is described as no risk or one risk factor. Moderate cardiac risk is defined 

as two risk factors and a 10-year Framingham risk of less than 10%. Moderate high risk is defined as 

two or more risk factors and a 10-year Framingham risk of 10%-20%. High risk individuals have 

existing CAD (previous history of MI, stable or unstable angina, or revascularization with coronary 

artery bypass grafting or percutaneous coronary angioplasty), or a CAD risk equivalent (e.g., diabetes 

mellitus, abdominal aortic aneurysm, PVD, significant coronary artery disease, a 10-year Framingham 

risk that exceeds 20%). 

In July 2004, the NCEP updated some elements of the ATP III guidelines based on review of 5 

additional clinical trials. In this update, very high risk patients (recent heart attack, or those who have 

cardiovascular disease combined with diabetes, continued smoking, PVD, or metabolic syndrome) had 

an optional goal LDL less than 70 mg/dL. The National Heart Lung and Blood Institute (NHLBI) 

anticipates the release of ATP IV in the Spring of 2012. 

CLINICAL EVIDENCE 

I. BASIC LIPOPROTEIN PROFILE 

A basic lipoprotein profile typically includes total cholesterol, HDL, triglycerides, and calculated LDL. 

In some clinical situations (e.g. presence of chylomicrons, elevated triglycerides >400 mg/dl), indirect 

LDL calculation may not be considered accurate (i.e. underestimated) and direct LDL calculations may 

be considered more appropriate. 

A. LDL. The ATP III guidelines identify elevated LDL cholesterol as the primary target of therapy 

and establish goals for LDL cholesterol that depend on a patient’s risk status. The ATP III guidelines 

do not define the total cholesterol: HDL ratio as a specified target of therapy; LDL remains the primary 

lipid lowering target. The data on LDL predicting CVD in randomized controlled trials (RCT) is 


obust. Among the earliest trials include the Framingham Heart Study, the Multiple Risk Factor 

Intervention Trial (MRFIT), and the Lipid Research Clinics (LRC) trials which established that 

lowering LDL cholesterol in patients with multiple cardiovascular risk factors lowers coronary heart 

disease (CHD) event rates. 

B. HDL. The most important function of HDL-C is reverse cholesterol transport. The data indicates 

that HDL cholesterol levels are strong inverse predictors of CHD events. Randomized intervention 

studies have demonstrated significant inhibition of atherosclerosis and/or improvement in 

cardiovascular event rates in treatments that increase HDL-cholesterol. The Veterans Administration 

HDL Intervention Trial (VA-HIT) trial demonstrated the benefits of Gemfibrozil in patients with low 

HDL levels with CHD. The HDL Atherosclerosis Treatment Study (HATS) trial demonstrated a 

reduction in major cardiovascular events of 90% vs. placebo in patients randomized to nicotinic acid 

and Simvastatin. In addition, patients in the Coronary Drug Project benefited from a significant 

reduction in mortality after 15 years, 9 years after the trial ended. However, it has been difficult to 

determine whether raising HDL cholesterol independently reduces CVD events because interventions 

that raise HDL also affect the concentration of other lipoproteins. The NCEP report states that 

although the potential benefit of HDL-raising therapy has evoked considerable interest, "current 

documentation of risk reduction through controlled clinical trials is not sufficient to warrant setting a 

specific goal value for raising HDL-C." The AIM-High trial's purpose was to determine if, in the 

setting of well-treated LDL and low HDL, there was an incremental benefit of adding extended-release 

niacin. The study was halted prematurely by the FDA as it met the criterion of “futility”. The 

evidence to correct low HDL-C in addition to reducing LDL-C therefore awaits support from a larger 

randomized controlled trial, HPS-2-THRIVE, which should help guide clinical decision as to the 

benefit of raising HDL. 

C. Triglycerides, in the fasting state, are primarily found in VLDL. Triglycerides are therefore used as 

a surrogate measure of VLDL. Because triglycerides are highly linked to abnormalities in HDL and 

LDL, triglycerides are often not an independent predictor in multivariate analyses. There has been no 

clinical trial establishing that lowering triglycerides in individuals leads to lower CHD event rates 

when adjusted for HDL cholesterol. 

D. Non-HDL. Non-HDL cholesterol includes all lipoproteins that contain apo B. The ATP III 

guidelines suggest non-HDL as a secondary target of therapy in patients with high triglycerides, after 

targeting LDL cholesterol levels. The targeted level for non-HDL cholesterol is the LDL cholesterol 

target plus 30. Some authors advocate that measuring non-HDL cholesterol is more practical than 

directly measuring apo B and is predictive of heart disease in individuals who have high triglycerides 

(see discussion on apo B below). Because many studies have demonstrated non-HDL's superiority in 

predicting CHD risk over LDL cholesterol, its ease of calculation from non fasting samples (total 

cholesterol-HDL), as well as its lack of additional expense in patients already getting lipid panel 

measurements, a consensus statement from the American Diabetes Association and American College 

of Cardiology Foundation (Brunzell, et al., 2008) recommend the calculation of non-HDL cholesterol 

in cardio-metabolic risk individuals with low to moderate LDL levels. 

II. ADVANCED LABORATORY TESTS 

A. Apolipoproteins. Because cholesterol is insoluble in blood, cholesterol is carried by lipoproteins. 


Apolipoproteins are proteins on the surface of a lipoprotein complex that bind to specific enzymes or 

transport proteins on the cell membranes; this directs the lipoprotein to the proper site of metabolism. 

The major apolipoproteins include A (apo A), B (apo B), C (apo C), and E (apo E) and their variants. 

• Apolipoprotein A1 (Apo A-1) a major protein that makes up high-density lipoprotein 

(HDL). Apo A-1 and Apo A-2 constitute 90% of total HDL proteins. Apo A-1 participates 

in the reverse cholesterol transport by forming pre-beta-1-HDL which transfers free 

cholesterol from cell membranes eventually becoming a cholesterol ester, to the liver for 

excretion. Levels are decreased with smoking, uncontrolled diabetes, chronic renal failure, 

and are increased with statins, niacin, fibrates, estrogen, ethanol, other prescription drugs, 

and physical exercise. Low levels are associated with impaired clearance of excess 

cholesterol from the body. Severely low HDL (as in Apo A-1 deficiency) is a rare disorder 

frequently associated with xanthomas. Severe apolipoprotein A1 deficiency (familial 

hypoalphalipoproteinemia) is associated with very premature coronary heart disease similar 

to heterozygous familial hypercholesterolemia. Apo A-1 is not routinely ordered, however, 

it may have a role in patients with strong family history of CAD, or accelerated CAD, and 

when a genetic cause is suspected. Although some proponents report the predictive power 

of apo A-1 testing, others have not found testing to be advantageous. Currently, the apo A-1 

does not add additional predictive power above a traditional HDL level. 

• Apolipoprotein B (apo B) is a major protein found in LDL and VLDL. Its most 

abundant form is known as B-100. Each major atherogenic lipoprotein (e.g. LDL, IDL, 

VLDL, Lp (a)) contains one molecule of Apo B-100. It has been suggested that apo B is a 

better marker of atherogenic particles than total LDL and even non-HDL. Serum total apo 

B has been shown to have a strong predictive power for severity of coronary atherosclerosis 

and CHD events. Because of the high correlation between non-HDL cholesterol and apo B 

levels, non-HDL cholesterol, according to ATP-3 guidelines, represents an acceptable 

surrogate marker for total apo (B) in routine clinical testing. However, a consensus 

statement from the American Diabetes Association and the American College of Cardiology 

Foundation (Brunzell, et al., 2008) discussed the issues surrounding the concept of global 

cardiometabolic risk (CMR), and the best approach for CAD risk reduction. The consensus 

panel recommended that apo B appeared to be a more sensitive index of residual CAD risk 

when LDL-C and non-HDL were

In summary, the ATP III guidelines do not recommend apo A-1 for routine risk assessment, apo E is not 

addressed in the guideline, and non-HDL serves as a surrogate for apo B. However, emerging data 

suggest that non-HDL and Apo B are highly correlated but only moderately concordant, apo B should 

therefore be used to guide adjustments to therapy in patients with residual cardiometabolic risk already 

on pharmacologic treatment. 

B. hs-CRP. High sensitivity C-reactive protein is a nonspecific reflection of a broad range of diverse 

pathologic processes. Hs-CRP levels correlate with multiple metabolic risk factors: the more risk 

factors, the higher the hs-CRP. In a study of 14,719 apparently healthy women followed for 8 years, it 

was found that at baseline, median hs-CRP levels with 0, 1, 2, 3, 4, or 5 characteristics of the metabolic 

syndrome were 0.68, 1.09, 1.93, 3.01, 3.88, and 5.75 mg/L, respectively (p (trend) 20% Framingham 10 year risk score), measuring CRP level would not be indicated because the 

initiation of lipid-lowering therapy is clearly indicated. The AHA/CDC panel considered 

recommending more widespread testing of CRP level, such as for those with a family history of CHD 

or the metabolic syndrome, but considered the evidence inadequate at this time. 

C. Homocysteine is an amino acid found in the body. Its role in vascular disease was spurred by the 

observation that over 50% of children with the genetic disorder homocysteinuria die of premature 

vascular disease. It was later proposed that individuals with severe homocysteinemia develop 

premature vascular injury and atherosclerosis. Some authors therefore favor measuring homocysteine 

levels with the aim of treating with supplemental vitamins. Other authors have reported that routine 

testing is not recommended and it is not known if lowering homocysteine levels will reduce 

cardiovascular morbidity and mortality. The ATP III does not recommend routine measurement of 

homocysteine as part of risk assessment to modify LDL-cholesterol goal for primary prevention, 

however, measurement remains an option in selected cases (e.g. with a strong family history of 

premature CHD in an otherwise low risk patient). The SEARCH collaborative group, a double-blind 

randomized clinical trials (RCT) evaluated the potential benefits and hazards of lowering 

homocysteine with folic acid and vitamin B12 supplementation in 12,064 survivors of an MI and 

reported that in high risk patients, supplementation did not have beneficial effects on major coronary 

events. A 2009 Cochrane review that included data from eight RCTs – CHAOS, FOLARDA, GOES, 

HOPE-2, NORVIT, VISP, WAFACS, and WENBIT - assessed the effects of homocysteine lowering for 

preventing cardiovascular events. It concluded that homocysteine lowering did not reduce the risk of 

nonfatal or fatal MI, stroke, or death from any cause. 

D. Kinesin-like protein 6 (KIF6) is a member of a family of molecular motors involved in intracellular 

transport of protein complexes, membrane organelles, and messenger RNA along microtubules. 

Observational studies such as ARIC and WHS demonstrated a modest increase in risk of CAD in 

carriers of the common KIF6719Arg variant allele. The PROVE IT-TIMI 22 trial demonstrated that 

intensive statin therapy provided significantly greater benefit in KIF6 carriers than non-carriers. 


However, a recent study questioned KIF6's link to CAD in a well-conducted meta-analysis of 19 casecontrolled 

studies involving 17,000 cases of CAD and 39,316 controls conducted around the world. It 

concluded that none of the 19 studies found an increased risk of CAD in carriers of the 719 Arg allele. 

Another study found that carriers of the KIF6 719Arg genetic variant in the TNT and IDEAL study 

were not at an increased cardiovascular risk and did not obtain consistent cardiovascular benefit from 

high-dose statin therapy compared to non-carriers. Until genome-wide association studies provide 

evidence to support KIF6's link to CAD and MI, this test should remain investigational. 

E. Lipoprotein(a). Enzyme Immunoassay Lp(a) was discovered in 1963. Lp(a) is a cholesterol-rich 

plasma lipoprotein particle, the structure and composition of which closely resemble LDL. In 2001, 

The NCEP ATP-III guidelines recommended that the measurement is best reserved for persons with a 

strong family history of premature CHD or those with genetic causes of hypercholesterolemia, such as 

familial hypercholesterolemia. Several studies have been published since this recommendation. In a 

meta-analysis of the general population, elevated Lp(a) was associated with increased risk of heart 

disease and stroke risk. Individuals with levels above 50 mg/dL have 2-3 fold risk of myocardial 

infarction, and the association between Lp(a) and increased cardiovascular disease risk was continuous 

without any threshold and did not depend on LDL cholesterol levels. 

A prospective study of 8,637 participants spanning 16 years of follow up (The Copenhagen City Heart 

Study), found the data were consistent with a causal association between elevated Lp(a) levels and 

increased risk for an MI. 

In special groups and populations, (in this study, emigrant Indians), a study to assess Lp(a) and lipid 

levels in 50 consecutive young north Indian patients less than 45 with myocardial infarction found 

familial clustering of high Lp(a) levels in first-degree relatives of young patients with myocardial 

infarction. 

Based on these recent data, the European Atherosclerosis Society 2010 Congress' consensus panel 

recommended that clinicians should consider screening statin-treated patients with recurrent heart 

disease, in addition to those considered at moderate to high risk of heart disease. 

F. Lipoprotein-Associated Phospholipase A2 (Lp-PLA2) is a vascular-specific inflammatory enzyme 

produced primarily in macrophages and bound to LDL. It is not affected by other inflammatory 

conditions and therefore identifies a population at an increased risk for MI and stroke. Elevated levels 

are associated with an increased risk for coronary heart disease similar in magnitude to that with non- 

HDL cholesterol or systolic blood pressure. It is commonly measured by the PLAC test (diaDexus, 

Inc, South San Francisco, CA) which is an enzyme-linked immunoabsorbant assay (ELISA) test. The 

ATP III guidelines published in May 2001 did not include measurement of Lp-PLA2, although several 

studies have been published since then. The West of Scotland Coronary Prevention Study (WOSCOPS) 

first demonstrated the potential association between L-PLA2 and cardiovascular outcome. It showed a 

positive association between elevated circulating concentrations of Lp-PLA2 and risk of coronary 

events in hypercholesterolemic men. WOSCOPS also reported the positive association between 

elevated Lp-PLA2 levels and coronary risk which was not confounded by classic cardiovascular risk 

factors, in contrast to other inflammatory biomarkers including CRP and fibrinogen (16). Ballantyne et 

al. (ARIC trial, 2005) and Elkind et al. (NOMAS trial, 2006) found that the subgroup of patients with 

the highest levels of Lp-PLA2 had a statistically significant 2.0- to 2.1-fold increase in risk of stroke or 


ecurrent stroke compared with the subgroup of patients with the lowest levels of Lp-PLA2. However, 

the reviewed studies overestimated the magnitude of the predictive ability of the PLAC test by 

subdividing the study populations into 3 or 4 subgroups and comparing only those patients who have 

the highest and lowest levels of Lp-PLA2. A study by Wallach in 2007 suggested that an elevated Lp- 

PLA2 with low LDL-C increases risk of heart disease by two times and that increased Lp-PLA2 with 

high CRP increases risk of heart disease by three times. Davidson et al (2008), in an expert consensus 

panel, evaluated how Lp-PLA2 might be used for determining CVD risk and concluded that it is not 

recommended for the general populations or persons who are at lower risk. However, the panel does 

recommend testing in moderate- or high-risk persons to further stratify risk. The 2010 ACCF/AHA 

Guideline for Assessment of Cardiovascular Risk in Asymptomatic Adults designated Lp-PLA2 a 

Class IIb indication, meaning the benefit outweighed the risk and the procedure may be considered. 

However, the guideline did not include the Lp-PLA2 Studies Collaboration (LSC), a meta-analysis of 

32 prospective studies which found that Lp-PLA2 levels remained an important risk factor for heart 

disease even after adjusting for existing risk factors such as high cholesterol and high blood pressure. 

This information can probably increase the current IIb recommendation to a higher level designation. 

As a highly specific biomarker for vascular inflammation, elevated Lp-PLA2 levels should prompt 

consideration of increasing the cardiovascular risk category from moderate to high or high to very high 

risk. Because intensification of lifestyle changes and low-density lipoprotein (LDL) cholesterol 

lowering is beneficial in high-risk patients, regardless of baseline LDL cholesterol levels, consideration 

should be given to lowering the LDL cholesterol target by 30 mg/dL in patients with high levels of Lp- 

PLA2. Lp-PLA2 is currently recommended as a diagnostic test for vascular inflammation to better 

identify patients at high or very high risk who will benefit from intensification of lipid-modifying 

therapies. However, it is not presently known whether lowering Lp-PLA2 levels will decrease the 

incidence of coronary disease or stroke and improve clinical health outcomes. 

G. Vertical Auto Profile (VAP). The VAP (Vertical Auto Profile) Cholesterol Test was developed in 

2006 by the privately held Atherotech, Inc., a cardio-diagnostic company. VAP utilizes the patented 

vertical density gradient ultracentrifugation method. The VAP test claims it detects a higher number of 

lipid abnormalities because it reports 15 different tests compared to four in the standard lipid test. It 

measures direct low-density lipoprotein (LDL) which is unaffected by triglycerides. It is the only 

available test that meets the new American Diabetes Association and American College of Cardiology 

(ADA-ACC) consensus guidelines because it reports all three measurements including apo B in 

addition to LDL and non-HDL in high-risk patients. The VAP provides LDL size phenotypes (A, B or 

AB) which represent either the small, dangerous particles, or the larger, more benign particles. It 

measures the HDL subtypes (HDL1 or HDL2), HDL2 being more beneficial. It also measures Lp(a) 

cholesterol content (see discussion above). It also provides non-HDL cholesterol, Triglycerides (TG), 

Intermediate Density Lipoprotein (IDL) cholesterol, and “real” LDL cholesterol values. A study by 

Maki et al published in January 2012 reported that the atherogenic lipoprotein phenotype identified by 

the VAP Test, which included higher TG-rich lipoprotein cholesterol, lower HDL-C and HDL-C 

subfractions, and greater proportion of LDL-C carried by more dense LDL particles was more strongly 

associated with carotid intimal media thickening (CIMT) progression. These atherogenic phenotypes 

may have an important role in the initiation and progression of early atherosclerosis. However, at this 

time, there is no available RCT in the peer-reviewed medical literature to support the efficacy of the 

VAP (Vertical Auto Profile) Cholesterol Test or determine if outcomes are equal to or better than 

testing currently being used. 


H. LDL Particle Number. LDL particle number is an emerging area of research. It can be measured 

by nuclear magnetic resonance (NMR), ultracentrifugation, and high pressure liquid chromatography 

(HPLC). In theory, small size LDL particles are more atherogenic as they are easily deposited into the 

coronary artery intima compared to large LDL particles. In addition, many studies have shown that 

individuals with predominantly small LDL particles (pattern B) experience greater CHD risk. 

However, the Multi-Ethnic Study of Atherosclerosis (MESA) multivariate analyses showed that both 

small and large LDL were strongly associated with subclinical atherosclerosis. The VA-HIT trial also 

showed both small and large particles to be significantly related to CHD events. These two studies 

seem to suggest that the association between small LDL and CVD may be due to the increased number 

of LDL particles. The more accurate method in measuring LDL particle number has been by NMR. 

With this method, the LDL particle number has consistently been shown to be a strong, independent 

predictor of CHD. 

The utility of NMR particle number testing is, however, limited by its availability and its relatively 

high cost. Also, there is a lack of independent data confirming the accuracy of the method and whether 

its CHD predictive power can be consistent across various ethnicities, ages, and conditions that affect 

lipid metabolism. 

U.S. FOOD AND DRUG ADMINISTRATION (FDA) 

The US Food and Drug Administration (FDA) has approved an immunoturbidimetric test for the 

quantitative determination of apo A-I and apo B in serum and plasma. In addition, the FDA has 

approved the product Apolipoprotein Control Serum CHD for use as a quality control material to 

monitor accuracy and precision of human serum protein assays, such as tests for the quantitative 

immunochemical determination of apo A-I and apo B using RID, the Behring Nephelometer Systems, 

and the TurbiTime System. 

The diaDexus PLAC® Test received initial 510(k) approval (K030477) from the FDA on July 18, 

2003. It was approved at that time as an enzyme immunoassay for the quantitative determination of 

Lp-PLA2 in human plasma, to be used in conjunction with clinical evaluation and patient risk 

assessment as an aid in predicting risk for coronary heart disease. On June 15, 2005, a second 510(k) 

approval (K050523) was issued for the PLAC Test for the same indications but also incorporating 

approval for prediction of risk of ischemic stroke associated with atherosclerosis. 

The FDA has approved a number of devices and reagents for testing blood levels of Lp(a). However, 

these approvals neither imply that the tests used for measuring Lp(a) are standardized nor that they are 

of value for coronary heart disease (CHD) risk prediction and patient management. 

LDL subclass testing, apoE testing, homocysteine testing and HDL subclass testing must be performed 

in accordance with the quality standard established in 1988 by the Clinical Laboratory Improvement 

Amendments (CLIA). 


APPLICABLE CODES 

The codes listed in this policy are for reference purposes only. Listing of a service or device code in 

this policy does not imply that the service described by this code is a covered or non-covered health 

service. Coverage is determined by the benefit document. This list of codes may not be all inclusive. 

CPT ® Code Description 

Lipid panel This panel must include the following: Cholesterol, serum, total 

80061 (82465) Lipoprotein, direct measurement, high density cholesterol (HDL 

cholesterol) (83718) Triglycerides (84478) 

82465 Cholesterol, serum or whole blood, total 

83090 Homocysteine 

83695 Lipoprotein (a) 

83698 Lipoprotein-associated phospholipase A2 (Lp-PLA2) 

83700 Lipoprotein, blood; electrophoretic separation and quantitation 

Lipoprotein, blood; high resolution fractionation and quantitation of 

83701 lipoproteins including lipoprotein subclasses when performed (eg, 

electrophoresis, ultracentrifugation) 

83704 

Lipoprotein, blood; quantitation of lipoprotein particle numbers and 

lipoprotein particle subclasses (eg, by nuclear magnetic resonance 

spectroscopy) 

83718 Lipoprotein, direct measurement; high density cholesterol (HDL cholesterol) 

83719 VLDL cholesterol 

83721 Lipoprotein, direct measurement; LDL cholesterol 

83727 Luteinizing releasing factor (LRH) 

84478 Triglycerides 

CPT ® is a registered trademark of the American Medical Association. 

REFERENCES 

Davidson, M. Proise, Challenges,and Disappointments. Apolipoprotein A1 Therapy. Am Coll Cardiol, 

2011; 57:1120-1121. 

Brewer Jr. HB, et al. Genetic dyslipoproteinemias. In: Pusler V, Ross R, Topol FJ eds. 

Atherosclerosis and coronary artery disease. Philadelphia: Lippincott-Raven; 1996;69-88 .(3) Schaefer 

EJ, Santos RD, Asztalos BF. Marked HDL deficiency and premature coronary heart disease Curr Opin 

Lipidol 2010;21:289-297. 

Brunzell, JD et al. Diabetes Care, 2008 Apr;31(4):811-22. Lipoprotein management in patients with 

cardiometabolic risk: consensus statement from the American Diabetes Association and the American 

College of Cardiology Foundation. 

Ridker P, et al: C-reactive protein, the metabolic syndrome, and risk of incident cardiovascular events: 

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PROTOCOL HISTORY/REVISION INFORMATION 

Date 

03/22/2012 

12/23/2010 

Action/Description 

Corporate Medical Affairs Committee

CAR039 Comprehensive Lipid Profile Testing in the Evaluation of ...

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