MEDICAL POLICY

POLICY
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DESCRIPTION
SCOPE
BENEFIT APPLICATION
RATIONALE
REFERENCES
CODING
APPENDIX
HISTORY

Cardiovascular Risk Panels

Number 2.04.509

Effective Date January 28, 2015

Revision Date(s) 01/13/15; 05/12/14

Replaces N/A

Policy

Cardiovascular risk panels, consisting of multiple individual biomarkers intended to assess cardiac risk (other than simple lipid panels – See Policy Guidelines), are considered not medically necessary.

Related Policies

2.02.16

Ultrasonographic Measurement of Carotid Intimal-Medial Thickness as an Assessment of Subclinical Atherosclerosis

12.04.67

KIF6 Genotyping for Predicting Cardiovascular Risk and/or Effectiveness of Statin Therapy

12.04.71

Genotyping for 9p21 Single Nucleotide Polymorphisms to Predict Risk of Cardiovascular Disease or Aneurysm

12.04.72

Gene Expression Testing to Predict Coronary Artery Disease

12.04.509

Genetic Testing for Inherited Thrombophilia

Policy Guidelines

A simple lipid panel is generally composed of the following lipid measures:

  • Total cholesterol
  • LDL cholesterol
  • HDL cholesterol
  • Triglycerides

Certain calculated ratios, such as the total/HDL cholesterol may also be reported as part of a simple lipid panel.

Other types of lipid testing, i.e., apolipoproteins, lipid particle number or particle size, lipoprotein (a), etc., are not considered to be components of a simple lipid profile.

This policy does not address the use of panels of biomarkers in the diagnosis of acute myocardial infarction (MI).

Coding

There is no specific CPT code for cardiovascular risk panels. If there are CPT codes for the component tests in the panel and there is no algorithmic analysis used.

CPT

83698

Lipoprotein-associated phospholipase A2 (Lp-PLA2)

Some examples of commercially available CV risk panels include but are not limited to the following (see Description):

  • Applied Genetics Cardiac Panel.
  • Atherotech® Diagnostics Lab CVD Risk Panel and VAP Lipid Panel
  • Berkeley Heart Lab (a Quest Diagnostics service) Cardio IQ® Lipid Panel
  • Boston Heart Cardiovascular Risk Markers Panels
  • Cleveland HeartLab CVD Inflammatory Profile
  • Genetiks Genetic Diagnosis and Research Center Cardiovascular Risk Panel
  • Genova Diagnostics CV Health Plus Genomics™ Panel, Cardiovascular Health Profile
  • Health Diagnostics Cardiac Risk Panel.
  • *Metametrix Cardiovascular Health Profile (now part of Genova Diagnostics, see above)
  • Singulex® cardiac-related test panels
  • Genova Diagnostics, Inc. acquired Metametrix, Inc. in 2012.

Description

Cardiovascular risk panels refer to different combinations of cardiac markers that are intended to evaluate risk of cardiovascular disease. There are numerous commercially available risk panels that include different combinations of lipids, non-cardiac biomarkers (e.g. troponin, BNP), measures of inflammation, metabolic parameters, genetic markers, and/or radiologic measures. Risk panels report the results of multiple individual tests, as distinguished from quantitative risk scores that combine the results of multiple markers into one score.

Background

Cardiovascular disease (CV) remains the single largest cause of morbidity and mortality in the developed world. As a result, accurate prediction of CV risk is a component of medical care that has the potential to focus and direct preventive and diagnostic activities. Current methods of risk prediction in use in general clinical care are not highly accurate, and as a result there is a potential unmet need for improved risk prediction instruments.

Components of CV risk include family history, cigarette smoking, hypertension, and lifestyle factors such as diet and exercise. In addition, numerous laboratory tests have been associated with CV risk, most prominently lipids such as LDL and HDL. These clinical and lipid factors are often combined into simple risk prediction instruments, such as the Framingham risk sore (FRS). (1) The Framingham risk score provides an estimate of the 10 year risk for developing cardiac disease, and is currently used in clinical care to determine the aggressiveness of risk factor intervention, such as the decision to treat hyperlipidemia with statins.

Many additional biomarkers, genetic factors and radiologic measures, have been associated with increased risk of CV disease. Over 100 emerging risk factors have been proposed as useful for refining estimates of cardiovascular risk. (2-4) Some general categories of these potential risk factors are as follows:

  • markers. In addition to LDL and HDL, other lipid markers may have predictive ability, including the apolipoproteins, Lipoprotein (a), lipid subfractions, and/or other measures.
  • markers. Many measures of inflammation have been linked to the likelihood of CV disease. High sensitivity CRP is one example of an inflammatory markers, other include fibrinogen, interleukins, and
  • syndrome biomarkers. Measures associated with metabolic syndrome, such as specific dyslipidemic profiles or serum insulin levels, have been associated with increased risk of CV disease.
  • markers. A number of mutations that associated with increased thrombosis risk, such as the MHTFR mutation or the prothrombin gene mutations have been associated with increased CV risk. In addition, numerous single-nucleotide polymorphisms (SNP’s) have been associated with CV disease in large genome-wide studies.
  • measures. Carotid artery CMT and coronary artery calcium scores are two radiologic measures that have been associated with increased risk.

CV risk panels may contain measures from one or all of the above categories. Some cardiovascular risk panels are relatively limited, including a few markers in addition to standard lipids. Others include a wide variety of potential risk factors from a number of different categories, often including both genetic and non-genetic risk factors. Other panels are composed entirely of genetic markers.

Some examples of commercially available CV risk panels follow:

  • Diagnostics Cardiac Risk Panel: MTHFR gene analysis, common variants; vitamin D; 1, 25 dihydroxy; BNP; Lp-PLA2; myeloperoxidase; apolipoprotein, each; immune complex assay; lipoprotein, blood; electrophoretic separation and quantitation; very long chain fatty acids; total cholesterol; HDL; LDL; triglycerides; (hsCRP); lipoprotein (a); Insulin, total; fibrinogen; apolipoprotein analysis; multiple SNP’s associated with CAD.
  • Heart Cardiovascular Risk Markers Panels:
  • Boston Heart HDL Map® Test
  • Boston Heart Cholesterol Balance® Test
  • Boston Heart Statin Induced Myopathy (SLCO1B1) Genotype Test
  • Boston Heart Fatty Acid Balance™ Test
  • Other advanced cardiovascular tests include but are not limited to: small dense LDL, lipoprotein (a), apolipoprotein B, hsCRP, lipoprotein-associated phospholipase A2, homocysteine
  • Diagnostics:
  • CV Health Plus Genomics™ Panel: Apo E; prothrombin; Factor V Leiden; fibrinogen; HDL; HDL size; HDL particle number; homocysteine; LDL; LDL size; LDL particle number; lipoprotein (a); LP-PLA2; MTHFR gene; triglycerides, VLDL; VLDL size; vitamin D; hs-CRP.
  • Cardiovascular Health Profile: Total cholesterol, HDL, LDL, triglycerides, lipoprotein (a), ferritin, fibrinogen, hsCRP, coenzyme Q, vitamin E, lipid peroxides, homocysteine, RBC magnesium, insulin, testosterone, sex hormone binding globulin, free androgen index.
  • HeartLab CVD Inflammatory Profile: hs-CRP, urinary microalbumin, myeloperoxidase, Lp-PLA2, F2-isoprostanes.
  • Genetics Cardiac Panel: Genetic mutations associated with: cytochrome p450 mutations associated with metabolism of clopidogrel, ticagrelor, warfarin, beta-blockers, rivaroxaban, and prasugrel (2C19, 2C9/VKORC1, 2D6, 3A4/3A5), Factor V Leiden, prothrombin gene, MTHFR gene, Apo-E gene.
  • Genetic Diagnosis and Research Center Cardiovascular Risk Panel: Factor V Leiden, Factor V R2, prothrombin gene, Factor XIII, fibrinogen -455, PAI-1, GPIIIs (HPA-1), MTHFR, ACE I/D, Apo B, Apo E
  • Heart Lab (a Quest Diagnostics service) Cardio IQ™: Total cholesterol, HDL, LDL, triglycerides, non-HDL and calculated components; LDL; LDL size; LDL particle number; HDL; HDL size; HDL particle number; separation of the spectrum of lipoprotein particles, lipoprotein subclass fraction.
  • Diagnostics Lab CVD Risk Panel and VAP Lipid Panel: direct LDL and HDL, total cholesterol, triglycerides, lipoprotein subclass, Apo A, Apo B, Lp(a), homocysteine. C-reactive protein-hs, cystatin C, GCT, Lp-PLA2, TSH, Uric Acid, vitamin D (20-OH), prothrombin gene.
  • cardiac-related test panels:
  • Cardiac Dysfunction panel: SMC™ cTnl (high-sensitivity troponin), NT-proBNP
  • Vascular Inflammation and Dysfunction panel: SMC™ IL-6, SMC™ IL-17A, SMC™ TNFα, SMC™ Endothelin, Lp-PLA2, hs-CRP, homocysteine, vitamin B12, folate.
  • Dyslipidemia panel: Total Cholesterol, LDL-C (direct), apo B, sdLDL, HDL-C, apo A-1, HDL2b, triglycerides, Lp(a)

Regulatory Status

Multiple assay methods for cardiac risk marker components, such as lipid panels and other biochemical assays, have clearance for marketing through the FDA 510(k) process. Other components of testing panels are laboratory-developed tests. Laboratory-developed tests performed by laboratories licensed for high-complexity testing under the Clinical Laboratory Improvement Amendments (CLIA) act do not require clearance from FDA for marketing.

Scope

Medical policies are systematically developed guidelines that serve as a resource for Company staff when determining coverage for specific medical procedures, drugs or devices. Coverage for medical services is subject to the limits and conditions of the member benefit plan. Members and their providers should consult the member benefit booklet or contact a customer service representative to determine whether there are any benefit limitations applicable to this service or supply. This medical policy does not apply to Medicare Advantage.

Benefit Application

N/A

Rationale

This policy was created in October 2013, and updated periodically with literature reviews through searches of the Medline database, most recently through September 29, 2014.

There is a large amount of literature on the association of individual risk factors with cardiovascular disease. The vast majority of this literature evaluates correlations between individual biomarkers and the presence of, or future development of, CV disease. A framework for evaluation the clinical utility of risk factor assessment includes the following steps:

  1. Standardization of the measurement of the risk factor.
  2. Determination of its contribution to risk assessment. As a risk factor, it is important to determine whether the novel risk factor independently contributes to risk assessment compared to established risk factors. In addition, as there are many potential novel risk factors that could be incorporated into existing CV risk panels, it is important to understand the relationship of each individual risk factor with other risk factors.
  3. Determination of how the novel risk assessment will be used in the management of the patient, compared to standard methods of assessing risk, and whether any subsequent changes in patient management result in an improvement in patient outcome.

Helfand et al. (2) have suggested a similar framework for evaluating the utility of risk factors that includes the concept of reclassifying patients into clinically relevant risk factors. These suggested criteria are as follows:

  • factor should be easily and reliably measured.
  • factor should be an independent predictor of major CV events in patients with an intermediate risk of CV disease and no history of CV disease.
  • factor should reclassify a substantial portion of intermediate risk patients as high-risk
  • individuals should be managed differently than they otherwise would have been
  • other risk factors provide similar prognostic information, then convenience, availability, cost and safety should be considered in choosing among them.

Literature Review

No published studies were identified that evaluated the use of commercially available cardiovascular risk panels as risk prediction instruments in clinical care. Some studies have attempted to incorporate novel risk markers into an overall quantitative risk score, (5, 6) but these risk scores are not the same as CV risk panels, which report the results of individual risk factors.

There is a large evidence base on the association of individual risk markers with cardiovascular risk. Many observational studies have established that individual risk markers are independent predictors of cardiac risk. (2, 4)

In 2013, van Holten et al conducted a systematic review of meta-analyses of prospective studies evaluating the association between serologic biomarkers and primary CV events (ie, CV disease events and stroke in CV disease-naïve populations) and secondary CV events (ie, CV disease events and stroke in populations with a history of CV disease).7 The final data synthesis included 85 studies published from 1988 to 2011. Sixty-five meta-analyses reported biomarkers’ association with primary CV events and 43 reported associations with secondary CV events. Eighteen meta-analyses reported biomarkers’ association with ischemic stroke in patients with a history of CV disease. Only 2 meta-analyses that reported associations with ischemic stroke in patients with no history of CV disease were identified, and results were not reported. CV disease risks for markers with the strongest associations are summarized in Table 1.

Table 1. Serum Biomarkers and Cardiovascular Risk in van Holten et al (2013)

Study Type

Marker

HR, OR, or RR,

95% Confidence Interval

Prediction of CV Events in Patients with No History of CV Disease

CRP

2.43 (RR)

2.10 to 2.83

 

Fibrinogen

2.33 (HR)

1.91 to 2.84

 

Cholesterol

0.44 (HR)

0.42 to 0.48

 

ApoB

1.99 (RR)

1.65 to 2.39

 

Apo A:Apo B ratio

1.86 (RR)

1.55 to 2.22

 

HDL

1.83 (HR)

1.65 to 2.03

 

Vitamin D

1.83 (HR)

1.19 to 2.80

Prediction of CV Events in Patients with Positive History of CV Disease

cTn I and T

9.39 (OR)

6.46 to 13.67

 

High sensitivity CRP

5.65 (OR)

1.71 to 18.73

 

Creatinine

3.98 (HR)

3.02 to 5.24

 

Cystatin C

2.62 (RR)

2.05 to 3.37

Prediction of Ischemic Stroke in Patients with Positive History of CV Disease

Fibrinogen

1.75 (HR)

1.55 to 1.98

 

Uric acid

1.47 (RR)

1.19 to 1.76

Apo: apolipoprotein; CRP: C-reactive protein; cTn: cardiac troponin; CV: cardiovascular; HDL: high density lipoprotein; HR; hazard radio; OR: odds ratio; RR: relative risk

Other studies have demonstrated that risk markers can be used to reclassify patients into different risk categories. However, there is there is no convincing evidence that addition of any individual risk marker, or combination or risk markers, leads to clinically meaningful changes in management that improve outcomes. In the available studies, the improvement in risk prediction has generally been of a small magnitude, and/or has not been found to be associated with clinically meaningful management changes. (2, 8, 9).

Because of this uncertain impact on management, the clinical utility for any of the individual risk markers is either low or uncertain. For some of the individual factors, there are existing medical policies (see Related Policies). In all cases where individual risk factors have been evaluated, the individual risk factors did not meet the criteria for medical necessity.

The available evidence on individual risk markers is only of limited value in evaluating CV risk panels. It is difficult to extrapolate the results of single risk factors to panels given the variable composition of panels. Ideally, panels should be evaluated individually as to their impact on clinical decision making

Furthermore, there are no standardized methods for combining multiple individual risk factors with each other, or with established risk prediction instruments such as the Framingham risk score. Therefore, there is a potential for both overestimation and underestimation of the true cardiac risk. This may lead to management decisions that are based on an inaccurate risk assessment. As a result of these deficiencies, it is not possible to make a reliable assessment of the impact of using CV risk panels on health outcomes.

Ongoing and Unpublished Clinical Trials

A search of online database ClinicalTrials.gov in September 2014 identified multiple studies designed to reduce cardiovascular risks, but no interventional studies to evaluate the utility of cardiac risk panels. One observational study evaluating a comprehensive cardiac risk panel in a case control design was identified:

  • Individualized Comprehensive Atherosclerosis Risk-reduction Evaluation Program (iCARE) – This is an observational, case control study to compare outcomes for patients with no known CAD but intermediate or high Framingham Risk Score who undergo individualized management (usual care plus genetic testing for CAD risk and coronary artery calcium scans) compared with standard management. The primary outcome will be to determine the proportion of subjects and patients who are diagnosed with subclinical and clinically significant coronary atherosclerosis with the individualized approach, compared with the current guideline-driven approach. Enrollment is planned for 670 subjects; the estimated study completion date was July 2014.

Summary of Evidence

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

Practice Guidelines and Position Statements

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

In 2013, the ACC and the AHA issued guidelines on the assessment of CV risk. (10) These guidelines recommend that age- and sex-specific pooled cohort equations which include total cholesterol and HDL to predict the 10-year risk of a first hard atherosclerotic CV disease event be used in non-Hispanic blacks and non-Hispanic whites age between 40 and 79 years (AHA/ACC class of recommendation: I; AHA/ACC level of evidence: B). Regarding newer risk markers after quantitative risk assessment, the guidelines state the following: “If, after quantitative risk assessment, a risk-based treatment decision is uncertain, assessment of ≥1 of the following—family history, hs-CRP, CAC [coronary artery calcium] score, or ABI [ankle-brachial index]—may be considered to inform treatment decision-making” (class of recommendation: IIb; level of evidence: B). The guidelines do not recommend other novel cardiac risk factors or panels of cardiac risk factors.

U.S. Preventive Services Task Force Recommendations

No recommendations specific to the use of cardiovascular risk panels were identified. In 2009, USPSTF made the following recommendation about using nontraditional risk factors in coronary heart disease risk assessment::

The U.S. Preventive Services Task Force (USPSTF) concludes that the evidence is insufficient to assess the balance of benefits and harms of using the nontraditional risk factors discussed in this statement to screen asymptomatic men and women with no history of CHD to prevent CHD events (select "Clinical Considerations" for suggestions for practice when evidence is insufficient). Grade: I

The nontraditional risk factors included in this recommendation are hsCRP, ABI, leukocyte count, fasting blood glucose level, periodontal disease, carotid intima-media thickness, coronary artery calcification score on electron beam computed tomography, homocysteine level, and lipoprotein (a) level.

Medicare National Coverage

There is no national coverage determination (NCD). In the absence of an NCD, coverage decisions are left to the discretion of local Medicare carriers.

References

  1. D'Agostino RB, Sr., Grundy S, Sullivan LM et al. Validation of the Framingham coronary heart disease prediction scores: results of a multiple ethnic groups investigation. JAMA: the journal of the American Medical Association 2001; 286(2):180-7. PMID 11448281
  2. Helfand M, Buckley DI, Freeman M et al. Emerging risk factors for coronary heart disease: a summary of systematic reviews conducted for the U.S. Preventive Services Task Force. Annals of internal medicine 2009; 151(7):496-507. PMID 19805772
  3. Brotman DJ, Walker E, Lauer MS et al. In search of fewer independent risk factors. Archives of internal medicine 2005; 165(2):138-45. PMID 15668358
  4. Greenland P, Alpert JS, Beller GA et al. 2010 ACCF/AHA guideline for assessment of cardiovascular risk in asymptomatic adults: a report of the American College of Cardiology Foundation/American Heart Association Task Force on Practice Guidelines. Journal of the American College of Cardiology 2010; 56(25):e50-103. PMID 21144964
  5. Ridker PM, Buring JE, Rifai N et al. Development and validation of improved algorithms for the assessment of global cardiovascular risk in women: the Reynolds Risk Score. JAMA: the journal of the American Medical Association 2007; 297(6):611-9. PMID 17299196
  6. Zethelius B, Berglund L, Sundstrom J et al. Use of multiple biomarkers to improve the prediction of death from cardiovascular causes. The New England journal of medicine 2008; 358(20):2107-16. PMID 18480203
  7. van Holten TC, Waanders LF, de Groot PG, et al. Circulating biomarkers for predicting cardiovascular disease risk; a systematic review and comprehensive overview of meta-analyses. PLoS One. 2013;8 (4):e62080. PMID 23630624
  8. Emerging Risk Factors C, Di Angelantonio E, Gao P et al. Lipid-related markers and cardiovascular disease prediction. JAMA: the journal of the American Medical Association 2012; 307(23):2499-506. PMID 22797450
  9. Paynter NP, Chasman DI, Pare G et al. Association between a literature-based genetic risk score and cardiovascular events in women. JAMA: the journal of the American Medical Association 2010; 303(7):631-637. PMID 20159871
  10. 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. November 12, 2013 2013. PMID
  11. BlueCross BlueShield Association (BCBSA). Cardiovascular Risk Panels. Medical Policy Reference Manual, Policy No. 2.04.100, 2014

Coding

Codes

Number

Description

CPT

83698

Lipoprotein-associated Phospholipase A2 (Lp-PLA2)

Appendix

N/A

History

Date

Reason

11/11/13

New policy. Policy created with literature review through July 31, 2013. Cardiovascular risk panels consisting of multiple individual markers intended to assess cardiac risk are considered not medically necessary.

05/12/14

Clarification. Additional cardiovascular risk panels added to the list of panel examples: Berkeley Heart Lab Cardio IQ™ Lipid Panel and Atherotech® Diagnostics Lab CVD Risk Panel and VAP Lipid Panel. Add Related Policy 12.04.509.

09/03/14

Coding update. CPT code 83698 added to the policy; this code was previously included on 2.04.32 Measurement of Lp-PLA in the Assessment of CV risk that was archived.

01/13/15

Annual Review. Added examples of commercially available CV risk panels to Policy Guidelines. Policy updated with literature review through September 29, 2014. Added Clinical Trials section. Added Practice Guidelines from ACC and AHA. Added U.S. Preventive Services Task Force Recommendations Section. References 7 and 10 added; others renumbered. Policy statement unchanged.


Disclaimer: This medical policy is a guide in evaluating the medical necessity of a particular service or treatment. The Company adopts policies after careful review of published peer-reviewed scientific literature, national guidelines and local standards of practice. Since medical technology is constantly changing, the Company reserves the right to review and update policies as appropriate. Member contracts differ in their benefits. Always consult the member benefit booklet or contact a member service representative to determine coverage for a specific medical service or supply. CPT codes, descriptions and materials are copyrighted by the American Medical Association (AMA).
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