Coverage Policy

The following Coverage Policy applies to health benefit plans administered by Cigna Companies. Certain Cigna Companies and/or lines of business only provide utilization review services to clients and do not make coverage determinations. References to standard benefit plan language and coverage determinations do not apply to those clients.

Coverage Policies are intended to provide guidance in interpreting certain standard benefit plans administered by Cigna Companies. Please note, the terms of a customer’s particular benefit plan document [Group Service Agreement, Evidence of Coverage, Certificate of Coverage, Summary Plan Description (SPD) or similar plan document] may differ significantly from the standard benefit plans upon which these Coverage Policies are based. For example, a customer’s benefit plan document may contain a specific exclusion related to a topic addressed in a Coverage Policy. In the event of a conflict, a customer’s benefit plan document always supersedes the information in the Coverage Policies.

In the absence of a controlling federal or state coverage mandate, benefits are ultimately determined by the terms of the applicable benefit plan document. Coverage determinations in each specific instance require consideration of 1) the terms of the applicable benefit plan document in effect on the date of service; 2) any applicable laws/regulations; 3) any relevant collateral source materials including Coverage Policies and; 4) the specific facts of the particular situation.

Each coverage request should be reviewed on its own merits. Medical directors are expected to exercise clinical judgment and have discretion in making individual coverage determinations. Coverage Policies relate exclusively to the administration of health benefit plans. Coverage Policies are not recommendations for treatment and should never be used as treatment guidelines.

In certain markets, delegated vendor guidelines may be used to support medical necessity and other coverage determinations.

This Coverage Policy addresses measurement of plasma brain natriuretic peptide (BNP) or NT-proBNP in an outpatient setting.

Coverage Policy

1. Outpatient testing of plasma brain natriuretic peptide (BNP) or NT-proBNP is considered medically necessary for ANY of the following indications:
• asymptomatic individual with severe aortic stenosis to aid in timing of intervention
• for risk stratification in chronic HF in Stage A and Stage B* HF individuals when ordered with cardiovascular team input as part of prevention and management of HF
• to distinguish between heart failure (HF) and primary lung disease in a dyspneic individual
2. monitoring response to treatment for HF
3. in children ages 14 and under at increased risk for endocardial biopsy who are status post heart transplant when ordered in combination with echocardiography or electrocardiogram

Outpatient testing of plasma brain natriuretic peptide (BNP) or NT-proBNP testing is considered experimental, investigational or unproven for any other indication. Outpatient testing of plasma brain natriuretic peptide (BNP) or NT-proBNP as part of cardiovascular disease risk panel/profile is considered experimental, investigational or unproven.

Stage A: At risk for HF

At risk for HF but without symptoms, structural heart disease, or cardiac biomarkers of stretch or injury (e.g., patients with hypertension, atherosclerotic CVD, diabetes, metabolic syndrome and obesity, exposure to cardiotoxic agents, genetic variant for cardiomyopathy, or positive family history of cardiomyopathy).

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Stage B: Pre-HF

Patients without current or previous symptoms/signs of HF but evidence of one of the following:

• Structural heart disease
• Evidence of increased filling pressures
• Risk factors and Increased natriuretic peptide levels or
• Persistently elevated cardiac troponin in the absence of competing diagnoses

General Background

Brain-type natriuretic peptide (BNP) or N-terminal (NT) pro hormone BNP (NT-proBNP) testing has been proposed as an adjunct to other clinical testing in numerous clinical situations including but not limited to heart failure (HF). BNP/ NT-proBNP is a hormone secreted primarily by the heart muscle. The heart releases more BNP and NT-proBNP when the heart is distended from working too hard, as in heart failure. Plasma levels of BNP are less than 100pg/mL in most healthy individuals; reference ranges depend on age and gender. Assays for both BNP and NT-proBNP are available; a clear advantage of one biomarker over the other for any particular application has not been established. A major limitation of BNP is that a wide range of values is observed in patients with and without HF, and all of the determinants of the circulating BNP level have not yet been well established. In individuals without heart failure, higher levels are associated with female gender, advanced age, and lower body mass index.

U.S. Food and Drug Administration (FDA)

A number of devices have received FDA 510(k) approval for evaluating circulating BNP and NT-proBNP levels. These devices can be found on the FDA Center for Devices and Radiological Health 510(k) database, product code NBC. An example of an FDA-approved BNP device is the Triage® B-Type Natriuretic Peptide (BNP) Test (Biosite, Inc., San Diego, CA). The test is intended to be used as an aid in the following (FDA, 2005):

• diagnosis of heart failure
• assessment of heart failure severity
• risk stratification of patients with acute coronary syndromes (ACS)
• risk stratification of patients with heart failure

An example of a NT-proBNP test system is the Elecsys® proBNP Immunoassay (Roche Diagnostics Corporation, Indianapolis, IN). The intended use is as an aid in the diagnosis of individuals suspected of having CHF. The test is further indicated for the risk stratification of patients with ACS and CHF. Although some of the components of Prevencio, Inc. panel tests are individually FDA-approved, at this time it does not appear that Prevencio's artificial-intelligence (AI)-driven algorithm panel tests are FDA-approved.

Professional Societies/Organizations – Heart Failure

American College of Cardiology: The American College of Cardiology (ACC) and the American Heart Association (AHA) Guideline for the Management of Heart Failure (Heidenreich, et al., 2022) lists the following Recommendations:

2022 AHA/ACC/HFSA Guideline for the Management of Heart Failure (Heidenreich, et al., 2022)

4.2.

Use of Biomarkers for Prevention, Initial Diagnosis, and Risk Stratification

Recommendations for Use of Biomarkers for Prevention, Initial Diagnosis, and Risk Stratification:

Class of Recommendation (COR) and Level of Evidence (LOE)*

• COR: 1; LOE: A
• COR: 1; LOE: A
• COR: 1; LOE: A
• COR: 1; LOE: A
• COR: 2a; LOE: B-R
• COR: 2a; LOE: B-NR

2022 AHA/ACC/HFSA Guideline for the Management of Heart Failure (Heidenreich, et al., 2022)

ACC/AHA Stages of Heart Failure (HF)

Stage A: At-risk for HF

At risk for HF but without symptoms, structural heart disease, or cardiac biomarkers of stretch or injury (e.g., patients with hypertension, atherosclerotic CVD, diabetes, metabolic syndrome and obesity, exposure to cardiotoxic agents, genetic variant for cardiomyopathy, or positive family history of cardiomyopathy).

Stage B: Pre-HF

Patients without current or previous symptoms/signs of HF but evidence of one of the following:

• Structural heart disease
  • ventricular hypertrophy
  • chamber enlargement
  • wall motion abnormalities
  • valvular heart disease
• Evidence of increased filling pressures
  • by invasive hemodynamic measurements
  • by noninvasive imaging suggesting elevated filling pressures (e.g., Doppler echocardiography)
• Risk factors and
  • increased natriuretic peptide levels or
  • persistently elevated cardiac troponin in the absence of competing diagnoses resulting in such biomarker elevations such as acute coronary syndrome, CKD, pulmonary embolus, or myopericarditis

Stage C:

Structural heart disease with current or previous symptoms of HF.

Stage D: Advanced HF

Symptomatic HF

Definition Marked HF symptoms that interfere with daily life and with recurrent hospitalizations despite attempts to optimize guideline-directed medical therapy (GDMT) (Heidenreich, et al., 2022)

The American Heart Association 2017 Scientific Statement ‘Role of Biomarkers for the Prevention, Assessment, and Management of Heart Failure’ (Chow, et al., 2017)

notes that monitoring natriuretic peptide concentrations in blood not only can provide the clinician information about the diagnosis and severity of HF but also can improve prognostication and treatment strategies.

Professional Societies/Organizations – Monitoring Treatment for Heart Failure

In the 2021 Update to the 2017 ACC Expert Consensus Decision Pathway for Optimization of Heart Failure Treatment (Maddox, et al., 2021), the ACC notes that biomarkers have been examined for their role as markers of clinical responsiveness to guideline directed medical therapy (GDMT). This is due, in part, to the fact that a wide range of GDMTs may reduce BNP and NT-proBNP concentrations in parallel with the benefits of these therapies. The ACC states that in the GUIDE-IT (Guiding Evidence Based Therapy Using Biomarker Intensified Treatment in HF) trial, among patients with HFrEF, lowering NT-proBNP to <1,000 pg/mL was associated with significant reverse remodeling and improved outcomes (Daubert, et al., 2019). Similarly, in the PROVE-HF study, the speed and magnitude of NT-proBNP–lowering after ARNI initiation were associated with greater degrees of reverse cardiac remodeling and improved outcomes (Januzzi, et al., 2018; Januzzi, et al., 2020).

Therefore, measurement of BNP or NT-proBNP is useful to monitor risk, assist in decision-making regarding the ordering of imaging studies to evaluate LV remodeling, and to provide helpful objective data regarding decision-making for referral to advanced HF therapies. Current evidence does not suggest targeting treatment to specific BNP or NT-proBNP levels (ACC/Maddox, et al., 2021).

Professional Societies/Organizations – Aortic Stenosis

The 2020 ACC/AHA Guideline for the Management of Patients With Valvular Heart Disease states

• In apparently asymptomatic patients with severe aortic stenosis (AS) (Stage C1) and low surgical risk, aortic valve replacement (AVR) is reasonable when the serum B-type natriuretic peptide (BNP) level is >3 times normal (Class IIa, Level of Evidence B-NR) (ACC/Otto/2021)

Professional Societies/Organizations – Heart Transplant

The International Society for Heart and Lung Transplantation (ISHLT) Guidelines for the Care of Heart Transplant Recipients (December 2022) noted the following:

The ISHLT 2023 Guideline Update Recommendations for Rejection Surveillance by Endomyocardial Biopsy (EMB) in Heart Transplant Recipients states:

• The standard of care for adolescents should be similar to adults, including surveillance endomyocardial biopsy (EMB) for heart allograft rejection for 3 to 12 months after HT. In younger children, especially infants, the risks associated with EMB and required general anesthesia may outweigh the surveillance benefit for comparably rare acute rejection; therefore, it is reasonable to use a combination of non-invasive screening methods (echocardiography, ECG, biomarkers) instead (Class IIa, Level of Evidence: C*)

The ISHLT 2023 Guideline Update Recommendations for the Non-Invasive Monitoring of Acute Heart Transplant Rejection states:

• It is reasonable to integrate biomarkers such as BNP and high-sensitivity troponins into a rejection monitoring strategy to identify higher risk patients who may benefit from additional evaluation for acute
• cellular rejection (ACR), antibody-mediated rejection (AMR), or cardiac allograft vasculopathy (CAV) (Class IIb, Level of Evidence C*). In younger children, especially infants, the risks associated with EMB and required general anesthesia may outweigh the surveillance benefit for comparably rare acute rejection; therefore, it is reasonable to use a combination of non-invasive screening methods (echocardiography, ECG, biomarkers) instead (Class IIa, Level of Evidence: C*)
• Other Non-Invasive Monitoring of Acute Heart Transplant Rejection Recommendations included but are not limited to:
• Gene Expression Profiling (GEP) (i.e., Allomap) of peripheral blood can be used in low-risk patients
• between 2 months and 5 years after HT to identify adult recipients who have low risk of current ACR to reduce the frequency of EMB. Data in children does not allow a general recommendation of GEP as a routine tool at present (Class IIa, Level of Evidence: B)
• In pediatric patients, echocardiography, especially detailed assessment of diastolic function, shows reasonable correlation with significant acute rejection; however, it should not be considered as a sole surveillance method in patients who have a low risk of endomyocardial biopsy (EMB) complications. In younger children, echocardiographic surveillance represents an alternative monitoring modality to avoid or reduce the frequency of EMB (Class IIb, Level of Evidence B)
• Post-transplant monitoring for donor-specific antibodies (DSA) should be performed at 1, 3, 6, and 12 months post-operatively and annually thereafter.

Sensitized patients should be monitored more frequently (Class IIa, Level of Evidence C)

International Society for Heart and Lung Transplantation Standards and Guidelines Committee Grading Criteria

• Class I Evidence and/or general agreement that a given treatment or procedure is beneficial, useful, and effective
• Class II Conflicting evidence and/or divergence of opinion about the usefulness/efficacy of the treatment or procedure
• Class IIa Weight of evidence/opinion is in favor of usefulness/efficacy
• Class IIb Usefulness/efficacy is less well established by evidence/opinion
• Class III Evidence or general agreement that the treatment or procedure is not useful or effective and in some cases may be harmful
• Level of evidence A: Data derived from multiple randomized clinical trials or meta-analyses
• Level of evidence B: Data derived from a single randomized clinical trial or large non-randomized studies
• Level of evidence C: Consensus of opinion of the experts and/or small studies, retrospective studies, registries

Disparities and Vulnerable Populations

The 2022 AHA/ACC/HFSA Guideline for the Management of Heart Failure (Heidenreich, et al., 2022) addresses \'Risk of HF and Outcomes in Special Populations\' (Table 27). Vulnerable Populations addressed include:

• Women
• Older adults (≥ 80y)
• Lower socioeconomic status populations (<$15,000/y)
• Black populations
• Hispanic populations
• Asian and Pacific Islander populations
• Native American and Alaskan Native populations

The ACC provides two Recommendations (both Class 1) for \'Disparities and Vulnerable Populations\':

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2022 AHA/ACC/HFSA Guideline for the Management of Heart Failure (Heidenreich, et al., 2022)

11.1 Recommendations for Disparities and Vulnerable Populations

In vulnerable patient populations at risk for health disparities, HF risk assessments and multidisciplinary management strategies should target both known risks for cardiovascular disease (CVD) and social determinants of health, as a means toward elimination of disparate HF outcomes. Evidence of health disparities should be monitored and addressed at the clinical practice and the health care system levels.

Class of Recommendation (COR) and Level of Evidence (LOE)*

• COR: 1; LOE: C-LD
• COR: 1; LOE: C-LD

The ACC notes:

There are important differences in HF incidence, risk factors, clinical care needs, and outcomes between specific patient populations. The highest incident of HF is consistently observed in self-identified Black patients. HF hospitalization and mortality rates for Black patients are also higher than for White patients, with the gap increasing over time for young men. These differences are driven mostly by social circumstances; a biological premise or genetic explanation for disease or disease severity should not be inferred by race or ethnicity. Important strategies to remove biases within health care professionals and systems impacting minority and socioeconomically disadvantaged patient populations include implicit bias training, recruiting a diverse workforce, and promoting broad access to HF care. In a Research Letter titled \'Racial Differences in Serial NT-proBNP Levels in Heart Failure Management Insights From the GUIDE-IT Trial\', Parcha et al. (2020) noted Black patients with HF had ≈21% lower NT-proBNP levels as compared with white patients. Despite this, NT-proBNP concentrations of ≤1,000 pg/mL had prognostic significance in both Black patients and white patients. Black patients with HF had a higher risk for adverse cardiovascular outcomes compared with their white counterparts. Parcha et al.

(2020) summarized achieving a target NT-proBNP level of ≤1000 pg/mL has favorable prognostic implications in both Black patients and white patients with HF, but the prognosis is worse for Black patients at either level of achieved NT-proBNP.

Other Indications

Any other indication for plasma brain natriuretic peptide (BNP) or NT-proBNP including but not limited to screening for various diagnoses, as part of a panel/profile test, or targeting treatment to specific BNP or NT- proBNP levels, is considered experimental. There is a lack of well-designed clinical trials in the peer-reviewed scientific literature addressing the impact to long-term health outcomes from using artificial intelligence (AI)-driven cardiac panel blood tests (Neumann, et al., 2020).

In the 2021 Update to the 2017 ACC Expert Consensus Decision Pathway for Optimization of Heart Failure Treatment (ACC/Maddox, et al., 2021), the ACC notes that current evidence does not suggest targeting treatment to specific BNP or NT-proBNP levels.

Further information on BNP or NT-proBNP-guided therapy includes the randomized Guiding Evidence-Based Therapy Using Biomarker-Intensified Treatment in HF (GUIDE-IT) trial which was conducted at 45 clinical sites in the United States and Canada to determine whether NT-proBNP-guided treatment strategy improves clinical outcomes compared to usual care in high-risk patients with HF and reduced ejection fraction (HFrEF). The trial was stopped for futility when 894 (median age, 63; 286 [32% women]) of the planned 1,100 patients had been enrolled and followed for a median of 15 months. Cardiovascular mortality was 12% in the biomarker guided group and 13% in the usual care group (p = 0.75). The authors concluded that in high-risk patients with HFrEF, a strategy of NT-proBNP-guided therapy was not more effective than a usual care strategy in improving outcomes (Felker, et al., 2017).

The American Board of Internal Medicine’s (ABIM) Foundation Choosing Wisely® Initiative

No information found.

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Use Outside of the US

The Heart Failure Association of the European Society of Cardiology (ESC) Practical Guidance on the use of natriuretic peptide concentrations (Mueller, et al., 2019) lists \'Key principles\' for the use of natriuretic peptides (NPs) in clinical practice:

• NPs should always be used in conjunction with all other clinical information
• NPs are reasonable surrogates for intracardiac volumes and filling pressures
• NPs should be measured in all patients presenting with symptoms suggestive of HF such as dyspnoea and/or fatigue, as their use facilitates the early diagnosis and risk stratification of HF

NPs have very high diagnostic accuracy in discriminating HF from other causes of dyspnoea: the higher the NP, the higher the likelihood that dyspnoea is caused by HF

Optimal NP cut-off concentrations for the diagnosis of acute HF (very high filling pressures) in patients presenting with acute dyspnoea to the emergency department are higher as compared with those used in the diagnosis of chronic HF in patients with dyspnoea on exertion (mild increase in filling pressures at rest)

Obese patients have lower NP concentrations, mandating the use of lower cut-off concentrations (about 50% lower)

In stable HF patients, but also in patients with other cardiac disorders such as myocardial infarction, valvular heart disease, atrial fibrillation, or pulmonary embolism, NP concentrations have high prognostic accuracy for death and HF hospitalization

Screening with NPs for the early detection of relevant cardiac disease including left ventricular systolic dysfunction in patients with cardiovascular risk factors may help identify patients at increased risk, therefore allowing targeted preventive measures to prevent HF

BNP, NT-proBNP and MR-proANP have comparable diagnostic and prognostic accuracy

In patients with shock, NPs cannot be used to identify cause (e.g. cardiogenic vs. septic shock), but remain prognostic

NPs cannot identify the underlying cause of HF and therefore, if elevated, must always be used in conjunction with cardiac imaging

The 2021 European Society of Cardiology (ESC) Guidelines for the diagnosis and treatment of acute and chronic heart failure (McDonagh, et al., 2021) addresses diagnostic tests in patients with heart failure (HF). Recommended diagnostic tests in all patients with suspected chronic heart failure:

• BNP/NT-proBNP (Class I recommendation, Level of evidence B)