mp-592
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Laboratory Tests for Chronic Heart Failure and Heart Transplant Rejection

Policy Number: MP-592

Latest Review Date: May 2020

Category: Laboratory

Policy Grade: B

POLICY:

The use of the Presage® ST2 Assay is considered not medically necessary and investigational for all indications, including but not limited to the following:

  • to evaluate the prognosis of patients diagnosed with chronic heart failure;
  • to guide management (pharmacological, device-based, exercise, etc.) of patients diagnosed with chronic heart failure
  • in the post cardiac transplantation period, including but not limited to predicting prognosis and predicting acute cellular rejection

The measurement of volatile organic compounds to assist in the detection of moderate grade 2R/grade 3 heart transplant rejection is considered not medically necessary and investigational.

DESCRIPTION OF PROCEDURE OR SERVICE:

Clinical assessment and noninvasive imaging of chronic heart failure (CHF) can be limited in accurately diagnosing patients with heart failure (HF) because symptoms and signs can poorly correlate with objective methods of assessing cardiac dysfunction. For management of HF, clinical signs and symptoms (e.g., shortness of breath) are relatively crude markers of decompensation and occur late in the course of an exacerbation. Thus, circulating biomarkers have potential benefit in HF diagnosis and management. A new protein biomarker, referred to as soluble suppression of tumorigenicity-2 (sST2), has elicited interest as a potential aid to predict risk and manage therapy of CHF. Soluble ST2 is also proposed for use in patients after heart transplant.

Commercially marketed laboratory testing is available to assess heart transplant rejection, including the Heartsbreath™ test which measures breath markers of oxidative stress. This test is proposed as an alternative or as an adjunct invasive endomyocardial biopsy.

Chronic Heart Failure: Suppression of Tumorigenicity-2 Protein Biomarker

A protein biomarker, referred to as suppression of tumorigenicity-2(ST2), has elicited interest as a potential aid to predict prognosis and manage therapy of HF. This protein is a member of the interleukin-1 (IL-1) receptor family. It is found as a transmembrane isoform (ST2L) and a soluble isoform (sST2), both of which have circulating IL-33 as their primary ligand. ST2 is a unique biomarker that has pluripotent effects in vivo. Thus, binding between IL-33 and ST2L is believed to have an immunomodulatory function via T-helper Type II lymphocytes and was initially described in the context of cell proliferation, inflammatory states, and autoimmune diseases. However, the IL-33‒ST2L signaling cascade also is strongly induced through mechanical strain of cardiac fibroblasts or cardiomyocytes. The net result is mitigation of adverse cardiac remodeling and myocardial fibrosis, which are key processes in the development of HF. The soluble isoform of ST2 is produced by lung epithelial cells and cardiomyocytes and is secreted into the circulation in response to exogenous stimuli, mechanical stress, and cellular stretch. This form of ST2 binds to circulating IL-33, acting as a “decoy,” thus inhibiting the IL- 33 associated anti-remodeling effects of the IL-33‒ST2L signaling pathway. Thus, on a biologic level, IL- 33‒ST2L signaling plays a role in modulating the balance of inflammation and neurohormonal activation and is viewed as pivotal for protection from myocardial remodeling, whereas sST2 is viewed as attenuating this protection. In the clinic, blood concentrations of sST2 appear to correlate closely with adverse cardiac structure and functional changes consistent with remodeling in patients with HF, including abnormalities in filling pressures, chamber size, systolic and diastolic function.

An enzyme-linked immunosorbent (ELISA) ‒based assay is commercially available for determining sST2 blood levels (Presage® ST2 Assay). The manufacturer claims a limit of detection of 1.8 ng/mL for sST2, and a limit of quantification of 2.4 ng/mL, as determined according to Clinical and Laboratory Standards Institute guideline EP-17-A. In one published study, a limit of detection of 2.0 ng/mL for sST2 was reported in their study. In the same study, the assay had a within-run coefficient of variation (CV) of 2.5% and a total CV less than 4.0%; demonstrated linearity within the dynamic range of the assay calibration curve; and, exhibited no relevant interference or cross-reactivity.

The ST2 biomarker is not intended to diagnose heart failure, because it is a relatively nonspecific marker that is increased in many other disparate conditions that may be associated with acute or chronic manifestations of HF. Although the natriuretic peptides, BNP and NT-proBNP, reflect different physiologic aspects of HF compared with sST2, they are considered the reference standard biomarkers when used with clinical findings to diagnose, prognosticate, and manage HF and as such are the comparator to sST2.

Noninvasive Heart Transplant Rejection Testing

The Heartsbreath™ test, a noninvasive test that measures breath markers of oxidative stress, has been developed to assist in the detection of heart transplant rejection. In heart transplant recipients, oxidative stress appears to accompany allograft rejection, which degrades membrane polyunsaturated fatty acids and evolving alkanes and methylalkanes that are in turn, excreted as volatile organic compounds in breath. The Heartsbreath test analyzes the breath methylated alkane contour (BMAC), which is derived from the abundance of C4 to C20 alkanes and monomethylalkanes and has been identified as a marker to detect Grade 3 (clinically significant) heart transplant rejection.

Other laboratory-tested biomarkers of heart transplant rejection have been evaluated. These include brain natriuretic peptide, troponin, and soluble inflammatory cytokines. Most of these have had low diagnostic accuracy in diagnosing rejection.  Preliminary studies have evaluated the association between heart transplant rejection and micro-RNAs or high-sensitivity cardiac troponin in cross-sectional analyses, but the clinical use has not been evaluated.

KEY POINTS:

The most recent literature update was performed through March 9, 2020.

Summary of Evidence

For individuals who have chronic heart failure (CHF) who receive soluble suppression of tumorigenicity-2 (sST2) assay to determine prognosis and/or to guide management, the evidence includes correlational studies and two meta-analyses. Relevant outcomes are overall survival, quality of life, and hospitalization. Most of the evidence is from reanalysis of existing randomized controlled trials and not from studies specifically designed to evaluate the predictive accuracy of sST2, and prospective and retrospective cross-sectional studies made up a large part of one meta-analysis. Studies have mainly found that elevated sST2 levels were statistically associated with elevated risk of mortality. A pooled analysis of study results found that sST2 significantly predicted overall mortality and cardiovascular mortality. Several studies, however, found that sST2 test results did not provide additional prognostic information compared with or N-terminal pro B-type natriuretic peptide levels. Moreover, no comparative studies were identified on the use of the sST2 assay to guide management of patients diagnosed with chronic HF. The evidence is insufficient to determine the effects of the technology on health outcomes.

For individuals who have heart transplantation who receive sST2 assay to determine prognosis and predict acute cellular rejection, the evidence includes a small number of retrospective observational studies on the Presage ST2 Assay. Relevant outcomes are overall survival, morbid events, and hospitalization. No prospective studies were identified that provide high-quality evidence on the ability of sST2 to predict transplant outcomes. One retrospective study (n=241) found that sST2 levels were associated with acute cellular rejection and mortality; another study (n=26) found that sST2 levels were higher during an acute rejection episode than before rejection. The evidence is insufficient to determine the effects of the technology on health outcome.

The evidence includes a diagnostic accuracy study for individuals who have a heart transplant who receive measurement of volatile organic compounds to assess cardiac allograft rejection. Relevant outcomes are overall survival, test validity, morbid events, and hospitalizations. The published study found that, for identifying Grade 3 (now Grade 2R) rejection, the negative predictive value of the breath test the study evaluated (97.2%) was similar to endomyocardial biopsy (96.7%) and the sensitivity of the breath test 78.6% was better than that for biopsy (42.4%). However, the breath test had lower specificity (62.4%) and a lower positive predictive value (5.6%) in assessing Grade 3 rejection than biopsy (specificity, 97%; positive predictive value, 45.2%). The breath test was also not evaluated for Grade 4 rejection. This single study is not sufficient to determine the clinical validity of the test measuring volatile organic compounds and no studies on clinical utility were identified. The evidence is insufficient to determine the effects of the technology on health outcomes.

Practice Guidelines and Positions Statements

American College of Cardiology et al

In 2017, the American College of Cardiology Foundation, American Heart Association, and Heart Failure Society published a focused update of their 2013 guideline on the management of heart failure. Part of the focus of the update was on biomarkers. The guidelines stated that soluble suppression of tumorigenicity-2 (ST2) is a biomarker for myocardial fibrosis that may predict hospitalization and death in patients with heart failure and provides additive prognostic information to natriuretic peptide levels. The guidelines were based on a class IIb recommendation (weak; benefit ≥ risk) with level B-NR evidence (moderate-quality, nonrandomized) for the use of ST2 as an option to provide additive prognostic information to established clinical evaluation and biomarkers. The guidelines did not address other uses of ST2.

U.S. Preventive Services Task Force Recommendations

Not applicable.

KEY WORDS:

Heart Failure, Heart transplant, HF, Presage® ST2 Assay, ST2 (suppression of tumorigenicity), soluble suppression of tumorigenicity-2 (sST2), Heartsbreath test

APPROVED BY GOVERNING BODIES:

In 2011, the Presage® ST2 Assay kit (Critical Diagnostics, San Diego, CA) was cleared for marketing by the U.S. Food and Drug Administration (FDA) through the 510(k) process for use in conjunction with clinical evaluation as an aid in assessing the prognosis of patients diagnosed with chronic HF. The assay had previously received Conformite Europeenne (CE) Mark in January 2011. The Presage® ST2 Assay kit is provided in a microplate configuration. The kit contains a ready-to-use 96- well microtiter plate coated with mouse monoclonal antihuman sST2 antibodies; a recombinant human sST2 standard calibrator (lyophilized); a standard diluent; an anti-ST2 biotinylated antibody reagent (mouse monoclonal antihuman sST2 antibodies) in phosphate-buffered saline; a sample diluent; a tracer concentrate and tracer diluent; a wash concentrate; a tetramethylbenzidine reagent; a stop solution; and two levels of controls provided in a sealed, lyophilized format (high and low control). FDA product code: OYG.

In February 2004, the Heartsbreath™ test (Menssana Research) was cleared for marketing by the U.S. Food and Drug Administration (FDA) through a humanitarian device exemption for use as an aid in the diagnosis of Grade 3 heart transplant rejection in patients who have received heart transplants within the preceding year. The device is intended to be used as an adjunct to, and not as a substitute for, endomyocardial biopsy and is also limited to patients who have had endomyocardial biopsy within the previous month.

BENEFIT APPLICATION:

Coverage is subject to member’s specific benefits.  Group specific policy will supersede this policy when applicable.

ITS: Home Policy provisions apply

FEP contracts: FEP does not consider investigational if FDA approved and will be reviewed for medical necessity.

CURRENT CODING: 

CPT codes:

0085T

Breath test for heart transplant rejection

83006

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

86849

Unlisted immunology procedure

REFERENCES:

  1. Aimo A, Vergaro G, Passino C, et al. Prognostic value of soluble suppression of tumorigenicity-2 in chronic heart failure: a meta-analysis. JACC Heart Fail. Apr 2017; 5(4):280-286.
  2. Anand IS, Rector TS, Kuskowski M, et al. Prognostic value of soluble ST2 in the Valsartan Heart Failure Trial. Circ Heart Fail. May 2014; 7(3):418-426.
  3. Bayes-Genis A, de Antonio M, Galan A, et al. Combined use of high-sensitivity ST2 and NTproBNP to improve the prediction of death in heart failure. Eur J Heart Fail. Jan 2012; 14(1):32-38.
  4. Bhardwaj A, Januzzi JL, Jr. ST2: a novel biomarker for heart failure. Expert Rev Mol Diagn. May 2010; 10(4):459-464.
  5. Broch K, Ueland T, Nymo SH, et al. Soluble ST2 is associated with adverse outcome in patients with heart failure of ischemic etiology. Eur J Heart Fail. Mar 2012; 14(3):268-277.
  6. Chowdhury P, Kehl D, Choudhary R, et al. The use of biomarkers in the patient with heart failure. Curr Cardiol Rep. Jun 2013; 15(6):372.
  7. Ciccone MM, Cortese F, Gesualdo M, et al. A novel cardiac bio-marker: ST2: a review. Molecules. 2013; 18(12):15314-15328.
  8. Cohn JN, Tognoni G, Valsartan Heart Failure Trial I. A randomized trial of the angiotensin-receptor blocker valsartan in chronic heart failure. N Engl J Med. Dec 2001; 345(23):1667-1675.
  9. Daniels LB, Bayes-Genis A. Using ST2 in cardiovascular patients: a review. Future Cardiol. Jul 2014; 10(4):525-539.
  10. Dieplinger B, Mueller T. Soluble ST2 in heart failure. Clin Chim Acta. Sep 2014.
  11. Dupuy AM, Curinier C, Kuster N, et al. Multi-marker strategy in heart failure: combination of st2 and crp predicts poor outcome. PLoS One. 2016; 11(6):e0157159.
  12. Felker GM, Fiuzat M, Thompson V, et al. Soluble ST2 in ambulatory patients with heart failure: Association with functional capacity and long-term outcomes. Circ Heart Fail. Nov 2013; 6(6):1172-1179.
  13. Gaggin HK, Januzzi JL, Jr. Biomarkers and diagnostics in heart failure. Biochim Biophys Acta. Dec 2013; 1832(12):2442-2450.
  14. Gaggin HK, Motiwala S, Bhardwaj A, et al. Soluble concentrations of the interleukin receptor family member ST2 and beta-blocker therapy in chronic heart failure. Circ Heart Fail. Nov 2013; 6(6):1206-1213.
  15. Heart Failure Society of America, Lindenfeld J, Albert NM, et al. HFSA 2010 Comprehensive Heart Failure Practice Guideline. J Card Fail. Jun 2010; 16(6):e1-194.
  16. Januzzi JL, Horne BD, Moore SA, et al. Interleukin receptor family member ST2 concentrations in patients following heart transplantation. Biomarkers. May 2013; 18(3):250-256.
  17. Januzzi JL, Jr., Rehman SU, Mohammed AA, et al. Use of amino-terminal pro-B-type natriuretic peptide to guide outpatient therapy of patients with chronic left ventricular systolic dysfunction. J Am Coll Cardiol. Oct 2011; 58(18):1881-1889.
  18. Kjekshus J, Apetrei E, Barrios V, et al. Rosuvastatin in older patients with systolic heart failure. N Engl J Med. Nov 2007; 357(22):2248-2261.
  19. Ky B, French B, McCloskey K, et al. High-sensitivity ST2 for prediction of adverse outcomes in chronic heart failure. Circ Heart Fail. Mar 2011; 4(2):180-187.
  20. Marcus GM, Gerber IL, McKeown BH, et al. Association between phonocardiographic third and fourth heart sounds and objective measures of left ventricular function. JAMA. May 2005; 293(18):2238-2244.
  21. McMurray JJ, Adamopoulos S, Anker SD, et al. ESC guidelines for the diagnosis and treatment of acute and chronic heart failure 2012: The Task Force for the Diagnosis and Treatment of Acute and Chronic Heart Failure 2012 of the European Society of Cardiology. Developed in collaboration with the Heart Failure Association (HFA) of the ESC. Eur J Heart Fail. Aug 2012; 14(8):803-869.
  22. Mueller T, Dieplinger B. The Presage ((R)) ST2 Assay: analytical considerations and clinical applications for a high-sensitivity assay for measurement of soluble ST2. Expert Rev Mol Diagn. Jan 2013; 13(1):13-30.
  23. O'Connor CM, Whellan DJ, Lee KL, et al. Efficacy and safety of exercise training in patients with chronic heart failure: HF-ACTION randomized controlled trial. JAMA. Apr 2009; 301(14):1439-1450.
  24. Pascual-Figal DA, Garrido IP, Blanco R, et al. Soluble ST2 is a marker for acute cardiac allograft rejection. Ann Thorac Surg. Dec 2011; 92(6):2118-2124.
  25. Phillips M, Boehmer JP, Cataneo RN, et al. Prediction of heart transplant rejection with a breath test for markers of oxidative stress. American Journal Cardiology 2004b; 94(12): 1593-1594.
  26. Phillips, M., Boehmer, J.P., Cataneo, R.N., et al. Heart allograft rejection:  Detection with breath alkanes in low levels (the HARDBALL study). J Heart Lung Transplant 2004; 23(6): 701-708.
  27. Roger VL, Go AS, Lloyd-Jones DM, et al. Heart disease and stroke statistics--2011 update: a report from the American Heart Association. Circulation. Feb 2011; 123(4):e18-e209.
  28. Rohde LE, Beck-da-Silva L, Goldraich L, et al. Reliability and prognostic value of traditional signs and symptoms in outpatients with congestive heart failure. Can J Cardiol. May 2004; 20(7):697-702.
  29. Savarese G, Trimarco B, Dellegrottaglie S, et al. Natriuretic peptide-guided therapy in chronic heart failure: a meta-analysis of 2,686 patients in 12 randomized trials. PLoS One. 2013; 8(3):e58287.
  30. Shah RV, Januzzi JL, Jr. ST2: a novel remodeling biomarker in acute and chronic heart failure. Curr Heart Fail Rep. Mar 2010; 7(1):9-14.
  31. Stevenson LW, Perloff JK. The limited reliability of physical signs for estimating hemodynamics in chronic heart failure. JAMA. Feb 1989; 261(6):884-888.
  32. Troughton RW, Frampton CM, Brunner-La Rocca HP, et al. Effect of B-type natriuretic peptide-guided treatment of chronic heart failure on total mortality and hospitalization: an individual patient meta-analysis. Eur Heart J. Jun 2014; 35(23):1559-1567.
  33. Weinberg EO, Shimpo M, De Keulenaer GW, et al. Expression and regulation of ST2, an interleukin-1 receptor family member, in cardiomyocytes and myocardial infarction. Circulation. Dec 2002; 106(23):2961-2966.
  34. Xu D, Chan WL, Leung BP, et al. Selective expression of a stable cell surface molecule on type II but not type 1 helper T cells. J Exp Med. Mar 1998; 187(5):787-794.
  35. Yancy CW, Jessup M, Bozkurt B, et al. 2013 ACCF/AHA guideline for the management of heart failure: a report of the American College of Cardiology Foundation/American Heart Association Task Force on Practice Guidelines. J Am Coll Cardiol. Oct 2013; 62(16):e147-239.
  36. Yancy CW, Jessup M, Bozkurt B, et al. 2017 ACC/AHA/HFSA Focused Update of the 2013 ACCF/AHA Guideline for the Management of Heart Failure: A Report of the American College of Cardiology/American Heart Association Task Force on Clinical Practice Guidelines and the Heart Failure Society of America. J Card Fail. Aug 2017; 23(8): 628-651.
  37. Zhang R, Zhang Y, An T, et al. Prognostic value of sST2 and galectin-3 for death relative to renal function in patients hospitalized for heart failure. Biomark Med. 2015; 9(5):433-441.

POLICY HISTORY:

Medical Policy Panel, January 2015

Medical Policy Group, March 2015 (3): Adopting as new medical policy

Medical Policy Administration Committee, March 2015

Available for comment March 3 through April 17, 2015

Medical Policy Group, June 2016 (3): Updates to Title, Description, Key Points, Key Words & References; clarified policy statement to be able to add to list of investigational indications – no change in policy intents – remains investigational

Medical Policy Panel, May 2017

Medical Policy Group, May 2017 (3): 2017 Updates to Description, Key Points, & References. No change in policy statement.

Medical Policy Panel, May 2018

Medical Policy Group, May 2018 (4): Updates to Description and Key Points. No change to policy statement.

Medical Policy Group, July 2018: Quarterly coding update. Added new CPT code 0055U to Current Coding. Added Key Words myTAIHEART, TAI

Medical Policy Panel, May 2019

Medical Policy Group, May 2019 (9): 2019 Updates to Description and Key Points. No change to policy statement.

Medical Policy Group, March 2020 (9): Removed CPT code 0055U from policy. Added CPT codes 0085T and 86849 to current coding section. Removed key words: myTAIHEART, TAI. Added key word: Heartsbreath test. Added policy statement regarding volatile organic compounds to this policy (moved from MP 212). No change to coverage intent, testing remains investigational. Changed name of this policy to: Laboratory Tests for Chronic Heart Failure and Heart Transplant Rejection.

Medical Policy Administration Committee, April 2020

Medical Policy Panel, May 2020

Medical Policy Group, May 2020 (9): 2020 Updates to Description, Key Points, and References related to ST2. No change to policy statement.


This medical policy is not an authorization, certification, explanation of benefits, or a contract. Eligibility and benefits are determined on a case-by-case basis according to the terms of the member’s plan in effect as of the date services are rendered. All medical policies are based on (i) research of current medical literature and (ii) review of common medical practices in the treatment and diagnosis of disease as of the date hereof. Physicians and other providers are solely responsible for all aspects of medical care and treatment, including the type, quality, and levels of care and treatment.

This policy is intended to be used for adjudication of claims (including pre-admission certification, pre-determinations, and pre-procedure review) in Blue Cross and Blue Shield’s administration of plan contracts.

The plan does not approve or deny procedures, services, testing, or equipment for our members. Our decisions concern coverage only. The decision of whether or not to have a certain test, treatment or procedure is one made between the physician and his/her patient. The plan administers benefits based on the member’s contract and corporate medical policies. Physicians should always exercise their best medical judgment in providing the care they feel is most appropriate for their patients. Needed care should not be delayed or refused because of a coverage determination.

As a general rule, benefits are payable under health plans only in cases of medical necessity and only if services or supplies are not investigational, provided the customer group contracts have such coverage.

The following Association Technology Evaluation Criteria must be met for a service/supply to be considered for coverage:

1. The technology must have final approval from the appropriate government regulatory bodies;

2. The scientific evidence must permit conclusions concerning the effect of the technology on health outcomes;

3. The technology must improve the net health outcome;

4. The technology must be as beneficial as any established alternatives;

5. The improvement must be attainable outside the investigational setting.

Medical Necessity means that health care services (e.g., procedures, treatments, supplies, devices, equipment, facilities or drugs) that a physician, exercising prudent clinical judgment, would provide to a patient for the purpose of preventing, evaluating, diagnosing or treating an illness, injury or disease or its symptoms, and that are:

1. In accordance with generally accepted standards of medical practice; and

2. Clinically appropriate in terms of type, frequency, extent, site and duration and considered effective for the patient’s illness, injury or disease; and

3. Not primarily for the convenience of the patient, physician or other health care provider; and

4. Not more costly than an alternative service or sequence of services at least as likely to produce equivalent therapeutic or diagnostic results as to the diagnosis or treatment of that patient’s illness, injury or disease.