Medical Policies - Surgery


Non-Invasive Tests for Heart Transplant Rejection

Number:SUR703.054

Effective Date:06-15-2018

Coverage:

*CAREFULLY CHECK STATE REGULATIONS AND/OR THE MEMBER CONTRACT*

The measurement of volatile organic compounds (i.e., Heartsbreath®) to assist in the detection of moderate grade 2R (formerly grade 3) heart transplant rejection is considered experimental, investigational and/or unproven.

Other laboratory tests for heart transplant rejection, including but not limited to measurements of brain natriuretic peptide, troponin, and/or soluble inflammatory cytokines are considered experimental, investigational and/or unproven.

NOTE 1: Refer to Medical Policy MED207.147 – Immune Cellular Function Assay to Monitor and Predict Immune Function for explanation of coverage for use of an immune cell function assay to monitor and predict immune function after solid organ transplantation.

Description:

Several commercially available, non-invasive laboratory tests, assess heart transplant rejection, including the Heartsbreath™ test, which measures breath markers of oxidative stress. These tests are proposed as an alternative to, or adjunct to, endomyocardial biopsy (EMB), which is invasive and its interpretation may have high interobserver variability.

Background

Most cardiac transplant recipients experience at least a single episode of rejection in the first year after transplantation. In 2005, the International Society for Heart and Lung Transplantation (ISHLT) modified its grading scheme for categorizing cardiac allograft rejection. (1) Revised (R) categories are listed in Table 1.

Table 1. Revised Grading Schema for Cardiac Allograft Rejection

New Grade

Definition

Old Grade

0R

No rejection

Not Applicable

1R

Mild rejection

1A, 1B and 2

2R

Moderate rejection

3A

3R

Severe rejection

3B and 4

Surveillance

Acute cellular rejection is most likely to occur in the first 6 months, with a significant decline in the incidence of rejection after this time. Although immunosuppressants are required on a life-long basis, dosing is adjusted based on graft function and the grade of acute cellular rejection determined by histopathology. Endomyocardial biopsies (EMBs) are typically taken from the right ventricle via the jugular vein periodically during the first 6- to 12-months post-transplant. The interval between biopsies varies among clinical centers. A typical schedule is weekly for the first month, once or twice monthly for the following 6-months, and several times (monthly to quarterly) between 6-months and 1 year post-transplant. Surveillance biopsies may also be performed after the first postoperative year (e.g., on a quarterly or semiannual basis). This practice, although common, has not been demonstrated to improve transplant outcomes. Some centers no longer routinely perform EMBs after 1 year in patients who are clinically stable.

While EMB is the criterion standard for assessing heart transplant rejection, it is limited by a high degree of interobserver variability in grading of results and potential morbidity that can occur with the biopsy procedure. Also, the severity of rejection may not always coincide with the grading of the rejection by biopsy. Finally, biopsy cannot be used to identify patients at risk of rejection, limiting the ability to initiate therapy to interrupt the development of rejection. For these reasons, EMB is considered a flawed criterion standard by many. Therefore, noninvasive methods of detecting cellular rejection have been explored. It is hoped that noninvasive tests will assist in determining appropriate patient management and avoid overuse or underuse of treatment with steroids and other immunosuppressants that can occur with false-negative and false-positive biopsy reports. Two techniques have become commercially available for the detection of heart transplant rejection.

Non-Invasive Heart Transplant Rejection Tests

Heartsbreath™ Test

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 methyl alkanes 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 monomethyl alkanes and has been identified as a marker to detect grade 3 (clinically significant) heart transplant rejection.

Other Laboratory Tests for 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 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. (2, 3)

Regulatory Status

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 (HDE) 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 EMB within the previous month.

Rationale:

The policy was originally created in 2006, moved to this policy in October 2016, in which the technology has been reviewed regularly with literature searches of the MedLine database. The most recent literature review was performed through January 22, 2018. The following is a summary of the key literature to date.

Measurement of Volatile Organic Compounds

Heartsbreath™ Test

Approval of the Heartsbreath™ test by the U.S. Food and Drug Administration (FDA) was based on the results of the Heart Allograft Rejection: Detection with Breath Alkanes in Low Levels (HARDBALL) study sponsored by the National Heart, Lung, and Blood Institute. (4) The HARDBALL study was a 3-year, multicenter study of 1061 breath samples in 539 heart transplant patients. Before scheduled endomyocardial biopsy (EMB), patient breath was analyzed by gas chromatography and mass spectroscopy for volatile organic compounds. The amount of C4 to C20 alkanes and monomethyl alkanes was used to derive the marker for rejection, known as the breath methylated alkane contour (BMAC). The BMAC results were compared with subsequent biopsy results, as interpreted by 2 readers using the International Society for Heart and Lung Transplantation (ISHLT) biopsy grading system as the criterion standard for rejection. (1)

The authors of the HARDBALL study reported that the abundance of breath markers that measured oxidative stress were found to be significantly greater in grades 0, 1, or 2 rejection than in healthy normal persons. In contrast, in grade 3 rejection, the abundance of breath markers that measure oxidative stress were found to be reduced -- most likely due to accelerated catabolism of alkanes and methyl alkanes that make up the BMAC. The authors also reported finding that in identifying grade 3 rejection, the negative predictive value (NPV) of the breath test (97.2%) was similar to EMB (96.7%) and that the breath test could potentially reduce the total number of biopsies performed to assess for rejection in patients at low-risk for grade 3 rejection. The sensitivity of the breath test was 78.6% versus 42.4% with biopsy. However, the breath test had lower specificity (62.4%) and a lower positive predictive value (PPV; 5.6%) in assessing grade 3 rejection than biopsy (specificity, 97%; PPV=45.2%). In addition, the breath test was not evaluated in grade 4 rejection.

Section Summary: Measurement of Volatile Organic Compounds (Heartsbreath™ Test)

Findings from the HARDBALL study were published in 2004. No subsequent studies evaluating the use of the Heartsbreath™ test to assess for graft rejection were identified in literature updates.

Other Laboratory Tests for Heart Transplant Rejection

A MedLine search identified no published literature in which other laboratory tests for heart transplant rejection were performed; therefore, it is not possible to reach conclusions concerning the safety or efficacy of heart rejection laboratory testing and is considered experimental, investigational and/or unproven.

Ongoing and Unpublished Clinical Trials

A search of the online registry ClinicalTrials.gov was conducted in October 2017 and revealed no ongoing or completed clinical trials that would affect the coverage of this medical policy.

Practice Guidelines and Position Statements

International Society for Heart and Lung Transplantation (ISHLT)

In 2010, the ISHLT issued guidelines for the care of heart transplant recipients. (5) The guidelines included the following recommendations (see Table 2).

Table 2. International Society for Heart and Lung Transplantation Recommendations

Recommendation

COR

LOE

“The standard of care for adult HT recipients is to perform periodic EMB during the first 6 to 12 post-operative months for surveillance of HT rejection.”

IIa

C

“After the first post-operative year, EMB surveillance for an extended period of time (e.g., every 4–6 months) is recommended in HT patients at higher risk for late acute rejection….”

IIa

C

Table Key:

COR: class of recommendation;

LOE: level of evidence;

EMB: endomyocardial biopsy;

HT: heart transplant.

Summary of Evidence

For individuals who have a heart transplant who receive measurement of volatile organic compounds to assess allograft rejection, the evidence includes a diagnostic accuracy study. Relevant outcomes are overall survival, test accuracy and 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. A search of scientific literature yielded no results and non-invasive testing to detect heart transplant rejection remains experimental, investigational and/or unproven.

Contract:

Each benefit plan, summary plan description or contract defines which services are covered, which services are excluded, and which services are subject to dollar caps or other limitations, conditions or exclusions. Members and their providers have the responsibility for consulting the member's benefit plan, summary plan description or contract to determine if there are any exclusions or other benefit limitations applicable to this service or supply. If there is a discrepancy between a Medical Policy and a member's benefit plan, summary plan description or contract, the benefit plan, summary plan description or contract will govern.

Coding:

CPT Code 0085T is the appropriate code for Heartsbreath® test.

CODING:

Disclaimer for coding information on Medical Policies

Procedure and diagnosis codes on Medical Policy documents are included only as a general reference tool for each policy. They may not be all-inclusive.

The presence or absence of procedure, service, supply, device or diagnosis codes in a Medical Policy document has no relevance for determination of benefit coverage for members or reimbursement for providers. Only the written coverage position in a medical policy should be used for such determinations.

Benefit coverage determinations based on written Medical Policy coverage positions must include review of the member’s benefit contract or Summary Plan Description (SPD) for defined coverage vs. non-coverage, benefit exclusions, and benefit limitations such as dollar or duration caps.

CPT/HCPCS/ICD-9/ICD-10 Codes

The following codes may be applicable to this Medical policy and may not be all inclusive.

CPT Codes

86849, 0085T

HCPCS Codes

None

ICD-9 Diagnosis Codes

Refer to the ICD-9-CM manual

ICD-9 Procedure Codes

Refer to the ICD-9-CM manual

ICD-10 Diagnosis Codes

Refer to the ICD-10-CM manual

ICD-10 Procedure Codes

Refer to the ICD-10-CM manual


Medicare Coverage:

The information contained in this section is for informational purposes only. HCSC makes no representation as to the accuracy of this information. It is not to be used for claims adjudication for HCSC Plans.

The Centers for Medicare and Medicaid Services (CMS) does have a national Medicare coverage position.

A national coverage position for Medicare may have been changed since this medical policy document was written. See Medicare's National Coverage at <http://www.cms.hhs.gov>.

References:

1. Stewart S, Winters GL, Fishbein MC, et al. Revision of the 1990 working formulation for the standardization of nomenclature in the diagnosis of heart rejection. J Heart Lung Transplant. Nov 2005; 24(11):1710-20. PMID 16297770

2. Duong Van Huyen JP, Tible M, Gay A, et al. MicroRNAs as non-invasive biomarkers of heart transplant rejection. Eur Heart J. Dec 1 2014; 35(45):3194-202. PMID 25176944

3. Patel PC, Hill DA, Ayers CR, et al. High-sensitivity cardiac troponin I assay to screen for acute rejection in patients with heart transplant. Circ Heart Fail. May 2014; 7(3):463-9. PMID 24733367

4. Phillips M, Boehmr JP, Cataneo RN, et al. Heart allograft rejection: detection with breath alkanes in low levels (the HARDBALL study). J Heart Lung Transplant. Jun 2004; 23(6):701-8. PMID 15366430

5. Costanzo MR, Dipchand A, Starlin R, et al. The International Society of Heart and Lung Transplantation guidelines for the care of heart transplant recipients. J Heart Lung Transplant. Aug 2010; 29(8):914-56. PMID 20643330

6. Laboratory Tests for Heart Transplant Rejection. Chicago, Illinois: Blue Cross Blue Shield Association Medical Policy Reference Manual (2017 October) Medicine 2.01.68.

Policy History:

Date Reason
6/15/2018 Document updated with literature review through January 22, 2018. The coverage statement was changed for Heartsbreath™ to: “The measurement of volatile organic compounds (i.e., Heartsbreath®) to assist in the detection of moderate grade 2R (formerly grade 3) heart transplant rejection is considered experimental, investigational and/or unproven.” No references added or removed.
8/15/2017 Reviewed. No changes.
10/1/2016 New medical document originating from SUR703.028, Laboratory Tests for Heart Transplant Rejection. The measurement of volatile organic compounds (such as the Heartsbreath® to assist in the detection of Grade 3 heart transplant rejection is considered experimental, investigational and/or unproven. Other non-invasive laboratory tests for heart transplant rejection, including but not limited to measurements of brain natriuretic peptide, troponin, and/or soluble inflammatory cytokines are considered experimental, investigational and/or unproven.

Archived Document(s):

Title:Effective Date:End Date:
Non-Invasive Tests for Heart Transplant Rejection08-15-201706-14-2018
Non-Invasive Tests for Heart Transplant Rejection10-01-201608-14-2017
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