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Several commercially available laboratory tests assess heart transplant rejection, including the HeartsBreath™ test, that measures breath markers of oxidative stress, and the AlloMap™ test, which uses gene expression profiling (GEP) to create a score based on the expression of a variety of immunomodulatory genes. These tests are proposed as an alternative to, or adjunct to, endomyocardial biopsy, which is invasive, and its interpretation may have high inter-observer variability.
Heart Transplant Rejection
The majority of cardiac transplant recipients experience at least one episode of rejection in the first year after transplantation. 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 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 eg, on a quarterly or semiannual basis. This practice, although common, has not been demonstrated to improve transplant outcomes. Some centers no longer routinely perform endomyocardial biopsies after 1 year in patients who are clinically stable.
While endomyocardial biopsy 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, endomyocardial biopsy is considered a flawed criterion standard by many. Therefore, noninvasive methods of detecting cellular rejection have been explored. It is hoped that non-invasive 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.
Noninvasive Heart Transplant Rejection Tests
The Heartsbreath™ test (Menssana Research, Newark, NJ), 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, which is derived from the abundance of C4 to C20 alkanes and monomethylalkanes and has been identified as a marker to detect grade 3 (significant) heart transplant rejection.
Another approach has focused on patterns of gene expression of immunomodulatory cells, as detected in the peripheral blood. For example, microarray technology permits the analysis of the gene expression of thousands of genes, including those with functions that are known or unknown. Patterns of gene expression can then be correlated with known clinical conditions, permitting a selection of a finite number of genes to compose a custom multigene test panel, which then can be evaluated using polymerase chain reaction (PCR) techniques. AlloMap™ (CareDx, Brisbane, CA; formerly XDx Inc.) is a commercially available molecular expression test that has been developed to detect acute heart transplant rejection or the development of graft dysfunction. The test involves PCR expression measurement of a panel of genes derived from peripheral blood cells and applies an algorithm to the results. The proprietary algorithm produces a single score that considers the contribution of each gene in the panel. The score ranges from 0 to 40. The XDx website states that a lower score indicates a lower risk of graft rejection; the website does not cite a specific cutoff for a positive test. All AlloMap testing is performed at the CareDx reference laboratory in Brisbane, CA.
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.
In February 2004, the Heartsbreath test (Menssana Research) received approval from the U.S. Food and Drug Administration (FDA) through a Humanitarian Device Exemption. The Heartsbreath test is indicated 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.
In August 2008, AlloMap Molecular Expression Testing (CareDx, Brisbane, CA; formerly XDx Inc.) was cleared for marketing by the FDA through the 510(k) process. The FDA determined that this device was substantially equivalent to existing devices, in conjunction with clinical assessment, for aiding in the identification of heart transplant recipients with stable allograft function who have a low probability of moderate/severe transplant rejection. It is intended for patients at least 15 years old who are at least 2 months post-transplant.
Also, see the Heart Transplant medical policy.
POLICYThe measurement of volatile organic compounds with the Heartsbreath test to assist in the detection of grade 3 heart transplant rejection is considered investigational.
The use of peripheral blood genetic profiling tests in the management of patients after heart transplantation, including, but not limited to, the detection of acute heart transplant rejection or heart transplant graft dysfunction is considered investigational.
POLICY EXCEPTIONSFederal Employee Program (FEP) may dictate that all FDA-approved devices, drugs or biologics may not be considered investigational and thus these devices may be assessed only on the basis of their medical necessity.
POLICY GUIDELINESThe U.S. Food and Drug Administration (FDA) has indicated that the Heartsbreath test is only 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 and who have had endomyocardial biopsy within the previous month.
Investigative is defined as the use of any treatment procedure, facility, equipment, drug, device, or supply not yet recognized as a generally accepted standard of good medical practice for the treatment of the condition being treated and; therefore, is not considered medically necessary. For the definition of Investigative, “generally accepted standards of medical practice” means standards that are based on credible scientific evidence published in peer-reviewed medical literature generally recognized by the relevant medical community, and physician specialty society recommendations, and the views of medical practitioners practicing in relevant clinical areas and any other relevant factors. In order for equipment, devices, drugs or supplies [i.e, technologies], to be considered not investigative, the technology must have final approval from the appropriate governmental bodies, and scientific evidence must permit conclusions concerning the effect of the technology on health outcomes, and the technology must improve the net health outcome, and the technology must be as beneficial as any established alternative and the improvement must be attainable outside the testing/investigational setting.
The coverage guidelines outlined in the Medical Policy Manual should not be used in lieu of the Member's specific benefit plan language.
POLICY HISTORY3/31/2005: Approved by Medical Policy Advisory Committee (MPAC)
6/6/2005: Code Reference section completed
2/20/2006: Peripheral blood gene expression section added
12/22/2008: Policy reviewed, no changes
04/20/2010: Policy description and guidelines updated regarding noninvasive methods of detecting cellular rejection; policy statement unchanged. FEP verbiage added to the Policy Exceptions section.
12/28/2010: Policy reviewed; no changes.
05/09/2012: Policy reviewed; no changes.
08/07/2013: Policy reviewed; no changes.
06/09/2014: Policy reviewed; description updated. Policy statement revised for clarity to state that the use of peripheral blood genetic profiling tests in the management of patients after heart transplantation, including, but not limited to, the detection of acute heart transplant rejection or heart transplant graft dysfunction is considered investigational. It previously stated: The evaluation of genetic expression in the peripheral blood, including, but not limited to, the detection of acute heart transplant rejection or graft dysfunction is considered investigational.
07/31/2015: Code Reference section updated for ICD-10.
09/10/2015: Policy description updated to add section headings. Policy statements unchanged. Investigative definition updated in the policy guidelines section.
SOURCE(S)Blue Cross Blue Shield Association policy # 2.01.68
CODE REFERENCEThis may not be a comprehensive list of procedure codes applicable to this policy.