DESCRIPTION
After heart transplantation, individuals are monitored for cellular rejection by endomyocardial biopsies that are typically obtained from the right ventricle on a weekly basis for the first month, monthly for the following 6 months, and yearly thereafter. Endomyocardial biopsy is invasive and carries a risk of adverse effects. Therefore, noninvasive methods of detecting cellular rejection are being explored.
Two techniques have become commercially available for the detection of heart transplant rejection. One technique is a breath test known as a breath methylated alkane contour (BMAC) test (e.g., the Heartsbreath test). The other technique is a peripheral blood test (e.g., AlloMap™).
In heart transplant recipients, oxidative stress appears to accompany allograft rejection that degrades membrane polyunsaturated fatty acids and evolving alkanes and methylalkanes that are in turn excreted as volatile organic compounds in breath. The Heartsbreath test is an example of a commercially available noninvasive test that measures breath markers of oxidative stress that has been developed to assist in the detection of heart transplant rejection. The Heartsbreath test analyzes the BMAC, which is derived from the abundance of C4-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 multi-gene test panel, which then can be evaluated using polymerase chain reaction (PCR) techniques. AlloMap™ is an example of 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 algorithm produces a single score that considers the contribution of each gene in the panel.
POLICY
The measurement of volatile organic compounds by breath test to assist in the detection of heart transplant rejection is considered investigational.
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.
ADDITIONAL INFORMATION
Breath Test (e.g., Heartsbreath test)
The Heartsbreath test received approval from the U.S. Food and Drug Administration (FDA) through a humanitarian device exemption in February 2004. The Heartsbreath test is indicated for use as an aid in the diagnosis of grade 3 heart transplant rejection in individuals 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 individuals who have had endomyocardial biopsy within the previous month.
The FDA approval of the Heartsbreath test was based on the results of the study sponsored by the National Heart, Lung, and Blood Institute entitled Heart Allograft Rejection: Detection with Breath Alkanes in Low Levels (the HARDBALL study). The HARDBALL study was a 3-year multicenter study of 1,061 breath samples in 539 heart transplant patients. Prior to scheduled endomyocardial biopsy, the individual’s breath was analyzed by gas chromatography and mass spectroscopy for volatile organic compounds. The amount of C4-C20 alkanes and monomethylalkanes was used to derive the marker for rejection known as the BMAC. The BMAC results were compared with subsequent biopsy results as interpreted by two readers using the International Society for Heart and Lung Transplantation (ISHLT) biopsy grading system as the "gold standard" for rejection.
The authors of the HARDBALL study reported that the abundance of breath markers of oxidative stress were significantly greater in grade 0, 1, or 2 rejection than in healthy normal persons. Whereas in grade 3 rejection, the abundance of breath markers of oxidative stress was reduced most likely due to accelerated catabolism of alkanes and methylalkanes that make up the BMAC. The authors also reported finding that in identifying grade 3 rejection, the negative predictive value of the breath test (97.2%) was similar to endomyocardial biopsy (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 (5.6%) in assessing grade 3 rejection than biopsy (specificity 97%, positive predictive value 45.2%). In addition, the breath test was not evaluated in grade 4 rejection.
How this test can be integrated into the management of the individual, either to select or deselect individuals for endomyocardial biopsy, or potentially replace endomyocardial biopsy altogether is not known. Therefore, the impact of this test on management decisions and health outcomes is unknown.
Peripheral Blood Test (e.g., AlloMap™)
Investigators from the CARGO (Cardiac Allograft Rejection Gene Expression Observation Study) study reported on gene expression profiling of peripheral blood mononuclear cells to identify individuals with moderate/severe cardiac allograft rejection. A set of 11 genes was selected and validated using well-described and robust methods. Primary validation was conducted using samples from 63 individuals independent from discovery phases of the study and enriched for biopsy-proven evidence of rejection. A prospectively defined test cutoff value of 20 resulted in correct classification of 84% of 63 individuals with moderate/severe rejection but just 38% of patients without rejection. Of note, in the “training set” used in the study, these rates were 80% and 59%, respectively. The authors evaluated the 11-gene expression profile on 281 samples collected at 1 year or more from 166 individuals’ representative of the expected distribution of rejection in the target population (and not involved in discovery or validation phases of the study). When a test cutoff of 30 was used, the negative predictive value (no moderate/severe rejection) was 99.6%; however, only 3.2% of specimens had grade 3 or higher rejection. In this population, grade 1B scores were found to be significantly higher than grade 0, grade 1A, and grade 2 scores; but similar to grade 3. The sensitivity and specificity for determining quiescent versus early stages of rejection was not addressed.
Additional clinical experience is needed to confirm and extend the current results, and to address several important questions such as the best cutoff value and when to test. In addition, the impact of this test on management decisions and health outcomes is unknown. Some of these issues will be addressed by an ongoing randomized clinical trial IMAGE (Invasive Monitoring Attenuation through Gene Expression) comparing AlloMap molecular testing with traditional biopsy-based surveillance for heart transplant rejection. The IMAGE trial began recruiting subjects in January 2005.
SOURCES
BlueCross BlueShield Association. Medical Policy Reference Manual. (11:2008). Laboratory tests for heart transplant rejection (2.01.68). Retrieved August 4, 2009 from BlueWeb. (12 articles and/or guidelines reviewed)
Complete Guide to Medicare Coverage Issues [Computer software]. (2009, April). Heartsbreath test for heart transplant rejection (NCD 260.10, p. 2-206). The Ingenix Complete Guide to Medicare Coverage Issues.
Deng, M. C., Eisen, H. J., Mehra, M. R., Billingham, M., Marboe, C. C., Berry, G., et al. (2006). Noninvasive discrimination of rejection in cardiac allograft recipients using gene expression profiling. American Journal of Transplantation, 6 (1), 150-160.
ECRI Institute. Health Technology Information Service. Emerging Technology (TARGET) Evidence Report. (2009, April). Gene expression profiling to monitor acute heart transplant rejection. Retrieved August 4, 2009 from ECRI Institute. (21 articles and/or guidelines reviewed)
Fang, K. C. (2007). Clinical utilities of peripheral blood gene expression profiling in the management of cardiac transplant patients. Journal of Immunotoxicology, 4 (3), 209-217.
Phillips, M., Boehmer, J. P., Cataneo, R. N., Cheema, T., Eisen, H. J., Fallon, J. T., et al. (2004). Heart allograft rejection: Detection with breath alkanes in low levels (the HARDBALL study). The Journal of Heart and Lung Transplant, 23 (6), 701-708. (Level 1 Evidence - Industry sponsored)
Phillips, M., Boehmer, J. P., Cataneo, R. N., Cheema, T., Eisen, H. J., Fallon, J. T., et al. (2004). Prediction of heart transplant rejection with a breath test for markers of oxidative stress. The American Journal of Cardiology, 94 (12), 1593-1594. (Level 1 Evidence - Industry sponsored)
U. S. Food and Drug Administration. (2004, February). Center for Devices and Radiological Health. Device Approvals and Clearances. Medical Devices. Heartsbreath - H030004. Retrieved August 4, 2009 from http://www.accessdata.fda.gov/cdrh_docs/pdf3/H030004b.pdf.
U. S. Food and Drug Administration. (2008, August). Center for Devices and Radiological Health. 510(k) Premarket Notification Database. AlloMap® Molecular Expression Testing - K073482. Retrieved August 4, 2009 from http://www.accessdata.fda.gov/cdrh_docs/reviews/K073482.pdf.
ORIGINAL EFFECTIVE DATE: 12/8/2007
MOST RECENT REVIEW DATE: 9/10/2009
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