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Medical Policy: 02.04.21
Original Effective Date: February 2009
Reviewed: May 2012
Revised:
Benefit Application
Benefit determinations are based on the applicable contract language in effect at the time the
services were rendered. Exclusions, limitations or exceptions may apply. Benefits may vary
based on contract, and individual member benefits must be verified. Wellmark determines medical
necessity only if the benefit exists and no contract exclusions are applicable. This medical
policy may not apply to FEP. Benefits are determined by the Federal Employee Program.
This Medical Policy document describes the status of medical technology at the time the document
was developed. Since that time, new technology may have emerged or new medical literature may
have been published. This Medical Policy will be reviewed regularly and be updated as scientific
and medical literature becomes available.
Description:
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 on a weekly basis 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 on a yearly basis following stabilization.
While endomyocardial biopsy is the gold standard for assessing heart transplant rejection, biopsy may be limited by the high degree of interobserver variability in grading of results and the significant morbidity and even mortality that can occur with the biopsy procedure. Also, the severity 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 considered a flawed gold 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 results. Two techniques have become commercially available for the detection of heart transplant rejection.
The Heartsbreath test (Mensanna Research, Inc.) is a noninvasive test that measures breath markers of oxidative stress that has been developed to assist in the detection of heart transplant rejection. 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 analyzes the breath methylated alkane contour (BMAC), which is derived from the abundance of C4-C20 alkanes and monomethylalkanes and has been identified as a marker to detect grade 3 heart transplant rejection.
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 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.
Another approach has focused on patterns of gene expression of immunomodulatory cells, as detected in 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 can then be evaluated using polymerase chain reaction (PCR) techniques. AlloMap™ (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 between 0 and 40 that considers the contribution of each gene in the panel. 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 XDx reference laboratory in Brisbane, CA.
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Prior Approval:
Not applicable
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Policy:
The measurement of breath markers of oxidative stress with the Heartsbreath test to assist in the detection of grade 3 heart transplant rejection is considered investigational because the evidence is insufficient to permit conclusions concerning the effect of the test on health outcomes.
The evaluation of genetic expression in the peripheral blood, including but not limited to, the detection of acute heart transplant rejection of graft dysfunction is considered investigational because the evidence is insufficient to permit conclusion concerning the effect of the test on health outcomes.
Rationale:
Approval of the Heartsbreath test by the 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. The HARDBALL study was a 3-year, multicenter study of 1,061 breath samples in 539 heart transplant patients. Prior to scheduled endomyocardial biopsy, patient 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 markers for oxidative stress were 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 (NPV) 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 (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.
Findings from the HARDBALL study were published in 2004. No subsequent studies that evaluate use of the Heartsbreath test to assess for graft rejection have been identified.
Patterns of gene expression for development of the AlloMap test were studied in the Cardiac Allograft Rejection Gene Expression Observation (CARGO) study which included 8 U.S. cardiac transplant centers enrolling 650 cardiac transplant recipients. The study included discovery and validation phases. Post-CARGO clinical observations have been published. A multicenter work group identified a number of factors that can affect AlloMap scores including the time post-transplant, corticosteroid dosing, and transplant vasculopathy. Scores of 34 and greater were considered positive, potentially indicating rejection, whereas scores below that threshold were considered negative, with no evidence of rejection. Analysis of data from a number of centers collected post-CARGO showed that at 1-year or more post-transplantation, an AlloMap threshold of 34 had a PPV of 7.8% for scores of 3A/2R or greater on biopsy and a NPV of 100% for AlloMap scores below 34. These findings were limited due to a very low number of events; only 5 biopsy samples (2.4%) were found to have a grade of 2Ror greater. At 1 year, 28% of the sample showed an elevated AlloMap score (>34) even though there was absence of evidence of rejection on biopsy. The significance of chronically elevated AlloMap scores in the absence of clinical manifestation of graft dysfunction and the actual impact on the number of biopsies performed is currently unknown.
Another post-CARGO publication was a retrospective statistical analysis of data from 76 heart transplant recipients who underwent AlloMap testing at a single institution. In multivariant analysis statistically significant predictors of a high gene expression profiling score were a higher serum creatinine level, a higher corrected QT interval, a lower oxygen saturation level, and a lower platelet count. The authors concluded that the complex relationship between gene expression profiling test results and biologic parameters warrants further study.
In 2010, results of the Invasive Monitoring Attenuation through Gene Expression (IMAGE) study were published. IMAGE was an industry-sponsored non-inferiority randomized controlled trial that compared outcomes in 602 patients managed with the AlloMap test (n=297) or routine endomyocardial biopsies (n=305). Blinding was not used. The study included adult patients from 13 centers who underwent cardiac transplantation between 1 and 5 years previously, were clinically stable, and had a left ventricular ejection fraction (LVEF) of at least 45%. In order to increase enrollment, the study protocol was later amended to include patients who had undergone transplantation between 6 months and 1 year earlier; this sub-group ultimately comprised only 15% of the sample (n=87). Each transplant center used its own protocol for determining the intervals for routine testing. At all sites, patients in both groups underwent clinical and echocardiographic assessments in addition to the assigned surveillance strategy. According to the study protocol, patients underwent biopsy if they had signs or symptoms of rejection or allograft dysfunction at clinic visits (or between visits) or if the echocardiogram showed a LVEF decrease of at least 25% compared to the initial visit. Additionally, patients in the AlloMap group underwent biopsy if their test score was above a specified threshold; however, if they had two elevated scores with no evidence of rejection found on two previous biopsies, no additional biopsies were required. The AlloMap test score varies from 0 to 40, with higher scores indicating a higher risk of transplant rejection. The investigators initially used 30 as the cutoff for a positive test score; the protocol was later amended to use a cutoff of 34 to minimize the number of biopsies needed. Fifteen patients in the AlloMap group and 26 in the biopsy group did not complete the study.
The primary outcome was a composite variable; the first occurrence of 1) rejection with hemodynamic compromise, 2) graft dysfunction due to other causes, 3) death, or 4) retransplantation. The trial was designed to test the noninferiority of gene expression profiling with the AlloMap test compared to endomyocardial biopsies with respect to the primary outcome. Use of the AlloMap test was considered noninferior to the biopsy strategy if the one-sided upper boundary of the 95% confidence interval (CI) for the hazard ratio (HR) comparing the 2 strategies was less than the prespecified margin of 2.054. The margin was derived using the estimate of a 5% event rate in the biopsy group, taken from published observational studies, and allowing for an event rate of up to 10% in the AlloMap group. Secondary outcomes included death, the number of biopsies performed, biopsy-related complications, and quality-of-life using the 12-item short-form (SF-12).
According to the Kaplan-Meier analysis, the 2-year event rate was 14.5% in the AlloMap group and 15.3% in the biopsy group. The corresponding HR was 1.04 (95% CI: 0.67 to 1.68). The upper boundary of the CI of the HR, 1.68, fell within the prespecified noninferiority margin (2.054); thus gene expression profiling was considered noninferior to endomyocardial biopsy. Median follow-up was 19 months. The number of patients remaining within the Kaplan-Meier analysis after 300 days was 221 in the biopsy group and 207 in the AlloMap group; the number remaining after 600 days was 137 and 133, respectively. The secondary outcome, death from all-causes at any time during the study, did not differ significantly between groups. There were a total of 13 deaths (6.3%) in the AlloMap group and 12 (5.5%) in the biopsy group (p=0.82). During the follow-up period, there were 34 treated episodes of graft rejection in the AlloMap group. Only 6 of the 34 (18%) patients presented solely with an elevated AlloMap score. Twenty patients (59%) presented with clinical signs/symptoms and/or graft dysfunction on echocardiogram, and 7 patients had an elevated AlloMap score plus clinical signs/symptoms with or without graft dysfunction on echocardiogram.
A total of 409 biopsies were performed in the AlloMap group and 1,249 in the biopsy group; the biopsy rate differed significantly between groups, (p<0.001). Most of the biopsies in the AlloMap group, 67%, were performed because of elevated risk scores. Another 17% were performed due to clinical or echocardiographic manifestations of graft dysfunction, and 13% were performed as part of routine follow-up after treatment for rejection. There was 1 (0.3%) adverse event associated with biopsy in the AlloMap group and 4 (1.4%) in the biopsy group. In terms of quality of life, the physical-health and mental-health summary scores of the SF-12 were similar in the 2 groups at baseline and did not differ significantly between groups at 2 years.
A limitation of the study was that the threshold for a positive AlloMap test was changed partway through the study; thus, the optimal test cutoff remains unclear. Moreover, the study was not blinded which could have impacted treatment decisions such as whether or not to recommend biopsy, based on clinical findings. In addition, the study did not include a group that only received clinical and echocardiographic assessment, and, therefore, the value of AlloMap testing beyond that of clinical management alone cannot be determined. The uncertain incremental benefit of the AlloMap test is highlighted by the finding that only 6 of the 34 treated episodes of graft rejection detected during follow –up in the AlloMap group were initially identified due solely to an elevated gene-profiling score. Finally, only 15% of the final study sample had undergone transplantation less than 1 year before the study participation; therefore, findings may not be generalizable to the population of patients 6-12 months post-transplant.
An editorial accompanying the publication of the IMAGE study notes that an important implication of the trial is that it calls into question the need for any type of long-term routine screening for early transplant rejection. They mention that some centers have reached the conclusion that clinical outcomes may not be substantially worse when rejection is not detected early and have stopped performing routine endomyocardial biopsies between 1 and 5 years post-transplant.
The California Technology Assessment Forum published an updated literature review on gene expression profiling with AlloMap in 2010. Their review concluded that there was sufficient evidence to conclude that AlloMap testing improves health outcomes for patients who are at least 1 year post-transplantation but not those between 6 and 12 months post-transplantation.
There is evidence on the diagnostic accuracy of the AlloMap test from the CARGO trial and post-CARGO publications. However, the threshold indicating a positive test that seems to be currently accepted, a score of 34, evolved partway through the data collection period of the subsequent noninferiority trial (IMAGE) evaluating the test’s clinical utility. The IMAGE study had several methodologic limitations, e.g., lack of blinding, and the incremental clinical utility of the test compared to clinical examination and echocardiography remains uncertain. In addition, there are insufficient data on the clinical utility of AlloMap in patients who are less than 1 year post-transplant, the group that is at the highest risk of transplant rejection.
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Procedure Codes and Billing Guidelines:
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To report provider services, use appropriate CPT* codes, Modifiers, Alpha Numeric (HCPCS level 2) codes, Revenue codes, and/or ICD-9-CM diagnostic codes.
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0085T Breath test for heart transplant rejection
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Selected References:
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California Technology Assessment Forum. Gene Expression Profiling for the Diagnosis of Heart Transplant Rejection. San Francisco, CA: 2006.
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Deng MC, Eisen HJ, Mehra MR et al. Noninvasive discrimination of rejection in cardiac allograft recipients using gene expression profiling. Am J transplant 2006; 6(1): 150-60.
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Phillips M, Boehmer JP, Cataneo RN et al. Heart allograft rejection: detection with breath alkanes in low levels (the HARDBALL study). J Heart Lung transplant 2004; 23(6): 701-8.
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Yamani MH, Taylor DO, Rodriguez ER et al. Transplant vasculopathy is associated with increased AlloMap gene expression score. J Heart Lung Transplant 2007; 26(4): 403-6.
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Starling RC, Pham M, Valentine H et al; Working Group on Molecular Testing in Cardiac transplantation. Molecular testing in the management of cardiac transplant recipients: initial clinical experience. J Heart Lung Transplant 2006; 25(12):1389-95.
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Pham MX, Deng MC, Kfoury AG et al. Molecular testing for long term rejection surveillance in heart transplant recipients: design of the Invasive Monitoring Attenuation Through Gene Expression (IMAGE) trial. J Heart Lung transplant 2007; 26(8): 808-14.
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ECRI Institute. Gene Expression Profiling to Monitor Acute Heart Transplant Rejection. Plymouth Meeting (PA): ECRI Institute; 2010 May 3. 7 p. [ECRI hotline response]. Also available: http://www.ecri.org
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Pham MX, Teuteberg JJ, Kfoury AG et al. Gene-Expression Profiling for Rejection Surveillance after Cardiac Transplantation. N Engl J Med. 2010 May 20; 362(20):1890-900.
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Jarcho JA. Fear of rejection- monitoring the heart transplant recipient. N Engl J Med 2010; 362(20):1932-3.
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Tice JA. Gene expression profiling for the diagnosis of heart transplant rejection. California Technology Assessment Forum. October 13, 2010. Avaialable online at: http://www.ctaf.org. Last accessed June 2011.
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Costanzo MR, Dipchand A, Starling R et al. The International Society of Heart and Lung Transplantation Guidelines for the care of heart transplant recipients. J Heart Lung Transplant 2010; 29(8):914-56.
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ECRI Institute. Gene expression profiling to monitor heart transplant rejection. Plymouth Meeting: (PA): ECRI Institute Health Technology Assessment Information Service; 2011 December 30. [Emerging Technology Evidence Report]. Also available: http://www.ecri.org.
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Blue Cross and Blue Shield Association Technology Evaluation Center (TEC). Gene expression profiling as a noninvasive method to monitor for cardiac allograft rejection. TEC Assessments 2011; volume 26, tab 8.
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Policy History:
Date Reason Action
June 2011 Annual review Policy renewed
May 2012 Annual review Policy renewed
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