mp-212
print Print Back Back

Laboratory Tests for Heart and Kidney Transplant Rejection

Policy Number: MP-212

Latest Review Date: November 2018

Category: Laboratory                                                             

Policy Grade: B

Description of Procedure or Service:

Several commercially available laboratory tests assess heart transplant rejection, including the Heartsbreath™ test which measures breath markers of oxidative stress, and the AlloMap® test, which uses gene expression profiling. These tests create a score based on the expression of a variety of immunomodulatory genes and are proposed as an alternative or as an adjunct invasive endomyocardial biopsy. Renal transplant rejection may be assessed by the AlloSure® test, which measures the donor-derived cell-free DNA in peripheral blood and is proposed as an alternative or adjunct treatment to invasive renal biopsy to assess kidney transplant rejection.

 

Heart Transplant Rejection

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 modified its grading scheme for categorizing cardiac allograft rejection. The 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

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 six 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 six 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 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 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.

 

Noninvasive Heart Transplant Rejection Tests

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.

 

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® 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 Allomap® 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.

 

Renal Transplant Rejection

Allograft dysfunction is typically asymptomatic and has a broad differential, including graft rejection. Diagnosis and rapid treatment are recommended to preserve graft function and prevent loss of the transplanted organ. For a primary kidney transplant, graft survival at 1 year is 94.7%; at 5 years, graft survival is 78.6%.

 

 

 

Surveillance

Surveillance of kidney transplant function relies on routine monitoring of serum creatinine, urine protein levels, and urinalysis. Allograft dysfunction may also be demonstrated by a drop in urine output or, rarely, as pain over the transplant site. With clinical suspicion of allograft dysfunction, additional noninvasive workup including ultrasonography or radionuclide imaging may be used. A renal biopsy allows a definitive assessment of graft dysfunction and is typically a percutaneous procedure performed with ultrasonography or computed tomography guidance. Biopsy of a transplanted kidney is associated with fewer complications than biopsy of a native kidney because the allograft is typically transplanted more superficially than a native kidney. Renal biopsy is a low-risk invasive procedure that may result in bleeding complications; loss of a renal transplant, as a complication of renal biopsy, is rare.

 

Kidney biopsies allow for diagnosis of acute and chronic graft rejection, which may be graded using the Banff Classification schema. Pathologic assessment of biopsies demonstrating acute rejection allows clinicians to further distinguish between acute cellular rejection (ACR) and antibody-mediated rejection (AMR), which are treated differently.

 

Donor-Derived Cell-Free DNA

Cell-free DNA (cfDNA), released by damaged cells, and is normally present in healthy individuals. In patients who have received transplants, donor-derived cfDNA (dd-cfDNA) may be also present. It is proposed that allograft rejection, which is associated with damage to transplanted cells, may result in an increase in dd-cfDNA. AlloSure® is a commercially available, next-generation sequencing assay that quantifies the fraction of dd-cfDNA in renal transplant recipients, relative to total cfDNA, by measuring 266 single nucleotide variants. Separate genotyping of the donor or recipient is not required, but patients who receive a kidney transplant from a monozygotic (identical) twin are not eligible for this test. The fraction of dd-cfDNA relative to total cfDNA present in the peripheral blood sample is cited in the report. All AlloSure® testing is performed at the CareDx reference laboratory.

 

 

 

Policy:

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.

 

 

The use of peripheral blood gene expression profile tests in the management of patients post-heart transplantation, including, but not limited to the detection of acute heart transplant rejection or heart transplant graft dysfunction is considered not medically necessary and investigational.

 

The use of peripheral blood measurement of donor-derived cell-free DNA in the management of patients after renal transplantation, including but not limited to the detection of acute renal transplant rejection or renal transplant graft dysfunction is considered not medically necessary and investigational.

 

 

Key Points:

The most recent literature update was performed through August 22, 2018.

Evidence reviews assess whether a medical test is clinically useful. A useful test provides information to make a clinical management decision that improves the net health outcome. The balance of benefits and harms is better when the test is used to manage the condition.

The first step in assessing a medical test is to formulate the clinical context and purpose of the test. The test must be technically reliable, clinically valid, and clinically useful for that purpose. Evidence reviews assess the evidence on whether a test is clinically valid and clinically useful. Technical reliability is outside the scope of these reviews, and credible information on technical reliability is available from other sources.

Measurement of Volatile Organic Compounds for Heart Transplant

Clinical Context and Test Purpose

The purpose of measuring volatile organic compounds in patients with a heart transplant is to assess for heart allograft rejection.

The question addressed in this evidence review is: Does the measurement of volatile organic compounds improve the diagnostic assessment of allograft rejection in heart transplant patients?

The following PICOTS were used to select literature to inform this review.

Patients

The relevant population of interest is individuals with a heart transplant.

Interventions

The test being considered measures volatile organic compounds to assess for allograft rejection.

Comparators

The following test is currently being used to diagnose heart allograft rejection: routine endomyocardial biopsy.

Outcomes

The general outcomes of interest are overall survival, test validity, morbid events, and hospitalizations.

Timing

Follow-up over months to years is to monitor for signs of allograft rejection.

Setting

Patients with a heart transplant are actively managed by cardiologists and transplant specialists.

Study Selection Criteria

For the evaluation of clinical validity of measuring volatile organic compounds, studies that met the following eligibility criteria were considered:

  • Reported on the accuracy of the marketed version of the technology (including any algorithms used to calculate scores)
  • Included a suitable reference standard (describe the reference standard)
  • Patient/sample clinical characteristics were described 
  • Patient/sample selection criteria were described.

Technically Reliable

Assessment of technical reliability focuses on specific tests and operators and requires review of unpublished and often proprietary information. Review of specific tests, operators, and unpublished data are outside the scope of this evidence review and alternative sources exist. This evidence review focuses on the clinical validity and clinical utility.

Clinically Valid

A test must detect the presence or absence of a condition, the risk of developing a condition in the future, or treatment response (beneficial or adverse).

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. The HARDBALL study was a three-year, multicenter study of 1061 breath samples in 539 heart transplant patients. Before scheduled endomyocardial biopsy, patient breath was analyzed by gas chromatography and mass spectroscopy for volatile organic compounds. The amount of C4 to C20 alkanes and monomethylalkanes was used to derive the marker for rejection, known as the breath methylated alkane contour. The breath methylated alkane contour 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 criterion standard for rejection.

The authors of the HARDBALL study reported that the abundance of breath markers that measured oxidative stress were found to be significantly greater in Grade 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 methylalkanes that make up the breath methylated alkane contour. 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% vs 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 evaluating the use of the Heartsbreath test to assess for graft rejection were identified in literature updates.

Clinically Useful

A test is clinically useful if the use of the results informs management decisions that improve the net health outcome of care. The net health outcome can be improved if patients receive correct therapy, or more effective therapy, or avoid unnecessary therapy, or avoid unnecessary testing.

Direct Evidence

Direct evidence of clinical utility is provided by studies that have compared health outcomes for patients managed with and without the test. Because these are intervention studies, the preferred evidence would be from randomized controlled trials (RCTs).

No RCTs assessing the measurement of volatile organic compounds to diagnose cardiac allograft rejection were identified.

Chain of Evidence

Indirect evidence on clinical utility rests on clinical validity. If the evidence is insufficient to demonstrate test performance, no inferences can be made about clinical utility.

Because the clinical validity of measuring volatile organic compounds to assess for cardiac allograft rejection has not been established, a chain of evidence to support clinical utility cannot be constructed.

Section Summary: Clinically Useful

The published study found that, for identifying grade 3 (now grade 2R) rejection, the NPV 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 a lower specificity (62.4%) and a lower PPV (5.6%) in assessing grade 3 rejection than a biopsy (specificity, 97%; PPV=45.2%). The breath test was also not evaluated for grade 4 rejection.

Gene Expression Profiling for Heart Transplant

Clinical Context and Test Purpose

The purpose of the gene expression profiling (GEP) of patients with a heart transplant is to assess for allograft rejection.

The question addressed in this evidence review is: Does the use of GEP improve the diagnostic assessment of allograft rejection in heart transplant patients?

The following PICOTS were used to select literature to inform this review.

Patients

The relevant population of interest is individuals with heart transplants.

Interventions

The test being considered is GEP to assess for allograft rejection (i.e., AlloMap®).

Comparators

The following test is currently being used to diagnose cardiac allograft rejection: routine endomyocardial biopsy.

Outcomes

The general outcomes of interest are overall survival, test validity, morbid events, and hospitalizations.

Timing

Follow-up over months to years to monitor for signs of allograft rejection.

Setting

Patients with heart transplant are actively managed by cardiologists and transplant specialists.

Study Selection Criteria

 For the evaluation of clinical validity of GEP testing, studies that met the following eligibility criteria were considered:

  •  Reported on the accuracy of the marketed version of the technology (including any algorithms used to calculate scores).
  •  Included a suitable reference standard (describe the reference standard).
  •  Patient/sample clinical characteristics were described.
  •  Patient/sample selection criteria were described.

Technically Reliable

Assessment of technical reliability focuses on specific tests and operators and requires review of unpublished and often proprietary information. Review of specific tests, operators, and unpublished data are outside the scope of this evidence review and alternative sources exist. This evidence review focuses on the clinical validity and clinical utility.

Clinically Valid

A test must detect the presence or absence of a condition, the risk of developing a condition in the future, or treatment response (beneficial or adverse).

Systematic Reviews

A 2011 TEC Assessment reviewed the evidence on the use of gene expression profiling (GEP) using the AlloMap® test. The Assessment concluded that the evidence was insufficient to permit conclusions about the effect of the AlloMap® test on health outcomes. Key evidence in the TEC Assessment and subsequent literature searches is described below.

Nonrandomized Studies

Patterns of gene expression for development of the AlloMap® test were studied in the Cardiac Allograft Rejection Gene Expression Observation (CARGO) study, which included eight U.S. cardiac transplant centers enrolling 629 cardiac transplant recipients. The study included discovery and validation phases. In the discovery phase, patient blood samples were obtained at the time of endomyocardial biopsy, and the expression levels of more than 7000 genes known to be involved in immune responses were assayed and compared with the biopsy results. A subset of 252 candidate genes were identified that showed promise as markers of transplant rejection from which a panel of eleven genes was selected that could be evaluated using polymerase chain reaction (PCR) assays. A proprietary algorithm is applied to the results of the analysis, producing a single score that considers the contribution of each gene in the panel.

The validation phase of the CARGO study, published in 2006, was prospective, blinded, and enrolled 270 patients.  Primary validation was conducted using samples from 63 patients 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 a sensitivity of 84% of patients with moderate/severe rejection but a specificity of 38%. Of note, in the “training set” used in the study, these rates were 80% and 59%, respectively. The authors evaluated the eleven-gene expression profile on 281 samples collected at one year or more from 166 patients who were 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 NPV (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, 1A, and 2 scores but were similar to Grade 3 scores.

A second prospective multicenter study, evaluating the clinical validity of GEP with the AlloMap® test (CARGO II), was published in 2016. The study enrolled 499 heart transplant recipients who were undergoing surveillance for allograft rejection. The reference standard for rejection status was histologic grade from an endomyocardial biopsy performed on the same day as blood samples were collected. Blood samples needed to be collected 55 days or more post-transplant, more than 30 days after blood transfusion, more than 21 days after administration of prednisone 20 mg/day or more, and more than 60 days after treatment for a prior rejection. Patients had a total of 1579 eligible blood samples for which paired GEP scores and endomyocardial biopsy rejection grades were available.

As in the original CARGO study, the proportion of cases of rejection was small. The prevalence of moderate-to-severe rejection (grade 2R/>3A) reported by local pathologists was 3.2%, which was reduced to 2.0% when confirmation from 1 or more other independent pathologist was required. At a GEP cutoff of 34, for patients who were at least two to six months post-transplant, the sensitivity of GEP for detecting grade 2R/>3A was 25.0% and the specificity was 88.7%. The PPV and NPV were 4.0% and 98.4%, respectively. Using the same cutoff of 34, for patients more than six months post-transplant, the sensitivity of GEP was 25.0% the specificity was 88.8%, the PPV was 4.3% and the NPV was 98.3%. The number of true positives used in the above calculations was five (9.1%) of 55 for patients at least two to six months post-transplant and six (10.2%) of 59 for patients more than six months post-transplant.

Section Summary: Clinical Validity

The two studies (CARGO, CARGO II) examining the diagnostic performance of GEP using the AlloMap® test for detecting moderate or severe rejection are flawed by lack of a consistent threshold (i.e., 20, 30, or 34) for determining positivity and a small number of positive cases. In the available studies, although the NPVs were relatively high (i.e., at least 88%), the performance characteristics were calculated based on detection of ten or fewer cases of rejection each. Moreover, the PPV in the CARGO II study was only 4.0% for patients who were at least two to six months post-transplant and 4.3% for patients more than six months post-transplant.

Clinically Useful

A test is clinically useful if the use of the results informs management decisions that improve the net health outcome of care. The net health outcome can be improved if patients receive correct therapy, or more effective therapy, or avoid unnecessary therapy, or avoid unnecessary testing.

Direct Evidence

Direct evidence of clinical utility is provided by studies that have compared health outcomes for patients managed with and without the test. Because these are intervention studies, the preferred evidence would be from RCTs.

Randomized Controlled Trials

In 2010, results of the Invasive Monitoring Attenuation through Gene Expression (IMAGE) study were published.  This was an industry-sponsored, non-blinded, noninferiority randomized controlled trial (RCT) that compared outcomes in 602 patients managed with the AlloMap® test (n=297) or with routine endomyocardial biopsies (n=305). The study included adults from 13 centers who underwent cardiac transplantation between one and five years prior to participating in the study, 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 six months and one year prior to participating in the study; this sub-group ultimately comprised only 15% of the final 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 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: (1) the first occurrence of rejection with hemodynamic compromise; (2) graft dysfunction due to other causes; (3) death; or (4) retransplantation. 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 two strategies was less than the prespecified margin of 2.054. The margin was derived using the estimate of a 5% event rate per year in the biopsy group, taken from published observational studies, and allowing for an event rate of up to 10% per year in the AlloMap® group.

According to Kaplan-Meier analysis, the two-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 GEP was considered noninferior to endomyocardial biopsy. Death from all causes, a secondary outcome, did not differ significantly between groups. There were 13 (6.3%) deaths in the AlloMap® group and 12 (5.5%) in the biopsy group (p=0.82). During follow-up, there were 34 treated episodes of graft rejection in the AlloMap® group. Only six (18%) of the 34 patients with graft rejection presented solely with elevated AlloMap® scores. Twenty (59%) patients presented with clinical signs/symptoms and/or graft dysfunction on echocardiogram, and seven patients had an elevated AlloMap® score plus clinical signs/symptoms with or without graft dysfunction on echocardiogram. In the biopsy group, 22 patients were detected solely due to an abnormal biopsy.

A total of 409 biopsies were performed in the AlloMap® group and 1,249 in the biopsy group. Most of the biopsies in the AlloMap® group, 67%, were performed because of elevated gene-profiling 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 one (0.3%) adverse event associated with biopsy in the AlloMap® group and four (1.4%) in the biopsy group. In terms of quality of life, the physical-health and mental-health summary scores of the 12-Item Short Form Health Survey, (SF-12) were similar in the two groups at baseline and did not differ significantly between groups at two 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 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 six of the 34 treated episodes of graft rejection detected during follow-up in the AlloMap® group were initially identified solely due to an elevated GPS score. Since 22 episodes of asymptomatic rejection were detected in the biopsy group, the AlloMap® test does not appear to be a sensitive test, possibly missing more than half of the episodes of asymptomatic rejection. Because clinical outcomes were similar in the two groups, there are at least two possible explanations: the clinical outcome of the study may not be sensitive to missed episodes of rejection, or it is not necessary to treat asymptomatic rejection. In addition, the study was only statistically powered to rule out more than a doubling of the rate of the clinical outcome, which some may believe is an insufficient margin of noninferiority. Finally, only 15% of the final study sample had undergone transplantation less than one year before study participation; therefore, findings may not be generalizable to the population of patients 6 to 12 months posttransplant.

In 2015, Kobashigawa et al published results of a pilot RCT evaluating the use of the AlloMap® test in patients who were 55 days to six months posttransplant. The study design was similar to that of the IMAGE RCT: 60 subjects were randomized to rejection monitoring with AlloMap® or with endomyocardial biopsy at prespecified intervals of 55 days and 3, 4, 5, 6, 8, 10, and 12 months posttransplant. The threshold for a positive AlloMap® test was set at 30 for patients two to six months posttransplant and 34 for patients after six months posttransplant, based on data from the CARGO study. Endomyocardial biopsy outside of the scheduled visits was obtained in either group if there was clinical or echocardiographic evidence of graft dysfunction and for the AlloMap® group if the score was above the specified threshold. The incidence of the primary outcome at 18 months posttransplant (composite outcome of first occurrence of any of the following: death or retransplant, rejection with hemodynamic compromise, or allograft dysfunction due to other causes) did not differ significantly between the AlloMap® and biopsy groups (10% vs 17%; p=0.44). The number of biopsy-proven rejection episodes (ISHLT ≥2R) within the first 18 months did not differ significantly between groups (three in the AlloMap® group vs 1 in the biopsy group; p=0.31). Of the rejections in the AlloMap® group, one was detected after an elevated routine AlloMap® test, while two were detected after patients presented with hemodynamic compromise. As in the IMAGE study described above, a high proportion of rejection episodes were detected by clinical signs/symptoms (however, this study had only three rejection episodes in the AlloMap® group).

Chain of Evidence

Indirect evidence on clinical utility rests on clinical validity. If the evidence is insufficient to demonstrate test performance, no inferences can be made about clinical utility. Because the clinical validity of GEP testing to assess for cardiac allograft rejection has not been established, a chain of evidence to support clinical utility cannot be constructed.

Section Summary: Clinical Utility  

The most direct evidence on the clinical utility of GEP using the AlloMap® test comes from a large RCT comparing a GEP-directed strategy with an endomyocardial biopsy-directed strategy for detecting rejection; it found that the GEP-directed strategy was noninferior. However, given the high proportion of rejection episodes in the GEP-directed strategy group detected by clinical signs/symptoms, the evidence is insufficient to determine that health outcomes are improved because of the uncertain incremental benefit of GEP. In addition, a minority of subjects assessed were in the first year posttransplant. Results from a pilot RCT suggests that GEP may have a role in evaluating for heart transplant rejection beginning at 55 days posttransplant, but the trial was insufficiently powered to permit firm conclusions about the noninferiority of early GEP use.

Donor-Derived Cell-Free DNA Testing for Renal Transplant

Clinical Context and Test Purpose

The purpose of donor-derived cell-free DNA (dd-cfDNA) testing in patients with renal transplant and clinical suspicion of allograft rejection is to detect allograft rejection.

The question addressed in this evidence review is: Does testing for dd-cfDNA improve outcomes in renal transplant patients with clinical suspicion of allograft rejection?

The following PICOTS were used to select literature to inform this review.

Patients

The relevant population of interest is individuals with renal transplants and clinical suspicion of allograft rejection.

Interventions

The test being considered is dd-cfDNA testing to assess for renal allograft rejection (i.e., AlloSure®).

Comparators

The following test is currently being used to confirm clinical suspicion of allograft rejection: renal biopsy.

Outcomes

The general outcomes of interest are overall survival, test validity, morbid events, and hospitalizations.

Timing

Follow-up over months to years is to monitor for signs of allograft rejection.

Setting

Patients with a renal transplant are actively managed by nephrologists and transplant specialists.

Study Selection Criteria

For the evaluation of clinical validity of dd-cfDNA testing, studies that met the following eligibility criteria were considered:

  •  Reported on the accuracy of the marketed version of the technology (including any algorithms used to calculate scores)
  •  Included a suitable reference standard (describe the reference standard)
  •  Patient/sample clinical characteristics were described
  •  Patient/sample selection criteria were described.

Technically Reliable

Assessment of technical reliability focuses on specific tests and operators and requires review of unpublished and often proprietary information. Review of specific tests, operators, and unpublished data are outside the scope of this evidence review and alternative sources exist. This evidence review focuses on the clinical validity and clinical utility.

Clinically Valid

A test must detect the presence or absence of a condition, the risk of developing a condition in the future, or treatment response (beneficial or adverse)

Development of the AlloSure® test was conducted in the multicenter prospective study by Bloom et al (2017), which both recruited patients who were less than 3 months after renal transplant (n=245) and recruited renal transplant patients requiring a biopsy for suspicion of graft rejection (n=139). For the primary analysis, active rejection was defined as the combined categories of T cell-mediated rejection, acute/active antibody-mediated rejection, and chronic/active antibody-mediated rejection as defined by the Banff Classification. Only patients undergoing biopsy were considered; further exclusion of biopsies which were not for cause, had an inadequate or incomplete collection of biopsies or corresponding blood samples, or had prior allograft in situ resulted in the main study cohorts (N=102 patients, 107 biopsies). Within this population, acute rejection was noted in 27 patients (27 biopsies). After statistical analysis accounting for multiple biopsies from the same patient, the threshold dd-cfDNA fraction corresponding to acute rejection was set to 1.0% or higher. In the main study group, this resulted in a sensitivity of 59% (95% CI, 44% to 74%) and specificity of 85% (95% CI, 79% to 81%) for detecting active rejection vs no rejection. Using the original data set, including all biopsies performed for clinical suspicion of rejection, 58 cases of acute rejection were diagnosed in 204 biopsies (170 patients). This PPV was 61% and the NPV 84%. Biopsies performed for surveillance (Nn34 biopsies) were excluded from analysis in this study as only one biopsy for surveillance demonstrated acute rejection. Study limitations included the absence of a validation data set.

Section Summary: Clinically Valid

A discovery phase prospective study using the AlloSure® test has been performed in a multicenter setting. Larger studies validating the dd-cfDNA threshold for active rejection are needed to develop conclusions.

Clinically Useful

A test is clinically useful if the use of the results informs management decisions that improve the net health outcome of care. The net health outcome can be improved if patients receive correct therapy, or more effective therapy, or avoid unnecessary therapy, or avoid unnecessary testing.

Direct Evidence

Direct evidence of clinical utility is provided by studies that have compared health outcomes for patients managed with and without the test. Because these are intervention studies, the preferred evidence would be from RCTs.

No RCTs assessing the clinical utility of the dd-cfDNA (AlloSure®) testing to diagnose renal allograft rejection were identified.

Chain of Evidence

Indirect evidence on clinical utility rests on clinical validity. If the evidence is insufficient to demonstrate test performance, no inferences can be made about clinical utility. Because the clinical validity of dd-cfDNA (AlloSure®) testing to assess for renal allograft rejection has not been established, a chain of evidence support clinical utility cannot be constructed.

Section Summary: Clinically Useful

At present, no studies evaluating the clinical utility for the dd-cfDNA (AlloSure®) testing were identified.

Summary of Evidence

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.

The evidence includes two diagnostic accuracy studies and several randomized controlled trials evaluating clinical utility for individuals who have a heart transplant who receive gene expression profiling (GEP) to assess cardiac allograft rejection. The evidence includes two diagnostic accuracy studies and several randomized controlled trials evaluating clinical utility. Relevant outcomes are overall survival, test validity, morbid events, and hospitalizations. The two studies (CARGO, CARGO II) examining the diagnostic performance of GEP for detecting moderate-to-severe rejection lacked a consistent threshold for defining a positive GEP test (i.e., 20, 30, or 34) and reported a low number of positive cases. In the available studies, although the negative predictive values were relatively high (i.e., at least 88%), the performance characteristics were only calculated based on ten or fewer cases of rejection; therefore, performance data may be imprecise. Moreover, the positive predictive value in CARGO II was only 4.0% for patients who were at least two to six months posttransplant and 4.3% for patients more than six months posttransplant. The clinical utility of GEP compared with routine endomyocardial biopsies has been evaluated in two RCTs, the IMAGE study assessing patients more than six months posttransplant and a small pilot randomized control trial assessing patients starting at 55 days posttransplant. The threshold indicating a positive test that seems to be currently accepted (a score of 34) was not prespecified; rather it evolved partway through the data collection period in the IMAGE study. In addition, the IMAGE study had several methodologic limitations (e.g., lack of blinding); further, the IMAGE study failed to provide evidence that GEP offers incremental benefit over biopsy performed on the basis of clinical exam or echocardiography. Patients at the highest risk of transplant rejection are patients within one year of the transplant, and for that subset there remains insufficient data on which to evaluate the clinical utility of GEP. The evidence is insufficient to determine the effects of the technology on health outcomes.

The evidence includes a diagnostic accuracy study for individuals with a renal transplant and clinical suspicion of allograft rejection who receive testing of dd-cfDNA to assess renal allograft rejection. Relevant outcomes are overall survival, test validity, morbid events, and hospitalizations. The study examined the diagnostic performance of dd-cfDNA for detecting moderate-to-severe rejection; the negative predictive value was moderately high (84%), and performance characteristics were calculated on 27 cases of active transplant rejection. The threshold indicating a positive test was not prespecified. The evidence is insufficient to determine the effects of the technology on health outcomes.

Practice Guidelines and Positions Statements

International Society of Heart and Lung Transplantation

In 2010, the International Society of Heart and Lung Transplantation issued guidelines for the care of heart transplant recipients. The guidelines included the following recommendations (see Table 2). 

Table 2. Guidelines for Postoperative Care of Heart Transplant Recipients

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

“Gene Expression Profiling (AlloMap®) can be used to rule out the presence of ACR of grade 2R or greater in appropriate low-risk patients, between 6 months and 5 years after HT.”

IIa

B

ACR: acute heart rejection; COR: class of recommendation; EMB: endomyocardial biopsy; HT: heart transplant; LOE: level of evidence.

Kidney Disease Improving Global Outcomes

The Kidney Disease Improving Global Outcomes (2009) issued guidelines for the care of kidney transplant recipients. The guidelines included the following recommendations (see Table 3).

Table 3. Guidelines for Biopsy in Renal Transplant Recipients

                                                                    Recommendation

SOR

LOE

“We recommend kidney allograft biopsy when there is a persistent, unexplained increase in serum creatinine.”

Level 1

C

“We suggest kidney allograft biopsy when serum creatinine has not returned to baseline after treatment of acute rejection.”

Level 2

D

“We suggest kidney allograft biopsy every 7–10 days during delayed function.”

Level 2

C

“We suggest kidney allograft biopsy if expected kidney function is not achieved within the first 1–2 months after transplantation.”

Level 2

D

“We suggest kidney allograft biopsy when there is new onset of proteinuria.”

Level 2

C

“We suggest kidney allograft biopsy when there is unexplained proteinuria ≥3.0 g/g creatinine or ≥3.0 g per 24 hours.”

Level 2

C

LOE: level of evidence; SOR: strength of recommendation.

U.S. Preventive Services Task Force Recommendations

Not applicable.

 

Key Words:

Heartsbreath test, endomyocardial biopsy, heart transplant rejection, AlloMap® Test, gene expression profiling, Cardiac Allograft Rejection Gene Expression Observation (CARGO) Study, Invasive Monitoring Attenuation through Gene Expression (IMAGE) Study, MyTAIHEART, TAI, AlloSure® Test, renal allograft rejection, kidney transplant rejection, GEP, Next Generation Sequencing (NGS), dd-cfDNA, donor-derived cell-free DNA, DART Study, Viracor, TRACTM dd-cfDNA

 

 

Approved by Governing Bodies:

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.

 

In August 2008, AlloMap® Molecular Expression Testing (CareDx, Brisbane, CA; formerly XDx) was cleared for marketing by FDA through the 510(k) process. 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 two months posttransplant.

 

 

 

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

81595         Cardiology (heart transplant), mRNA, gene expression profiling by real-time quantitative

                   PCR of 20 genes (11 content and 9 housekeeping), utilizing subfraction of peripheral blood,

                   algorithm reported as a rejection risk score (Effective 01/01/16) (i.e., Allomap®)

86849         Unlisted immunology procedure

0055U        Cardiology (heart transplant), cell-free DNA, PCR assay of 96 DNA target sequences

                   (94 single nucleotide polymorphism targets and two control targets), plasma

                   (Effective 07/01/2018)

0118U           Transplantation medicine, quantification of donor-derived cell-free DNA using whole genome next generation sequencing, plasma,

                         reported as percentage of donor- derived cell-free DNA in the total cell-free DNA (Effective 10/01/19)

 

 

 

 

 

References:

  1. Ahmad I. Biopsy of the transplanted kidney. Semin Intervent Radiol. Dec 2004;21(4):275-28

  2. AlloMap®: A Non-Invasive, Test Service for Heart Transplant Patients. www.allomap.com. Accessed April, 2016.

  3. Bernstein D, et al.  Gene expression profiling distinguishes moderate to severe from mild acute cellular rejection in cardiac allograft recipient. J Heart Lung Transplant. 2007 Dec; 26(12):1270-80.

  4. Bernstein D, Mital S, Addonizio L, et al. Gene expression profiling of cardiac allograft recipients with mild acute cellular rejection. Journal Heart Lung Transplant 2005; 24(2): S65.

  5. Bloom RD, Bromberg JS, Poggio ED, et al. Cell-free DNA and active rejection in kidney allografts. J Am Soc Nephrol. Jul 2017;28(7):2221-2232.

  6. 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.

  7. Cadeiras M, Shahzad K, John MM, et al. Relationship between a validated molecular cardiac transplant rejection classifier and routine organ function parameters. Clinical Transplant. May-June 2010; 24(3):321-32

  8. CareDx. Overview: AlloMap® Testing: Answering Unmet Needs in Heart Transplant Surveillance. n.d.; www.allomap.com/providers/overview/. Accessed October 1, 2018.

  9. Celec P, Vlkova B, Laukova L, et al. Cell-free DNA: the role in pathophysiology and as a biomarker in kidney diseases. Expert Rev Mol Med. Jan 18 2018; 20:e1.

  10. Costanzo MR, Costanzo MR, Dipchand A et al. The International Society of Heart and Lung Transplantation guidelines for heart transplant recipients. J Heart Lung Transplant 2010; 29(8):914-56.

  11. Crespo-Leiro MG, Stypmann J, Schulz U, et al. Clinical usefulness of gene-expression profile to rule out acute rejection after heart transplantation: CARGO II. Eur Heart J. Jan 7 2016.

  12. Deng MC, Eisen HJ, et al. Noninvasive discrimination of rejection in cardiac allograft recipients using gene expression profiling. American Journal Transplant 2006; 6(1): 150-160.

  13. Deng MC, Elashoff B, Pham MX et al. Utility of Gene Expression Profiling Score Variability to Predict Clinical Events in Heart Transplant Recipients. Transplantation 2014.

  14. Deng MC, et al. Early detection of cardiac allograft vasculopathy through gene expression profiling-Insights of the CARGO study. J Heart Lung Transplant 2006; 25(2), Supplement, S98.

  15. 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):3194-3202.

  16. Eisen HJ, Deng MC, Klinger TM, et al. Longitudinal monitoring of cardiac allograft recipients using peripheral blood gene expression profiling: A retrospective observational analysis of molecular testing in 19 case studies. Journal Heart Lung Transplant 2005; 24(2): S162.

  17. Evans RW, Williams GE, Baron HM. The economic implications of non-invasive molecular testing for cardiac allograft rejection. American Journal Transplantation 2005; 5(6): 1553-1558.

  18. Goldberg RJ, Weng FL, Kandula P. Acute and chronic allograft dysfunction in kidney transplant recipients. Med Clin North Am. May 2016; 100(3):487-503.

  19. Haas M. The Revised (2013) Banff Classification for antibody-mediated rejection of renal allografts: update, difficulties, and future considerations. Am J Transplant. May 2016; 16(5):1352-1357.

  20. Jarcho JA. Fear of rejection- monitoring the heart-transplant recipient. New England Journal of Medicine 2010; 362(20): 1932-1933.

  21. Kasiske BL, Zeier MG, Chapman JR, et al. KDIGO clinical practice guideline for the care of kidney transplant recipients: a summary. Kidney Int. Feb 2010; 77(4):299-311.

  22. Kobashigawa J, Patel J, Azarbal B, et al. Randomized Pilot Trial of Gene Expression Profiling Versus Heart Biopsy in the First Year After Heart Transplant: Early Invasive Monitoring Attenuation Through Gene Expression Trial (EIMAGE). Circ Heart Fail. Feb 19 2015.

  23. Kobashigawa J, Patel J, Azarbal B, et al. Randomized pilot trial of gene expression profiling versus heart biopsy in the first year after heart transplant: early invasive monitoring attenuation through gene expression trial. Circ Heart Fail. May 2015; 8(3):557-564.

  24. Marboe CC, et al. Increased molecular testing scores associated with agreement among cardiac pathologists for the diagnosis of ISHLT 3A and higher rejection. J Heart Lung Transplant 2006; 25(2), Supplement, S105-S106.

  25. Marboe CC, Lal PG, Chu K, et al. Distinctive peripheral blood gene expression profiles in patients forming nodular endocardial infiltrates (Quilty lesions) following heart transplantation. Journal Heart Lung Transplant 2005; 24(2): S97.

  26. Mehra M, et al. Does induction therapy influence the utility of gene expression testing for cardiac allograft rejection? J Heart Lung Transplant 2007; 26(2), Supplement, S121.

  27. Mehra M, et al. The clinical role of gene expression testing in anticipating the future development of acute cardiac allograft rejection. J Heart Lung Transplant 2006; 25(2), Supplement, S110.

  28. Organ Procurement and Transplantation Network. National Data. 2018; optn.transplant.hrsa.gov/data/view-data-reports/national-data/#. Accessed October 1, 2018.

  29. 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):463-469.

  30. Pham MX, Deng MC, et al. Molecular testing for long-term rejection surveillance in heart transplant recipients: Design of the invasive monitoring attenuation through gene expression (IMAGE) trial. Journal of Heart and Lung Transplant 2007; 26(8): 808-814.

  31. Pham MX, Teuteberg JJ, et al. Gene-Expression profiling for rejection surveillance after cardiac transplantation. New England Journal of Medicine 2010; 362:1890-1900.

  32. 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.

  33. 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.

  34. Solez K, Colvin RB, Racusen LC, et al. Banff 07 classification of renal allograft pathology: updates and future directions. Am J Transplant. Apr 2008; 8(4):753-760.

  35. Starling RC, Deng MC, Kobashigawa JA, et al. The influence of corticosteroids on the alloimmune molecular signature or cardiac allograft rejection. Journal Heart and Lung Transplant 2005; 24(2): S65-S66.

  36. Starling RC, Pham M, et al.  Molecular testing in the management of cardiac transplant recipients: initial clinical experience. Journal of Heart Lung Transplant. December 2006; 25(12):1389-1395.

  37. 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):1710-1720.

  38. Tice JA. Gene expression profiling for the diagnosis of heart transplant rejection. California Technology Assessment Forum. 2010. Available online at: www.ctaf.org/sites/default/files/assessments/1208_file_AlloMap_2010_W.pdf.  Last accessed December 2010.

  39. XDX Expression Diagnostics, Brisbane, CA. 2010. Available online at: www.allomap.com. Last accessed March 2013.

  40. Yamani MH, Taylor DO, et al. Transplant vasculopathy is associated with increased AlloMap® gene expression score. Journal of Heart Lung Transplant.  April 2007; 26(4):403-406.

 

 

 

Policy History:

Medical Policy Group, December 2004 (4)

Medical Policy Administration Committee, January 2005

Available for comment January 21-March 7, 2005

Medical Policy Group, December 2006 (1)

Medical Policy Administration Committee, January 2007

Available for comment January 30-March 8, 2007

Medical Policy Group, September 2007 (3)

Medical Policy Administration Committee October 2007

Medical Policy Group, September 2009 (1)

Medical Policy Group, November 2010 (1): No change in policy statement

Medical Policy Group, April 2012 (1): Update to Key Points and References related to MPP update; no change to policy statement

Medical Policy Panel, April 2013

Medical Policy Group, April 2013 (1): Literature search updated; no change to policy statement

Medical Policy Panel, April 2014

Medical Policy Group, April 2014 (1): Policy statements edited for clarity, no change in coverage or intent; update to Description, Key Points and References; addition of CPT code 86849 related to usage for AlloMap®

Medical Policy Panel, April 2015

Medical Policy Group, May 2015 (3):  2015 Updates to Title, Description, Key Points, Governing Bodies, Coding, & References; no change in policy statement; title updated to clarify as Heart Transplant Rejection Laboratory Testing

Medical Policy Group, November 2015: 2016 Annual Coding Update.  Updated CPT code 81495 to 81595 per coding update.

Medical Policy Group, June 2016 (3):  2016 Updates to Description, Key Points, Policy and References: No change in intent of policy statement-clarifying information only added.

Medical Policy Panel, October 2017

Medical Policy Group, October 2017 (3): 2017 Updates to Title, Description, Key Points & References; edits made to policy statement with no change in policy intent.

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

Medical Policy Panel, October 2018

Medical Policy Group, November 2018 (3): Updates to Description, Key Points, Practice Guidelines, References, and Key Words: added AlloSure® Test, renal allograft rejection, kidney transplant rejection, GEP, Next Generation Sequencing (NGS), dd-cfDNA, donor-derived cell-free DNA, and DART Study. Added policy statement: “The use of peripheral blood measurement of donor-derived cell-free DNA in the management of patients after renal transplantation, including but not limited to the detection of acute renal transplant rejection or renal transplant graft dysfunction, is considered investigational.” Title expanded to include kidney transplant rejection laboratory testing.

Medical Policy Group, September 2019: October 2019 quarterly coding update. Added CPT code 0018U.  Added Key Words Viracor and TRACTM dd-cfDNA.


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.