1. Human Heart Transplantation

   Aetna considers heart transplantation medically necessary for any of the following conditions (not an all-inclusive list) when the member meets the transplanting institution's protocol eligibility criteria.  In the absence of a protocol, Aetna considers heart transplantation medically necessary for the following indications when the selection criteria listed below are met and none of the absolute contraindications is present:

   1. Cardiac arrhythmia
   2. Cardiac re-transplantation due to graft failure
   3. Cardiomyopathy due to nutritional, metabolic, hypertrophic or restrictive etiologies
   4. Congenital heart disease
   5. End-stage ventricular failure
   6. Idiopathic dilated cardiomyopathy
   7. Inability to be weaned from temporary cardiac-assist devices after myocardial infarction or non-transplant cardiac surgery
   8. Intractable coronary artery disease
   9. Myocarditis
   10. Post-partum cardiomyopathy
   11. Right ventricular dysplasia/cardiomyopathy
   12. Valvular heart disease.

   Selection Criteria for Human Heart Transplantation (for members off protocol, all criteria listed below must be met):

   1. New York Heart Association (NYHA) classification of heart failure III or IV (see Note below), -- does not apply to pediatric members; and
   2. Member has potential for conditioning and rehabilitation after transplant (i.e., member is not moribund); and
   3. Life expectancy (in the absence of cardiovascular disease) is greater than 2 years; and
   4. No malignancy (except for non-melanomatous skin cancers) or malignancy has been completely resected or (upon individual case review) malignancy has been adequately treated with no substantial likelihood of recurrence with acceptable future risks; and
   5. Adequate pulmonary, liver and renal function; and
   6. Absence of active infections that are not effectively treated; and
   7. Absence of uncontrolled HIV infection, defined as:
      
      
      1. CD4 count greater than 200 cells/mm³ for greater than 6 months; and
      2. HIV-1 RNA (viral load) undetectable; and
      3. On stable anti-viral therapy greater than 3 months; and
      4. No other complications from AIDS, such as opportunistic infections (e.g., aspergillus, tuberculosis, coccidiodomycosis, resistant fungal infections) or neoplasms (e.g., Kaposi's sarcoma, non-Hodgkin's lymphoma); and
          
   8. Absence of active or recurrent pancreatitis; and
   9. Absence of diabetes with severe end-organ damage (neuropathy, nephropathy with declining renal function and proliferative retinopathy); and
   10. No uncontrolled and/or untreated psychiatric disorders that interfere with compliance to a strict treatment regimen; and
   11. No active alcohol or chemical dependency that interferes with compliance to a strict treatment regimen.

   Note: NYHA Class III and Class IV for heart failure are defined as follows:

   Class III:	Persons with cardiac disease resulting in marked limitation of physical activity.  They are comfortable at rest.  Less than ordinary activity (i.e., mild exertion) causes fatigue, palpitation, dyspnea, or anginal pain.
   Class IV:	Persons with cardiac disease resulting in inability to carry on any physical activity without discomfort.  Symptoms of cardiac insufficiency or of the anginal syndrome may be present even at rest.  If any physical activity is undertaken, discomfort is increased.

   Contraindications: Heart transplant is considered not medically necessary for persons with any of the following contraindications:

   1. Presence of systemic diseases (e.g., autoimmune, collagen vascular disease); or
   2. Presence of irreversible end-organ diseases (e.g., renal, hepatic, pulmonary) (unless person is to undergo dual organ transplantation, e.g., heart-lung, heart-kidney, etc.); or
   3. Presence of severe pulmonary hypertension with irreversibly high pulmonary vascular resistance; or
   4. Presence of a recent intra-cranial cerebrovascular event with significant persistent deficit; or
   5. Presence of bleeding peptic ulcer; or
   6. Presence of hepatitis B antigen; or
   7. Presence of diverticulitis; or
   8. Presence of life-threatening neuromuscular disorders; or
   9. Presence of HIV/AIDS with profound immunosuppression (CD4 count of less than 200 cells/mm3); or
   10. Presence of amyloidosis (although amyloidosis is considered a contraindication to heart transplantation, exceptions may be made in circumstances where curative therapy of amyloidosis has been performed or is planned (e.g., stem cell transplantation in primary amyloidosis, liver transplantation in familial amyloidosis).
        

2. Xenotransplantation of the Heart

   Aetna considers cardiac xenotransplantation (e.g., porcine xenografts) experimental and investigational because its safety and effectiveness has not been established.

3. Left Ventricular Assist Device as Destination Therapy

   For Aetna's CPB policy on left ventricular assist devices as destination therapy for persons with severe heart failure, see CPB 0654 - Ventricular Assist Devices.

4. Total Artificial Heart

   Aetna considers the use of a total artificial heart (e.g., ABIOCOR Total Artificial Heart, CardioWest Total Artificial Heart) as permanent treatment (destination therapy) (i.e., as an alternative to heart transplantation) experimental and investigational because its safety and effectiveness for this indication has not been established.

   Aetna considers an Food and Drug Administration-approved total artificial heart (e.g., CardioWest Total Artificial Heart, SynCardia Systems, Tucson, AZ) medically necessary when used as a bridge to transplant for transplant-eligible members who are at imminent risk of death (NYHA Class IV) due to biventricular failure who are awaiting heart transplantation. See CPB 0654 - Ventricular Assist Devices.

5. Breath Test for Heart Transplant Rejection

   Aetna considers the Heartsbreath Test (Menassana Research, Inc, Fort Lee, NJ) experimental and investigational for diagnosing heart transplant rejection and for all other indications because its clinical value has not been established.  

6. AlloMap™ Molecular-Expression Blood Test

   Aetna considers the Allomap gene expression profile medically necessary for monitoring rejection in heart transplant recipients more than 1 year post-heart transplant.

   Aetna considers the Allomap gene expression profile experimental and investigational for all other indications because its clinical value has not been established.

Heart transplantation has become a commonly used therapeutic option for the treatment of end-stage heart disease.  It has been projected that patients who receive cardiac transplants have an in-hospital mortality rate of less than 5 %, a 1-year survival rate of about 85 %, and a 5-year survival rate of 75 % to 80 %.  Moreover, 90 % of cardiac transplant patients lead a relatively normal lifestyle having no limitations in their activity and 40 % return to work.

In adults, cardiac transplantation is most frequently performed for patients with cardiomyopathy (about 50 %), coronary artery disease (about 40 %), valvular disease (about 4 %), re-transplantation following a failed primary transplantation (about 2 %) and congenital heart disease (about 2 %).

In children, the most common indications for cardiac transplantation are congenital heart disease (about 47 %), dilated cardiomyopathy (about 45 %), and re-transplantation (about 3 %).  Moreover, survival in children with dilated cardiomyopathy relies on accurate diagnosis and aggressive treatment.  The literature indicates that patients may respond to conventional treatment for heart failure or may deteriorate, requiring mechanical support.  Extracorporeal membrane oxygenation (see CPB 0546 - Extracorporeal Membrane Oxygenation (ECMO)) has been used effectively for mechanical support in children until improvement occurs or as a bridge to transplantation.  For individuals who are listed to receive a heart transplant, the mortality rate while waiting for a donor organ averages approximately 20 %.  Survival after transplantation is good, with an intermediate survival rate of about 70 %.

The New York Heart Association (NYHA) classification of heart failure is one of the many parameters used for selecting heart recipients.  It is a 4-tier system that categorizes patients based on subjective impression of the degree of functional compromise.  The 4 NYHA functional classes are as follows:

Contraindications to cardiac transplantation include irreversible end-organ diseases (e.g., renal, hepatic, pulmonary), active malignancy or infections, systemic diseases (e.g., autoimmune, vascular), chronic gastro-intestinal disease (e.g., diverticulitis, active or recurrent pancreatitis, bleeding peptic ulcer), psychiatric disorders, and intra-cranial cerebrovascular disease.  Amyloidosis has also been considered a contraindication to cardiac transplantation due to the high likelihood of development of amyloid in the transplanted organ.  Good outcomes of cardiac transplantation have been reported after curative liver transplantation for familial amyloidosis or stem cell transplantation for primary amyloidosis.  HIV infection is not an absolute contraindication to cardiac transplantation if the HIV infection is well-controlled.  Because of the potential impact of transplant-related immunosuppression, it is especially important for HIV-infected transplant recipients to be followed by an HIV-AIDS multi-disciplinary team with expertise in this area.

Cardiac transplantation is currently the only proven curative treatment for end-stage heart disease, but the supply of donor hearts has not kept pace with the demand.  Therefore, surgical techniques such as reduction ventriculoplasty, transmyocardial laser revascularization (see CPB 0163 - Transmyocardial and Endovascular Laser Revascularization), myoreduction operations (see CPB 0182- Ventricular Remodeling Operation (Batista Operation) and Surgical Ventricular Restoration (Dor Procedure)) or dynamic cardiomyoplasty are employed to maintain heart function or provide a bridge to heart transplantation.  In addition, ventricular assist devices (see CPB 0654 - Ventricular Assist Devices) and the total artificial heart have been approved by the Food and Drug Administration (FDA) for use as a bridge to transplant in selected persons who are awaiting heart transplantation.

The FDA approval of the CardioWest Total Artificial Heart (TAH) (SynCardia Systems, Inc., Tucson, AZ) as a bridge to heart transplantation in transplant eligible patients at imminent risk of death from non-reversible biventricular failure was based on the results of a controlled multi-center clinical study that found that such patients who were implanted with the CardioWest TAH did better than similar control patients who underwent emergency cardiac transplantation (SynCardia, 2004; Copeland et al, 2004).  In this study, 95 patients were implanted with the CardioWest TAH and 35 patients were controls.  Of the 95 patients implanted, 81 met all inclusion criteria and were designated the core implant group.  All patients were in NYHA Class IV at time of enrollment.  The control group did not receive the TAH but met study inclusion criteria.  Both groups were on maximal medical therapy and were at imminent risk of death before a donor heart could be obtained.  Treatment success was defined as patients who, at 30 days post transplant, were (i) alive, (ii) NYHA Class I or II, (iii) not bedridden; (iv) not ventilator dependent, and (v) not requiring dialysis.  Trial success was achieved in 56 (69 %) of the 81 core patients and in 13 (37 %) of the 35 control patients, a difference that was statistically significant (p = 0.0019).  There was also statistically significant differences in favor of the core patients with respect to survival to transplant (p = 0.0008) and survival to 30 days post transplant (p = 0.0018).  Of the core patients, 64 of the 81 (79 %) reached transplant after an average of 79 days (range of 1 to 414); whereas 16 of the 35 (46 %) controls reached transplant after an average of 9 days (range of 1 to 44).  Fifty-eight (72 %) core patients and 14 (40 %) controls survived to 30 days post-transplant.

Renlund (2004) explained that a variety of devices can be used as a bridge to heart transplant.  The selection of a device depends on the type of heart failure, as well as the size of the patient, the surgeon's experience, and the institutional preference.  Implantable left ventricular assist devices, which channel blood from the left ventricle to the pump and back to the aorta, are generally inadequate for bridging to transplantation in patients with severe biventricular heart failure.  The replacement of both ventricles with a TAH may be warranted when replacement of both ventricles may be warranted in severe biventricular failure (Renlund, 2004).  Such circumstances frequently arise in patients with severe aortic insufficiency, intractable ventricular arrhythmias, an aortic prosthesis, an acquired ventricular septal defect, or irreversible biventricular failure requiring a high pump output.  Paracorporeal devices, with the pump placed outside of the body, can provide an alternative to either the ventricular assist device for supporting 1 ventricle, or to the TAH for supporting both ventricles.

The scarcity of donor organs has also resulted in intense research on xenotransplantation.  As a consequence of physiological compatibility as well as infectious consideration, pig is the most likely source of xenotransplantation.  The advent of transgenic pigs expressing human complement regulatory proteins and new immunosuppressive therapies have provided early promising results in the laboratory.  However, more research is needed to advance porcine xenotransplantation to clinical trials.

Menssana Research, Inc. (Fort Lee, NJ) has received a humanitarian device approval (see note below) for the Heartsbreath Test for evaluation of heart transplant rejection.  According to the FDA-approved product labeling, the product is to be used as an aid in diagnosis of grade 3 heart transplant rejection in patients who have received heart transplants within the preceding year (FDA, 2004).  The labeling states that the Heartsbreath test is intended to be used as an adjunct to, and not as a substitute for endomyocardial biopsy.  The labeling states that the use of the Heartsbreath Test is limited to patients who have had endomyocardial biopsy within the previous month.

The Heartsbreath test assesses heart transplant rejection by measuring the amount of methylated alkanes, a marker of oxidative stress, in the patient's breath.  Heart transplant rejection appears to be accompanied by oxidative stress which degrades membrane polyunsaturated fatty acids, creating methylated alkanes, which are excreted in the breath as volatile organic compounds.  The value generated by the Heartsbreath Test is compared to the results of a biopsy performed the previous month to measure the probability of the implant being rejected.

According to the FDA (2004), the Heartsbreath test's greatest potential value may be in helping to separate less severe organ rejection (grades 0, 1, and 2) from more severe rejection (grade 3).  The FDA-approved labeling states that the Heartsbreath test should not be used for patients who have received a heart transplant more than 1 year ago, or who have grade 4 heart transplant rejection because the Heartsbreath test has not been evaluated in these patients.

The FDA's Humanitarian Device Approval of the Heartsbreath Test was based on the results of a multi-center clinical study entitled Heart Allograft Rejection: Detection with Breath Alkanes in Low Levels (HARDBALL), which compared the sensitivity and specificity of the Heartsbreath Test with myocardial biopsy reading by a single pathologist at the transplant site (usually a general pathologist) in distinguishing grade 3 heart transplant rejection from lesser grades of rejection, using biopsy reading by 2 cardiac pathologists as the gold standard for comparison (Phillips et al, 2004; FDA, 2004).  In this study, 1,061 breath samples were collected from 539 heart transplant recipients prior to scheduled endomyocardial biopsy.  Compared to the gold standard, the Heartsbreath Test had a sensitivity of 59.5 %, a specificity of 58.8 %, a positive- predictive value of 5.6 % and a negative-predictive value of 97.2 %.  The biopsy reading by the general pathologist had a sensitivity of 42.4 %, a specificity of 97.0 %, a positive- predictive value of 45.2 %, and a negative-predictive value of 96.7 %.  The investigators concluded that the Heartsbreath Test was more sensitive but less specific for grade 3 heart transplant rejection than a biopsy reading by a single general pathologist, but the negative-predictive values of the 2 tests are similar.  Therefore, a screening breath test may provide supportive information to help identify heart transplant recipients who are at low-risk for grade 3 rejections (Phillips et al, 2004).

In a report of the HARDBALL study results published in the New England Journal of Medicine, the investigators explained that the major potential benefit of the Heartsbreath test is in reducing the number of heart biopsies (Phillips et al, 2004).  If the breath analysis is negative, a biopsy is not needed because, with a negative-predictive value of 97 %, this test accurately predicts where there is not any organ rejection.  If the breath analysis is positive, however, the patient will need a biopsy to determine whether there is rejection, because the Heartsbreath test, with a positive-predictive value of 6 %, does not accurately predict the presence of rejection.  The investigators explained that the low positive-predictive value of this test means that it does not predict the presence of rejection.

A commentary on the HARDBALL study (Williams and Miller, 2002) noted that the study results are “difficult to evaluate” because of a “surprising inconsistency” between the biopsy interpretations of the general pathologist at the transplant site and the biopsy interpretation by the 2 cardiac pathologists used as the gold standard.  The commentary also noted that only 9 of 42 biopsies with grade 3 rejection were predicted by the Heartsbreath test.  Finally, the commentary stated that there needs to be further study of the effect of concurrent illness, such as hemodynamic compromise and infection, on the Heartsbreath test, because such illnesses could theoretically decrease the sensitivity and specificity of the Heartsbreath or any other test that is a marker of oxidative stress.

The FDA-approved product labeling of the Heartsbreath test states that the effectiveness of this device for diagnosis of grade 3 heart transplant rejection “has not been demonstrated” (FDA, 2004).  The FDA, however, approved this device based on the Center for Devices and Radiological Health conclusion that the probable benefit of this test outweighs the risk.  The FDA approval also was based on the assumption that this test would not be used as a substitute for a heart biopsy, as has been suggested by the HARDBALL study investigators (Phillips et al, 2004), but to be used as a confirmatory test in combination with myocardial biopsy to detect grade 3 heart transplant rejection (FDA, 2004).  The Humanitarian Device Exemption for the Heartsbreath was not referred to the FDA's Clinical Chemistry and Clinical Toxicology Devices Panel for review and recommendation because the Heartsbreath is used as an adjunct to myocardial biopsy rather than replacing myocardial biopsy.

According to the FDA, the major benefit of the Heartsbreath test is that it may reduce the risk of a patient getting the wrong treatment because of an erroneous biopsy report:

The benefits are of 2 kinds: (i) the Heartsbreath test may help identify patients with grade 3 rejections and a false-negative biopsy report, which may help protect them from under-treatment of a life-threatening condition, and (ii) the Heartsbreath test may help identify patients with a false-positive biopsy report who do not have grade 3 rejections, and may help protect them from the hazards of unnecessary treatment with steroids and other immunosuppressant medications.

The FDA states that the major risk of the Heartsbreath Test is a result that conflicts with a biopsy report.  According to the FDA, this risk, however, can be minimized by recommending secondary biopsy review of any discordant results by a 2nd pathologist prior to considering any change in treatment.

Note: A Humanitarian Use Device (HUD) is a device that has been given special approval by the FDA under the Humanitarian Device Exemption (HDE) regulations.  The standard approval process for devices requires that companies demonstrate that the devices are safe and effective (better than medicine or another procedure).  However, the FDA recognizes that sometimes a condition is so unusual that it would be difficult for a company to scientifically demonstrate effectiveness of their device in the large number of patients that usually must be tested.  In these special situations, they may grant a HDE provided that: (i) the device does not pose an unreasonable or significant risk of illness or injury; and (ii) the probable benefit to health outweighs the risk of injury or illness from its use, taking into account the probable risks and benefits of currently available devices or alternative forms of treatment.

A HUD may only be used in facilities that have an Institutional Review Board (IRB) to supervise clinical testing of devices and after the IRB has approved the use of the device to treat or diagnose the specific disease.

On December 8, 2008, the Centers for Medicare and Medicaid Services (CMS) issued a decision memorandum in response to a formal request for Menssana Research, Inc., to consider national coverage of the Heartsbreath test as an adjunct to the heart biopsy to detect grade 3 heart transplant rejection in patients who have had a heart transplant within the last year and an endomyocardial biopsy in the prior month.  The CMS determined that the evidence does not adequately define the technical characteristics of the test nor demonstrate that Heartsbreath testing to predict heart transplant rejection improves health outcomes.

The AlloMap™ molecular expression blood test was developed by XDx Expression Diagnostics.  The test evaluates the expression of 20 genes, about half of which are directly involved in rejection while the remainder provide other information needed for rejection risk assessment.  It is hoped that the results of this test will reduce the number of endomyocardial biopsies.  Among the proposed benefits are the AlloMap test's ability to differentiate mild rejection for which histological findings may be the least accurate and the potential for monitoring physiological responses to steroid weaning.  It has been recognized that the test is not effective in monitoring rejection within the first 6 months of transplantation, and it is yet unclear what a high AlloMap score might mean in the setting of no histological rejection.

In a multi-center study called CARGO (Cardiac Allograft Rejection Gene Expression Observational study), Deng et al (2006) examined gene expression profiling of peripheral blood mononuclear cells to discriminate International Society of Heart and Lung Transplantation (ISHLT) grade 0 rejection (quiescence) from moderate/severe rejection (ISHLT greater than or equal to 3A).  Patients were followed prospectively with blood sampling at post-transplant visits.  Biopsies were graded by ISHLT criteria locally and by 3 independent pathologists blinded to clinical data.  Known alloimmune pathways and leukocyte microarrays identified 252 candidate genes for which real-time polymerase chain reaction (PCR) assays were developed.  An 11 gene real-time PCR test was derived from a training set (n = 145 samples, 107 patients) using linear discriminant analysis, converted into a score (0 to 40), and validated prospectively in an independent set (n = 63 samples, 63 patients).  The test distinguished biopsy-defined moderate/severe rejection from quiescence (p = 0.0018) in the validation set, and had agreement of 84 % (95 % confidence interval [CI]: 66 % to 94 %) with grade ISHLT greater than or equal to 3A rejection.  Patients over 1 year post-transplant with scores below 30 (approximately 68 % of the study population) are very unlikely to have grade greater than or equal to 3A rejection (negative-predictive value  = 99.6 %).  Gene expression testing can detect absence of moderate/severe rejection, thus avoiding biopsy in certain clinical settings.  The authors concluded that more research is needed to establish the role of molecular testing for prediction of clinical event prediction and management of immunosuppression.  Furthermore, an editorial (Halloran et al, 2006) that accompanied the CARGO study questioned the biological plausibilty of this technology and emphasized the need for replication of these findings.

In a subsequent study, the investigators from the CARGO study (Starling et al, 2006) provided recommendations regarding the use of the gene expression profiling (GEP) test.  However, none of the recommendations received Class I classification and/or Level A evidence.

Candidates for GEP Testing:

Class IIa:

• GEP testing can be used in clinically stable cardiac transplant recipients who are 15 years of age or older and 6 months or more post-transplant to identify patients at low-risk for moderate/severe (Grade greater than or equal to 3A/2R) cellular rejection.  (Level of Evidence: B)
• At the time of GEP testing, a thorough history and physical examination should be obtained/performed by an appropriately trained transplant physician, and a non-invasive assessment of cardiac allograft function utilizing echocardiography should be performed to evaluate allograft function.  (Level of Evidence: C)

Class III:

• GEP testing should not be used in patients at high-risk for acute rejection or graft failure, including those with (a) signs/symptoms of cardiac allograft dysfunction or hemodynamic compromise (including LVEF less than 40 % and cardiac index less than 2 L/min), (b) recurrent Grade greater than or equal to 3A/2R cellular rejection (greater than or equal to 2 episodes within the past year), or (c) a history of Grade greater than or equal to 3A/2R cellular rejection within the preceding 6 months or antibody-mediated rejection within the preceding 12 months.  (Level of Evidence: C)
• GEP testing should not be performed in pregnant women, in patients who have had a blood transfusion in the previous 30 days, or in patients who have received hematopoietic growth factors affecting leukocytes within the previous 30 days.  (Level of Evidence: C)
• GEP testing should not be used to rule out rejection in patients who have received high-dose steroids (intravenous bolus or oral augmentation) within the past 21 days or who are currently on greater than or equal to 20 mg/day of prednisone equivalent.  (Level of Evidence: C)
• Molecular testing should not be used in patients less than 15 years of age.  (Level of Evidence C)

Classification of Recommendations:

Class I: Conditions for which there is evidence and/or general agreement that a given procedure/therapy is beneficial, useful, and/or effective.

Class II: Conditions for which there is conflicting evidence and/or a divergence of opinion about the usefulness/efficacy of a procedure/therapy.

Class IIa: Weight of evidence/opinion is in favor of usefulness/efficacy.

Class III: Conditions for which there is evidence and/or general agreement that a procedure/therapy is not useful/effective and in some cases may be harmful.

Level of Evidence:

A: Data are derived from multiple randomized clinical trials or meta-analyses.

B: Data are derived from a single randomized trial, or nonrandomized studies.

C: Only consensus opinion of experts, case studies, or standard of care.

Starling and colleagues (2006) noted that while the performance of the GEP test has been validated in a large number of transplant recipients, the clinical outcomes associated with using a GEP-based strategy to monitor for rejection are currently unknown.  A multi-center randomized clinical study is currently underway to assess a GEP-based strategy, compared to a biopsy-based strategy, for evaluating rejection in cardiac transplant patients who are 2 to 5 years post-transplant.  This study will examine the impact of these 2 strategies with respect to clinical outcomes (e.g., graft dysfunction, death, and clinically apparent rejection), incidence of biopsy-related complications, quality of life, as well as resource utilization.

The AlloMap was assessed by the California Technology Assessment Forum (CTAF, 2006), which concluded that this technology does not meet CTAF's assessment criteria.  The CTAF assessment stated that GEP offers the potential for a non-invasive test that may replace endomyocardial biopsy as the gold standard for transplant rejection.  However, given the history of poor reproducibility of other GEP in the recent past, it is prudent to require independent confirmation of the CARGO Study results before widespread adoption of the AlloMap gene expression profile to detect early rejection in cardiac transplant recipients.  This is particularly true given the post-hoc change in the threshold used to define a positive test result in the study and the small size of the primary validation study.  Additionally, there are no studies published to date comparing the clinical outcomes of patients monitored with GEP to those of patients monitored with endomyocardial biopsies.

A subsequent randomized, controlled study of the Allomap GEP concluded that, among selected patients who had received a cardiac transplant more than 6 months previously and who were at a low-risk for rejection, a strategy of monitoring for rejection that involved Allomap GEP, as compared with routine biopsies, was not associated with an increased risk of serious adverse outcomes and resulted in the performance of significantly fewer biopsies.  In the Invasive Monitoring Attenuation Through Gene Expression (IMAGE) study (Pham et al, 2010), investigators randomly assigned 602 patients who had undergone cardiac transplantation 6 months to 5 years previously to be monitored for rejection with the use of GEP or with the use of routine endomyocardial biopsies, in addition to clinical and echocardiographic assessment of graft function.  The investigators performed a non-inferiority comparison of the 2 approaches with respect to the composite primary outcome of rejection with hemodynamic compromise, graft dysfunction due to other causes, death, or re-transplantation.  During a median follow-up period of 19 months, patients who were monitored with GEP and those who underwent routine biopsies had similar 2-year cumulative rates of the composite primary outcome (14.5 % and 15.3 %, respectively; hazard ratio with GEP, 1.04; 95 % CI: 0.67 to 1.68).  The 2-year rates of death from any cause were also similar in the 2 groups (6.3 % and 5.5 %, respectively; p = 0.82).  Patients who were monitored with the use of GEP underwent fewer biopsies per person-year of follow-up than did patients who were monitored with the use of endomyocardial biopsies (0.5 versus 3.0, p < 0.001).

An editorial accompanying the IMAGE trial (Jarcho, 2010) commented that the most notable implication of the IMAGE trial may be the evidence it offers that calls into question the importance of any form or routine screening for the early detection of rejection in the longer term after transplantation.  The editorialist explained that, of 34 rejection episodes identified in the GEP group in the trial, only 6 were detected solely on the basis of the GEP test.  All other episodes of rejection were associated with clinical manifestations of heart failure or echocardiographic evidence of allograft dysfunction.  "This observation suggests that, even if rejjection is not identified until graft dysfunction is present, the clinical outcomes may not be substantially worse than when rejection is detected early."  Other limitations of the trial include the fact that the investigators only enrolled patients who had undergone transplantation at least 6 months previously, a group that was a much lower risk of rejection than patients within 6 months of transplantation.  In addition, the non-inferiority margin was wide; the actual 95 % CI was consistent with as much as a 68 % increase in risk with the GEP strategy.

A re-assessment of the AlloMap by the California Technology Assessment Forum (Tice, 2010), considering the results of the IMAGE trial, concluded that this technology meets CTAF's assessment criteria.  The CTAF assessment stated that the AlloMap GEP has a high negative-predictive value, but a low positive-predictive value.  Thus, it may be useful to avoid biopsy in stable patients, but the high false-positive rate precludes its use to definitively diagnose acute cellular rejection.  The assessment states that endomyocardial biopsies will still need to be performed in all patients with elevated AlloMap scores and all patients with clinical signs of rejection.  CTAF found that the IMAGE trial provides data supporting the non-inferiority of a monitoring strategy for heart transplant patients incorporating the AlloMap GEP in lieu of routine endomyocardial biopsy.  However, the data only support such strategies in patients more than 1 year post-transplant.  CTAF stated that more data are needed to confirm the tests utility earlier in the post-transplant period when the majority of endomyocardial biopsies are performed.

Mehra and Uber (2007) stated that clinicians have entered a new era for managing heart transplant recipients with the use of multi-marker GEP.  Early after transplantation, when steroid modification is the main concern, gene expression testing might aid in optimizing the balance of immunosuppression, defraying the occurrence of rejection, and avoiding crisis intervention.  Late after transplantation, the reliance on endomyocardial biopsy could be reduced.  These advances, if continually validated in practice, could result in decreased immunosuppression complications, lesser need for invasive surveillance, and more clinical confidence in immunosuppressive strategies.