National health insurance provider Anthem Blue Cross and Blue Shield has decided to cover XDx's AlloMap heart transplant rejection test in clinically stable patients in order to assess their risk for rejection.
"AlloMap molecular expression testing is considered medically necessary as a non-invasive method of determining the risk of rejection in heart transplant recipients between one and five years post transplant," Anthem wrote in an updated medical policy dated May 19. Outside of this setting, the test is considered "investigational and not medically necessary."
Currently, the gold standard for monitoring whether a heart transplant patient is at risk for rejection is through endomyocardial biopsy, which is an invasive procedure that requires a tissue sample from the innermost lining of the heart and can lead to adverse events. According to Anthem, transplant patients are usually biopsied weekly for six weeks after they receive their new heart, then the biopsies taper off to biweekly until the third month, monthly to six months, and then every one to three months depending on physicians' recommendations.
AlloMap measures the expression levels of 20 genes in order to predict rejection risk. The US Food and Drug Administration granted a 510(k) clearance for the test in 2008.
In 2010, the International Society of Heart and Lung Transplantation issued guidelines recommending the use of AlloMap to "rule out acute heart rejection (grade 2 or greater) in appropriate low-risk patients between six months and five years post-transplant." The ISHLT gave the AlloMap test a "B" for the level of evidence on which this recommendation was based. Cardiac biopsy has a "C" grade from ISHLT, and there is no intervention that has received an "A" for heart transplant rejection.
Anthem based its recommendation for AlloMap on the results from several studies, among them, the Cardiac Allograft Rejection Gene Expression Observation Study, or CARGO, and the Invasive Monitoring Attenuation through Gene Expression study, or IMAGE. Based on published data, Anthem identified several "proposed benefits" of the test, including AlloMap's ability to assess mild rejection, for which tissue biopsies may be less accurate. The test can also potentially be used to monitor patients' physiologic responses as they wean off of steroids.
However, Anthem also found that the test is not effective at monitoring rejection within the first six months of transplantation, and "it is yet unclear what a high AlloMap score might mean in the setting of no histologic rejection."
According to the study authors of the IMAGE trial, published in the New England Journal of Medicine in May 2010, although AlloMap was found to be noninferior to cardiac biopsies in monitoring whether patients who had received heart transplants at least six months prior were experiencing acute cellular rejection, many of the episodes of transplant rejection in the gene-profiling arm were identified by observation of "overt symptoms of heart failure or echocardiographic evidence of graft dysfunction," not by gene expression patterns. Out of 34 transplant rejection cases in the gene-expression group — who were monitored observationally, by genetic testing, and by echocardiographs — only six were detected through profiling with AlloMap alone, according to the paper (PGx Reporter 04/13/2011).
"These observations raise the possibility that clinical observation may detect the majority of serious rejection episodes," the IMAGE study authors pointed out in the NEJM paper, adding that most transplant centers in the US still perform biopsies since there hasn't been a comparison of patient outcomes when transplant rejection is monitored by biopsy versus clinical observation.
Anthem also cited the review conducted by the California Technology Assessment Forum, which considered available published evidence on the AlloMap test in 2010, including six observational studies and one randomized trial. CTAF concluded after its evidence review that the IMAGE trial provides data "supporting the non-inferiority of a monitoring strategy for heart transplant patients incorporating the AlloMap gene expression profile in lieu of routine endomyocardial biopsy."
However, in line with Anthem's stance, CTAF found that the available data only support using the gene expression test to monitor patients more than a year post-transplant. "More data are needed to confirm the test's utility earlier in the post-transplant period when the majority of endomyocardial biopsies are performed," CTAF said.
CTAF added that the AlloMap test "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." As a result, "endomyocardial biopsies will still need to be performed in all patients with elevated AlloMap scores and all patients with clinical signs of rejection."
Insurers other than Anthem that cover AlloMap under similar policies include Medicare and Aetna.