Originally published Feb. 7.
By Turna Ray
In the coming months, researchers from XDx and Cedars-Sinai Heart Institute hope to announce results from a key clinical trial designed to show the usefulness of XDx's AlloMap test in gauging heart transplantation patients' risk of rejection in the critical months immediately following surgery.
The results of this study, if positive, may help bolster AlloMap's use as a routine medical tool for determining which cardiac transplant patients are at low risk of rejection two to six months after they've received a new heart.
Around 2,000 heart transplants are performed each year in the US. Currently, endomyocardial biopsies are the standard method by which physicians track whether patients are taking to their new hearts. The invasive and painful procedure – which requires a resection of a small piece of the heart tissue – can lead to serious adverse events in patients, such as perforations of the heart and lung, or death.
By comparison, AlloMap is a blood test that measures the expression of 20 genes and yields a score of between zero and 40. The lower the score, the lower the risk of transplant rejection, says the company. By growing adoption of this test in medical practice, XDx is hoping to reduce the number of endomyocardial biopsies that a transplant patient must endure — up to one per month in the first year following surgery for some patients.
At the Personalized Medicine World Conference in January, lead study investigator Jon Kobashigawa from the Cedars-Sinai Heart Institute said that results from the Early Invasive Monitoring Attenuation through Gene Expression, or EIMAGE, study, will likely be presented in the spring. According to ClinicalTrials.gov, the study has enrolled 40 patients.
The randomized EIMAGE trial is comparing the safety and efficacy of the AlloMap test to endomyocardial biopsy in assessing the risk of heart transplant rejection in patients who have undergone a transplant procedure two to six months prior. Patients in the study will be followed for up to 18 months.
"The key period of time, the first six months after transplantation, is when the most rejections occur," Kobashigawa said.
The study's primary outcome is the impact AlloMap testing has on the development of hemodynamic compromise with rejection, graft dysfunction, death or re-transplantation. The study will also compare the number of biopsies performed in the AlloMap arm versus the biopsy arm. Researchers will further analyze whether the risk score provided by AlloMap can inform whether physicians should reduce administration of corticosteroids after transplantation.
XDx launched AlloMap as a laboratory-developed test in 2005. Three years later, the US Food and Drug Administration approved the test as an in vitro diagnostic multivariate index assay. The test is indicated as a diagnostic to help doctors identify patients who have a low probability of rejecting their heart transplants. According to the FDA-cleared label, patients who are younger than 15 years or have had their new hearts for less than two months should not be monitored for rejection with AlloMap.
In a study published in the New England Journal of Medicine in May 2010, researchers led by Stanford University Medical Center's Michael Pham reported that AlloMap wasn't inferior to cardiac biopsies in monitoring whether patients who had received heart transplants at least six months prior were experiencing acute cellular rejection. In that study, called Invasive Monitoring Attenuation through Gene Expression, or IMAGE, patients who were profiled for the risk of transplant rejection by gene expression testing, monitored clinically, and received echocardiographic assessments had fewer biopsies and fewer adverse events than patients who were followed with just endomyocardial biopsies (PGx Reporter 4/13/2011).
Based on the results from IMAGE, the International Society of Heart and Lung Transplantation included AlloMap in its guidelines, recommending the test as a tool to rule out acute cardiac rejection in low-risk patients who had received a heart transplant between six months and five years prior. The ISHLT also gave AlloMap a higher evidence grading than cardiac biopsy.
A weakness of this earlier study was that the majority of study participants, around 69 percent, had heart transplants between 12 and 36 months prior to entering the study, and were therefore at low risk of rejection. The EIMAGE trial will try to mitigate this issue by enrolling patients who had surgery within two to six months before enrolling,
AlloMap has a 99 percent negative predictive value and a positive predictive value of 7.8 percent when the cut off test score separating high risk and low risk patients is 34. Therefore, while the test can be used to inform whether a patient will not experience a transplant rejection, it cannot inform physicians if a patient will definitely reject a transplant.
"When there is a rejection there is a risk of death for the patient. So we wanted to be absolutely sure when we were saying that a patient isn't rejecting, meaning the physician was not going to do anything to that patient," XDx CEO Pierre Cassigneul said at the PMWC. "We traded a very high negative predictive value for a relatively low positive predictive value. Meaning …when we say there is a high risk, it only means there is a high risk. It doesn't mean the patient is actually rejecting."
According to the NEJM paper on the IMAGE trial, many 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.
"These observations raise the possibility that clinical observation may detect the majority of serious rejection episodes," the study authors pointed out. They noted that absent a comparison of patient outcomes when transplant rejection is monitored by biopsy versus clinical observation, most transplant centers in the US still perform biopsies.
Meanwhile, in an effort to raise patient awareness and grow physician adoption of AlloMap, XDx has been reaching out to hospital administrators, nurse coordinators, advocacy organizations, patient groups, and payors. According to the company, it has performed 34,000 AlloMap tests on 9,400 patients to date. Aetna, Highmark, Anthem Blue Cross Blue Shield, and several other payors reimburse for the test. However, other payors, such as Cigna, consider AlloMap investigational and don't cover it. As of Jan. 1, 67 percent of heart transplantation patients are covered for the test, according to Cassigneul.
AlloMap carries a price tag of more than $3,000 per test. In comparison, cardiac biopsies can range from between $4,000 and $10,000 each time. Given that heart transplant patients often undergo 12 biopsies in the first year following transplantation, positive results from the EIMAGE study would bolster XDx's cost-effectiveness arguments for AlloMap with payor groups.
According to Kobashigawa, the EIMAGE trial is the first study to critically evaluate the use of AlloMap within the first six months post transplantation in a randomized setting. "The question is, 'Will AlloMap become routine use in heart transplant?'" Kobashigawa posited. "Stay tuned."
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