There is not enough evidence to determine whether or not erythropoiesis-stimulating agents (ESAs) extend renal graft survival. This was the consensus of the Medicare Evidence Development & Coverage Advisory Committee, which met in Baltimore in January.
The average vote of the committee members on this point was 1.33 on a scale of 1 to 5, meaning they had “low confidence” that there was adequate evidence to make such a determination on ESAs and graft survival.
“We have evidence that improving anemia would improve graft survival; we have evidence that ESA would improve anemia, but the connection there is a fairly good leap, and we don't have prospective studies to show that,” said health policy consultant and Committee Vice Chair Saty Satya-Murti, MD.
“All we rely on is two discrete pieces of evidence and then link them together and say ergo there should be an improvement, but this to me is the largest hiatus so far.”
The panel gave a vote of intermediate confidence that current panel-reactive antibody (PRA) assays predict renal transplant graft survival in individual patients, with an average confidence score of 3.25 to 3.33, and a vote of low confidence that there is enough evidence on whether or not blood transfusions decrease renal transplant graft survival, with an average vote of 1.56 to 1.58.
“I was concerned that the specific questions that were asked of the panel and were published ahead of time were slightly off-the-mark questions that really couldn't be answered by the available medical data and published articles,” said William Harmon, MD, Director of Pediatric Nephrology at Children's Hospital Boston and Professor of Pediatrics at Harvard Medical School, in a phone interview after the meeting.
“Indeed that came through because much of the conclusion of the meeting was that there was not sufficient data to answer those questions. I think those specific questions are not ones we've been terribly concerned about in the transplant community, and I was not surprised that that was the conclusion they reached.”
Dr. Harmon, who is a member of the Public Policy Board of the American Society of Nephrology (ASN), spoke on behalf of the ASN at the meeting.
“The issue is that these erythropoietin-stimulating agents, the ESAs, were developed and are indicated for treatment of anemia, and that's their primary indication,” he said.
“They may have secondary benefits. In the transplant community, we think there may be some benefit to their use both before and after transplantation, but since improvement of kidney transplant graft survival is not one of the intended benefits of the drug, it's difficult to do studies and then to develop the data to show that there is either benefit or harm from doing it.”
Asking the Right Question
The Centers for Medicare and Medicaid Services (CMS) called the MEDCAC meeting to review the available evidence on the use of ESAs to affect kidney transplant graft survival in patients who have chronic kidney disease (CKD) and anemia, as some parties claim that prior ESA use may predict the long-term success of subsequent renal transplantation in patients with CKD, according to the agency.
CMS received a formal request for a national coverage determination for ESAs in the treatment of CKD and dialysis-related anemia. The expected completion of the national coverage analysis is June 16, and the proposed decision memo due date is March 16.
“I don't believe that we have done complete homework yet, and I think it was clearly brought up at the meeting that more information, more homework, needs to be done, and more evaluation of what's available out there,” said Ruben Velez, MD, President-Elect of the Renal Physicians Association (RPA) and President & CEO of Dallas Nephrology Associates, in a phone interview after the meeting.
“That would be the appropriate thing to do before CMS develop a policy that will probably restrict the use of ESAs, but we want to be sure that all the work has been done before this happens.” Dr. Velez spoke on behalf of the RPA at the meeting.
While the questions posed to the committee are important, they may have missed the mark, he noted.
“I still feel that the right question was not asked,” he said. “The question that I think should have been asked in this arena would be more in the direction of, what is the impact of ESA in transplantation—in the whole transplantation world, not just in transplant survival.
“When you do transplant survival, you're limiting the question to only people who were transplanted, so you're missing the other huge number of patients who for some reason are not transplanted or are not transplantable. I think the right question is, what is the total impact of ESA in the transplant patient in general, not just transplant survival.”
Type 2 Error
Dr. Velez's point brings up one of the major criticisms of the technology assessment (TA) on the impact of pretransplant red blood cell transfusions in renal allograft rejection that was presented at the meeting by C. Michael White, PharmD, of the University of Connecticut/Hartford Hospital Evidence-Based Practice Center (EPC). Much of the discussion at the meeting centered on the assessment.
While the TA concluded that the data on the topic generally is weak and the strength of evidence low to insufficient, it did also conclude that transfusions generally have a beneficial-to-neutral effect on renal allograft outcomes, with the needle moving from beneficial toward neutral over differing time periods.
However, the technology assessment noted a potential confounder—in some studies, those who developed high PRAs with transfusion did not undergo transplantation.
“I wanted to reiterate my strong concern that one of the problems with this weak evidence that seems to have some kind of a neutral or beneficial effect on transfusions related to graft outcome is there's a substantial type 2 error effect,” said Lawrence T. Goodnough, MD, Director of the Transfusion Service at the Stanford Medical Center and Associate Medical Director of the Stanford Blood Center, who spoke at the meeting.
“We're not counting the patients who were censored, who were sensitized by transfusions and never came to transplant.”
Indeed, some of the distinctions critical to the discussion at hand were not addressed by the technology assessment.
“A difference that may be important for you but can't be answered by our technology assessment: What is the impact of being sensitized and not getting a transplant on outcomes?” Dr. White said at the meeting. “That's not something that we were charged with assessing and not something we did assess.”
Another point of discussion during the proceedings had to do with the historical approach to preventing transplant rejection versus the modern approach in the immunosuppression era.
“One of the issues that was raised at the meeting was that there may be a benefit to blood transfusions prior to transplantation, and therefore the use of erythropoietin-stimulating agents may indeed be harmful insofar as it prevents people from getting transfusions,” Dr. Harmon said.
“That seems a little convoluted, but indeed there has been some basis for that concept. Prior to the development of modern immunosuppressants, there clearly was a beneficial effect of pre-transplant transfusions, so that people who received transfusions had better graft survival than those who had not received transfusions.
“Indeed, that was extended to what's called donor-specific transfusions, which was a process in which blood was transfused from the potential donor into the candidate recipient prior to transplant.
“If the transplant candidate did not develop sensitization, did not develop a positive crossmatch after their blood transfusion, they would get the transplant and they'd do better than expected. However, 30 percent of people who got these donor-specific transfusions became sensitized to their potential donor and therefore couldn't get the graft from the donor.
“The beneficial effect may not have been some sort of active tolerance process by the transfusion. It may have been an elimination of the potential donor-recipient pairs who were high risk or may have identified people who reacted against the blood cells and therefore would have had substantial reaction against the transplant.”
The approach is no longer practiced in this era of modern immunosuppression.
“Some of the non-transplant experts who were called went through the literature and found this old information, didn't find any new information to counter it because nobody's giving deliberate transfusion anymore, no one's looking for a transplant effect, and could conclude that there may be a beneficial effect to blood transfusions,” Dr. Harmon said. “And so they reported that to the committee.
“The bottom line was some medical phenomena, whatever kind of findings, have to be put in the context of modern treatment. What we saw 20, 30 years ago is not necessarily true today, and that's what the panel had to deal with.”
In terms of a response to the dearth of evidence on the relationship between erythropoiesis-stimulating agents and renal graft survival, the committee suggested some questions for future research.
“The panel concluded that there should be more research into the use of the ESAs and whether or not you could directly answer the question do the ESAs affect transplant outcome, either beneficial or detrimental,” Dr. Harmon said.
“To be honest, I don't think anybody's going to do that research. It's not a hot topic among the transplant community. The transplant community is much more focused on how to avoid the complications of immunosuppressants, how to better measure the response of the patients to immunosuppression.
“Although they raised some interesting scientific questions that are valid questions, I just don't see the community rising up to answer those.”
The Doctor-Patient Relationship
During the public comment period at the meeting, transplant professionals commented on the clinical path to take in the meantime, emphasizing the relationship between transfusion and sensitization and the relationship of sensitization with more time on the waiting list, a lower chance of ever getting a transplant, and a higher chance of graft loss if transplanted.
“The RPA is concerned that an overly restrictive ESA policy revision that does not account for the need to minimize the use of transfusions will have an unintended detrimental impact on transplant recipients' waiting list and organ survival,” Dr. Velez said at the meeting.
“The RPA recommends that the panel not allow policy revisions that could create serious patient care issues at the lower end of the hemoglobin range.
“We also urge MEDCAC to preserve the ability of physicians and patients to make individualized treatment decisions that incorporate not only the physician's clinical expertise but also the patient's preference and resulting quality of life. An effective process for determining appropriate administration of ESAs to kidney patients will include a discussion of the risks and benefits of ESA therapy.” •