“On the good side, it shows that what most people are using—tacrolimus-MMF—is pretty darn good, and it's going to be hard to have something else replace that.
“Sirolimus is not very well tolerated, and some of the things we thought it might be good for, it's not showing. Those include viral infections and NODAT [new-onset diabetes after transplantation]. Also, sirolimus is supposed to have an antineoplastic, anti-malignancy property, but it didn't. There were just as many cancers, if not more, in the sirolimus arms than there were in the TAC-MMF arm.”
Less Acute Rejection
The researchers' objectives in conducting this trial were twofold.
“Number one, we wanted to compare the newer agents of sirolimus versus mycophenolate mofetil in combination with one of the calcineurin inhibitors [CNIs], and the other thing that we wanted to accomplish was to evaluate simultaneously very low trough levels for TAC or cyclosporine when they are used in combination with these two other agents,” Dr. Guerra said.
In order to accomplish this, Dr. Guerra and colleagues randomized 150 recipients of a deceased donor or non-HLA-identical living donor first kidney to one of three groups—tacrolimus-MMF, tacrolimus-sirolimus, and cyclosporine-sirolimus—with 50 patients in each arm.
Randomization took place between May 2000 and December 2001, and median follow-up was eight years posttransplant. All participants received daclizumab induction and maintenance corticosteroids.
Acute rejection rates were significantly lower in the tacrolimus-MMF group—12%—compared with the tacrolimus-sirolimus and cyclosporine-sirolimus groups—30% and 28%, respectively. The rate of death with a functioning graft was significantly higher in the tacrolimus-sirolimus group—26%—compared with the tacrolimus-MMF and cyclosporine–sirolimus groups—12% and 4%, respectively.
Mean estimated glomerular filtration rate (eGFR) was consistently higher in the tacrolimus-MMF group. For example, at 84 months, the mean eGFR in recipients of a younger donor kidney was 72.8 mL/min/1.73 m2 with tacrolimus-MMF, 65.2 mL/min/1.73 m2 with tacrolimus-sirolimus, and 60.5 mL/min/1.73 m2 with cyclosporine-sirolimus. In recipients of an older donor kidney, mean eGFR at that same time point was 60.7 mL/min/1.73 m2 in the tacrolimus-MMF group, 45.8 mL/min/1.73 m2 in the tacrolimus-sirolimus group, and 45.4 mL/min/1.73 m2 in the cyclosporine-sirolimus group. In terms of proteinuria, there were no statistical differences observed among the three groups at Months 36 and 84, but levels trended lower in the tacrolimus-MMF arm.
While the incidence of infection requiring hospitalization was comparable across treatment groups, there was a trend toward fewer viral infections in patients receiving tacrolimus-MMF.
Similarly, while the risk for developing NODAT did not significantly differ across the three arms, the condition was less common with tacrolimus-MMF—19% of patients, versus 32% with tacrolimus-sirolimus and 31% with cyclosporine-sirolimus. Mean cholesterol and triglyceride levels, on the other hand, were consistently and significantly lower in the tacrolimus-MMF group.
“The other important conclusion that we made was that many times centers shoot for very high trough levels of tacrolimus to try to avoid rejection, but we were still able to avoid rejection in our population while using it to very low levels,” Dr. Guerra said.
Astellas Pharma US provided partial salary support to the Kidney and Kidney/Pancreas Transplant Program at the University of Miami for the completion of this study, but Astellas representatives had no direct involvement in the study, the authors disclosed.
‘Notoriously Difficult to Use’
The sirolimus regimens proved hard to handle. The protocol violation rates were significantly higher in the groups receiving that agent—68% of patients in the tacrolimus-sirolimus group and 78% of patients in the cyclosporine-sirolimus group, compared with 18% in the tacrolimus-MMF group. In terms of treatment discontinuation, 46% of patients discontinued sirolimus in the tacrolimus-sirolimus or the cyclosporine-sirolimus groups, while 10% discontinued mycophenolate mofetil in the tacrolimus-MMF group.
“It's been known that regimens that contain a calcineurin inhibitor and sirolimus are notoriously difficult to use and have been related to poorer outcomes, so that part is not terribly surprising,” said Bruce Kaplan, MD, when asked to comment on the study in a phone interview. “The major problem has been enhancement of the calcineurin nephrotoxicity by the mTOR [mammalian target of rapamycin] inhibitor, by sirolimus,” added Dr. Kaplan, who is Kathy and Harry Jentsch Professor of Medicine, Professor of Pharmacology and Surgery, Chief of the Section of Nephrology, and Medical Director of Transplantation at the University of Arizona College of Medicine.
“What is perhaps surprising, but is backed up now by other data, is the greater mortality in the group that receives sirolimus,” he said. “This is now one of I believe two or three reports out on greater mortality, so in terms of robustness, this may be a real phenomenon, and that may be the most important part of this.”
The results add to the growing body of evidence prescribing caution when it comes to sirolimus.
“I think it's a further setback to the idea of using at least tacrolimus or a CNI with sirolimus,” Dr. Kaplan said. “I want to be careful that we don't know if there are any differences with everolimus, the other mTOR inhibitor—this was with sirolimus—and I think it just adds another note of caution to what is already a combination that's fraught with caution.
“Rather than condemn the drug, I'd say perhaps it's the way we are using it. Certainly I think many of us in the community, if someone has a malignancy, seriously consider using sirolimus.”
Sirolimus can't be used with a calcineurin inhibitor safely, as indicated by the trial, and it can't be used without a calcineurin inhibitor, as it provides inadequate protection against rejection, Dr. Brennan noted.
“Sirolimus should be reserved for very special situations, and I'm not sure what those situations are now,” he said.© 2011 Lippincott Williams & Wilkins, Inc.