ATC 2012 Report – Everolimus gives results similar to MMF, study says

by Thomas R. Collins – Using everolimus for immunosuppression in heart transplant recipients, along with a reduced amount of cyclosporine, produces results comparable to mycophenolate mofetil, according to 2-year results from a randomized trial presented here at the 2012 American Transplant Congress.

But kidney function was reduced for patients taking everolimus compared to the MMF group before stabilizing, said Jon Kobashigawa, MD, Director of the Heart Transplant Program at Cedars-Sinai Medical Center in Los Angeles.

The trial, known as the A2310 Study, includes more than 700 patients randomized into three groups. In one, heart transplant recipients were given 1.5mg of everolimus a day, along with steroids and a reduced dose of cyclosporine.  In another, transplant recipients were given 3g a day of MMF, plus a standard dose of cyclosporine, plus steroids.

Dr Kobashigawa said the trial is the largest in heart transplantation.

There was also a third group, with a dose of 3mg a day of everolimus, but enrollment into that arm was stopped because of a higher mortality rate within three months after the transplants.

The use of induction therapy depended on the center, with some using basiliximab, some using thymoglobulin or no induction.

At 12 months, results had showed that the everolimus regimen with reduced cyclosporine was non-inferior for efficacy, based on biopsy-proven acute rejection of grade 3A or higher; acute rejection associated with haemodynamic compromise, or problems with blood flow; graft loss; re-transplant; or death.

Those results also showed a statistically significant difference in the change in maximum intimal thickness — 0.03mm in the everolimus 1.5mg group compared to 0.07 in the MMF group. Also at 12 months, the percentage of patients with cardiac allograft vasculopathy (CAV) — vascular injury due to a variety of factors associated with heart transplants — was significantly lower in the 1.5mg everolimus group — 12.5% to 26.7%. CAV is measured by the pace of intimal thickening.

Dr Kobashigawa drew attention to this finding.

“This is very important because validation studies have demonstrated that when you do have this rapidly progressing intimal thickening… at five years there’s an increase in death, increase in non-fatal major adverse cardiac events, such as myocardial infarction and heart failure and increase in angiographic atherosclerosis,” he said. “So certainly this may be a marker for long-term outcome.”

At 24 months, researchers gauged composite efficacy failure in more detail, along with renal function and safety events.

After the two years, 39.4% of patients in the everolimus 1.5mg group had suffered composite efficacy failure, compared to 41.3% in the MMF group — not a statistically significant difference.

Failure because of acute rejection associated with haemodynamic compromise occurred in 4.3% of everolimus patients and in 5.2% of MMF patients, which was not statistically significant.

Biopsy-proven acute rejection of at least grade 3A was also not statistically different between the groups.

In the first 12 months of the study, there were 14 patients (5%) who died due to infections in the everolimus group, compared to 4 (1.5%) in the MMF group. There were two cases of deaths due to infection in each group between the first and second year.

In all, there were 21 deaths in the everolimus group and 13 in the MMF group in the first year, and 8 and 12 deaths, respectively, in the second year.

Overall death rates were not statistically significant, though, Dr Kobashigawa said.

After two years, the estimated glomerular filtration rate was 58.8 in the everolimus group compared to 65.3 in the MMF group — a significant difference statistically. But researchers noted that the eGFR rates among the everolimus patients hit a plateau after six months.

“Much of this may have been due to cyclosporine drug level targets and exposure achieved,” with the MMF group staying within its exposure target but with the everolimus group sometimes above its target.

As for adverse events, there was a higher chance of suffering anaemia and pericardial effusion in the everolimus arm (relative risk of 1.24 compared to MMF for anaemia and 1.5 for pericardial effusion). But there was a lower chance of a decrease in white blood cell count (RR of 0.52 compared to MMF).

“The safety profile,” Dr Kobashigawa said, “was more or less as expected for everolimus and mycophenolate.”