Everolimus Versus Mycophenolate Mofetil in Heart Transplantation: A Randomized, Multicenter Trial

Abstract

In an open-label, 24-month trial, 721 de novo heart transplant recipients were randomized to everolimus 1.5 mg or 3.0 mg with reduced-dose cyclosporine, or mycophenolate mofetil (MMF) 3 g/day with standarddose cyclosporine (plus corticosteroids ± induction). Primary efficacy endpoint was the 12-month composite incidence of biopsy-proven acute rejection, acute rejection associated with hemodynamic compromise, graft loss/retransplant, death or loss to follow-up. Everolimus 1.5 mg was noninferior to MMF for this endpoint at month 12 (35.1% vs. 33.6%; difference 1.5% [97.5% CI: -7.5%, 10.6%]) and month 24. Mortality to month 3 was higher with everolimus 1.5 mg versus MMF in patients receiving rabbit antithymocyte globulin (rATG) induction, mainly due to infection, but 24-month mortality was similar (everolimus 1.5 mg 10.6% [30/282], MMF 9.2% [25/271]). Everolimus 3.0 mg was terminated prematurely due to higher mortality. The mean (SD) 12-month increase in maximal intimal thickness was 0.03 (0.05) mm with everolimus 1.5 mg versus 0.07 (0.11) mm with MMF (p < 0.001). Everolimus 1.5 mg was inferior to MMF for renal function but comparable in patients achieving predefined reduced cyclosporine trough concentrations. Nonfatal serious adverse events were more frequent with everolimus 1.5 mg versus MMF. Everolimus 1.5 mg with reduced-dose cyclosporine offers similar efficacy to MMF with standard-dose cyclosporine and reduces intimal proliferation at 12 months in de novo heart transplant recipients.

Everolimus Initiation With Early Calcineurin Inhibitor Withdrawal in De Novo Heart Transplant Recipients: Three-Year Results From the Randomized SCHEDULE Study

“…In our study, although numbers were low, there was a nonsignificant trend toward higher mGFR in the cohort of patients who remained on a CNI-free everolimus-based regimen versus those in whom low-dose CNI was reintroduced. The between-group differences are all the more striking given the relatively low trough concentrations of cyclosporine in the control arm compared with previous comparative trials of everolimus-based immunosuppression versus conventional cyclosporine therapy in heart transplant patients (9,10).…”

“…Everolimus does not induce the nephrotoxicity that is associated with CNI therapy. In addition, blockade of the mTOR pathway inhibits the proliferation of fibroblasts and smooth muscle cells that characterizes cardiac allograft vasculopathy (CAV), and randomized trials have shown a reduced incidence of CAV in de novo heart transplant patients receiving everolimus (9,10). Nevertheless, the optimal time for introduction of everolimus and the relative benefit of CNI withdrawal versus ongoing lowexposure CNI therapy remain uncertain, especially with regard to long-term follow-up.…”

“…In the SCHEDULE (Scandinavian heart transplant everolimus de novo study with early calcineurin inhibitors avoidance) trial, patients were randomized to everolimus with reduced CNI followed by CNI withdrawal at week [7][8][9][10][11] or to a conventional CNI-based regimen. At the end of the 12-month trial, the everolimus-treated patient cohort had significantly better renal function than the control group and significantly lower incidence of CAV, but mild to moderate acute rejection was more frequent after CNI therapy was withdrawn (11).…”

Rapamycin Prolongs Cardiac Allograft Survival in a Mouse Model by Inducing Myeloid-Derived Suppressor Cells

“…Although, survival prolongation was not due to the induction of immunological tolerance, this prolongation of allograft survival seems to have a great influence on clinical organ transplantation. Considering the facts that the acute phase mortality of organ transplantation is primarily due to infectious complications (41)(42)(43), it is an attractive alternative way to reduce systemic immunosuppression with local immunosuppression of adoptive-transfer MDSCs. These strategies can be clinically applicable and might bring paramount benefits to organ transplant recipients.…”

The Effect of Everolimus Initiation and Calcineurin Inhibitor Elimination on Cardiac Allograft Vasculopathy in De Novo Recipients: One-Year Results of a Scandinavian Randomized Trial

“…A small number of previous studies have demonstrated the feasibility of CNI minimization protocols with concomitant introduction of mTOR inhibitors early after HTx (7,9). However, the prospect of mTOR inhibitors introduction with early CNI elimination in de novo recipients has largely been considered unrealistic due to serious safety concerns (10,11).…”