A 1-year randomized controlled study of everolimus versus mycophenolate mofetil with reduced-dose cyclosporine in maintenance heart transplant recipients.
Bara C, Dengler MA, et alTransplantation Proceedings 2013; 45(6): 2387-2392.
Aims
To investigate the non inferiority of everolimus with reduced cyclosporine A versus mycophenolate mofetil with reduced cyclosporine A in improving renal function in maintenance heart transplant patients.
Interventions
Patients received everolimus with a start dose of 0.75mg twice a day or mycophenolate mofetil at 2g/d, both groups received reduced dose cyclosporine A.
Participants
70 primary heart transplant recipients with impaired renal function.
Outcomes
The primary outcome was the serum creatinine value at six months after randomization. The secondary outcomes included the estimated glomerular filtration rate, the incidence of acute rejection (AR), suspected AR, AR associated with haemodynamic compromise, major adverse cardiac events, and a composite endpoint of graft loss, death, loss to follow up, AR≥3A, suspected AR and AR associated with hemodynamic compromise.
Follow-up
6 and 12 months.
CET Conclusions
This study reports the results of a non-blinded RCT comparing everolimus and MMF in conjunction with low-dose cyclosporine in stable heart transplant recipients. The aim was to demonstrate non-inferiority; this aim was not reached with statistically (but perhaps not clinically) significant worse renal function seen in the everolimus group at 6 months. These findings are perhaps not surprising given that previous studies in renal and cardiac transplant recipients have demonstrated synergistic nephrotoxicity with the combination of an mTOR inhibitor and CNI. Perhaps for this reason, and the dwindling number of patients on cyclosporine-based immunosuppression, the present study failed to recruit the required number of participants and was terminated early. Other criticisms are the lack of recruitment dates given in the paper, lack of information about concomitant steroid use, and high rates (>30% in both arms) of protocol deviations. It should also be noted that cyclosporine reduces biliary excretion of MPAG, so dose reductions may increase exposure to MPA. This effect was not accounted for in the current trial, and no measurements of trough CsA or MPA levels are presented. What is clear is that the very low levels of CsA exposure targeted, in combination with MMF, is unlikely to represent sufficient immunosuppression in even stable cardiac transplant recipients.
Data analysis
Strict intention-to-treat analysis
Trial registration
Not reported.