Comparing everolimus-based immunosuppression with reduction or withdrawal of calcineurin inhibitor reduction from six months after heart transplantation: the randomized MANDELA study.
Barten, M. J., Hirt, S. W. et al. (2019).American Journal of Transplantation: [record in progress].
Aims
This study aimed to compare everolimus-based immunosuppression with reduction or withdrawal of calcineurin inhibitor (CNI) reduction from six months after heart transplantation.
Interventions
Patients were randomised 6 months after transplant to either (1) convert to CNI-free immunosuppression with everolimus and mycophenolic acid (MPA) or (2) to continue reduced-exposure CNI with concomitant everolimus.
Participants
162 patients that were 6 months post-heart transplantation (18-70 years; eGFR >30-<100). Patients were only eligible if between 3 and 6 months post-transplantation were receiving tacrolimus at a trough concentration of 5–10 ng/mL or cyclosporine (CsA) with tacrolimus in the range 100–200 ng/mL, with either everolimus (C05–10 ng/mL) or MPA, and corticosteroids.
Outcomes
Primary outcomes were assessed as eGFR at month 18 post-transplant based on the MDRD formula. Secondary outcomes was renal function, assessed as creatinine clearance, serum creatinine and creatinine slope, occurrence of treatment failure, acute rejection associated with haemodynamic compromise, graft loss or retransplantation, death or loss to follow-up, the incidence of major adverse cardiac events (MACE), myocardial infarction or coronary artery bypass grafting);and safety and tolerability parameters including incidence of adverse events, serious adverse events, adverse events leading to stu
Follow-up
18 months.
CET Conclusions
The MANDELA trial compared two renal-sparing regimens, i.e. everolimus plus mycophenolic acid (calcineurin-inhibitor (CNI) free) versus reduced exposure CNI and everolimus (reduced CNI) in heart transplant patients randomised at 6 months posttransplant. Patients were eligible if the eGFR was >30 mL/min/1.73m2¬¬¬, had not undergone changes to the immunosuppressive regimen due to immunologic reasons, and did not have severe rejection or intractable immunosuppression-related complications or side effects. Patients were randomised by an automated, central system hence allocation was concealed. The sample size calculation was based on the primary endpoint eGFR at 18 months and showed that 172 patients were needed for 90% power. The analysis was based on intention to treat (ITT) using the last observation carried forward method for missing data. 162 patients were randomised and 145 patients were included in the ITT analysis. eGFR at baseline was similar between groups but at 18 months eGFR was significantly higher in the CNI-free group (difference 11.3 mL/min/1.73m2).
Data analysis
Strict intention-to-treat analysis
Trial registration
ClinicalTrials.gov - NCT00862979