A Randomized Trial of Everolimus and Low-dose Cyclosporine in Renal Transplantation: With or Without Steroids?
Ponticelli C, Carmellinib M, Tisonec G, et al.Transplantation Proceedings 2014; 46:3375-3382.
Aims
To demonstrate the effects of early steroid discontinuation and noninferiority of a steroid withdrawal regimen in comparison with standard triple therapy at 1 year post-transplant.
Interventions
Patients were randomized to standard triple therapy with CsA, twice-daily everolimus, and steroids (group A), steroid-free immunosuppression (group B), or triple therapy given in a single morning administration (group C).
Participants
184 patients >18 years old at transplant receiving a first or second kidney transplant from a donor aged ≥14 years.
Outcomes
Primary outcomes were treatment failure rate (composite end point of biopsy-proven acute rejection, graft loss, death, or loss to follow-up). Secondary outcomes were death-censored graft survival, graft survival and patient survival, glomerular filtration rate (eGFR), creatinine clearance, biopsy-proven acute rejection (BPAR) rate, incidence of new onset diabetes after transplantation (NODAT), cholesterol, blood pressure, CMV infection, anaemia, proteinuria and cardiovascular risk.
Follow-up
12 months.
CET Conclusions
In this multicentre randomised prospective controlled trial investigators failed to demonstrate non-inferiority of early steroid withdrawal in transplant recipients treated with everolimus, low dose cyclosporine (CSA) and steroids, the steroids being withdrawn at around 6 weeks after randomisation which took place at month 3. There were three arms in the trial, but recruitment was very slow in the group that was to receive standard triple therapy once per day and this arm was eventually discontinued. Group A – triple therapy with CSA, twice daily everolimus and steroids. Group B – steroid withdrawal around 6 weeks after randomisation. All patients received Basiliximab induction and high dose steroids. Primary endpoint was a composite endpoint of death, graft loss, biopsy proven acute rejection and loss to follow up between randomisation and month 12. Although 330 patients were eligible for enrolment only 184 met the criteria for enrolment, 71 for Group A and 68 for Group B . Using an intention to treat analysis (139 patients) and per protocol analysis (135 patients) there was really no difference between the groups and the steroid withdrawal group could not be shown to be non-inferior to the standard triple therapy with twice daily everolimus. Thus no conclusive statements could be made by the authors concerning non-inferiority of the steroid withdrawal regime. The authors feel that additional studies with longer follow up are required but that their arguments for redoing this are not very persuasive. They also seem unaware of the systematic review by Knight et al (2010) showing a reduction in cardiovascular risk factors with steroid withdrawal.
Data analysis
Per protocol analysis
Trial registration
The EVIDENCE study: ClinicalTrials.gov - NCT01023815.