Everolimus With Reduced Tacrolimus Improves Renal Function in De Novo Liver Transplant Recipients: A Randomized Controlled Trial

Abstract

In a prospective, multicenter, open-label study, de novo liver transplant patients were randomized at day 30±5 to (i) everolimus initiation with tacrolimus elimination (TAC Elimination) (ii) everolimus initiation with reduced-exposure tacrolimus (EVR+Reduced TAC) or (iii) standard-exposure tacrolimus (TAC Control). Randomization to TAC Elimination was terminated prematurely due to a higher rate of treated biopsy-proven acute rejection (tBPAR). EVR+Reduced TAC was noninferior to TAC Control for the primary efficacy endpoint (tBPAR, graft loss or death at 12 months posttransplantation): 6.7% versus 9.7% (−3.0%; 95% CI −8.7, 2.6%; p<0.001 for noninferiority [12% margin]). tBPAR occurred in 2.9% of EVR+Reduced TAC patients versus 7.0% of TAC Controls (p = 0.035). The change in adjusted estimated GFR from randomization to month 12 was superior with EVR+Reduced TAC versus TAC Control (difference 8.50 mL/min/1.73 m2, 97.5% CI 3.74, 13.27 mL/min/1.73 m2, p<0.001 for superiority). Drug discontinuation for adverse events occurred in 25.7% of EVR+Reduced TAC and 14.1% of TAC Controls (relative risk 1.82, 95% CI 1.25, 2.66). Relative risk of serious infections between the EVR+Reduced TAC group versus TAC Controls was 1.76 (95% CI 1.03, 3.00). Everolimus facilitates early tacrolimus minimization with comparable efficacy and superior renal function, compared to a standard tacrolimus exposure regimen 12 months after liver transplantation.

De Novo Sirolimus and Reduced-Dose Tacrolimus Versus Standard-Dose Tacrolimus After Liver Transplantation: The 2000–2003 Phase II Prospective Randomized Trial

“…Though no increased rates of HAT were observed, there were increased rates of discontinuations and risk of minor infections in the everolimus arm. In a separate multicenter open-label study, de novo liver transplant patients were randomized at 30 days to everolimus plus reduced tacrolimus, tacrolimus (standard of care) or everolimus monotherapy (arm subsequently discontinued) (25). Similar rates of graft loss or death and lower rates of acute cellular rejection were noted in persons receiving everolimus and reduced-dose tacrolimus.…”

“…Furthermore, subsequent single-center observational studies (not clinical trials) comparing de novo sirolimus initiation at time of LTx have not shown an increased risk of graft failure or HAT as compared to other strategies, which underscore the importance of making the data of this multicenter study available to clinicians (15,20). Second, given emerging literature on the role of another mTOR inhibitor, everolimus, it is important to gauge whether similarities exist in the risk and benefit profile for these two medications (21)(22)(23)(24)(25)(26)(27). Above all, transparency in the full presentation of the results of the study are important given that it may impact our current approach to management of immunosuppression after LTx.…”

Current Status of Immunosuppression in Liver Transplantation

“…56,57,60 Two recently published studies have shown a better glomerular filtration rate in Everolimus group as compared to CNIs. 61,62 Metabolic Syndrome (MS)…”

Complications of Post-Transplant Immunosuppression

“…Its half life is shorter and is administred twice daily. Everolimus is currently undergoing clinical trials in transplantation in attempt to reduce the nephrotoxicity of calcineurin inhibitors [8,9]. The adverse effects of mTOR inhibitors include thrombocytopenia, leukopenia, anemia, arthralgias, hyperlipidemia, pneumonitis, and diarrhea.…”