Three-year Outcomes in De Novo Liver Transplant Patients Receiving Everolimus With Reduced Tacrolimus: Follow-Up Results From a Randomized, Multicenter Study

Background. Data are lacking regarding the long-term effect of preemptive conversion to everolimus from calcineurin inhibitors early after liver transplantation to avoid renal deterioration. Methods. In a prospective, multicenter, open-label study, de novo liver transplant patients were randomized at day 30 to (i) everolimus + reduced exposure tacrolimus (EVR + Reduced TAC), (ii) everolimus + tacrolimus elimination (TAC Elimination), or (iii) standard exposure tacrolimus (TAC Control). Results. Randomization to TAC Elimination was terminated prematurely due to a higher rate of treated biopsy-proven acute rejection (tBPAR) during TAC withdrawal. Of 370 patients who completed the 24-month core study on-treatment, 282 (76.2%) entered an additional 12-month extension phase. The composite efficacy failure endpoint (tBPAR, graft loss or death) occurred in 11.5% of EVR+ Reduced TAC patients versus 14.6% TAC Controls from randomization to month 36 (difference, -3.2%; 95% confidence interval, -10.5% to 4.2%; P = 0.334). Treated BPAR occurred in 4.8% versus 9.2% of patients (P = 0.076). From randomization to month 36, mean (SD) estimated glomerular filtration rate decreased by 7.0 (31.3) mL/min per 1.73 m(2) in the EVR+ Reduced TAC group, and 15.5 (22.7) mL/min per 1.73 m(2) in the TAC Control group (P = 0.005). Rates of adverse events, serious adverse events, and discontinuation due to adverse events were similar in both groups during the extension. Conclusions. A clinically relevant renal benefit after introduction of everolimus with reduced-exposure tacrolimus at 1 month after liver transplantation was maintained to 3 years in patients who continued everolimus therapy to the end of the core study, with comparable efficacy and no late safety concerns.