Renal Function at Two Years in Liver Transplant Patients Receiving Everolimus: Results of a Randomized, Multicenter Study

Abstract

In a 24‐month prospective, randomized, multicenter, open‐label study, de novo liver transplant patients were randomized at 30 days to everolimus (EVR) + Reduced tacrolimus (TAC; n = 245), TAC Control (n = 243) or TAC Elimination (n = 231). Randomization to TAC Elimination was stopped prematurely due to a significantly higher rate of treated biopsy‐proven acute rejection (tBPAR). The incidence of the primary efficacy endpoint, composite efficacy failure rate of tBPAR, graft loss or death postrandomization was similar with EVR + Reduced TAC (10.3%) or TAC Control (12.5%) at month 24 (difference −2.2%, 97.5% confidence interval [CI] −8.8%, 4.4%). BPAR was less frequent in the EVR + Reduced TAC group (6.1% vs. 13.3% in TAC Control, p = 0.010). Adjusted change in estimated glomerular filtration rate (eGFR) from randomization to month 24 was superior with EVR + Reduced TAC versus TAC Control: difference 6.7 mL/min/1.73 m2 (97.5% CI 1.9, 11.4 mL/min/1.73 m2, p = 0.002). Among patients who remained on treatment, mean (SD) eGFR at month 24 was 77.6 (26.5) mL/min/1.73 m2 in the EVR + Reduced TAC group and 66.1 (19.3) mL/min/1.73 m2 in the TAC Control group (p < 0.001). Study medication was discontinued due to adverse events in 28.6% of EVR + Reduced TAC and 18.2% of TAC Control patients. Early introduction of everolimus with reduced‐exposure tacrolimus at 1 month after liver transplantation provided a significant and clinically relevant benefit for renal function at 2 years posttransplant.

Efficacy and Safety of Everolimus and Mycophenolic Acid With Early Tacrolimus Withdrawal After Liver Transplantation: A Multicenter Randomized Trial

“…The difference in eGFR by the end of the study was substantial (14.3 mL/min/1.73m 2 ), and although patients were only followed to week 24 post-transplant, there was no suggestion that values in the two groups were set to converge subsequently. BPAR, however, was significantly more frequent in the CNI-free cohort although episodes were mild in more than half the cases and the incidence (10.0%) was acceptable and substantially lower than reported for a CNI-free regimen of everolimus (9,10). No graft losses occurred.…”

“…The rate of biopsy-proven acute rejection (BPAR) was significantly lower in the everolimus/reduced tacrolimus arm versus standard tacrolimus, but tacrolimus withdrawal resulted in a high incidence of acute rejection (26.4%) and recruitment to this group was discontinued. Renal function during the two-year study was significantly higher in the everolimus/reduced tacrolimus group than the control arm, and was even higher in the tacrolimus withdrawal group despite the fact that more than half of the patients had reverted to CNI therapy (8,9). In the H2304 study, patients did not receive induction therapy and MPA was not permitted after randomization.…”

“…Randomized trials have investigated various approaches to using the mTOR inhibitor everolimus to support CNI withdrawal after liver transplantation. The H2304 study randomized 719 de novo liver transplant patients to everolimus with tacrolimus minimization, everolimus with tacrolimus withdrawal, or a standard tacrolimus regimen (8,9). Everolimus was introduced at day 30 post-transplant, and tacrolimus was withdrawn from month 4 over a three-week period.…”

Everolimus in clinical practice after liver transplantation: a single-center experience

“…В проспективном рандомизированном многоцент-ровом открытом исследовании, длившемся 24 мес., скорректированное увеличение СКФ от рандоми-зации до 24-го месяца отмечалось на фоне приема эверолимуса с такролимусом в сниженной дозе по сравнению с теми больными, кто принимал только такролимус (p < 0,001). Однако рандомизация на от-мену такролимуса была остановлена раньше срока из-за значительного повышения частоты острого отторжения, подтвержденного биопсией [5,20].…”

“…Несколько лет спустя появился новый представитель m-TOR-ингибиторов, эверолимус, который сначала стали использовать для лечения отторжения при трансплантации сердца и лег-ких [3,4]. C 2012 г. препарат сертикан был одобрен к применению после трансплантации печени Евро-пейским медицинским агентством [5].…”