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

Abstract

International audienceSIMCER was a 6-mo, multicenter, open-label trial. Selected de novo liver transplant recipients were randomized (week 4) to everolimus with low-exposure tacrolimus discontinued by month 4 (n = 93) or to tacrolimus-based therapy (n = 95), both with basiliximab induction and enteric-coated mycophenolate sodium with or without steroids. The primary end point, change in estimated GFR (eGFR; MDRD formula) from randomization to week 24 after transplant, was superior with everolimus (mean eGFR change +1.1 vs. −13.3 mL/min per 1.73 m2 for everolimus vs. tacrolimus, respectively; difference 14.3 [95% confidence interval 7.3–21.3]; p < 0.001). Mean eGFR at week 24 was 95.8 versus 76.0 mL/min per 1.73 m2 for everolimus versus tacrolimus (p < 0.001). Treatment failure (treated biopsy-proven acute rejection [BPAR; rejection activity index score >3], graft loss, or death) from randomization to week 24 was similar (everolimus 10.0%, tacrolimus 4.3%; p = 0.134). BPAR was more frequent between randomization and month 6 with everolimus (10.0% vs. 2.2%; p = 0.026); the rate of treated BPAR was 8.9% versus 2.2% (p = 0.055). Sixteen everolimus-treated patients (17.8%) and three tacrolimus-treated patients (3.2%) discontinued the study drug because of adverse events. In conclusion, early introduction of everolimus at an adequate exposure level with gradual calcineurin inhibitor (CNI) withdrawal after liver transplantation, supported by induction therapy and mycophenolic acid, is associated with a significant renal benefit versus CNI-based immunosuppression but more frequent BPAR

Very Early Introduction of Everolimus in De Novo Liver Transplantation: Results of a Multicenter, Prospective, Randomized Trial

“…As far as efficacy is concerned, the study showed that even though in the EVR group there was a trend toward a higher prevalence of tBPAR ( P = 0.09, the sample size was properly powered to obtain a sufficiently active treatment), the overall tBPAR rate (12.9%) was <25% at 3 months after transplantation in the study group. The SIMCER study reported a higher incidence of tBPAR in the EVR cohort ( P = 0.02) in a 24‐month follow‐up.…”

Everolimus-Based Immunosuppression in Liver Transplant Recipients

“…My co-authors and I thank Dr Cholongitas for such thoughtful comments (1) on the findings of the randomized SIMCER trial (2). We concur with many of the points raised.…”

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].…”

“…Но такое сочетание возможно. Дан-ные рандомизированного мультицентрового иссле-дования, завершенного в 2016 г., подтверждают это положение [20]: 4 больных из исследованной нами группы принимают сертикан и микофеноловую кислоту более двух лет, при этом гематологические показатели стабильны.…”