Hepatobiliary Center, AP-HP Hôpital Paul Brousse, Université Paris-Sud, Villejuif, France.
Am J Transplant. 2013 Jul;13(7):1734-45. doi: 10.1111/ajt.12280. Epub 2013 May 28.
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 m(2) (97.5% CI 1.9, 11.4 mL/min/1.73 m(2), p = 0.002). Among patients who remained on treatment, mean (SD) eGFR at month 24 was 77.6 (26.5) mL/min/1.73 m(2) in the EVR + Reduced TAC group and 66.1 (19.3) mL/min/1.73 m(2) 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.
在一项 24 个月的前瞻性、随机、多中心、开放标签研究中，新诊断的肝移植患者在 30 天时随机分为依维莫司（EVR）+ 低剂量他克莫司（TAC；n = 245）、TAC 对照组（n = 243）或 TAC 消除组（n = 231）。由于治疗后活检证实的急性排斥反应（tBPAR）发生率显著升高，TAC 消除组的随机分组提前停止。EVR+低剂量 TAC（10.3%）或 TAC 对照组（12.5%）在 24 个月时的主要疗效终点复合疗效失败率（tBPAR、移植物丢失或随机后死亡）相似（差异为-2.2%，97.5%置信区间[CI]为-8.8%，4.4%）。EVR+低剂量 TAC 组的 BPAR 发生率较低（6.1% vs. TAC 对照组的 13.3%，p = 0.010）。与 TAC 对照组相比，EVR+低剂量 TAC 从随机分组到 24 个月时估计肾小球滤过率（eGFR）的调整变化更优：差异 6.7 mL/min/1.73 m(2)（97.5%CI 为 1.9，11.4 mL/min/1.73 m(2)，p = 0.002）。在继续接受治疗的患者中，EVR+低剂量 TAC 组在 24 个月时的平均（SD）eGFR 为 77.6（26.5）mL/min/1.73 m(2)，TAC 对照组为 66.1（19.3）mL/min/1.73 m(2)（p < 0.001）。由于不良事件，EVR+低剂量 TAC 组有 28.6%的患者和 TAC 对照组有 18.2%的患者停止使用研究药物。肝移植后 1 个月时早期引入依维莫司联合低剂量他克莫司，可显著改善移植后 2 年的肾功能，具有显著的临床相关性。
