肝移植儿童中他克莫司与类固醇联用对比环孢素微乳剂、类固醇及硫唑嘌呤：欧洲多中心随机试验

Tacrolimus and steroids versus ciclosporin microemulsion, steroids, and azathioprine in children undergoing liver transplantation: randomised European multicentre trial.

作者信息

Kelly Deirdre, Jara Paloma, Rodeck Burkhard, Lykavieris Panayotis, Burdelski Martin, Becker Michael, Gridelli Bruno, Boillot Olivier, Manzanares Javier, Reding Raymond

机构信息

Liver Unit, Birmingham Children's Hospital NHS Trust, Birmingham, UK.

出版信息

Lancet. 2004;364(9439):1054-61. doi: 10.1016/S0140-6736(04)17060-8.

DOI:10.1016/S0140-6736(04)17060-8

PMID:15380964

Abstract

BACKGROUND

Results of studies in adult recipients of liver allograft suggest that tacrolimus is more efficacious than ciclosporin microemulsion in the prevention of acute rejection. We aimed to compare these drugs in children undergoing liver transplantation.

METHODS

This 12-month multicentre, open-label, parallel-group, randomised study compared a dual tacrolimus regimen (tacrolimus/corticosteroids, n=93) with a triple ciclosporin microemulsion regimen (ciclosporin microemulsion/corticosteroids/azathioprine, n=92) in children who had had liver transplants (age < or =16 years, bodyweight < or =40 kg). Initial oral daily doses were 0.30 mg/kg for tacrolimus and 10 mg/kg for ciclosporin microemulsion. Primary endpoint was the incidence of and time to first histologically proven acute rejection. We excluded patients from analysis if they did not receive the study drug, or were given incorrect medication. Otherwise patients were analysed in accordance with their random treatment allocation, irrespective of whether they switched medication during the trial.

FINDINGS

Median age was 22 months (IQR 9-56) in the tacrolimus group and 17 months (9-54) in the ciclosporin microemulsion group. We noted no difference between treatment groups with respect to patient survival (93.4% vs 92.2%; p=0.77) or graft survival (92.3% vs 85.4%; p=0.16) at month 12 after transplant. The acute rejection free rate at study end (Kaplan-Meier method) was 55.5% for patients on tacrolimus and 40.2% for patients on ciclosporin microemulsion (p=0.0288). The Kaplan-Meier estimate of patients free from corticosteroid-resistant acute rejection at study end was 94.0% for tacrolimus-treated patients and 70.4% for ciclosporin-microemulsion-treated patients (p<0.0001). Overall, incidence of adverse events did not differ between groups.

INTERPRETATION

Tacrolimus is a safe and effective treatment for the prevention of rejection after liver transplantation in children.

摘要

背景

针对肝移植成年受者的研究结果表明，在预防急性排斥反应方面，他克莫司比环孢素微乳剂更有效。我们旨在比较这两种药物在儿童肝移植中的效果。

方法

这项为期12个月的多中心、开放标签、平行组随机研究，比较了他克莫司双药方案（他克莫司/皮质类固醇，n = 93）与环孢素微乳剂三药方案（环孢素微乳剂/皮质类固醇/硫唑嘌呤，n = 92）在肝移植儿童（年龄≤16岁，体重≤40 kg）中的效果。他克莫司初始口服每日剂量为0.30 mg/kg，环孢素微乳剂为10 mg/kg。主要终点是首次组织学证实的急性排斥反应的发生率和发生时间。如果患者未接受研究药物或用药错误，则将其排除在分析之外。否则，患者按照随机分配的治疗方案进行分析，无论他们在试验期间是否更换药物。

结果

他克莫司组的中位年龄为22个月（四分位间距9 - 56），环孢素微乳剂组为17个月（9 - 54）。我们发现，移植后12个月时，治疗组在患者生存率（93.4%对92.2%；p = 0.77）或移植物生存率（92.3%对85.4%；p = 0.16）方面没有差异。研究结束时（采用Kaplan-Meier方法），他克莫司治疗患者的无急性排斥反应率为55.5%，环孢素微乳剂治疗患者为40.2%（p = 0.0288）。研究结束时，采用Kaplan-Meier估计法，他克莫司治疗患者无皮质类固醇抵抗性急性排斥反应的比例为94.0%，环孢素微乳剂治疗患者为70.4%（p<0.0001）。总体而言，两组不良事件的发生率没有差异。