Rodríguez-Perálvarez Manuel, Guerrero-Misas Marta, Thorburn Douglas, Davidson Brian R, Tsochatzis Emmanuel, Gurusamy Kurinchi Selvan
Hepatology and Liver Transplantation, Reina Sofía University Hospital, IMIBIC, CIBERehd, Avenida Menéndez Pidal s/n, Córdoba, Spain, 14004.
Reina Sofía University Hospital, IMIBIC, CIBERehd, Córdoba, Spain.
Cochrane Database Syst Rev. 2017 Mar 31;3(3):CD011639. doi: 10.1002/14651858.CD011639.pub2.
As part of liver transplantation, immunosuppression (suppressing the host immunity) is given to prevent graft rejections resulting from the immune response of the body against transplanted organ or tissues from a different person whose tissue antigens are not compatible with those of the recipient. The optimal maintenance immunosuppressive regimen after liver transplantation remains uncertain.
To assess the comparative benefits and harms of different maintenance immunosuppressive regimens in adults undergoing liver transplantation through a network meta-analysis and to generate rankings of the different immunosuppressive regimens according to their safety and efficacy.
We searched CENTRAL, MEDLINE, Embase, Science Citation Index Expanded, World Health Organization International Clinical Trials Registry Platform, and trials registers until October 2016 to identify randomised clinical trials on immunosuppression for liver transplantation.
We included only randomised clinical trials (irrespective of language, blinding, or publication status) in adult participants undergoing liver transplantation (or liver retransplantation) for any reason. We excluded trials in which participants had undergone multivisceral transplantation or participants with established graft rejections. We considered any of the various maintenance immunosuppressive regimens compared with each other.
We performed a network meta-analysis with OpenBUGS using Bayesian methods and calculated the odds ratio, rate ratio, and hazard ratio (HR) with 95% credible intervals (CrI) based on an available-case analysis, according to National Institute of Health and Care Excellence Decision Support Unit guidance.
We included a total of 26 trials (3842 participants) in the review, and 23 trials (3693 participants) were included in one or more outcomes in the review. The vast majority of the participants underwent primary liver transplantation. All of the trials were at high risk of bias, and all of the evidence was of low or very low quality. In addition, because of sparse data involving trials at high risk of bias, it is not possible to entirely rely on the results of the network meta-analysis. The trials included mainly participants undergoing primary liver transplantation of varied aetiologies. The follow-up in the trials ranged from 3 to 144 months. The most common maintenance immunosuppression used as a control was tacrolimus. There was no evidence of difference in mortality (21 trials; 3492 participants) or graft loss (15 trials; 2961 participants) at maximal follow-up between the different maintenance immunosuppressive regimens based on the network meta-analysis. In the direct comparison, based on a single trial including 222 participants, tacrolimus plus sirolimus had increased mortality (HR 2.76, 95% CrI 1.30 to 6.69) and graft loss (HR 2.34, 95% CrI 1.28 to 4.61) at maximal follow-up compared with tacrolimus. There was no evidence of differences in the proportion of people with serious adverse events (1 trial; 719 participants), proportion of people with any adverse events (2 trials; 940 participants), renal impairment (8 trials; 2233 participants), chronic kidney disease (1 trial; 100 participants), graft rejections (any) (16 trials; 2726 participants), and graft rejections requiring treatment (5 trials; 1025 participants) between the different immunosuppressive regimens. The network meta-analysis showed that the number of adverse events was lower with cyclosporine A than with many other immunosuppressive regimens (12 trials; 1748 participants), and the risk of retransplantation (13 trials; 1994 participants) was higher with cyclosporine A than with tacrolimus (HR 3.08, 95% CrI 1.13 to 9.90). None of the trials reported number of serious adverse events, health-related quality of life, or costs.
14 trials were funded by pharmaceutical companies who would benefit from the results of the trial; two trials were funded by parties who had no vested interest in the results of the trial; and 10 trials did not report the source of funding.
AUTHORS' CONCLUSIONS: Based on low-quality evidence from a single small trial from direct comparison, tacrolimus plus sirolimus increases mortality and graft loss at maximal follow-up compared with tacrolimus. Based on very low-quality evidence from network meta-analysis, we found no evidence of difference between different immunosuppressive regimens. We found very low-quality evidence from network meta-analysis and low-quality evidence from direct comparison that cyclosporine A causes more retransplantation compared with tacrolimus. Future randomised clinical trials should be adequately powered; performed in people who are generally seen in the clinic rather than in highly selected participants; employ blinding; avoid postrandomisation dropouts or planned cross-overs; and use clinically important outcomes such as mortality, graft loss, renal impairment, chronic kidney disease, and retransplantation. Such trials should use tacrolimus as one of the control groups. Moreover, such trials ought to be designed in such a way as to ensure low risk of bias and low risks of random errors.
作为肝移植的一部分，会进行免疫抑制（抑制宿主免疫）以防止身体对来自组织抗原与受体不匹配的他人的移植器官或组织产生免疫反应而导致的移植物排斥。肝移植后最佳的维持免疫抑制方案仍不确定。
通过网状Meta分析评估不同维持免疫抑制方案在接受肝移植的成年人中的相对益处和危害，并根据其安全性和有效性对不同免疫抑制方案进行排序。
我们检索了截至2016年10月的Cochrane系统评价数据库、医学期刊数据库、Embase数据库、科学引文索引扩展版、世界卫生组织国际临床试验注册平台以及各试验注册库，以识别关于肝移植免疫抑制的随机临床试验。
我们仅纳入因任何原因接受肝移植（或再次肝移植）的成年参与者的随机临床试验（无论语言、盲法或发表状态如何）。我们排除了参与者接受多脏器移植或已发生移植物排斥的试验。我们考虑了相互比较的各种维持免疫抑制方案中的任何一种。
我们使用OpenBUGS软件，采用贝叶斯方法进行网状Meta分析，并根据美国国立卫生研究院和保健卓越研究所决策支持单位的指导，基于有效病例分析计算比值比、率比和风险比（HR）以及95%可信区间（CrI）。
我们共纳入了26项试验（3842名参与者）进行综述，其中23项试验（3693名参与者）被纳入综述中的一个或多个结局。绝大多数参与者接受了初次肝移植。所有试验均存在较高的偏倚风险，所有证据的质量均为低或极低。此外，由于涉及高偏倚风险试验的数据稀少，无法完全依赖网状Meta分析结果。试验纳入的主要是病因各异的初次肝移植参与者。试验中的随访时间为3至144个月。最常用作对照的维持免疫抑制剂是他克莫司。基于网状Meta分析，在最大随访期时，不同维持免疫抑制方案之间在死亡率（21项试验；3492名参与者）或移植物丢失（15项试验；2961名参与者）方面没有差异的证据。在直接比较中，基于一项纳入222名参与者的单一试验，与他克莫司相比，他克莫司加西罗莫司在最大随访期时死亡率增加（HR 2.76，95% CrI 1.30至6.69）且移植物丢失增加（HR 2.34，95% CrI 1.28至4.61）。在不同免疫抑制方案之间，严重不良事件发生比例（1项试验；719名参与者）､任何不良事件发生比例（2项试验；940名参与者）､肾功能损害（8项试验；2233名参与者）､慢性肾病（1项试验；100名参与者）､移植物排斥（任何类型）（16项试验；2726名参与者）以及需要治疗的移植物排斥（5项试验；1025名参与者）方面均无差异的证据。网状Meta分析显示，与许多其他免疫抑制方案相比，环孢素A导致的不良事件数量更少（12项试验；1748名参与者），且与他克莫司相比，环孢素A导致再次移植的风险更高（13项试验；1994名参与者）（HR 3.08，95% CrI 1.13至9.90）。没有试验报告严重不良事件的数量、健康相关生活质量或成本。
14项试验由可能从试验结果中获益的制药公司资助；2项试验由对试验结果没有既得利益的机构资助；10项试验未报告资金来源。
基于直接比较的一项小型单一试验的低质量证据，与他克莫司相比，他克莫司加西罗莫司在最大随访期时增加死亡率和移植物丢失。基于网状Meta分析的极低质量证据，我们未发现不同免疫抑制方案之间存在差异的证据。我们从网状Meta分析中发现极低质量证据，从直接比较中发现低质量证据，表明与他克莫司相比，环孢素A导致更多的再次移植。未来的随机临床试验应具备足够的样本量；在临床常见人群而非高度选择的参与者中进行；采用盲法；避免随机分组后的失访或计划中的交叉设计；并使用死亡率、移植物丢失、肾功能损害、慢性肾病和再次移植等具有临床重要意义的结局。此类试验应以他克莫司作为对照组之一。此外，此类试验的设计应确保低偏倚风险和低随机误差风险。
