Penninga Luit, Penninga Elisabeth I, Møller Christian H, Iversen Martin, Steinbrüchel Daniel A, Gluud Christian
Copenhagen Trial Unit, Centre for Clinical Intervention Research, Department 7812, Rigshospitalet, Copenhagen University Hospital,Copenhagen, Denmark.
Cochrane Database Syst Rev. 2013 May 31(5):CD008817. doi: 10.1002/14651858.CD008817.pub2.
Lung transplantation is a well-accepted treatment for people with most end-stage lung diseases. Although both tacrolimus and cyclosporin are used as primary immunosuppressive agents in lung transplant recipients, it is unclear which of these drugs is better in reducing rejection and death without causing adverse effects.
To assess the benefits and harms of tacrolimus versus cyclosporin for primary immunosuppression in lung transplant recipients.
We searched the Cochrane Renal Group's Specialised Register to 10 April 2013 through contact with the Trials Search Co-ordinator using search terms relevant to this review. We also searched Science Citation Index Expanded and the Transplant Library to 20 April 2013.
We included all randomised controlled trials (RCT) that compared any dose and duration of administration of tacrolimus versus cyclosporin as primary immunosuppressive treatment in lung transplant recipients. Our selection criteria required that all included patients received the same additional immunosuppressive therapy within each study.
Three authors extracted data. For dichotomous data we used risk ratio (RR) and used mean difference (MD) for continuous data, each with 95% confidence intervals (CI). Methodological components of the included studies were used to assess risk of systematic errors (bias). Trial sequential analysis was used to assess risk of random errors (play of chance).
We included three studies that enrolled a total of 413 adult patients that compared tacrolimus with microemulsion or oral solution cyclosporin. All studies were found to be at high risk of bias. Tacrolimus seemed to be significantly superior to cyclosporin regarding the incidence of bronchiolitis obliterans syndrome (RR 0.46, 95% CI 0.29 to 0.74), lymphocytic bronchitis score (MD -0.60, 95% CI -1.04 to -0.16), treatment withdrawal (RR 0.27, 95% CI 0.16 to 0.46), and arterial hypertension (RR 0.67, 95% CI 0.50 to 0.89). However, the finding for arterial hypertension was not confirmed when analysed using a random-effects model (RR 0.54, 95% CI 0.17 to 1.73). Furthermore, trial sequential analysis found that none of the meta-analyses reached the required information sizes and cumulative Z-curves did not cross trial sequential monitoring boundaries. Diabetes mellitus occurred more frequently among people in the tacrolimus group compared with the cyclosporin group when the fixed-effect model was applied (RR 4.24, 95% CI 1.58 to 11.40), but no difference was found when the random-effects model was used for analysis (RR 4.43, 95% CI 0.75 to 26.05). Again, trial sequential analysis found that the required information threshold was not reached and cumulative Z-curve did not cross the trial sequential monitoring boundary. No significant difference between treatment groups was observed regarding mortality (RR 1.06, 95% CI 0.75 to 1.49), incidence of acute rejection (RR 0.89, 95% CI 0.77 to 1.03), numbers of infections/100 patient-days (MD -0.15, 95% CI -0.30 to 0.00), cancer (RR 0.21, 95% CI 0.04 to 1.16), kidney dysfunction (RR 1.41, 95% CI 0.93 to 2.14), kidney failure (RR 1.57, 95% CI 0.28 to 8.94), neurotoxicity (RR 7.06, 95% CI 0.37 to 135.19), and hyperlipidaemia (RR 0.60, 95% CI 0.30 to 1.20). Trial sequential analysis showed the required information thresholds were not reached for any of these outcome measures.
AUTHORS' CONCLUSIONS: Tacrolimus may be superior to cyclosporin regarding bronchiolitis obliterans syndrome, lymphocytic bronchitis, treatment withdrawal, and arterial hypertension, but may be inferior regarding development of diabetes. No difference in mortality and acute rejection was observed between patients treated with tacrolimus and cyclosporin. There were few studies comparing tacrolimus and cyclosporin after lung transplantation, and the numbers of patients and events in the included studies were limited. Furthermore, the included studies were deemed to be at high risk of bias. Hence, more RCTs are needed to assess the results of the present review. Such studies ought to be conducted with low risks of systematic errors (bias) and of random errors (play of chance).
肺移植是大多数终末期肺病患者广泛接受的治疗方法。虽然他克莫司和环孢素均被用作肺移植受者的主要免疫抑制剂，但尚不清楚这两种药物中哪种在减少排斥反应和死亡且不引起不良反应方面效果更佳。
评估他克莫司与环孢素用于肺移植受者进行初始免疫抑制的利弊。
我们通过与试验检索协调员联系，使用与本综述相关的检索词，检索了截至2013年4月10日的Cochrane肾脏组专业注册库。我们还检索了截至2013年4月20日的科学引文索引扩展版和移植文库。
我们纳入了所有比较他克莫司与环孢素的任何剂量和给药持续时间作为肺移植受者初始免疫抑制治疗的随机对照试验（RCT）。我们的入选标准要求每项研究中所有纳入的患者接受相同的额外免疫抑制治疗。
三位作者提取数据。对于二分法数据，我们使用风险比（RR），对于连续性数据使用均值差（MD），均带有95%置信区间（CI）。纳入研究的方法学组成部分用于评估系统误差（偏倚）风险。采用试验序贯分析评估随机误差（机遇影响）风险。
我们纳入了三项研究，共413例成年患者，比较了他克莫司与微乳剂或口服溶液环孢素。所有研究均被发现存在高偏倚风险。在闭塞性细支气管炎综合征发生率（RR 0.46，95% CI 0.29至0.74）、淋巴细胞性支气管炎评分（MD -0.60，95% CI -1.04至 -0.16）、治疗中断（RR 0.27，95% CI 0.16至0.46）和动脉高血压（RR 0.67，95% CI 0.50至0.89）方面，他克莫司似乎显著优于环孢素。然而，使用随机效应模型分析时，动脉高血压这一结果未得到证实（RR 0.54，95% CI 0.17至1.73）。此外，试验序贯分析发现，没有一项荟萃分析达到所需的信息规模，累积Z曲线未越过试验序贯监测边界。当应用固定效应模型时，他克莫司组患者中糖尿病的发生频率高于环孢素组（RR 4.24，95% CI 1.58至11.40），但使用随机效应模型分析时未发现差异（RR 4.43，95% CI 0.75至26.05）。同样，试验序贯分析发现未达到所需的信息阈值，累积Z曲线未越过试验序贯监测边界。在死亡率（RR 1.06，95% CI 0.75至1.49）、急性排斥反应发生率（RR 0.89，95% CI 0.77至1.03）、每100患者 - 日感染数（MD -0.15，95% CI -0.30至0.00）、癌症（RR 0.21，95% CI 0.04至1.16）、肾功能障碍（RR 1.41，95% CI 0.93至2.14）、肾衰竭（RR 1.57，95% CI 0.28至8.94）、神经毒性（RR 7.06，95% CI 0.37至135.19）和高脂血症（RR 0.60，95% CI 0.30至1.20）方面，未观察到治疗组之间存在显著差异。试验序贯分析表明，这些结局指标均未达到所需的信息阈值。
在闭塞性细支气管炎综合征、淋巴细胞性支气管炎、治疗中断和动脉高血压方面，他克莫司可能优于环孢素，但在糖尿病发生方面可能较差。接受他克莫司和环孢素治疗的患者在死亡率和急性排斥反应方面未观察到差异。比较肺移植后他克莫司和环孢素的研究较少，纳入研究中的患者数量和事件有限。此外，纳入研究被认为存在高偏倚风险。因此，需要更多的随机对照试验来评估本综述的结果。此类研究应在系统误差（偏倚）和随机误差（机遇影响）风险较低的情况下进行。
