Gluud Lise Lotte, Vilstrup Hendrik, Morgan Marsha Y
Gastrounit, Medical Division, Copenhagen University Hospital Hvidovre, Kettegaards Alle, Hvidovre, Denmark, 2650.
Cochrane Database Syst Rev. 2016 May 6;2016(5):CD003044. doi: 10.1002/14651858.CD003044.pub4.
Non-absorbable disaccharides (lactulose and lactitol) are recommended as first-line treatment for hepatic encephalopathy. The previous (second) version of this review included 10 randomised clinical trials (RCTs) evaluating non-absorbable disaccharides versus placebo/no intervention and eight RCTs evaluating lactulose versus lactitol for people with cirrhosis and hepatic encephalopathy. The review found no evidence to either support or refute the use of the non-absorbable disaccharides and no differences between lactulose versus lactitol.
To assess the beneficial and harmful effects of i) non-absorbable disaccharides versus placebo/no intervention and ii) lactulose versus lactitol in people with cirrhosis and hepatic encephalopathy.
We carried out electronic searches of the Cochrane Hepato-Biliary Group Controlled Trials Register, the Cochrane Central Register of Controlled Trials (CENTRAL 2015, Issue 10), MEDLINE, EMBASE, and Science Citation Index Expanded to 19 October 2015; manual searches of meetings and conference proceedings; checks of bibliographies; and correspondence with investigators and pharmaceutical companies.
We included RCTs, irrespective of publication status, language, or blinding.
Two review authors, working independently, retrieved data from published reports and correspondence with investigators. The primary outcomes were mortality, hepatic encephalopathy, and serious adverse events. We presented the results of meta-analyses as risk ratios (RR) and mean differences (MD) with 95% confidence intervals (CI). We assessed the quality of the evidence using 'Grading of Recommendations Assessment Development and Evaluation' (GRADE) and bias control using the Cochrane Hepato-Biliary Group domains. Our analyses included regression analyses of publication bias and other small study effects, Trial Sequential Analyses to detect type 1 and type 2 errors, and subgroup and sensitivity analyses.
We included 38 RCTs with a total of 1828 participants. Eight RCTs had a low risk of bias in the assessment of mortality. All trials had a high risk of bias in the assessment of the remaining outcomes. Random-effects meta-analysis showed a beneficial effect of non-absorbable disaccharides versus placebo/no intervention on mortality when including all RCTs with extractable data (RR 0.59, 95% CI 0.40 to 0.87; 1487 participants; 24 RCTs; I(2) = 0%; moderate quality evidence) and in the eight RCTs with a low risk of bias (RR 0.63, 95% CI 0.41 to 0.97; 705 participants). The Trial Sequential Analysis with the relative risk reduction (RRR) reduced to 30% confirmed the findings when including all RCTs, but not when including only RCTs with a low risk of bias or when we reduced the RRR to 22%. Compared with placebo/no intervention, the non-absorbable disaccharides were associated with beneficial effects on hepatic encephalopathy (RR 0.58, 95% CI 0.50 to 0.69; 1415 participants; 22 RCTs; I(2) = 32%; moderate quality evidence). Additional analyses showed that non-absorbable disaccharides can help to reduce serious adverse events associated with the underlying liver disease including liver failure, hepatorenal syndrome, and variceal bleeding (RR 0.47, 95% CI 0.36 to 0.60; 1487 participants; 24 RCTs; I(2) = 0%; moderate quality evidence). We confirmed the results in Trial Sequential Analysis. Tests for subgroup differences showed no statistical differences between RCTs evaluating prevention, overt, or minimal hepatic encephalopathy. The evaluation of secondary outcomes showed a potential beneficial effect of the non-absorbable disaccharides on quality of life, but we were not able to include the data in an overall meta-analysis (very low quality evidence). Non-absorbable disaccharides were associated with non-serious (mainly gastrointestinal) adverse events (very low quality evidence). None of the RCTs comparing lactulose versus lactitol evaluated quality of life. The review found no differences between lactulose and lactitol for the remaining outcomes (very low quality evidence).
AUTHORS' CONCLUSIONS: This review includes a large number of RCTs evaluating the prevention or treatment of hepatic encephalopathy. The analyses found evidence that non-absorbable disaccharides may be associated with a beneficial effect on clinically relevant outcomes compared with placebo/no intervention.
不可吸收双糖（乳果糖和乳糖醇）被推荐作为肝性脑病的一线治疗药物。本综述的上一版（第二版）纳入了10项评估不可吸收双糖与安慰剂/无干预措施对比的随机临床试验（RCT），以及8项评估乳果糖与乳糖醇对肝硬化合并肝性脑病患者疗效对比的RCT。该综述未发现支持或反驳使用不可吸收双糖的证据，也未发现乳果糖与乳糖醇之间存在差异。
评估：i）不可吸收双糖与安慰剂/无干预措施对比；ii）乳果糖与乳糖醇对比，对肝硬化合并肝性脑病患者的有益和有害影响。
我们对Cochrane肝胆疾病组对照试验注册库、Cochrane对照试验中央注册库（CENTRAL 2015年第10期）、MEDLINE、EMBASE以及截至2015年10月19日的科学引文索引扩展版进行了电子检索；对会议和会议论文集进行了手工检索；检查了参考文献；并与研究者和制药公司进行了通信联系。
我们纳入了RCT，无论其发表状态、语言或是否设盲。
两名综述作者独立工作，从已发表报告和与研究者的通信中检索数据。主要结局为死亡率、肝性脑病和严重不良事件。我们将荟萃分析结果表示为风险比（RR）和平均差（MD），并给出95%置信区间（CI）。我们使用“推荐分级评估、制定与评价”（GRADE）评估证据质量，并使用Cochrane肝胆疾病组领域进行偏倚控制。我们的分析包括发表偏倚和其他小研究效应的回归分析、用于检测I类和II类错误的试验序贯分析，以及亚组分析和敏感性分析。
我们纳入了38项RCT，共1828名参与者。8项RCT在死亡率评估方面偏倚风险较低。所有试验在其余结局评估方面均存在较高偏倚风险。随机效应荟萃分析显示，当纳入所有有可提取数据的RCT时（RR 0.59，95%CI 0.40至0.87；1487名参与者；24项RCT；I² = 0%；中等质量证据），以及在8项偏倚风险较低的RCT中（RR 0.63，95%CI 0.41至0.97；705名参与者），不可吸收双糖与安慰剂/无干预措施相比对死亡率有有益影响。当相对危险度降低（RRR）降至30%时，试验序贯分析在纳入所有RCT时证实了这一结果，但在仅纳入偏倚风险较低的RCT时或当我们将RRR降至22%时未证实。与安慰剂/无干预措施相比，不可吸收双糖对肝性脑病有有益影响（RR 0.58，95%CI 0.50至0.69；1415名参与者；22项RCT；I² = 32%；中等质量证据）。进一步分析表明，不可吸收双糖有助于减少与潜在肝脏疾病相关的严重不良事件，包括肝衰竭、肝肾综合征和静脉曲张出血（RR 0.47，95%CI 0.36至0.60；1487名参与者；24项RCT；I² = 0%；中等质量证据）。我们在试验序贯分析中证实了这一结果。亚组差异检验显示，评估预防、显性或轻微肝性脑病的RCT之间无统计学差异。次要结局评估显示，不可吸收双糖对生活质量可能有有益影响，但我们无法将这些数据纳入总体荟萃分析（极低质量证据）。不可吸收双糖与非严重（主要是胃肠道）不良事件相关（极低质量证据）。比较乳果糖与乳糖醇的RCT均未评估生活质量。该综述发现，在其余结局方面，乳果糖与乳糖醇之间无差异（极低质量证据）。
本综述纳入了大量评估肝性脑病预防或治疗的RCT。分析发现，与安慰剂/无干预措施相比，不可吸收双糖可能对临床相关结局有有益影响。
