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Meta-Analysis
. 2016 May 6;2016(5):CD003044.
doi: 10.1002/14651858.CD003044.pub4.

Non-absorbable disaccharides versus placebo/no intervention and lactulose versus lactitol for the prevention and treatment of hepatic encephalopathy in people with cirrhosis

Lise Lotte Gluud  1 , Hendrik Vilstrup, Marsha Y Morgan
Affiliations
Meta-Analysis

Non-absorbable disaccharides versus placebo/no intervention and lactulose versus lactitol for the prevention and treatment of hepatic encephalopathy in people with cirrhosis

Lise Lotte Gluud et al. Cochrane Database Syst Rev. .

Abstract

Background: 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.

Objectives: 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.

Search methods: 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.

Selection criteria: We included RCTs, irrespective of publication status, language, or blinding.

Data collection and analysis: 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.

Main results: 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.

PubMed Disclaimer

Conflict of interest statement

Lise L Gluud received payment for presentations given at scientific meetings sponsored by Norgine.

All review authors have conducted previous reviews on hepatic encephalopathy and two authors (Hendrik Vilstrup and Marsha Morgan) have conducted RCTs on hepatic encephalopathy. These previous research activities are an academic bias based on the definitions given in the Cochrane Hepato‐Biliary Group module.

Figures

1
1
Trial flow diagram.
2
2
'Risk of bias' summary: review authors' judgements about each risk of bias item for each included study.
3
3
Trial Sequential Analysis of mortality in 24 RCTs evaluating non‐absorbable disaccharides versus placebo/no intervention. The primary meta‐analysis found a RR of 0.59 (95% CI 0.40 to 0.87). When we set the RRR to 30% and CGR to 15%, (power 80%, alpha 5%, and diversity 0%), the cumulative Z‐curve (the green line) crossed the monitoring boundary (inward sloping line) after 1037 participants before reaching the heterogeneity adjusted information size. The cumulative Z‐curve did not cross the monitoring boundary when we increased the diversity to 20% and reduced the RRR to 20%.
4
4
Trial Sequential Analysis of mortality in 8 RCTs with a low risk of bias. The RCTs compare non‐absorbable disaccharides versus placebo/no intervention and the primary meta‐analysis found an effect of non‐absorbable disaccharides with a RR of 0.63 (95% CI 0.41 to 0.97). When we set the RRR to 30% and CGR to 45% (power 80%, alpha 5%, and diversity 0%), the cumulative Z‐curve (the green line) did not cross the monitoring boundary (inward sloping line). The heterogeneity adjusted information size was 1725 participants.
5
5
Trial Sequential Analysis of hepatic encephalopathy in 22 RCTs evaluating non‐absorbable disaccharides versus placebo/no intervention. A meta‐analysis including all trials found a RR of 0.58 (95% CI 0.48 to 0.69). The analysis includes a RRR of 30% and CGR of 45% (power 80%, alpha 5%, and diversity 30%). The analysis found that the Z‐curve (green line) crossed the monitoring boundary (inward sloping black line) before reaching the information size of 581 participants. None of the RCTs were low risk of bias in the overall assessment. The Z‐curve crossed the monitoring boundary before reaching the information size when we decreased the RRR to 20% (information size 1337 participants) and when we increased diversity to 50% (814 participants).
6
6
Trial Sequential Analysis of serious adverse events including 24 RCTs evaluating non‐absorbable disaccharides versus placebo/no intervention. The primary meta‐analysis found a beneficial intervention effect with a RR of 0.47 (95% CI 0.36 to 0.60). None of the included RCTs had a low risk of bias in the overall assessment. When conducting the Trial Sequential Analysis with RRR 30%, CGR 30%, power 80%, alpha 5%, and diversity 0%, the Z‐curve crossed the monitoring boundary before reaching the required information size of 737 participants. The Z‐curve also crossed the monitoring boundary before reaching the required information size when we reduced the RRR to 20% (information size 1719 participants) and when we increased diversity to 20% (information size 921 participants).
1.1
1.1. Analysis
Comparison 1 Non‐absorbable disaccharides versus placebo/no intervention, Outcome 1 Mortality.
1.2
1.2. Analysis
Comparison 1 Non‐absorbable disaccharides versus placebo/no intervention, Outcome 2 Mortality in trials with a low risk of bias.
1.3
1.3. Analysis
Comparison 1 Non‐absorbable disaccharides versus placebo/no intervention, Outcome 3 Hepatic encephalopathy.
1.4
1.4. Analysis
Comparison 1 Non‐absorbable disaccharides versus placebo/no intervention, Outcome 4 Serious adverse events.
1.5
1.5. Analysis
Comparison 1 Non‐absorbable disaccharides versus placebo/no intervention, Outcome 5 Quality of life: sickness impact profile.
1.6
1.6. Analysis
Comparison 1 Non‐absorbable disaccharides versus placebo/no intervention, Outcome 6 Non‐serious adverse events.
1.7
1.7. Analysis
Comparison 1 Non‐absorbable disaccharides versus placebo/no intervention, Outcome 7 Number connection test, end of treatment.
1.8
1.8. Analysis
Comparison 1 Non‐absorbable disaccharides versus placebo/no intervention, Outcome 8 Ammonia end of treatment.
1.9
1.9. Analysis
Comparison 1 Non‐absorbable disaccharides versus placebo/no intervention, Outcome 9 Ammonia change from baseline.
1.10
1.10. Analysis
Comparison 1 Non‐absorbable disaccharides versus placebo/no intervention, Outcome 10 Mortality in worst‐case scenario analyses.
1.11
1.11. Analysis
Comparison 1 Non‐absorbable disaccharides versus placebo/no intervention, Outcome 11 Hepatic encephalopathy worst‐case scenario analysis.
1.12
1.12. Analysis
Comparison 1 Non‐absorbable disaccharides versus placebo/no intervention, Outcome 12 Serious adverse events worst‐case scenario analysis.
2.1
2.1. Analysis
Comparison 2 Prevention trials: non‐absorbable disaccharides versus placebo/no intervention, Outcome 1 Mortality.
2.2
2.2. Analysis
Comparison 2 Prevention trials: non‐absorbable disaccharides versus placebo/no intervention, Outcome 2 Mortality and bias control.
2.3
2.3. Analysis
Comparison 2 Prevention trials: non‐absorbable disaccharides versus placebo/no intervention, Outcome 3 Hepatic encephalopathy.
2.4
2.4. Analysis
Comparison 2 Prevention trials: non‐absorbable disaccharides versus placebo/no intervention, Outcome 4 Serious adverse events.
2.5
2.5. Analysis
Comparison 2 Prevention trials: non‐absorbable disaccharides versus placebo/no intervention, Outcome 5 Non‐serious adverse events.
3.1
3.1. Analysis
Comparison 3 Treatment trials: non‐absorbable disaccharides versus placebo/no intervention, Outcome 1 Mortality.
3.2
3.2. Analysis
Comparison 3 Treatment trials: non‐absorbable disaccharides versus placebo/no intervention, Outcome 2 Mortality in trials with a low risk of bias.
3.3
3.3. Analysis
Comparison 3 Treatment trials: non‐absorbable disaccharides versus placebo/no intervention, Outcome 3 Mortality in acute or chronic hepatic encephalopathy.
3.4
3.4. Analysis
Comparison 3 Treatment trials: non‐absorbable disaccharides versus placebo/no intervention, Outcome 4 Hepatic encephalopathy.
3.5
3.5. Analysis
Comparison 3 Treatment trials: non‐absorbable disaccharides versus placebo/no intervention, Outcome 5 Acute or chronic hepatic encephalopathy.
3.6
3.6. Analysis
Comparison 3 Treatment trials: non‐absorbable disaccharides versus placebo/no intervention, Outcome 6 Serious adverse events.
3.7
3.7. Analysis
Comparison 3 Treatment trials: non‐absorbable disaccharides versus placebo/no intervention, Outcome 7 Serious adverse events in acute or chronic hepatic encephalopathy.
3.8
3.8. Analysis
Comparison 3 Treatment trials: non‐absorbable disaccharides versus placebo/no intervention, Outcome 8 Non‐serious adverse events.
4.1
4.1. Analysis
Comparison 4 Lactulose versus lactitol, Outcome 1 Mortality.
4.2
4.2. Analysis
Comparison 4 Lactulose versus lactitol, Outcome 2 Hepatic encephalopathy.
4.3
4.3. Analysis
Comparison 4 Lactulose versus lactitol, Outcome 3 Serious adverse events.
4.4
4.4. Analysis
Comparison 4 Lactulose versus lactitol, Outcome 4 Non‐serious adverse events.
4.5
4.5. Analysis
Comparison 4 Lactulose versus lactitol, Outcome 5 Number Connection Test: end of treatment.
4.6
4.6. Analysis
Comparison 4 Lactulose versus lactitol, Outcome 6 Number Connection Test: change from baseline.
4.7
4.7. Analysis
Comparison 4 Lactulose versus lactitol, Outcome 7 Venous blood ammonia: end of treatment.
4.8
4.8. Analysis
Comparison 4 Lactulose versus lactitol, Outcome 8 Venous blood ammonia: change from baseline.
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References

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References to studies excluded from this review

Bajaj 2010a {published data only}
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