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Non-absorbable disaccharides versus placebo/no intervention and lactulose versus lactitol for the prevention and treatment of hepatic encephalopathy in people with cirrhosis.
Cochrane Database Syst Rev. 2016 Apr 18; 4:CD003044.CD

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.

Authors+Show Affiliations

Gastrounit, Medical Division, Copenhagen University Hospital Hvidovre, Kettegaards Alle, Hvidovre, Denmark, 2650.No affiliation info availableNo affiliation info available

Pub Type(s)

Journal Article
Meta-Analysis
Review
Systematic Review

Language

eng

PubMed ID

27089005

Citation

Gluud, Lise Lotte, et al. "Non-absorbable Disaccharides Versus Placebo/no Intervention and Lactulose Versus Lactitol for the Prevention and Treatment of Hepatic Encephalopathy in People With Cirrhosis." The Cochrane Database of Systematic Reviews, vol. 4, 2016, p. CD003044.
Gluud LL, Vilstrup H, Morgan MY. Non-absorbable disaccharides versus placebo/no intervention and lactulose versus lactitol for the prevention and treatment of hepatic encephalopathy in people with cirrhosis. Cochrane Database Syst Rev. 2016;4:CD003044.
Gluud, L. L., Vilstrup, H., & Morgan, M. Y. (2016). Non-absorbable disaccharides versus placebo/no intervention and lactulose versus lactitol for the prevention and treatment of hepatic encephalopathy in people with cirrhosis. The Cochrane Database of Systematic Reviews, 4, CD003044. https://doi.org/10.1002/14651858.CD003044.pub3
Gluud LL, Vilstrup H, Morgan MY. Non-absorbable Disaccharides Versus Placebo/no Intervention and Lactulose Versus Lactitol for the Prevention and Treatment of Hepatic Encephalopathy in People With Cirrhosis. Cochrane Database Syst Rev. 2016 Apr 18;4:CD003044. PubMed PMID: 27089005.
* Article titles in AMA citation format should be in sentence-case
TY - JOUR T1 - Non-absorbable disaccharides versus placebo/no intervention and lactulose versus lactitol for the prevention and treatment of hepatic encephalopathy in people with cirrhosis. AU - Gluud,Lise Lotte, AU - Vilstrup,Hendrik, AU - Morgan,Marsha Y, Y1 - 2016/04/18/ PY - 2016/4/19/entrez PY - 2016/4/19/pubmed PY - 2016/7/22/medline SP - CD003044 EP - CD003044 JF - The Cochrane database of systematic reviews JO - Cochrane Database Syst Rev VL - 4 N2 - 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. SN - 1469-493X UR - https://www.unboundmedicine.com/medline/citation/27089005/Non_absorbable_disaccharides_versus_placebo/no_intervention_and_lactulose_versus_lactitol_for_the_prevention_and_treatment_of_hepatic_encephalopathy_in_people_with_cirrhosis_ L2 - https://doi.org/10.1002/14651858.CD003044.pub3 DB - PRIME DP - Unbound Medicine ER -