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Meta-Analysis
. 2017 Jul 26;7(7):CD002798.
doi: 10.1002/14651858.CD002798.pub3.

Flumazenil versus placebo or no intervention for people with cirrhosis and hepatic encephalopathy

Ee Teng Goh  1 , Mette L Andersen, Marsha Y Morgan, Lise Lotte Gluud
Affiliations
Meta-Analysis

Flumazenil versus placebo or no intervention for people with cirrhosis and hepatic encephalopathy

Ee Teng Goh et al. Cochrane Database Syst Rev. .

Update in

Abstract

Background: Hepatic encephalopathy is a common complication of cirrhosis which results in poor brain functioning. The spectrum of changes associated with hepatic encephalopathy ranges from the clinically 'indiscernible' or minimal hepatic encephalopathy to the clinically 'obvious' or overt hepatic encephalopathy. Flumazenil is a synthetic benzodiazepine antagonist with high affinity for the central benzodiazepine recognition site. Flumazenil may benefit people with hepatic encephalopathy through an indirect negative allosteric modulatory effect on gamma-aminobutyric acid receptor function. The previous version of this review, which included 13 randomised clinical trials, found no effect of flumazenil on all-cause mortality, based on an analysis of 10 randomised clinical trials, but found a beneficial effect on hepatic encephalopathy, based on an analysis of eight randomised clinical trials.

Objectives: To evaluate the beneficial and harmful effects of flumazenil versus placebo or no intervention for people with cirrhosis and hepatic encephalopathy.

Search methods: We searched The Cochrane Hepato-Biliary Group Controlled Trials Register, CENTRAL, MEDLINE, Embase, Science Citation Index Expanded, and LILACS; meeting and conference proceedings; and bibliographies in May 2017.

Selection criteria: We included randomised clinical trials regardless of publication status, blinding, or language in the analyses of benefits and harms, and observational studies in the assessment of harms.

Data collection and analysis: Two review authors extracted data independently. We undertook meta-analyses and presented results using risk ratios (RR) with 95% confidence intervals (CI) and I2 values as a marker of heterogeneity. We assessed bias control using the Cochrane Hepato-Biliary Group domains; determined the quality of the evidence using GRADE; evaluated the risk of small-study effects in regression analyses; and conducted trial sequential, subgroup, and sensitivity analyses.

Main results: We identified 14 eligible randomised clinical trials with 867 participants, the majority of whom had an acute episode of overt hepatic encephalopathy. In addition, we identified one ongoing randomised clinical trial. We were unable to gather outcome data from 2 randomised clinical trials with 25 participants. Thus, our analyses include 842 participants from 12 randomised clinical trials comparing flumazenil versus placebo. We classified one randomised clinical trial at low risk of bias in the overall assessment and the remaining randomised clinical trials at high risk of bias. The duration of follow-up ranged from a few minutes to two weeks, but it was less than one day in the majority of the trials.In total, 32/433 (7.4%) participants allocated to flumazenil versus 38/409 (9.3%) participants allocated to placebo died (RR 0.75, 95% CI 0.48 to 1.16; 11 randomised clinical trials; low quality evidence). The Trial Sequential Analysis and the one randomised clinical trial assessed as low risk of bias (RR 0.76, 95% CI 0.37 to 1.53) found no beneficial or harmful effects of flumazenil on all-cause mortality. The methods used to evaluate hepatic encephalopathy included several different clinical scales, electrophysiological variables, and psychometric tests. Flumazenil was associated with a beneficial effect on hepatic encephalopathy when including all randomised clinical trials (RR 0.75, 95% CI 0.71 to 0.80; 824 participants; 9 randomised clinical trials; low quality evidence), or just the trial at low risk of bias (RR 0.78, 95% CI 0.72 to 0.84; 527 participants). The Trial Sequential Analysis supported a beneficial effect of flumazenil on hepatic encephalopathy. The randomised clinical trials included little information about causes of death and little information on non-fatal serious adverse events.

Authors' conclusions: We found low quality evidence suggesting a short-term beneficial effect of flumazenil on hepatic encephalopathy in people with cirrhosis, but no evidence of an effect on all-cause mortality. Additional evidence from large, high quality randomised clinical trials is needed to evaluate the potential benefits and harms of flumazenil in people with cirrhosis and hepatic encephalopathy.

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Conflict of interest statement

LLG: acted as investigator in studies funded by Norgine, Abbvie, Intercept, and Merck; received funding for travel expenses from Novo Nordisk; and received funding for lectures from Eli Lilly and Norgine. MYM: no conflicts of interest. ETG: no conflicts of interest. MLA: no conflicts of interest.

Figures

Figure 1
Figure 1
Trial Sequential Analysis of randomised clinical trials evaluating flumazenil versus placebo for people with hepatic encephalopathy. The outcome is all‐cause mortality. The original meta‐analysis included 11 randomised clinical trials with 842 participants. The Trial Sequential Analysis ignored three randomised clinical trials due to insufficient information size (Cadranel 1995; Gyr 1996; Zhu 1998). The analysis was made with alpha 3%, power 90%, relative risk reduction 20%, assumed control risk 10%, and diversity 10%. The blue line (Z‐curve) corresponds to the cumulative meta‐analysis, the black horizontal line is the conventional boundary (3% level of significance), and the inward sloping green line is the Trial Sequential Monitoring Boundary. Futility boundaries are ignored because the information is insufficient. The analysis found no evidence to support or refute a beneficial or harmful effect of flumazenil on mortality.
Figure 2
Figure 2
Study flow diagram for identification and selection of randomised clinical trials.
Figure 3
Figure 3
Risk of bias summary: review authors' judgements about each risk of bias item for each included study.
Figure 4
Figure 4
Trial Sequential Analysis of randomised clinical trials evaluating flumazenil versus placebo for people with cirrhosis and hepatic encephalopathy. The outcome is hepatic encephalopathy. The original meta‐analysis included 11 randomised clinical trials with 824 participants. The Trial Sequential Analysis is made with alpha 3%, power 90%, relative risk reduction 20%, assumed control risk 60%, and diversity 10%. The blue line (Z‐curve) corresponds to the cumulative meta‐analysis, the black horizontal line is the conventional boundary (3% level of significance), and the inward sloping green line is the Trial Sequential Monitoring Boundary. The analysis found that the Z‐curve crossed the monitoring boundary before reaching the diversity‐adjusted required information size of 914 participants.
Analysis 1.1
Analysis 1.1
Comparison 1 Flumazenil versus placebo, Outcome 1 All‐cause mortality.
Analysis 1.2
Analysis 1.2
Comparison 1 Flumazenil versus placebo, Outcome 2 All‐cause mortality and bias control.
Analysis 1.3
Analysis 1.3
Comparison 1 Flumazenil versus placebo, Outcome 3 All‐cause mortality and trial design.
Analysis 1.4
Analysis 1.4
Comparison 1 Flumazenil versus placebo, Outcome 4 All‐cause mortality and duration of follow‐up.
Analysis 1.5
Analysis 1.5
Comparison 1 Flumazenil versus placebo, Outcome 5 Hepatic encephalopathy.
Analysis 1.6
Analysis 1.6
Comparison 1 Flumazenil versus placebo, Outcome 6 Hepatic encephalopathy and bias control.
Analysis 1.7
Analysis 1.7
Comparison 1 Flumazenil versus placebo, Outcome 7 Hepatic encephalopathy and trial design.
Analysis 1.8
Analysis 1.8
Comparison 1 Flumazenil versus placebo, Outcome 8 Hepatic encephalopathy and duration of follow‐up.
Analysis 1.9
Analysis 1.9
Comparison 1 Flumazenil versus placebo, Outcome 9 Hepatic encephalopathy and acute liver failure.
Analysis 1.10
Analysis 1.10
Comparison 1 Flumazenil versus placebo, Outcome 10 Number Connection Test.
Analysis 1.11
Analysis 1.11
Comparison 1 Flumazenil versus placebo, Outcome 11 All‐cause mortality and acute liver failure.
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Update of

References

References to studies included in this review

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References to studies excluded from this review

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References to ongoing studies

    1. Treatment of Hepatic Encephalopathy with Flumazenil and Change in Cortical Gamma Aminobutyric Acid Levels in MRS [magnetic resonance spectroscopy].. Ongoing study November 2014..

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References to other published versions of this review

    1. Als‐Nielsen B, Kjaergaard LL, Gluud C. Benzodiazepine receptor antagonists for hepatic encephalopathy. Cochrane Database of Systematic Reviews 2001, Issue 4. [DOI: 10.1002/14651858.CD002798.pub2; PUBMED: 15106178] - DOI - PubMed
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