Gyr 1996.
Methods | Double‐blind, multi‐centre, parallel‐arm, placebo controlled RCT. | |
Participants | 49 participants with cirrhosis and chronic overt hepatic encephalopathy (Grades I to III; Table 3). Mean age ± SD: flumazenil: 55.5 ± 9.4 years; placebo: 53.6 ± 10.3 years. Proportion of men: 69%. Aetiology of cirrhosis: alcohol 51%; hepatitis B/C 35%. Proportion testing positive for benzodiazepines at baseline (Table 6): 11% in flumazenil group; 5% in placebo group. |
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Interventions |
Intervention comparison: intravenous boluses of flumazenil 0.4 mg, 0.8 mg, and 1 mg at 1‐minute intervals followed by a 3‐hour infusion of flumazenil 1 mg/hour versus placebo (saline). Total dose of flumazenil: 5.2 mg. Cointerventions: none reported. |
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Outcomes | Outcomes included in meta‐analyses: mortality, hepatic encephalopathy (Table 2), and serious adverse events (Table 7) assessed after a maximum of 4 weeks. | |
Neuropsychiatric assessment |
Baseline and post infusion:
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Inclusion period (date) | Not reported. | |
Country | Switzerland (primary), France, Germany, Italy, Canada, the Netherlands, the UK, and Korea. | |
Notes | Included data: authors reported intention‐to‐treat analyses including all participants randomised and a per‐protocol analysis excluding protocol violators (25 participants). We included data on all participants in our analyses. | |
Risk of bias | ||
Bias | Authors' judgement | Support for judgement |
Random sequence generation (selection bias) | Low risk | Computer‐generated list of random numbers. |
Allocation concealment (selection bias) | Low risk | Sealed envelopes used in double‐blind administration of flumazenil and placebo. |
Blinding of participants and personnel (performance bias) All outcomes | Unclear risk | Blinding of participants and personnel. |
Blinding of outcome assessment (detection bias) All outcomes | Low risk | Blinding of outcome assessment. |
Incomplete outcome data (attrition bias) All outcomes | Low risk | No missing outcome data. |
Selective reporting (reporting bias) | Low risk | Trial described clinically relevant outcomes. We had no access to information about outcomes described in the original protocol or information in trial registries. |
For‐profit funding | High risk | Support from Hoffmann‐La Roche Ltd. |
Other bias | Low risk | No other biases. |
Overall assessment | High risk | High risk of bias. |