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Pharmacotherapies that specifically target ammonia for the prevention and treatment of hepatic encephalopathy in adults with cirrhosis

Background

Hepatic encephalopathy is a common complication of cirrhosis, with high related morbidity and mortality. Its presence is associated with a wide spectrum of change ranging from clinically obvious neuropsychiatric features, known as ‘overt’ hepatic encephalopathy, to abnormalities manifest only on psychometric or electrophysiological testing, ‘minimal’ hepatic encephalopathy. The exact pathogenesis of the syndrome is unknown but ammonia plays a key role. Drugs that specifically target ammonia include sodium benzoate, glycerol phenylbutyrate, ornithine phenylacetate, AST‐120 (spherical carbon adsorbent), and polyethylene glycol.

Objectives

To evaluate the beneficial and harmful effects of pharmacotherapies that specifically target ammonia versus placebo, no intervention, or other active interventions, for the prevention and treatment of hepatic encephalopathy in people with cirrhosis.

Search methods

We searched the Cochrane Hepato‐Biliary Controlled Trials Register, CENTRAL, MEDLINE, Embase, and three other databases to March 2019. We also searched online trials registries such as ClinicalTrials.gov, European Medicines Agency, WHO International Clinical Trial Registry Platform, and the Food and Drug Administration for ongoing or unpublished trials. In addition, we searched conference proceedings, checked bibliographies, and corresponded with investigators.

Selection criteria

We included randomised clinical trials comparing sodium benzoate, glycerol phenylbutyrate, ornithine phenylacetate, AST‐120, and polyethylene glycol versus placebo or non‐absorbable disaccharides, irrespective of blinding, language, or publication status. We included participants with minimal or overt hepatic encephalopathy or participants who were at risk of developing hepatic encephalopathy.

Data collection and analysis

Two review authors independently extracted data from the included reports. The primary outcomes were mortality, hepatic encephalopathy, and serious adverse events. We undertook meta‐analyses and presented results using risk ratios (RR) or mean differences (MD), both with 95% confidence intervals (CIs), and I2 statistic values as a marker of heterogeneity. We assessed bias control using the Cochrane Hepato‐Biliary domains and the certainty of the evidence using GRADE.

Main results

Eleven randomised clinical trials fulfilled our inclusion criteria. Two trials evaluated the prevention of hepatic encephalopathy while nine evaluated the treatment of hepatic encephalopathy. The trials assessed sodium benzoate (three trials), glycerol phenylbutyrate (one trial), ornithine phenylacetate (two trials), AST‐120 (two trials), and polyethylene glycol (three trials). Overall, 499 participants received these pharmacotherapies while 444 participants received a placebo preparation or a non‐absorbable disaccharide. We classified eight of the 11 trials as at ‘high risk of bias’ and downgraded the certainty of the evidence to very low for all outcomes.

Eleven trials, involving 943 participants, reported mortality data, although there were no events in five trials. Our analyses found no beneficial or harmful effects of sodium benzoate versus non‐absorbable disaccharides (RR 1.26, 95% CI 0.49 to 3.28; 101 participants; 2 trials; I2 = 0%), glycerol phenylbutyrate versus placebo (RR 0.65, 95% CI 0.11 to 3.81; 178 participants; 1 trial), ornithine phenylacetate versus placebo (RR 0.73, 95% CI 0.35 to 1.51; 269 participants; 2 trials; I2 = 0%), AST‐120 versus lactulose (RR 1.05, 95% CI 0.59 to 1.85; 41 participants; 1 trial), or polyethylene glycol versus lactulose (RR 0.50, 95% CI 0.09 to 2.64; 190 participants; 3 trials; I2 = 0%).

Seven trials involving 521 participants reported data on hepatic encephalopathy. Our analyses showed a beneficial effect of glycerol phenylbutyrate versus placebo (RR 0.57, 95% CI 0.36 to 0.90; 178 participants; 1 trial; number needed to treat for an additional beneficial outcome (NNTB) 6), and of polyethylene glycol versus lactulose (RR 0.19, 95% CI 0.08 to 0.44; 190 participants; 3 trials; NNTB 4). We did not observe beneficial effects in the remaining three trials with extractable data: sodium benzoate versus non‐absorbable disaccharides (RR 1.22, 95% CI 0.51 to 2.93; 74 participants; 1 trial); ornithine phenylacetate versus placebo (RR 2.71, 95% CI 0.12 to 62.70; 38 participants; 1 trial); or AST‐120 versus lactulose (RR 1.05, 95% CI 0.59 to 1.85; 41 participants; 1 trial).

Ten trials, involving 790 participants, reported a total of 130 serious adverse events. Our analyses found no evidence of beneficial or harmful effects of sodium benzoate versus non‐absorbable disaccharides (RR 1.08, 95% CI 0.44 to 2.68; 101 participants; 2 trials), glycerol phenylbutyrate versus placebo (RR 1.63, 95% CI 0.85 to 3.13; 178 participants; 1 trial), ornithine phenylacetate versus placebo (RR 0.92, 95% CI 0.62 to 1.36; 264 participants; 2 trials; I2 = 0%), or polyethylene glycol versus lactulose (RR 0.57, 95% CI 0.18 to 1.82; 190 participants; 3 trials; I2 = 0%). Likewise, eight trials, involving 782 participants, reported a total of 374 non‐serious adverse events and again our analyses found no beneficial or harmful effects of the pharmacotherapies under review when compared to placebo or to lactulose/lactitol.

Nine trials, involving 733 participants, reported data on blood ammonia. We observed significant reductions in blood ammonia in placebo‐controlled trials evaluating sodium benzoate (MD −32.00 µg/dL, 95% CI −46.85 to −17.15; 16 participants; 1 trial), glycerol phenylbutyrate (MD −12.00 µmol/L*week, 95% CI −23.37 to −0.63; 178 participants; 1 trial), ornithine phenylacetate (MD −27.10 µmol/L, 95% CI −48.55 to −5.65; 231 participants; 1 trial), and AST‐120 (MD −22.00 µg/dL, 95% CI −26.75 to −17.25; 98 participants; 1 trial). However, there were no significant differences in blood ammonia concentrations in comparison with lactulose/lactitol with sodium benzoate (MD 9.00, 95% CI −1.10 to 19.11; 85 participants; 2 trials; I2 = 0% ), AST‐120 (MD 5.20 units not specified, 95% CI −2.75 to 13.15; 35 participants; 1 trial), and polyethylene glycol (MD −29.28 µmol/L, 95% CI −95.96 to 37.39; 90 participants; 2 trials; I2 = 88%).

Five trials received support from pharmaceutical companies while four did not; two did not provide this information.

Authors’ conclusions

There is insufficient evidence to determine the effects of these pharmacotherapies on the prevention and treatment of hepatic encephalopathy in adults with cirrhosis. They have the potential to reduce blood ammonia concentrations when compared to placebo, but their overall effects on clinical outcomes of interest and the potential harms associated with their use remain uncertain. Further evidence is needed to evaluate the potential beneficial and harmful effects of these pharmacotherapies in this clinical setting.

Plain language summary

Drug treatments that specifically target ammonia for adults with cirrhosis and hepatic encephalopathy

Background

Cirrhosis is a chronic disorder of the liver. People with cirrhosis may develop hepatic encephalopathy, a condition that results in poor brain functioning. Some people with hepatic encephalopathy show clear evidence of brain dysfunction and are said to have ‘overt’ hepatic encephalopathy. They may have a poor memory, difficulty concentrating, speech problems, a tremor, particularly of their hands, or stiffness of their limbs. These changes may occur in bouts or may be persistent. Other people with cirrhosis may not show any obvious signs of brain dysfunction, but some aspects of their brain function, such as attention and the ability to perform complex tasks are found to be impaired when tested. They are said to have ‘minimal’ hepatic encephalopathy. The reason why people develop hepatic encephalopathy is complex, but the build up in the blood of toxins from the gut, particularly of a compound called ammonia, plays a key role. Certain drugs have been developed specifically to lower blood ammonia levels and may help prevent people from developing hepatic encephalopathy and have beneficial effects in those already suffering from this disorder. However, the evidence that they are beneficial is unclear. The five drugs (pharmacotherapies) considered in this review are sodium benzoate, glycerol phenylbutyrate, ornithine phenylacetate, AST‐120 (spherical carbon adsorbent), and polyethylene glycol.

Review question

We investigated the use of five pharmacotherapies that specifically target ammonia for the prevention and treatment of hepatic encephalopathy in people with cirrhosis. We did this by reviewing clinical trials in which people with cirrhosis were randomly allocated to treatment with one of these drugs or to an inactive dummy (placebo), to no treatment or to other drugs that are also used to manage this condition, such as, lactulose and lactitol (these are non‐absorbable disaccharides). We included people with cirrhosis who had minimal or overt hepatic encephalopathy and people who were at risk of developing this complication.

Search date

5 March 2019

Study funding sources

Five of the 11 randomised clinical trials we included in the review received support from pharmaceutical companies. Two trials did not provide information on potential financial support or links to pharmaceutical companies. Four trials did not receive funding or other support from this source.

Study characteristics

We identified 11 randomised clinical trials comparing drugs that specifically target ammonia with inactive placebo or a non‐absorbable disaccharide; two trials evaluated prevention of hepatic encephalopathy while nine trials evaluated treatment of hepatic encephalopathy. The trials assessed sodium benzoate (three trials), glycerol phenylbutyrate (one trial), ornithine phenylacetate (two trials), AST‐120 (two trials) and polyethylene glycol (three trials). Participants were treated for varying periods ranging from five days to 16 weeks.

Key results

Sodium benzoate, glycerol phenylbutyrate, ornithine phenylacetate, and AST‐120 lowered blood ammonia levels when compared to placebo, but none of the drugs lowered the blood ammonia levels when compared to a non‐absorbable disaccharide. Glycerol phenylbutyrate seemed to have a beneficial effect on hepatic encephalopathy when compared to placebo, as did polyethylene glycol when compared to lactulose. None of the drugs appeared to affect the risk of death and did not have any notable adverse effects.

Quality of the evidence

The evidence we found was very uncertain, and so we are not confident that these drugs are useful for preventing or treating hepatic encephalopathy in people with cirrhosis. There were very few trials available, and not all of them provided sufficient data for us to include in our analyses. In addition, many of the published trials received support from the pharmaceutical industry which introduces an element of bias. Thus, we need more information to obtain a better idea if these drugs are useful and safe for use in this context.

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