Beta-blockers versus placebo or no intervention for primary prophylaxis of oesophageal varices in children

Background

Portal hypertension is defined as an increase in the blood pressure within a system of veins (a type of blood vessel) called the portal venous system. This system drains blood from the gastrointestinal tract (gut) and spleen into the liver. Portal hypertension commonly accompanies advanced liver disease and often gives rise to life-threatening complications, including haemorrhage (bleeding) from oesophageal (gullet) and gastrointestinal varices (enlarged or swollen veins) in the tube that connects the throat and stomach (the oesophagus) and the digestive tract. Portal vein thrombosis (a vascular disease of the liver) occurs when a blood clot lodges in the hepatic portal vein. Portal vein thrombosis results in portal hypertension leading among others to the formation of varices (e.g. oesophageal or gastric).

In adults, numerous randomised clinical trials (studies where people are randomly allocated to one of two or more treatment groups) have demonstrated benefits of medicines called non-selective beta-blockers in decreasing the risk of first variceal haemorrhage. These preventive interventions have become the established standard in adults. However, it is unknown whether the preventive interventions are of benefit or cause harm when used in children and adolescents.

Aims
We aimed to assess the benefits and harms of beta-blockers versus placebo or no intervention for the prevention of oesophageal variceal bleeding in children with chronic liver disease or portal vein thrombosis. We searched for trials until April 2020.

Key results
We found no randomised clinical trials to include in this systematic review. Therefore, we are unable to conclude whether beta-blockers, when compared to placebo or no intervention, may be beneficial or not for children with oesophageal varices. There is a need for well-designed and sufficiently large randomised clinical trials that include important clinical outcomes, such as death, quality of life, failure to control bleeding, and adverse events.

Authors' conclusions: 

Randomised clinical trials assessing the benefits or harms of beta-blockers versus placebo or no intervention for primary prophylaxis of oesophageal variceal bleeding in children with chronic liver disease or portal vein thrombosis are lacking. Therefore, trials with adequate power and proper design, assessing the benefits and harms of beta-blockers versus placebo on patient-relevant clinical outcomes, such as mortality, quality of life, failure to control variceal bleeding, and adverse events are needed. Unless such trials are conducted and the results become published, we cannot make any conclusions regarding the benefits or harms of the two interventions.

Read the full abstract...
Background: 

Portal hypertension commonly accompanies advanced liver disease and often gives rise to life-threatening complications, including haemorrhage from oesophageal and gastrointestinal varices. Variceal haemorrhage commonly occurs in children with chronic liver disease or portal vein thrombosis. Therefore, prevention is important.

Band ligation, beta-blockers, and sclerotherapy have been proposed as alternatives for primary prophylaxis of oesophageal variceal bleeding in children. However, primary prophylaxis is not the current standard of care in paediatric patients because it is unknown whether those treatments are of benefit or harm when used for primary prophylaxis in children and adolescents.

Objectives: 

To determine the benefits and harms of beta-blockers compared with placebo or no intervention for primary prophylaxis of oesophageal variceal bleeding in children with chronic liver disease or portal vein thrombosis.

Search strategy: 

We searched the Cochrane Hepato-Biliary Group Controlled Trials Register, CENTRAL, PubMed, Embase, LILACS, and Science Citation Index Expanded (April 2020). We screened the reference lists of the retrieved publications and manually searched the main paediatric gastroenterology and hepatology conference (NASPGHAN and ESPGHAN) abstract books from 2008 to December 2019. We searched clinicaltrials.gov, the United States Food and Drug Administration (FDA), the European Medicines Agency (EMA), and the World Health Organization (WHO) for ongoing clinical trials. We imposed no language or document type restrictions on our search.

Selection criteria: 

We planned to include randomised clinical trials, irrespective of blinding, language, or publication status to assess benefits and harms. We included observational studies, retrieved with the searches for randomised clinical trials, for a narrative report of harm.

Data collection and analysis: 

We planned to summarise data from randomised clinical trials by standard Cochrane methodologies. We planned to asses risk of bias and use GRADE to assess the certainty of evidence. Our primary outcomes were all-cause mortality, serious adverse events and liver-related morbidity, and health-related quality of life. Our secondary outcomes were oesophageal variceal bleeding and adverse events not considered serious. We planned to use intention-to-treat principle. We planned to analyse data with RevMan Analysis.

Main results: 

We found no randomised clinical trials that assessed beta-blockers compared with sham or no intervention for primary prophylaxis of oesophageal variceal bleeding in children with chronic liver disease or portal vein thrombosis. We found four observational studies that reported on harms. As a systematic search for observational studies was not planned, we only listed the reported harms in a table.

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