In children with liver disease, who have enlarged veins in the oesophagus (food pipe), does placing an elastic ring around the vein prevent it from bleeding?

Bleeding in the oesophagus
A blood clot in the veins that drain blood from the digestive tract into the liver (known as portal vein thrombosis) causes increased pressure in these veins. Increased blood pressure in the veins supplying blood to the liver is also common in serious liver disease. The increased pressure can make the veins in the oesophagus (the tube running from the throat to the stomach) swollen and enlarged. Bleeding from enlarged veins in the oesophagus is a life-threatening condition.

How are enlarged veins in the oesophagus treated?
In adults, studies have shown two treatments work well to treat bleeding from enlarged veins:

- taking medicines called beta-blockers; and
- placing an elastic ring around the vein to cut off the blood flow through it.

These two treatments have become the main ways to prevent bleeding from enlarged veins in the oesophagus in adults. However, we do not know how well these treatments work in children and young people, or if they cause any unwanted effects or harms.  

Why we did this Cochrane Review
We wanted to assess the benefits and harms of placing an elastic ring around an enlarged vein to prevent it from bleeding, in children with long-lasting liver disease or portal vein thrombosis.

What we did
We searched for studies that tested the effects of placing an elastic ring around an enlarged vein in the oesophagus to prevent it from bleeding, compared with a sham treatment (the same procedure, but no band was placed) or no treatment, in children with long-lasting liver disease or portal vein thrombosis.

We looked for randomised clinical studies, in which the people taking part are randomly placed into different intervention groups. This type of study, if performed correctly, usually gives the most reliable evidence about the effects of a treatment.

We wanted to find out about:

- how many children died;

- how many children had serious unwanted effects (effects considered life-threatening or that needed hospital treatment) or liver-related diseases;

- the children's well-being (quality of life);

- how many children had oesophageal bleeding; and

- how many children had any unwanted effects that were not considered serious.

How current is the evidence?
The evidence in this review includes research published up to 27 April 2020.

What we found
We found only one report of a study that took place at three hospitals in the UK. It was a feasibility study: it looked at whether it would be possible to conduct larger and more conclusive randomised studies. A summary of the study data was published and presented at a conference. The study report was not good enough to judge the quality of the study. No information about funding was given.

We did not find any other studies that could be included in this review, and there are no ongoing randomised studies.

What are the main results?
The study randomised 22 children with portal hypertension and enlarged veins into two groups:

- one group had an elastic ring placed around the enlarged vein (12 children); and
- one group had no active treatment (10 children).

There was no information about the diagnosis, or age, of any of the children. The children were followed for at least six months. Two children were lost to follow-up by one year. Only 10 children in total completed the trial study at two-year follow-up.

In the group who had an elastic ring placed:

- one child died;
- no children had any other serious unwanted effects;
- one child needed a liver transplant; and 
- one child had oesophageal bleeding.

In the group who received no active treatment:

- no children died; 
- one child had a serious unwanted effect: an immune disorder in which blood does not clot properly (idiopathic thrombocytopaenic purpura); 
- no children needed a liver transplant; and
- three children had oesophageal bleeding.

No unwanted effects that were less serious were reported in either group. The study did not report any information about the children's well-being (quality of life).

Conclusions
The insufficient and poor reporting of results from one small, randomised study, and the lack of other randomised studies, mean that we cannot draw trustworthy conclusions. We do not know how well elastic rings work to prevent bleeding from enlarged veins in the oesophagus in children and young people, or about any unwanted effects they might cause.

Until good-quality randomised studies take place and measure the numbers of deaths, quality of life, failure to control bleeding, and unwanted effects, we will not know if elastic rings are a good treatment to prevent bleeding in children and young people with long-lasting liver disease or portal vein thrombosis.

Authors' conclusions: 

The evidence, obtained from only one feasibility randomised clinical trial at high risk of bias, is very scanty. It is very uncertain about whether prophylactic band ligation versus sham or no (active) intervention may affect mortality, serious adverse events and liver-related morbidity, or oesophageal variceal bleeding in children and adolescents with portal hypertension and large oesophageal varices. We have no data on quality of life. No adverse events considered non-serious were reported. The results presented in the trial need to be interpreted with caution. In addition, the highly limited data cover only part of our research question; namely, children with portal hypertension and large oesophageal varices. Data on children with portal vein thrombosis are lacking.

Larger randomised clinical trials assessing the benefits and harms of band ligation compared with sham treatment for primary prophylaxis of oesophageal variceal bleeding in children and adolescents with chronic liver disease or portal vein thrombosis are needed. The trials should include important clinical outcomes such as death, quality of life, failure to control bleeding, and adverse events.

Read the full abstract...
Background: 

Portal hypertension commonly accompanies advanced liver disease and often gives rise to life-threatening complications, including bleeding (haemorrhage) from oesophageal and gastrointestinal varices. Variceal bleeding commonly occurs in children and adolescents with chronic liver disease or portal vein thrombosis. Prevention is, therefore, important. Randomised clinical trials have shown that non-selective beta-blockers and endoscopic variceal band ligation decrease the incidence of variceal bleeding in adults. In children and adolescents, band ligation, beta-blockers, and sclerotherapy have been proposed as primary prophylaxis alternatives for oesophageal variceal bleeding. However, it is unknown whether these interventions are of benefit or harm when used for primary prophylaxis in children and adolescents.

Objectives: 

To assess the benefits and harms of band ligation compared with sham or no intervention for primary prophylaxis of oesophageal variceal bleeding in children and adolescents with chronic liver disease or portal vein thrombosis.

Search strategy: 

We searched the Cochrane Hepato-Biliary Group Controlled Trials Register, CENTRAL, PubMed, Embase, and two other databases (April 2020). We scrutinised the reference lists of the retrieved publications, and we also handsearched abstract books of the two main paediatric gastroenterology and hepatology conferences from January 2008 to December 2019. We also 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 aimed to include randomised clinical trials irrespective of blinding, language, or publication status, to assess the benefits and harms of band ligation versus sham or no intervention for primary prophylaxis of oesophageal variceal bleeding in children with chronic liver disease or portal vein thrombosis. If the search for randomised clinical trials retrieved quasi-randomised and other observational studies, then we read them through to extract information on harm.

Data collection and analysis: 

We used standard Cochrane methodology to perform this systematic review. We used GRADE to assess the certainty of evidence for each outcome. Our primary outcomes were all-cause mortality, serious adverse events and liver-related morbidity, and quality of life. Our secondary outcomes were oesophageal variceal bleeding and adverse events not considered serious. We used the intention-to-treat principle. We analysed data using Review Manager 5.

Main results: 

One conference abstract, describing a feasibility multi-centre randomised clinical trial, fulfilled our review inclusion criteria. We judged the trial at overall high risk of bias. This trial was conducted in three hospital centres in the United Kingdom. The aim of the trial was to determine the feasibility and safety of further larger randomised clinical trials of prophylactic band ligation versus no active treatment in children with portal hypertension and large oesophageal varices. Twelve children received prophylactic band ligation and 10 children received no active treatment. There was no information on the age of the children included, or about the diagnosis of any child included. All children were followed up for at least six months. Mortality was 8% (1/12) in the band ligation group versus 0% (0/10) in the no active intervention group (risk ratio (RR) 2.54, 95% confidence interval (CI) 0.11 to 56.25; very low certainty of evidence). The abstract did not report when the death occurred, but we assume it happened between the six-month follow-up and one year. No child (0%) in the band ligation group developed adverse events (RR 0.28, 95% CI 0.01 to 6.25; very low certainty of evidence) but one child out of 10 (10%) in the no active intervention group developed idiopathic thrombocytopaenic purpura. One child out of 12 (8%) in the band ligation group underwent liver transplantation versus none in the no active intervention group (0%) (RR 2.54, 95% CI 0.11 to 56.25; very low certainty of evidence). The trial reported no other serious adverse events or liver-related morbidity. Quality of life was not reported. Oesophageal variceal bleeding occurred in 8% (1/12) of the children in the band ligation group versus 30% (3/10) of the children in the no active intervention group (RR 0.28, 95% CI 0.03 to 2.27; very low certainty of evidence). No adverse events considered non-serious were reported. Two children were lost to follow-up by one-year. Ten children in total completed the trial at two-year follow-up. There was no information on funding. 

We found two observational studies on endoscopic variceal ligation when searching for randomised trials. One found no harm, and the other reported E nterobacter cloacae septicaemia in one child and mild, transient, upper oesophageal sphincter stenosis in another. We did not assess these studies for risk of bias.

We did not find any ongoing randomised clinical trials of interest to our review.

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