Beta‐blockers versus placebo or no intervention for primary prophylaxis of oesophageal variceal bleeding in children with chronic liver disease or portal vein thrombosis

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 methods

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.

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.

Plain language summary

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.

Background

Description of the condition

There are scarce data on the prevalence and burden of liver disease in children and adolescents, and the natural history of portal hypertension in children is different than in adults. In adults, the cause of portal hypertension is mostly intrahepatic, whereas the cause of portal hypertension in children is mostly extrahepatic. The main underlying condition that results in the development of portal hypertension in children is extrahepatic portal vein thrombosis (Di Giorgio 2019), followed by cirrhotic aetiologies, such as biliary atresia (Shneider 2016; Chapin 2018). 

In adults with portal hypertension, hepatic venous pressure gradient (HVPG) of 10 mmHg or more has been associated with the formation of oesophageal varices, variceal bleeding or ascites, or both (Ebel 2019). The risk of oesophageal variceal bleeding is increased at HVPG of 12 mmHg or more (de Franchis 2015). However, there are limited data on HVPG gradient values in children. One study in children with portal hypertension found that HVPG was not associated with the presence of varices or history of variceal bleeding, suggesting the possibility of intrahepatic shunting in children with advanced liver disease (Ebel 2019). The study by Ebel 2019 also suggested that "the use of HVPG measurements alone may not capture all children at risk for adverse clinical outcomes secondary to portal hypertension".

Variceal haemorrhage also commonly occurs in children with chronic liver disease or portal vein thrombosis (Lykavieris 2000; Miga 2001; van Heurn 2004; Duche 2013; Di Giorgio 2019). One study of 125 children with biliary atresia with signs of portal hypertension or previous history of gastrointestinal bleeding, reported that 88 (70%) developed oesophageal varices (Duche 2010). In children with biliary atresia, the incidence of variceal haemorrhage ranges from 17% to 29% over a five‐ to ten‐year period (Miga 2001; van Heurn 2004; Duche 2013; Angelico 2019; Parolini 2019). One prospective study of 50 children with oesophageal varices, primarily due to cirrhosis, who did not receive active prevention of variceal bleeding, showed that 42% of the children had upper gastrointestinal haemorrhage during a median follow‐up period of 4.5 years (Goncalves 2000). Available studies in children with portal hypertension due to portal vein thrombosis, suggest that up to 50% of children experience a major variceal haemorrhage by 16 years of age (Lykavieris 2000). Variceal bleeding in children with portal hypertension has been associated with significant morbidity and variable mortality rates. In a study of children with portal hypertension due to chronic liver disease or portal vein thrombosis, post acute variceal bleeding morbidity occurred in 64% of patients after their first episode of bleeding (Carneiro 2018). Mortality rates in children with variceal bleeding of cirrhotic aetiologies were between 2% and 19% (Eroglu 2004; van Heurn 2004; Carneiro 2018). In contrast, variceal bleeding in children with portal vein thrombosis and no parenchymal liver disease seemed to carry less than 3% risk of mortality (Lykavieris 2000; Di Giorgio 2019).

Description of the intervention

According to numerous randomised clinical trials in adults, non‐selective beta‐blockers and endoscopic variceal band ligation decrease the risk of variceal haemorrhage and have now become standard primary prophylaxis (Garcia‐Tsao 2007; Garcia‐Tsao 2017). However, the use of beta‐blockers has been associated with poor survival in adult patients with refractory ascites; therefore, precautions must be considered (Serste 2010; Ge 2014). Several publications have reported results for the use of sclerotherapy, band ligation, and beta‐blockers for primary prophylaxis of variceal bleeding in children (Goncalves 2000; Samanta 2011; Lampela 2012; Duche 2013; Duche 2017; Galand 2018; Angelico 2019; Quintero 2019). Various surveys regarding primary prophylaxis for variceal bleeding in children, conducted by paediatric gastroenterologists, have shown different approaches to the management of children with portal hypertension (Gana 2011a; Verdaguer 2016; Jeanniard‐Malet 2017). This suggests that many paediatric specialists apply the guidelines for management of portal hypertension in adults to children. However, there is an important variation of care provided by physicians, probably secondary to the lack of good‐quality studies.

There are several differences in the pathophysiology of portal hypertension between adults and children. Therefore, precautions must be taken before extrapolating facts and data from adults to children or adolescents. Children are more dependent on chronotropic for maintenance of systemic blood pressure during hypovolaemia than adults who depend mainly on vasoconstriction. The main concern is that by limiting tachycardia in children, the use of a non‐selective beta‐blocker may impair tolerance to hypovolaemia and may lead to a more adverse outcome from variceal bleeding. The efficacy, pharmacokinetics, and adverse event profiles of the drugs may also differ significantly between children and adults (Ling 2005). Finally, the principal aetiologies of liver disease and portal hypertension are different in these populations, as described above.

How the intervention might work

The mechanisms of action of the beta‐blockers include reduction of cardiac output, reduction of portal venous flow, and antagonism of the norepinephrine‐induced constriction of intrahepatic myofibroblasts, activated stellate cells, and vascular smooth muscle cells. Meta‐analyses in adult populations have shown that non‐selective beta‐blockers reduce the incidence of variceal haemorrhage by 50% in adults with cirrhosis (Hayes 1990; Plevris 1994). Although paediatric data are lacking, and there is some concern on the use of non‐selective beta‐blockers in the youngest children, beta‐blockers could be considered as a prophylaxis option for children with oesophageal varices (Verdaguer 2016: Jeanniard‐Malet 2017).

Why it is important to do this review

Primary prophylaxis with band ligation or beta‐blockers is the standard of care for the management of adults with chronic liver disease and portal hypertension with medium or large varices, to prevent variceal bleeding (Garcia‐Tsao 2017). Variceal bleeding is common in children with oesophageal varices secondary to chronic liver disease or portal vein thrombosis, and has been associated with mortality. Therefore, prevention in children with portal hypertension is important (Gana 2010; Ling 2011; Gana 2011b; Shneider 2012).

Currently, there are no evidence‐based recommendations for the prophylactic management of children at risk of variceal bleeding. Various surveys conducted by paediatric gastroenterologists have found a wide range of practices regarding primary prophylaxis of variceal bleeding in children (Groszmann 2004; Gana 2011b; Shneider 2016; Verdaguer 2016; Jeanniard‐Malet 2017). In one survey of 30 paediatric gastroenterologists in the USA, approaches to the management of children with portal hypertension, using screening endoscopy and primary prophylaxis of variceal bleeding, varied considerably among the respondents. In this survey, 63% of gastroenterologists conducted surveillance of oesophageal varices and 84% offered primary prophylaxis of variceal bleeding in children (Groszmann 2004). In one survey in Canada, 70% of paediatric gastroenterologists reported that they would consider screening for oesophageal varices in children with liver disease and evidence of cirrhosis or portal hypertension (such as splenomegaly, thrombocytopenia, or portosystemic collaterals on sonography). However, only 58% of respondents who would screen for varices would provide primary prophylactic treatment (Gana 2011b). One survey of 35 Chilean paediatric gastroenterologists showed that 29 (83%) gastroenterologists had screened children for oesophageal varices because of clinical evidence of portal hypertension and 12 (34%) gastroenterologists had screened every child with chronic liver disease. Twenty‐eight (80%) respondents had used primary prophylaxis, mainly beta‐blockers, but also band ligation and sclerotherapy (Verdaguer 2016). One survey conducted in 38 French‐speaking hospitals showed that more than 75% of the centres had used endoscopy to screen children diagnosed with chronic liver diseases with suspected portal hypertension (Jeanniard‐Malet 2017). Among these 28 centres, 20 (71%) had performed primary prophylaxis for portal hypertension within their institution, one (4%) had done so only for children with cystic fibrosis because of its particular medical recruitment, and seven (25%) had referred the children to a tertiary centre. In cases of grade 2 varices with red marks and grade 3 varices, more than 90% of the centres had performed sclerotherapy or endoscopic variceal ligation. Approximately 20% of centres had used beta‐blockers (Jeanniard‐Malet 2017). This suggests that there is an important variation of care provided by physicians, probably secondary to the lack of good‐quality studies.

Different treatments have been proposed for the primary prophylaxis of oesophageal varices bleeding in children. This systematic review is one of six reviews that examines the utility of these treatment modalities, i.e. beta‐blockers versus placebo for primary prophylaxis of oesophageal varices bleeding in children with chronic liver disease or portal vein thrombosis (Gana 2015). The remaining reviews examine band ligation versus beta‐blockers (Gana 2019), band ligation versus sclerotherapy (Gana 2020), sclerotherapy versus sham or no intervention (Gattini 2020a), sclerotherapy versus beta‐blockers (Gattini 2020b), band ligation versus sham or no intervention (Cifuentes 2021), for the same target population and disease.

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.

Methods

Criteria for considering studies for this review

Types of studies

Randomised clinical trials, regardless of publication status, format, language, blinding, or outcomes. The trials should have compared any type of beta‐blocker versus placebo or no intervention, administered as primary prophylaxis of oesophageal variceal bleeding in children with chronic liver disease or portal vein thrombosis.

We planned to examine the full texts of quasi‐randomised (studies in which the method of allocation is not truly random) and observational studies for report of harm only, provided that these were retrieved with the searches for randomised clinical trials. We reported the occurrence of adverse events in a narrative and tabular way. We did not plan to assess observational studies for risk of bias as a systematic search for observational studies was not planned. In addition, observational studies are considered high risk bias studies.

Types of participants

Paediatric participants (up to 18 years old) with chronic liver disease or portal vein thrombosis, irrespective of the aetiology, severity of disease, and duration of illness, in whom the presence of oesophageal varices is confirmed by oesophagogastroduodenoscopy. We planned to focus on therapy questions related to children and adolescents who had not yet suffered gastrointestinal bleeding from oesophageal varices (primary prophylaxis).

Children and adolescents with a previous surgical portal‐systemic shunt procedure or insertion of a transjugular intrahepatic portal‐systemic shunt (TIPS), previous band ligation or sclerotherapy of oesophageal varices, or previous history of upper gastrointestinal bleeding are a distinct group of trial participants in whom the diagnosis or natural history of oesophageal varices has been modified. These children and adolescents constituted an exclusion criteria of this review, unless study data were subdivided following patient groups.

Types of interventions

Experimental group:

• any type of beta‐blocker, dosage, and duration of treatment

Control group:

• placebo or no intervention

Any co‐interventions were to be allowed as long as they were administered comparably to the experimental and control groups.

Types of outcome measures

Primary outcomes

1. All‐cause mortality

2. Serious adverse events and liver‐related morbidity (i.e. proportion of participants who developed ascites, hepatorenal syndrome, hepatocellular carcinoma, or hepatic encephalopathy). A serious adverse event, defined according to the International Conference on Harmonization (ICH) Guidelines for Good Clinical Practice (ICH‐GCP 1997), was any untoward medical occurrence that results in death, is life‐threatening, requires inpatient hospitalisation or prolongation of existing hospitalisation, results in persistent or significant disability or incapacity, or is a congenital anomaly or birth defect. All other adverse events were considered non‐serious adverse events.

3. Health‐related quality of life, determined exclusively by means of validated scales, classifications, and measurement systems, like the Paediatric Quality of Life Inventory (PedsQL), Child Health Questionnaire (CHQ), and DISABKIDS questionnaires.

Secondary outcomes

1. Oesophageal variceal bleeding

2. Adverse events considered not serious (any adverse event that do not meet the above criteria for serious adverse events).

We planned to consider follow‐up, up to five years after treatment, for our main analysis.

Search methods for identification of studies

Electronic searches

We searched the Cochrane Hepato‐Biliary Group Controlled Trials Register (maintained and searched internally by the CHBG Information Specialist via the Cochrane Register of Studies Web; April 2020); Cochrane Central Register of Controlled Trials (CENTRAL; 2020, Issue 4) in the Cochrane Library (searched April 2020); PubMed (1809 to April 2020), Embase (Elsevier; 1974 to April 2020), LILACS (Latin American and Caribbean Health Science Information database; 1982 to April 2020), and Science Citation Index Expanded (Web of Science; 1900 to April 2020) (Royle 2003). We also searched the trial registries ClinicalTrial.gov (clinicaltrials.gov/), European Medicines Agency (EMA; www.ema.europa.eu/ema/), World Health Organization International Clinical Trial Registry Platform (www.who.int/ictrp), and the Food and Drug Administration (FDA; www.fda.gov) for ongoing trials. Due to heavy traffic generated by the COVID‐19 outbreak, the ICTRP Search Portal was not accessible from outside WHO temporarily. However, trials from both ClinicalTrials.gov and the WHO trials register are also included in CENTRAL. We applied no language or document type restrictions. Search strategies with the time spans of the searches are listed in Appendix 1.

Searching other resources

We tried to identify additional randomised clinical trials by manually searching the reference lists of the 12 full‐text papers retrieved from the electronic databases. Furthermore, we performed a manual search of the main paediatric gastroenterology and hepatology conferences abstract books from 2008 to 2019, such as North American Society for Pediatric Gastroenterology, Hepatology and Nutrition (NASPGHAN), and European Society for Paediatric Gastroenterology, Hepatology and Nutrition (ESPGHAN). We applied no language or document type restrictions.

Data collection and analysis

We followed the guidelines provided in the Cochrane Handbook for Systematic Reviews of Interventions (Higgins 2011). We planned to use Review Manager 5 for our analyses (Review Manager 2014).

Selection of studies

We planned to decide on the potentially eligible trials for inclusion based on a review of the abstracts, or if they were identified in relevant review articles, including reference lists. We planned to include trials regardless if they reported on the outcomes of our review or not. Two review authors (LC and DG) independently assessed the publications for eligibility, using the inclusion criteria. The two review authors (LC and DG) resolved any disagreements by consensus, including a third author, JCG.

Data extraction and management

Two authors (LC and DG), using a pre‐piloted form, planned to independently extract the following data from all included studies.

1. General information: title, journal, year, publication status, and trial design

2. Sample size: number of participants meeting the criteria and total number screened

3. Baseline characteristics: baseline diagnosis, age, sex, race, disease severity, and concurrent medications used

4. Severity of liver disease of the studied population, using the Child‐Pugh score (Pugh 1973), the paediatric end‐stage liver disease (PELD) scores for ages less than 12 years (McDiarmid 2002), and model for end‐stage liver disease (MELD) for ages 12 and older (Kamath 2001)

5. All‐cause mortality, non‐variceal bleeding of the upper gastrointestinal tract, oesophageal variceal bleeding, and quality of life, determined exclusively by validated scales

6. Adverse events: serious and non‐serious

7. The follow‐up times for all outcomes, as defined in each trial

8. Funding

One review author (JCG) was to arbitrate in case of disagreements in data extraction.

Assessment of risk of bias in included studies

Two review authors (LC and DG) planned to independently assess the risk of bias of each included trial, following recommendations and the following definitions from the Cochrane Handbook for Systematic Reviews of Interventions (Higgins 2011), and methodological studies (Schulz 1995; Moher 1998; Kjaergard 2001; Wood 2008; Savović 2012a; Savović 2012b; Savović 2018).

Allocation sequence generation

• Low risk of bias: sequence generation was achieved using computer random number generation or a random number table. Drawing lots, tossing a coin, shuffling cards, and throwing dice were adequate if performed by an independent person not otherwise involved in the trial.

• Unclear risk of bias: the method of sequence generation was not specified.

• High risk of bias: the sequence generation method was not random. Such studies were to be excluded from the assessment of benefit.

Allocation concealment

• Low risk of bias: the participant allocations could not have been foreseen in advance of, or during, enrolment. Allocation was controlled by a central and independent randomisation unit. The allocation sequence was unknown to the investigators (e.g. if the allocation sequence was hidden in sequentially numbered, opaque, and sealed envelopes).

• Unclear risk of bias: the method used to conceal the allocation was not described, so that intervention allocations may have been foreseen in advance of, or during, enrolment.

• High risk of bias: the allocation sequence was likely to be known to the investigators who assigned the participants. Such studies were to be excluded from the assessment of benefit.

Blinding of participants and personnel

• Low risk of bias: blinding of participants and personnel performed adequately using a placebo. We defined lack of blinding as unlikely to affect the evaluation of mortality (Savović 2012a; Savović 2012b).

• Unclear risk of bias: insufficient information to assess blinding.

• High risk of bias: no blinding or incomplete blinding.

Blinding of outcome assessors

• Low risk of bias: blinding of outcome assessors performed adequately using a placebo. We defined lack of blinding as unlikely to affect the evaluation of mortality (Savović 2012a; Savović 2012b).

• Unclear risk of bias: insufficient information to assess blinding.

• High risk of bias: no blinding or incomplete blinding.

Incomplete outcome data

• Low risk of bias: missing data were unlikely to make treatment effects depart from plausible values. Sufficient methods, such as multiple imputation, were employed to handle missing data.

• Unclear risk of bias: there was insufficient information to assess whether missing data in combination with the method used to handle missing data were likely to induce bias on the results.

• High risk of bias: the results were likely to be biased due to missing data.

Selective outcome reporting

• Low risk of bias: the trial reported the following predefined primary outcomes: all‐cause mortality, serious adverse events, and oesophageal variceal bleeding. If the original trial protocol was available, the outcomes should have been those called for in that protocol. If the trial protocol was obtained from a trial registry (e.g. www.clinicaltrials.gov), the outcomes sought were those enumerated in the original protocol, if the trial protocol was registered before or at the time that the trial was begun. If the trial protocol was registered after the trial was begun, those outcomes were not considered to be reliable.

• Unclear risk of bias: not all predefined outcomes were reported fully, or it was unclear whether data on these outcomes were recorded or not.

• High risk of bias: one or more predefined outcomes were not reported.

Overall bias risk assessment

• Low risk of bias: all domains in a trial are at low risk of bias.

• High risk of bias: one or more of the bias domains in a trial are at unclear or high risk of bias.

We expected lack of blinding of participants in the trials considering the different treatment modalities (endoscopic versus oral), and this could lead to bias that might have necessitated analysis.

We planned to generate a 'Risk of bias' graph and 'Risk of bias' summary to show a summary of this assessment.

Measures of treatment effect

For dichotomous outcomes, we planned to calculate the risk ratio (RR) with 95% confidence intervals (CI). For continuous outcomes, such as health‐related quality of life, we planned to calculate the mean difference (MD) with 95% CI if all studies reported it using the same scale, and standardised mean difference (SMD) with 95% CI if the studies used different scales for its reporting.

Unit of analysis issues

The unit of analysis was to be the participant undergoing treatment (i.e. primary prophylaxis of oesophageal variceal bleeding in children with chronic liver disease or portal vein thrombosis) according to the intervention group to which the participant was randomly assigned. In case of trials with multiple intervention groups, we planned to collect data for all trial intervention groups that met our inclusion criteria. We planned to divide the control intervention group into two to avoid double‐counting in case this was a common comparator. In the case of cross‐over trials, we planned to use the outcome data after the period of the first intervention because the assigned treatments could have residual effects (Higgins 2011). Due to the clinical situation, we did not expect to find cluster‐randomised trials. 

Dealing with missing data

We planned to perform an intention‐to‐treat analysis whenever possible; otherwise, we planned to use the data available to us and contact the original investigators to request the missing data.

Regarding the dichotomous primary outcomes, whenever possible, we planned to conduct the following two sensitivity analyses.

• Extreme case analysis favouring the experimental intervention group ('best‐worse' case scenario): none of the dropouts or participants lost from the experimental group, but all of the dropouts and participants lost from the control intervention group experienced the outcome; including all randomised participants in the denominator.

• Extreme case analysis favouring the control intervention group ('worst‐best' case scenario): all dropouts or participants lost from the experimental group, but none from the control group experienced the outcome; including all randomised participants in the denominator.

For the continuous primary outcome, health‐related quality of life, we planned to impute the standard deviation from P values, according to guidance in the Cochrane Handbook for Systematic Reviews of Interventions (Higgins 2011). If the data were likely to be normally distributed, we planned to use the median for meta‐analysis when the mean was not available; otherwise, we planned to provide a median and interquartile range of the difference in medians. If it was not possible to calculate the standard deviation from the P value or the CIs, we planned to impute the standard deviation using the largest standard deviation in other trials for that outcome. This form of imputation can decrease the weight of the study for calculation of MDs and may bias the effect estimate to no effect for calculation of SMDs (Higgins 2011).

Assessment of heterogeneity

We planned to identify heterogeneity by visual inspection of the forest plots, by using a standard Chi² test and a significance level of α = 0.1, in view of the low power of such tests. We planned to use the Chi² test for heterogeneity to detect between‐trial heterogeneity. In addition, we planned to specifically examine the degree of heterogeneity observed in the results with the I² test according to the following classification: from 0% to 40%, heterogeneity may not be important; from 30% to 60%, heterogeneity may be moderate; from 50% to 90%, heterogeneity may be substantial; and from 75% to 100%, heterogeneity may be considerable (Higgins 2003). If there was heterogeneity, we planned to determine the potential reasons for it by examining the individual trial and subgroup characteristics.

Assessment of reporting biases

We planned to assess reporting biases with funnel plots of the relative risk estimates from the individual trials (plotted on a logarithmic scale) against trial size or precision (variance) or the estimators.

Data synthesis

We planned to conduct this systematic review according to the Cochrane Handbook for Systematic Reviews of Interventions (Higgins 2011). We planned to use the Cochrane software Review Manager 5 to analyse data and produce summary estimates of the treatment effect (Review Manager 2014). We planned to present results with a random‐effects meta‐analysis because we expected that the included trials would be heterogeneous. We planned to present results of continuous outcomes as mean difference (MD) or standardised mean difference (SMD), with 95% CI (Higgins 2011).

Subgroup analysis and investigation of heterogeneity

We planned to perform the following subgroup analyses because we expected that we would observe heterogeneity.

• Trials at low risk of bias compared to trials at high risk of bias because trials at high risk of bias may overestimate or underestimate a treatment effect (Higgins 2011)

• Primary prophylaxis of small varices compared to primary prophylaxis of only medium or large varices because of the different risk of bleeding according to the variceal size (Garcia‐Tsao 2017)

• Children with chronic liver disease compared to children with extrahepatic portal vein thrombosis because of the differences in the physiopathology of the cause of the portal hypertension in patients with liver disease and alteration in the portal inflow (Chapin 2018)

• Severity of liver disease (Child‐Pugh A, B, or C, and PELD or MELD) because of the different risk of bleeding according to the impaired liver function (Garcia‐Tsao 2017)

• Children with cholestatic compared to children with non‐cholestatic liver disease because of the different risk of bleeding according to different etiologies (Chapin 2018).

Sensitivity analysis

In addition to the sensitivity analyses specified under Dealing with missing data, and in order to assess the robustness of the eligibility criteria, our intention was to undertake sensitivity analyses in an attempt to explain our findings as well as any observed heterogeneity.

We planned to conduct Trial Sequential Analysis to assess imprecision of our primary and secondary outcome results (Thorlund 2017; TSA 2017), and then we planned to compare the result of our assessment with the assessment of imprecision using GRADEpro GDT.

Trial Sequential Analysis

We planned to perform Trial Sequential Analyses (Thorlund 2017; TSA 2017; Wetterslev 2017) because cumulative meta‐analyses are at risk of producing random errors due to sparse data and repetitive testing of the accumulating data (Brok 2008; Wetterslev 2008; Brok 2009; Thorlund 2009; Wetterslev 2009; Thorlund 2010; Wetterslev 2017). To minimise random errors, we planned to calculate the diversity‐adjusted required information size (DARIS) (i.e. the number of children needed in a meta‐analysis to detect or reject a certain intervention effect) (Brok 2008; Wetterslev 2008; Brok 2009; Thorlund 2009, Wetterslev 2009; Thorlund 2010; Wetterslev 2017).

The required information size calculation should also account for the heterogeneity or diversity present in the meta‐analysis (Wetterslev 2008; Wetterslev 2009; Wetterslev 2017). In our meta‐analyses, we planned to base the diversity‐adjusted required information size (DARIS) on the event proportion in the control group; assumption of a plausible relative risk reduction of 20% on the relative risk reduction observed in the included trials with low risk of bias; a risk of type I error of 2.5% because of three primary outcomes and 3.30% because of two secondary outcomes; a risk of type II error of 20%; and the assumed diversity of the meta‐analysis (Wetterslev 2009).

The underlying assumption of Trial Sequential Analysis is that testing for significance may be performed each time a new trial is added to the meta‐analysis. We planned to add the trials according to the year of publication, and if more than one trial was published in a year, we planned to add trials alphabetically according to the last name of the first author. Based on the required information size, we planned to construct trial sequential monitoring boundaries (Wetterslev 2008; Thorlund 2017; Wetterslev 2017). These boundaries determine the statistical inference one may draw regarding the cumulative meta‐analysis that has not reached the required information size; if the trial sequential monitoring boundary for benefit or harm is crossed before the required information size is reached, firm evidence may be established and further trials may be superfluous.

However, if the boundary is not surpassed, it is most probably necessary to continue conducting trials in order to detect or reject a certain intervention effect. This can be determined by assessing if the cumulative Z‐curve crosses the trial sequential monitoring boundaries for futility.

We planned to downgrade our assessment for imprecision in Trial Sequential Analysis by two levels if the accrued number of participants was below 50% of the DARIS, and one level if the number was between 50% and 100% of DARIS. We planned to not downgrade our assessment of imprecision if the cumulative Z‐curve reached futility or DARIS.

Summary of findings and assessment of the certainty of the evidence

We planned to create a 'Summary of findings' table to present information on the certainty of the evidence, magnitude of effects of the interventions, and summary data, using GRADEpro GDT, for all‐cause mortality, serious adverse events and liver‐related morbidity, health‐related quality of life, oesophageal bleeding, and adverse events considered not serious. We also planned to provide the time and range of follow‐up. The GRADE approach appraises the certainty of a body of evidence based on the extent to which one can be confident that an estimate of effect or association reflects the item being assessed. The certainty of a body of evidence considers within‐study risk of bias, indirectness of the evidence (population, intervention, control, outcomes), unexplained inconsistency (heterogeneity) of results (including problems with subgroup analyses), imprecision of results, and risk of publication bias. We defined the certainty of the evidence as 'high', 'moderate', 'low', or 'very low' as follows:

• High certainty: we are very confident that the true effect lies close to that of the estimate of the effect.

• Moderate certainty: we are moderately confident in the effect estimate; the true effect is likely to be close to the estimate of the effect, but there is a possibility that it is substantially different.

• Low certainty: our confidence in the effect estimate is limited; the true effect may be substantially different from the estimate of the effect.

• Very low certainty: we have very little confidence in the effect estimate; the true effect is likely to be substantially different from the estimate of effect.

Results

Description of studies

We found no randomised clinical trials that qualified for inclusion in our systematic review. We found four observational studies that reported certain harms.

Results of the search

We identified 4977 records in the initial electronic searches for interventions for primary prophylaxis of oesophageal variceal bleeding in children. Two additional records were identified through manual searching in ESPGHAN and NASPGHAN congress abstracts book 2008‐2019. After excluding duplicates, 3640 records remained. Out of these, we identified 67 records of possible interest. Based on their abstract, we excluded 55 because of their irrelevance to our research question (Figure 1). We retrieved the full‐text of the remaining 12 publications and assessed them for eligibility. None of them met the inclusion criteria of our review. We did not find any ongoing studies relevant to our research question.

1.

Study flow diagram. Date of search 27 April 2020

Included studies

We found no randomised clinical trials that matched our inclusion criteria. We found four observational  studies, within the search result for randomised clinical trials, that reported on harms.

Excluded studies

We provided the reasons for exclusion of the 12 studies in 'Characteristics of excluded studies' table. Four of the twelve excluded studies were paediatric studies, and we read them through to find reports on harm (Samanta 2011; El‐Karaksy 2015; Pimenta 2016; Ozsoylu 2000).

Risk of bias in included studies

Not assessed as no randomised clinical trials fulfilled our inclusion criteria.

Effects of interventions

No trial results due to lack of trials on the topic of this review.

Harms reported in observational studies, retrieved with the searches for randomised trials

Four of the twelve excluded studies disclosed information on harm (Ozsoylu 2000; Samanta 2011; El‐Karaksy 2015; Pimenta 2016; Table 1). In these, chest symptoms, drowsiness, bronchospasm, and hypotension with convulsion were described (El‐Karaksy 2015; Pimenta 2016).

1. Harms reported in observational studies.

Study ID	Short summary	Report on harms
Ozsoylu 2000	An observational study assessing the effectiveness of propranolol ‐ a beta‐blocker ‐ for primary and secondary prophylaxis of variceal bleeding in 60 children with cirrhosis. The children received propranolol (1 mg/kg/day to 2 mg/kg/day) for a period of 1 to 14 years. Fifteen children received propanolol as secondary prophylaxis and 45 children received propanolol for primary prophylaxis.	No serious or non‐serious adverse events were reported.
Samanta 2011	Randomised controlled trial of 62 children with portal hypertension randomised to two different beta‐blockers, administered as primary prophylaxis of variceal bleeding. The randomised children were under 12 years of age. Thirty‐one children received propanolol, and 31 children received carvedilol.	No serious or non‐serious adverse events were reported.
El‐Karaksy 2015	Retrospective study of 156 children with portal hypertension due to extrahepatic portal vein obstruction. Propanolol was prescribed in 92.3% of patients as prophylactic therapy to prevent variceal bleeding. The median age at the start of propranolol was 53 months, the median starting dose was 15 mg/day, and the median adjusted dose was 1 mg/kg.	Chest symptoms occurred in 15.9% of the children after administration of propranolol compared with 2.1% of the children before they received propranolol (P < 0.01).
Pimenta 2016	Cohort study including 26 children and adolescents with cirrhosis.Nine (34.6%) of the participants had contraindications to using propranolol and were referred for endoscopic prophylaxis. All remaining children were administered a beta‐blocker (propranolol) as primary prophylaxis. The doses of propranolol varied from 1 mg/kg/day to 3.1 mg/kg/day.	Seven (41.2%) participants had to suspend propanolol due to failure of treatment, or adverse effects such as drowsiness (2 participants), bronchospasm (1 participant), and hypotension with convulsion (1 participant).

Discussion

Summary of main results

We found no randomised clinical trials evaluating the use 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. We found four observational studies, within the search result for randomised clinical trials, that reported on harms. This is, of course, not representing a systematic review of observational evidence (Storebø 2018), and such a review should await the results of randomised clinical trials demonstrating benefit of beta‐blockers.

Overall completeness and applicability of evidence

The lack of randomised clinical trials could potentially be explained by the small number of children with oesophageal varices, seen in each centre. On the other hand, due to the lack of efficacy and safety data, the use of propanolol has not been approved for use in children with portal hypertension. Also, the screening for oesophageal varices in children with portal hypertension using endoscopy is not the current standard of care, and therefore, several clinical practice, ethical, and financial challenges must be overcome if endoscopy and band ligation were to be included in a clinical trial protocol.

In paediatric observational studies, chest symptoms, drowsiness, bronchospasm, and hypotension with convulsion were described (Ozsoylu 2000; Samanta 2011; El‐Karaksy 2015; Pimenta 2016). However, results from these paediatric studies are limited for use by the fact that they do not result from prospective controlled trials, comparable to what has been done for adults. In addition to the limited study design and high risk of bias, these studies are characterised by limited sample sizes and follow‐up periods. Therefore, we need to be cautious when interpreting their results.

Since the description of efficacy and safety of non‐selective beta‐blockers therapy for primary prophylaxis of variceal haemorrhage derives from trials of adult participants with chronic liver disease, with very different etiologies compared with children, there is a need for randomised trials to evaluate this question in children. The paediatric trials should evaluate non‐selective beta‐blockers on the haemodynamic changes, the effect on portal pressure, and the adequate doses of non‐selective beta‐blockers in children before their use in clinical practices (Ling 2011). Other issues associated with the use of beta‐blockers in children that need to be addressed are the need for prolonged therapy, the risk of bleeding after suspending treatment, and the frequent adverse effects and contraindications (Samanta 2011; El‐Karaksy 2015; Pimenta 2016).

Quality of the evidence

We were unable to identify evidence from randomised clinical trials to support or refute the use of beta‐blockers versus placebo or no intervention for primary prophylaxis of oesophageal variceal bleeding in children and adolescents with chronic liver disease or portal vein thrombosis.

Potential biases in the review process

We have not searched systematically for observational studies, and we have not assessed the identified studies for risk of bias.

Agreements and disagreements with other studies or reviews

We found no further reviews prepared by other authors on the subject. Our reviews, in addition to the current one, compared band ligation versus beta‐blockers (Gana 2019); band ligation versus sclerotherapy (Gana 2020); sclerotherapy versus sham or no intervention (Gattini 2020a); sclerotherapy versus beta‐blockers (Gattini 2020b); and band ligation versus sham or no intervention (Cifuentes 2021). The results of two of these reviews comparing sclerotherapy versus sham or no intervention (Gattini 2020a) and band ligation versus sham or no intervention (Cifuentes 2021), with one randomised clinical trial each, are insufficient to compare and discuss results.

Authors' conclusions

Implications for practice.

Randomised clinical trials assessing the benefits or harms of beta‐blockers versus placebo or no intervention for the primary prophylaxis of oesophageal variceal bleeding in children with chronic liver disease or portal vein thrombosis are lacking. Therefore, we are unable to make any conclusions regarding the benefits or harms of beta‐blockers.

Implications for research.

This systematic review identified the need for well‐designed, adequately powered, randomised clinical trials to assess the benefits and harms of beta‐blockers versus placebo for primary prophylaxis of oesophageal variceal bleeding in children with chronic liver disease or portal vein thrombosis. Those randomised clinical trials should include patient‐relevant clinical outcomes, such as mortality, failure to control bleeding, adverse events, and quality of life. The trials should follow the Spirit Statement (Chan 2013), Patient‐Centered Outcomes Research Institute recommendations (PCORI 2012), and the CONSORT Statement.

What's new

Date	Event	Description
26 February 2021	Amended	References within the review text updated

History

Protocol first published: Issue 11, 2015
Review first published: Issue 1, 2021

Appendices

Appendix 1. Search strategies

Database	Time span	Search strategy
Cochrane Hepato‐Biliary Group Controlled Trials Register	April 2020	(((non‐selectiv* OR non selectiv* OR adrenergic*) AND (beta OR b‐block*) AND (antagonist* OR block* OR receptor*)) OR (oxprenolol OR sotalol OR carteolol OR nadolol OR penbutolol OR timolol OR carvedilol OR tertatolol OR nipradiol OR mepindolol OR propranolol)) AND (placebo* OR ((sham OR dummy) AND (treatment* or procedure*)) OR no*intervention*) AND (child* OR pediat* OR paediat* OR infant* OR bab* OR newborn* OR pre‐school* OR preschool OR school* OR lactant* OR neonat* OR adolescent* OR youth OR young* OR toddler* OR teen* OR boy* OR girl* OR student* OR juvenil* OR minor* OR pubescen*)
Cochrane Central Register of Controlled Trials (CENTRAL) in The Cochrane Library	2020; Issue 4	#1 MeSH descriptor: [Child, Preschool] explode all trees   #2 MeSH descriptor: [Child] explode all trees          #3 MeSH descriptor: [Adolescent] explode all trees            #4 MeSH descriptor: [Infant, Newborn] explode all trees #5 MeSH descriptor: [Infant] explode all trees       #6 child* or p*ediat* or infant* or baby or pre‐school* or lactant* or neonate* or adolescent* or school‐child or youth or toddler* or teen* or boy* or girl* or preschool* or student* or juvenile or minor* or pubescen* or young* or babies or newborn  In Trials #7 #1 or #2 or #3 or #4 or #5 or #6                 #8 MeSH descriptor: [Placebos] explode all trees  #9 placebo* In Trials       #10 (sham procedure*) or (sham treatment*) In Trials   #11 (dummy procedure*) or (dummy treatment*) In Trials                #12 (no intervention* or non intervention* or nonintervention*) In Trials #13 #8 or #9 or #10 or #11 or #12     #14 MeSH descriptor: [Adrenergic beta‐Antagonists] explode all trees        #15 (beta Antagonist* or beta‐Antagonist* or beta‐block* or beta block* or beta‐receptor* or b‐block*) and Adrenergic*  In Trials    #16 (b‐block* or beta‐block*) and (non‐selective* or nonselective*) In Trials         #17 beta‐adrenergic* or beta adrenergic* or adrenergic* or adrenergic* beta receptor* or adrenergic* beta‐receptor* and block*  In Trials               #18 receptor blockaders, beta‐adrenergic* In Trials #19 MeSH descriptor: [Oxprenolol] explode all trees             #20 MeSH descriptor: [Sotalol] explode all trees      #21 MeSH descriptor: [Carteolol] explode all trees #22 MeSH descriptor: [Propranolol] explode all trees            #23 MeSH descriptor: [Nadolol] explode all trees    #24 MeSH descriptor: [Penbutolol] explode all trees             #25 MeSH descriptor: [Timolol] explode all trees     #26 (oxprenolol or sotalol or carteolol or nadolol or penbutolol or timolol or carvedilol or tertatolol or nipradilol or mepindolol or propranolol) In Trials   #27 #14 or #15 or #16 or #17 or #18 or #19 or #20 or #21 or #22 or #23 or #24 or #25 or #26                 #28 #7 and #13 and #27
PubMed	1809 to April 2020	#1 "Adrenergic beta‐Antagonists"[Mesh] #2 ((beta Antagonist* OR beta‐Antagonist* OR beta‐Block* OR beta Block* OR beta‐Receptor*  OR b‐block*) Adrenergic*) #3 (B‐block* OR beta‐block* OR beta block*) AND (non‐selective* OR nonselective*) #4 (beta‐Adrenergic* OR  beta Adrenergic* OR Adrenergic*  OR Adrenergic* beta Receptor* OR Adrenergic* beta‐Receptor* (Block*)) #5 Receptor Blockaders, beta‐Adrenergic* #6 "Oxprenolol"[Mesh] #7 "Sotalol"[Mesh] #8 "Carteolol"[Mesh] #9 "Propranolol"[Mesh] #10 "Nadolol"[Mesh] #11 "Penbutolol"[Mesh] #12 "Timolol"[Mesh] #13 "carvedilol" [Supplementary Concept] #14 (oxprenolol OR sotalol OR carteolol OR nadolol OR penbutolol OR timolol OR carvedilol OR tertatolol  OR nipradilol  OR mepindolol  OR propranolol) #15 #1 OR #2 OR #3 OR #4 OR #5 OR #6 OR #7 OR #8 OR #9 OR #10 OR #11 OR #12 OR #13 OR #14 #16 placebo* #17 "Placebos"[Mesh] #18 sham (treatment* OR procedure*) #19 dummy (treatment* OR procedure*) #20 no intervention* #21 non intervention* #22 nonintervention* #23 #16 OR #17 OR #18 OR #19 OR #20 OR #21 OR #22 #24 "Child, Preschool"[Mesh] #25 "Child"[Mesh] #26 "Adolescent"[Mesh] #27 "Infant, Newborn"[Mesh] #28 "Infant"[Mesh] #29 child* OR pediat* OR paediat* #30 infant* OR baby OR pre‐school* #31 lactant* OR neonate* OR adolescent* #32 school‐child OR youth OR toddler* OR teen* #33 boy* OR girl* OR preschool* OR student* #34 juvenile OR minor* OR pubescen* #35 young* OR babies OR newborn* #36 #24 OR #25 OR #26 OR #27 OR #28 OR #29 OR #30 OR #31 OR #32 OR #33 OR #34 OR #35 #37 #15 AND #23 AND #36
Embase (Elsevier)	April 2020	#1 'beta adrenergic receptor blocking agent'/exp AND [embase]/lim #2 (beta AND antagonist*):ab,ti OR (beta AND block* ):ab,ti OR (beta AND receptor*):ab,ti OR (b AND block*):ab,ti AND adrenergic*:ab,ti AND [embase]/lim #3 (b AND block*):ab,ti OR (beta AND block*):ab,ti AND (non AND selective* OR nonselective*):ab,ti AND [embase]/lim #4 beta:ab,ti AND adrenergic*:ab,ti OR adrenergic*:ab,ti OR (adrenergic* AND beta AND receptor*):ab,ti AND (block*):ab,ti AND [embase]/lim #5 Receptor:ab,ti AND blockaders:ab,ti AND beta: ab,ti AND adrenergic*:ab,ti AND [embase]/lim #6 'oxprenolol'/exp AND [embase]/lim #7 'sotalol'/exp AND [embase]/lim #8 'carteolol'/exp AND [embase]/lim #9 'propranolol'/exp AND [embase]/lim #10 'nadolol'/exp AND [embase]/lim #11 'penbutolol'/exp AND [embase]/lim #12 'timolol'/exp AND [embase]/lim #13 'carvedilol'/exp AND [embase]/lim #14 oxprenolol:ab,ti OR sotalol:ab, ti OR carteolol:ab,ti OR nadolol:ab,ti OR penbutolol:ab,ti OR timolol:ab,ti OR carvedilol:ab,ti OR tertatolol:ab,ti OR nipradilol:ab,ti OR mepindolol:ab,ti OR propranolol:ab,ti AND [embase]/lim #15 #1 OR #2 OR #3 OR #4 OR #5 OR #6 OR #7 OR #8 OR #9 OR #10 OR #11 OR #12 OR #13 OR #14 #16 placebo*:ab,ti AND [embase]/lim #17 'placebo'/exp AND [embase]/lim #18 'sham procedure'/exp AND [embase]/lim #19 (sham NEAR/1 (treatment* OR procedure*)):ab,ti OR (dummy NEAR/1 (treatment* OR procedure*)):ab,ti OR 'no intervention':ab,ti OR 'no interventions':ab,ti OR 'non intervention':ab,ti OR 'non interventions':ab,ti OR nonintervention*:ab,ti AND [embase]/lim #20 #16 OR #17 OR #18 OR #19 #21 'preschool child'/exp AND [embase]/lim #22 'child'/exp AND [embase]/lim #23 'adolescent'/exp AND [embase]/lim #24 'newborn'/exp AND [embase]/lim #25 'infant'/exp AND [embase]/lim #26 (child* OR pediat* OR paediat* OR infant* OR 'baby'/exp OR baby OR  'pre school' OR  lactant* OR neonate* OR adolescent* OR 'school‐child' OR youth OR  toddler* OR teen* OR boy* OR girl* OR preschool* OR student*OR juvenile OR minor* OR pubescen* OR young* OR babies OR newborn*) AND [embase]/lim #27 #21 OR #22 OR #23 OR #24 OR #25 OR #26 #28 #15 AND #20 AND #27
LILACS (Bireme)	1982 to April 2020	(((non‐selectiv$ OR non selectiv$ OR adrenergic$) AND (beta OR b‐block$) AND (antagonist$ OR block$ OR receptor$)) OR (oxprenolol OR sotalol OR carteolol OR nadolol OR penbutolol OR timolol OR carvedilol OR tertatolol OR nipradiol OR mepindolol OR propranolol)) [Words] and (placebo$ OR ((sham OR dummy) AND (treatment$ or procedure$)) OR no$intervention$) [Words] and (child$ OR pediat$ OR paediat$ OR infant$ OR bab$ OR newborn$ OR pre‐school$ OR preschool OR school$ OR lactant$ OR neonat$ OR adolescent$ OR youth OR young$ OR toddler$ OR teen$ OR boy$ OR girl$ OR student$ OR juvenil$ OR minor$ OR pubescen$) [Words]
Science Citation Index Expanded (Web of Science)	1900 to April 2020	#1 TS=Placebo* #2 TS=“Sham procedure*” #3 TS=“Sham treatment*” #4 TS=“Dummy procedure*”     #5 TS=“Dummy treatment*”     #6 TS=”No intervention*” #7 TS=”Non intervention*” #8 TS=”Nonintervention*” #9 #1 OR #2 OR #3 OR 4 OR #5 OR #6 OR #7 OR #8      #10 TS=(adrenergic and beta and (antagonist* or block* or receptor*)) #11 TS=(child* OR P*ediat* OR infant* OR baby OR pre‐school* OR lactant* OR neonate* OR adolescent* OR school‐child* OR youth OR toddler* OR teen* OR boy* OR girl* OR preschool* OR student* OR juvenile OR minor* OR pubescen* OR young* OR babies OR newborn*) #12 #9 AND #10 AND #11

Characteristics of studies

Characteristics of excluded studies [ordered by study ID]

Study	Reason for exclusion
Andreani 1990	We excluded this randomised controlled trial because all included participants were adults. The trial randomised 126 people with cirrhosis and with oesophageal varices, and no histories of bleeding, to receive propranolol, sclerotherapy, or placebo.
Conn 1991	We excluded this randomised controlled trial because all included participants were adults. The trial assessed propranolol versus placebo in the prevention of first haemorrhage from oesophagogastric varices in 102 participants with cirrhosis (78% alcoholic), hepatic venous pressure gradients greater than 12 mmHg and endoscopically proven oesophageal varices.
El‐Karaksy 2015	A retrospective study of 169 children with portal hypertension due to extrahepatic portal vein obstruction. Primary and secondary prophylaxis with propanolol, endoscopic variceal ligation, and sclerotherapy were described.
Gatta 1987	We excluded this randomised controlled trial because all included participants were adults. All participants had cirrhosis, with a documented episode of variceal haemorrhage. The trial participants were randomised to receive nadolol or placebo (secondary prophylaxis trial).
Ozsoylu 2000	An observational study. It assessed the effectiveness of propranolol ‐ a beta‐blocker ‐ for primary and secondary prophylaxis of variceal bleeding in 60 children with cirrhosis. The children received propranolol (1 mg/kg/day to 2 mg/kg/day) for a period of 1 to 14 years. Based on the Child‐Pugh classification, 33 children were Child‐Pugh Class A, 22 Class B, and five Class C. Fifteen children received propanolol as secondary prophylaxis (previous history of bleeding) and 45 children received propanolol for primary prophylaxis. Seven (15.6%) of the 45 children experienced bleeding on propranolol therapy in the primary prevention group.
Pagliaro 1989	We excluded this randomised controlled trial because all included participants were adults. The trial was a multicentre, randomised, single‐blind trial of propranolol for prophylaxis of first bleeding in cirrhosis. A total of 174 people with large oesophageal varices were randomly assigned to receive either propranolol or placebo (vitamin K).
Pascal 1987	We excluded this randomised, multicentre, single‐blind, controlled trial because all included participants were adults. The trial randomised 230 participants, with cirrhosis of the liver (90% with alcoholism and 46% with a Child‐Pugh grade C classification) and large oesophageal varices without previous bleeding, to either propranolol or placebo. The trial aimed to prevent first upper gastrointestinal tract bleeding.
Pimenta 2016	A cohort study of 26 children and adolescents with cirrhosis, evaluating primary prophylaxis with a beta‐blocker. Of the 17 participants who received propanolol, six (35.3%) presented with variceal bleeding after a median follow‐up of 1.9 years.
Plevris 1994	We excluded this randomised double‐blind controlled trial because all included participants were adults. The trial randomised 319 people with chronic liver disease to receive propranolol or placebo in order to assess the effect of propranolol on prevention of first variceal bleed and survival in people with chronic liver disease.
Samanta 2011	We excluded this randomised controlled trial because children were randomised to two different beta‐blockers, administered as primary prophylaxis of variceal bleeding. The 62 randomised children were under 12 years of age. Thirty‐one children received propanolol, and 31 children received carvedilol. All children had portal hypertension. For both drugs, the efficacy was higher and the response was achieved much faster in children with pre‐sinusoidal aetiologies than those with sinusoidal causes of portal hypertension. Carvedilol was found to be more effective than propranolol at only four‐month treatment (P = 0.035) and five‐month follow‐up (P = 0.034).
Sarin 2013	We excluded this randomised controlled trial because all included participants were adults. It assessed the effect of propranolol on the growth of small varices, and whether single or serial hepatic venous pressure gradient measurements resulted in a better outcome compared to no measurement in people with small varices. A total of 150 people with cirrhosis and small varices, without any history of variceal bleed, received either propranolol or placebo.
Villeneuve 1986	We excluded this randomised controlled trial because all included participants were adults. The trial included 79 people, with shown variceal haemorrhage at endoscopy, within 72 hours following diagnosis. Trial participants received propranolol for primary prevention of recurrent variceal bleeding, or placebo.

Differences between protocol and review

• The title of our published protocol was 'Beta‐blockers versus placebo or no intervention for primary prophylaxis of oesophageal varices in children'. Following advice from peer reviewers and the contact editor, we modified the title and it now reads: 'Beta‐blockers versus placebo or no intervention for primary prophylaxis of oesophageal variceal bleeding in children with chronic liver disease or portal vein thrombosis'

• We updated text in the background section.

• We updated the methodological part of our protocol to reflect methodology developments at the time of the review preparation. This also includes removal the 'for‐profit' bias risk domain as it is included in the GRADE factor: publication bias.

• We modified outcomes as follows:

  1. We removed 'bleeding‐related mortality from the primary outcomes because it is included in the 'all‐cause mortality' and 'serious adverse events' outcomes. We removed 'overall gastrointestinal bleeding' outcome from the secondary outcomes in this review.

  2. We defined the 'serious‐adverse events' outcome better, by adding liver‐related morbidity (i.e. proportion of participants who developed ascites, hepatorenal syndrome, hepatocellular carcinoma, or hepatic encephalopathy).

  3. We defined quality of life, that is, we planned to measure health‐related quality of life exclusively by means of validated scales, classification, and measurement systems, like the Paediatric Quality of Life Inventory (PedsQL), Child Health Questionnaire (CHQ), and DISABKIDS.

  4. We modified the formulation of the ’non‐serious adverse events’ in the protocol into ‘Adverse events considered not serious (any adverse event that do not meet the above criteria for serious adverse events)’ in this review in order to increase the clarity.

  5. We removed the secondary third outcome in the protocol ‘Overall gastrointestinal bleeding’ at contact editor’s request.In addition, we have added information about the timing of outcomes.

• We formulated the text in Subgroup analysis and investigation of heterogeneity better.

• We updated the methodological part of our protocol to reflect methodology developments at the time of the review preparation.

• We expanded our search methods.

• We detailed 'Unit of analysis issues'.

• We moved the text on Trial Sequential Analysis in sensitivity analysis.

• We defined the outcomes for presentation in 'Summary of findings' table.

• We created a Table for report of harms from observational studies.

• Jaime Cerda, Luis Villarroel, Alfredo Peña, and Marcela Rivera are no longer authors of the review due to other obligations. Romina Torres‐Robles joined the team of authors for the search strategy and reviewed the final product.

• The review authors now are: Lorena I Cifuentes, Daniela Gattini, Romina Torres‐Robles, Juan Cristóbal Gana.

Contributions of authors

LC: provided methodological expert opinion, participated in the selection of titles, abstracts and full texts, and reviewed the final product.
DG: participated in the selection of titles, abstracts and full texts and reviewed the final product.
RTR: provided the search strategies and reviewed the final product.
JCG: formulated the research question, drafted and reviewed the final product.
All authors agreed on the publication of the review in its present form.

Sources of support

Internal sources

• None, Other

External sources

• None, Other

Declarations of interest

LC: none to be declared
DG: none to be declared
RTR: none to be declared
JCG: none to be declared

Edited (no change to conclusions)