Criteria for considering studies for this review
Types of studies
We will include randomised clinical trials for assessment of benefits and harms.
Non-randomised studies that may be retrieved with the searches will be included for data on harm only.
Types of participants
Participants will include paediatric patients (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 was confirmed by oesophagogastroduodenoscopy. The review will focus on therapy questions related to children who have not yet suffered gastrointestinal bleeding from oesophageal varices (primary prophylaxis).
Children with a previous surgical portal-systemic shunt procedure or insertion of a transjugular intrahepatic portal-systemic shunt (TIPS), previous sclerotherapy of oesophageal varices, or previous history of upper gastrointestinal bleeding are a distinct group in whom the diagnosis or natural history of oesophageal varices has been modified. These children will not be the focus of this review, hence studies that include such children will be excluded unless data are presented in such a way as to allow this patient group to be isolated from other included children.
Types of interventions
Endoscopic variceal ligation versus beta-blockers as primary prophylaxis of variceal bleeding in children.
Types of outcome measures
We will consider patient-oriented outcomes.
1. All-cause mortality.
2. Bleeding-related mortality.
3. Serious adverse events. A serious adverse event, defined according to the International Conference on Harmonisation (ICH) Guidelines for Good Clinical Practice (ICH-GCP 1997), is 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 will be considered non-serious adverse events.
4. Quality of life.
1. Oesophageal bleeding.
2. Overall gastrointestinal bleeding.
3. Non-serious adverse events.
Search methods for identification of studies
Searches will be conducted in the Cochrane Hepato-Biliary Group Controlled Trials Register (Gluud 2013), Cochrane Central Register of Controlled Trials (CENTRAL) in The Cochrane Library, MEDLINE, EMBASE, and Science Citation Index Expanded (Royle 2003). No language or document type restrictions will be applied. Search strategies with the time spans of the searches are listed in Appendix 1.
Searching other resources
Additional references will be identified by manually searching the references of articles from the computerised databases and relevant review articles. Unpublished studies will be sought by contacting experts in the field and pharmaceutical companies to inquire about additional trials.
Data collection and analysis
We will follow the available guidelines provided in the Cochrane Handbook for Systematic Reviews of Interventions (Higgins 2011) and the Cochrane Hepato-Biliary Group Module (Gluud 2013). The analyses will be performed using Review Manager 5 (RevMan 2012).
Selection of studies
Publications will be retrieved if they are potentially eligible for inclusion based on an abstract review, or if they are relevant review articles for a manual reference search. The publications will be reviewed independently for eligibility by JC and AP. To be eligible, each publication will be assessed to determine if participants meet the inclusion criteria detailed above. Abstracts will only be included if sufficient data are provided for analysis. Any disagreements will be resolved by consensus between JC, AP, and JCG.
Data extraction and management
Two authors (JC and AP) will independently complete a data extraction form on all included studies. The following data will be retrieved.
General information: title, journal, year, publication status, and study design.
Sample size: number of participants meeting the criteria and total number screened.
Baseline characteristics: baseline diagnosis, age, sex, race, disease severity, and concurrent medications used. Severity of liver disease of the studied population may be considered 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).
Oesophageal bleeding, all-cause mortality, bleeding-related mortality, and non-variceal bleeding of the upper gastrointestinal tract.
Adverse events: serious and non-serious.
Primary authors of the trial publications will be contacted for missing data.
Assessment of risk of bias in included studies
Two review authors will independently assess the risk of bias of each included trial according to the recommendations in the Cochrane Handbook for Systematic Reviews of Interventions (Higgins 2011), the Cochrane Hepato-Biliary Group Module (Gluud 2013), and methodological studies (Schulz 1995; Moher 1998; Kjaergard 2001; Wood 2008; Lundh 2012; Savovic 2012; Savovic 2012a). We will use the following definitions in the assessment of risk of bias.
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 are adequate if performed by an independent person not otherwise involved in the trial.
- Uncertain risk of bias: the method of sequence generation was not specified.
- High risk of bias: the sequence generation method was not random.
- 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 (for example, if the allocation sequence was hidden in sequentially numbered, opaque, and sealed envelopes).
- Uncertain 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.
Blinding of participants, personnel, and outcome assessors
- Low risk of bias: blinding was performed adequately, or the assessment of outcomes was not likely to be influenced by lack of blinding.
- Uncertain risk of bias: there was insufficient information to assess whether blinding was likely to induce bias on the results.
- High risk of bias: no blinding or incomplete blinding, and the assessment of outcomes was likely to be influenced by lack of 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, have been employed to handle missing data.
- Uncertain 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: all outcomes were pre-defined and reported, or all clinically relevant and reasonably expected outcomes were reported.
- Uncertain risk of bias: it is unclear whether all pre-defined and clinically relevant and reasonably expected outcomes were reported.
- High risk of bias: one or more clinically relevant and reasonably expected outcomes were not reported, and data on these outcomes were likely to have been recorded.
For a trial to be assessed with low risk of bias in the selective outcome reporting domain, the trial should have been registered either on the www.clinicaltrials.gov web site or a similar register, or there should be a protocol, for example published in a paper journal. In the case where the trial was run and published in the years when trial registration was not required, we will carefully scrutinise all publications reporting on the trial to identify the trial objectives and outcomes. If usable data on all outcomes specified in the trial objectives are provided in the publication's results section, then the trial can be considered low risk of bias in the 'Selective outcome reporting' domain.
- Low risk of bias: the trial appears to be free of industry sponsorship or other kind of for-profit support that may result in manipulation of the trial design, conduct, or results of the trial.
- Uncertain risk of bias: the trial may or may not be free of for-profit bias as no information on clinical trial support or sponsorship is provided.
- High risk of bias: the trial is sponsored by industry or has received other kinds of for-profit support.
- Low risk of bias: the trial appears to be free of other sources of bias.
- Uncertain risk of bias: there is insufficient information to assess whether other sources of bias are present.
- High risk of bias: it is likely that potential sources of bias related to the specific trial design used or other bias risks are present.
We expect a lack of blinding of participants in the trials in view of the different treatment modalities (endoscopic versus oral), and this could lead to a bias that will need to be analysed.
Trials assessed as having 'low risk of bias' in all of the specified domains will be considered 'trials with low risk of bias'. Trials assessed as having 'uncertain risk of bias' or 'high risk of bias' in one or more of the above domains will be considered trials with 'high risk of bias'.
A 'Risk of bias' graph and 'Risk of bias' summary will be generated to show a summary of this assessment.
Measures of treatment effect
The effect measures will be relative risks (RR) with 95% confidence intervals (CI).
Unit of analysis issues
The number of observations in the analysis is the number of patients that were randomised. Participants are individually randomised to two or more intervention groups, and a single measurement for each outcome from each participant is collected and analysed.
Dealing with missing data
We will only analyse available data. We will also address the potential impact of missing data on the findings using intention-to-treat analyses.
Regarding the primary outcomes, we will include patients with incomplete or missing data in the sensitivity analyses by imputing them according to the following scenarios.
- Poor outcome analysis: assuming that dropouts and participants lost from both the experimental and the control arms experienced the outcome; all randomised participants will be included in the denominator.
- Good outcome analysis: assuming that none of the dropouts and participants lost from the experimental and the control arms experienced the outcome; all randomised participants will be included in the denominator.
- Extreme case analysis favouring the experimental intervention ('best-worse' case scenario): none of the dropouts or participants lost from the experimental arm, but all of the dropouts and participants lost from the control group experienced the outcome; including all randomised participants in the denominator.
- Extreme case analysis favouring the control ('worst-best' case scenario): all dropouts or participants lost from the experimental arm, but none from the control arm experienced the outcome; including all randomised participants in the denominator.
Assessment of heterogeneity
Heterogeneity will be addressed in both clinical and statistical ways. First, depending on the number of eligible trials, we plan to add co-variates that may explain heterogeneity to the regression model, such as severity of the underlying liver disease.
The primary meta-analyses will be performed using random-effects models stratified by severity of liver disease (Child Pugh A, B, or C and PELD or MELD).
To assess heterogeneity between the trials, we will use the Chi2 heterogeneity statistic, and we will present the heterogeneity statistic I2.
Assessment of reporting biases
Reporting biases will be assessed 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. Funnel plots will be constructed if there are at least 10 included trials.
The analyses will be performed in Review Manager 5.2 (RevMan 2012) and R Program 2.15 (RDCT 2012).
We will apply both fixed-effect model and random-effects model meta-analyses. In the case of statistically significant discrepancies in the results (for example one giving a significant intervention effect and the other no significant intervention effect), we will report both; otherwise we will report the results with the random-effects model.
The results of dichotomous outcomes of individual studies will be presented as relative risk (RR) with 95% CI, and continuous outcomes as mean difference ± SD, combining trials using Mantel-Haenszel or DerSimonian-Lair methods, or both.
The results of individual trials will be presented as RR with 95% CI, and heterogeneity with the I2 statistic. The main results of the individual trials and meta-analyses will be illustrated in the form of forest plots.
Trial sequential analysis
Trial sequential analysis (TSA) is a tool for quantifying the statistical reliability of the data in a cumulative meta-analysis (CTU 2011; Thorlund 2011), controlling alpha and beta values for sparse data and repetitive testing on accumulating data (Brok 2008; Wetterslev 2008; Brok 2009; Thorlund 2009, Wetterslev 2009; Thorlund 2010; Thorlund 2011a). TSA is a methodology that combines a required information size calculation (cumulated sample sizes of trials to prove or disprove a certain intervention effect) with the threshold of statistical significance. In order to control for the risks of random errors due to sparse data and multiplicity, we will perform TSA for the dichotomous outcomes (Brok 2008; Wetterslev 2008; Brok 2009; Thorlund 2009, Wetterslev 2009; Thorlund 2010; Thorlund 2011a). We will base our calculations on the diversity-adjusted required information size on the proportion of patients with the outcome in the conventional group, a relative risk reduction of 20%, an alpha (type I error) of 5%, a beta (type II error) of 20% (power 80%), and the diversity of the meta-analysis (Wetterslev 2009). We may perform sensitivity analyses choosing other variables.
Subgroup analysis and investigation of heterogeneity
We aim to perform subgroup analyses and, therefore, we will perform separate meta-analyses for trials according to their bias risk (comparing trials with low (or lower) risk of bias to trials with high risk of bias, primary prophylaxis of small varices compared to only medium or large varices, and for trials in patients with chronic liver disease and extrahepatic portal vein obstruction.
Sources of heterogeneity that we will attempt to investigate will include chronic liver disease compared to portal vein thrombosis, severity of liver disease, different aetiologies of liver disease (for example viral cirrhosis compared to alcoholic cirrhosis, cholestatic compared to non-cholestatic liver disease), and co-morbidities.
In addition to the sensitivity analyses specified under 'Dealing with missing data', in order to assess the robustness of the eligibility criteria, we will undertake sensitivity analyses that may explain our findings as well as any observed heterogeneity. The publications will be reviewed independently by JC and AP for the sensitivity analysis. Any disagreements will be resolved by consensus with JCG.
Summary of findings tables
'Summary of findings' tables provide information about quality of evidence, magnitude of effects of the interventions, and summarise data on outcomes. They are created using GRADEpro (http://ims.cochrane.org/revman/other-resources/gradepro). We plan to create such tables presenting all review outcomes.