Types of studies

We included all randomised controlled trials, regardless of sample size, publication status, language, or publication date, that compared fibrin sealant with control for the prevention of postoperative pancreatic fistula (POPF) in people undergoing pancreatic resections. We excluded quasi‐randomised trials, in which the allocation was performed on the basis of a pseudo‐random sequence (e.g. odd/even hospital number or date of birth, alternation), and non‐randomised studies because of the potential for bias (Reeves 2011).

Types of participants

We included people, regardless of age, sex, or race, who underwent elective pancreatic resections (open or laparoscopic) for any pancreatic or extra‐pancreatic disease.

We excluded people who underwent total pancreatectomy, as this eliminates any source for a POPF.

Types of interventions

Intervention: fibrin sealant, regardless of glue or patch, which was applied to stump closure reinforcement, pancreatic anastomosis reinforcement, or main pancreatic duct occlusion.

Comparison: placebo or no fibrin sealant treatment.

Types of outcome measures

Electronic searches

For the last version of this review, we searched the Cochrane Central Register of Controlled Trials (CENTRAL) (2018, Issue 4), MEDLINE (1946 to 12 April 2018), Embase (1980 to 12 April 2018), Science Citation Index Expanded (1900 to 12 April 2018), and Chinese Biomedical Literature Database (CBM) (1978 to 12 April 2018) (Gong 2018). For this updated review, we updated the search strategies and re‐searched the following electronic databases, with no language or date of publication restrictions:

1. Cochrane Library (CENTRAL and Cochrane Database of Systematic Reviews) (Ovid) (to 2019, Issue 2; Appendix 2);

2. MEDLINE (Ovid) (1946 to 13 March 2019; Appendix 3);

3. Embase (Ovid) (1980 to 13 March 2019; Appendix 4);

4. Science Citation Index Expanded (Web of Science; 1900 to 13 March 2019; Appendix 5); and

5. Chinese Biomedical Literature Database (CBM; 1978 to 13 March 2019; Appendix 6).

Searching other resources

We checked reference lists of all primary studies and review articles for additional references. We contacted authors of identified studies and asked them to identify other published and unpublished studies.

We searched PubMed for errata or retractions from eligible studies and reported the date this was done within the review (www.ncbi.nlm.nih.gov/pubmed). We also searched the meeting abstracts via the HPB journal (onlinelibrary.wiley.com/journal/10.1111/(ISSN)1477‐2574; accessed 13 March 2019) and Conference Proceedings Citation Index to explore further relevant clinical studies.

Selection of studies

Two review authors (Junhua Gong, ZL) independently screened the titles and abstracts of all the studies we identified as a result of the search and coded them as 'retrieve' (eligible or potentially eligible/unclear) or 'do not retrieve'. We retrieved the full‐text study reports/publications and two review authors (Junhua Gong, ZL) independently screened the full text and identified studies for inclusion, and identified and recorded reasons for exclusion of the ineligible studies. We resolved any disagreements through discussion or, if required, we consulted a third review author (YD). We identified and excluded duplicates and collated multiple reports of the same study, so that each study, rather than each report, was the unit of interest in the review. We recorded the selection process in sufficient detail to complete a PRISMA flow diagram and a Characteristics of excluded studies table (Moher 2009).

Data extraction and management

We used a standard data collection form for study characteristics and outcome data, which had been piloted on at least one study in the review. Two review authors (NC, Jianping Gong) extracted the following study characteristics from included studies.

1. Methods: study design, total duration of study and run‐in, number of study centres and location, study setting, withdrawals, and date of study.

2. Participants: number (N), mean age, age range, gender, severity of condition, diagnostic criteria, inclusion criteria, and exclusion criteria.

3. Interventions: intervention, comparison.

4. Outcomes: primary and secondary outcomes specified and collected, time points reported.

5. Notes: funding for study, notable conflicts of interest of study authors.

Two review authors (NC, Jianping Gong) independently extracted outcome data from included studies. We noted in the Characteristics of included studies table if outcome data were not reported in a usable way. We resolved disagreements by consensus or by involving a third review author (YD). One review author (YC) copied across the data from the data collection form into Review Manager 5. We double‐checked that the data were entered correctly by comparing the study reports with how the data were presented in the systematic review. A second review author spot‐checked study characteristics for accuracy against the study report.

Assessment of risk of bias in included studies

Two review authors (Junhua Gong, YC) independently assessed risk of bias for each study using the criteria outlined in the Cochrane Handbook for Systematic Reviews of Interventions (Higgins 2011b). We resolved any disagreements by discussion or by involving a third review author (ZZ). We assessed the risk of bias for the following domains:

1. random sequence generation;

2. allocation concealment;

3. blinding of participants and personnel;

4. blinding of outcome assessment;

5. incomplete outcome data;

6. selective outcome reporting;

7. other bias.

We graded each potential source of bias as high, low, or unclear risk, and provided a quote from the study report together with a justification for our judgement in the 'Risk of bias' table. We summarised the 'Risk of bias' judgements across different studies for each of the domains listed. We considered blinding separately for different key outcomes, where necessary (e.g. for unblinded outcome assessment, risk of bias for all‐cause mortality may be very different than for a participant‐reported pain scale). Where information on risk of bias related to unpublished data or correspondence with a trialist, we noted this in the 'Risk of bias' table.

We considered a trial to be at low risk of bias if we assessed the trial as at low risk of bias across all domains. Otherwise, we considered trials at unclear risk of bias, or at high risk of bias when one or more domains were at high risk of bias. We resolved any difference in opinion by discussion.

When considering treatment effects, we took into account the risk of bias for the studies that contributed to that outcome.

Measures of treatment effect

We analysed dichotomous data as risk ratios (RRs) and continuous data as mean differences (MDs) with 95% confidence intervals (CIs). In the case of rare events (e.g. mortality), we calculated the Peto odds ratio (Peto OR) (Deeks 2011). We ensured that higher scores for continuous outcomes had the same meaning for the particular outcome, explained the direction to the reader and reported where the directions were reversed if this was necessary.

We undertook meta‐analyses only where this was meaningful, that is, if the treatments, participants, and underlying clinical question were similar enough for pooling to make sense.

In the case of a study which only reported standard error (SE), we converted the SE to the standard deviation (SD) using the formula in the Cochrane Handbook for Systematic Reviews of Interventions (Higgins 2011a). A common way that trialists indicated when they had skewed data was by reporting medians and interquartile ranges. When we encountered this, we considered that the data were skewed and it was not suitable to pool them with studies that reported means and SDs. Instead, we reported them in separate table.

Where multiple study arms were reported in a single study, we included only the relevant arms. If two comparisons (e.g. drug A versus placebo and drug B versus placebo) were entered into the same meta‐analysis, we halved the control group to avoid double counting.

Unit of analysis issues

The unit of analysis was the individual participant. We did not find any cross‐over or cluster‐randomised trials.

Dealing with missing data

We contacted investigators or study sponsors in order to verify key study characteristics, and obtained missing numerical outcome data, where possible (e.g. when a study was identified as abstract only). However, there was no reply in most of the cases. Thus, we used only the available data in the analyses.

Assessment of heterogeneity

We intended to describe the heterogeneity by using the Chi² test (Higgins 2011a). A P value less than 0.10 was considered to be significant heterogeneity. We also planned to use the I² statistic to measure heterogeneity among the studies in each analysis (Higgins 2003). When we identified substantial heterogeneity (I² greater than 50% or p < 0.10), we explored it by prespecified subgroup analysis, and we interpreted summary effect measures with caution.

Assessment of reporting biases

We did not perform funnel plots to assess reporting biases because the number of studies included under each comparison was fewer than 10 (Sterne 2011).

Data synthesis

We performed the meta‐analyses using Review Manager 5 software (RevMan 2014). For all analyses, we employed the random‐effects model for conservative estimation, except for the Peto odds ratio (OR) which only has a fixed method.

Subgroup analysis and investigation of heterogeneity

We intended to perform the following subgroup analyses.

1. Randomised controlled trials with low risk of bias versus randomised controlled trials with high risk of bias;

2. The type of fibrin sealants (glue and patch);

3. Different aetiologies (pancreatic cancer, chronic pancreatitis, and others);

4. High‐risk people (e.g. fatty pancreas, soft pancreas, small pancreatic duct) versus low‐risk people.

In previous versions of this review, we performed a meta‐analysis of fibrin sealants versus no fibrin sealants for overall pancreatic surgery, with subgroups of sealing location and type of operation. We have restructured this version of the review and the changes are detailed in the Differences between protocol and review section.

Sensitivity analysis

We performed sensitivity analyses to determine whether the conclusions were robust according to the decisions made during the review process, as follows.

1. Changing between a fixed‐effect model and a random‐effects model;

2. Changing statistics between risk ratios (RR), risk differences (RD), and odds ratios (OR) for dichotomous outcomes;

3. Changing statistics between mean difference (MD) and standardised mean differences (SMD) for continuous outcomes;

4. Excluding randomised controlled trials with low quality;

5. Excluding studies published in languages other than English.

If the results did not change, they were considered to have low sensitivity. If the results changed, they were considered to have high sensitivity.