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. 2019 Mar 15;2019(3):CD013289. doi: 10.1002/14651858.CD013289

Biliary anastomosis using T‐tube versus no T‐tube for liver transplantation in adults

Jose Jeova de Oliveira Filho 1,✉, Rachel Riera 2, Delcio Matos 3, Diego R Kleinubing 4, Marcelo Moura Linhares 5
PMCID: PMC6419317

Abstract

This is a protocol for a Cochrane Review (Intervention). The objectives are as follows:

To assess the benefits and harms of biliary anastomosis, with or without the use of T‐tube in adults undergoing liver transplantation.

Background

Description of the condition

Liver transplantation is the only definitive treatment for people with acute or chronic end‐stage liver disease, for whom pharmacological treatment is not effective. Mortality following conservative treatment can reach up to 70% at the end of 12 months, while for transplant treatment, overall three‐year and five‐year survivals are 80% and 69%, respectively (Azzam 2015; Kienlein 2015; Miyagi 2018).

The first attempt of liver transplantation in people was performed by Thomas Starzl, in the USA, in Denver, Colorado, in 1963 (Kienlein 2015; Miyagi 2018). Adults and paediatric patients can undergo liver transplantation. Donors can be living individuals or cadavers; cadavers can provide liver transplants for one or two recipients (split liver transplantation).

Primary indications for liver transplantation can be primary biliary cirrhosis, primary sclerosing cholangitis, biliary atresia, chronic autoimmune hepatitis, severe acute liver failure, metabolic disorders, chronic liver diseases of viral nature (hepatitis B virus, hepatitis C, and other viruses), alcohol cirrhosis, and hepatocellular carcinoma, developed as a complication of chronic liver disease (Adam 2009; Azzam 2015).

In liver transplantation, biliary complications, especially fistulas and stenosis, remain the leading causes of morbidity (from 5% to 35%) and mortality (> 10%) (Lopez‐Andujar 2013). For some authors, this is considered the 'Achilles' heel' of liver transplantation (Amador 2007). Biliary anastomotic technique is one of the most important factors in evading these complications, but there is no consensus on the best approach to conduct biliary reconstruction (Scatton 2001;Wojcicki 2009; Gastaca 2014).

Description of the intervention

The most frequently used biliary reconstruction techniques are end‐to‐end or side‐to‐side choledochocholedochostomies or hepaticojejunostomies. The choledochocholedochostomies are the most used techniques because they maintain the anatomical‐physiology of the biliary tract. Hepaticojejunostomies are used when there is incompatibility of diameter between the bile ducts of donor and recipient, or the main bile ducts are diseased or absent (Scatton 2001; Amador 2007; Weiss 2009; Lopez‐Andujar 2013; Kim 2014).

During a liver transplant, the most often used method of drainage of the biliary tract is through a T‐tube. The end‐to‐end choledochocholedochostomy technique is the most commonly adopted approach associated with or without the use of a T‐tube. The horizontal part of the T‐tube is placed through the bile anastomosis and the vertical part is exteriorised leading the bile duct away from the anastomosis (Vougas 1996; Weiss 2009; Lopez‐Andujar 2013)

How the intervention might work

The T‐tube decompresses and monitors biliary flow, believing that it reduces the early and late risks of fistula and stenosis. T‐tubes also facilitate access for radiological investigation and endoscopic therapeutic approach of post‐anastomotic complications. However, there are complications directly related to T‐tube use, such as, cholangitis, accidental displacement leading to biliary obstruction, peritonitis after leakage of bile from the insertion of the tube and late stenosis. These complications correspond to 30% to 50% of all post‐anastomotic biliary complications and result in higher hospital costs (Vougas 1996; Scatton 2001; Amador 2007; Weiss 2009).

Why it is important to do this review

There is no consensus on the use of the T‐tube as a drainage technique during biliary reconstruction. The question has been queried and debated for decades (Scatton 2001; Lopez‐Andujar 2013; García Bernardo 2016). The insertion of a T‐tube during liver transplantation remains controversial because of the different published results of several randomised clinical trials, assessing various outcomes (Scatton 2001; Amador 2007; Lopez‐Andujar 2013).

Nonproven preventative effects on biliary complications and consequent increase in overall costs due to the many diagnostic and therapeutic resources and longer length of stay discouraged a growing number of centres to use T‐tubes (Vougas 1996; Amador 2007; Lopez‐Andujar 2013). Other studies conclude that the insertion of T‐tubes is a safe and cost‐effective measure and should be considered for biliary anastomosis after liver transplantation (Ferraz‐Neto 1996; Nuno 1997; Weiss 2009; Gastaca 2014). We have been unable to identify meta‐analysis or systematic reviews of insertion or no insertion of T‐tube for people who have undergone a liver transplant. In people undergoing open exploration of the common bile duct for possible common bile duct stones, T‐tube drainage appeared to result in longer operation time and hospital stay without evidence of benefits compared with no T‐tube (Gurusamy 2013). Comparable findings were observed in patients with laparoscopic common bile duct exploration (Gurusamy 2013).

Considering the inconsistencies on the findings among the available studies, it is relevant to develop this Cochrane systematic review which may settle the inconsistent research findings and provide the best scientific evidence on the benefits and harms of T–tube biliary drainage after liver transplantation.

Objectives

To assess the benefits and harms of biliary anastomosis, with or without the use of T‐tube in adults undergoing liver transplantation.

Methods

Criteria for considering studies for this review

Types of studies

We will include randomised clinical trials that evaluate the benefits and harms of biliary anastomosis, with or without the use of T‐tube in people undergoing liver transplantation, irrespective of publication type, publication status, and language. We will consider observational studies (quasi‐randomised studies, cohort studies, patient series and case reports for their report on harms, if they are retrieved during our searches for randomised trials. By choosing this strategy, we are aware that we will put more focus on potential benefits and may overlook late occurring or rare harms which are often missed in randomised clinical trials (Storebø 2018). If we demonstrate benefits from using biliary anastomosis, with or without the use of T‐tube in people undergoing liver transplantation, then a systematic review of harms of biliary anastomosis with or without the use of T‐tube in people undergoing liver transplantation ought to be launched (Storebø 2018). We will not analyse the extracted data on harms from non‐randomised clinical studies together with the data on harms from the included in the review randomised clinical trials; neither we will assess the bias risk in these studies. However, at the end of the Results section, we will refer to the extracted narrative data on harm with a link to the table in Appendix or we may present a narrative analysis.

Types of participants

We will include adult participants undergoing liver transplantation (open or laparoscopic).

Types of interventions

Experimental intervention: end–to–end or side–to–side choledochocholedochostomy biliary anastomosis with a T–tube. The end‐to‐end or side‐to‐side choledochocholedochostomy biliary anastomosis to be performed using a running or interrupted layer suture. The horizontal part of the T–tube is placed inside the bile duct and its vertical portion is exteriorised leading the bile duct away from the anastomosis. The T‐tube is generally of latex, silicone, or rubber and with a diameter between 8 French (Fr) and 9 French (Fr) (Scatton 2001; Amador 2007; Lopez‐Andujar 2013). At the end of the surgery, a cholangiography is performed through the T‐tube. It is closed between seven and 14 days after a cholangiographic control. The T‐tube is removed between six and 12 weeks after radiological study.

Control intervention: end–to‐end or side–to–side choledochocholedochostomy biliary anastomosis without a T–tube biliary drainage system. The end‐to‐end or side‐to‐side choledochocholedochostomy biliary anastomosis is to be performed using a running or interrupted layer suture.

Cholangiography is only performed in the presence of clinical cholestasis, cholangitis, and biliary enzymes alteration (alkaline phosphatases, gamma glutamyltransferase (GT), bilirubin, and fractions). It is to be performed through the endoscopic retrograde cholangiopancreatography (ERCP) or cholangioresonance (Vougas 1996; Scatton 2001; Amador 2007; Weiss 2009; Lopez‐Andujar 2013).

Types of outcome measures

Primary outcomes

  • All‐cause mortality.

  • Serious adverse events: a serious adverse event is defined as any important medical event that might have jeopardised the person or required intervention to prevent it, or any event that would increase mortality, life‐threatening, required patient hospitalisation or resulted in persistent or significant disability. Serious adverse events correspond to Grade III or above of the Clavien‐Dindo classification, also being evaluated by the Postoperative Morbity Survey (POMS) (ICH‐GCP 1997; Bennet‐Guerrero 1999; Dindo‐Clavien 2004; Grocott 2007).

The serious adverse effects related to the biliary tract and anastomoses will be: biliary leakage/fistula (anastomotic or non‐anastomotic) ‐ diagnosis is made by clinical suspect, mainly pain and fever, bile loss through the abdominal drain, or by the presence of intra‐abdominal biloma confirmed by ultrasound or computerised tomography (CT Scan). Cholangiopancreatography (ERCP) and T–tube cholangiography establish the precise diagnosis of bile leakage. It will be measured from first to ninth post‐operative day and the time point will be on the tenth day (Scatton 2001; Amador 2007; Lopez‐Andujar 2013). Stenosis (anastomotic or non‐anastomotic), confirmed by the transhepatic cholangiography or T–tube, cholangioresonance or endoscopic retrograde cholangiopancreatography (ERCP) associated to clinical cholestasis and biliary enzymes alteration (alkaline phosphatases, gamma glutamyltransferase (GT), bilirubin, and fractions). Most present from five to eight months after transplantation, and the time point will be 12 months (Vougas 1996; Scatton 2001; Amador 2007; Weiss 2009; Lopez‐Andujar 2013). Complications related to the T‐ tube: cholangitis, fistula, peritonitis, and displacement of the tube with biliary obstruction. Confirmed by ultrasound or CT scan, ERCP, and T–tube cholangiography. The diagnosis is made from first to ninth post operative day, and the time point will be 12 weeks (Scatton 2001; Amador 2007; Lopez‐Andujar 2013). Retransplantation: biliary stenosis (anastomotic or non‐anastomotic) leads to chronic graft rejection, and secondary biliary cirrhosis can lead to retransplantation. It occurs from day 30 to the end of the follow‐up, usually nine months (Vougas 1996; Scatton 2001; Lopez‐Andujar 2013).

Acute rejection, thrombosis of portal vein, hepatic artery thrombosis, septicaemia, pneumonia, infection by cytomegalovirus, ischaemia‐perfusion syndrome, deep abscess, blood type ABO incompatibility, partial or total occlusions by intestinal adhesions, haemobilia, ischaemic cholangitis will be considered as serious adverse events.

  • Health‐related quality of life: measured by any general or specific validated tool, as the SF‐36, and Gastrointestinal Quality of Life Index (GIQLI) ‐ (Eypasch 1995; Ware 1999).

Secondary outcomes

We will analyse separately the outcomes and their time points. We will primarily base our conclusions on the time point of two years, which is the time required for observation and analysis of all studied primary outcomes and for the secondary outcomes, they are usually occurring the days after transplantation.

Search methods for identification of studies

We will conduct a systematic search with no language limits to find all relevant randomised clinical trials using a sensitive strategy. We will not design search strategies for observational studies; however, for report of harms, we will consider screening publications of references of observational studies, retrieved alongside with references of randomised clinical trials.

Electronic searches

We will search The Cochrane Hepato‐Biliary Group Controlled Trials Register (Cochrane Hepato‐Biliary Group Module), Cochrane Central Register of Controlled Trials (CENTRAL) in the Cochrane Library, MEDLINE Ovid, Embase Ovid, Latin American and Caribbean Health Science Information Database (LILACS; Bibioteca Virtual em Saúde ‐ BVS), Science Citation Index Expanded (Web of Science), Conference Proceedings Citation Index – Science (Web of Science) (Royle 2003), Cumulative Index to Nursing and Allied Health Literature (CINAHL; EBSCO), and the Physiotherapy Evidence Database (PEDro). Appendix 1 lists the preliminary search strategies and the expected time spans of the searches.

Searching other resources

We will search on‐line trial registries such as ClinicalTrial.gov (clinicaltrials.gov/), European Medicines Agency (EMA) (www.ema.europa.eu/ema/), WHO International Clinical Trial Registry Platform (www.who.int/ictrp), the Food and Drug Administration (FDA) (www.fda.gov), as well as pharmaceutical company sources for ongoing or unpublished trials. We will also examine the lists of references of identified studies in order to identify additional studies, as well as contact the main authors of studies and content experts for further unpublished or ongoing studies. We will also search for grey literature in the System for Information on Grey Literature in Europe “OpenGrey” (www.opengrey.eu/).

Data collection and analysis

We will perform the review following the recommendations of Cochrane (Higgins 2011) and the Cochrane Hepato‐Biliary Group Module. We will perform the analyses using Review Manager 5 (Review Manager 2014), STATA 14 (www.stata.com), and Trial Sequential Analysis (Thorlund 2011; TSA 2011; Wetterslev 2017).

We will present the data on harm from observational studies (quasi‐randomised and cohorts), case reports, or letters to the editors, if retrieved during our searches for randomised trials, only in a narrative format.

Selection of studies

Two review authors (JJOF and DK), independently of each other, will assess all identified articles. If a trial is identified as relevant by one author, but not by another, the authors will discuss the reasoning behind their decision. If they still disagree, review author DM will serve as arbitrator. In addition, we will include trials only if they describe or declare ethical practices in liver donor removal, as described in The Declaration of Instanbul on Organ Trafficking and Transplant Tourism. If the obtained liver donor is not ethically obtained, then, we will exclude the trial, providing the reason for its exclusion in the Excluded studies (Chin 2012). If the trial does not provide any information, we will inquire publication authors for data on the origin of the liver donor.

Data extraction and management

Three review authors (JJOF, DK, MML), independently, will extract the following data.

  • Publication data (i.e. year, country, authors)

  • Study design

  • Setting, inclusion/exclusion criteria, methods of randomisation, allocation concealment, and blinding

  • Population data (i.e. age, sex, modes of liver uptake, type of liver transplant, primary liver disease)

  • Intervention data (i.e. type of biliary anastomosis, type of biliary drainage: with or without T‐tube)

  • Outcome measures (primary and secondary, including benefits and adverse events)

  • Dropouts

  • Length of follow‐up

  • Types of data analyses (i.e. per protocol, intention‐to‐treat, modified intention‐to‐treat).

We will use pre‐piloted data extraction forms designed for the purpose. The same three review authors will discuss any disagreement concerning the extracted data. If the authors still disagree, DM will serve as arbitrator. In the case of relevant data not being available, we will contact the trial authors.

Two review authors (JJOF and DK) will transfer data into Review Manager 5 software (Review Manager 2014). A third review author (RR) will double‐check if data are properly entered by comparing the data with those provided in the study. We will contact the authors of randomised clinical trials in the case of missing or unclear data.

Assessment of risk of bias in included studies

Three review authors (JJOF, MML, DM) will independently evaluate the risk of bias of each included trial according to the recommendations in theCochrane Handbook for Systematic Reviews of Interventions (Higgins 2011) and the Cochrane Hepato‐Biliary Group Module. We will use the following definitions in the assessment of risk of bias (Schulz 1995; Moher 1998; Kjaergard 2001; Wood 2008; Higgins 2011; Savović 2012a; Savović 2012b; Lundh 2017; 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.

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

  • High risk of bias: the sequence generation method was not random.

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; or 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 and personnel

  • Low risk of bias: either of the following: blinding of participants and key study personnel ensured, and it was unlikely that the blinding could have been broken; or rarely no blinding or incomplete blinding, but the review authors judged that the outcome was not likely to be influenced by lack of blinding.

  • Unclear risk of bias: either of the following: insufficient information to permit judgement of 'low risk' or 'high risk;' or the trial did not address this outcome.

  • High risk of bias: either of the following: no blinding or incomplete blinding, and the outcome was likely to be influenced by lack of blinding; or blinding of key study participants and personnel attempted, but likely that the blinding could have been broken, and the outcome was likely to be influenced by lack of blinding.

Blinded outcome assessment

  • Low risk of bias: either of the following: blinding of outcome assessment ensured, and unlikely that the blinding could have been broken; or rarely no blinding of outcome assessment, but the review authors judged that the outcome measurement was not likely to be influenced by lack of blinding.

  • Unclear risk of bias: either of the following: insufficient information to permit judgement of 'low risk' or 'high risk;' or the trial did not address this outcome.

  • High risk of bias: either of the following: no blinding of outcome assessment, and the outcome measurement was likely to be influenced by lack of blinding; or blinding of outcome assessment, but likely that the blinding could have been broken, and the outcome measurement 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. The study used sufficient methods, such as multiple imputation, 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 pre‐defined primary outcomes: all‐cause mortality and serious adverse events. If the original trial protocol was available, the outcomes should be those called for in that protocol. If the trial protocol was obtained from a trial registry (e.g. www.clinicaltrials.gov), the outcomes sought should be 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: the study authors did not report all predefined outcomes fully, or it was unclear whether the study authors recorded data on these outcomes or not.

  • High risk of bias: the study authors did not report one or more predefined outcomes.

Other bias

  • Low risk of bias: the trial appeared free of other factors that could put it at risk of bias (source of funding: non‐for‐profit).

  • Unclear risk of bias: the trial may or may not have been free of other factors that could put it at risk of bias (source of funding: unclear).

  • High risk of bias: there were other factors in the trial that could put it at risk of bias (source of funding: for‐profit).

Overall risk of bias

We will assess the overall risk of bias in the trials as follows.

  • Low risk of bias: if all the above risk of bias sources are assessed at low risk of bias.

  • High risk of bias: if one or more of the above risk of bias sources are assessed at 'unclear risk of bias' or 'high risk of bias'.

We will assess 'Blinding of participants and personnel, 'Blinding of outcome assessment,' 'Incomplete outcome data,' and 'Selective outcome reporting' source of bias for each outcome. Thus, we will be able to assess the bias risk for each outcome in addition to each trial. We will attempt to base our primary conclusions on the results of our primary outcomes at low risk of bias.

Measures of treatment effect

For dichotomous outcomes, we will express results as risk ratio (RR) with 95% confidence intervals (CIs). If trials used continuous scales of measurement to assess effects of treatment, we will use the mean difference (MD), or if different scales had been used, we will utilise the standardised mean difference (SMD) (Thompson 2002).

Unit of analysis issues

Trial participants as randomised per intervention group. Due to the nature of the intervention and the clinical situation, we do not expect to find cluster‐randomised trials or trials with a cross‐over design. In the latter case, we will include only data from the first phase of the trial (Qizilbash 1998).

Dealing with missing data

We will perform all analyses according to the intention‐to‐treat method including all participants irrespective of compliance or follow‐up.

Regarding the primary outcomes, we will include participants with incomplete or missing data in the sensitivity analyses by imputing them according to the following scenarios (Hollis 1999; Gluud 2016).

  • 'Best‐worst' case scenario analyses: participants with missing outcome data are considered successes in the experimental group and failures in the control group. The denominator will include all the participants in the trial.

  • 'Worst‐best' case scenario analyses: participants with missing outcome data are considered failures in the experimental group and successes in the control group. The denominator will include all the participants in the trial.

Regarding missing continuous data, we will use the available case analysis or intention‐to‐treat (ITT) analysis using imputation. Available case analysis uses data whose results are known, and ITT analysis is performed on the total number of randomised participants, independent of the original analysis, encompassing imputable results for the absent participants (Higgins 2011).

Assessment of heterogeneity

We will address heterogeneity both clinically and statistically. In the case of heterogeneity, we will perform the primary meta‐analyses using both a random‐effects model and a fixed‐effect model, and we will report the most conservative result as our main result (Jakobsen 2014).

To assess heterogeneity between the trials, we will specifically examine the degree of heterogeneity that we observe in the results with the I² statistic (Higgins 2002), where an I² statistic value of 50% or more indicates a substantial level of heterogeneity (Higgins 2002). The importance of the observed value of I² depends on the magnitude and direction of effects and the strength of evidence for heterogeneity (e.g., P value from the chi‐squared test, or a CI for I²). For the heterogeneity adjustment of the required information size in the Trial Sequential Analysis, we will use diversity (D2) because the I2 statistics used for this purpose underestimates the required information size (Wetterslev 2009).

Assessment of reporting biases

We will conduct a comprehensive search for eligible studies. We will contact trial authors to request missing data. If there are more than 10 trials in a comparison, we will use funnel plots to assess the reporting biases as recommended in the Cochrane Handbook for Systematic Reviews of Interventions (Higgins 2011). We will interpret the funnel plots with caution because asymmetric funnel plots are not necessarily caused by publication bias.

Data synthesis

Meta‐analysis

We will perform the meta‐analyses according to Cochrane recommendations (Higgins 2011) and according to the Cochrane Hepato‐Biliary Group Module. We will use RevMan to perform meta‐analyses (Review Manager 2014).

We will apply both a fixed‐effect model (DeMets 1987) and a random‐effects model (DerSimonian 1986) when we perform meta‐analyses. In the event of statistically significant discrepancies in the results (e.g. one giving a significant intervention effect and the other no significant intervention effect), we will report both. If the results differ, we will validate which method should be the main one reported, according to Jakobsen 2014.

We will present the results of dichotomous outcomes of individual studies as RR values with 95% CI, and continuous outcomes as MD and standard deviation (SD) values. We will combine trials using either the Mantel‐Haenszel or DerSimonian and Laird methods, or both (DerSimonian 1986; DeMets 1987).

Trial Sequential Analysis

We will apply Trial Sequential Analysis (Thorlund 2011; TSA 2011; Wetterslev 2017) because cumulative meta‐analyses are at risk of producing random errors due to sparse data and repetitive testing of the accumulating data (Wetterslev 2008; Thorlund 2009; Imberger 2015; Imberger 2016; Wetterslev 2017). To minimise random errors, we will calculate the required information size (i.e. the number of participants needed in a meta‐analysis to detect or reject a certain intervention effect) (Wetterslev 2008). For the heterogeneity adjustment of the required information size in the Trial Sequential Analysis, we will use diversity‐adjusted required information size (DARIS) (i.e. the number of participants needed in a meta‐analysis to detect or reject a certain intervention effect) (Brok 2008; Wetterslev 2008; Brok 2009; Thorlund 2010; Wetterslev 2017), as the use of the I² statistic for this purpose consistently underestimates the required information size (Wetterslev 2009).

In our Trial Sequential Analyses, we will base the required information size on the event proportion in the control group; assumption of a plausible risk ratio reduction of 20% or the RR reduction observed in the included trials; an alpha of 0.025 because of our three primary outcomes; a beta of 10% (Castellini 2017); and the assumed diversity of the meta‐analysis (Wetterslev 2009; Jakobsen 2014). We will not adjust the alpha value for the secondary and exploratory outcomes, but we will interpret significant findings conservatively due to the risks of random errors.

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 will add the trials according to the year of publication. If more than one trial is published in the same year, we will add trials alphabetically according to the last name of the first study author. On the basis of the required information size, we will construct trial sequential monitoring boundaries (Wetterslev 2008; Thorlund 2010). These boundaries will 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 perhaps be established and further trials may turn out to be superfluous.

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

Subgroup analysis and investigation of heterogeneity

In order to establish whether the intervention effect differs in different situations, we plan to perform the following subgroup analyses. We will present the results of the tests for subgroup differences based on random‐effects models in order to minimise the high risk of false‐positive results when comparing subgroups in a fixed‐effect model (Higgins 2004).

  • Trials at low risk of bias compared to trials at high risk of bias.

  • For‐profit funded trials compared to trials without for‐profit funding.

  • Sex.

  • Age (younger than 65 compared to 65 or older).

  • People with or without cholangitis.

  • Pathological conditions (patient acuity at time of operation, estimated blood loss (EBL), malignancy).

  • Choledochojejunostomy or choledochocholedochostomy for the biliary tract reconstruction.

Sensitivity analysis

In addition to the sensitivity analyses described in Dealing with missing data, we will perform sensitivity analysis to evaluate whether findings are sensitive to restricting the analyses to studies with low risk of bias for mortality, and we will evaluate the influence of missing outcome data as described in Dealing with missing data.

We will also compare our assessments of imprecision in the included trials, performed by GRADE and Trial Sequential Analysis, for each of the Primary outcomes and Secondary outcomes (Castellini 2018; Gartlehner 2019).

'Summary of findings' table

We will create 'Summary of findings' tables for all clinically relevant outcomes (all‐cause mortality, serious adverse events, health‐related quality of life, non‐serious adverse events, and pain) reported in the review using GRADE Interactive software (GRADEpro). We will assess the following five factors referring to limitations in the study design and implementation of included studies that suggest the quality of the evidence: risk of bias; indirectness of evidence (population, intervention, control, outcomes); unexplained heterogeneity or inconsistency of results (including problems with subgroup analyses); imprecision of results (wide CIs); and a high probability of publication bias (Balshem 2011; Guyatt 2008; Guyatt 2011a; Guyatt 2011b; Guyatt 2011c; Guyatt 2011d; Guyatt 2011e; Guyatt 2011f; Guyatt 2011g; Guyatt 2011h; Guyatt 2013a; Guyatt 2013b; Guyatt 2013c; Guyatt 2013d; Mustafa 2013; Guyatt 2017). We will define the levels of evidence as 'high', 'moderate', 'low', or 'very low'. These grades are defined 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.

Acknowledgements

Peer reviewers: Junnarkar Sameer Padmakumar, Singapore; Rachel Beard, USA Contact editor: Kurinchi S Gurusamy, UK Sign‐off editor: Christian Gluud, Denmark

Cochrane Review Group funding acknowledgement: the Danish State is the largest single funder of the Cochrane Hepato‐Biliary Group through its investment in The Copenhagen Trial Unit, Centre for Clinical Intervention Research, Rigshospitalet, Copenhagen University Hospital, Denmark. Disclaimer: the views and opinions expressed in this review are those of the authors and do not necessarily reflect those of the Danish State or The Copenhagen Trial Unit.

Appendices

Appendix 1. Search strategies

Database Time span Search strategy
The Cochrane Hepato‐Biliary Group Controlled Trials Register Date will be given at review stage. (liver OR hepatic) AND (transplant* OR graft*) AND 'duct anastomosis' OR "biliary anastomosis" OR 'Biliary reconstruction' OR (choledochocholedochostomy OR "t‐tube" OR drain* OR )
Cochrane Central Register of Controlled Trials (CENTRAL) Latest issue #1 liver OR hepatic
#2 transplant* OR graft*
#3 (#1 AND #2)
#4 MeSH descriptor Liver Transplantation explode all trees
#5 (#3 OR #4)
#6 MeSH descriptor Biliary Tract Surgical Procedures explode all trees
#7 MeSH descriptor Anastomosis, Surgical explode all trees
#8 MeSH descriptor Drainage explode all trees
#9 choledochocholedochostomy OR "duct anastomosis" OR "biliary anastomosis" OR "t‐tube" OR drain*
#10 (#6 OR #7 OR #8 OR #9)
#11 (#5 AND #10)
MEDLINE Ovid 1946 to the date of search ("Biliary Tract Surgical Procedures"[MeSH] OR "Anastomosis, Surgical"[MeSH] OR "duct anastomosis" OR "biliary anastomosis" OR "biliary reconstruction" OR "Drainage"[MeSH] OR "t‐tube" OR drain* OR choledochocholedochostomy ) AND (((liver OR hepatic) AND (transplant* OR graft*)) OR "Liver Transplantation"[MeSH]) AND (((randomized controlled trial [pt] OR controlled clinical trial [pt] OR randomized controlled trials [mh] OR random allocation [mh] OR double‐blind method [mh] OR single‐blind method [mh] OR clinical trial [pt] OR clinical trials [mh] OR ("clinical trial" [tw]) OR ((singl* [tw] OR doubl* [tw] OR trebl* [tw] OR tripl* [tw]) AND (mask* [tw] OR blind* [tw])) OR (placebos [mh] OR placebo* [tw] OR random* [tw] OR research design [mh:noexp]) NOT (animals [mh] NOT human [mh]))))
Embase Ovid 1974 to the date of search 1 LIVER OR HEPATIC
2 TRANSPLANT$ OR GRAFT$
3 1 AND 2
4 LIVER‐TRANSPLANTATION#.DE.
5 3 OR 4
6 5 AND 11
7 BILIARY‐TRACT‐SURGERY#.DE.
8 BILE‐DUCT#.DE. AND ANASTOMOSIS#.W..DE.
9 DUCT ADJ ANASTOMOSIS OR BILIARY ADJ ANASTOMOSIS OR BILIARY ADJ RECONSTRUCTIONC OR CHOLEDOCHOCHOLEDOCHOSTOMY OR T‐TUBE OR DRAIN$
10 SURGICAL‐DRAINAGE#.DE. OR DRAIN#.W..DE.
11 7 OR 8 OR 9 OR 10
12 RANDOMIZED‐CONTROLLED‐TRIAL#.DE. OR RANDOMIZATION#.W..DE. OR CONTROLLED‐STUDY#.DE. OR MULTICENTER‐STUDY#.DE. OR PHASE‐3‐CLINICAL‐TRIAL#.DE. OR PHASE‐4‐CLINICAL‐TRIAL#.DE. OR DOUBLE‐BLIND‐PROCEDURE#.DE. OR SINGLE‐BLIND‐PROCEDURE#.DE.
13 RANDOM$ OR CROSSOVER$ OR CROSS‐OVER OR CROSS ADJ OVER OR FACTORIAL$ OR PLACEBO$ OR VOLUNTEER$
14 (SINGLE OR DOUBLE OR TREBLE OR TRIPLE) NEAR (BLIND OR MASK)
15 12 OR 13 OR 14
16 15 AND HUMAN=YES
17 6 AND 16
LILACS (Bibioteca Virtual em Saúde ‐ BVS) 1982 to the date of search (Liver transplantation) [Word] and biliary anastom$ [Word]
Science Citation Index Expanded (Web of Science) 1900 to the date of search #1 TS=('duct anastomosis' OR "biliary anastomosis" OR 'Biliary reconstruction' OR choledochocholedochostomy OR "t‐tube" OR drain*)
#2 TS=(liver OR hepatic)
#3 TS=(transplant* OR graft*)
#4 TS=(random* OR blind* OR placebo* OR meta‐analysis)
#5 #4 AND #3 AND #2 AND #1
Conference Proceedings Citation Index ‐ Science (Web of Science) 1990 to the date of search #1 TS=('duct anastomosis' OR "biliary anastomosis" OR 'Biliary reconstruction' OR choledochocholedochostomy OR "t‐tube" OR drain*)
#2 TS=(liver OR hepatic)
#3 TS=(transplant* OR graft*)
#4 TS=(random* OR blind* OR placebo* OR meta‐analysis)
#5 #4 AND #3 AND #2 AND #1
CINAHL (EBSCO) 1961 to the date of search S7 S3 AND S6
S6 S4 OR S5
S5 MW biliary anastomosis
S4 TX duct anastomosis
S3 S1 OR S2
S2 MW liver transplantation
S1 TX liver
PEDro 1955 to the date of search Liver transplantation
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Contributions of authors

Jose Jeova de Oliveira Filho: clinical expertise Diego Kleinubing: clinical expertise Rachel Riera: review methods and statistics expertise Delcio Matos: review methods expertise Marcelo Linhares: review methods and clinical expertise All authors approved the protocol for publication.

Sources of support

Internal sources

  • UNIFESP: Post‐graduation Scholarship, Brazil, Brazil.

    Interdisciplinary post‐graduation program at doctoral level

  • CAPES, Brazil, Brazil.

External sources

  • Unit ‐ Universidade Tiradentes, Brazil, Brazil.

Declarations of interest

Jose Jeova de Oliveira Filho: no conflict of interest Diego Kleinubing: no conflict of interest Rachel Riera: no conflict of interest Delcio Matos: no conflict of interest Marcelo Linhares: no conflict of interest

New

References

Additional references

  1. Adam R, Hoti E. Liver transplantation: the current situation. Seminars in Liver Disease 2009;29(1):3‐18. [DOI] [PubMed] [Google Scholar]
  2. Amador A, Charco R, Martì J, Navasa M, Rimola A, Calatayud D, et al. Clinical trial on the cost‐effectiveness of T‐tube use in an established deceased door liver transplantation program. Clinical Transplantation 2007;21:548‐53. [DOI] [PubMed] [Google Scholar]
  3. Azzam AZ. Liver transplantation as a management of hepatocellular carcinoma. World Journal of Hepatology 2015;7(10):1347‐54. [DOI] [PMC free article] [PubMed] [Google Scholar]
  4. Balshem H, Helfand M, Schünemann HJ, Oxman AD, Kunz R, Guyatt GH, et al. GRADE guidelines: 3. Rating the quality of evidence. Journal of Clinical Epidemiology 2011;64(4):401‐6. [DOI] [PubMed] [Google Scholar]
  5. Bennett‐Guerrero E, Welsby I, Dunn TJ, Young LR, Wahl TA, Diers TL, et al. The use of a postoperative morbidity survey to evaluate patients with prolonged hospitalization after routine, moderate‐risk, elective surgery. Anesthesia and Analgesia 1999;89:514‐9. [DOI] [PubMed] [Google Scholar]
  6. Berríos‐Torres SI, Umscheid CA, Bratzler DW, Leas B, Stone EC, Kelz RR, et al. Healthcare infection control practices advisory committee. Centers for disease control and prevention guideline for the prevention of surgical site infection. JAMA Surgery 2017;152:784‐91. [DOI] [PubMed] [Google Scholar]
  7. Brok J, Thorlund K, Gluud C, Wetterslev J. Trial sequential analysis reveals insufficient information size and potentially false positive results in many meta‐analyses. Journal of Clinical Epidemiology 2008;61(8):763‐9. [DOI] [PubMed] [Google Scholar]
  8. Brok J, Thorlund K, Wetterslev J, Gluud C. Apparently conclusive meta‐analyses may be inconclusive ‐ Trial sequential analysis adjustment of random error risk due to repetitive testing of accumulating data in apparently conclusive neonatal meta‐analyses. International Journal of Epidemiology 2009;38(1):287‐98. [DOI] [PubMed] [Google Scholar]
  9. Castellini G, Nielsen EE, Gluud C. Comment on: "Cell therapy for heart disease: trial sequential analyses of two Cochrane reviews". Clinical Pharmacology and Therapeutics 2017;102(1):21‐4. [DOI] [PubMed] [Google Scholar]
  10. Castellini G, Bruschettini M, Gianola S, Gluud C, Moja L. Assessing imprecision in Cochrane systematic reviews: a comparison of GRADE and Trial Sequential Analysis. Systematic Reviews 2018;7(110):1‐10. [DOI] [PMC free article] [PubMed] [Google Scholar]
  11. Mangram AJ, Horan TC, Pearson ML, Silver LC, Jarvis WR. Guideline for prevention of surgical site infection. Infection control and hospital. Epidemiology 1999;20(4):247–78. [DOI] [PubMed] [Google Scholar]
  12. Chapman CR, Casey KL, Dubner R, Foley KM, Gracely RH, Reading AE. Pain measurement: an overview. Pain 1985;22:1‐31. [DOI] [PubMed] [Google Scholar]
  13. Chin JJL, Campbell AV. Transplant tourism or international transplant medicine? A case for making the distinction. American Journal of Transplantation 2012;12(7):1700‐7. [DOI] [PubMed] [Google Scholar]
  14. DeMets DL. Methods for combining randomized clinical trials: strengths and limitations. Statistics in Medicine 1987;6(3):341‐50. [DOI] [PubMed] [Google Scholar]
  15. DerSimonian R, Laird N. Meta‐analysis in clinical trials. Controlled Clinical Trials 1986;7:177‐88. [DOI] [PubMed] [Google Scholar]
  16. Dindo D, Demartines N, Clavien PA. Classification of surgical complications: a new proposal with evaluation in a cohort of 6336 patients and results of a survey. Annals of Surgery 2004;240(2):205‐13. [DOI] [PMC free article] [PubMed] [Google Scholar]
  17. Eypasch E, Williams JI, Wood‐Dauphince S, Ure BM, Schmulling C, Neugebauer E, et al. Gastrointestinal quality of life: development, validation and application of a new instrument. British Journal of Surgery 1985;82(2):216‐22. [DOI] [PubMed] [Google Scholar]
  18. Ferraz‐Neto BH, Mirza DF, Gunson BK, Ismail T, Mayer AD, Buckels JA, et al. Bile duct splintage in liver transplantation: is it necessary?. Transplant International 1996;9(Suppl 1):S185‐7. [DOI] [PubMed] [Google Scholar]
  19. García Bernardo CM, González‐Pinto Arrillaga I, Miyar de León A, Cadahia Rodrigo V, González Dieguez L, Barneo Serra L, et al. Systematic use in the biliary anastomosis: comparison of two consecutive series of liver transplantation. Transplantation Proceedings 2016;48(9):3003‐5. [DOI] [PubMed] [Google Scholar]
  20. Gartlehner G, Nussbaumer‐Streit B, Wagner G, Patel S, Swinson‐EvansT, Dobrescu A, et al. Increased risks for random errors are common in outcomes graded as high certainty of evidence. Journal of Clinical Epidemiology 2019;106:50‐9. [DOI: 10.1016/j.jclinepi.2018.10.009] [DOI] [PubMed] [Google Scholar]
  21. Gastaca M, Matarranz A, Martinez L, Valdivieso A, Ruiz P, Ventoso A, et al. Risk factors for biliary complications after orthotopic liver transplantation with T‐tube: a single‐center cohort of 743 transplants. Transplantation Proceedings 2014;46(9):3097‐9. [DOI] [PubMed] [Google Scholar]
  22. Gluud LL, Vilstrup H, Morgan MY. Nonabsorbable disaccharides for hepatic encephalopathy: a systematic review and meta‐analysis. Hepatology (Baltimore, Md.) 2016;64(3):908‐22. [DOI] [PubMed] [Google Scholar]
  23. McMaster University (developed by Evidence Prime). GRADEpro. Version accessed 8 January 2018. Hamilton (ON): McMaster University (developed by Evidence Prime), 2015.
  24. Grocott MP, Browne JP, Meulen J, Matejowsky M, Mutch M, Hamilton MA, et al. The postoperative morbidity survey was validated and used to describe morbidity after major surgery. Journal of Clinical Epidemiology 2007;60(9):919‐28. [DOI] [PubMed] [Google Scholar]
  25. Gurusamy KS, Koti R, Davidson BR. T‐tube drainage versus primary closure after open common bile duct exploration. Cochrane Database of Systematic Reviews 2013, Issue 6. [DOI: 10.1002/14651858.CD005640.pub3] [DOI] [PMC free article] [PubMed] [Google Scholar]
  26. Guyatt GH, Oxman AD, Kunz R, Jaeschke R, Helfand M, Liberati A, et al. GRADE Working Group. Incorporating considerations of resources use into grading recommendations. BMJ (Clinical Research Ed.) 2008;336(7654):1170‐3. [DOI] [PMC free article] [PubMed] [Google Scholar]
  27. Guyatt G, Oxman AD, Akl EA, Kunz R, Vist G, Brozek J, et al. GRADE guidelines: 1. Introduction‐GRADE evidence profiles and summary of findings tables. Journal of Clinical Epidemiology 2011;64(4):383‐94. [DOI] [PubMed] [Google Scholar]
  28. Guyatt GH, Oxman AD, Kunz R, Atkins D, Brozek J, Vist G, et al. GRADE guidelines: 2. Framing the question and deciding on important outcomes. Journal of Clinical Epidemiology 2011;64(4):395‐400. [DOI] [PubMed] [Google Scholar]
  29. Guyatt GH, Oxman AD, Sultan S, Glasziou P, Akl EA, Alonso‐Coello P, et al. GRADE WorkingGroup. GRADE guidelines: 9. Rating up the quality of evidence. Journal of Clinical Epidemiology 2011;64(12):1311‐6. [DOI] [PubMed] [Google Scholar]
  30. Guyatt GH, Oxman AD, Vist G, Kunz R, Brozek J, Alonso‐Coello P, et al. GRADE guidelines: 4. Rating the quality of evidence‐‐study limitations (risk of bias). Journal of Clinical Epidemiology 2011;64(4):407‐15. [DOI] [PubMed] [Google Scholar]
  31. Guyatt GH, Oxman AD, Montori V, Vist G, Kunz R, Brozek J, et al. GRADE guidelines: 5. Rating the quality of evidence‐‐publication bias. Journal of Clinical Epidemiology 2011;64(12):1277‐82. [DOI] [PubMed] [Google Scholar]
  32. Guyatt GH, Oxman AD, Kunz R, Brozek J, Alonso‐Coello P, Rind D, et al. GRADE guidelines 6. Rating the quality of evidence‐‐imprecision. Journal of Clinical Epidemiology 2011;64(12):1283‐93. [DOI] [PubMed] [Google Scholar]
  33. Guyatt GH, Oxman AD, Kunz R, Woodcock J, Brozek J, Helfand M, et al. GRADE guidelines: 7. Rating the quality of evidence‐‐inconsistency. Journal of Clinical Epidemiology 2011;64(12):1294‐302. [DOI] [PubMed] [Google Scholar]
  34. Guyatt GH, Oxman AD, Kunz R, Woodcock J, Brozek J, Helfand M, et al. GRADE guidelines: 8. Rating the quality of evidence‐‐indirectness. Journal of Clinical Epidemiology 2011;64(12):1303‐10. [DOI] [PubMed] [Google Scholar]
  35. Guyatt GH, Oxman AD, Schünemann HJ. GRADE guidelines‐an introduction to the10th‐13th articles in the series. Journal of Clinical Epidemiology 2013;66(2):121‐3. [DOI] [PubMed] [Google Scholar]
  36. Guyatt G, Eikelboom JW, Akl EA, Crowther M, Gutterman D, Kahn SR, et al. A guide to GRADE guidelines for the readers of JTH. Journal of Thrombosis and Haemostasis : JTH 2013;11(8):1603‐8. [DOI] [PubMed] [Google Scholar]
  37. Guyatt G, Oxman AD, Sultan S, Brozek J, Glasziou P, Alonso‐Coello P, et al. GRADE guidelines: 11. Making an overall rating of confidence in effect estimates for a single outcome and for all outcomes. Journal of Clinical Epidemiology 2013;66(2):151‐7. [DOI] [PubMed] [Google Scholar]
  38. Guyatt GH, Oxman AD, Santesso N, Helfand M, Vist G, Kunz R, et al. GRADE guidelines: 12. Preparing summary of findings tables ‐ binary outcomes. Journal of Clinical Epidemiology 2013;66(2):158‐72. [DOI] [PubMed] [Google Scholar]
  39. Guyatt GH, Ebrahim S, Alonso‐Coello P, Johnston BC, Mathioudakis AG, Briel M, et al. GRADE guidelines 17: assessing the risk of bias associated with missing participant outcome data in a body of evidence. Journal of Clinical Epidemiology 2017;87:14‐22. [PUBMED: 28529188] [DOI] [PubMed] [Google Scholar]
  40. Higgins JP, Thompson SG. Quantifying heterogeneity in a meta‐analysis. Statistics in Medicine 2002;21(11):1539–58. [DOI] [PubMed] [Google Scholar]
  41. Higgins JPT, Thompson SG. Controlling the risk of spurious findings from meta‐regression. Statistics in Medicine 2004;23:1663‐82. [DOI] [PubMed] [Google Scholar]
  42. Higgins JP, Green S, editor(s). Cochrane Handbook for Systematic Reviews of Interventions Version 5.1.0 (updated March 2011). The Cochrane Collaboration, 2011. Available from handbook.cochrane.org.
  43. Hollis S, Campbell F. What is meant by intention to treat analysis? Survey of published randomised controlled trials. BMJ (Clinical Research Ed.) 1999;319(7211):670‐4. [DOI] [PMC free article] [PubMed] [Google Scholar]
  44. International Conference on Harmonisation Expert Working Group. International Conference on Harmonisation of Technical Requirements for Registration of Pharmaceuticals for Human Use. ICH Harmonised Tripartite Guideline. Guideline for Good Clinical Practice CFR & ICH Guidelines. Vol. 1, Philadelphia (PA): Barnett International/PAREXEL, 1997. [Google Scholar]
  45. Imberger G, Gluud C, Boylan J, Wetterslev J. Systematic reviews of anesthesiologic interventions reported as statistically significant: problems with power, precision, and type 1 error protection. Anesthesia and Analgesia 2015;121(6):1611‐22. [DOI] [PubMed] [Google Scholar]
  46. Imberger G, Thorlund K, Gluud C, Wetterslev J. False‐positive findings in Cochrane meta‐analyses with and without application of trial sequential analysis: an empirical review. BMJ Open 2016;6(8):e011890. [DOI] [PMC free article] [PubMed] [Google Scholar]
  47. Jakobsen J, Wetterslev J, Winkel P, Lange T, Gluud C. Thresholds for statistical and clinical significance in systematic reviews with meta‐analytic methods. BMC Medical Research Methodology 2014;14:120. [DOI] [PMC free article] [PubMed] [Google Scholar]
  48. Jensen MP, Karoly P, Braver S. Themeasurement of clinical pain intensity: a comparison of six methods. Pain 1986;27:117‐26. [DOI] [PubMed] [Google Scholar]
  49. Kienlein S, Schoening W, Andert A, Kroy D, Neumann UP, Schmeding M. Biliary complications in liver transplantation: impact of anastomotic technique and ischemic time on short‐ and long‐term outcome. World Journal of Transplantation 2015;5(4):300‐9. [DOI] [PMC free article] [PubMed] [Google Scholar]
  50. Kim JM, Cho W, Kwon CH, Joh JW, Ko JS, Gwak MS, et al. Bile duct reconstruction by a young surgeon in living donor liver transplantation using right liver graft. Medicine 2014;93:84. [DOI] [PMC free article] [PubMed] [Google Scholar]
  51. Kjaergard LL, Villumsen J, Gluud C. Reported methodologic quality and discrepancies between large and small randomized trials in meta‐analyses. Annals of Internal Medicine 2001;135(11):982‐9. [DOI] [PubMed] [Google Scholar]
  52. López‐Andújar R, Orón EM, Carregnato AF, Suárez FV, Herraiz AM, Rodríguez FS, et al. T‐tube or no T‐tube in cadaveric orthotopic liver transplantation: the eternal dilemma: results of a prospective and randomized clinical trial. Annals of Surgery 2013;258(1):21‐9. [DOI] [PubMed] [Google Scholar]
  53. Lundh A, Lexchin J, Mintzes B, Schroll JB, Bero L. Industry sponsorship and research outcome. Cochrane Database of Systematic Reviews 2017, Issue 2. [DOI: 10.1002/14651858.MR000033.pub3] [DOI] [PMC free article] [PubMed] [Google Scholar]
  54. Miyagi S, Kakizaki Y, Shimizu K, Miyazawa K, Nakanishi W, Hara Y, et al. Arterial and biliary complications after living donor liver transplantation: a single‐center retrospective study and literature review. Surgery Today2018; Vol. 48, issue 2:131‐9. [DOI: 10.1007/s00595-017-1515-9] [DOI] [PubMed]
  55. Moher D, Pham B, Jones A, Cook DJ, Jadad AR, Moher M, et al. Does quality of reports of randomised trials affect estimates of intervention efficacy reported in meta‐analyses?. Lancet 1998;352(9128):609‐13. [DOI] [PubMed] [Google Scholar]
  56. Mustafa RA, Santesso N, Brozek J, Akl EA, Walter SD, Norman G, et al. The GRADE approach is reproducible in assessing the quality of evidence of quantitative evidence syntheses. Journal of Clinical Epidemiology 2013;66(7):736‐42. [DOI] [PubMed] [Google Scholar]
  57. Nuno J, Vicente E, Turrion VS, Pereira F, Ardaiz J, Cuervas V, et al. Biliary tract reconstruction after liver transplantation: with or without T‐tube?. Transplantation Proceedings 1997;29:564‐5. [DOI] [PubMed] [Google Scholar]
  58. Qizilbash N, Whitehead A, Higgins J, Wilcock G, Schneider L, Farlow M. Cholinesterase inhibition for Alzheimer disease: a meta‐analysis of the tacrine trials. Dementia Trialists' Collaboration. JAMA 1998;280(20):1777‐82. [DOI] [PubMed] [Google Scholar]
  59. The Nordic Cochrane Centre, The Cochrane Collaboration. Review Manager (RevMan). Version 5.3. Copenhagen: The Nordic Cochrane Centre, The Cochrane Collaboration, 2014.
  60. Royle P, Milne R. Literature searching for randomized controlled trials used in Cochrane reviews: rapid versus exhaustive searches. International Journal of Technology Assessment in Health Care 2003;19(4):591‐603. [DOI] [PubMed] [Google Scholar]
  61. Savović J, Jones HE, Altman DG, Harris RJ, Jüni P, Pildal J, et al. Influence of reported study design characteristics on intervention effect estimates from randomized controlled trials. Annals of Internal Medicine 2012;157:429‐38. [DOI] [PubMed] [Google Scholar]
  62. Savović J, Jones HE, Altman DG, Harris RJ, Jüni P, Pildal J, et al. Influence of reported study design characteristics on intervention effect estimates from randomized controlled trials. Health Technology Assessment 2012;16(35):1‐82. [DOI] [PubMed] [Google Scholar]
  63. Savović J, Turner RM, Mawdsley D, Jones HE, Beynon R, Higgins JP, et al. Association between risk‐of‐bias assessments and results of randomized trials in Cochrane Reviews: The ROBES Meta‐Epidemiologic Study. American Journal of Epidemiology 2018;187(5):1113‐22. [DOI] [PMC free article] [PubMed] [Google Scholar]
  64. Scatton O, Meunier B, Cherqui D, Boillot O, Sauvanet A, Boudjema K, et al. Randomized trial of choledocho‐choledochostomy with or without a T‐tube in orthotopic liver transplantation. Annals of Surgery 2001;233:432‐7. [DOI] [PMC free article] [PubMed] [Google Scholar]
  65. Schulz KF, Chalmers I, Hayes RJ, Altman DG. Empirical evidence of bias. Dimensions of methodological quality associated with estimates of treatment effects in controlled trials. JAMA 1995;273(5):408‐12. [DOI] [PubMed] [Google Scholar]
  66. Storebø OJ, Pedersen N, Ramstad E, Kielsholm ML, Nielsen SS, Krogh HB, et al. Methylphenidate for attention deficit hyperactivity disorder (ADHD) in children and adolescents – assessment of adverse events in non‐randomised studies. Cochrane Database of Systematic Reviews 2018, Issue 5. [DOI: 10.1002/14651858.CD012069.pub2] [DOI] [PMC free article] [PubMed] [Google Scholar]
  67. Higgins J, Thompson S, Deeks J, Altman D. Statistical heterogeneity in systematic reviews of clinical trials: a critical appraisal of guidelines and practice. Journal of Health Services Research & Policy 2002;7(1):51‐61. [DOI] [PubMed] [Google Scholar]
  68. Thorlund K, Devereaux PJ, Wetterslev J, Guyatt G, Ioannidis JP, Thabane, et al. Can trial sequential monitoring boundaries reduce spurious inferences from meta‐analyses?. International Journal of Epidemiology 2009;38(1):276‐86. [DOI] [PubMed] [Google Scholar]
  69. Thorlund K, Anema A, Mills E. Interpreting meta‐analysis according to the adequacy of sample size. An example using isoniazid chemoprophylaxis for tuberculosis in purified protein derivative negative HIV‐infected individuals. Clinical Epidemiology 2010;2:57‐66. [DOI] [PMC free article] [PubMed] [Google Scholar]
  70. Thorlund K, Engstrøm J, Wetterslev J, Brok J, Imberger G, Gluud C. User manual for Trial Sequential Analysis (TSA). ctu.dk/tsa/files/tsa_manual.pdf 2011 (accessed 10 January 2018).
  71. Copenhagen Trial Unit. TSA ‐ Trial Sequential Analysis. Version 0.9.5.10 Beta. Copenhagen: Copenhagen Trial Unit, 2011.
  72. Vougas V, Rela M, Gane E, Muiesan P, Melendez HV, Williams R, et al. A prospective randomised trial of bile duct reconstruction at liver transplantation: T‐tube or no T‐tube?. Transplant International 1996;9(4):392‐5. [DOI] [PubMed] [Google Scholar]
  73. Ware JE Jr, Kosinski M, Keller SD. SF‐36 Physical and Mental Health Summary Scales: a User Manual. Boston, MA: The Health Institute, 1994. [Google Scholar]
  74. Weiss S, Schmidt SC, Ulrich F, Pascher A, Schumacher G, Stockmann M, et al. Biliar reconstruction using aside‐to‐side choledochocholedochostomy with or without T‐tube in deceased donor liver transplantation: a prospective randomized trial. Annals of Surgery 2009;250:766‐71. [DOI] [PubMed] [Google Scholar]
  75. Wetterslev J, Thorlund K, Brok J, Gluud C. Trial sequential analysis may establish when firm evidence is reached in cumulative meta‐analysis. Journal of Clinical Epidemiology 2008;61(1):64‐75. [DOI] [PubMed] [Google Scholar]
  76. Wetterslev J, Thorlund K, Brok J, Gluud C. Estimating required information size by quantifying diversity in a random‐effects meta‐analysis. BMC Medical Research Methodology 2009;9:86. [DOI] [PMC free article] [PubMed] [Google Scholar]
  77. Wetterslev J, Jakobsen JC, Gluud C. Trial Sequential Analysis in systematic reviews with meta‐analysis. BMC Medical Research Methodology 2017;17(1):39. [DOI] [PMC free article] [PubMed] [Google Scholar]
  78. Wojcicki M, Lubikowski J, Klek R, Post M, Jarosz K, Białek A, et al. Reduction of biliary complication rate using continuous suture and no biliary drainage for duct‐to‐duct anastomosis in whole‐organ liver transplantation. Transplantation Proceedings 2009;41:3126–30. [DOI] [PubMed] [Google Scholar]
  79. Wood L, Egger M, Gluud LL, Schulz KF, Jüni P, Altman GD, et al. Empirical evidence of bias in treatment effect estimates in controlled trials with different interventions and outcomes: meta‐epidemiological study. BMJ (Clinical Research Ed.) 2008;336:601‐5. [DOI] [PMC free article] [PubMed] [Google Scholar]

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