Intervention Protocol

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Pharmacological interventions for the primary prevention of gallbladder stones in adults

  1. Caroline S. Stokes1,*,
  2. Lise Lotte Gluud2,
  3. Markus Casper1,
  4. Frank Lammert1

Editorial Group: Cochrane Hepato-Biliary Group

Published Online: 21 MAR 2014

DOI: 10.1002/14651858.CD011037


How to Cite

Stokes CS, Gluud LL, Casper M, Lammert F. Pharmacological interventions for the primary prevention of gallbladder stones in adults (Protocol). Cochrane Database of Systematic Reviews 2014, Issue 3. Art. No.: CD011037. DOI: 10.1002/14651858.CD011037.

Author Information

  1. 1

    Saarland University Hospital, Department of Medicine II, Homburg/Saar, Germany

  2. 2

    Copenhagen University Hospital Hvidovre, Gastro Unit, Medical Division, Hvidovre, Denmark

*Caroline S. Stokes, Department of Medicine II, Saarland University Hospital, Kirrberger Str. 1, Homburg/Saar, 66421, Germany. caroline.stokes@uks.eu.

Publication History

  1. Publication Status: New
  2. Published Online: 21 MAR 2014

SEARCH

 

Background

  1. Top of page
  2. Background
  3. Objectives
  4. Methods
  5. Acknowledgements
  6. Appendices
  7. What's new
  8. Contributions of authors
  9. Declarations of interest
  10. Sources of support
 

Description of the condition

Gallstone disease is a metabolic disorder whereby solid calculi (stones) form in the biliary tract due to alterations in the chemical constituents of bile. Gallbladder stones (cholelithiasis) and bile duct stones (choledocholithiasis) are further categorised into cholesterol or pigment stones depending on their main contributing constituents. Cholesterol stones are seen in more than 90% of people with cholelithiasis (Schafmayer 2006). The main component is cholesterol monohydrate crystals. The black and brown pigment stones are primarily composed of calcium bilirubinate (Schafmayer 2006). Alterations in the physical properties of the gallbladder and the chemistry composition of bile, such as bile saturation with cholesterol or bilirubin, gallbladder hypomotility, and bile destabilisation related to kinetic protein factors increase the risk of gallbladder stones (Maurer 2009). Moreover, intestinal hypomotility increases the development of cholelithiasis given its ability to promote lithogenic bile through increased bacterial colonic deoxycholate formation. Increased concentrations of this secondary bile salt and slow intestinal transit have both been reported in patients with cholesterol stones (Portincasa 1996).

Gallbladder stones result from an intricate interaction between multiple genetic, environmental, and lifestyle determinants (Stokes 2011). Non-modifiable risk factors include genetics, female sex, and increasing age. Modifiable (environmentally-related) risk factors comprise hormonal therapy, obesity, rapid weight loss, and weight cycling; as well as physical inactivity and chronic hypercaloric, high carbohydrate, and low fibre intake, synonymous with 'Westernised' lifestyle habits (Stampfer 1992; Weinsier 1993; Storti 2005; Stinton 2010). The prevalence of gallbladder stones in Europe and America is currently at 10% to 20% of the population with a projected rise in the coming years given the obesity epidemic and the increasing ageing population (Everhart 1999; Völzke 2005; Go 2013). Gallbladder stones are asymptomatic in the majority of people. However, an estimated 25% of people with cholelithiasis develop symptoms and complications such as cholecystitis. Also bile duct stones may cause cholangitis and pancreatitis (Friedman 1993). A meta-analysis of 21 controlled trials associated gallbladder stones with symptoms of biliary colic, characterised by pain in the upper abdominal quadrant (Kraag 1995). Upon complications, patients with symptomatic cholelithiasis frequently require hospital admission and cholecystectomy. In gastroenterology, gallbladder stones are one of the most common hospital discharge diagnosis, only secondary to gastroesophageal reflux disease (Peery 2012). The management of gallbladder stones incurs one of the largest medical expenses from all gastroenterological disorders (Everhart 2009). Over 700,000 cholecystectomies are performed each year in the United States alone, which corresponds to annual cholelithiasis-related medical expenses that surpassed USD $6.5 billion in the year 2000 (Everhart 2009).

Cholecystectomies are also undertaken for protection against gallbladder stones in highly selected risk groups such as patients undergoing bariatric surgery (Grimaldi 1993; Bonatsos 2001; Liem 2004). Post-cardiac surgery patients have an increased risk of cholelithiasis (Azemoto 1996), but are not candidates for cholecystectomy (Neugebauer 1995). Although the operative mortality associated with cholecystectomy is less than 0.6%, there are specific risks associated with damage to the bile ducts (Rosenmüller 2007). Morbidly obese patients undergoing gastric bypass surgery with concomitant cholecystectomy often require longer hospital stays (Hamad 2003) and have a risk of post-operative complications. A Cochrane overview of systematic reviews reported symptom recurrence in 40% of post-cholecystectomised patients (Keus 2010). In fact, post-cholecystectomy syndrome has been reported in 5% to 47% of patients (Bisgaard 2005; Jaunoo 2010) and includes a wide range of symptoms (biliary and extra-biliary) which is often characterised by pre-surgery symptom recurrence. A Swedish population based cohort study reported a weak association between oesophageal adenocarcinoma and patients with cholecystectomy (Lagergren 2011a). Confounders, such as obesity, were not controlled for in the study. However, this observed association may be attributed to increased concentrations of bile in gastric fluid, which consequently may come into contact with the oesophagus during gastro-oesophageal reflux. The study also found an association between hepatocellular carcinoma and cholecystectomy (Lagergren 2011b). Accordingly, research groups have investigated alternative preventive approaches to gallbladder stones that are related to its pathophysiology and its established risk factors.

 

Description of the intervention

Pharmacotherapies have been investigated for their potential use in gallbladder stone prevention. The oral administration of bile acids such as ursodeoxycholic acid are used to prevent the bile from becoming lithogenic, particularly during weight loss. The advantage with ursodeoxycholic acid, which is a naturally occurring hydrophilic bile acid - is that adverse effects (the most common being diarrhoea) are rare. Patients completing prophylactic treatment of ursodeoxycholic acid for gallstone prevention reportedly had a significantly lower need for cholecystectomy (Villegas 2004). A meta-analysis on five randomised clinical trials using ursodeoxycholic acid for the prevention of gallbladder stones in post-bariatric surgery patients reported a protective effect against cholelithiasis (Uy 2008). Non-steroidal anti-inflammatory drugs have also been suggested to be anti-lithogenic and drugs inhibiting cholesterol synthesis and/or intestinal absorption, or modulators of nuclear receptors involved in cholesterol and bile acid homeostasis are hypothesised to hold promise in the prevention of gallbladder stones (Caroli-Bosc 2001; Moschetta 2004; Krawczyk 2011; Wang 2013).

 

How the intervention might work

Pharmacological interventions may help prevent cholelithiasis through their beneficial effect on preventing the bile from becoming prone to forming stones (i.e., lithogenic). The increased risk of gallbladder stones during weight loss may be attributable to unfavourable changes in bile lithogenicity, with increased cholesterol secretion from fatty tissues and reduced bile salt secretion, which results in cholesterol supersaturated bile (Bennion 1975; Gustafsson 2005). Moreover, nucleation time may be shorted due to increased biliary mucin concentrations (Sahlin 1990). In terms of lifestyle interventions, low calorie diets in conjunction with ursodeoxycholic acid are suggested to increase intestinal motility thus reducing the risk of gallbladder stones (Broomfield 1988; Wudel 2002). Ursodeoxycholic acid decreases the lithogenicity of bile by reducing the intestinal absorption and biliary secretion of cholesterol as well as shifting the phase separation of bile towards solubilisation in micelles and vesicles (Salvioli 1983; Broomfield 1988).

Non-steroidal anti-inflammatory drugs are suggested to reduce the precipitation of cholesterol in bile in both preclinical and in non-randomised studies (Lee 1981), and may thus decrease the risk of gallbladder stones. Moreover, cholesterol lowering agents such as ezetimibe reduced the risk of cholesterol gallbladder stones in mouse studies and in a small cohort of humans (Wang 2008; Zuniga 2008). In humans, statin use was shown to reduce the risk of cholecystectomy in studies conducted in Denmark, UK, and US, possibly through a reduced secretion of cholesterol into bile (Bodmer 2009; Tsai 2009; Erichsen 2011).

 

Why it is important to do this review

Given the invasiveness and costs associated with the surgical treatment and prevention of gallbladder stones, successful non-invasive preventive options are warranted. There are no Cochrane systematic reviews on the evaluation of pharmacological interventions for the primary prevention of gallbladder stones and most randomised clinical trials are small and their combined result is not clear. Evidence-based guidelines are needed to identify interventions that could be feasible to use in practice, particularly in high risk individuals (e.g., in obese individuals and/or in carriers of lithogenic genes such as the ABCG8 p.D19H risk variant which confers an increased risk of cholelithiasis (Krawczyk 2011)).

 

Objectives

  1. Top of page
  2. Background
  3. Objectives
  4. Methods
  5. Acknowledgements
  6. Appendices
  7. What's new
  8. Contributions of authors
  9. Declarations of interest
  10. Sources of support

To evaluate the benefits and harms of pharmacological interventions in the primary prevention of gallbladder stones in adults.

 

Methods

  1. Top of page
  2. Background
  3. Objectives
  4. Methods
  5. Acknowledgements
  6. Appendices
  7. What's new
  8. Contributions of authors
  9. Declarations of interest
  10. Sources of support
 

Criteria for considering studies for this review

 

Types of studies

In our analysis we plan to include all randomised clinical trials irrespective of blinding, language, sample size, or publication status. Controlled clinical trials where quasi-randomisation methods have been used, such as day of the week, date of birth, medical record number, and other non-randomised studies if obtained through the searches for randomised clinical trials will only be included for the reported data on harm. Only data from the first period of cross-over trials will be included (as if they were parallel trials), since the carry-over effect of the intervention may be conducive to confounding. Trials where ultrasonography is not primarily used to diagnose gallbladder stones will be excluded, as other diagnostic methods are lower in sensitivity and specificity (e.g., intravenous cholangiogram).

 

Types of participants

This review will include both hospital and community-based male and female adults (older than 18 years) from all ethnicity groups who do not have gallbladder stones as confirmed by ultrasonography. Studies using self-reported outcomes will also be included when relating specifically to cholecystectomy as they are deemed reliable. In terms of age groups, this review will only focus on the adult human population. However, studies conducted in children will be included to assist with the extraction of data on harm.

 

Types of interventions

Trials will be considered for inclusion when at least one study group has been allocated to receive a pharmacological intervention (irrespective of the time, dose, or pharmacological class of the administered drug) following a standard (within trial) protocol for prophylaxis against gallstone formation. This may include the following pharmacological interventions (single or multiple per trial): ursodeoxycholic acid, Non-steroidal anti-inflammatory drugs, cholesterol lowering agents or other hypolipidaemic drugs.

For the above interventions, special consideration will be given to what is delivered (e.g., drug preparation) as well as to the intensity, frequency, and route of administration. Pharmacological regimens for gallstone prevention are usually taken once or twice per day, This discrepancy is deemed unlikely to cause substantial differences in treatment effect, and thus, it will not be separated.

Settings: both community and hospital-based interventions will be considered.

Duration: The duration of therapy will be set to a minimum of four weeks because studies have shown gallbladder stones to develop after this time frame (e.g., Liddle 1989; Gebhard 1996).

Acceptable comparator groups will include:

  1. inactive control intervention such as placebo or no treatment;
  2. active control intervention such as a variant of the same intervention or other pharmacological treatments.

 

Types of outcome measures

We will include the following primary and secondary outcome measures based on the specifications provided in the Cochrane Hepato-Biliary Group module (Gluud 2014).

 

Primary outcomes

  1. All-cause mortality.
  2. Morbidity (formation of ultrasonically verified gallbladder stones and symptomatic gallbladder stones).
  3. Number and type of adverse events during or within a reasonable post intervention time frame e.g., patient and clinician reporting of side effects, poor quality of life scores, morbidity, and mortality. The International Conference on Harmonisation of Technical Requirements for Registration of Pharmaceuticals for Human Use (ICH) defines an adverse event as any untoward medical occurrence that does not have a causal relationship with the particular treatment and can include any unfavourable and unintended sign (e.g., abnormal laboratory findings), symptoms, or disease, which is temporarily associated with the use of the respective medicinal product being assessed, regardless of whether it is related to this medicinal product (ICH-GCP 1997). A severe adverse event is defined as that which results in death; is life threatening; requires hospitalisation or prolongation of existing hospitalisation; results in persistent or significant disability/incapacity or any medical event which may jeopardise the patient or require an intervention to prevent it (ICH-GCP 1997). Evidence of adverse events will not only be sought from randomised trials but also from open studies and case reports.

 

Secondary outcomes

  1. Quality of life measures.
  2. Cholecystectomy.
  3. Bile lithogenicity (defined as changes in physiological parameters of bile composition indicative of an increased risk of gallbladder stones e.g., cholesterol saturation index (Carey 1978), nucleation time for cholesterol crystal formation (Holan 1979), presence of cholesterol crystals).
  4. Weight loss (reduction in body weight assessed in kg or using the body mass index (BMI)).

 

Search methods for identification of studies

We will restrict search strategies to identify randomised clinical trials in adults. We will screen duplicate publications by comparing publications of the same authors with respect to study populations, date, location, and follow-up time of the study. The time frame when examining the literature will include searching electronic databases from the time of their inception to present.

 

Electronic searches

We will search the Cochrane Hepato-Biliary Group Controlled Trials Register (Gluud 2014), the Cochrane Central Register of Controlled Trials (CENTRAL), MEDLINE, EMBASE, and Science Citation Index Expanded. These cites are reported to yield approximately 95% or more of the relevant studies (Royle 2003). Preliminary search strategies are given in Appendix 1, which encompasses a broad search taking into account studies relevant to both pharmacological but also to dietary interventions (for the complementary Cochrane review on dietary interventions to prevent primary gallbladder stones). We may consequently modify the search strategies as the review progresses if necessary.

 

Searching other resources

We will scan reference lists of relevant articles for further trial references as will conference proceedings. We will contact principal authors of identified studies and other experts (authors of reviews) to elicit information regarding additional trials known to them. We will also scan trial registries in two search portals: ClinicalTrials.gov (clinicaltrials.gov/) and the World Health Organization (WHO) International Clinical Trial Registry Platform (ICTRP) search portal (apps.who.int/trialsearch/).

 

Data collection and analysis

We will perform this systematic review according to the instructions in the Cochrane Handbook for Systematic Reviews of Intervention (Higgins 2011) and the Cochrane Hepato-Biliary Group Module (Gluud 2014). We will analyse data using the Cochrane Collaboration's statistical software Review Manager 5 (RevMan 2012).

 

Selection of studies

Two review authors will independently review titles and abstracts in order to select potentially relevant trials; the full text of these potentially relevant trials will be assessed to determine if the inclusion criteria are met. Any differences in opinion will be resolved by discussion and if necessary, by consulting a third review author. Excluded studies will also be listed, together with reasons for their exclusion.

 

Data extraction and management

At least two review authors will independently extract the data listed below from identified randomised trials (although this list is not yet exhaustive). We will contact authors of individual trials for any unclear or missing information.

  • General
    • Published, unpublished
    • Year and language of publication (if published)
    • Year of study (conduct of trial)
    • Title
    • Authors
    • Country
    • Funding
    • Duplicate publication

  • Trial characteristics
    • Design
    • Duration (and duration of follow-up period)
    • Randomisation
    • Concealment of allocation
    • Blinding
    • Checking of blinding

  • Intervention
    • Length of intervention
    • Main intervention: pharmacological drug name and dose (e.g., ursodeoxycholic acid, acetylsalicylic acid, ibuprofen)
    • Co interventions/comparison intervention (as above)
    • Control group intervention
    • Duration of follow-up
  • Participants
    • Population characteristics (means, standard deviations and/or ranges for: age, sex, BMI, health condition etc will be extracted, where possible)
    • Diagnostic criteria used to define presence/absence of gallbladder stones
    • Inclusion and exclusion criteria
    • Sample size (total, per compared groups)
    • Similarity of groups at baseline
    • Other medication/therapy used
    • Assessment of compliance
    • Withdrawals/losses to follow-up
    • Confounders

  • Outcomes
    • Main outcomes specified in study
    • Incidence of symptomatic gallbladder stones
    • Incidence of cholecystectomy
    • Bile lithogenicity changes
    • Weight loss during the trial
    • Adverse events reported

  • Results for outcomes and times of assessment (including a measure of variation) intention-to-treat/per protocol analysis
  • Methodological quality/risk of bias

 

Assessment of risk of bias in included studies

Trials with inadequate methodological quality increase the risk of overestimating beneficial intervention effects (Gluud 2006). Two review authors will independently assess the methodological quality/risk of bias in the included trials based on instructions given in the Cochrane Handbook for Systematic Reviews of Intervention (Higgins 2011) and the Cochrane Hepato-Biliary Group Module (Gluud 2014). The process will be conducted without masking the trial names. We will obtain any unavailable information that is deemed necessary from the authors of the relevant trials.

We will assess the following domains to determine extent of systematic error and the risk of bias for each trial (Schulz 1995; Moher 1998; Kjaergard 2001; Wood 2008; Lundh 2012; Savović 2012; Savović 2012a). We will present our findings in the 'Characteristics of studies' tables.

 

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. Quasi-randomised studies, those using dates, names, or admittance numbers in order to allocate patients are inadequate and will be excluded for the assessment of benefits but not for harms.

 

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).
  • 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 were 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, were 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 on the www.clinicaltrials.gov web site or a similar register, or there should be a protocol (e.g., published in a paper journal). In the case when 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 were provided in the publications results section, then the trial can be considered a low risk of bias trial in the 'Selective outcome reporting' domain.

 

For-profit bias

  • Low risk of bias: the trial appears to be free of industry sponsorship or other type of for-profit support that may manipulate the trial design, conductance, 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 was provided.
  • High risk of bias: the trial was sponsored by the industry or has received other type of for-profit support.

 

Other risk of bias

  • Low risk of bias: the trial appears to be free of other components (e.g., academic bias) that could put it at risk of bias.
  • Uncertain risk of bias: the trial may or may not be free of other components that could put it at risk of bias.
  • High risk of bias: there are other factors in the trial that could put it at risk of bias (e.g., authors have conducted trials on the same topic, etc.).

We will consider trials assessed as having 'low risk of bias' in all of the above specified individual domains as trials with 'low risk of bias', and trials that are assessed as having 'uncertain risk of bias' or 'high risk of bias' in one or more of the specified individual domains will be considered as trials with 'high risk of bias'. If disagreements among review authors' evaluation occur, we will resolve them by discussion.

 

Measures of treatment effect

Where study outcomes are reported as dichotomous data (as opposed to continuous variables), we will present odds ratios (ORs) or risk ratios (RRs), 95% confidence intervals (CIs) and P values for significance level. We may also include the risk difference if this is presented in order to illustrate the above results in absolute terms (e.g., number of participants who develop gallbladder stones), which may then be converted to provide a number-needed-to-treat (NNT) estimate.

 

Unit of analysis issues

Patients in some of the trials may undergo more than one intervention (e.g., ursodeoxycholic acid with a low calorie diet/weight loss regimen), which increases the risk of unit of analysis related errors in the meta-analysis. If possible, we will combine groups from a single trial to create a single pair-wise comparison, as recommended by the Cochrane Handbook for Systematic Reviews of Intervention (Higgins 2011). Alternatively, we may apply a Bayesian framework so that all interventions in the analysis can be ranked using probabilistic methods.

Moreover, there may be multiple observations for the same outcome across studies (e.g., the follow-up assessments for presence of gallbladder stones at different time points may require that multiple ultrasonographies are performed for instance, at six months, one year and at 18 months). In this case, we may need to compute an effect measure for each individual participant, which incorporates all time points (e.g., trend over time).

Timing of outcome measurements being assessed post intervention may differ between studies. For studies with differing time frames (e.g., for follow-up), we will use the following intervals:

  • short-term (three months or less than three months);
  • medium-term (between four and eleven months);
  • long-term (12 months or more than 12 months).

 

Dealing with missing data

We will use data on all participants randomised to allow intention-to-treat analyses including all participants irrespective of compliance or follow-up; we will also perform available case analysis. Where data on the outcome of excluded patients are missing, we will contact trial authors for the original data. We will collect drop-out rates together with reasons for drop-outs as reported by trial authors. We will document this information in the ‘Characteristics of included studies’ tables. We will further evaluate the importance of missing data by performing the following sensitivity analyses:

  • poor outcome analyses assuming that losses to follow-up are treatment failures;
  • good outcome analyses assuming that losses to follow-up are treatment successes.

 

Assessment of heterogeneity

We will use the chi2 test to confirm the expected between-study heterogeneity and the I2 statistic (which incorporates the Chi2 statistic [Q]) to inform on the degree of heterogeneity (Higgins 2002). If multiple intervention trials are combined, a unit of analysis error may occur when attempting to assess heterogeneity. Therefore, the analysis will be planned accordingly: a fixed-effect analysis across comparisons within a trial, followed by a random-effects meta-analysis across trials. We will conduct subgroup analyses investigating the possible source of heterogeneity (Subgroup analysis and investigation of heterogeneity), and if sufficient trials are present, we will carry out meta-regression.

 

Assessment of reporting biases

Where possible, we will perform a funnel plot using Review Manager 5 (RevMan 2012) to investigate for presence of bias by illustrating the study size against the treatment effect. We will use linear regression approach to determine funnel plot asymmetry (Egger 1997).

 

Data synthesis

We plan to perform the meta-analysis and display the results according to recommendations by the Cochrane Collaboration (Higgins 2011). We will group data based on similarities of interventions implemented. We will present dichotomous data (e.g., presence of gallbladder stones) using pooled ORs or RRs with 95% CIs, with their corresponding log transformed values. For continuous data, we will use the mean differences (MDs) and 95% CIs to estimate intervention effect (or the standard mean differences (SMDs), if diverse scales are used). We will derive precise P values for all comparisons where possible. We will perform analyses using the intention-to-treat (ITT) principle (e.g., for all randomised patients in the randomised trials) wherever possible; otherwise, we will conduct an 'available case analysis'.

Between-study variation may exist for the dosage or quantity of an intervention, particularly in regard to pharmacological interventions. Where varying pharmacological doses exist, we may group them together if significances are observed in all treatment levels. Alternatively, we will group doses based on predetermined clusters such as low, medium, or high. For example, ursodeoxycholic acid is often prescribed as mg/kg body weight or in standard doses ranging from 300, 500, 600,1000, or 1200 mg/day, and it can, therefore, be grouped into the following: low dose (less than or equal to 600 mg/day) and medium dose (more than 600 mg/day) of ursodeoxycholic acid. Our understanding is that high doses of ursodeoxycholic acid have not been investigated for gallstone disease in randomised trials.

If a small number of trials are identified, or if sample sizes are small, we will consider using the Mantel-Haenszel method for pooling data (Mantel 1959). The Mantel-Haenszel method assumes a fixed-effect meta-analysis and is used for dichotomous data. It is reported by the Cochrane Handbook for Systematic Reviews of Interventions as the best method for combining trials with small sample sizes (Higgins 2011). For continuous data, we will use MDs or SMDs to pool results. In the absence of heterogeneity between study results, we will analyse data using the fixed-effect model meta-analysis (Demets 1987). Alternatively, we will use the random-effects model win the presence of heterogeneous results, and perform subgroup/sensitivity analyses to assess for potential causes (DerSimonian 1986). We will consider conducting analyses with both models (fixed-effect and random-effects) to determine whether there is a discrepancy between their results.

 

Trial sequential analysis

Cumulative meta-analyses are at risk of producing random errors due to sparse data and multiple testing of accumulating data (Brok 2008; Wetterslev 2008; Brok 2009; Thorlund 2009, Wetterslev 2009; Thorlund 2010). Therefore, we can apply trial sequential analysis as specified in the Cochrane Hepato-Biliary Group module in order to assess this risk (CTU 2011; Thorlund 2011). The required information size (that is, the number of participants needed in a meta-analysis to detect or reject a certain intervention effect) can be calculated in order to minimise random errors (Wetterslev 2008; Wetterslev 2009). The required information size takes into account: the event proportion in the control group; assumption of a plausible RR reduction or the RR reduction observed in the included trials with low risk of bias and the assumed heterogeneity or diversity of the meta-analysis (Wetterslev 2008; Wetterslev 2009). Trial sequential analysis enables testing for significance to be conducted each time a new trial is included in the meta-analysis. On the basis of the required information size, trial sequential monitoring boundaries can be constructed. This enables one to determine statistical inference concerning cumulative meta-analysis that has not yet reached the required information size (Wetterslev 2008). Firm evidence may be established if the trial sequential monitoring boundary is crossed before reaching the required information size, in which case further trials may turn out to be superfluous. In contrast, if the boundary is not surpassed one may conclude that it is necessary to continue with further trials before a certain intervention effect can be detected or rejected. Firm evidence for lack of a postulated intervention effect can also be assessed with trial sequential analysis. This occurs when the cumulative Z-score crossed the trial sequential beta spending monitoring boundaries and enters the area of futility.

 

Subgroup analysis and investigation of heterogeneity

Where appropriate, we will perform subgroup analysis to assess for possible sources of heterogeneity. Specifically, if enough trials are found to justify subgroup analysis, it will be used to identify differences or similarities among results of trials that have common features e.g., trials could be stratified by duration of therapy or by patient subgroup. Moreover, subgroup analyses may be carried out to help answer specific questions about particular patient groups, types of intervention, or types of studies.

We will investigate the following subgroups for effect modification.

  1. Intervention type: pharmacological (in combination or alone, differing doses etc).
  2. Intervention type based on patients receiving bariatric surgery versus those not receiving bariatric surgery.
  3. Intervention type based on patients actively trying to lose weight versus those not trying to lose weight.
  4. Outcome of symptomatic gallbladder stones or cholecystectomy, or both versus asymptomatic gallbladder stones.
  5. Quality of bias control (e.g., high versus low).
  6. Treatment duration/duration of follow-up.
  7. Sex, since gallbladder stones are more prevalent amongst females (Portincasa 2006).
  8. Different geographical locations or ethnicity, or both due to the fact that both ethnic and geographical disparities exist regarding the prevalence of gallbladder stones.

 

Sensitivity analysis

If a sufficient number of randomised trails are identified, we will perform sensitivity analysis to explore the impact of study quality. Specifically, if appropriate (e.g., where meta-analysis has shown heterogeneity among trial results), we will conduct a sensitivity analysis to explore the influence of the following factors on effect size:

  1. publication status (e.g., excluding unpublished studies);
  2. methodological quality and risk of bias (e.g., excluding studies of low quality, i.e., with missing drop-out rates);
  3. blinding (e.g., removal of unclear or inadequate);
  4. allocation concealment (e.g., removal of unclear or inadequate allocation procedure);
  5. duration (e.g., impact of short and long intervention duration);
  6. language of publication.

 

Economic issues

Though a full economic evaluation in this review is predicted to be unfeasible, we will address costs and cost-effectiveness of the interventions and, if data availability permits, a preliminary reflection of efficient use of resources with respect to the efficacy of interventions, for example, quality of life (as assessed by a validated questionnaire), and length of hospital stays.

 

Summary of Findings tables

If possible, we will also assess the quality of evidence across trials at the outcome level using the Grading of Recommendations Assessment, Development and Evaluation (GRADE) approach (Guyatt 2008). We will include the three primary outcomes plus two of the secondary outcomes (treatment with cholecystectomy and bile lithogenicity) in the 'Summary of findings' tables.

 

Acknowledgements

  1. Top of page
  2. Background
  3. Objectives
  4. Methods
  5. Acknowledgements
  6. Appendices
  7. What's new
  8. Contributions of authors
  9. Declarations of interest
  10. Sources of support

To Sarah Klingenberg, Trial Search Co-ordinator, for preliminary searching the electronic databases and to the Cochrane Hepato-Biliary Group for their support.

Peer reviewers: Hanns-Ulrich Marschall, Sweden; Marc Besselink, the Netherlands.
Contact Editor: Vanja Giljaca, Croatia.

 

Appendices

  1. Top of page
  2. Background
  3. Objectives
  4. Methods
  5. Acknowledgements
  6. Appendices
  7. What's new
  8. Contributions of authors
  9. Declarations of interest
  10. Sources of support
 

Appendix 1. Search strategies for identification of studies


Database Period of Search Search Strategy

Cochrane Hepato-Biliary Group Controlled Trials Register Date will be given at the review stage(ultrasonograph* OR ultrasound* OR ecograph* OR 'ursodeoxycholic acid*' OR ursodiol OR UDCA OR ('non-steroid* anti-inflammatory' AND (drug* OR agent*)) OR ibuprofen OR aspirin OR obesity OR 'bariatric surger*' OR 'weight loss' OR 'diet therap*' OR 'caloric restriction' OR 'low calorie diet*' OR 'liquid diet*' OR fat* OR protein* OR carbohydrate* OR fibre OR micronutrient* OR 'physical activit*' OR exercise*) AND (cholelithiasis OR gallstone* OR 'gall* stone*' OR 'black pigment stone*')

Cochrane Central Register of Controlled Trials (CENTRAL)

 
Latest issue#1 MeSH descriptor Ultrasonography explode all trees

#2 ultrasonograph* OR ultrasound* OR ecograph*

#3 (#1 OR #2)

#4 MeSH descriptor Ursodeoxycholic Acid explode all trees

#5 ursodeoxycholic acid* OR ursodiol OR UDCA

#6 (#4 OR #5)

#7 MeSH descriptor Anti-Inflammatory Agents, Non-Steroidal explode all trees

#8 (non-steroid* anti-inflammatory AND (drug* OR agent*)) OR ibuprofen OR aspirin

#9 (#7 OR #8)

#10 MeSH descriptor Obesity explode all trees

#11 obesity

#12 (#10 OR #11)

#13 MeSH descriptor Bariatric Surgery explode all trees

#14 bariatric surger*

#15 (#13 OR #14)

#16 MeSH descriptor Weight Loss explode all trees

#17 weight loss*

#18 (#16 OR #17)

#19 MeSH descriptor Diet Therapy explode all trees

#20 diet therap* OR caloric restriction OR low calorie diet* OR liquid diet* OR fat* OR protein* OR carbohydrate* OR fibre

#21 (#19 OR #20)

#22 MeSH descriptor Micronutrients explode all trees

#23 micronutrient*

#24 (#22 OR #23)

#25 MeSH descriptor Exercise explode all trees

#26 physical activit* OR exercise*

#27 (#25 OR #26)

#28 (#3 OR #6 OR #9 OR #12 OR #15 OR #18 OR #21 OR #24 OR #27)

#29 MeSH descriptor Cholelithiasis explode all trees

#30 cholelithiasis OR gallstone* OR gall* stone* OR 'black pigment stone*'

#31 (#29 OR #30)

#32 (#28 AND #31)

MEDLINE (Ovid SP)         

 
Date will be given at the review status1. exp Ultrasonography/

2. (ultrasonograph* or ultrasound* or ecograph*).mp. [mp=protocol supplementary concept, rare disease supplementary concept, title, original title, abstract, name of substance word, subject heading word, unique identifier]

3. 1 or 2

4. exp Ursodeoxycholic Acid/

5. (ursodeoxycholic acid* or ursodiol or UDCA).mp. [mp=protocol supplementary concept, rare disease supplementary concept, title, original title, abstract, name of substance word, subject heading word, unique identifier]

6. 4 or 5

7. exp Anti-Inflammatory Agents, Non-Steroidal/

8. ((non-steroid* anti-inflammatory and (drug* or agent*)) or ibuprofen or aspirin).mp. [mp=protocol supplementary concept, rare disease supplementary concept, title, original title, abstract, name of substance word, subject heading word, unique identifier]

9. 7 or 8

10. exp Obesity/

11. obesity.mp. [mp=protocol supplementary concept, rare disease supplementary concept, title, original title, abstract, name of substance word, subject heading word, unique identifier]

12. 10 or 11

13. exp Bariatric Surgery/

14. bariatric surger*.mp. [mp=protocol supplementary concept, rare disease supplementary concept, title, original title, abstract, name of substance word, subject heading word, unique identifier]

15. 13 or 14

16. exp Weight Loss/

17. weight loss*.mp. [mp=protocol supplementary concept, rare disease supplementary concept, title, original title, abstract, name of substance word, subject heading word, unique identifier]

18. 16 or 17

19. exp Diet Therapy/

20. (diet therap* or caloric restriction or low calorie diet* or liquid diet* or fat* or protein* or carbohydrate* or fibre).mp. [mp=protocol supplementary concept, rare disease supplementary concept, title, original title, abstract, name of substance word, subject heading word, unique identifier]

21. 19 or 20

22. exp Micronutrients/

23. micronutrient*.mp. [mp=protocol supplementary concept, rare disease supplementary concept, title, original title, abstract, name of substance word, subject heading word, unique identifier]

24. 22 or 23

25. exp Exercise/

26. (physical activit* or exercise*).mp. [mp=protocol supplementary concept, rare disease supplementary concept, title, original title, abstract, name of substance word, subject heading word, unique identifier]

27. 25 or 26

28. 3 or 6 or 9 or 12 or 15 or 18 or 21 or 24 or 27

29. exp Cholelithiasis/

30. (cholelithiasis or gallstone* or gall* stone* or 'black pigment stone*').mp. [mp=protocol supplementary concept, rare disease supplementary concept, title, original title, abstract, name of substance word, subject heading word, unique identifier]

31. 29 or 30

32. 28 and 31

33. (random* or blind* or placebo* or meta-analysis).mp. [mp=protocol supplementary concept, rare disease supplementary concept, title, original title, abstract, name of substance word, subject heading word, unique identifier]

34. 32 and 33

EMBASE (Ovid SP)Date will be given at the review status1. exp echography/

2. (ultrasonograph* or ultrasound* or ecograph*).mp. [mp=title, abstract, subject headings, heading word, drug trade name, original title, device manufacturer, drug manufacturer]

3. 1 or 2

4. exp ursodeoxycholic acid/

5. (ursodeoxycholic acid* or ursodiol or UDCA).mp. [mp=title, abstract, subject headings, heading word, drug trade name, original title, device manufacturer, drug manufacturer]

6. 4 or 5

7. exp nonsteroid antiinflammatory agent/

8. ((non-steroid* anti-inflammatory and (drug* or agent*)) or ibuprofen or aspirin).mp. [mp=title, abstract, subject headings, heading word, drug trade name, original title, device manufacturer, drug manufacturer]

9. 7 or 8

10. exp OBESITY/

11. obesity.mp. [mp=title, abstract, subject headings, heading word, drug trade name, original title, device manufacturer, drug manufacturer]

12. 10 or 11

13. exp bariatric surgery/

14. bariatric surger*.mp. [mp=title, abstract, subject headings, heading word, drug trade name, original title, device manufacturer, drug manufacturer]

15. 13 or 14

16. exp weight reduction/

17. weight loss*.mp. [mp=title, abstract, subject headings, heading word, drug trade name, original title, device manufacturer, drug manufacturer]

18. 16 or 17

19. exp diet therapy/

20. (diet therap* or caloric restriction or low calorie diet* or liquid diet* or fat* or protein* or carbohydrate* or fibre).mp. [mp=title, abstract, subject headings, heading word, drug trade name, original title, device manufacturer, drug manufacturer]

21. 19 or 20

22. exp trace element/

23. micronutrient*.mp. [mp=title, abstract, subject headings, heading word, drug trade name, original title, device manufacturer, drug manufacturer]

24. 22 or 23

25. exp EXERCISE/

26. (physical activit* or exercise*).mp. [mp=title, abstract, subject headings, heading word, drug trade name, original title, device manufacturer, drug manufacturer]

27. 25 or 26

28. 3 or 6 or 9 or 12 or 15 or 18 or 21 or 24 or 27

29. exp CHOLELITHIASIS/

30. (cholelithiasis or gallstone* or gall* stone* or 'black pigment stone*').mp. [mp=title, abstract, subject headings, heading word, drug trade name, original title, device manufacturer, drug manufacturer]

31. 29 or 30

32. 28 and 31

33. (random* or blind* or placebo* or meta-analysis).mp. [mp=title, abstract, subject headings, heading word, drug trade name, original title, device manufacturer, drug manufacturer]

34. 32 and 33

Science Citation Index ExpandedDate will be given at the review status# 4 #3 AND #2 AND #1

# 3 TS=(random* or blind* or placebo* or meta-analysis)

# 2 TS=(cholelithiasis OR gallstone* OR gall* stone* OR black pigment stone*)

# 1 TS=(ultrasonograph* OR ultrasound* OR ecograph* OR ursodeoxycholic acid* OR ursodiol OR UDCA OR (non-steroid* anti-inflammatory AND (drug* OR agent*)) OR ibuprofen OR aspirin OR obesity OR bariatric surger* OR weight loss OR diet therap* OR caloric restriction OR low calorie diet* OR liquid diet* OR fat* OR protein* OR carbohydrate* OR fibre OR micronutrient* OR physical activit* OR exercise*)



 

What's new

  1. Top of page
  2. Background
  3. Objectives
  4. Methods
  5. Acknowledgements
  6. Appendices
  7. What's new
  8. Contributions of authors
  9. Declarations of interest
  10. Sources of support


DateEventDescription

11 March 2014New citation required and minor changesSplit and updated protocol (Stokes 2012).



 

Contributions of authors

  1. Top of page
  2. Background
  3. Objectives
  4. Methods
  5. Acknowledgements
  6. Appendices
  7. What's new
  8. Contributions of authors
  9. Declarations of interest
  10. Sources of support

C Stokes drafted the protocol. M Casper provided input to the protocol. F Lammert and LL Gluud provided guidance to the protocol. All review authors agreed to the published protocol version.

 

Declarations of interest

  1. Top of page
  2. Background
  3. Objectives
  4. Methods
  5. Acknowledgements
  6. Appendices
  7. What's new
  8. Contributions of authors
  9. Declarations of interest
  10. Sources of support

None known.

 

Sources of support

  1. Top of page
  2. Background
  3. Objectives
  4. Methods
  5. Acknowledgements
  6. Appendices
  7. What's new
  8. Contributions of authors
  9. Declarations of interest
  10. Sources of support
 

Internal sources

  • None known, Other.

 

External sources

  • None known, Other.

References

Additional references

  1. Top of page
  2. Abstract
  3. Background
  4. Objectives
  5. Methods
  6. Acknowledgements
  7. Appendices
  8. What's new
  9. Contributions of authors
  10. Declarations of interest
  11. Sources of support
  12. Additional references
  13. References to other published versions of this review
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References to other published versions of this review

  1. Top of page
  2. Abstract
  3. Background
  4. Objectives
  5. Methods
  6. Acknowledgements
  7. Appendices
  8. What's new
  9. Contributions of authors
  10. Declarations of interest
  11. Sources of support
  12. Additional references
  13. References to other published versions of this review
Stokes 2012
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