4Evidence Review and Recommendations

Publication Details

4.1. Signs, symptoms and risk factors for gallstone disease

4.1.1. Review Question 1

What signs, symptoms, and risk factors should prompt a clinician to suspect symptomatic gallstone disease in adults presenting to healthcare services?

4.1.2. Evidence Review

The aim of this question was to identify the specific signs, symptoms, and risk factors that can predict gallstone disease in adults who present at healthcare services. This question did not aim to identify signs, symptoms and risk factors for gallstone disease in the general population. This is because the majority of people with gallstone disease in the general population are asymptomatic, and the potential signs, symptoms and risk factors identified at a population level may be different to the signs, symptoms and risk factors that cause people to seek medical attention.

A systematic search was conducted (see appendix D.1), which identified 7802 references. After removing duplicates the references were screened by their titles and abstracts. This led to 74 references being obtained and reviewed against the inclusion and exclusion criteria as described in the review protocol (appendix C.1).

Primary research of any study design was eligible for inclusion if it satisfied the following criteria:

  • The included participants were adults presenting to healthcare services: studies were not eligible if they recruited a sample of the general population. This is because the use of evidence from populations in non-healthcare settings may misrepresent the type and severity of the signs, symptoms and risk factors that cause people to present at healthcare services.
  • Results were analysed using a multivariate method, such as multiple regression: Multivariate analyses enable independent risk factors for gallstone disease to be identified, as this type of analysis can account for the effects of other risk factors. For example, a bivariate analysis may reveal that there are 4 risk factors for gallstone disease (being over the age of 40, smoking, being obese, and having more than 1 pregnancy). From this analysis it is impossible to tell if a person presenting with all 4 risk factors has a different risk of gallstone disease to a person with just 2 of the risk factors. It is not known if the risk factors are dependent or independent of each other. Multivariate analysis can take the interrelationships between risk factors into consideration and identify independent risk factors for gallstone disease. If a multivariate analysis shows that all 4 risk factors are independently related to gallstone disease, then someone presenting with all 4 risk factors has a different risk status to someone presenting with fewer risk factors.

Overall, 73 studies were excluded as they did not meet the eligibility criteria. A list of excluded studies and reasons for their exclusion is provided in appendix F.

One study met the eligibility criteria and was included. Data were extracted into detailed evidence tables (see appendix G.1) and are summarised in Table 1 below.

Table 1. Summary of included studies for review question 1.

Table 1

Summary of included studies for review question 1.

The GRADE framework was modified for this review. As prospective studies were considered to be the highest quality evidence, these were rated initially as high quality while retrospective studies were downgraded to start as low quality. The evidence for the outcomes was then assessed in the normal GRADE framework by downgrading or upgrading on the basis of inconsistency, imprecision and indirectness. The modified GRADE profiles are in appendix I.1. After applying the modified GRADE framework the evidence was judged to be very low in quality. Full GRADE profiles are in appendix I.1

4.1.3. Health economic evidence

A literature search was conducted jointly for review questions 1 and 2 by applying standard health economic filters to the clinical search strategies (see Appendix D). For review questions 1 and 2, 914 references were retrieved, of which 16 were retained after title and abstract screening. No health economic studies were found for question 1. Health economic modelling was not prioritised for this review question.

4.1.4. Evidence Statements

Very low quality evidence from 1 retrospective cohort study did not identify any factors that could predict gallstone disease in those presenting with upper abdominal pain lasting less than one week.

4.1.5. Evidence to Recommendations

4.1.6. Recommendations

No recommendations were made in relation to this review question.

4.1.7. Research recommendations

No research recommendations were made in relation to this review question.

4.1.8. References

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4.2. Diagnosing gallstone disease

4.2.1. Review Question 2

What is the most accurate strategy for diagnosing gallstone disease in adults suspected of the condition?

4.2.2. Evidence Review

The aim of this question was to assess all available methods for diagnosing gallstone disease and establish which methods are the most accurate.

A systematic search was conducted (appendix D.2), which identified 6312 references. After removing duplicates and screening the references based on their titles and abstracts, 310 references were obtained. These were reviewed against the inclusion and exclusion criteria as detailed in the review protocols (appendix C.2).

Primary research utilising a randomised controlled trial, cohort, or cross sectional design was eligible for inclusion. Studies also had to have utilised a valid reference standard. Currently there is no accepted reference standard for confirming the presence or absence of gallstone disease, so studies were only included if they met the following criteria:

  • Surgery as the reference standard for evaluating the gallbladder: this is the best available method for diagnosing gallstones in the gallbladder and cholecystitis.
  • Endoscopic retrograde cholangiopancreatography (ERCP) as the reference standard for evaluating the biliary tract: this is the best available method for diagnosing common bile duct stones.

These procedures can accurately confirm the presence of gallstone disease by extracting the gallstone(s). Other tests such as endoscopic ultrasound, magnetic resonance cholangiopancreatographydo do not extract gallstones, so were considered unsuitable as reference standards.

It is much more difficult to confirm the absence of gallstone disease. Gallstones or common bile duct stones may be missed during endoscopic or surgical investigations. Patients can be followed up to establish if signs and symptoms persist, which can indicate that gallstone disease is present but was missed during previous investigations. However, this can be misleading, as the patient's signs and symptoms can be caused by other conditions, or new gallstone disease could have developed since the original investigations. As there is no alternative method for definitively confirming the absence of gallstone disease, surgery and ERCP were accepted as the best available reference standards, and their potential inaccuracies are acknowledged.

During the review, a date restriction was also imposed on all studies that utilised endoscopic, surgical, or radiological methodologies. This was because technological advances have made older studies of limited relevance to clinical practice today. An arbitrary publication of date of 1993 or later was used as it coincides with the approximate introduction of laparoscopic cholecystectomy into clinical practice in the UK. The only exceptions to this date restriction were studies that focused on predicting the presence of gallstone disease using clinical history taking, physical examination and simple blood tests, as these factors are not as dependent on technology, and studies conducted over 20 years ago are likely to still be relevant to clinical practice today.

Overall, 23 studies met the eligibility criteria and were included in the review. Evidence was extracted into detailed evidence tables (see appendix G.2). Diagnostic test accuracy data were provided by 20 studies, and where possible these data were pooled in relevant meta-analyses. Some of these studies compared to see whether diagnostic test accuracy differed depending on who interpreted the test results (for example, radiologist compared with ultrasonographer, or experienced radiologist compared with inexperienced radiologist). This produced different results for the same sets of patients. It would be inappropriate to use both results in the meta-analysis as this would be double counting. Instead the results reported by the interpreter most similar to those intended to use the test in clinical practice were included in the analysis. If both interpreters were intended to use the test, their test results were averaged and this was taken into the meta-analysis.

Data about predictive factors for gallstone disease were provided by 3 studies. It was not possible to pool the data from these studies, as each study investigated different predictive factors.

Data from the included studies were extracted into detailed evidence Table 2 and Table 3 below, and the GRADE framework for diagnostic evidence was used to quality assess the evidence. However, for this review, the GDG took a liberal approach to set the threshold for accuracy of 0.50 for both sensitivity and specificity on the basis that they wanted to identify the test(s) that were better than chance. Any test that did not meet this threshold was not considered clinically useful. Full GRADE profiles are presented in Appendix I.2.

Table 2. Summary of included studies reporting diagnostic test accuracy.

Table 2

Summary of included studies reporting diagnostic test accuracy.

Table 3. Studies reporting prognostic data.

Table 3

Studies reporting prognostic data.

4.2.3. Health economic evidence

A literature search was conducted jointly for review questions 1 and 2 by applying standard health economic filters to the clinical search strategies (see Appendix D). Searches for review questions 1 and 2 retrieved 914 studies, of which 16 were retained after title and abstract screening. For review question 2, 2 health economic studies were found (Howard et al. 2006; Kaltenthaler et al. 2004). An assessment of the quality of the economic evidence is given in Table 4. This review question was not prioritised for original health economic modelling.

Table 4. Economic Evidence – MRCP versus ERCP for detection of CBDS.

Table 4

Economic Evidence – MRCP versus ERCP for detection of CBDS.

Howard et al (2006) used a decision tree analysis to compare MRCP with ERCP for diagnosing post-cholecystectomy CBDS in patients with abdominal pain and/or abnormal liver function tests. Kaltenhaler et al. (2004) used a decision tree analysis to compare MRCP with diagnostic ERCP for patients with suspected CBDS. The GDG felt that, as it was based on UK data and covered a wider patient population, Kaltenhaler et al (2004) provided slightly higher quality evidence. However, both studies were felt to be of use. Both studies found that MRCP dominated ERCP, but this depended on the prior probability of CBDS. In probabilistic sensitivity analysis, Howard et al. (2006) was found to be 83% cost effective (at Australian $50,000/QALY threshold) and Kaltenhaler et al. (2004) was found to be 100% cost effective (at UK £20,000/QALY threshold). Indeed, Kaltenhaler et al. (2004) was found to be 97% cost saving.

MRCP appeared to be cost effective compared with ERCP for diagnosing CBDS under the majority of assumptions. The GDG considered that the results from the 2 studies reflected what they would expect to occur in standard clinical practice.

4.2.4. Evidence Statements

While most of the diagnostic tests had sensitivities and specificities above 50%, some had confidence intervals below 50% for either sensitivity or specificity. This means that there is uncertainty in the evidence as some of the tests may actually perform worse than chance alone. The quality of this evidence was mainly moderate to low in quality.

Two partially applicable health economic studies with minor limitations found that, under a variety of assumptions, MRCP appeared cost effective compared with ERCP for diagnosing CBDS.

4.2.5. Evidence to Recommendations

4.2.6. Recommendations

  1. Offer liver function tests and ultrasound to people with suspected gallstone disease, and to people with abdominal or gastrointestinal symptoms that have been unresponsive to previous management
  2. Consider magnetic resonance cholangiopancreatography (MRCP) if ultrasound has not detected common bile duct stones but the:
    • bile duct is dilated and/or
    • liver function test results are abnormal.
  3. Consider endoscopic ultrasound (EUS) if MRCP does not allow a diagnosis to be made.
  4. Refer people for further investigations if conditions other than gallstone disease are suspected.

4.2.7. Research recommendations

  1. What are the long-term benefits and harms, and cost effectiveness of endoscopic ultrasound (EUS) compared with magnetic resonance cholangiopancreatography (MRCP) in adults with suspected common bile duct stones?

Why this is important

MRCP and EUS have both been found to be sufficiently accurate for diagnosing common bile duct stones, with EUS regarded as the most accurate test. MRCP is non-invasive and so carries negligible risks to the patient. However, EUS carries a small but significant risk of patient harms, including death. There is insufficient evidence available to determine whether the benefits of improved diagnosis associated with EUS outweigh its procedural risks. Therefore, research is needed to compare MRCP with EUS to evaluate the subsequent management of common bile duct stones.

4.2.8. References

  1. Ahmed M, Diggory R. The correlation between ultrasonography and histology in the search for gallstones. Annals of the Royal College of Surgeons of England. 2011;93:81–3. [PMC free article: PMC3293280] [PubMed: 20955654]
  2. Alponat A, Kum CK, Rajnakova A, et al. Predictive factors for synchronous common bile duct stones in patients with cholelithiasis. Surgical Endoscopy. 1997;11:928–32. [PubMed: 9294275]
  3. Altun E, Semelka RC, Elias J Jr, et al. Acute cholecystitis: MR findings and differentiation from chronic cholecystitis. Radiology. 2007;244:174–83. [PubMed: 17581902]
  4. Barr LL, Frame BC, Coulanjon A. Proposed criteria for preoperative endoscopic retrograde cholangiography in candidates for laparoscopic cholecystectomy. Surgical Endoscopy. 1999;13:778–81. [PubMed: 10430683]
  5. Chan YL, Chan AC, Lam WW, et al. Choledocholithiasis: comparison of MR cholangiography and endoscopic retrograde cholangiography. Radiology. 1996;200:85–9. [PubMed: 8657949]
  6. De Vargas MM, Lanciotti S, De Cicco ML, et al. Ultrasonographic and spiral CT evaluation of simple and complicated acute cholecystitis: diagnostic protocol assessment based on personal experience and review of the literature. Radiologia Medica. 2006;111:167–80. [PubMed: 16671375]
  7. Griffin N, Wastle ML, Dunn WK, et al. Magnetic resonance cholangiopancreatography versus endoscopic retrograde cholangiopancreatography in the diagnosis of choledocholithiasis. European Journal of Gastroenterology & Hepatology. 2003;15:809–13. [PubMed: 12811312]
  8. Hakansson K, Leander P, Ekberg O, et al. MR imaging in clinically suspected acute cholecystitis. A comparison with ultrasonography. Acta Radiologica. 2000;41:322–8. [PubMed: 10937751]
  9. Holzknecht N, Gauger J, Sackmann M, et al. Breath-hold MR cholangiography with snapshot techniques: prospective comparison with endoscopic retrograde cholangiography. Radiology. 1998;206:657–64. [PubMed: 9494483]
  10. Howard K, Lord SJ, Speer A, et al. Value of magnetic resonance cholangiopancreatography in the diagnosis of biliary abnormalities in postcholecystectomy patients: A probabilistic cost-effectiveness analysis of diagnostic strategies. International Journal of Technology Assessment in Health Care. 2006;22:109–18. [PubMed: 16673687]
  11. Jovanovic P, Salkic NN, Zerem E, et al. Biochemical and ultrasound parameters may help predict the need for therapeutic endoscopic retrograde cholangiopancreatography (ERCP) in patients with a firm clinical and biochemical suspicion for choledocholithiasis. European Journal of Internal Medicine. 2011;22:e110–e114. [PubMed: 22075294]
  12. Kaltenthaler E, Vergel YB, Chilcott J, et al. A systematic review and economic evaluation of magnetic resonance cholangiopancreatography compared with diagnostic endoscopic retrograde cholangiopancreatography. Health Technology Assessment. 2004;8:iii–89. [PubMed: 14982656]
  13. Karki S. Role of ultrasound as compared with ERCP in patient with obstructive jaundice. Kathmandu University Medical Journal. 2013;43:237–40. [PubMed: 24442173]
  14. Kondo S, Isayama H, Akahane M, et al. Detection of common bile duct stones: comparison between endoscopic ultrasonography, magnetic resonance cholangiography, and helical-computed-tomographic cholangiography. European Journal of Radiology. 2005;54:271–5. [PubMed: 15837409]
  15. Park MS, Yu JS, Kim YH, et al. Acute cholecystitis: comparison of MR cholangiography and US. Radiology. 1998;209:781–5. [PubMed: 9844674]
  16. Polkowski M, Palucki J, Regula J, et al. Helical computed tomographic cholangiography versus endosonography for suspected bile duct stones: a prospective blinded study in non-jaundiced patients. Gut. 1999;45:744–9. [PMC free article: PMC1727710] [PubMed: 10517914]
  17. Regan F, Fradin J, Khazan R, et al. Choledocholithiasis: evaluation with MR cholangiography. AJR American. 1996:1441–5. [PubMed: 8956574]
  18. Rickes S, Treiber G, Monkemuller K, et al. Impact of the operator's experience on value of high-resolution transabdominal ultrasound in the diagnosis of choledocholithiasis: a prospective comparison using endoscopic retrograde cholangiography as the gold standard. Scandinavian Journal of Gastroenterology. 2006;41:838–43. [PubMed: 16785198]
  19. Shiozawa S, Tsuchiya A, Kim DH, et al. Useful predictive factors of common bile duct stones prior to laparoscopic cholecystectomy for gallstones. Hepato-Gastroenterology. 2005;52:1662–5. [PubMed: 16334752]
  20. Soto JA, Alvarez O, Munera F, et al. Diagnosing bile duct stones: comparison of unenhanced helical CT, oral contrast-enhanced CT cholangiography, and MR cholangiography. AJR American. 2000:1127–34. [PubMed: 11000177]
  21. Soto JA, Velez SM, Guzman J. Choledocholithiasis: diagnosis with oral-contrast-enhanced CT cholangiography. AJR American. 1999:943–8. [PubMed: 10587126]
  22. Stiris MG. MR cholangiopancreaticography and endoscopic retrograde acholangiopancreaticography in patients with suspected common bile duct stones. Acta Radiologica. 2000;41:269–72. [PubMed: 10866083]
  23. Sugiyama M, Atomi Y. Endoscopic ultrasonography for diagnosing choledocholithiasis: a prospective comparative study with ultrasonography and computed tomography. Gastrointestinal Endoscopy. 1997;45:143–6. [PubMed: 9040999]
  24. Sugiyama M, Atomi Y, Hachiya J. Magnetic resonance cholangiography using half-Fourier acquisition for diagnosing choledocholithiasis. American Journal of Gastroenterology. 1998;93:1886–90. [PubMed: 9772049]
  25. Tseng CW, Chen CC, Chen TS, et al. Can computed tomography with coronal reconstruction improve the diagnosis of choledocholithiasis? Journal of Gastroenterology & Hepatology. 2008;23:1586–9. [PubMed: 18713297]

4.3. Asymptomatic gallbladder stones

4.3.1. Review Question 3

What factors predict which patients with asymptomatic gallbladder stones will develop acute complications?

4.3.2. Evidence Review

The aim of this review question was to establish whether some people with asymptomatic gallbladder stones are at a higher risk of developing complications than others.

A systematic search (appendix D.3) retrieved 12,256 references. After removing duplicates and screening the references based on their titles and abstracts, 56 references were obtained and reviewed against the inclusion and exclusion criteria as described in the review protocol (appendix C.3).

Primary research using a randomised controlled trial, cohort or cross sectional design was eligible for inclusion. Two main types of study were expected to be found by the search: prospective studies recruiting a sample of the general population to identify and follow up people with asymptomatic gallbladder stones, and retrospective reviews of people presenting with symptomatic gallstone disease whose prior medical history was examined to identify whether asymptomatic gallbladder stones had previously been diagnosed. Both types of study were eligible for inclusion.

From the review, 55 studies were excluded, mainly because they provided prevalence and/or incidence data only. A list of the excluded studies and reasons for their exclusion is provided in appendix F.

One prospective cohort study met the eligibility criteria and was included. Data were extracted into detailed evidence tables (see appendix G.3) and are summarised in Table 5 below.

Table 5. Summary of included studies for question 3.

Table 5

Summary of included studies for question 3.

Appropriate methodology checklists were used to appraise the methodological quality of individual studies, and a modified version of the GRADE framework was applied to summarise the overall quality of the evidence (see appendix I.3). In this approach the prospective cohort study was started with a ‘high’ quality rating and was further downgraded as appropriate, according to standard GRADE framework. Overall this evidence was rated as very low in quality.

4.3.3. Health economic evidence

A literature search was conducted for review question 3 by applying standard health economic filters to the clinical search strategies (see Appendix D). From the search, 1004 references were retrieved, of which 9 were retained after title and abstract screening. No health economic studies were found for question 3. Health economic modelling was not prioritised for this review question.

4.3.4. Evidence Statements

Very low quality evidence from a single study examined predictors of symptomatic gallstone disease in patients who were asymptomatic at the time the trial was conducted. Insufficient data were reported in the study to validate the author's findings that the following variables are not significant predictors of the development of biliary colic, other complications, or death:

  • age
  • sex
  • body mass index
  • awareness of having gallstones before diagnosis
  • gallbladder opacification
  • number of stones
  • diameter of stones
  • radiopacity of stones.

Occurrence of biliary colic was not found to be a predictor of additional complications or death.

4.3.5. Evidence to Recommendations

Image

Table

Asymptomatic gallbladder stones: stones in the gallbladder that are found incidentally, as a result of imaging investigations unrelated to gallstone disease, in people who have been completely symptom-free for at least 12 months before diagnosis.

4.3.6. Recommendations & Research Recommendations

No specific recommendations were made in relation to this question.

4.3.7. References

  1. Attili AF, De SA, Capri R, et al. The natural history of gallstones: the GREPCO experience. The GREPCO Group. Hepatology. 1995;21:655–60. [PubMed: 7875663]

4.4. Managing asymptomatic gallbladder stones

4.4.1. Review Question 4a

Which strategies should be used for managing asymptomatic gallbladder stones?

4.4.2. Evidence Review

This question aimed to establish if prophylactic treatment should be offered to people with asymptomatic gallbladder stones, to prevent them from developing symptoms in the future.

A single search was performed for questions 4a, 4b, 4c and 5, which identified 10,976 references. After removing duplicates and screening the references based on their titles and abstracts, 210 references were obtained and reviewed against the inclusion and exclusion criteria for this review question (appendix C)., and 47 references met the overall inclusion criteria. Details of excluded studies and reasons for their exclusion are in appendix F.4.

None of the 47 included references met the criteria for this specific review question (see study flow chart, appendix E.4).

4.4.3. Health economic evidence

A literature search was conducted jointly for questions 4 and 5 by applying standard health economic filters to the clinical search strategies (see Appendix D). From the literature search, 1,396 references were retrieved for questions 4 and 5, of which none were retained for question 4a. Health economic modelling was not prioritised for this review question.

4.4.4. Evidence Statements

No evidence that met the inclusion and exclusion criteria for this question was found.

4.4.5. Evidence to Recommendations

Image

Table

Dissolution therapy is used to painlessly dissolve gallbladder stones using oral tablets. This is safe, relatively cheap and patients may express a preference for this type of treatment. However, patients have to take dissolution drugs over a long time (more...)

4.4.6. Recommendations

5.

Reassure people with asymptomatic gallbladder stones found in a normal gallbladder and normal biliary tree that they do not need treatment unless they develop symptoms.

4.4.7. Research Recommendations

No research recommendations were made in relation to this review question.

4.4.8. References

No references

4.5. Managing symptomatic gallbladder stones

4.5.1. Review Question 4b

Which strategies should be used for managing symptomatic gallbladder stones?

This question aimed to establish which management strategies offer optimal outcomes for patients with symptomatic gallbladder stones, including patients with acute cholecystitis.

4.5.2. Evidence Review

A single search was performed for review questions 4a, 4b, 4c and 5, which identified 10,976 references. After removing duplicates and screening the references based on their titles and abstracts, 210 references were obtained and reviewed against the inclusion and exclusion criteria for this review question (appendix C), and 47 references met the overall inclusion criteria. Details of excluded studies and reasons for their exclusion are in appendix F.4.

Of the 47 included references, 15 references relating to 9 randomised controlled trials met the inclusion criteria for this review question (see study flow chart in appendix E.4), which specifically focussed on comparisons of the following strategies for managing symptomatic gallbladder stones:

  • Laparoscopic cholecystectomy alone vs laparoscopic cholecystectomy with intraoperative cholangiography (3 studies)
  • Laparoscopic cholecystectomy vs cholecystostomy (no studies)
  • Laparoscopic cholecystectomy vs conservative management (1 study, 6 references)
  • Day-case laparoscopic cholecystectomy vs inpatient laparoscopic cholecystectomy for acute cholecystitis (5 studies)

Data from the 9 included randomised controlled trials were extracted into detailed evidence tables (see appendix G) and are summarised in Table 6 below. The included studies were critically appraised using randomised controlled trial methodology checklists. Data were then analysed using meta-analysis wherever appropriate (see appendix H.5 for all data analysis outputs).

Table 6. Summary of included studies for question 4b.

Table 6

Summary of included studies for question 4b.

Outcomes were assessed using the standard GRADE approach (see appendix I.5 for full GRADE profiles). In this approach, randomised controlled trials are started with a ‘high’ quality rating and are further downgraded as appropriate. Overall the evidence was moderate to low in quality.

4.5.3. Health economic evidence

A literature search was conducted jointly for questions 4 and 5 by applying standard health economic filters to the clinical search strategies (see Appendix D). From the search, 1,396 references were retrieved for questions 4 and 5, of which 1 was retained for question 4b and 1 was retained for question 5. As no existing health economic studies were found that addressed all the comparisons in questions 4 and 5, an original economic model was constructed.

4.5.3.1. Original health economic modelling – methods

A full description of the health economic model can be found in in Appendix J; a summary is presented here. The model was developed in line with the NICE reference case (National Institute for Health and Care Excellence 2013). A single health economic model structure was developed to address all prioritised comparisons under questions 4b, 4c and 5. For question 4b, no evidence was found to enable the modelling of the percutaneous cholecystostomy comparison.

A single Markov structure with 2-week cycles was used to assess all comparisons (see Figure 1). Not all states and transitions were used in each comparison (see Appendix J for descriptions of the states and transitions available for each comparison). A lifetime horizon was adopted to capture the long term impact of bile duct injuries and mortality differences. The model is a natural history rather than a diagnosis model, so the model “knows” whether a patient has CBDS, irrespective of whether the patient or clinician knows.

Figure 1. Gallstones Health Economic Model Diagram.

Figure 1

Gallstones Health Economic Model Diagram. Arrows indicate possible transitions (dotted arrows indicate transitions that are only possible where a procedure fails). States with stippled background represent procedures that can only be undertaken in the (more...)

Surgical interventions (laparoscopic cholecystectomy and ERCP, or both together) are represented as 2-week states, with short term surgical consequences (including mortality) modelled as cost and QALY impacts within one 2-week state. Laparoscopic cholecystectomy can cause bile duct injury.

Symptoms modelled are mutually exclusive and specific to gallbladder stones (biliary colic, acute cholecystitis) or CBDS (cholangitis, jaundice, pancreatitis [with associated mortality risk], sepsis).

Where possible, model parameters (symptoms at baseline or during treatment, operative consequences as prioritised by the GDG) are sourced from the included clinical studies, with data from standard laparoscopic cholecystectomy or ERCP trial arms combined to increase parameter accuracy.

Costs are based on 2011–12 NHS reference costs (Department of Health 2012). As the GDG identified length of stay as a critical outcome, resource use was based on length of stay differences reported in the included clinical studies.

There are few EQ-5D-based utility values for gallstones, so SF36 data were converted to utility values (Ara and Brazier 2008). The quality of life impact of interventional procedures reflects length of stay, but is assumed to return to normal within 2 weeks, unless a bile duct injury occurred (assumed to have lifelong impact). All symptoms are assumed to have the same utility impact. The utility impact of living with asymptomatic gallbladder stones were taken from a study of urinary stones (Penniston and Nakada 2007).

The health economic model has a number of limitations that should be considered. A number of key parameters are based on the included clinical evidence that has wide confidence intervals; zero event rates in 1 arm are common. A lack of gallstone-specific utility values required a number of assumptions to be made regarding the QALY outcomes. Interventions are costed using average costs – micro-costing of interventions may help identify differences between options, but may limit the generalisability of the model.

4.5.3.2. Original health economic modelling – results

The health economic model found that conservative management is more costly and produces fewer QALYs than laparoscopic cholecystectomy and is therefore said to be dominated (see Table 7). This remained true in 100% of probabilistic model runs. It appears that not removing the gallbladder increases the need for and exposure to further ERCPs and also gallbladder cancer.

Table 7. Cost effectiveness results for laparoscopic cholecystectomy versus conservative management.

Table 7

Cost effectiveness results for laparoscopic cholecystectomy versus conservative management.

The health economic model found that, on average, laparoscopic cholecystectomy with routine intraoperative cholangiography is more costly and produces fewer QALYs than laparoscopic cholecystectomy alone and is therefore said to be dominated (see Table 8). This result is driven by the increased costs of higher laparoscopic to open cholecystectomy conversion rates and uncertain rates of bile duct injury and bile leak in the intraoperative cholangiography arm - neither of the latter were statistically significant. In probabilistic sensitivity analysis, laparoscopic cholecystectomy alone has a 67% chance of being cost effective at a threshold of £20,000 per QALY compared with laparoscopic cholecystectomy with intraoperative cholangiography.

Table 8. Cost effectiveness results for laparoscopic cholecystectomy with intraoperative cholangiography versus laparoscopic cholangiography alone.

Table 8

Cost effectiveness results for laparoscopic cholecystectomy with intraoperative cholangiography versus laparoscopic cholangiography alone.

Inpatient laparoscopic cholecystectomy costs more and produces more QALYs than day-case laparoscopic cholecystectomy, at an acceptable cost of QALY of £3568/QALY (see Table 9). The increased costs are driven by the additional length of stay in the inpatient arm. The QALY gains result from a higher estimated bile duct injury rate in the day-case cohort; however, this rate should be interpreted with caution as it is based on 1 event in the day-case arm and 0 events in the inpatient arm. This uncertainty is reflected in probabilistic sensitivity analysis, in which inpatient laparoscopic cholecystectomy has a 56% chance of being cost effective at a threshold of £20,000 per QALY compared with day case laparoscopic cholecystectomy. Therefore, it may be more appropriate to view inpatient laparoscopic cholecystectomy as more expensive than day-case laparoscopic cholecystectomy with comparable QALY outcomes.

Table 9. Cost Effectiveness Results for Day Case versus Inpatient Laparoscopic Cholecystectomy.

Table 9

Cost Effectiveness Results for Day Case versus Inpatient Laparoscopic Cholecystectomy.

4.5.4. Evidence Statements

One study provided low quality evidence about conservative management in comparison with laparoscopic cholecystectomy, and there was some evidence that laparoscopic cholecystectomy was superior to conservative management. Readmission rates were lower in the laparoscopic cholecystectomy group than the conservative management group, and 44% of people in the conservative management group also required cholecystectomy

Three studies provided moderate to low quality evidence about laparoscopic cholecystectomy in comparison with laparoscopic cholecystectomy with intraoperative cholangiography and there was uncertainty about whether the addition of intraoperative cholangiography was beneficial or not since there were no significant differences between the groups on any of the outcomes.

No evidence was available comparing cholecystostomy to laparoscopic cholecystectomy, and so no conclusions can be drawn.

Five studies providing moderate to low quality evidence compared day-case laparoscopic cholecystectomy with planned inpatient laparoscopic cholecystectomy. No differences in readmission rate or quality of life were found. Unplanned inpatient admissions were required in 12.1% of planned day case procedures.

A directly applicable original health economic model analysis with minor limitations suggests laparoscopic cholecystectomy is cost effective compared with conservative management. Comparisons of laparoscopic cholecystectomy with laparoscopic cholecystectomy and intra-operative cholangiography and day-case with inpatient laparoscopic cholecystectomy were limited by the quality of the clinical evidence.

4.5.5. Evidence to Recommendations

4.5.6. Recommendations

6.

Offer laparoscopic cholecystectomy to people diagnosed with symptomatic gallbladder stones.

7.

Offer day-case laparoscopic cholecystectomy for people having it as an elective planned procedure, unless their circumstances or clinical condition make an inpatient stay more appropriate.

8.

Offer percutaneous cholecystostomy to manage gallbladder empyema when:

  • surgery is not appropriate at presentation and
  • conservative management is unsuccessful.
9.

Reconsider laparoscopic cholecystectomy for people who have had percutaneous cholecystostomy once they are well enough for surgery.

4.5.7. Research recommendations

2.

What are the benefits and harms, and cost effectiveness of routine intraoperative cholangiography in people with low to intermediate risk of common bile duct stones?

Why this is important

In the evidence reviewed for this guideline, there was a lack of randomised controlled trials of intraoperative cholangiography. Therefore, there is a need for large, high-quality trials to address clinical questions about the benefits and harms of intraoperative cholangiography.

4.5.8. References

  1. Amott D, Webb A, Tulloh B. Prospective comparison of routine and selective operative cholangiography. ANZ Journal of Surgery. 2005;75:378–82. [PubMed: 15943720]
  2. Ara R, Brazier J. Deriving an algorithm to convert the eight mean SF-36 dimension scores into a mean EQ-5D preference-based score from published studies (where patient level data are not available). Value in Health. 2008;11:1131–43. [PubMed: 18489495]
  3. Barthelsson C, Anderberg B, Ramel S, et al. Outpatient versus inpatient laparoscopic cholecystectomy: a prospective randomized study of symptom occurrence, symptom distress and general state of health during the first post-operative week. Journal of Evaluation in Clinical Practice. 2008;14:577–84. [PubMed: 18462280]
  4. Department of Health. National Schedule of Reference Costs 2011-2012. 2012.
  5. Hollington P. A prospective randomized trial of day-stay only versus overnight-stay laparoscopic cholecystectomy. The Australian and New Zealand Journal of Surgery. 1999;69:841–3. [PubMed: 10613279]
  6. Johansson M, Thune A, Nelvin L, et al. Randomized clinical trial of day-care versus overnight-stay laparoscopic cholecystectomy. British Journal of Surgery. 2006;93:40–5. [PubMed: 16329083]
  7. Keulemans Y, Eshuis J, de HH, et al. Laparoscopic cholecystectomy: day-care versus clinical observation. Annals of Surgery. 1998;228:734–40. [PMC free article: PMC1191590] [PubMed: 9860471]
  8. Khan OA, Balaji S, Branagan G, et al. Randomized clinical trial of routine on-table cholangiography during laparoscopic cholecystectomy. British Journal of Surgery. 2011;98:362–7. [PubMed: 21254008]
  9. National Institute for Health and Care Excellence. Guide to Methods of Technology Appraisal. 2013. [PubMed: 27905712]
  10. Penniston KL, Nakada SY. Health Related Quality of Life Differs Between Male and Female Stone Formers. The Journal of Urology. 2007;178:2435–40. [PubMed: 17937947]
  11. Schmidt M, Sondenaa K, Vetrhus M, et al. A randomized controlled study of uncomplicated gallstone disease with a 14-year follow-up showed that operation was the preferred treatment. Digestive Surgery. 2011;28:270–6. [PubMed: 21757915]
  12. Schmidt M, Sondenaa K, Vetrhus M, et al. Long-term follow-up of a randomized controlled trial of observation versus surgery for acute cholecystitis: non-operative management is an option in some patients. Scandinavian Journal of Gastroenterology. 2011;46:1257–62. [PubMed: 21736531]
  13. Soper NJ, Dunnegan DL. Routine versus selective intra-operative cholangiography during laparoscopic cholecystectomy. World Journal of Surgery. 1992;16:1133–40. [PubMed: 1455885]
  14. Vetrhus M, Soreide O, Eide GE, et al. Quality of life and pain in patients with acute cholecystitis. Results of a randomized clinical trial. Scandinavian Journal of Surgery: SJS. 2005;94:34–9. [PubMed: 15865114]
  15. Vetrhus M, Soreide O, Eide GE, et al. Pain and quality of life in patients with symptomatic, non-complicated gallbladder stones: results of a randomized controlled trial. Scandinavian Journal of Gastroenterology. 2004;39:270–6. [PubMed: 15074398]
  16. Vetrhus M, Soreide O, Nesvik I, et al. Acute cholecystitis: delayed surgery or observation. A randomized clinical trial. Scandinavian Journal of Gastroenterology. 2003;38:985–90. [PubMed: 14531537]
  17. Vetrhus M, Soreide O, Solhaug JH, et al. Symptomatic, non-complicated gallbladder stone disease. Operation or observation? A randomized clinical study. Scandinavian Journal of Gastroenterology. 2002;37:834–9. [PubMed: 12190099]

4.6. Managing common bile duct stones

4.6.1. Review Question 4c

Which strategies should be used for managing common bile duct stones?

4.6.2. Evidence Review

A single search was performed for questions 4a, 4b, 4c and 5 which identified 10,976 references. After removing duplicates and screening the references based on their titles and abstracts, 210 references were obtained and reviewed against the inclusion and exclusion criteria for this review question (appendix C), and 47 references met the inclusion criteria overall. Details of excluded studies and reasons for their exclusion are in appendix F.4.

Of the 47 included references, 24 references relating to 24 randomised controlled trials were included in this review question (see study flow chart, appendix E.4) which specifically addressed the following comparisons for managing common bile duct stones:

  • ERCP vs conservative management (9 studies)
  • ERCP and laparoscopic cholecystectomy vs ERCP alone (2 studies)
  • (pre-, intra-, post- operative) ERCP clearance of the bile duct plus laparoscopic cholecystectomy compared with surgical clearance of the bile duct plus laparoscopic cholecystectomy (12 studies)
  • Uncleared duct with biliary stent vs cleared duct (1 study)
  • Day-case ERCP vs planned inpatient ERCP (no studies)

Data were extracted into detailed evidence tables (see appendix G.4) and are summarised in Table 10 below. Each study was assessed for methodological quality using randomised controlled trial checklists, and some studies had methodological flaws which impacted on the overall quality of the evidence. For example, some studies didn't report randomisation procedures and those that did sometimes used inappropriate methods (patient identifying numbers - Hong, 2006), or had methods that led to differences in baseline characteristics of the groups (for example, Hui, 2002) which could bias results.

Table 10. Summary of included studies for question 4c.

Table 10

Summary of included studies for question 4c.

Data from multiple studies were available for most of the comparisons; therefore, meta-analysis was performed wherever possible (see appendix H.7). In addition, network meta-analysis was possible to compare the different methods for ERCP clearance of the duct (pre-, intra-, or post- operative) in comparison with surgical clearance. Standard GRADE approaches were used to assess pairwise comparisons, and a modified version of the GRADE framework was used to assess the evidence analysed using network meta analysis (see appendix I.6 for full GRADE profiles). In the modified approach, the standard GRADE criteria still apply but additional factors are also considered such as how each ‘link’ or pairwise comparison within the network applies to the others (see NICE clinical guideline CG173, appendix D for details of the additional factors that may be considered in a network meta analysis). However, since the network of evidence for this review question was relatively small, very few of the additional criteria actually applied. Details of the specific reasons for downgrading are stated in the footnotes of the relevant GRADE profiles in appendix I.6.

4.6.3. Health economic evidence

A literature search was conducted jointly for questions 4 and 5 by applying standard health economic filters to the clinical search strategies (see Appendix D). For questions 4 and 5, 1,396 references were retrieved, of which 1 was retained for question 4b and 1 was retained for question 5.

Gurusamy et al. (2012) (see Table 11) used a decision tree to compare intraoperative and preoperative ERCP for patients with gallbladder stones and CBDS. The study modelled the success or failure (and subsequent repeat ERCP) of CBDS extraction, complications of ERCP, consequent cholecystectomy (laparoscopic or open) and mortality from symptoms and open operations. Whilst this analysis was directly relevant to the UK NHS, the model did not compare all the interventions included in this guideline question (as postoperative ERCP and intraoperative bile duct exploration were not included).

Table 11. Health Economic Evidence – Intra-Operative Versus Pre-Operative ERCP for CBDS.

Table 11

Health Economic Evidence – Intra-Operative Versus Pre-Operative ERCP for CBDS.

4.6.3.1. Original health economic modelling – methods

As no existing health economic studies were found that addressed all the comparisons in questions 4 and 5, an original economic model was constructed. A full description of the health economic model can be found in in Appendix J; a summary is presented in section 4.5.3). For questions 4c (managing symptomatic CBDS), the GDG did not prioritise the biliary stents comparison and no evidence was found to enable the modelling of the day case versus inpatient ERCP comparison.

4.6.3.2. Original health economic modelling – results

The health economic model found that conservative management is more costly and produces fewer QALYs than ERCP and is therefore said to be dominated (see Table 12). This remained true in 100% of probabilistic model runs. The increased costs and decreased QALYs are driven by patients retaining their gallstones, having further symptomatic episodes and requiring additional ERCPs that would be undertaken non-electively in the conservative management arm.

Table 12. Cost effectiveness results for ERCP versus conservative management.

Table 12

Cost effectiveness results for ERCP versus conservative management.

ERCP and laparoscopic cholecystectomy is more costly and produces more QALYs than ERCP alone, at an acceptable cost per QALY of £4680 (see Table 13). The increased costs and QALYs are driven by all patients having a laparoscopic cholecystectomy that avoids patients living with asymptomatic gallstones or having further symptomatic episodes. In probabilistic sensitivity analysis, ERCP with laparoscopic cholecystectomy has a 98.5% chance of being cost effective at a threshold of £20,000 per QALY, compared with ERCP alone.

Table 13. Cost effectiveness results for ERCP with laparoscopic cholecystectomy versus ERCP alone.

Table 13

Cost effectiveness results for ERCP with laparoscopic cholecystectomy versus ERCP alone.

In an incremental analysis of the 4 options for managing CBDS with laparoscopic cholecystectomy, laparoscopic cholecystectomy with intraoperative ERCP was less costly and produced more QALYS than either laparoscopic cholecystectomy with bile duct exploration, laparoscopic cholecystectomy with preoperative ERCP or laparoscopic cholecystectomy with postoperative ERCP. Therefore, laparoscopic cholecystectomy with intraoperative ERCP is the dominant option (Table 14). In probabilistic sensitivity analysis, laparoscopic cholecystectomy with intraoperative ERCP is cost effective in 84.6% of simulations (see Table 15).

Table 14. Cost effectiveness results for laparoscopic cholecystectomy with bile duct exploration versus laparoscopic cholecystectomy with pre-, intra- or postoperative ERCP.

Table 14

Cost effectiveness results for laparoscopic cholecystectomy with bile duct exploration versus laparoscopic cholecystectomy with pre-, intra- or postoperative ERCP.

Table 15. Probabilistic Sensitivity Analysis Results.

Table 15

Probabilistic Sensitivity Analysis Results.

Pre- and postoperative ERCP options have increased costs as they require 2 hospital admissions. The differences between intraoperative ERCP and bile duct exploration are driven by higher rates of bile leaks and extra ERCPs required to clear the CBDS, both of which are worse for bile duct exploration. However, the QALY differences are small and both these parameters are based on non-statistically significant differences from 1 or 2 RCTs.

The model does not take account of any additional implementation costs or wider opportunity costs that occur to facilitate laparoscopic cholecystectomy with intraoperative ERCP or bile duct exploration.

4.6.4. Evidence Statements

Low to very low quality evidence provided by up to 8 randomised controlled trials showed that there were no significant differences between ERCP and conservative management. The only exception to this was a statistically significantly lower requirement for additional ERCP in the ERCP group than the conservative management group.

Moderate quality evidence was provided by 2 randomised controlled trials and showed that ERCP followed by laparoscopic cholecystectomy was preferable to ERCP alone.

Very low quality evidence provided by up to 11 randomised controlled trials comparing ERCP clearance of the bile duct plus laparoscopic cholecystectomy with surgical clearance of the bile duct plus laparoscopic cholecystectomy was inconclusive. Where network meta-analyses were conducted, all options had wide credibility intervals meaning there was uncertainty about which option was best. Furthermore, some outcomes had evidence that couldn't be meaningfully compared.

Low quality evidence was provided by a single study and showed there were no statistically significant differences between biliary stenting and clearing the bile duct. The only exception to this was a statistically significantly lower requirement for additional ERCP in the stent group than in the cleared duct group.

No evidence comparing day-case ERCP to planned inpatient ERCP was found

A directly applicable published cost–utility study with potentially serious limitations suggested that intraoperative ERCP is cost saving and generates more QALYs when compared with preoperative ERCP.

A directly applicable original health economic model analysis with minor limitations suggests ERCP is cost effective compared with conservative management and ERCP with laparoscopic cholecystectomy is cost effective compared with ERCP alone. Based on limited and inconclusive clinical evidence, laparoscopic cholecystectomy with intra-operative ERCP dominates other options but without taking account of any additional implementation costs.

4.6.5. Evidence to Recommendations

4.6.6. Recommendations

10.

Offer bile duct clearance and laparoscopic cholecystectomy to people with symptomatic or asymptomatic common bile duct stones.

11.

Clear the bile duct:

  • surgically at the time of laparoscopic cholecystectomy or
  • with endoscopic retrograde cholangiopancreatography (ERCP) before or at the time of laparoscopic cholecystectomy.
12.

If the bile duct cannot be cleared with ERCP, use biliary stenting to achieve biliary drainage only as a temporary measure until definitive endoscopic or surgical clearance.

13.

Use the lowest-cost option suitable for the clinical situation when choosing between day-case and inpatient procedures for elective ERCP.

4.6.7. Research recommendations

3.

What models of service delivery enable intraoperative endoscopic retrograde cholangiopancreatography (ERCP) for bile duct clearance to be delivered within the NHS? What are the costs and benefits of different models of service delivery?

Why this is important

Evidence reviewed for this guideline identified that intraoperative ERCP is both clinically and cost effective, but it is unclear whether delivery of this intervention is feasible in the NHS because of the way current services are organised. It is also unclear whether intraoperative ERCP will remain cost effective if services are reorganised.

4.6.8. References

  1. Acosta JM, Katkhouda N, Debian KA, et al. Early ductal decompression versus conservative management for gallstone pancreatitis with ampullary obstruction: a prospective randomized clinical trial. Annals of Surgery. 2006;243:33–40. [PMC free article: PMC1449963] [PubMed: 16371734]
  2. Bansal VK, Misra MC, Garg P, et al. A prospective randomized trial comparing two-stage versus single-stage management of patients with gallstone disease and common bile duct stones. Surgical Endoscopy. 2010;24:1986–9. [PubMed: 20135172]
  3. Boerma D, Rauws EA, Keulemans YC, et al. Wait-and-see policy or laparoscopic cholecystectomy after endoscopic sphincterotomy for bile-duct stones: a randomised trial. Lancet. 2002;360:761–5. [PubMed: 12241833]
  4. Chopra KB, Peters RA, O'Toole PA, et al. Randomised study of endoscopic biliary endoprosthesis versus duct clearance for bileduct stones in high-risk patients. Lancet. 1996;348:791–3. [PubMed: 8813987]
  5. Cuschieri A, Lezoche E, Morino M, et al. E.A.E.S. multicenter prospective randomized trial comparing two-stage vs single-stage management of patients with gallstone disease and ductal calculi. Surgical Endoscopy. 1999;13:952–7. [PubMed: 10526025]
  6. Ding YB, Deng B, Liu XN, et al. Synchronous vs sequential laparoscopic cholecystectomy for cholecystocholedocholithiasis. World journal of gastroenterology : WJG. 2013;19:2080–6. [PMC free article: PMC3623986] [PubMed: 23599628]
  7. ElGeidie AA. Laparoscopic exploration versus intraoperative endoscopic sphincterotomy for common bile duct stones: A prospective randomized trial. Digestive Surgery. 2011;28:424–31. [PubMed: 22236538]
  8. ElGeidie AA. Preoperative versus intraoperative endoscopic sphincterotomy for management of common bile duct stones. Surgical Endoscopy. 2011;25:1230–7. [PubMed: 20844893]
  9. Fan ST, Lai EC, Mok FP, et al. Early treatment of acute biliary pancreatitis by endoscopic papillotomy. New England Journal of Medicine. 1993;328:228–32. [PubMed: 8418402]
  10. Folsch UR, Nitsche R, Ludtke R, et al. Early ERCP and papillotomy compared with conservative treatment for acute biliary pancreatitis. The German Study Group on Acute Biliary Pancreatitis. New England Journal of Medicine. 1997;336:237–42. [PubMed: 8995085]
  11. Gurusamy K, Wilson E, Burroughs AK, et al. Intra-operative vs pre-operative endoscopic sphincterotomy in patients with gallbladder and common bile duct stones: cost-utility and value-of-information analysis. Applied Health Economics & Health Policy. 2012;10:15–29. [PubMed: 22077427]
  12. Hong DF, Xin Y, Chen DW. Comparison of laparoscopic cholecystectomy combined with intraoperative endoscopic sphincterotomy and laparoscopic exploration of the common bile duct for cholecystocholedocholithiasis. Surgical Endoscopy. 2006;20:424–7. [PubMed: 16395539]
  13. Hui CK, Lai KC, Wong WM, et al. A randomised controlled trial of endoscopic sphincterotomy in acute cholangitis without common bile duct stones. Gut. 2002;51:245–7. [PMC free article: PMC1773318] [PubMed: 12117888]
  14. Koc B, Karahan S, Adas G, et al. Comparison of laparoscopic common bile duct exploration and endoscopic retrograde cholangiopancreatography plus laparoscopic cholecystectomy for choledocholithiasis: a prospective randomized study. American Journal of Surgery. 2013;206:457–63. [PubMed: 23871320]
  15. Lau JY, Leow CK, Fung TM, et al. Cholecystectomy or gallbladder in situ after endoscopic sphincterotomy and bile duct stone removal in Chinese patients. Gastroenterology. 2006;130:96–103. [PMC free article: PMC7094506] [PubMed: 16401473]
  16. Nathanson LK, O'Rourke NA, Martin IJ, et al. Postoperative ERCP versus laparoscopic choledochotomy for clearance of selected bile duct calculi: a randomized trial. Annals of Surgery. 2005;242:188–92. [PMC free article: PMC1357723] [PubMed: 16041208]
  17. Neoptolemos JP, Carr-Locke DL, London NJ, et al. Controlled trial of urgent endoscopic retrograde cholangiopancreatography and endoscopic sphincterotomy versus conservative treatment for acute pancreatitis due to gallstones. Lancet. 1988;2:979–83. [PubMed: 2902491]
  18. Nitsche R, Folsch UR, Ludtke R, et al. Urgent ERCP in all cases of acute biliary pancreatitis? A prospective randomized multicenter study. European Journal of Medical Research. 1995;1:127–31. [PubMed: 9389673]
  19. Noble H, Tranter S, Chesworth T, et al. A randomized, clinical trial to compare endoscopic sphincterotomy and subsequent laparoscopic cholecystectomy with primary laparoscopic bile duct exploration during cholecystectomy in higher risk patients with choledocholithiasis. Journal of Laparoendoscopic & Advanced Surgical Techniques Part. 2009:713–20. [PubMed: 19792866]
  20. Oria A, Cimmino D, Ocampo C, et al. Early endoscopic intervention versus early conservative management in patients with acute gallstone pancreatitis and biliopancreatic obstruction: a randomized clinical trial. Annals of Surgery. 2007;245:10–7. [PMC free article: PMC1867927] [PubMed: 17197959]
  21. Rhodes M, Sussman L, Cohen L, et al. Randomised trial of laparoscopic exploration of common bile duct versus postoperative endoscopic retrograde cholangiography for common bile duct stones. Lancet. 1998;351:159–61. [PubMed: 9449869]
  22. Rogers SJ, Cello JP, Horn JK, et al. Prospective randomized trial of LC+LCBDE vs ERCP/S+LC for common bile duct stone disease. Archives of Surgery. 2010;145:28–33. [PubMed: 20083751]
  23. Sgourakis G, Karaliotas K. Laparoscopic common bile duct exploration and cholecystectomy versus endoscopic stone extraction and laparoscopic cholecystectomy for choledocholithiasis. A prospective randomized study. Minerva Chirurgica. 2002;57:467–74. [PubMed: 12145577]
  24. Vracko J, Markovic S, Wiechel KL. Conservative treatment versus endoscopic sphincterotomy in the initial management of acute cholecystitis in elderly patients at high surgical risk. Endoscopy. 2006;38:773–8. [PubMed: 17001566]
  25. Zhou LK, Prasoon P. Mechanical and preventable factors of bile duct injuries during laparoscopic cholecystectomy. Hepato-Gastroenterology. 2012;59:51–3. [Review] [PubMed: 22251523]

4.7. Timing of laparoscopic cholecystectomy

4.7.1. Review Question 5

In adults with acute cholecystitis or symptomatic common bile duct stones, should cholecystectomy be performed during the acute episode (early) or should intervention be delayed until the acute episode has subsided (delayed)?

4.7.2. Evidence Review

A single search was performed for questions 4a, 4b, 4c and 5 which identified 10,976 references. After removing duplicates and screening the references based on their titles and abstracts, 210 references were obtained and reviewed against the inclusion and exclusion criteria for this review question (appendix C), and 47 references met the inclusion criteria overall. Details of excluded studies and reasons for their exclusion are in appendix F.4

Of the 47 included references, 8 references relating to 8 randomised controlled trials were included in this review question (see study flow chart) which specifically addressed the timing of intervention for gallstone disease, and for the purposes of this review the following definitions were used:

  • early laparoscopic cholecystectomy: performed within the first 7 days of the acute presentation
  • delayed laparoscopic cholecystectomy: performed more than 4 weeks after presentation.

Studies that didn't use these definitions were not eligible for inclusion.

Of the 8 included studies, 7 related to acute cholecystitis (Gul, 2013; Johansson, 2003; Kolla, 2004; Lai, 1998; Lo, 1998; Macafee, 2009; Yadav, 2009) and one related to common bile duct stones (Reinders, 2010). All studies were assessed for methodological quality using randomised controlled trial checklists, and meta-analysis was performed wherever possible (see appendix H.7).

Standard GRADE processes were applied to assess the quality of the evidence in relation to the following outcomes:

  • Readmission due to symptoms
  • Readmission due to surgical complications
  • Length of stay
  • Mortality
  • Quality of life

Full GRADE profiles are available in appendix (I.7).

Overall, the individual studies had good methodological quality, with adequate randomisation and appropriate study conduct. Evidence was available in relation to readmission and length of stay, but outcomes such as mortality and quality of life were not reported by any of the studies. There was a lack of evidence in relation to common bile duct stones.

Table 16. Summary of included studies for question 5.

Table 16

Summary of included studies for question 5.

4.7.3. Health economic evidence

A literature search was conducted jointly for questions 4 and 5,by applying standard health economic filters to the clinical search strategies (see Appendix D). 1,396 references were retrieved for questions 4 and 5, of which 1 was retained for question 4b and 1 was retained for question 5.

Wilson et al. (2010) (see Table 17) used a decision tree to compare early and delayed laparoscopic cholecystectomy for acute cholecystitis. The model estimated the development of 4 symptoms at 9 weeks during an 18-week delay period, with a time horizon of 1 year.

Table 17. Health Economic Evidence – Early versus Delayed Laparoscopic Cholecystectomy For Acute Cholecystitis.

Table 17

Health Economic Evidence – Early versus Delayed Laparoscopic Cholecystectomy For Acute Cholecystitis.

Whilst Wilson et al. (2010) was directly relevant, it had a number of limitations, including the delay length, time horizon, no consideration of CBDS and utility data.

4.7.3.1. Original health economic modelling – methods

Because Wilson et al.'s (2010) analysis had potentially serious limitations, and did not address all relevant questions in this area, an original economic model was constructed. A full description of the health economic model can be found in in Appendix J, a summary is presented in section 4.5.3.

4.7.3.2. Original health economic modelling – results

The health economic model found that delayed laparoscopic cholecystectomy is more costly and produces more QALYs than early laparoscopic cholecystectomy, but an ICER of over £200,000 per QALY is above that which is usually accepted as being cost effective (see Table 18). In probabilistic sensitivity analysis, early laparoscopic cholecystectomy has an 88% chance of being cost effective at a threshold of £20,000 per QALY compared with delayed laparoscopic cholecystectomy. The increased costs are driven by the additional length of stay and the small QALY gains are sensitive to estimated rates of bile duct injury.

Table 18. Cost effectiveness results for early laparoscopic cholecystectomy versus delayed laparoscopic cholecystectomy.

Table 18

Cost effectiveness results for early laparoscopic cholecystectomy versus delayed laparoscopic cholecystectomy.

Delayed laparoscopic cholecystectomy after ERCP is more costly and produces fewer QALYs than early laparoscopic cholecystectomy after ERCP and is therefore said to be dominated (see Table 19). In probabilistic sensitivity analysis, early laparoscopic cholecystectomy post ERCP has a 100% chance of being cost effective at a threshold of £20,000 per QALY compared with delayed laparoscopic cholecystectomy after ERCP. The increased costs are driven by the additional length of stay and the QALY differences are small.

Table 19. Cost effectiveness results for early laparoscopic cholecystectomy after ERCP versus delayed laparoscopic cholecystectomy after ERCP.

Table 19

Cost effectiveness results for early laparoscopic cholecystectomy after ERCP versus delayed laparoscopic cholecystectomy after ERCP.

4.7.4. Evidence Statements

Acute cholecystitis

Moderate to low quality evidence was provided by 6 randomised controlled trials comparing early versus delayed laparoscopic cholecystectomy for acute cholecystitis, and demonstrated that readmission rates and length of stay were lower in the early compared with the delayed group and quality of life was higher.

A published cost–utility analysis and an original health economic model both suggest that early laparoscopic cholecystectomy for acute cholecystitis is cost effective compared with delayed laparoscopic cholecystectomy.

Common bile duct stones

One randomised controlled trial provided low quality evidence comparing early versus delayed laparoscopic cholecystectomy following ERCP for common bile duct stones. Evidence was provided for only 1 of the 5 outcomes for this comparison. This is because the study either didn't report the data, or because data were reported but zero events occurred. The 1 outcome for which moderate quality evidence was available showed that there was no statistically significant difference in length of stay between the 2 groups.

A directly applicable original health economic model analysis with minor limitations suggests that early laparoscopic cholecystectomy following ERCP for common bile duct stones is cost effective compared with delayed laparoscopic cholecystectomy.

4.7.5. Evidence to Recommendations

4.7.6. Recommendations

14.

Offer early laparoscopic cholecystectomy (to be carried out within 1 week of diagnosis) to people with acute cholecystitis.

4.7.7. Research recommendations

4.

In adults with common bile duct stones, should laparoscopic cholecystectomy be performed early (within 2 weeks of bile duct clearance), or should it be delayed (until 6 weeks after bile duct clearance)?

Why this is important

In the evidence reviewed for this guideline, there was a lack of randomised controlled trials of intraoperative cholangiography, and the evidence that was available did not support the knowledge and experience of the Guideline Development Group. Therefore, there is a need for large, high-quality trials to address clinical questions about the benefits and harms of intraoperative cholangiography

4.7.8. References

  1. Gul R. Comparison of early and delayed laparoscopic cholecystectomy for acute cholecystitis: experience from a single centre. North American Journal of Medical Sciences. 2013;5:414–8. [PMC free article: PMC3759068] [PubMed: 24020050]
  2. Johansson M, Thune A, Blomqvist A, et al. Management of acute cholecystitis in the laparoscopic era: results of a prospective, randomized clinical trial. Journal of Gastrointestinal Surgery. 2003;7:642–5. [PubMed: 12850677]
  3. Kolla SB, Aggarwal S, Kumar A, et al. Early versus delayed laparoscopic cholecystectomy for acute cholecystitis: a prospective randomized trial. Surgical Endoscopy. 2004;18:1323–7. [PubMed: 15803229]
  4. Lai PB, Kwong KH, Leung KL, et al. Randomized trial of early versus delayed laparoscopic cholecystectomy for acute cholecystitis. British Journal of Surgery. 1998;85:764–7. [PubMed: 9667702]
  5. Lo CM. Prospective randomized study of early versus delayed laparoscopic cholecystectomy for acute cholecystitis. Annals of Surgery. 1998;227:461–7. [PMC free article: PMC1191296] [PubMed: 9563529]
  6. Macafee DA, Humes DJ, Bouliotis G, et al. Prospective randomized trial using cost-utility analysis of early versus delayed laparoscopic cholecystectomy for acute gallbladder disease. British Journal of Surgery. 2009;96:1031–40. [PubMed: 19672930]
  7. Reinders JSK, Goud A, Timmer R, et al. Early Laparoscopic Cholecystectomy Improves Outcomes After Endoscopic Sphincterotomy for Choledochocystolithiasis. Gastroenterology. 2010;138:2315–20. [PubMed: 20206179]
  8. Wilson E, Gurusamy K, Gluud C, et al. Cost-utility and value-of-information analysis of early versus delayed laparoscopic cholecystectomy for acute cholecystitis. British Journal of Surgery. 2010;97:210–9. [PubMed: 20035545]
  9. Yadav RP, Adhikary S, Agrawal CS, et al. A comparative study of early vs. delayed laparoscopic cholecystectomy in acute cholecystitis. Kathmandu University Medical Journal. 2009;7:16–20. [PubMed: 19483447]

4.8. Information for patients and their carers

4.8.1. Review Question 6

What are the information and education needs of patients and carers of people with gallstone disease?

4.8.2. Evidence Review

The aim of this review question was to identify areas for which information and education should be provided. This question did not aim to compare the effectiveness of different education programmes/strategies.

A systematic search was conducted (see appendix D) which identified 7,862 references. After removing duplicates the references were screened on their titles and abstracts and 61 references were obtained and reviewed against the inclusion and exclusion criteria as described in the review protocols (appendix C).

Overall, 56 studies were excluded as they did not meet the eligibility criteria. A list of excluded studies and reasons for their exclusion is provided in appendix F.

Five studies met the eligibility criteria and were included. Data were extracted into detailed evidence tables (see appendix G) and are summarised in the table below.

Table 20. Summary of included studies for question 6.

Table 20

Summary of included studies for question 6.

Studies were quality assessed using methodology checklists. For qualitative studies, the NICE qualitative checklist was used. The NICE guidelines manual does not provide a checklist for surveys, and so a checklist originally published in the British Medical Journal (see appendix K) was used to aid the quality assessment of these studies.

The GRADE framework for assessing quality was modified for this review in that studies, rather than outcomes, were assessed for quality (see appendix I.8) on the following basis. Overall, the studies were of very low quality and had serious limitations; Survey studies lacked detailed analysis and qualitative studies lacked rigour as they did not utilise adequate research design and methodology, and they failed to provide rich data to support findings; studies were limited because 4 of the 5 studies were conducted outside the UK and so lack transferability, and most studies were from the perspective of elective cholecystectomy, meaning that non elective surgery and other treatment options are not adequately represented in the evidence base. Specific details about the reasons for this approach and the judgements made are provided in the footnotes of the profiles in appendix I.8.

4.8.3. Health economic evidence

A literature search was conducted for review question 6, by applying standard health economic filters to the clinical search strategies (see Appendix D). From the search, 504 references were retrieved, of which none were retained at title and abstract screening. Health economic modelling was not prioritised for this review question.

4.8.4. Evidence Statements

Very low quality evidence from 5 studies on people waiting for or undergoing surgery for gallbladder disease showed that patients requested more information on diet, wound management, pain management, and resuming normal activities. Some patients had no memory of the information that was provided to them, and some consulted the internet to acquire additional information. Some people did not know why they had to wait for elective surgery.

4.8.5. Evidence to Recommendations

4.8.6. Recommendations

15.

Advise people to avoid food and drink that triggers their symptoms until they have their gallbladder or gallstones removed.

16.

Advise people that they should not need to avoid food and drink that triggered their symptoms after they have their gallbladder or gallstones removed.

17.

Advise people to seek further advice from their GP if eating or drinking triggers existing symptoms or causes new symptoms to develop after they have recovered from having their gallbladder or gallstones removed.

4.8.7. Research recommendations

5.

What is the long-term effect of laparoscopic cholecystectomy on outcomes that are important to patients?

Why this is important

There is a lack of information on the long-term impact of cholecystectomy on patient outcomes. Many patients report a continuation of symptoms or the onset of new symptoms after laparoscopic cholecystectomy, and these affect quality of life. Research is needed to establish the long-term patient benefits and harms, so that appropriate information can be provided to patients to aid decision-making and long-term management of their condition.

4.8.8. References

  1. Barthelsson C, Lutzen K, Anderberg B, et al. Patients' experiences of laparoscopic cholecystectomy in day surgery. Journal of Clinical Nursing. 2003;12:253–9. [PubMed: 12603558]
  2. Blay N, Donoghue J. The effect of pre-admission education on domiciliary recovery following laparoscopic cholecystectomy. Australian Journal of Advanced Nursing. 2005;22:14–9. [PubMed: 16496831]
  3. Blay N, Donoghue J. Source and content of health information for patients undergoing laparoscopic cholecystectomy. International Journal of Nursing Practice. 2006;12:64–70. [PubMed: 16529592]
  4. Tamhankar AP, Mazari FA, Everitt NJ, et al. Use of the internet by patients undergoing elective hernia repair or cholecystectomy. Annals of the Royal College of Surgeons of England. 2009;91:460–3. [PMC free article: PMC2966195] [PubMed: 19558769]
  5. Young J, O'Connell B. Recovery following laparoscopic cholecystectomy in either a 23 hour or an 8 hour facility. Journal of Quality in Clinical Practice. 2008;21:2–7. [PubMed: 11422706]