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Biliary and pancreatic disease

Incremental net benefit of cholecystectomy

compared with alternative treatments in
people with gallstones or cholecystitis: a
systematic review and meta-­analysis of
cost–utility studies
Bhavani Shankara Bagepally  ‍ ‍,1 S Sajith Kumar  ‍ ‍,2 Meenakumari Natarajan,2
Akhil Sasidharan2

To cite: Bagepally BS, Sajith ABSTRACT disorders and cause significant epidemio-

Kumar S, Natarajan M, et al. Introduction  Cholecystectomy is a standard treatment logical and economic burdens worldwide.
Incremental net benefit of in the management of symptomatic gallstone disease.
cholecystectomy compared with
Approximately 20% of people with gallstones
Current literature has contradicting views on the cost-­ experience symptoms requiring medical
alternative treatments in people
effectiveness of different cholecystectomy treatments. attention or surgery, while the remaining
with gallstones or cholecystitis:
We have conducted a systematic reappraisal of literature
a systematic review and 80% remain asymptomatic for many years.1
meta-­analysis of cost–utility concerning the cost-­effectiveness of cholecystectomy in
Treatment options for cholecystitis include
studies. BMJ Open Gastro management of gallstone disease.
2022;9:e000779. doi:10.1136/ Methods  We systematically searched for economic surgical (cholecystectomy-­ open and laparo-
bmjgast-2021-000779 evaluation studies from PubMed, Embase and Scopus for scopic) or conservative management. The

copyright.
eligible studies from inception up to July 2020. We pooled treatment of gallstone disease is expensive
► Additional supplemental and often engenders substantial economic
the incremental net benefit (INB) with a 95% CI using a
material is published online
only. To view, please visit the
random-­effects model. We assessed the heterogeneity and social burdens if symptoms or compli-
journal online (http://d​ x.​doi.​ using the Cochrane-­Q test, I2 statistic. We have used the cations occur. The healthcare system in
org/​10.​1136/b​ mjgast-​2021-​ modified economic evaluation bias (ECOBIAS) checklist for the USA alone reported treatment costs as
000779). quality assessment of the selected studies. We assessed US$6.5 billion per year.2
the possibility of publication bias using a funnel plot and The optimal timing and the treatment
Egger’s test.
Received 31 August 2021 choice for cholecystectomy in patients with
Results  We have selected 28 studies for systematic
Accepted 17 December 2021 acute cholecystitis have always been conten-
review from a search that retrieved 8710 studies. Among
them, seven studies were eligible for meta-­analysis, tious.3 In earlier days, several weeks of
all from high-­income countries (HIC). Studies mainly hospital stay and an initial intense medical
reported comparisons between surgical treatments, but management were the norm before an open
non-­surgical gallstone disease management studies were cholecystectomy (OC).4 Introducing early
limited. The early laparoscopic cholecystectomy (ELC) cholecystectomy (open or laparoscopic)
was significantly more cost-­effective compared with reduced the overall treatment duration
the delayed laparoscopic cholecystectomy (DLC) with considerably.3 Performing early surgery for
an INB of US$1221 (US$187 to US$2255) but with high cholecystitis has the advantage of reducing
© Author(s) (or their heterogeneity (I2=73.32%). The subgroup and sensitivity hospital stay and circumvents the risk of
employer(s)) 2022. Re-­use analysis also supported that ELC is the most cost-­effective
permitted under CC BY-­NC. No emergency surgery in the wake of a non-­
option for managing gallstone disease or cholecystitis.
commercial re-­use. See rights resolved or recurrent issue.4
Conclusion  ELC is more cost-­effective than DLC in the
and permissions. Published Delayed laparoscopic cholecystectomy
by BMJ. treatment of gallstone disease or cholecystitis in HICs.
There was insufficient literature on comparison with other (DLC) and OC require multiple hospital visits
1
Non Communicable diseases, considering conservative treatment, surgery
ICMR-­National Institute of
treatment options, such as conservative management and
Epidemiology, Chennai, India limited evidence from other economies. and recovery period. Hence, it was associated
2
Health Technology Assessment PROSPERO registration number  CRD42020194052. with a higher rate of morbidity, hospital stays,
Resource Centre, ICMR-­National pain and time to return to work.5 Early lapa-
Institute of Epidemiology, roscopic cholecystectomy (ELC) was asso-
Chennai, India ciated with a lower risk of wound infection,
Correspondence to INTRODUCTION shorter hospital stay, better cost-­effectiveness,
Dr Bhavani Shankara Bagepally; Gallstones constitute one of the most and higher patient satisfaction and quality of
b​ shankara@​gmail.c​ om common and expensive gastrointestinal life.4 Studies have confirmed that ELC also

Bagepally BS, et al. BMJ Open Gastro 2022;9:e000779. doi:10.1136/bmjgast-2021-000779 1

 BMJ Open Gastroenterol: first published as 10.1136/bmjgast-2021-000779 on 21 January 2022. Downloaded from http://bmjopengastro.bmj.com/ on February 4, 2022 by guest. Protected by
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reduces treatment costs significantly.6–8 However, uncer- 8710, including 2977 from PubMed, 3696 from Scopus and
tainty still prevailed around the ELC as the standard of 2037 from Embase. After removing the duplicates (n=1414),
care, conceivably due to fear of complication. The unpre- 7296 studies were selected for an initial title and abstract
dictability in health outcomes and costs makes compar- screening.
ison of the overall cost-­effectiveness of ELC over DLC Titles and abstracts of the studies listed from the electronic
debatable as well as imperative.7 database search were screened independently by the authors
Most of the reported studies on gallstone disease (BSB, MN and AS) for potential inclusion using the Rayyan
management were clinical or partial economic evalua- software.16 After screening, the authors (BSB, MN and AS)
tions. These studies covered the costs of treatments but independently reviewed the full-­text articles (n=660). The
failed to capture the combined measure of the cost and final list of studies that met the inclusion and exclusion
effectiveness of both interventions and comparators criteria was prepared by the authors’ mutual consensus (BS,
in terms of the monetary cost and a generic measure MN and AS).
of health gain.9 Concurrently, even the reported cost-­ All full economic evaluation studies with a study population
effectiveness studies depict conflicting results, as some of cholelithiasis or cholecystitis that compared the costs and
studies have reported ELC as cost-­effective (CE).7 10 11 consequences of intervention with a comparator in terms of
In contrast, some others12 13 concluded it was only cost QALYs, ICERs or INBs were included in the study. Studies
saving and not CE. The lack of existing evidence and other than cost–utility analysis (CUA), reviews, letters, edito-
its discord on the cost-­effectiveness of cholecystectomy rials, abstracts, books, reports, grey literature and method-
compared with other treatment options was evident; ological articles were excluded from the study. We identified
hence, a systematic reappraisal of the literature is crit- 28 studies for systematic review based on these inclusion–
ical. Therefore, we systemically reviewed the economic exclusion criteria, and the data were extracted from these
evaluation studies of cholecystitis and cholelithiasis papers using a data extraction form. The PRISMA flow chart
management. Also, we synthesised the evidence on the of the screening process is appended as figure 1.
cost-­effectiveness of the various treatment options. This The data extraction form captured general study charac-
systematic review and meta-­analysis summarise the cost-­ teristics, characteristics of the studied population, economic
effectiveness of an intervention (early/open-­laparoscopic input parameters—cost and incremental/delta costs (C and
Cholecystectomy (LC)) compared with a comparator ΔC), clinical effectiveness and incremental/delta effective-
ness (E and ΔE), ICERs, INB values and their measures of

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intervention (delayed/open- LC, conservative manage-
ment). Therefore, the results could provide appropriate dispersion (ie, SD, SE or 95% CI), and willingness-­to-­pay
information to choose the most CE method. (WTP) threshold (K) as well as details of intervention and
comparator outcomes data for the pooling domain. From
the CE plane graph, we have extracted ΔC and ΔE using
METHODS WebPlotDigitizer software.17 The intervention of interest
We conducted a systematic literature search in PubMed, was early surgical removal (within 7 days of symptoms) of the
Scopus and Embase databases in compliance with the gallbladder (OC or LC). The comparator delayed surgical
Preferred Reporting Items for Systematic Reviews and removal (after 6–8 weeks) of the gallbladder (OC or LC) and
Meta-­Analyses (PRISMA).14 This study is part of a more included non-­ surgical methods like conservative manage-
extensive economic evaluation study.15 ment, wait-­and-­watch and endoscopic management. Three
reviewers (BSB, AS and SKS) independently extracted the
Data sources, screening and study selection data from the finally selected 28 studies; any disagreement
The search was performed from inception to 1 July was resolved by consensus.
2020, in PubMed, Embase and Scopus databases. We We assessed the risk of bias using the modified economic
followed the Population, Intervention, Comparator, evaluation bias (ECOBIAS) checklist.18 It considers overall
Outcome approach to construct the search terms. The biases (11 items) and biases from model-­specific aspects, that
desired population for the study included all the adult is, structure (4 items), data (6 items) and internal consistency
patients presenting with cholelithiasis or acute cholecys- (1 item). Each item was graded as yes, partly, unclear, no or
titis who were being considered for a cholecystectomy. not applicable (online supplemental figure 1).
Surgical removal of the gallbladder using early, open or
LC was the intervention, and non-­surgical methods like The outcome of interest
conservative management, wait-­and-­watch or endoscopic The primary outcome parameter of interest was INB,
management covered the comparator strategy. The defined as, INB=K*ΔE-ΔC, where K was the WTP threshold,
possible economic outcomes included were incremental ΔC-­incremental cost (ie, the difference in costs between
cost-­effectiveness ratio (ICER), incremental net benefit intervention and comparator), ΔE-­incremental effectiveness
(INB), quality-­ adjusted life-­
years (QALYs) gained, life (ie, the difference in effectiveness between intervention and
years saved and costs saved. comparator). The positive INB favours treatment, that i, the
The detailed search terms and search strategies are intervention was CE. In contrast, a negative INB suggests
reported in online supplemental material 1. The total favouring the comparator, that is, the intervention was not
number of studies identified from the database search was CE. We used INB instead of ICER as the effect measure

2 Bagepally BS, et al. BMJ Open Gastro 2022;9:e000779. doi:10.1136/bmjgast-2021-000779

 BMJ Open Gastroenterol: first published as 10.1136/bmjgast-2021-000779 on 21 January 2022. Downloaded from http://bmjopengastro.bmj.com/ on February 4, 2022 by guest. Protected by
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copyright.
Figure 1  PRISMA flow chart of selection of studies. CUA, cost–utility analysis; PRISMA, Preferred Reporting Items for
Systematic Reviews and Meta-­Analyses.

because of limitations with ICER and the ambiguity in by the primary research publications and following the
interpreting them.19 20 In addition, since all monetary units approach detailed in Bagepally et al, we calculated the
were being reported in different currencies and at different INB and its variances for each intervention comparator
periods (years), we converted them to purchasing power duo.19
parity (PPP), adjusted to US$ for the year 2019.21 Following the data preparation, INBs were pooled
income, lower-­
across studies stratified by low-­ middle-­
Data preparation and statistical analysis
We followed the data preparation method and analysis as income (LMIC), upper-­middle-­income and high- income
detailed in Bagepally et al.22 In brief, to calculate the INB countries (HICs) as per the World Bank classification.
and its variance, mean values along with dispersions (SD, A meta-­analysis was applied to pool the INBs using a
SE and 95% CI) of ΔC and ΔE were required. However, random-­effects model if heterogeneity was present (ie,
economic studies reported different parameters; there- I2 ≥25% or Q, p<0.1). We did subgroup analysis wherever
fore, we designed five scenarios to deal with the data avail- appropriate to explore the source of heterogeneity and
able from different studies. Using the data as reported provide subgroup-­ specific pooled INBs. Subsequently,

Bagepally BS, et al. BMJ Open Gastro 2022;9:e000779. doi:10.1136/bmjgast-2021-000779 3

 BMJ Open Gastroenterol: first published as 10.1136/bmjgast-2021-000779 on 21 January 2022. Downloaded from http://bmjopengastro.bmj.com/ on February 4, 2022 by guest. Protected by
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we assessed the publication bias using funnel plots and Teerawattananon and Mugford found that LC was not CE
Egger’s test. Furthermore, we explored the sources of compared with OC.43
asymmetry using contour-­enhanced funnel plots. All data
were prepared using Microsoft Excel version 2016 and Risk of bias assessment
analysed by Stata software V.16.23 Two-­sided p<0.05 was The ECOBIAS checklist shows that best current practice
considered statistically significant. was chosen as a comparator for most of the studies, and all
the comparators have been described in adequate detail.
Studies also reported a clear presentation of the data
RESULTS used in the model, provided sufficient detail on the costs,
We retrieved 8710 potentially relevant studies through applied recommended discount rates and outwardly
our search. Twenty-­ eight studies were eligible for the disclosed details of funding received. Bias related to
systematic review, as shown in the PRISMA flow diagram time horizon was high because most of the studies used
(figure 1). Of the identified 28 studies, 12 were diag- a short-­term horizon. Limited scope bias is very likely in
nostic,24–35 and the remaining 16 were therapeutic. Only almost all studies, and the internal consistency related to
7 out of the16 therapeutic studies were included in the mathematical logic was unclear (see online supplemental
meta-­analysis.8 11–13 36–38 The remaining nine studies were figure 1).
excluded because two39 40 of them were conducted before
the year 2000 and had considerable variation in their cost Pooled INBs of early versus DLC
data; and seven had no similar intervention comparator The INBs of ELC vs DLC varied across the seven
duos to pool (table 1). studies,8 11–13 36–38 with high heterogeneity (I2=73.32)
Based on analytical approach and design, 78.57% and a pooled INB of US$1221 (US$187 to US$2255)
(N=22) studies were model- based, and the remaining (figure 2). The calculated overall INB and 95% CI values
21.43% (N=6) studies were primary economic evalua- of the selected studies favour the intervention; infers that
tions.10 13 28 40–42 The model-­ based techniques used in ELC is CE compared with the DLC in HICs. We found that
these studies were decision tree (N=19, 67.86%) and the meta-­analysis results are dominated by two studies11 12
Markov model (N=3, 10.71%).7 8 39 Most studies (N=11, with 48% weightage each. We further conducted sensi-
39.29%) adopted the payer perspective, followed by the tivity analysis by omitting each of these studies one after

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health system perspective (N=10, 35.71%). Four studies the other, the results indicated these are source of heter-
adopted a societal perspective,24 29 42 43 and the remaining ogeneity but still ELC is CE; On omitting Kerwat et al,
three studies did not mention the study perspective.13 35 44 study the pooled INB US$1798 (US$1442 to US$2154,
The time horizons used in these studies vary from I2=0),11 while on omitting Morris et al, the pooled INB
1 year to a lifetime. The majority of the studies used a US$588 (US$232 to US$944, I2=0).12 However, on sensi-
1-­year time horizon (N=13, 46.43%), followed by 5 years tivity analysis by omitting both the studies reduced the
(N=5, 17.86%). Two studies each used 2-­year and 3-­year heterogeneity (US$2146 (US$−3427 to 7719), I2=0), but
time horizons,11 43–45 and only one study used lifetime the statistical significance of ELC being CE is lost.
horizons.27 Five studies failed to mention a time horizon, Examination of the evidence of publication bias on the
and three were from before the year 2000.10 24 30 35 40 funnel plot shows evidence of asymmetry. Egger’s test
All the diagnostic studies evaluating the effectiveness of with a p value of 0.912 also indicated a significant asym-
endoscopic retrograde cholangiopancreatography and metry. No study fell in the area of significance on contour
endoscopic ultrasound over MR cholangiopancreatog- enhanced funnel plot, making publication bias plausible
raphy (MRCP) reported MRCP as the dominant strategy, (online supplemental figure 2). To distinguish between
either as CE or by providing more QALYs compared with publication bias or other causes would be a challenge
the alternatives. The initial diagnosis with MRCP was due to high between-­study heterogeneity.
reported as the most CE option, with the highest mone- Subgroup analysis of the time horizon used for
tary net benefit.30–34 the study also indicates that ELC was significantly CE
Among the three therapeutic studies7 8 44 that compared compared with DLC for 1-­year and 5-­year time frames.
conservative management with surgery (LC), two studies The pooled INBs of studies with 1-­year and 5-­year time
reported that early detection and treatment of cholecys- horizon with 95% CI values was US$1797 (US$1441 to
titis is cost saving and that ELC was less expensive and US$2154) and US$583 (US$227 to US$940), respectively
provided greater QALY gains compared with DLC and (online supplemental figure 3). In addition, six out of the
watchful waiting. Both these studies confirmed that DLC seven selected studies for meta-­analysis were model-­based
was the most expensive treatment and implied the need studies, and the sensitivity analysis of these six studies also
for early treatment.7 8 In contrast, the study conducted supports the Intervention (ELC) with a pooled INBs of
by Parmar et al reported that observation was the most US$1223 (US$161 to US$2285) (online supplemental
CE approach.44 Similarly, three other studies comparing figure 4).
the cost-­effectiveness of LC with OC also favoured lapa- The countrywise pooled INB statistic from the subgroup
roscopic surgery as it was less costly and more effective, analysis revealed that intervention was not CE in Canada
concluding that LC dominates OC.10 39 40 Contrastingly, (US$1922 (−US$5244 to US$9088)), and there was no

4 Bagepally BS, et al. BMJ Open Gastro 2022;9:e000779. doi:10.1136/bmjgast-2021-000779

 Table 1  Characteristics of studies included in the systematic review
Time
Study horizon Discount
Author, year Country Setting perspective Target population (Year) rate (%) Intervention Comparator Findings
24
Weinstein et al USA Risk group Societal Biliary colic, non-­calcified NA 5 Elective Chole Ursodiol with Not Cost
1990 gallstones surgery effective
Bass et al25 1991 USA Others Payers Bile duct stones with gallstones 5 No ESWL Surgery NA
39
Bass et al 1993 USA Others Payers Acute/chronic biliary pain 5 5 LC OC Dominant
40
Cook et al 1994 Australia Others Payers Underwent cholecystectomy NA No LC, OC LC, ESWL LC dominant
Gregor et al30 Canada Others Third Party CBD patients NA 5 ERCP No ERCP ERCP dominant
1996 Payers
Teerawattananon Thailand Country Societal Gallstone pancreatitis, bile duct 3 3.5 LC OC Not cost-­
et al43 2005 stones effective
Howard et al34 Australia NA Health System Post cholecystectomy patients with 1 No MRCP ERCP Dominant
2006 biliary obstruction
Vergel et al32 UK Risk group Healthcare CBD patients with biliary 1 No MRCP ERCP Dominant
2006 provider obstruction
Poulose et al26 USA Others Payers symptomatic Cholelithiasis and 1 No LCBDE ERCP Dominant
2007 incidental CDL at the time of LC
Keränen et al41 Finland Hospital Healthcare Bile duct stone, diagnosed with 1 No From home to Ward Dominant

Bagepally BS, et al. BMJ Open Gastro 2022;9:e000779. doi:10.1136/bmjgast-2021-000779

2007 Provider cholelithiasis operation
Macafee et al13 UK Hospital Societal Acute Biliary Cholic 1 No Early LC Delayed LC ELC cost-­saving
2009
Wilson et al37 2010 UK Country Payers Gallstone pancreatitis, cholecystitis 1 No Emergency LC Delayed LC  ELC dominant
29
Dageforde et al USA Others Societal Underwent cholecystectomy 1 3 Early HBS Late HBS, Dominant
2012
Gurusamy et al45 UK Country Payers gall bladder stones with CBD 3 3.5 IOES POES Dominant
2012 stones
Johner et al38 Canada Others Healthcare Acute cholecystitis 1 No Early LC Delayed LC  Dominant
2013 Provider
Parmar et al44 USA NA  NA bile duct stones/cholecholithiasis 2 No CM Elective LC  CM cost-­
2014 effective
Morris et al12 UK Others UK NHS LC for Mild, acute gallstone 1 No Early LC Late LC  ELC cost
2014 pancreatitis saving
Brazzelli et al7 UK NA UK NHS symptomatic uncomplicated 5 3.5 Surgery (LC) CM  LC cost-­
2014 gallstone, cholecystitis effective
Morris et al31 UK NA UK NHS  CBD stone patients 1 No EUS, MRCP ERCP MRCP cost-­
2015 effective
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Continued

5
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Table 1  Continued
Time
Study horizon Discount
Author, year Country Setting perspective Target population (Year) rate (%) Intervention Comparator Findings
33
Oliver et al 2015 USA Others Healthcare Biliary stricture without mass 5 3 ERCP EUS, Surgery EUS cost-­
provider effective
Javid et al10 2016 Iran Hospital Healthcare Undergone cholecystectomy NA No LC OC Cost-­effective
Provider
de Mestral et al8 Canada Hospital Third-­party Cholecystitis 5 5 Delayed LC Early LC ELC cost-­saving
2016 payer
Sun et al35 2016 USA Others NA Intermediate bile duct stones NA No IOUS, IOCP EM IOUS dominat
36
Sutton et al UK NA Payers Bile duct stones with gallstones 1 No Delayed LC Early LC  ELC dominant
2016
Rosenmüller et Sweden Others Societal Acute emergency gallstone 1 No LC SIOC SIOC cost
al42 2017 pancreatitis bile duct stones saving
Kang et al27 2017 USA Country US health Symptomatic bile duct stones with Lifetime 3 MRCP ASGE Cost-­effective
system gallstones
Rystedt et al28 Sweden Country Payers Symptomatic bile duct stones with 10 3 Routine IOCP On demand Not cost-­
2017 gallstones IOCP effective
Kerwat et al11 UK Country Payers Acute bile duct stones with 2 No Early LC Delayed LC ELC cost-­
2018 gallstones effective
ASGE, American Society for Gastrointestinal Endoscopy; CBD, Common bile duct; CDL, choledocholithiasis; ELC, early laparoscopic cholecystectomy; ERCP, endoscopic retrograde
cholangiopancreatography; ESWL, Extracorporeal Shock Wave Lithotripsy; HBS, Hepatobiliary surgeon; IOCP, Intra operative Cholangiography; IOUS, Intraoperative ultrasonography; LC,
laparoscopic cholecystectomy; LCBDE, Laparoscopic common bile duct Exploration; MRCP, MR cholangiopancreatography; NA, not available; OC, open cholecystectomy; SIOC, Single
Incision open cholecystectomy.

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BMJ Open Gastroenterol: first published as 10.1136/bmjgast-2021-000779 on 21 January 2022. Downloaded from http://bmjopengastro.bmj.com/ on February 4, 2022 by guest. Protected by
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Many retrospectives46 47 and prospective studies48

reported ELC as the best treatment of choice for patients
with acute cholecystitis. Updated Tokyo guidelines made
ELC mandatory for patients with mild cholecystitis and
DLC for moderate or severe cholecystitis patients.49 Over-
lapping meta-­analysis has reported discordant results and
conclusions. A systematic review of meta-­analyses by Song
et al suggested ELC as the standard treatment option and
indicated a non-­significant difference in mortality and
Figure 2  Comparision of incremental net benefit between
complications, with a significant reduction in hospitalisa-
early and delayed cholecystectomy. INB, incremental net
benefit; LC, laparoscopic cholecystectomy. tion and improvement in quality of life when compared
with DLC.50 Recent meta-­ analyses also suggested ELC
as safe and effective against DLC for acute cholecystitis
heterogeneity between these studies (I2=0). Conversely, within 7 days from presentation51; also, ELC should be
ELC was CE in the UK with a positive pooled INB of preferred to DLC when feasible within 72 hours of the
US$1209 (US$106 to US$2311) but with substantial onset of symptoms.52 In 2020, the World Society of Emer-
heterogeneity (I2=82.17%) (online supplemental figure gency Surgery recommended that ELC should be the
5). The study by Sutton, 2017 has examined cholecystec- standard of care whenever possible.53
tomy outcomes in both the UK and Ireland. However, Previous Randomised control trials have reported
to make a sufficient capacity to be pooled for INBs, we quality improvements and cost savings through same-­day
considered the country UK only in subgroup analysis. surgery (ELC) over preoperative admission.6 41 Model-­
All the selected studies followed the payer’s perspective, based CUAs have reported ELC as the optimal manage-
except Macafee et al13 which followed a societal perspec- ment for uncomplicated gallstones and less expensive,
tive. The pooled INB values from the sensitivity analysis with more significant QALY gains than DLC or watchful
of all these studies, excluding the Macafee et al with a waiting.8 11 38 However, reported studies are mostly
95% CI, was US$$1221 (US$161 to US$2285) (online incongruous and clustered around the specific geog-
supplemental figure 6), depicts that ELC is CE over DLC. raphy of HICs. Furthermore, it depends on the different

copyright.
study conditions and perspectives. Some studies have
reported conflicting results, primarily because of
DISCUSSION different analytical perspectives or different healthcare
We conducted a systematic review and meta-­analysis of contexts.54 Although early detection and treatment is
various treatment options for gallstone diseases. On meta-­ clinically an effective strategy, synthesised economic
analysis of CE evidence, the ELC was significantly more evidence was limited. The present meta-­analysis of cost-­
CE than the DLC. Subgroup analysis, as well as sensitivity effectiveness evidence fills the knowledge gap in this
analysis, strengthened the robustness of this finding. regard.
However, limited studies across different settings and The majority of the studies included in the analysis
lifetime horizons warrant the need for primary economic reported ELC as CE and superior to DLC, except for two
evaluation studies to fill the knowledge gap. studies.43 44 Full economic evaluation studies in people
The subgroup analysis revealed that ELC was CE with gallstones or cholecystitis comparing the cost–utility
compared with DLC from the payer’s perspective. effectiveness of cholecystectomy to other treatments,
However, only one study reported non-­cost effectiveness especially conservative management, were largely limited.
from a societal perspective, thus postulating unpredict- Our study has several limitations. Most of the selected
ability in the overall cost-­effectiveness of the ELC with studies were from HICs, either the UK or Canada,
societal perspectives. Similarly, ELC was CE in studies limiting results to other countries, especially the LMICs.
from Canada but not from the UK; both are HICs, and We had only one study with a societal perspective, and
this points out the high heterogeneity across available studies with indirect cost would provide a real-­ world
studies. Studies are limited in terms of different econ- comparison scenario. Hence, synthesised findings have
omies, mainly from LMICs, societal perspectives, and limited generalisability when extrapolating the results to
longer time horizons. Sensitivity analysis identified both all other healthcare contexts. The inadequacy of similar
Kerwat et al and Morris et al are the sources of heteroge- studies to be pooled for the INB values for interven-
neity, even though both of them had precise estimates or tion and comparators only permitted us to perform the
shorter 95% CI. Since, Kerwat et al is in scenario 5 and we meta-­analysis with seven studies. Due to a lack of peer-­
used the variance from Morris et al (most similar study), reviewed published literature, the idea of meta-­analysis
hence, possibly the Morris et al study is the main source with the conservative gallstone disease management was
of heterogeneity. Further the study population of Morris curtailed. Further, due to limited information in the
et al study is mild acute gallstone disease with pancreatitis, primary literature, sensitivity and subgroup analysis to
which may the reason for heterogeneity, while most of explore comorbidity-­ related costs, gender differences,
the other studies were with only gallstone disease. patient’s age, etc could not be performed.

Bagepally BS, et al. BMJ Open Gastro 2022;9:e000779. doi:10.1136/bmjgast-2021-000779 7

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Future research from various economies, primarily symptomatic gallstones or cholecystitis. Surg Endosc
2015;29:637–47.
LMICs, societal perspectives and longer time horizons 2 Shaffer EA. Epidemiology and risk factors for gallstone disease: has
are needed. Future research should be context-­specific, the paradigm changed in the 21st century? Curr Gastroenterol Rep
include primary economic evaluations based on well-­ 2005;7:132–40.
3 Papi C, Catarci M, D'Ambrosio L, et al. Timing of cholecystectomy
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estimate of costs and benefits. Furthermore, timely cost-­ Gastroenterol 2004;99:147–55.
4 Wu X-­D, Tian X, Liu M-­M, et al. Meta-­Analysis comparing
effectiveness evaluations of such interventions, will facili- early versus delayed laparoscopic cholecystectomy for acute
tate the incorporation of such health economic evidence cholecystitis. Br J Surg 2015;102:1302–13.
into clinical practise. Thereby reducing barriers and 5 Gurusamy K, Samraj K, Gluud C, et al. Meta-­analysis of randomized
controlled trials on the safety and effectiveness of early versus
overall poor uptake of economic evidence outside of delayed laparoscopic cholecystectomy for acute cholecystitis. Br J
health technology assessment and may positively influ- Surg 2010;97:141–50.
6 Minutolo V, Licciardello A, Arena M, et al. Laparoscopic
ence the adoption and resource allocations for those cholecystectomy in the treatment of acute cholecystitis: comparison
interventions for greater societal benefit. of outcomes and costs between early and delayed cholecystectomy.
Eur Rev Med Pharmacol Sci 2014;18:40–6.
Conclusion 7 Brazzelli M, Cruickshank M, Kilonzo M, et al. Clinical effectiveness
and cost-­effectiveness of cholecystectomy compared with
The synthesised results from the available studies showed observation/conservative management for preventing recurrent
ELC is a CE option compared with DLC in the treat- symptoms and complications in adults presenting with
uncomplicated symptomatic gallstones or cholecystitis: a
ment of gallstone disease or cholecystitis in HICs. There systematic review and economic evaluation. Health Technol Assess
is a need to generate comparative economic evidence 2014;18:1–102.
between surgical and conservative management as well as 8 de Mestral C, Hoch JS, Laupacis A, et al. Early Cholecystectomy
for Acute Cholecystitis Offers the Best Outcomes at the Least
other aspects of gallstone disease management, such as Cost: A Model-­Based Cost-­Utility Analysis. J Am Coll Surg
endoscopic approaches and diagnostic aspects. 2016;222:185–94.
9 Gallagher TK, Kelly ME, Hoti E. Meta-­analysis of the cost-­
Twitter Bhavani Shankara Bagepally @bshankara effectiveness of early versus delayed cholecystectomy for acute
cholecystitis. BJS Open 2019;3:146–52.
Contributors  BBS: guarantor, conceptualisation, data curation, formal analysis, 10 Javid M, Hadian M, Rezapour A. Cost-­Utility analysis of laparoscopic
investigation, methodology, software, original draft, review and editing. SKS: data cholecystectomy and open cholecystectomy in Kashani Hospital,
Shahr-­e-­Kord, Iran. Iranian Red Crescent Medical Journal 2018;20.
curation, formal analysis, original draft. AS: conceptualisation, data curation, formal
11 Kerwat Doa'a, Zargaran A, Bharamgoudar R, et al. Early
analysis, original draft. MN: data curation, review and editing. laparoscopic cholecystectomy is more cost-­effective than

copyright.
Funding  We received no specific funding for this work. However, the Dept. of delayed laparoscopic cholecystectomy in the treatment of acute
Health Research, Govt. of India funds the Health Technology Assessment Resource cholecystitis. Clinicoecon Outcomes Res 2018;10:119–25.
12 Morris S, Gurusamy KS, Patel N, et al. Cost-­Effectiveness of early
Centre, ICMR-­NIE. Grant Number: T.11011/08/2017-­HR(Part-­1)/E-­office -8025571.
laparoscopic cholecystectomy for mild acute gallstone pancreatitis.
Disclaimer  Funders had no role in the conceptualisation, conduction and Br J Surg 2014;101:828–35.
manuscript preparation. 13 Macafee DAL, Humes DJ, Bouliotis G, et al. Prospective randomized
trial using cost-­utility analysis of early versus delayed laparoscopic
Competing interests  None declared. cholecystectomy for acute gallbladder disease. Br J Surg
Patient consent for publication  Not applicable. 2009;96:1031–40.
14 Shamseer L, Moher D, Clarke M, et al. Preferred reporting items for
Provenance and peer review  Not commissioned; externally peer reviewed. systematic review and meta-­analysis protocols (PRISMA-­P) 2015:
elaboration and explanation. BMJ 2015;350:g7647.
Data availability statement  All data relevant to the study are included in the
15 Cost-­Effective management of cholelithiasis or cholecystitis: a
article or uploaded as online supplemental information. systematic review and meta-­analysis of full economic evaluation
Supplemental material  This content has been supplied by the author(s). It has studies. Available: https://www.crd.york.ac.uk/prospero/display_​
not been vetted by BMJ Publishing Group Limited (BMJ) and may not have been record.php?ID=CRD42020194052
16 Ouzzani M, Hammady H, Fedorowicz Z, et al. Rayyan-­a web and
peer-­reviewed. Any opinions or recommendations discussed are solely those
mobile APP for systematic reviews. Syst Rev 2016;5:210.
of the author(s) and are not endorsed by BMJ. BMJ disclaims all liability and 17 WebPlotDigitizer - Extract data from plots, images, and maps, 2018.
responsibility arising from any reliance placed on the content. Where the content Available: https://automeris.io/WebPlotDigitizer/download.html
includes any translated material, BMJ does not warrant the accuracy and reliability 18 Adarkwah CC, van Gils PF, Hiligsmann M, et al. Risk of bias in
of the translations (including but not limited to local regulations, clinical guidelines, model-­based economic evaluations: the ECOBIAS checklist. Expert
terminology, drug names and drug dosages), and is not responsible for any error Rev Pharmacoecon Outcomes Res 2016;16:513–23.
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Open access  This is an open access article distributed in accordance with the metformin monotherapy failed type 2 diabetes patients: a systematic
Creative Commons Attribution Non Commercial (CC BY-­NC 4.0) license, which review and meta-­analysis. Value Health 2019;22:1458–69.
permits others to distribute, remix, adapt, build upon this work non-­commercially, 20 O’Mahony JF. The limitations of Icers in screening interventions and
and license their derivative works on different terms, provided the original work is the relative net benefit alternative. Value in Health2015;18.
properly cited, appropriate credit is given, any changes made indicated, and the 21 World economic and financial surveys world economic outlook
use is non-­commercial. See: http://creativecommons.org/licenses/by-nc/4.0/. database, 2021. Available: https://www.imf.org/en/Publications/​
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22 Bagepally BS, Chaikledkaew U, Gurav YK, et al. Glucagon-­Like
Bhavani Shankara Bagepally http://orcid.org/0000-0003-0856-767X
peptide 1 agonists for treatment of patients with type 2 diabetes
S Sajith Kumar http://orcid.org/0000-0001-7938-9255 who fail metformin monotherapy: systematic review and meta-­
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Online Supplementary Material

1. Supplementary Figures - Page 2 to 6

2. Appendix Tables - Page 7 to 10

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Supplementary Figures

Y- Yes, N- No, UC- Unclear, P- partly, NA- Not Available

Supplementary Figure 1: Assessment of Risk of Bias using ECOBIAS Checklist

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Supplementary Figures

Supplementary Figure 2: Funnel plot and contour-enhanced funnel plot to distinguish

publication bias

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Supplementary Figures

Supplementary Figure 3: Subgroup analysis of pooled INBs based on different Time

horizon

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Supplementary Figures

Supplementary Figure 4: Sensitivity analysis of Pooled INBs based on Analytical Design of the
study

Supplementary Figure 5: Subgroup analysis of ccountry wise Pooled INBs

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Appendix

Supplementary Figure 6: Sensitivity analysis of Pooled INBs based on study perspective

Supplementary Figure 7: Sensitivity analysis of Pooled INBs based on threshold (k) used

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Appendix

APPENDIX 1

SEARCH STRATEGY

PUBMED Search No of Hits on

21st July 2020

P "gall bladder" OR gallbladder OR cholecystitis OR Cholelithiasis OR 154,847

gallstone OR “gall stone” OR “gall stones” OR cholecystolithiasis OR "bile
duct stone" OR “common bile duct” OR "biliary disease" OR "biliary tract
disease" OR cholec* OR “gallbladder inflammation” OR cholecystectomy
OR "gallbladder removal" OR "gallbladder excision" OR ("surgical
removal" AND ("gall bladder" OR gallbladder)) OR ("surgical excision"
AND ("gall bladder" OR gallbladder)) OR "restrictive strategy" OR
cholecystectomy OR "biliary tract surgery" OR "bile duct operation" OR
"bile duct surgery" OR "bile tract surgery" OR "biliary surgery" OR "biliary
tract operation" OR "biliary tract reoperation" OR "biliary tract surgery" OR
"biliary tract surgical procedures" OR "gall bladder surgery" OR
"gallbladder operation" OR "gallbladder surgery" OR “Sphincterotomy” OR
(“robotic” AND “cholecystectomy”)

Costs cost OR costs OR (“Expenditure” NOT energy) OR “money” OR “finance” 1,265,302

OR “budget” OR “payment” OR "economics"[MeSH Terms] OR price

Outcomes benefi* OR “minimi*”OR “quality of life” OR “QALY” OR “quality 13,202,634

adjusted” OR “life year” OR “life years” OR “DALY” OR “disability
adjusted” OR “ICER” OR “ICERS” OR “utility” OR “benefit ratio” OR INB
OR “healthy year equivalent” OR “healthy years equivalent” OR
“willingness to pay” OR markov OR “decision tree” OR “decision model”
OR “decision analytic” OR horizon OR “discounting” OR “discount rate”
OR "inflation, economic"[MeSH Terms] OR "economics"[MeSH Terms]
OR "economics, pharmaceutical"[MeSH Terms] OR averted OR prevented
OR “saved” OR “cured” OR recovered OR “outcome” OR “outcomes” OR
efficacy OR effectiveness

PCO 2,977

EMBASE Search No of Hits on

21st July 2020

P cholecystitis OR Cholelithiasis OR gallstone OR ‘gall stone’ OR ‘gall stones’ 180,575

OR cholecystolithiasis OR ‘bile duct stone’ OR ‘biliary disease’ OR ‘biliary
tract disease’ OR cholec* OR ‘gallbladder inflammation’ OR
cholecystectomy OR ‘gallbladder removal’ OR ‘gallbladder excision’ OR
(‘surgical removal’ AND (‘gall bladder’ OR gallbladder)) OR (‘surgical
excision’ AND (‘gall bladder’ OR gallbladder)) OR ‘restrictive strategy’ OR
cholecystectomy OR ‘biliary tract surgery’ OR ‘bile duct operation’ OR ‘bile
duct surgery’ OR ‘bile tract surgery’ OR ‘biliary surgery’ OR ‘biliary tract
operation’ OR ‘biliary tract reoperation’ OR ‘biliary tract surgery’ OR

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Appendix

‘biliary tract surgical procedures’ OR ‘gall bladder surgery’ OR ‘gallbladder

operation’ OR ‘gallbladder surgery’ OR ‘Sphincterotomy’

Costs 'cost benefit analysis'/exp OR 'cost analysis' OR 'cost benefit' OR 'cost benefit 833,703
analysis' OR 'cost benefit ratio' OR 'cost-benefit analysis' OR 'cost
minimization analysis'/exp OR 'cost minimization' OR 'cost minimization
analysis' OR ‘quality of life’ OR ‘QALY’ OR ‘quality adjusted’ OR ‘life
year’ OR ‘life years’ OR ‘DALY’ OR ‘disability adjusted’ OR ‘ICER’ OR
‘ICERS’ OR INB OR 'cost effectiveness analysis'/exp OR 'cost effectiveness'
OR 'cost effectiveness analysis' OR 'cost effectiveness ratio' OR 'cost
efficiency analysis' OR ‘willingness to pay’ OR 'cost utility analysis'/exp OR
'cost utility' OR 'cost utility analysis'

PC 4,065
P&C

2,037
P & C (restricted to journal articles + in press)

Scopus Search No of Hits on

21st July 2020

P cholecystitis OR Cholelithiasis OR gallstone OR “gall stone” OR “gall 312,298

stones” OR “cholecystolithiasis” OR “bile duct stone” OR “biliary disease”
OR “biliary tract disease” OR cholec* OR “gallbladder inflammation” OR
cholecystectomy OR “gallbladder removal” OR “gallbladder excision” OR
cholecystectomy OR “biliary tract surgery” OR “bile duct operation” OR
“bile duct surgery” OR “bile tract surgery” OR “biliary surgery” OR “biliary
tract operation” OR “biliary tract reoperation” OR “biliary tract surgery” OR
“gall bladder surgery” OR “gallbladder operation” OR “gallbladder surgery”
OR “Sphincterotomy”

Costs cost* OR "cost effectiv*" OR "cost utility" OR "Cost benefit" OR "Cost- 557,452
Benefit" OR "Quality Adjusted Life Years" OR qaly OR ly OR "life year$"
OR daly OR “disability adjusted” OR "incremental cost effective ratio" OR
"ICER" OR "incremental net benefit" OR inb OR “benefit ratio” OR ‘cost
benefit’ OR ‘cost minimisation’ OR “cost-effectiveness” OR “cost
effectiveness ratio” OR “cost efficiency analysis” OR “cost utility”

PC 6,678
P&C

3,696
P & C (restricted to articles + in press)

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PRISMA CHECKLIST TABLE

Reported
Section/topic # Checklist item
on page #
TITLE: Incremental net benefit of cholecystectomy compared with alternative treatments in people with gallstones or cholecystitis: A Systematic Review and
Meta-analysis of cost-utility studies
Title 1 Identify the report as a systematic review, meta-analysis, or both. Yes, 1

ABSTRACT
Provide a structured summary including, as applicable: background; objectives; data sources; study eligibility criteria,
Structured summary 2 participants, and interventions; study appraisal and synthesis methods; results; limitations; conclusions and implications of key Yes, 2
findings; systematic review registration number.
INTRODUCTION
Rationale 3 Describe the rationale for the review in the context of what is already known. Yes, 4,5
Provide an explicit statement of questions being addressed with reference to participants, interventions, comparisons, outcomes,
Objectives 4 Yes, 5
and study design (PICOS).
METHODS
Indicate if a review protocol exists, if and where it can be accessed (e.g., Web address), and, if available, provide registration
Protocol and registration 5 Yes, 5
information including registration number.
Specify study characteristics (e.g., PICOS, length of follow-up) and report characteristics (e.g., years considered, language,
Eligibility criteria 6 Yes, 5
publication status) used as criteria for eligibility, giving rationale.
Describe all information sources (e.g., databases with dates of coverage, contact with study authors to identify additional studies) Yes, 6 &
Information sources 7
in the search and date last searched. appendix 1
Yes,
Search 8 Present full electronic search strategy for at least one database, including any limits used, such that it could be repeated.
appendix 1
State the process for selecting studies (i.e., screening, eligibility, included in systematic review, and, if applicable, included in the Yes, 6,
Study selection 9
meta-analysis). Figure 1
Describe method of data extraction from reports (e.g., piloted forms, independently, in duplicate) and any processes for obtaining
Data collection process 10 Yes, 7
and confirming data from investigators.
List and define all variables for which data were sought (e.g., PICOS, funding sources) and any assumptions and simplifications
Data items 11 Yes, 6
made.
Risk of bias in individual Describe methods used for assessing risk of bias of individual studies (including specification of whether this was done at the
12 Yes, 7
studies study or outcome level), and how this information is to be used in any data synthesis.
Summary measures 13 State the principal summary measures (e.g., risk ratio, difference in means). Yes, 7
Describe the methods of handling data and combining results of studies, if done, including measures of consistency (e.g., I 2) for
Synthesis of results 14 Yes, 8
each meta-analysis.

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PRISMA CHECKLIST TABLE

Section/topic # Checklist item Reported on page #

Risk of bias across studies 15 Specify any assessment of risk of bias that may affect the cumulative evidence (e.g., publication bias, selective Yes, 8
reporting within studies).
Additional analyses 16 Describe methods of additional analyses (e.g., sensitivity or subgroup analyses, meta-regression), if done, indicating Yes,8
which were pre-specified.
RESULTS
Study selection 17 Give numbers of studies screened, assessed for eligibility, and included in the review, with reasons for exclusions at Yes, 8 and Figure 1
each stage, ideally with a flow diagram.
Study characteristics 18 For each study, present characteristics for which data were extracted (e.g., study size, PICOS, follow-up period) and Yes, 8-9
provide the citations.
Risk of bias within studies 19 Present data on risk of bias of each study and, if available, any outcome level assessment (see item 12). Yes, 10 & Suppl Fig 1
Results of individual studies 20 For all outcomes considered (benefits or harms), present, for each study: (a) simple summary data for each Yes, 10,
intervention group (b) effect estimates and confidence intervals, ideally with a forest plot. Figure 2, Table 1,
Synthesis of results 21 Present results of each meta-analysis done, including confidence intervals and measures of consistency. Yes, 10,11
Risk of bias across studies 22 Present results of any assessment of risk of bias across studies (see Item 15). Yes, 10 & Supp Figure
1
Additional analysis 23 Give results of additional analyses, if done (e.g., sensitivity or subgroup analyses, meta-regression [see Item 16]). Yes, Supp Figures 2-7
DISCUSSION
Summary of evidence 24 Summarize the main findings including the strength of evidence for each main outcome; consider their relevance to Yes, 11,12
key groups (e.g., healthcare providers, users, and policy makers).
Limitations 25 Discuss limitations at study and outcome level (e.g., risk of bias), and at review-level (e.g., incomplete retrieval of Yes, 13
identified research, reporting bias).
Conclusions 26 Provide a general interpretation of the results in the context of other evidence, and implications for future research. Yes,14
FUNDING
Funding 27 Describe sources of funding for the systematic review and other support (e.g., supply of data); role of funders for Yes, 1
the systematic review.
From: Moher D, Liberati A, Tetzlaff J, Altman DG, The PRISMA Group (2009). Preferred Reporting Items for Systematic Reviews and Meta-Analyses: The PRISMA Statement. PLoS Med 6(7): e1000097.
doi:10.1371/journal.pmed1000097

10 | P a g e

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