Laparoscopic cholecystectomy is the most effective treatment for patients with complicated gallstone disease, including cholecystitis, choledocholithiasis, biliary pancreatitis. It is also proven effective in the treatment of uncomplicated gallstone disease presenting with recurrent biliary colic. However, the effectiveness of cholecystectomy in patients with abdominal pain and cholecystolithiasis (uncomplicated gallstone disease) remains debated and is the central focus of this guideline module. The 2016 guideline recommends laparoscopic cholecystectomy for patients with symptomatic gallstone disease, while acknowledging controversy in the literature and noting that 30–40% of patients experience persistent abdominal pain postoperatively.

Surgical indication is based on the Rome III criteria for biliary colic combined with radiologically confirmed gallstones and/or sludge. While the Rome III criteria are useful in identifying patients with biliary colic, recent studies have shown that they do not reliably predict which patients will be completely pain-free after cholecystectomy.

Determining the appropriate indication for laparoscopic cholecystectomy remains challenging due to the lack of long-term data on conservative management. Persistent postoperative pain is often attributed to non-biliary causes of abdominal pain, including underlying functional gastrointestinal disorders.

Summary of Findings

Population: Patients with gallstones and abdominal complaints

Intervention: Restrictive strategy (conservative management)

Comparison: usual care (surgery)

_{^1. Risk of bias: serious. Due to lack of blinding, frequent loss-to-follow-up, other problems such as protocol deviations and differences in baseline characteristics.}

_{Imprecision: serious. Due to overlap of the lower limit of the 95% confidence interval with the minimal clinically important difference.}

_{^2. Risk of bias: serious. Due to lack of blinding, frequent loss-to-follow-up, other problems such as protocol deviations and differences in baseline characteristics.}

_{Inconsistency: serious. Due to conflicting results.}

_{Imprecision: serious. Due to overlap of the upper limit of the 95% confidence interval with the minimal clinically important difference.}

_{^3. Risk of bias: serious. Due to lack of blinding, frequent loss-to-follow-up, other problems such as protocol deviations and differences in baseline characteristics.}

_{Imprecision: serious. Due to overlap of the lower limit of the 95% confidence interval with the minimal clinically important difference.}

_{^4. Risk of bias: serious. Due to lack of blinding, frequent loss-to-follow-up, other problems such as protocol deviations and differences in baseline characteristics.}

_{Imprecision: serious. Due to overlap of the lower limit of the 95% confidence interval with the minimal clinically important difference.}

_{^5. Risk of bias: serious. Due to lack of blinding, frequent loss-to-follow-up, other problems such as protocol deviations and differences in baseline characteristics.}

_{Inconsistency: serious. Due to conflicting results.}

_{Imprecision: very serious. Due to overlap of both limits of the 95% confidence interval with the minimal clinically important difference.}

Description of studies

A total of six studies were included in the analysis of the literature. Important study characteristics and results are summarized in table 2. The assessment of the risk of bias is summarized in the risk of bias tables (under the tab ‘Evidence tabellen’).

Van Dijk (2019) performed a multicenter, parallel-arm, noninferiority randomized clinical trial (SECURE trial). The inclusion criteria of the SECURE trial were: age 18-95 years, abdominal pain and ultrasound-proven gallstones (or symptomatic with ultrasound proven sludge), referred to a surgical outpatient clinic, and contacted for participation before their first visit.

Comes (2024) performed a five year follow-up analysis of a multicenter, parallel-arm, noninferiority, prospective randomized clinical trial (SECURE trial). The inclusion criteria of the SECURE trial were: age 18-95 years, abdominal pain and ultrasound-proven gallstones (or symptomatic with ultrasound proven sludge), referred to a surgical outpatient clinic, and contacted for participation before their first visit.

Latenstein (2022) performed a cost-effectiveness analysis of a multicenter, parallel-arm, noninferiority, prospective randomized clinical trial (SECURE trial). The inclusion criteria of the SECURE trial were: age 18-95 years, abdominal pain and ultrasound-proven gallstones (or symptomatic with ultrasound proven sludge), referred to a surgical outpatient clinic, and contacted for participation before their first visit.

Innes (2024) performed a multicenter parallel-group patient randomized superiority trial (C-GALL trial). The inclusion criteria of the C-GALL trial were: adults, confirmed symptomatic gallstones (diagnosis by any imaging technique), elective referral to a secondary care setting for consultation.

Vetrhus (2004) performed a multicenter, randomized controlled trial. The inclusion criteria were: symptomatic, uncomplicated gallbladder stones (GBS).

Schmidt (2011) performed a fourteen year follow-up analysis of a multicenter, randomized controlled trial (see Vetrhus, 2004). The inclusion criteria were: uncomplicated, symptomatic gallstone disease.

Table 2. Characteristics of included studies

_{*For further details, see risk of bias table in the appendix}

Results

Complications (critical)

Surgical complications

Three studies reported the outcome measure surgical complications (Comes, 2024; Innes, 2024; Van Dijk, 2019). Since two of the three publications used data from the same trial, the results were not pooled.

Van Dijk (2019) reported surgical complications at one year. In total, 74 of the 530 patients (14.0%) who received the restrictive strategy suffered from surgical complications after one year, compared with 88 of the 537 patients (16.4%) who received usual care. The risk ratio was 0.84 (95% CI 0.63 to 1.12), in favor of the patients who received the restrictive strategy. The risk difference was -0.02 (95% CI -0.07 to 0.02), in favor of the patients who received the restrictive strategy. This difference is not considered clinically relevant. 

Comes (2024) reported surgical complications at five years. In total, 81 of the 530 patients (15.3%) who received the restrictive strategy suffered from surgical complications after five years, compared with 100 of the 537 patients (18.6%) who received usual care. The risk ratio was 0.82 (95% CI 0.63 to 1.07), in favor of the patients who received the restrictive strategy. The risk difference was -0.03 (95% CI -0.08 to 0.01), in favor of the patients who received the restrictive strategy. This difference is not considered clinically relevant. 

Innes (2024) reported the number of patients who suffered from intraoperative and postoperative complications (surgical) up to 24 months. In total, 16 of the 217 patients (7.4%) who received observation/conservative management suffered from surgical complications, compared with 40 of the 217 patients (18.4%) who received usual care. The risk ratio was 0.40 (95% CI 0.23 to 0.69), in favor of the patients who received observation/conservative management. The risk difference was -0.11 (95% CI -0.17 to -0.05), in favor of the patients who received observation/conservative management. This difference is considered clinically relevant.

Biliary complications

Four studies reported the outcome measure biliary complications (Comes, 2024; Innes, 2024; Van Dijk, 2019; Vetrhus, 2004). Since the publications used different follow-up times, and two studies used data from the same trial, the results were not pooled.

Van Dijk (2019) reported gallstone complications (choledocholithiasis, acute cholecystitis, biliary pancreatitis, cholangitis, colic with hospitalization) at one year. In total, 40 of the 530 patients (7.5%) who received the restrictive strategy suffered from biliary complications, compared with 38 of the 537 patients (7.1%) who received usual care. The risk ratio was 1.07 (95% CI 0.70 to 1.64), in favor of the patients who received usual care. The risk difference was 0.00 (95% CI -0.03 to 0.04). This difference is not considered clinically relevant.

Comes (2024) reported gallstone complications (choledocholithiasis, acute cholecystitis, biliary pancreatitis, cholangitis, colic with hospitalization) at five years. In total, 79 of the 530 patients (14.9%) who received the restrictive strategy suffered from biliary complications, compared with 77 of the 537 patients (14.3%) who received usual care. The risk ratio was 1.04 (95% CI 0.78 to 1.39), in favor of the patients who received usual care. The risk difference was 0.01 (95% CI -0.04 to 0.05), in favor of the patients who received usual care. This difference is not considered clinically relevant.

Innes (2024) reported the number of patients who suffered from presurgery (biliary) complications up to 24 months. In total, 25 of the 217 patients (11.5%) who received observation/conservative management suffered from biliary complications, compared with 11 of the 217 patients (5.1%) who received usual care. The risk ratio was 2.27 (95% CI 1.15 to 4.50), in favor of the patients who received usual care. The risk difference was 0.06 (95% CI 0.01 to 0.12), in favor of the patients who received usual care. This difference is considered clinically relevant.

Vetrhus (2004) reported gallstone-related (acute cholecystitis, common bile duct stone, acute pancreatitis) events at five years. In total, 15 of the 69 patients (22%) who received observation suffered from gallstone-related events, compared with 3 of the 68 patients (4%) who received surgery. The risk ratio was 4.93 (95% CI 1.49 to 16.25), in favor of the patients who received surgery. The risk difference was 0.17 (95% CI 0.06 to 0.28), in favor of the patients who received surgery. This difference is considered clinically relevant.

Pain (important)

Four studies reported the outcome measure pain (Comes, 2024; Innes, 2024; Van Dijk, 2019; Vetrhus, 2004). Due to differences in reporting the outcome measure, the results were not pooled.

Van Dijk (2019) reported time to being pain free in months (irrespective of surgical or conservative treatment). The patients who received restrictive strategy (n=530) were pain free within 7.87 months, compared with 7.29 months for the patients who received usual care (n=537). The mean difference between the groups was 0.58 months, in favor of the patients  who received usual care. This difference is not considered clinically relevant.

Comes (2024) reported patients being pain-free at one year and at five years. In total, 298 of the 530 patients (56.3%) who received restrictive strategy reported being pain-free at one year, compared with 321 of the 537 patients (59.9%) who received usual care. The risk ratio was 0.94 (95% CI 0.85 to 1.04), in favor of the patients who received usual care. The risk difference was -0.04 (95% CI -0.09 to 0.02), in favor of the patients who received usual care. This difference is not considered clinically relevant.

Innes (2024) reported pain (SF-36 norm-based bodily pain score) at 24 months. The patients who received conservative management (n=217) had a mean pain score of 48.0 (SD ± 12.0), compared with a mean pain score of 49.1 (SD ± 12.3) for the patients who received cholecystectomy (n=217). The mean difference between the groups was -1.10 (95% CI -3.39 to 1.19), in favor of the patients who received conservative management. This difference is not considered clinically relevant.

Vetrhus (2004) reported mean pain score at five years. The patients who received observation (n=56) had a mean pain score of 2.4, compared with a mean pain score of 2.0 for the patients who received surgery (n=56). The mean difference between the groups was 0.4, in favor of the patients who received surgery. This difference is not considered clinically relevant.

Cholecystectomies (important)

Five studies reported the outcome measure cholecystectomies (Comes, 2024; Latenstein, 2022; Schmidt, 2011; Van Dijk, 2019; Vetrhus, 2004).

Comes (2024), Schmidt (2011), Van Dijk (2019), and Vetrhus (2004) reported the number of patients who underwent cholecystectomy, at different follow-up durations. Since Comes and Van Dijk (SECURE), and Schmidt and Vetrhus used the same patient data, the data were not pooled.

Van Dijk (2019) reported cholecystectomies at one year, and Comes (2024) reported cholecystectomies at five years using data of the SECURE study. At one year, 358 of the 530 patients (67.5%) who received restrictive strategy underwent a cholecystectomy, compared with 404 of the 537patients (75.2%) who received usual care. The risk ratio at one year was 0.90 (95% CI 0.83 to 0.97), in favor of the patients who received restrictive strategy. The risk difference was -0.08 (95% CI -0.13 to -0.02), in favor of the patients who received restrictive strategy. This difference is considered clinically relevant.

Latenstein (2022) reported use of resources, mean volume of cholecystectomies. The patients who received restrictive strategy (n=530) used a mean volume of 0.68 (95% CI 0.64 to 0.72), compared with a mean volume of 0.75 (95% CI 0.72 to 0.79) for the patients who received usual care (n=537). The mean difference was 0.08 (95% CI 0.02 to 0.13), in favor of the patients who received restrictive strategy. This difference is not considered clinically relevant.

Health-related quality of life (important)

Three studies reported the outcome measure quality of life (Innes, 2024; Van Dijk, 2019; Vetrhus, 2004). Due to differences in reporting the outcome measure, the results were not pooled.

Innes (2024) reported patient-reported quality of life, measured by the SF-36, at 24 months. The patients who received conservative treatment (n=217) had a mean quality of life score of 47.2 (SD ± 8.6), compared with a mean quality of life score of 47.3 (SD ± 8.7) for the patients who received surgery (n=217). The mean difference is -0.10 (95% CI -1.73 to 1.53), in favor of the patients who received surgery. This difference is considered clinically relevant.

Van Dijk (2019) reported quality of life, measured by Gastrointestinal Quality of Life Index, at one year. The study concluded that the quality of life score did not differ between the groups.

Vetrhus (2004) reported quality of life, measured by Psychological General Well-Being Index, at five years. The patients who received observation (n=55) had a mean quality of life score of 104.1, compared with a mean quality of life score of 101.6 for the patients who received surgery (n=56). The mean difference was 2.5, in favor of the patients who received observation. This difference is not considered clinically relevant.

Cost-effectiveness (important)

Two studies reported the outcome measure cost-effectiveness (Innes, 2024; Latenstein, 2022). Since only two studies reported this outcome measure, the results were not pooled.

Innes (2024) reported mean total NHS costs up to 24 months. The patients who received observation (n=217) had total NHS costs of 885 pounds (SD ± 1954 pounds), compared with 2184 pounds (SD ± 1486 pounds) for the patients who received surgery (n=217). This results in an unadjusted difference of 1299 pounds, in favor of the patients who received observation.

Latenstein (2022) reported cost-effectiveness. They conclude that restrictive strategy saves between 162 and 277 euros per patient compared with usual care, from a societal perspective. From a health care perspective, 168 euros were saved when using restrictive strategy instead of usual care. 

A systematic review of the literature was performed to answer the following question(s):

What are (un)favorable effects of a restrictive strategy compared with usual care for cholecystectomy in patients with gallstones and abdominal pain?

Table 1. PICO

Relevant outcome measures

The guideline panel considered PROMs: pain and health-related quality of life as critical outcome measures for decision making; and complications (surgical and biliary), number of cholecystectomies, and cost-effectiveness as important outcome measures for decision making.

A priori, the guideline panel did not define the outcome measures listed above but used the definitions used in the studies.

The guideline panel defined the following as a minimal clinically (patient) important difference.

• Patients being pain-free: ARD 5%.
• Pain-free score:  % of patients with VAS < 4 – ARD 5%.
• Health-related quality of life: 0.10 utility difference.
• Complications: ARD 5%.
• Cholecystectomies: ARD 5%.

Search and select (Methods)

A systematic literature search was performed by a medical information specialist using the following bibliographic databases: Embase.com and Ovid/Medline. Both databases were searched for systematic reviews and RCTs published from 2000 to 7 November 2024. Systematic searches were completed using a combination of controlled vocabulary/subject headings (e.g., Emtree-terms, MeSH) wherever they were available and natural language keywords. The overall search strategy was derived from the following primary search concepts: systematic reviews and randomized controlled trials comparing conservative treatment or restrictive strategy with usual care (surgery) in patients with uncomplicated symptomatic gallstones and abdominal complaints. The patients in the control group received surgery based on discretion of surgeon in shared decision with the patient. For the intervention group the goal was to minimize the amount of surgeries.

Duplicates were removed using EndNote software. After deduplication a total of 376 records were imported for title/abstract screening. Initially, thirteen studies were selected based on title and abstract screening. After reading the full text, seven studies were excluded (see the exclusion table under the tab ‘Evidence tabellen’), and six studies were included. Three publications reported on the SECURE trial, two publications reported on the Vetrhus trial and one publication reported on the C-GALL trial.

1. Comes DJ, Wennmacker SZ, Latenstein CSS, van der Bilt J, Buyne O, Donkervoort SC, Heisterkamp J, In't Hof K, Jansen J, Nieuwenhuijs VB, Steenvoorde P, Stockmann HBAC, Boerma D, Drenth JPH, van Laarhoven CJHM, Boermeester MA, Dijkgraaf MGW, de Reuver PR. Restrictive Strategy vs Usual Care for Cholecystectomy in Patients With Abdominal Pain and Gallstones: 5-Year Follow-Up of the SECURE Randomized Clinical Trial. JAMA Surg. 2024 Nov 1;159(11):1235-1243. doi:10.1001/jamasurg.2024.3080. PMID: 39167382; PMCID: PMC11339699.
2. Innes K, Ahmed I, Hudson J, Hernández R, Gillies K, Bruce R, Bell V, Avenell A, Blazeby J, Brazzelli M, Cotton S, Croal B, Forrest M, MacLennan G, Murchie P, Wileman S, Ramsay C. Laparoscopic cholecystectomy versus conservative management for adults with uncomplicated symptomatic gallstones: the C-GALL RCT. Health Technol Assess. 2024 Jun;28(26):1-151. doi: 10.3310/MNBY3104. PMID: 38943314; PMCID:PMC11228691.
3. Latenstein CSS, Wennmacker SZ, van Dijk AH, Drenth JPH, Westert GP, van Laarhoven CJHM, Boermeester MA, de Reuver PR, Dijkgraaf MGW; SECURE trial collaborators. Cost- effectiveness of Restrictive Strategy Versus Usual Care for Cholecystectomy in Patients With Gallstones and Abdominal Pain (SECURE-trial). Ann Surg. 2022 Aug 1;276(2):e93-e101. doi: 10.1097/SLA.0000000000004532. Epub 2020 Oct 15. PMID:33065642.
4. Schmidt M, Søndenaa K, Vetrhus M, Berhane T, Eide GE. A randomized controlled study of uncomplicated gallstone disease with a 14-year follow-up showed that operation was the preferred treatment. Dig Surg. 2011;28(4):270-6. doi: 10.1159/000329464. Epub 2011 Jul 9. PMID: 21757915.
5. van Dijk AH, Wennmacker SZ, de Reuver PR, Latenstein CSS, Buyne O, Donkervoort SC, Eijsbouts QAJ, Heisterkamp J, Hof KI', Janssen J, Nieuwenhuijs VB, Schaap HM, Steenvoorde P, Stockmann HBAC, Boerma D, Westert GP, Drenth JPH, Dijkgraaf MGW, Boermeester MA, van Laarhoven CJHM. Restrictive strategy versus usual care for cholecystectomy in patients with gallstones and abdominal pain (SECURE): a multicentre, randomised, parallel-arm, non-inferiority trial. Lancet. 2019 Jun 8;393(10188):2322-2330. doi: 10.1016/S0140-6736(19)30941-9. Epub 2019 Apr 27. Erratum in: Lancet. 2019 May 11;393(10184):1936. doi: 10.1016/S0140-6736(19)31008-6. PMID:31036336.
6. Vetrhus M, Søreide O, Eide GE, Solhaug JH, Nesvik I, Søndenaa K. Pain and quality of life in patients with symptomatic, non-complicated gallbladder stones: results of a randomized controlled trial. Scand J Gastroenterol. 2004 Mar;39(3):270-6. doi: 10.1080/00365520310008502. PMID: 15074398.
7. Wennmacker SZ, Dijkgraaf MGW, Westert GP, Drenth JPH, van Laarhoven CJHM, de Reuver PR. Persistent abdominal pain after laparoscopic cholecystectomy is associated with increased healthcare consumption and sick leave. Surgery. 2018 Apr;163(4):661-666. doi: 10.1016/j.surg.2017.09.004. Epub 2017 Nov 10. PMID:29133112.