Cost-effectiveness of Restrictive Strategy Versus Usual Care for Cholecystectomy in Patients With Gallstones and Abdominal Pain (SECURE-trial).

OBJECTIVE: To perform a cost-effectiveness analysis of restrictive strategy versus usual care in patients with gallstones and abdominal pain. SUMMARY OF BACKGROUND DATA: A restrictive selection strategy for surgery in patients with gallstones reduces cholecystectomies, but the impact on overall costs and cost-effectiveness is unknown. METHODS: Data of a multicentre, randomized-controlled trial (SECURE-trial) were used. Adult patients with gallstones and abdominal pain were included. Restrictive strategy was economically evaluated against usual care from a societal perspective. Hospital-use of resources was gathered with case-report forms and out-of-hospital consultations, out-of-pocket expenses, and productivity loss were collected with questionnaires. National unit costing was applied. The primary outcome was the cost per pain-free patient after 12 months. RESULTS: All 1067 randomized patients (49.0 years, 73.7% females) were included. After 12 months, 56.2% of patients were pain-free in restrictive strategy versus 59.8% after usual care. The restrictive strategy significantly reduced the cholecystectomy rate with 7.7% and reduced surgical costs with €160 per patient, €162 was saved from a societal perspective. The cost-effectiveness plane showed that restrictive strategy was cost saving in 89.1%, but resulted in less pain-free patients in 88.5%. Overall, the restrictive strategy saved €4563 from a societal perspective per pain-free patient lost. CONCLUSIONS: A restrictive selection strategy for cholecystectomy saves €162 compared to usual care, but results in fewer pain-free patients. The incremental cost per pain-free patient are savings of €4563 per pain-free patient lost. The higher societal willingness to pay for 1 extra pain-free patient, the lower the probability that the restrictive strategy will be cost-effective. TRIAL REGISTRATION: The Netherlands National Trial Register NTR4022. Registered on 5 June 2013.

Budget Impact of Restrictive Strategy Versus Usual Care for Cholecystectomy (SECURE-Trial).

OBJECTIVES: A cost-effectiveness analysis of a multicenter randomized-controlled trial comparing restrictive strategy versus usual care in patients with gallstones showed that savings by restrictive strategy could not compensate for the lower proportion of pain-free patients. However, four subgroups based on combined stratification factors resulted in less cholecystectomies and more pain-free patients in restrictive strategy (female-low volume-BMI > 30, female-low volume-BMI25-30, female-high volume-BMI25-30, and male-low volume-BMI < 25). The aim of this study was to explore the budget impact from a hospital healthcare perspective of implementation of restrictive strategy in these subgroups. METHODS: Data of the SECURE-trial were used to calculate the hospital budget impact with a time horizon of four years. Based on a study into practice variation, about 19% of hospitals treat patients according restrictive strategy. This represents the proportion of patients treated according restrictive strategy at the start of budget period. Three subanalyses were performed: a scenario analysis in which 30% of patients fall under a restrictive strategy in clinical practice, a sensitivity analysis in which we calculated the budget impact with the low and high 95% confidence limits of the expected future number of patients, a subgroup analysis in which restrictive strategy was also implemented in two additional subgroups (male-high volume-BMI < 25 and female-high volume-BMI >30). RESULTS: Budget impact analysis showed savings of €6.7-€15.6 million (2.2%-5.6%) for the period 2021-2024/2025 by implementing the restrictive strategy in the four subgroups and provision of usual care in other patients. Sensitivity analysis with 30% of patients already in the restrictive strategy at the start of the budget period, resulted in savings between €5.4 million and €14.0 million (1.7%-5.0%). CONCLUSION: Performing a restrictive strategy for selection of cholecystectomy in subgroups of patients and provision of usual care in other patients will result in a lower overall hospital budget needed to treat patients with abdominal pain and gallstones. TRIAL REGISTRATION: The Netherlands National Trial Register NTR4022. Registered on June 5, 2013.

Unsuspected choledocholithiasis found by routine intra-operative cholangiography during laparoscopic cholecystectomy.

BACKGROUND: The true incidence of unsuspected choledocholithiasis found during laparoscopic cholecystectomy (LC) is unknown. Untreated 'silent' stones may be associated with significant long-term risks. The aim of this study was to establish the incidence of unsuspected common bile duct stones (CBDS) and to determine the management and associated risk factors for unsuspected CBDS. METHODS: Retrospective review of a large consecutive series of patients from Australia who underwent LC in a tertiary referral setting. Percentages of unsuspected CBDS, management and complications were reported. Pre-operative and intra-operative factors associated with unsuspected CBDS were determined using multivariable logistic regression analysis. RESULTS: From a total of 1998 patients who underwent LC, 747 (37.4%) patients with no pre-operative suspicious factors were the subject of this study. CBDS were detected in 24 (3.2%) patients and all were managed either laparoscopically or endoscopically. Risk factors independently associated with unsuspected CBDS included patients >55 years of age (odds ratio 2.93, P = 0.038) and a large cystic duct size (odds ratio = 3.13, P < 0.001) on multivariable analysis. CONCLUSION: The incidence of patients with unsuspected CBDS on intra-operative cholangiography is low. Complete clearance of these stones can be achieved using a combination of laparoscopic and endoscopic methods.

Bile leakage after loop closure vs clip closure of the cystic duct during laparoscopic cholecystectomy: A retrospective analysis of a prospective cohort.

BACKGROUND: Laparoscopic cholecystectomy (LC) is one of the most frequently performed surgical procedures. Cystic stump leakage is an underestimated, potentially life threatening complication that occurs in 1%-6% of the patients. With a secure cystic duct occlusion technique during LC, bile leakage becomes a preventable complication. AIM: To investigate the effect of polydioxanone (PDS) loop closure of the cystic duct on bile leakage rate in LC patients. METHODS: In this retrospective analysis of a prospective cohort, the effect of PDS loop closure of the cystic duct on bile leakage complication was compared to patients with conventional clip closure. Logistic regression analysis was used to develop a risk score to identify bile leakage risk. Leakage rate was assessed for categories of patients with increasing levels of bile leakage risk. RESULTS: Of the 4359 patients who underwent LC, 136 (3%) underwent cystic duct closure by a PDS loop. Preoperatively, loop closure patients had significantly more complicated biliary disease compared to the clipped closure patients. In the loop closure cohort, zero (0%) bile leakage occurred compared to 59 of 4223 (1.4%) clip closure patients. For patients at increased bile leakage risk (risk score ≥ 1) rates were 1.6% and up to 13% (4/30) for clip closure patients with a risk score ≥ 4. This risk increase paralleled a stepwise increase of actual bile leakage complication for clip closure patients, which was not observed for loop closure patients. CONCLUSION: Cystic duct closure with a PDS loop during LC may reduce bile leakage in patients at increased risk for bile leakage.

Predicting operative difficulty of laparoscopic cholecystectomy in patients with acute biliary presentations.

BACKGROUND: Early laparoscopic cholecystectomy (LC) is advocated in patients with an acute biliary presentation but may require some precaution. We aimed to assess the intra-operative difficulty of cholecystectomy in patients who underwent early intervention, and to establish a prediction model for a 'complicated' LC. METHODS: Retrospective analysis of prospectively collected data from patients presenting to the emergency department with acute biliary symptoms, and who subsequently underwent early LC between 2015 and 2018. Operative difficulty was assessed by standardized grading of intra-operative findings (grades 1-4). Pre-operative predictors for a 'complicated' LC (grades 3/4) were assessed using univariable and multivariable logistic regression analysis. A prediction model was created using variable regression coefficients. Cut-off and accuracy of the model were assessed using a receiver operating characteristic curve. RESULTS: A total of 185 patients were included and 59% presented with acute cholecystitis. In this cohort 113 (61%) patients underwent a 'complicated' LC. A prediction model for a 'complicated' LC (0-4.5 points) included: clinical diagnosis of acute cholecystitis (2 points), C-reactive protein >10.5 mg/L (1.5 points) and pericholecystic fluid on pre-operative imaging (1 point). A score ≥2.5 had a sensitivity of 77.7%, specificity of 81.7% and positive and negative predictive values of 87.0% and 69.9%, respectively. CONCLUSION: Early LC may be 'complicated' in up to 60% of cases. The presented prediction model uses readily available information in the emergency department and is a simple but accurate way to predict a likely 'complicated' LC in patients with acute biliary presentations.

Restrictive strategy versus usual care for cholecystectomy in patients with gallstones and abdominal pain (SECURE): a multicentre, randomised, parallel-arm, non-inferiority trial.

BACKGROUND: International guidelines advise laparoscopic cholecystectomy to treat symptomatic, uncomplicated gallstones. Usual care regarding cholecystectomy is associated with practice variation and persistent post-cholecystectomy pain in 10-41% of patients. We aimed to compare the non-inferiority of a restrictive strategy with stepwise selection with usual care to assess (in)efficient use of cholecystectomy. METHODS: We did a multicentre, randomised, parallel-arm, non-inferiority study in 24 academic and non-academic hospitals in the Netherlands. We enrolled patients aged 18-95 years with abdominal pain and ultrasound-proven gallstones or sludge. Patients were randomly assigned (1:1) to either usual care in which selection for cholecystectomy was left to the discretion of the surgeon, or a restrictive strategy with stepwise selection for cholecystectomy. For the restrictive strategy, cholecystectomy was advised for patients who fulfilled all five pre-specified criteria of the triage instrument: 1) severe pain attacks, 2) pain lasting 15-30 min or longer, 3) pain located in epigastrium or right upper quadrant, 4) pain radiating to the back, and 5) a positive pain response to simple analgesics. Randomisation was done with an online program, implemented into a web-based application using blocks of variable sizes, and stratified for centre (academic versus non-academic and a high vs low number of patients), sex, and body-mass index. Physicians and patients were masked for study-arm allocation until after completion of the triage instrument. The primary, non-inferiority, patient-reported endpoint was the proportion of patients who were pain-free at 12 months' follow-up, analysed by intention to treat and per protocol. A 5% non-inferiority margin was chosen, based on the estimated clinically relevant difference. Safety analyses were also done in the intention-to treat population. This trial is registered at the Netherlands National Trial Register, number NTR4022. FINDINGS: Between Feb 5, 2014, and April 25, 2017, we included 1067 patients for analysis: 537 assigned to usual care and 530 to the restrictive strategy. At 12 months' follow-up 298 patients (56%; 95% CI, 52·0-60·4) were pain-free in the restrictive strategy group, compared with 321 patients (60%, 55·6-63·8) in usual care. Non-inferiority was not shown (difference 3·6%; one-sided 95% lower CI -8·6%; pnon-inferiority=0·316). According to a secondary endpoint analysis, the restrictive strategy resulted in significantly fewer cholecystectomies than usual care (358 [68%] of 529 vs 404 [75%] of 536; p=0·01). There were no between-group differences in trial-related gallstone complications (40 patients [8%] of 529 in usual care vs 38 [7%] of 536 in restrictive strategy; p=0·16) and surgical complications (74 [21%] of 358 vs 88 [22%] of 404, p=0·77), or in non-trial-related serious adverse events (27 [5%] of 529 vs 29 [5%] of 526). INTERPRETATION: Suboptimal pain reduction in patients with gallstones and abdominal pain was noted with both usual care and following a restrictive strategy for selection for cholecystectomy. However, the restrictive strategy was associated with fewer cholecystectomies. The findings should encourage physicians involved in the care of patients with gallstones to rethink cholecystectomy, and to be more careful in advising a surgical approach in patients with gallstones and abdominal symptoms. FUNDING: The Netherlands Organization for Health Research and Development, and CZ healthcare insurance.

Efficacy of Antibiotic Agents after Spill of Bile and Gallstones during Laparoscopic Cholecystectomy.

Background: Perforation of the gallbladder during laparoscopic cholecystectomy (LC) results in spill of bile or gallstones in the abdominal cavity. The aim of this study was to assess whether antibiotic agents after spill have an effect on post-operative and infectious complications. Patients and Methods: Operative reports and clinical data of patients undergoing LC between 2012 and 2016 in three hospitals were screened retrospectively for spill of bile and spill of gallstones. Included patients were divided into two groups: Patients who were treated with antibiotic agents (either prophylactic or a single administration during or directly post-operatively because of spill) and patients who did not receive any antibiotic agents. Patients were also categorized as to uncomplicated or complicated gallstone disease. Multi-variable logistic regression was used to assess risk factors for overall and infectious complications after spill. Results: Spill was reported in 14.7% (481 of 3,262). The infectious complication rate was 8.7% (42/481). Of 481 patients, 295 (61.3%) had uncomplicated gallstone disease and 239 (49.7%) received antibiotic treatment. Rates of infectious complications were comparable among patients receiving antibiotic agents or no antibiotic agents (8% vs. 9%, respectively; p = 0.779); also when analysis only included patients with complicated gallstone disease (11% vs. 10% respectively, p = 0.861). Spill of stones was the only independent risk factor associated with post-operative complications (odds ratio 2.55, 95% confidence interval 1.23-5.29, p = 0.012). Conclusion: Antibiotic agents (prophylaxis or intra-operative) after spill of bile and spill of gallstones do not reduce the risk of overall and infectious complications. Spill of stones is associated independently with post-operative complications. The present study sample may leave small differences in complication rates undetected.

Polyp size of 1 cm is insufficient to discriminate neoplastic and non-neoplastic gallbladder polyps.

BACKGROUND: A significant proportion of gallbladder polyps are non-neoplastic, for which resection is not necessary. However, international guidelines advocate cholecystectomy for all polyps ≥ 1 cm. This study assessed a national cohort of histopathologically proven gallbladder polyps to distinguish neoplastic from non-neoplastic polyps. METHODS: PALGA, the nationwide network and registry of histo- and cytopathology, was searched to identify all histopathologically proven gallbladder polyps between 2003 and 2013. All polyps and (focal) wall thickenings > 5 mm were included, and classified as neoplastic or non-neoplastic. Polyp subtype, size, distribution, presentation as wall thickening or protruding polyp, and presence of gallstones were assessed for neoplastic and non-neoplastic polyps. A decision tree to distinguish neoplastic and non-neoplastic polyps was made and diagnostic accuracy of 1 cm surgical threshold was calculated. RESULTS: A total of 2085 out of 220,612 cholecystectomies contained a polyp (0.9%). Of these polyps, 56.4% were neoplastic (40.1% premalignant, 59.9% malignant) and 43.6% non-neoplastic (41.5% cholesterol polyp, 37.0% adenomyomatosis, 21.5% other). Polyp size, distribution, and presence of gallstones were reported in 1059, 1739 and 1143 pathology reports, respectively. Neoplastic polyps differed from non-neoplastic polyps in size (18.1 mm vs 7.5 mm, p < 0.001), singularity (88.2% vs 68.2%, p < 0.001), wall thickening (29.1% vs 15.6%, p < 0.001), and presence of gallstones (50.1% vs 40.4%, p = 0.001). However, adenomyomatosis presented with similar characteristics as neoplastic polyps. Fifty percent of polyps were ≥ 1 cm surgical threshold (optimal surgical threshold based on ROC-curve); sensitivity for indicating neoplastic polyps was 68.1%, specificity was 70.2%, and positive and negative predictive values were 72.9% and 65.1%. CONCLUSIONS: The prevalence of gallbladder polyps on cholecystectomy is low and many of the polyps are non-neoplastic. Clinicopathological characteristics differ between neoplastic and non-neoplastic polyps in general, but these cannot properly indicate neoplasia. The 1 cm surgical threshold has moderate diagnostic accuracy and is insufficient to indicate surgery for neoplastic gallbladder polyps.

Statistical analysis plan of a randomized controlled trial to compare a restrictive strategy to usual care for the effectiveness of cholecystectomy (SECURE trial).

BACKGROUND: Cholecystectomy is the preferred treatment for symptomatic cholecystolithiasis. However, persistent pain after cholecystectomy for symptomatic cholecystolithiasis is reported in up to 40% of patients. The aim of the SECURE trial is to compare the effectiveness of usual care with a restrictive strategy using a standardized work-up with stepwise selection for cholecystectomy in patients with gallstones and abdominal complaints. The SECURE trial is designed as a multicenter, randomized, parallel-arm, non-inferiority trial in patients with abdominal symptoms and ultrasound-proven gallstones or sludge. Randomization was performed to either usual care (standard practice, according to the physician's knowledge and experience, and physician's and patient's preference) or a restrictive standardized strategy: treated with interval evaluation and stepwise selection for laparoscopic cholecystectomy based on fulfilment of pre-specified criteria. This article presents in detail the statistical analysis plan (SAP) of this trial and was submitted before outcomes were available to the investigators. RESULTS: The primary end point of this trial is defined as the proportion of patients being pain-free at 12 months' follow-up. Pain will be assessed with the Izbicki Pain Score. Secondary endpoints will be the proportion of patients with complications due to gallstones or cholecystectomy, quality of life, the association between the patients' symptoms and treatment, work performance, and cost-effectiveness. DISCUSSION: The data from the SECURE trial will provide evidence whether or not a restrictive strategy in patients with symptomatic cholecystolithiasis is associated with similar patient reported outcomes and a reduction in the number of cholecystectomies compared to usual care. The data from this trial will be analyzed according to this pre-specified SAP. TRIAL REGISTRATION: The Netherlands National Trial Register NTR4022 . Registered on 5 June 2013.

Systematic review of cystic duct closure techniques in relation to prevention of bile duct leakage after laparoscopic cholecystectomy.

AIM: To study the effect of different techniques of cystic duct closure on bile leakage after laparoscopic cholecystectomy (LC) for biliary disease. METHODS: A systematic search of MEDLINE, Cochrane and EMBASE was performed. Rate of cystic duct leakage (CDL) was the primary outcome. Risk of bias was evaluated. Odds ratios were analyzed for comparison of techniques and pooled event rates for non-comparative analyses. Pooled event rates were compared for each of included techniques. RESULTS: Out of 1491 articles, 38 studies were included. A total of 47491 patients were included, of which 38683 (81.5%) underwent cystic duct closure with non-locking (metal) clips. All studies were of low-moderate methodological quality. Only two studies reported separate data on uncomplicated and complicated gallbladder disease. For overall CDL, an odds ratio of 0.4 (95%CI: 0.06-2.48) was found for harmonic energy vs clip closure and an odds ratio of 0.17 (95%CI: 0.03-0.93) for locking vs non-locking clips. Pooled CDL rate was around 1% for harmonic energy and metal clips, and 0% for locking clips and ligatures. CONCLUSION: Based on available evidence it is not possible to either recommend or discourage any of the techniques for cystic duct closure during LC with respects to CDL, although data point out a slight preference for locking clips and ligatures vs other techniques. No separate recommendation can be made for complicated gallbladder disease.

Short- and Long-Term Outcomes after a Reconstituting and Fenestrating Subtotal Cholecystectomy.

BACKGROUND: Multiple surgical techniques are recommended to perform cholecystectomy safely in difficult cases, such as conversion to open operation or subtotal cholecystectomy (STC). Reconstituting and fenestrating STC are 2 techniques for STC. The aim of this study was to investigate the short and long-term morbidity and quality of life associated with STC and to compare the outcomes after reconstituting and fenestrating STC. STUDY DESIGN: Patients who underwent STC were identified. Short-term morbidity assessed included bile leakage, bile duct injury, intra-abdominal infection, reinterventions, and readmittance. Long-term morbidity included bile duct stenosis and recurrent biliary events. Differences in the outcomes of fenestrating and reconstituting STC were assessed. Quality of life was assessed by EuroQol 5 Dimensions, Short-Form 36 Questionnaire, and Gastrointestinal Quality of Life Index questionnaires. RESULTS: Subtotal cholecystectomy was performed in 191 patients, of which 102 (53%) underwent fenestrating STC and 73 (38%) underwent reconstituting STC. Bile leakage was significantly more common after fenestrating STC (18% vs 7%, respectively; p < 0.022). After a median of 6 years follow-up (interquartile range 5 to 10 years), recurrence rate of biliary events was lower after fenestrating than reconstituting STC (9% vs 18%, respectively; p < 0.022). Overall reintervention rate did not differ between the 2 groups: 32% in the fenestrating STC group and 26% in the reconstituting STC group (p = 0.211). Completion cholecystectomy was performed significantly more in patients after fenestrating STC (9% vs 4%; p < 0.022). CONCLUSIONS: Subtotal cholecystectomy is a safe and feasible technique for difficult cases for which conversion only will not solve the difficulty of an inflamed hepatocystic triangle. The choice for reconstituting or fenestrating STC depends on intraoperative conditions and both techniques are associated with specific complications.

Assessment of available evidence in the management of gallbladder and bile duct stones: a systematic review of international guidelines.

BACKGROUND: Gallstone disease is a frequent disorder in the Western world with a prevalence of 10-20%. Recommendations for the assessment and management of gallstones vary internationally. The aim of this systematic review was to assess quality of guideline recommendations for treatment of gallstones. METHODS: PubMed, EMBASE and websites of relevant associations were systematically searched. Guidelines without a critical appraisal of literature were excluded. Quality of guidelines was determined using the AGREE II instrument. Recommendations without consensus or with low level of evidence were considered to define problem areas and clinical research gaps. RESULTS: Fourteen guidelines were included. Overall quality of guidelines was low, with a mean score of 57/100 (standard deviation 19). Five of 14 guidelines were considered suitable for use in clinical practice without modifications. Ten recommendations from all included guidelines were based on low level of evidence and subject to controversy. These included major topics, such as definition of symptomatic gallstones, indications for cholecystectomy and intraoperative cholangiography. CONCLUSION: Only five guidelines on gallstones are evidence-based and of a high quality, but even in these controversy exists on important topics. High quality evidence is needed in specific areas before an international guideline can be developed and endorsed worldwide.