Use of incretin agents and risk of acute and chronic pancreatitis: A population-based cohort study.

AIM: To determine the association between the use of incretin agents (dipeptidyl peptidase-4 inhibitors and glucagon-like peptide-1 receptor agonists) for the treatment of type 2 diabetes mellitus (T2DM) and the risk of any, acute and chronic pancreatitis. RESEARCH DESIGN AND METHODS: A population-based cohort study was conducted using data from the UK Clinical Practice Research Datalink (CPRD 2007-2012). A total of 182 428 adult patients with ≥1 non-insulin antidiabetic drug (NIAD) prescription were matched to control subjects without diabetes. Cox regression was used to estimate adjusted hazard ratios (HRs) and 95% confidence intervals (CIs) of pancreatitis in incretin-users (N = 28 370) compared with controls and with other NIAD users. Adjustments were made for lifestyle, disease and drug history. In a sensitivity analysis, a new-user design was used. RESULTS: Current incretin users had a 1.5-fold increased risk of any pancreatitis compared with NIAD users (adjusted HR 1.47, 95% CI 1.06-2.04). In incident current incretin users the risk of any and acute pancreatitis was increased 2.1- and 2.0-fold compared with NIAD users (adjusted HR 2.12, 95% CI 1.31-3.43 and adjusted HR 1.96, 95% CI 1.13-3.41), whereas there was no increased risk found for chronic pancreatitis. CONCLUSIONS: Incretin use was associated with an increased risk of any pancreatitis. Moreover, risk of any and acute pancreatitis was higher when applying a new-user design. We were not able to detect an association with chronic pancreatitis, but the number in this subgroup was small.

Vegetable, fruit and nitrate intake in relation to the risk of Barrett's oesophagus in a large Dutch cohort.

There are few epidemiological data on the dietary risk factors of Barrett's oesophagus, a precursor of oesophageal adenocarcinoma. The present study investigated the association between vegetable, fruit and nitrate intake and Barrett's oesophagus risk in a large prospective cohort. The Netherlands Cohort Study recruited 120,852 individuals aged 55-69 years in 1986. Vegetable and fruit intake was assessed using a 150-item FFQ, and nitrate intake from dietary sources and drinking water was determined. After 16.3 years of follow-up, 433 cases (241 men and 192 women) of Barrett's oesophagus with specialised intestinal metaplasia and 3717 subcohort members were analysed in a case-cohort design using Cox proportional hazards models while adjusting for potential confounders. Men exhibited a lower risk of Barrett's oesophagus in the highest v. the lowest quintile of total (multivariable-adjusted hazard ratio (HR): 0.66, 95% CI 0.43, 1.01), raw (HR 0.63, 95% CI 0.40, 0.99), raw leafy (HR 0.55, 95% CI 0.36, 0.86) and Brassica (HR 0.64, 95% CI 0.41, 1.00) vegetable intake. No association was found for other vegetable groups and fruits. No significant associations were found between vegetable and fruit intake and Barrett's oesophagus risk among women. Total nitrate intake was inversely associated with Barrett's disease risk in men (HR 0.50, 95% CI 0.25, 0.99) and positively associated with it in women (HR 3.77, 95% CI 1.68, 8.45) (P for interaction = 0.04). These results suggest that vegetable intake may contribute to the prevention of Barrett's oesophagus. The possible differential effect in men and women should be evaluated further.

Percutaneous radiofrequency ablation of the splanchnic nerves in patients with chronic pancreatitis: results of single and repeated procedures in 11 patients.

BACKGROUND: Pain is a major problem for chronic pancreatitis (CP) patients. Unfortunately, medical therapy often fails. Endoscopic and surgical treatments are invasive, and results vary. Percutaneous radiofrequency ablation of the splanchnic nerves (RFSN) is a relatively new and minimally invasive procedure for treatment of intractable pain in CP patients. MATERIALS AND METHODS: We retrospectively evaluated 18 RFSN procedures in 11 CP patients, all refractory to analgesics. Five patients underwent a second procedure; two patients underwent a third procedure. NRS pain scores were assessed. Complications, analgesics usage, and length of the pain-free period were recorded. RESULTS: Radiofrequency ablation of the splanchnic nerves was effective in 15/18 interventions. The mean NRS pain score decreased from 7.7 ± 1.0 to 2.8 ± 2.7 (P ≤ 0.001). The pain-free period lasted for a median period of 45 weeks. The effect of repeated interventions was comparable to the initial procedure. One transient side effect was reported. Four patients reported significantly reduced analgesic usage; 4 patients completely stopped their pain medication. CONCLUSION: Radiofrequency ablation of the splanchnic nerves is a minimally invasive, effective procedure for pain relief. After the effect has subsided, RFSN can be successfully repeated. RFSN might become an alternative treatment in a selected group of CP patients. A larger, randomized trial is justified to substantiate these findings.

Total cancer incidence and overall mortality are not increased among patients with Barrett's esophagus.

BACKGROUND & AIMS: Barrett's esophagus (BE) increases risk for esophageal adenocarcinoma, but it is not clear how it affects risk for other cancers or overall mortality. We analyzed data from a population-based cohort of subjects with BE. METHODS: The Netherlands Cohort Study was initiated in 1986 and included 120,852 participants (55-69 years old at baseline). Until December 2002, 626 incident cases of BE (excluding nonintestinal metaplasia) were identified by record linkage with the nationwide Pathology Registry. This cohort was followed for a median period of 5.7 years; data on cancer and mortality were obtained from record linkage to the Netherlands Cancer Registry and Statistics Netherlands. The expected number of cases was calculated using national cancer incidence and mortality data. RESULTS: In the BE cohort, 13 individuals developed esophageal cancer and 5 developed gastric cancer. The ratio of observed:expected (O:E) incidence of esophageal and gastric cancer was 10.0 (95% confidence interval [CI], 5.3-17.1) and 1.8 (95% CI, 0.6-4.2), respectively. Total cancer incidence (excluding esophageal and gastric cancer) increased in the BE cohort, although not by a statistically significant amount (O:E, 1.3; 95% CI, 1.0-1.6). Of cancer subtypes, incidences of small intestinal and pancreatic cancer increased in subjects with BE, but not by a statistically significant amount, after exclusion of data from the first 6 months of follow-up. During the follow-up period, 225 individuals with BE died. Mortality from all causes (excluding esophageal and gastric cancer) was not increased among subjects with BE (O:E, 1.0; 95% CI, 0.9-1.2), nor was mortality from specific causes of death. CONCLUSIONS: The incidence of esophageal cancer was increased in a population-based cohort of subjects with BE. However, when esophageal and gastric cancers were excluded, total cancer incidence and overall mortality were not increased among subjects with BE.

26. Pain in chronic pancreatitis.

Chronic pancreatitis is defined as a progressive inflammatory response of the pancreas that has lead to irreversible morphological changes of the parenchyma (fibrosis, loss of acini and islets of Langerhans, and formation of pancreatic stones) as well as of the pancreatic duct (stenosis and pancreatic stones). Pain is one of the most important symptoms of chronic pancreatitis. The pathogenesis of this pain can only partly be explained and it is therefore often difficult to treat this symptom. The management of pain induced by chronic pancreatitis starts with lifestyle changes and analgesics. For the pharmacological management, the three-step ladder of the World Health Organization extended with the use of co-analgesics is followed. Interventional pain management may consist of radiofrequency treatment of the nervi splanchnici, spinal cord stimulation, endoscopic stenting or stone extraction possibly in combination with lithotripsy, and surgery. To date, there are no randomized controlled trials supporting the efficacy of radiofrequency and spinal cord stimulation. The large published series reports justify a recommendation to consider these treatment options. Radiofrequency treatment, being less invasive than spinal cord stimulation, could be tested prior to considering spinal cord stimulation. There are several other treatment possibilities such as endoscopic or surgical treatment, pancreatic enzyme supplementation and administration of octreotide and antioxidants. All may have a role in the management of pain induced by chronic pancreatitis.

Aggressive fluid hydration plus non-steroidal anti-inflammatory drugs versus non-steroidal anti-inflammatory drugs alone for post-endoscopic retrograde cholangiopancreatography pancreatitis (FLUYT): a multicentre, open-label, randomised, controlled trial.

BACKGROUND: Pancreatitis is the most common complication of endoscopic retrograde cholangiopancreatography (ERCP). Prophylactic rectal administration of non-steroidal anti-inflammatory drugs (NSAIDs) is considered as standard of care to reduce the risk of post-ERCP pancreatitis. It has been suggested that aggressive hydration might further reduce this risk. Guidelines already recommend aggressive hydration in patients who are unable to receive rectal NSAIDs, although it is laborious and time consuming. We aimed to evaluate the added value of aggressive hydration in patients receiving prophylactic rectal NSAIDs. METHODS: FLUYT, a multicentre, open-label, randomised, controlled trial done across 22 Dutch hospitals, included patients aged between 18 and 85 years with moderate to high risk of post-ERCP pancreatitis. Patients were randomly assigned (1:1) by a web-based module with varying block sizes to a combination of aggressive hydration and rectal NSAIDs (100 mg diclofenac or indomethacin; aggressive hydration group) or rectal NSAIDs (100 mg diclofenac or indomethacin) alone (control group). Randomisation was stratified according to treatment centre. Aggressive hydration comprised 20 mL/kg intravenous Ringer's lactate solution within 60 min from the start of ERCP, followed by 3 mL/kg per h for 8 h. The control group received normal intravenous saline with a maximum of 1·5 mL/kg per h and 3 L per 24 h. The primary endpoint was post-ERCP pancreatitis and was analysed on a modified intention-to-treat basis (including all patients who underwent randomisation and an ERCP and for whom data regarding the primary outcome were available). The trial is registered with the ISRCTN registry, ISRCTN13659155. FINDINGS: Between June 5, 2015, and June 6, 2019, 826 patients were randomly assigned, of whom 388 in the aggressive hydration group and 425 in the control group were included in the modified intention-to-treat analysis. Post-ERCP pancreatitis occurred in 30 (8%) patients in the aggressive hydration group and in 39 (9%) patients in the control group (relative risk 0·84, 95% CI 0·53-1·33, p=0·53). There were no differences in serious adverse events, including hydration-related complications (relative risk 0·99, 95% CI 0·59-1·64; p=1·00), ERCP-related complications (0·90, 0·62-1·31; p=0·62), intensive care unit admission (0·37, 0·07-1·80; p=0·22), and 30-day mortality (0·95, 0·50-1·83; p=1·00). INTERPRETATION: Aggressive periprocedural hydration did not reduce the incidence of post-ERCP pancreatitis in patients with moderate to high risk of developing this complication who routinely received prophylactic rectal NSAIDs. Therefore, the burden of laborious and time-consuming aggressive periprocedural hydration to further reduce the risk of post-ERCP pancreatitis is not justified. FUNDING: Netherlands Organisation for Health Research and Development and Radboud University Medical Center.

Toenail selenium status and the risk of Barrett's esophagus: the Netherlands Cohort Study.

OBJECTIVE: To investigate the association between selenium and the risk of Barrett's esophagus (BE), the precursor lesion of esophageal adenocarcinoma. METHODS: Data from the prospective Netherlands Cohort Study were used. This cohort study was initiated in 1986, when 120,852 subjects aged 55-69 years completed a questionnaire on dietary habits and lifestyle, and provided toenail clippings for the determination of baseline selenium status. After 16.3 years of follow-up, 253 BE cases (identified through linkage with the nationwide Dutch pathology registry) and 2,039 subcohort members were available for case-cohort analysis. Cox proportional hazards models were used to calculate incidence rate ratios (RR). RESULTS: The multivariable-adjusted RR for the highest versus the lowest quartile of toenail selenium was 1.06 (95% CI 0.71-1.57). No dose-response trend was seen (p trend = 0.99). No association was found in subgroups defined by sex, smoking status, body mass index (BMI), or intake of antioxidants. For BE cases that later progressed to high-grade dysplasia or adenocarcinoma, the RR for a selenium level above the median vs. below the median was 0.64 (95% CI 0.24-1.76). CONCLUSIONS: In this large prospective cohort study, we found no evidence of an association between selenium and risk of BE.

Predictive accuracy and feasibility of risk stratification scores for 28-day mortality of patients with sepsis in an emergency department.

OBJECTIVES: Sepsis is associated with high mortality. Because early therapy has proven to decrease mortality, a risk stratification tool that quickly and easily quantifies mortality risk of patients will be helpful to guide appropriate treatment. We investigated five scores in terms of (a) predicting 28-day mortality and (b) their feasibility for use in the emergency department (ED). MATERIALS AND METHODS: We carried out a historical cohort study in the ED of Maastricht University Medical Centre (MUMC). Patients who fulfilled the criteria for sepsis were included if they had been admitted to the hospital by an internist between August 2009 and August 2010. The Mortality in Emergency Department Sepsis (MEDS), Confusion, Urea, Respiratory rate, Blood pressure, age>65 (CURB-65), Acute Physiology And Chronic Health Evaluation II (APACHE II), Rapid Acute Physiology Score (RAPS), and Rapid Emergency Medicine Score (REMS) scores were calculated using ED charts. The primary outcome was total 28-day mortality. Receiver operating characteristic curves and calibration plots were constructed to evaluate predictive accuracy. Feasibility was defined as the proportion of patients for whom all data were available. RESULTS: We included 600 patients, of whom 90 (15%) died within 28 days. Discriminating ability for total 28-day mortality of the MEDS [area under the curve (AUC): 0.82, 95% confidence interval (CI) 0.78-0.87], CURB-65 (AUC: 0.78, 95% CI 0.73-0.83), and APACHE II (AUC: 0.71, 95% CI 0.64-0.79) was the highest, but only the difference between the MEDS and REMS (P=0.007) and the RAPS score (P<0.001) was significant. Both the MEDS and the CURB-65 had higher AUCs for predicting 28-day in-hospital mortality than the other three scores, but this was only significant for the MEDS score compared with the RAPS (P=0.003). Both the MEDS and the CURB-65 underestimated mortality, especially for the higher scores. The MEDS, CURB-65, REMS, and RAPS were most feasible as they could be calculated in more than 96% of patients. CONCLUSION: The MEDS and CURB-65 scores are the most adequate and feasible tools for the prediction of total 28-day mortality in septic patients presenting at the ED, but they need local recalibration before use in the ED.

Prospective multicenter validation of the Glasgow Blatchford bleeding score in the management of patients with upper gastrointestinal hemorrhage presenting at an emergency department.

BACKGROUND/AIMS: The Glasgow Blatchford Bleeding Score (GBS) has been developed to assess the need for treatment in patients with acute upper gastrointestinal hemorrhage (UGIH) presenting at emergency departments (EDs). We aimed (a) to determine the validity of the GBS and Rockall scoring systems for prediction of need for treatment and (b) to identify the optimal cut-off value of the GBS. METHODS: We carried out a population-based, prospective multicenter study of 520 consecutive patients presenting with acute UGIH at EDs of three hospitals. The accuracy of GBS and Rockall scores in predicting the need for treatment (i.e. endoscopic, surgical, or radiological intervention and blood transfusion) was analyzed using receiver operating characteristic curves. RESULTS: Receiver operating characteristic curve analysis showed that the GBS had a good discriminative ability to determine the need for treatment in patients with acute UGIH (area under the curve: 0.88; 95% confidence interval: 0.85-0.91). The GBS was superior to both the clinical Rockall and the full Rockall score in predicting the need for treatment (area under the curve: 0.86 vs. 0.70 vs. 0.77). At a cut-off value of up to 2, the GBS had the optimal combination of sensitivity (99.4%) and specificity (42.4%). CONCLUSION: The GBS is superior compared with both Rockall scores in predicting the need for treatment in patients with suspected acute UGIH presenting at EDs in the Netherlands. Patients with a GBS of 2 or less form a subgroup of low-risk patients. These low-risk patients are eligible for outpatient management, which might reduce hospital admissions and healthcare costs.

[Transfusions in the acutely bleeding patient: the borders between too little too late and too much too early]. / Transfusie bij de acuut bloedende patiënt: de grens tussen 'te weinig te laat' en 'te veel te vroeg'.

A restrictive regime regarding the initiation of blood transfusions was found to be safe in a Spanish study that included 921 patients with upper gastrointestinal bleeding. Survival after 6 weeks was higher (95 vs. 91%) in the restrictive group (Hb 4.3 mmol/l) than in the liberal group (Hb 5.6 mmol/l). The restrictive regimen was found favourable in patients with cirrhosis (class Child-Pugh A and B). In the Netherlands, guidelines prescribe the use of the 4-5-6 rule for initiating blood transfusions, depending on comorbidity (according to ASA classification) for patients who are haemodynamically stable and an aggressive regime when unstable. Starting blood transfusions can be lifesaving and must not be withheld in those who are haemodynamically unstable, but when stable, nuance is needed. In conclusion, the right balance needs to be found between too little too late and too much too early.

Meat consumption and the risk of Barrett's esophagus in a large Dutch cohort.

BACKGROUND: Increasing meat intake and its possible role in the development of esophageal adenocarcinoma raises the question whether meat consumption is associated with the premalignant lesion, Barrett's esophagus. METHODS: Associations between the risk of Barrett's esophagus and meat consumption, intake of N-nitrosodimethylamine, nitrite, and heme iron were examined in the Netherlands Cohort Study among 120,852 subjects aged 55 to 69 years in 1986. Exposure was measured on the basis of a 150-item food frequency questionnaire. After 16.3 years of follow-up, 447 Barrett's esophagus cases with specialized intestinal metaplasia and 3,919 subcohort members were analyzed in a case-cohort design. RESULTS: There was no association of any of the examined exposures with Barrett's risk in men or women. Results were similar in age-adjusted and fully adjusted models and in models excluding the first two years of follow-up. CONCLUSIONS: Our results do not support a role of meat consumption and N-nitrosation related factors in the development of Barrett's esophagus. IMPACT: The possible causal association between red meat intake and esophageal adenocarcinoma is unlikely to be mediated by mechanisms through the development of Barrett's esophagus.

Predictive validity of the Glasgow Blatchford Bleeding Score in an unselected emergency department population in continental Europe.

BACKGROUND AND AIM: Glasgow Blatchford Bleeding Score stratifies patients presenting with acute upper gastrointestinal haemorrhage at the emergency department according to the likelihood of the need for treatment. The objective of this study was to validate the Glasgow Blatchford Bleeding Score for use in an emergency department in the Netherlands. Furthermore, we assessed its clinical usefulness for safe discharge of low-risk acute upper gastrointestinal haemorrhage patients and compared its test validity to that of other scoring systems. METHODS: This multicentre historic cohort study was conducted in two hospitals in the Netherlands. All 478 patients presenting with a suspicion of acute upper gastrointestinal haemorrhage at our emergency departments during a 1-year period were included. For each patient we calculated Glasgow Blatchford Bleeding Score and other commonly used scores. Test validity was assessed using the receiver operated characteristics curve analysis; calibration plots were used to assess the probability of the need for treatment of different levels of the scores. RESULTS: Glasgow Blatchford Bleeding Score had a good discriminative ability in predicting the need for treatment, receiver operated characteristics curve analysis showed an area under the curve of 0.879. Counting a score of 2 or less as low risk (negative), 104 patients (21.7%) were classified as low-risk, with a negative predictive value of 98.1%. These results were superior to those of the other scoring systems. CONCLUSION: Patients presenting at an emergency department in continental Europe with acute upper gastrointestinal haemorrhage and a Glasgow Blatchford Bleeding Score of 2 or less can be safely discharged. The Glasgow Blatchford Bleeding Score performed better than the other commonly used scoring systems.

A prospective cohort study on overweight, smoking, alcohol consumption, and risk of Barrett's esophagus.

BACKGROUND: Barrett's esophagus (BE) is a precursor lesion of esophageal adenocarcinoma. Besides gastroesophageal reflux, possible risk factors for BE include overweight, cigarette smoking, and alcohol consumption. Our objective was to study these associations by using prospective data. METHODS: The prospective Netherlands Cohort Study, initiated in 1986, consists of 120,852 men and women, aged 55 to 69 years at baseline. At baseline, all subjects completed a questionnaire on dietary habits and lifestyle. After 16.3 years of follow-up, 370 BE cases with specialized intestinal metaplasia and 3,866 subcohort members were available for case-cohort analysis. Cox proportional hazards models were used to calculate incidence rate ratios (RR) and 95% CIs. RESULTS: Body mass index (BMI) at baseline was associated with risk of BE in women [multivariable adjusted RR per 1 kg/m(2), 1.07 (1.03-1.11)] but not in men [RR per 1 kg/m(2), 0.99 (0.93-1.05)]. The association in women was not specifically due to abdominal overweight. Former cigarette smokers were at increased risk of BE (RR = 1.33, 95% CI: 1.00-1.77), but current smokers were not. Smoking duration showed a positive association with BE risk (P(trend) = 0.03). For alcohol consumption, the RR per 10 g ethanol/d was 0.95 (0.87-1.03). CONCLUSIONS: Increased BMI was a risk factor for BE in women but not in men. Several aspects of cigarette smoking were positively associated with BE risk. Alcohol consumption was not associated with an increased risk of BE. IMPACT: Future research should focus on risk factors both for development and for progression of BE to esophageal adenocarcinoma.

Ursodeoxycholic acid exerts no beneficial effect in patients with symptomatic gallstones awaiting cholecystectomy.

Ursodeoxycholic acid (UDCA) and impaired gallbladder motility purportedly reduce biliary pain and acute cholecystitis in patients with gallstones. However, the effect of UDCA in this setting has not been studied prospectively. This issue is important, as in several countries (including the Netherlands) scheduling problems result in long waiting periods for elective cholecystectomy. We conducted a randomized, double-blind, placebo-controlled trial on effects of UDCA in 177 highly symptomatic patients with gallstones scheduled for cholecystectomy. Patients were stratified for colic number in the preceding year (<3: 32 patients; > or =3: 145 patients). Baseline postprandial gallbladder motility was measured by ultrasound in 126 consenting patients. Twenty-three patients (26%) receiving UDCA and 29 (33%) receiving placebo remained colic-free during the waiting period (89 +/- 4; median [range]: 75[4-365] days) before cholecystectomy (P = .3). Number of colics, non-severe biliary pain, and analgesics intake were comparable. A low number of prior colics was associated with a higher likelihood of remaining colic-free (59% vs. 23%, P < .001), without effects on the risk of complications. In patients evaluated for gallbladder motility, 57% were weak and 43% were strong contractors (minimal gallbladder volume > respectively < or = 6 mL). Likelihood to remain colic-free was comparable in strong and weak contractors (31% vs. 33%). In weak contractors, UDCA decreased likelihood to remain colic-free (21% vs. 47%, P = .02). In the placebo group, 3 preoperative and 2 post-cholecystectomy complications occurred. In contrast, all 4 complications in the UDCA group occurred after cholecystectomy. In conclusion, UDCA does not reduce biliary symptoms in highly symptomatic patients. Early cholecystectomy is warranted in patients with symptomatic gallstones.

Effects of regular physical activity on defecation pattern in middle-aged patients complaining of chronic constipation.

OBJECTIVE: It is not well known whether physical activity (PA) is useful in the management of patients complaining of constipation. The aim of this study was to test the influence of regular PA on colonic transit time and defecation in middle-aged inactive patients suffering from chronic idiopathic constipation. MATERIAL AND METHODS: Forty-three subjects (> 45 years) were randomly divided into group A (n = 18, 16 F, 2 M) and group B (n = 25, 20 F, 5 M). Group A subjects maintained their normal lifestyle during 12 weeks, followed by a 12-week PA programme. Group B performed a 12-week PA programme after randomization. PA comprised 30 min of brisk walking and a daily 11-min home-based programme. Both groups received dietary advice. Colonic transit time was measured using a radiographic multiple marker single film technique. RESULTS: Despite dietary advice, mean fibre and fluid intake did not change. In group B a significant reduction in 3 out of 4 of the Rome I criteria for constipation was observed, i.e. percentage of incomplete defecations, percentage of defecations requiring straining and percentage of hard stools (p < 0.05). As a consequence, the number of fulfilled Rome criteria for constipation decreased (2.7 to 1.7; p < 0.05). Furthermore, the rectosigmoid and total colonic transit time decreased (17.5 to 9.6 h and 79.2 to 58.4 h, respectively; p < 0.05). After PA the number of fulfilled Rome criteria also decreased in group A (2.6 to 1.7; p < 0.05). CONCLUSIONS: In middle-aged inactive subjects with symptoms of chronic constipation, it is advisable to promote regular physical activity since it improves both the defecation pattern and rectosigmoid or total colonic transit time.

Wait-and-see policy or laparoscopic cholecystectomy after endoscopic sphincterotomy for bile-duct stones: a randomised trial.

BACKGROUND: Patients who undergo endoscopic sphincterotomy for common bile-duct stones, who have residual gallbladder stones, are referred for laparoscopic cholecystectomy. However, only 10% of patients who do not have this operation are reported to develop recurrent biliary symptoms. We aimed to assess whether a wait-and-see policy is justified. METHODS: We did a prospective, randomised, multicentre trial in 120 patients (age 18-80 years) who underwent endoscopic sphincterotomy and stone extraction, with proven gallbladder stones. Patients were randomly allocated to wait and see (n=64) or laparoscopic cholecystectomy (56). Primary outcome was recurrence of at least one biliary event during 2-year follow-up, and secondary outcomes were complications of cholecystectomy and quality of life. Analysis was by intention to treat. FINDINGS: 12 patients were lost to follow-up immediately. Of 59 patients allocated to wait and see, 27 (47%) had recurrent biliary symptoms compared with one (2%) of 49 patients after laparoscopic cholecystectomy (relative risk 22.42, 95% CI 3.16-159.14, p<0.0001). 22 (81%) of 27 patients underwent cholecystectomy, mainly for biliary pain (n=13) or acute cholecystitis (7). Conversion rate to open surgery was 55% in patients allocated to wait and see who underwent cholecystectomy compared with 23% in those who were allocated laparoscopic cholecystectomy (p=0.0104). Morbidity was 32% versus 14% (p=0.1048), and median hospital stay was 9 versus 7 days. Quality of life returned to normal within 3 months after either treatment policy. INTERPRETATION: A wait-and-see policy after endoscopic sphincterotomy in combined cholecystodocholithiasis cannot be recommended as standard treatment, since 47% of expectantly managed patients developed at least one recurrent biliary event and 37% needed cholecystectomy. No major biliary complications arose, but conversion rate was high.