Rectal indometacin dose escalation for prevention of pancreatitis after endoscopic retrograde cholangiopancreatography in high-risk patients: a double-blind, randomised controlled trial.

BACKGROUND: Although rectal indometacin 100 mg is effective in reducing the frequency and severity of pancreatitis after endoscopic retrograde cholangiopancreatography (ERCP) in high-risk patients, the optimal dose is unknown, and pancreatitis incidence remains high. The aim of this study was to compare the efficacy of two dose regimens of rectal indometacin on the frequency and severity of pancreatitis after ERCP in high-risk patients. METHODS: In this randomised, double-blind, comparative effectiveness trial, we enrolled patients from six tertiary medical centres in the USA. Eligible patients were those at high risk for the development of pancreatitis after ERCP. We randomly assigned eligible patients (1:1) immediately after ERCP to receive either two 50 mg indometacin suppositories and a placebo suppository (standard-dose group) or three 50 mg indometacin suppositories (high-dose group). 4 h after the procedure, patients assigned to the high-dose group received an additional 50 mg indometacin suppository, whereas patients in the standard-dose group received an additional placebo suppository. The randomisation schedule, stratified according to study centre and with no other restrictions, was computer generated by an investigator who was uninvolved in the clinical care of any participants, distributed to the sites, and kept by personnel not directly involved with the study. These same personnel were responsible for packaging the drug and placebo in opaque envelopes. Patients, study personnel, and treating physicians were masked to study group assignment. The primary outcome of the study was the development of pancreatitis after ERCP. Analyses were done on an intention-to-treat basis. This trial is registered with ClinicalTrials.gov, number NCT01912716, and enrolment is complete. FINDINGS: Between July 9, 2013, and March 22, 2018, 1037 eligible patients were enrolled and randomly assigned to receive either standard-dose (n=515) or high-dose indometacin (n=522). Pancreatitis after ERCP occurred in 141 (14%) of 1037 patients-76 (15%) of 515 patients in the standard-dose indometacin group and 65 (12%) of 522 patients in the high-dose indometacin group (risk ratio [RR] 1·19, 95% CI 0·87-1·61; p=0·32). We observed 19 adverse events that were potentially attributable to study drug. Clinically significant bleeding occurred in 14 (1%) of 1037 patients-six (1%) of 515 patients in the standard-dose indometacin group and eight (2%) of 522 patients in the high-dose indometacin group (p=0·79). Three (1%) of 522 patients in the high-dose indometacin group developed acute kidney injury versus none in the standard-dose group (p=0·25). A non-ST elevation myocardial infarction occurred in the standard-dose indometacin group 2 days after ERCP. A transient ischaemic attack occurred in the high-dose indometacin group 5 days after ERCP. All 19 adverse events, in addition to the 141 patients who developed pancreatitis after ERCP, were considered serious as all required admission to hospital. We observed no allergic reactions or deaths at 30 day follow-up. INTERPRETATION: Dose escalation to rectal indometacin 200 mg did not confer any advantage compared with the standard 100 mg regimen, with pancreatitis incidence remaining high in high-risk patients. Current practice should continue unchanged. Further research should consider the pharmacokinetics of non-steroidal anti-inflammatory drugs to determine the optimal timing of their administration to prevent pancreatitis after ERCP. FUNDING: American College of Gastroenterology.

The risk of post-ERCP pancreatitis and the protective effect of rectal indomethacin in cases of attempted but unsuccessful prophylactic pancreatic stent placement.

BACKGROUND: It is believed, based on limited observational data, that an unsuccessful attempt to place a prophylactic pancreatic stent substantially increases the risk of post-ERCP pancreatitis (PEP). OBJECTIVE: To better understand the risk of PEP in patients with failed pancreatic stent placement (FPS) and the impact of rectal indomethacin on this risk. DESIGN: Secondary analysis of randomized, controlled trial data. SETTING: University of Michigan and Indiana University. PATIENTS: A total of 577 clinical trial participants at elevated risk for PEP. INTERVENTIONS: Pancreatic stent placement. MAIN OUTCOME MEASUREMENTS: Within the placebo group, we compared PEP rates in patients with FPS, patients who underwent successful stent placement, and in those without a stent attempt. We also performed a regression analysis evaluating the association between FPS and PEP. To define the protective effect of indomethacin, we repeated these analyses in the indomethacin group and in the full study cohort. RESULTS: The incidence of PEP among patients in the placebo group who experienced FPS was 34.7%, significantly exceeding rates in patients who underwent successful stent placement (16.4%) and in those without a stent attempt (12.1%). After we adjusted for known PEP risk factors, FPS was found to be independently associated with PEP. Among the indomethacin group and in the full cohort, FPS was not associated with a higher risk of PEP. LIMITATIONS: Low event rate, FPS not prospectively captured. CONCLUSION: FPS appears to confer an increased risk of PEP, which is attenuated by rectal indomethacin administration. These findings highlight the importance of adequate training and proficiency before endoscopists attempt pancreatic stent placement and the routine use of rectal indomethacin in high-risk ERCP cases.

Performance characteristics of EUS for locoregional evaluation of ampullary lesions.

BACKGROUND: The accuracy of EUS in the locoregional assessment of ampullary lesions is unclear. OBJECTIVES: To compare EUS with ERCP and surgical pathology for the evaluation of intraductal extension and local staging of ampullary lesions. DESIGN: Retrospective cohort study. SETTING: Tertiary-care referral center. PATIENTS: All patients who underwent EUS primarily for the evaluation of an ampullary lesion between 1998 and 2012. INTERVENTION: EUS. MAIN OUTCOME MEASUREMENTS: Comparison of EUS sensitivity/specificity for intraductal and local extension with ERCP and surgical pathology by using the area under the receiver-operating characteristic (AUROC) curves and outcomes of the subgroup referred for endoscopic papillectomy. RESULTS: We identified 119 patients who underwent EUS for an ampullary lesion, of whom 99 (83%) had an adenoma or adenocarcinoma. Compared with ERCP (n = 90), the sensitivity/specificity of EUS for any intraductal extension was 56%/97% (AUROC = 0.77; 95% confidence interval [CI], 0.64-0.89). However, when using surgical pathology as the reference (n = 102), the sensitivity/specificity of EUS (80%/93%; AUROC = 0.87; 95% CI, 0.76-0.97) and ERCP (83%/93%; AUROC = 0.88; 95% CI, 0.77-0.99) were comparable. The overall accuracy of EUS for local staging was 90%. Of 58 patients referred for endoscopic papillectomy, complete resection was achieved in 53 (91%); in those having intraductal extension by EUS or ERCP, complete resection was achieved in 4 of 5 (80%) and 4 of 7 (57%), respectively. LIMITATION: Retrospective design. CONCLUSIONS: EUS and ERCP perform similarly in evaluating intraductal extension of ampullary adenomas. Additionally, EUS is accurate in T-staging ampullary adenocarcinomas. Future prospective studies should evaluate whether EUS can identify characteristics of ampullary lesions that appropriately direct patients to endoscopic or surgical resection.

Endoscopic papillectomy: risk factors for incomplete resection and recurrence during long-term follow-up.

BACKGROUND: Endoscopic papillectomy is increasingly used as an alternative to surgery for ampullary adenomas and other noninvasive ampullary lesions. OBJECTIVE: To measure short-term safety and efficacy of endoscopic papillectomy, define patient and lesion characteristics associated with incomplete endoscopic resection, and measure adenoma recurrence rates during long-term follow-up. DESIGN: Retrospective cohort study. SETTING: Tertiary-care academic medical center. PATIENTS: All patients who underwent endoscopic papillectomy for ampullary lesions between July 1995 and June 2012. INTERVENTION: Endoscopic papillectomy. MAIN OUTCOME MEASUREMENTS: Patient and lesion characteristics associated with incomplete endoscopic resection and ampullary adenoma-free survival analysis. RESULTS: We identified 182 patients who underwent endoscopic papillectomy, 134 (73.6%) having complete resection. Short-term adverse events occurred in 34 (18.7%). Risk factors for incomplete resection were jaundice at presentation (odds ratio [OR] 0.21; 95% confidence interval [CI] 0.07-0.69; P = .009), occult adenocarcinoma (OR 0.06; 95% CI, 0.01-0.36; P = .002), and intraductal involvement (OR 0.29; 95% CI, 0.11-0.75; P = .011). The en bloc resection technique was strongly associated with a higher rate of complete resection (OR 4.05; 95% CI, 1.71-9.59; P = .001). Among patients with ampullary adenoma who had complete resection (n = 107), 16 patients (15%) developed recurrence up to 65 months after resection. LIMITATIONS: Retrospective analysis. CONCLUSION: Jaundice at presentation, occult adenocarcinoma in the resected specimen, and intraductal involvement are associated with a lower rate of complete resection, whereas en bloc papillectomy increases the odds of complete endoscopic resection. Despite complete resection, recurrence was observed up to 5 years after papillectomy, confirming the need for long-term surveillance.

Early measures of hemoconcentration and inflammation are predictive of prolonged hospitalization from post- endoscopic retrograde cholangiopancreatography pancreatitis.

OBJECTIVES: Hemoconcentration markers are predictors of severe acute pancreatitis but have not been specifically evaluated in post-endoscopic retrograde cholangiopancreatography pancreatitis (PEP). METHODS: Case-control study of patients undergoing ERCP for suspected sphincter of Oddi dysfunction. We identified patients with PEP (PEP positive) and controls (PEP negative) in a 1:2 ratio. blood urea nitrogen (BUN) and hematocrit (Hct) were measured before procedure, upon admission, and 24 hours later. Preprocedure levels of BUN and Hct were analyzed to control for confounders. Among the PEP-positive patients, BUN level, Hct level, and systemic inflammatory response syndrome are compared between severe and mild/moderate cases. RESULTS: There were 149 PEP-positive patients, including 18 patients (12.1%) with severe PEP and 301 PEP-negative controls. After adjusting, higher preprocedure BUN level (odds ratio [OR], 1.05 [1.01, 1.10]; P < 0.02) and pancreatic sphincterotomy (OR, 1.60 [1.01, 2.55]; P < 0.05) were associated with PEP, whereas older age (OR, 0.98 [0.96, 0.99]; P < 0.02) and a greater body mass index (OR, 0.97 [0.94, 0.99]; P < 0.03) with a lower rate.Difference in BUN level of 0.0 or greater (failure to decline) had a sensitivity of 71% and a specificity of 79% for differentiating severe from mild/moderate PEP. Patients with severe PEP were more likely to have systemic inflammatory response syndrome upon admission (44.4% [21.5, 67.4]) and after 24 hours (61.1% [38.6, 83.6] versus mild/moderate (9.2% [4.2, 14.1], 10.6% [5.4,16.0]; P < 0.0001 for each). CONCLUSIONS: Preprocedure BUN level is associated with the development of PEP. The preprocedure BUN level and failure of the BUN level to decline during the first 24 hours are associated with prolonged hospitalization.

Does rectal indomethacin eliminate the need for prophylactic pancreatic stent placement in patients undergoing high-risk ERCP? Post hoc efficacy and cost-benefit analyses using prospective clinical trial data.

OBJECTIVES: A recent large-scale randomized controlled trial (RCT) demonstrated that rectal indomethacin administration is effective in addition to pancreatic stent placement (PSP) for preventing post-endoscopic retrograde cholangiopancreatography (ERCP) pancreatitis (PEP) in high-risk cases. We performed a post hoc analysis of this RCT to explore whether rectal indomethacin can replace PSP in the prevention of PEP and to estimate the potential cost savings of such an approach. METHODS: We retrospectively classified RCT subjects into four prevention groups: (1) no prophylaxis, (2) PSP alone, (3) rectal indomethacin alone, and (4) the combination of PSP and indomethacin. Multivariable logistic regression was used to adjust for imbalances in the prevalence of risk factors for PEP between the groups. Based on these adjusted PEP rates, we conducted an economic analysis comparing the costs associated with PEP prevention strategies employing rectal indomethacin alone, PSP alone, or the combination of both. RESULTS: After adjusting for risk using two different logistic regression models, rectal indomethacin alone appeared to be more effective for preventing PEP than no prophylaxis, PSP alone, and the combination of indomethacin and PSP. Economic analysis revealed that indomethacin alone was a cost-saving strategy in 96% of Monte Carlo trials. A prevention strategy employing rectal indomethacin alone could save approximately $150 million annually in the United States compared with a strategy of PSP alone, and $85 million compared with a strategy of indomethacin and PSP. CONCLUSIONS: This hypothesis-generating study suggests that prophylactic rectal indomethacin could replace PSP in patients undergoing high-risk ERCP, potentially improving clinical outcomes and reducing healthcare costs. A RCT comparing rectal indomethacin alone vs. indomethacin plus PSP is needed.

Oral administration of edible oil before ERCP: effect on selective biliary cannulation.

BACKGROUND: A fatty meal before ERCP relaxes the sphincter of Oddi and may facilitate biliary cannulation. OBJECTIVE: To assess the effect of an oral fatty meal before ERCP on time to and success rate of biliary cannulation. DESIGN: Human clinical study. SETTING: Tertiary ERCP center. PATIENTS: Adult patients with intact papilla undergoing ERCP for presumed biliary pathology. INTERVENTIONS: Patients arriving more than 1 hour before the procedure were given oil by mouth. Patients not receiving oil served as controls. The need for a precut sphincterotomy was considered a failure of initial cannulation. MAIN OUTCOME MEASUREMENTS: Appearance of the papillary orifice, bile flow, cannulation success rate, cannulation and fluoroscopy times. RESULTS: A total of 86 patients received oil (mean age 52.8 years; 40% male), and 103 patients served as controls (mean age 53.3 years; 49% male). The papillary orifice was open in 52 of 86 (61%) and 38 of 103 (37%) patients in the oil and control groups, respectively (P = .002). Bile flow was seen in 59 of 86 (68%) and 50 of 103 (49%) patients, respectively (P = .009). The overall initial biliary cannulation success rate was 80 of 86 (93%) and 97 of 103 (94%), respectively (P = .77). There was no difference in cannulation success rates, cannulation, and fluoroscopy times for fellows or faculty endoscopists in each group. No pulmonary aspiration was seen in either group. LIMITATIONS: Unblinded study. CONCLUSIONS: The biliary orifice appeared more open and bile flow was seen in more patients receiving oil, but there was no difference in successful biliary cannulation rates and cannulation and fluoroscopy times in the 2 groups.

Similar efficacies of biliary, with or without pancreatic, sphincterotomy in treatment of idiopathic recurrent acute pancreatitis.

BACKGROUND & AIMS: The role of sphincter of Oddi manometry (SOM) in the management of patients with idiopathic recurrent acute pancreatitis requires clarification. We evaluated the therapeutic effects of endoscopic sphincterotomy in patients with recurrent acute pancreatitis and the prognostic significance of pancreatic sphincter dysfunction (SOD). METHODS: We performed a randomized trial of endoscopic retrograde cholangiopancreatography with SOM for patients with idiopathic recurrent acute pancreatitis. Patients with pancreatic SOD (n = 69) were assigned randomly to groups that received only biliary sphincterotomy (BES) or a combination of biliary and pancreatic sphincterotomy (DES); patients who underwent normal SOM (n = 20) were assigned randomly to groups that received BES or a sham surgery. The primary outcome was incidence of recurrent acute pancreatitis during the follow-up period (minimum, 1 year; maximum, 10 years). We also determined the incidence of chronic pancreatitis and analyzed factors associated with recurrence of acute pancreatitis. RESULTS: Among the 69 patients with SOD, 48.5% who received BES and 47.2% who received DES had recurrent acute pancreatitis (95% confidence interval, -22.3 to 24.9; P = 1.0). In patients with normal SOM (n = 20), 27.3% of those who received BES and 11.1% of those who received the sham surgery had recurrent acute pancreatitis (95% confidence interval, -49.5 to 17.2; P = .59). Overall, 16.9% of subjects developed chronic pancreatitis during a median follow-up period of 78 months (interquartile range, 35-108 mo). The odds of recurrent acute pancreatitis during follow-up evaluation were significantly greater among patients with SOD than those with normal SOM (unadjusted hazard ratio, 3.5; 95% confidence interval, 1.07-11.4; P < .04), and remained so after adjusting for potential confounders (hazard ratio, 4.3; 95% confidence interval, 1.3-14.5; P < .02). CONCLUSIONS: Among patients with pancreatic SOD, DES and BES have similar effects in preventing recurrence of acute pancreatitis. Pancreatic SOD is an independent prognostic factor, identifying patients at higher risk for recurrent acute pancreatitis. CLINICAL TRIALS REGISTRATION: Clinicaltrials.gov (NCT01583517).

A randomized trial of rectal indomethacin to prevent post-ERCP pancreatitis.

BACKGROUND: Preliminary research suggests that rectally administered nonsteroidal antiinflammatory drugs may reduce the incidence of pancreatitis after endoscopic retrograde cholangiopancreatography (ERCP). METHODS: In this multicenter, randomized, placebo-controlled, double-blind clinical trial, we assigned patients at elevated risk for post-ERCP pancreatitis to receive a single dose of rectal indomethacin or placebo immediately after ERCP. Patients were determined to be at high risk on the basis of validated patient- and procedure-related risk factors. The primary outcome was post-ERCP pancreatitis, which was defined as new upper abdominal pain, an elevation in pancreatic enzymes to at least three times the upper limit of the normal range 24 hours after the procedure, and hospitalization for at least 2 nights. RESULTS: A total of 602 patients were enrolled and completed follow-up. The majority of patients (82%) had a clinical suspicion of sphincter of Oddi dysfunction. Post-ERCP pancreatitis developed in 27 of 295 patients (9.2%) in the indomethacin group and in 52 of 307 patients (16.9%) in the placebo group (P=0.005). Moderate-to-severe pancreatitis developed in 13 patients (4.4%) in the indomethacin group and in 27 patients (8.8%) in the placebo group (P=0.03). CONCLUSIONS: Among patients at high risk for post-ERCP pancreatitis, rectal indomethacin significantly reduced the incidence of the condition. (Funded by the National Institutes of Health; ClinicalTrials.gov number, NCT00820612.).

Association between volume of endoscopic retrograde cholangiopancreatography at an academic medical center and use of pancreatobiliary therapy.

BACKGROUND & AIMS: Many advances have been made in pancreatobiliary imaging and endoscopy techniques. However, little is known about trends in use of endoscopic retrograde cholangiopancreatography (ERCP). METHODS: We performed a retrospective cohort study that analyzed data from 33,596 ERCPs performed at Indiana University Medical Center from 1994 to 2009. Data from all patients were entered into an endoscopy database. We compared changes in patient demographics, indications for ERCP, and utilization of specific ERCP therapies during this time period. RESULTS: The annual volume of ECRP increased steadily from 1175 in 1994 to 2802 in 2009 (P < .0001). Of all patients, 33.9% had previously undergone an ERCP at a different facility; 42.3% of these were unsuccessful. The odds of having undergone a failed ERCP at another facility increased slightly each year (odds ratio, 1.02; P < .001). Among patients who had a failed ERCP elsewhere, the success rate at Indiana University Medical Center was 96.1%. The frequency of patients with American Society of Anesthesiologists class ≥3 (odds ratio, 1.12; P < .001) who received anesthesia-administered sedation increased each year (odds ratio, 1.25; P < .001). Most ERCPs were performed for common bile duct stones or strictures and suspected sphincter of Oddi dysfunction (77.2%). The most rapid increase was among procedures for common bile duct strictures or leaks, pancreatic duct stones or strictures, and suspected sphincter of Oddi dysfunction. Rates of biliary sphincterotomy did not change (P = .252), but the frequency of pancreatic sphincterotomy, common bile duct, or pancreatic duct stent placement and pancreatic duct stricture dilation increased during this time (P < .001 for each). CONCLUSIONS: At a referral center, ERCP has become increasingly complex. From 1994 to 2009, increasing numbers of ERCPs have been performed for patients with more comorbidities, higher-grade disease, history of failed ERCPs, and on those receiving endotherapy.