Rectal NSAIDs For The Prevention Of Post-ERCP Pancreatitis:Multicentre,Clinical Trials

Background:Acute pancreatitis is the most common complication of endoscopic retrograde cholangiopancreatography(ERCP).The frequency of post-ERCP pancreatitis(PEP)varies between 3.8%and 13.3%in unselected prospective series.It accounts for substantial morbidity,mortality and represents a substantial cost to health-care systems.Non-steroidal anti-inflammatory drugs(NSAIDs)have been shown as effective in the prevention of PEP by inhibiting the inflammatory cascade of pancreatitis.Although rectal indomethacin has been used increasingly since the publication of the study by Elmunzer et al.Further studies are necessary to evaluate the potential benefits and risks of indomethacin in common patients and to determine the optimal timing of indomethacin administration to prevent PEPEven with the use of rectal NSAIDs,PEP still develops in 4%to 9%of patients Because of the possibly different mechanisms of preventing PEP,the combination of rectal NSAIDs and other methods may be more effective to reduce the incidence of PEP compared with rectal NSAIDs alone.Papillary edema may cause temporary outflow obstruction of pancreatic juice and increased ductal pressure,resulting in the occurrence of pancreatitis.Papillary epinephrine spraying represents an inexpensive and convenient method for the reduction of papillary edema.It may prevent PEP through direct relaxation of the sphincter of Oddi and reduction of papillary edema by decreasing capillary permeability.A meta-analysis suggested that papillary epinephrine spraying and rectal NSAIDs are the two most efficacious agents for PEP prevention.It is worth testing whether the combination of indomethacin and epinephrine was superior to indomethacin alone in PEP prevention in common patientsAims:1.To compare the PEP prevention effects and risks of routine pre-procedural rectal indomethacin versus selective post-procedural rectal indomethacin in mixed-risk ERCP patients.2.To compare the PEP prevention effects and risks of combination of rectal indomethacin and papillary epinephrine spraying versus rectal indomethacin alone in mixed-risk ERCP patientsMethods:1.We did a multicentre,single-blinded,randomized controlled trial at six centers in China.Eligible patients with native papilla undergoing ERCP were randomly assigned in a 1:1 ratio to universal pre-procedural indomethacin or risk-stratified,post-procedural indomethacin groups.In the universal indomethacin group,all patients received a single dose(100 mg)of rectal indomethacin within 30 min before ERCP.In the risk-stratified,post-procedural indomethacin group,only patients at predicted high risk received rectal indomethacin,immediately after ERCP.The primary outcome was overall occurrence of post-ERCP pancreatitis.Secondary outcome was incidence of moderate-to-severe PEP.The analysis followed the intention-to-treat principle.This study was registered with ClinicalTrials.gov,number NCT020026502.We performed a double-blind,randomized controlled trial at ten centers in China from February 2017 to October 2017.The patients were randomly assigned to groups given indomethacin and epinephrine(IE group)or indomethacin plus saline(IS group).All patients received a single dose of rectal indomethacin within 30 minutes before ERCP;20 mL of dilute epinephrine(IE group)or saline(IS group)then was sprayed on the duodenal papilla at the end of ERCP.The primary outcome was the incidence of overall PEP.Secondary outcomes included moderate-to-severe PEP and overall adverse events related to ERCP.Data were analyzed on an intention-to-treat principle This study was registered with ClinicalTrials.gov,number NCT03057769Results:1.Between Dec 2013,and Sept 2015,2600 patients were randomly assigned to universal,pre-procedural indomethacin(n=1297)or risk-stratified,post-procedural indomethacin(n=1303).The groups had similar baseline characteristics.Overall,post-ERCP pancreatitis occurred in 47 of 1297 patients(3.6%)assigned to universal indomethacin and 100 of 1303 patients(7.7%)assigned to risk-stratified indomethacin(RR=0.47,95%CI 0.34-0.66;p<0.0001).Compared with the risk-stratified group,the universal group had significant reduction in the frequency of moderate-to-severe PEP(0.8%vs 1.8%;p=0.04).Post-ERCP pancreatitis occurred in 18 of 305 high-risk patients(5.9%)in the universal group and 35 of 281 high-risk patients(12.5%)in the risk-stratified group(p=0.0057).Post-ERCP pancreatitis was also less frequent in average-risk patients in the universal group(2.9%[29/992]),in which they received indomethacin,than in the risk-stratified group(6.4%[65/1022]),in which they did not receive the drug(p=0.0003).Clinically significant gastrointestinal bleeding did not significantly differ between the two groups(1.0%vs 0.8%;p=0.52)2.The study was terminated at the interim analysis for safety concerns and futility Between Feb 2017 and Nov 2017,1158 patients were randomly assigned to the IE group(n=576)or the IS group(n=582).The groups had similar baseline characteristics.PEP developed in 49 patients in the IE group(8.5%)and in 31 patients in the IS group(5.3%)(RR=1.60,95%CI,1.03-2.47;P=0.03).the incidence of moderate-to-severe PEP(1.6%vs 0.7%)tended to be higher in the IE group.However,the differences were not statistically significant.For high-risk patients,PEP was found in 20 of 193 patients(10.4%)in the IE group and in 15 of 222 patients(6.8%)in the IS group,respectively(P=0.19).There was also no significant between-groups difference in the incidence of PEP in average-risk patients(7.6%vs 4.4%;P=0.074).Locally sprayed epinephrine at the end of ERCP did not decrease the incidence of delayed bleeding(2.1%vs 1.5%;p=0.50)Conclusions:1.Compared with a risk-stratified,post-procedural strategy,pre-procedural administration of rectal indomethacin in unselected patients further reduced the overall occurrence of post-ERCP pancreatitis without increasing risk of bleeding.Our results favor the routine use of rectal indomethacin in patients without contraindications before ERCP2.In a randomized trial,we found the combination of rectal indomethacin with papillary epinephrine spraying increased the risk of PEP compared with indomethacin alone Spray epinephrine should not be used with rectal indomethacin for prevention of post-ERCP pancreatitis.