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American Society for Gastrointestinal Endoscopy guideline on post-ERCP pancreatitis prevention strategies: methodology and review of evidence

2022; Elsevier BV; Volume: 97; Issue: 2 Linguagem: Inglês

10.1016/j.gie.2022.09.011

1097-6779

James Buxbaum, Martin L. Freeman, Stuart K. Amateau, Jean M. Chalhoub, Aneesa R Chowdhury, Nayantara Coelho–Prabhu, Rishi Das, Madhav Desai, Sherif Elhanafi, Nauzer Forbes, Larissa L. Fujii‐Lau, Divyanshoo R. Kohli, Richard S. Kwon, Jorge D. Machicado, Neil B. Marya, Swati Pawa, Wenly H. Ruan, Jonathan Sadik, Sunil G. Sheth, Nikhil R. Thiruvengadam, Nirav Thosani, Selena Zhou, Bashar Qumseya,

Esophageal and GI Pathology

This guideline document was prepared by the Standards of Practice Committee of the American Society for Gastrointestinal Endoscopy (ASGE) using the best available scientific evidence and considering a multitude of variables including, but not limited to, adverse events, patients' values, and cost implications. The purpose of these guidelines is to provide the best practice recommendations that may help standardize patient care, improve patient outcomes, and reduce variability in practice. We recognize that clinical decision making is complex. Guidelines, therefore, are not a substitute for a clinician's judgment. Such judgements may, at times, seem contradictory to our guidance because of many factors that are impossible to fully consider by guideline developers. Any clinical decisions should be based on the clinician's experience, local expertise, resource availability, and patient values and preferences. This document is not a rule and should not be construed as establishing a legal standard of care, or as encouraging, advocating for, mandating, or discouraging any particular treatment. Our guidelines should not be used in support of medical complaints, legal proceedings, and/or litigation because they were not designed for this purpose. Postendoscopic retrograde cholangiopancreatography pancreatitis (PEP) is the most common serious adverse event of GI endoscopy, occurring in approximately 8% of all endoscopic retrograde cholangiopancreatography (ERCP) procedures.1Kochar B. Akshintala V.S. Afghani E. et al.Incidence, severity, and mortality of post-ERCP pancreatitis: a systematic review by using randomized, controlled trials.Gastrointest Endosc. 2015; 81: 143-149.e9Abstract Full Text Full Text PDF PubMed Scopus (296) Google Scholar PEP is fatal in 0.2% of cases and results in an annual cost of several hundred million dollars each year.1Kochar B. Akshintala V.S. Afghani E. et al.Incidence, severity, and mortality of post-ERCP pancreatitis: a systematic review by using randomized, controlled trials.Gastrointest Endosc. 2015; 81: 143-149.e9Abstract Full Text Full Text PDF PubMed Scopus (296) Google Scholar Therefore, the American Society for Gastrointestinal Endoscopy (ASGE) aimed to develop evidence-based guidelines for the prevention of PEP based on GRADE (Grading of Recommendations, Assessment, Development, and Evaluation) methodology.2Wani S. Sultan S. Qumseya B. et al.The ASGE'S vision for developing clinical practice guidelines: the path forward.Gastrointest Endosc. 2018; 87: 932-933Abstract Full Text Full Text PDF PubMed Scopus (15) Google Scholar,3Jackson R. Feder G. Guidelines for clinical guidelines.BMJ. 1998; 317: 427-428Crossref PubMed Scopus (176) Google Scholar In formulating these guidelines, we conducted extensive literature reviews, including formal systematic reviews of the literature and meta-analyses. To make all the information that we collected and analyzed readily assessable, this guideline is presented in 2 documents. The aim of this document is to describe the methodology used in this process and to provide a detailed review of the evidence used to inform the guideline. It details the formulation of clinical questions, literature searches, data analyses, panel composition, evidence profiles, and other considerations such as cost effectiveness, patient preferences, and health equity. For each clinical question, this document includes outcomes of interest, pooled effect estimates, and evidence that was considered by the panel in making final recommendations. A separate publication provides a summary of the main findings and final recommendations of the ASGE Standards of Practice (SOP) Committee for strategies to prevent PEP. The panel addressed 5 questions relevant to the prevention of PEP by using GRADE methodology (Table 1). For these questions we followed the PICO format: P, population in question; I, intervention; C, comparator; and O, outcomes of interest. For all clinical questions, potentially relevant patient-important outcomes were identified a priori and rated from "critical" to "important" through a consensus process.Table 1List of PICO questions addressedPopulationInterventionComparatorOutcomesRating1. Unselected patients undergoing ERCPRectal NSAIDsNo rectalNSAIDs1) Post-ERCP pancreatitis2) Severe post-ERCP pancreatitis3) Adverse eventsCriticalImportant2. High risk for PEPRectal NSAIDsNo rectal NSAIDs1) Post-ERCP pancreatitis2) Severe post-ERCP pancreatitis3) Adverse eventsCriticalImportant3. Unselected patients undergoing ERCPWire guided cannulationContrast guided cannulation1) Post-ERCP pancreatitis2) Severe post-ERCP pancreatitis3) Adverse eventsCriticalImportant4. High risk for PEPPancreatic stentsNo pancreatic stents1) Post-ERCP pancreatitis2) Severe post-ERCP pancreatitis3) Adverse eventsCriticalImportant5. Unselected patients undergoing ERCPAggressive peri- and postprocedural hydrationStandard hydration1) Post-ERCP pancreatitis2) Severe post-ERCP pancreatitis3) Adverse eventsCriticalImportantNSAIDs, Nonsteroidal anti-inflammatory drugs; PEP, post-ERCP pancreatitis; PICO, P, population in question; I, intervention; C, comparator; O, outcomes of interest. Open table in a new tab NSAIDs, Nonsteroidal anti-inflammatory drugs; PEP, post-ERCP pancreatitis; PICO, P, population in question; I, intervention; C, comparator; O, outcomes of interest. For each PICO question, we searched for existing systematic reviews of available randomized controlled trials (RCTs). We performed systematic reviews and meta-analyses (SRMAs) to address the PICO questions 1 and 2 and 4 and 5. PICO question 3 was addressed with a Cochrane systematic review and meta-analysis, which was updated for this guideline.4Tse F. Liu J. Yuan Y. et al.Guidewire-assisted cannulation of the common bile duct for the prevention of post-endoscopic retrograde cholangiopancreatography (ERCP) pancreatitis.Cochrane Database Syst Rev. 2022; 3: CD009662PubMed Google Scholar A health sciences librarian developed the search strategy and searched the following databases on March 25, 2021, for PICOs 1 and 2; on March 24, 2021, for PICOs 4 and 5, and on March 23, 2021, for PICO 6. This included PubMed (coverage 1946–present), Embase and Embase Classic (coverage 1947–present), Cochrane Library (coverage 1898–present), and Web of Science (coverage 1900–present). Filters were applied to include only RCTs published in English on human subjects. The updated systematic review by Tse et al4Tse F. Liu J. Yuan Y. et al.Guidewire-assisted cannulation of the common bile duct for the prevention of post-endoscopic retrograde cholangiopancreatography (ERCP) pancreatitis.Cochrane Database Syst Rev. 2022; 3: CD009662PubMed Google Scholar (PICO 3) included a search through February 26, 2021. A combination of subject headings (when available) and keywords was used and is provided in Appendix 1. Cross-referencing (snowballing) and forward searches of the citations from articles fulfilling the inclusion criteria and other pertinent articles were performed with the use of Web of Science. Only RCTs were included in the literature search. Citations were imported into EndNote x9.2 (Clarivate Analytics, Philadelphia, Penn, USA), and duplicates were removed by use of the Bramer method and uploaded into Covidence (Melbourne, Australia) for screening.5Bramer W.M. Giustini D. de Jonge G.B. et al.De-duplication of database search results for systematic reviews in EndNote.J Med Libr Assoc. 2016; 104: 240-243Crossref PubMed Scopus (799) Google Scholar Two or more independent reviewers (S.Z., J.S., A.C., R.D., J.B.) performed data extraction for all of the systematic reviews and meta-analyses by using Covidence (Melbourne, Australia). Summary statistics included odds ratios (ORs) for PICOs 1 and 2 and 4 and 5; risk ratios (RRs) for PICO 3; and proportions for PICO 4. Pooled effects were calculated by the use of random-effects models, given the anticipation of heterogeneity among the source studies Statistical heterogeneity was quantified by the use of the I2 statistic, and other potential sources of heterogeneity were assessed by performing subgroup and sensitivity analyses. Studies were weighted on the basis of size. Publication bias was assessed with funnel plots. Statistical analyses were performed with STATA 14.2 (College Station, Tex, USA). On November 13, 2021, we assembled a panel of stakeholders to review evidence and make recommendations. The panel consisted of the lead author (J.B.); a content expert independent of the SOP committee (M.F.); a GRADE methodologist (N.F.); SOP committee members with expertise in methodology, systematic reviews, and meta-analysis; and the committee chair (B.Q.). A patient representative (T.T.) from the National Organization for Transplant Enlightenment (N.O.T.E.) was also included. Per ASGE policy, members were asked to disclose conflicts of interests (https://www.asge.org/forms/conflict-of-interest-disclosure and https://www.asge.org/docs/default-source/about-asge/mission-andgovernance/asge-conflict-of-interest-and-disclosure-policy.pdf). Panel members who received funding for any technologies or companies associated with any of the PICOs or who had other relevant conflicts of interest were asked to declare this before the discussion and did not vote on the final recommendation addressing that specific PICO question. The GRADE approach was used to determine the quality of the evidence and confidence in the estimated effects. The following domains were addressed: bias of individual studies, imprecision, inconsistency, indirectness, and publication bias. Certainty was categorized into 1 of 4 levels: high, moderate, low, and very low (Table 2). The Evidence profiles were generated by use of the GRADEpro/GDT applications (https://gdt.guidelinedevelopment.org/app).Table 2GRADE categories of quality of evidenceGRADE quality of evidenceMeaningInterpretationHighWe are confident that the true effect lies close to that of the estimate of the effect.Further research is very unlikely to change our confidence in the estimate of the effect.ModerateWe are moderately confident in the estimate of the effect; the true effect is likely to be close to the estimate of the effect, but there is a possibility that it is substantially different.Further research is likely to have an impact on our confidence in the estimate of the effect and may change the estimate.LowOur confidence in the estimate of the effect is limited; the true effect may be substantially different from the estimate of the effect.Further research is very likely to have an impact on our confidence in the estimate of the effect and is likely to change the estimate.Very lowWe have very little confidence in the estimate of the effect; the true effect is likely to be substantially different from the estimate of the effect.Any estimate of the effect is very uncertain.GRADE, Grading of Recommendations, Assessment, Development, and Evaluation. Open table in a new tab GRADE, Grading of Recommendations, Assessment, Development, and Evaluation. Question 1: In unselected patients undergoing ERCP, should rectal NSAIDs be given to prevent post-ERCP pancreatitis? Recommendation 1: Among unselected patients undergoing ERCP, the ASGE recommends periprocedural rectal NSAIDs be given to prevent PEP (strong recommendation/moderate quality of evidence). Recommendation 1: Among unselected patients undergoing ERCP, the ASGE recommends periprocedural rectal NSAIDs be given to prevent PEP (strong recommendation/moderate quality of evidence). We performed an SRMA of RCTs among unselected patients. Unselected patients were defined by the authors of the source studies as those without specific risk factors for PEP. A search through March 25, 2021, yielded 738 citations, which were all screened by 2 independent reviewers (Appendix 1, available online at www.giejournal.org). Eighteen RCTs fulfilled the inclusion criteria and compared rectal nonsteroidal anti-inflammatory drugs with placebo in 4554 patients (Supplementary Table 1, available online at www.giejournal.org). Fourteen of the trials were full-text publications, and the remainder were abstracts. The most frequently used NSAID was diclofenac (56%), followed by indomethacin, (36%), ketoprofen, (4%), and naproxen, (4%). The most frequent exclusion criteria for NSAID use were acute pancreatitis, NSAID allergy, renal insufficiency (ie, creatinine level >1.4 mg/dL), and active peptic ulcer disease. The consensus criteria were used to diagnose PEP in 14 of the studies, limiting the ability to perform subanalyses addressing diagnostic criteria.6Cotton P.B. Lehman G. Vennes J. et al.Endoscopic sphincterotomy complications and their management: an attempt at consensus.Gastrointest Endosc. 1991; 37: 383-393Abstract Full Text PDF PubMed Scopus (2506) Google Scholar On the basis of the random-effects model, prophylactic rectal NSAIDs were associated with significantly lower odds of the development of PEP in unselected patients when compared with placebo (OR, 0.49; 95% CI, 0.37-0.65; I2 = 38.6%) (Fig. 1; Supplementary Fig. 1A, available online at www.giejournal.org). There was no significant difference in postsphincterotomy bleeding (OR, 1.68; 95% CI, 0.50-5.68; I2 = 39%) (Supplementary Figs. 1B, 2A, available online at www.giejournal.org). No renal failure occurred in either group. Prophylactic rectal NSAIDs were associated with a statistically nonsignificant trend toward lower occurrence of moderately severe and severe pancreatitis (OR, 0.47; 95% CI, 0.21-1.06; P = −.52; I2 = 0) (Supplementary Figs. 1C, 2B, available online at www.giejournal.org). In most of the studies, severity was graded by the consensus criteria (Supplementary Table 1). Rectal NSAIDs remained protective in subanalysis restricting to full-text documents (Supplementary Fig. 3A, available online at www.giejournal.org). NSAIDs were given before ERCP in all but 3 studies. Stratified meta-analysis revealed that NSAIDs remained protective regardless of exact timing (>30 minutes vs 100 mg and 4 studies used a dose <100 mg; a subanalyses of studies that used only a specific 100-mg dose revealed consistent results (Supplementary Fig. 3F). For the main outcome of PEP, there was a nonserious risk of bias (Table 3). The included studies concealed allocation and followed proper random sequence generation; furthermore, funnel plots were symmetric, indicating an absence of serious publication bias (Supplementary Fig. 1A, 4, available online at www.giejournal.org). The certainty was downgraded to moderate, given the inconsistency suggested by the high I2 (Fig. 1). Whereas the I2 was low for renal insufficiency and bleeding, the certainty was downgraded to moderate for imprecision indicated by wide confidence intervals (Supplementary Figs. 1C, 5A, 2B, 5B, available online at www.giejournal.org). The certainty for the outcome of moderately severe and severe PEP was low, given the wide confidence intervals and asymmetric funnel plot (Supplementary Figs. 1A, 2A) suggesting possible publication bias.Table 3Evidence profile for population, intervention, comparator, outcomes 1: rectal NSAIDs versus placebo to prevent PEP in unselected patientsCertainty assessmentNo. of patientsEffectCertaintyImportanceNo. of studiesStudy designRisk of biasInconsistencyIndirectnessImprecisionOther considerationsRectal NSAIDsNoneRelative (95% CI)Absolute (95% CI)Overall rate of PEP18Randomized trialsNot seriousSerious∗High I2.Not seriousNot seriousNone167/2288 (7.3%)306/2272 (13.5%)OR 0.50 (0.30 to 0.83)62 fewer per 1000 (from 90 fewer to 20 fewer)⨁⨁⨁◯ModerateCriticalModerately severe and severe PEP8Randomized trialsNot seriousNot seriousNot seriousSerious†Low number of events.Publication bias strongly suspected‡Funnel plot,8/1577 (0.5%)24/1569 (1.5%)OR 0.5 (0.2 to 1.1)8 fewer per 1000 (from 12 fewer to 2 more)⨁⨁◯◯LowCriticalRenal insufficiency18Randomized trialsNot seriousNot seriousNot seriousSerious†Low number of events.None0/22880.0%)0/2272 (0.0%)Not estimable⨁⨁⨁◯ModerateCriticalBleeding (define)18Randomized trialsNot seriousNot seriousNot seriousSerious†Low number of events.None15/2288 (0.7%)9/2272 (0.4%)OR 1.7 (0.5 to 5.7)3 more per 1000 (from 2 fewer to 18 more)⨁⨁⨁◯ModerateCriticalCI, Confidence interval; NSAIDs, nonsteroidal anti-inflammatory drugs; OR, odds ratio; PEP, post-ERCP pancreatitis.∗ High I2.† Low number of events.‡ Funnel plot, Open table in a new tab CI, Confidence interval; NSAIDs, nonsteroidal anti-inflammatory drugs; OR, odds ratio; PEP, post-ERCP pancreatitis. Cost-effectiveness analyses indicate that for average-risk patients, the incremental cost per quality-adjusted life year (QALY) was $33,812/QALY, which was significantly less than the willingness-to-pay threshold of $100,000/QALY.7Thiruvengadam N.R. Saumoy M. Schneider Y. et al.A cost-effectiveness analysis for post-endoscopic retrograde cholangiopancreatography pancreatitis prophylaxis in the United States.Clin Gastroenterol Hepatol. 2022; 20: 216-226.e42Abstract Full Text Full Text PDF PubMed Scopus (6) Google Scholar Over the past 15 years, the approximate wholesale acquisition cost of rectal indomethacin has increased from $2 in 2005 to $340 in 2019.8Elmunzer B.J. Hernandez I. Gellad W.F. The skyrocketing cost of rectal indomethacin.JAMA Intern Med. 2020; 180: 631-632Crossref PubMed Scopus (12) Google Scholar Nevertheless, a sensitivity analysis indicates that rectal indomethacin would remain cost effective for prophylaxis of PEP in an average-risk patient to the threshold of $1134.7Thiruvengadam N.R. Saumoy M. Schneider Y. et al.A cost-effectiveness analysis for post-endoscopic retrograde cholangiopancreatography pancreatitis prophylaxis in the United States.Clin Gastroenterol Hepatol. 2022; 20: 216-226.e42Abstract Full Text Full Text PDF PubMed Scopus (6) Google Scholar NSAIDs that are not available as rectal formulations on the market, however, may be formulated from oral medications by compounding pharmacies at significantly lower cost. In regard to patient preferences, there is little published information. Patient representatives on the guideline panel viewed rectal NSAIDs favorably. NSAIDs are potent inhibitors of prostaglandin synthesis and phospholipase A2 activity.9Vane J.R. Inhibition of prostaglandin synthesis as a mechanism of action for aspirin-like drugs.Nat New Biol. 1971; 231: 232-235Crossref PubMed Scopus (7464) Google Scholar,10Makela A. Kuusi T. Schroder T. Inhibition of serum phospholipase-A2 in acute pancreatitis by pharmacological agents in vitro.Scand J Clin Lab Invest. 1997; 57: 401-407Crossref PubMed Scopus (117) Google Scholar The cardinal role of these mediators in the pancreatitis inflammatory cascade is the basis for the use of NSAIDs to prevent PEP. Although they were originally trialed for high-risk patients undergoing pancreatography or sphincter of Oddi evaluation, the low cost and favorable risk profile of NSAIDs has led to their use in unselected patients.11Murray B. Carter R. Imrie C. et al.Diclofenac reduces the incidence of acute pancreatitis after endoscopic retrograde cholangiopancreatography.Gastroenterology. 2003; 124: 1786-1791Abstract Full Text Full Text PDF PubMed Scopus (236) Google Scholar Although the initial studies of rectal indomethacin to prevent PEP for unselected patients had favorable results, several trials, including the double-blind trial by Levenick et al,14Levenick J.M. Gordon S.R. Fadden L.L. et al.Rectal indomethacin does not prevent post-ERCP pancreatitis in consecutive patients.Gastroenterology. 2016; 150 (quiz e19): 911-917Abstract Full Text Full Text PDF PubMed Scopus (130) Google Scholar did not show a significant benefit.12Sotoudehmanesh R. Khatibian M. Kolahdooan S. et al.Indomethacin may reduce the incidence and severity of acute pancreatitis after ERCP.Am J Gastroenterol. 2007; 102: 978-983Crossref PubMed Scopus (172) Google Scholar, 13Khoshbaten M. Khorram H. Madad L. et al.Role of diclofenac in reducing post-endoscopic retrograde cholangiopancreatography pancreatitis.J Gastroenterol Hepatol. 2008; 23: e11-e16Crossref PubMed Scopus (102) Google Scholar, 14Levenick J.M. Gordon S.R. Fadden L.L. et al.Rectal indomethacin does not prevent post-ERCP pancreatitis in consecutive patients.Gastroenterology. 2016; 150 (quiz e19): 911-917Abstract Full Text Full Text PDF PubMed Scopus (130) Google Scholar Additionally, NSAID administration by nonrectal routes such as intramuscular or intravenous administration does not reliably confer a protective effect.15Park S.W. Chung M.J. Oh T.G. et al.Intramuscular diclofenac for the prevention of post-ERCP pancreatitis: a randomized trial.Endoscopy. 2015; 47: 33-39PubMed Google Scholar, 16Cheon Y.K. Cho K.B. Watkins J.L. et al.Efficacy of diclofenac in the prevention of post-ERCP pancreatitis in predominantly high-risk patients: a randomized double-blind prospective trial.Gastrointest Endosc. 2007; 66: 1126-1132Abstract Full Text Full Text PDF PubMed Scopus (88) Google Scholar, 17de Quadros Onofrio F. Lima J.C.P. Watte G. et al.Prophylaxis of pancreatitis with intravenous ketoprofen in a consecutive population of ERCP patients: a randomized double-blind placebo-controlled trial.Surg Endosc. 2017; 31: 2317-2324Crossref PubMed Scopus (11) Google Scholar Nevertheless, a meta-analysis of the 18 randomized trials on the topic indicates a decrease in the overall risk of PEP in unselected patients. These results are in agreement with those from a trial of 2600 patients randomized to universal preprocedure indomethacin versus risk-stratified postprocedure indomethacin by Luo et al.18Luo H. Zhao L. Leung J. et al.Routine pre-procedural rectal indometacin versus selective post-procedural rectal indometacin to prevent pancreatitis in patients undergoing endoscopic retrograde cholangiopancreatograhy: a multicentre, single-blinded, randomised controlled trial.Lancet. 2016; 387: 2293-2301Abstract Full Text Full Text PDF PubMed Scopus (148) Google Scholar In this trial the rate of PEP in unselected patients given preprocedure indomethacin was 4% compared with 8% in patients who received only postprocedure indomethacin if stratified to have higher risk. The risk of PEP with universal preprocedure NSAIDs was significantly lower in both high-risk patients—6% versus 12% (P= .0057)—and those at average risk: 3% versus 6% (P= .0003). Given that the overall incidence of PEP in the control group of RCTs of unselected patients was 9.7% (95% CI, 8.6%-10.7%) and mortality was 0.7% (95% CI, 0.5%-0.9%), the panel recognized that the benefit of prevention is high. Inasmuch as rectal indomethacin does confer a protective effect in unselected patients and is cost effective, feasible, and associated with only minimal discomfort and adverse effects, the GRADE panel recommended its use in this population. Nevertheless, the efficacy of NSAIDs in the prevention of moderate and severe pancreatitis was not statistically significant in the systematic review of the literature. This may be a consequence of the rarity of this event and the principle that the studies were not powered to detect more severe PEP. Similarly, there was no difference in adverse events, including postsphincterotomy bleeding, although the rarity of these events similarly diminished the power to detect differences. Additionally, the panel recognized that the source studies excluded many patients, including those with ongoing NSAID use, abnormal renal function, aspirin or NSAID allergy, and a history of peptic ulcer disease, which are features common in the adult population. The inclusion criteria also varied, with most studies excluding patients undergoing ERCP for "very low risk" indications such as biliary stent exchange. Interestingly, these patients were included in the negative study by Levenick et al.14Levenick J.M. Gordon S.R. Fadden L.L. et al.Rectal indomethacin does not prevent post-ERCP pancreatitis in consecutive patients.Gastroenterology. 2016; 150 (quiz e19): 911-917Abstract Full Text Full Text PDF PubMed Scopus (130) Google Scholar Hence, studies are needed to specifically measure the impact of NSAIDs in patients at low risk for PEP. Overall, rectal NSAID use is associated with a 50% relative reduction in the rate of PEP and is therefore recommended for all patients undergoing ERCP unless there is a contraindication such as renal insufficiency or active peptic ulcer disease. This also assumes that the price will not exceed the threshold of cost effectiveness. Question 2: In high-risk patients undergoing ERCP, should rectal NSAIDs be given to prevent post-ERCP pancreatitis? Recommendation 2: For high-risk patients undergoing ERCP, the ASGE recommends that periprocedural rectal NSAIDs be given to prevent post-ERCP pancreatitis (strong recommendation/moderate quality of evidence). Recommendation 2: For high-risk patients undergoing ERCP, the ASGE recommends that periprocedural rectal NSAIDs be given to prevent post-ERCP pancreatitis (strong recommendation/moderate quality of evidence). A systematic review and meta-analysis were performed to address the main outcomes of interest for this clinical question and including PEP, moderately severe or severe PEP, postsphincterotomy bleeding, and acute renal failure in populations that were defined by the authors of the RCTs as high risk for PEP (Supplementary Table 2). After a systematic literature search (Appendix 1), 270 manuscripts and conference abstracts were screened by 2 investigators (J.S., A.C.). We identified 10 RCTs comparing NSAIDs with placebo in 2006 patients. One trial included 2 randomized comparisons in which patients in both the NSAID and control groups were given either normal saline solution or lactated Ringer's solution.19Mok S.R.S. Ho H.C. Shah P. et al.Lactated Ringer's solution in combination with rectal indomethacin for prevention of post-ERCP pancreatitis and readmission: a prospective randomized, double-blinded, placebo-controlled trial.Gastrointest Endosc. 2017; 85: 1005-1013Abstract Full Text Full Text PDF PubMed Scopus (62) Google Scholar Two trials of rectal NSAIDs in unselected patients presented a subgroup analysis reporting the risk of PEP specifically for high-risk subgroups.20Katoh T. Kawashima K. Fukuba N. et al.Low-dose rectal diclofenac does not prevent post-ERCP pancreatitis in low- or high-risk patients.J Gastroenterol Hepatol. 2020; 35: 1247-1253Crossref PubMed Scopus (17) Google Scholar,21Li L. Liu M. Zhang T. et al.Indomethacin down-regulating HMGB1 and TNF-alpha to prevent pancreatitis after endoscopic retrograde cholangiopancreatography.Scand J Gastroenterol. 2019; 54: 793-799Crossref PubMed Scopus (8) Google Scholar The designation of high risk was based on the authors' definition of their study population. The earlier published trials predominantly enrolled patients with suspected sphincter of Oddi dysfunction, whereas difficult cannulation was the more common indication among recent studies (Supplementary Table 2, available online at www.giejournal.org). All but 1 study used a 100-mg dose of rectal diclofenac or indomethacin. Based on the random-effects model, there was a significant reduction in post-ERCP pancreatitis in high-risk patients treated with rectal NSAIDs compared with placebo (OR, 0.50; 95% CI, 0.30-0.83; I2 = 56.6%) (Fig. 2; Supplementary Fig. 6A, available online at www.giejournal.org). There were no significant differences in renal failure (OR, 0.63; 95% CI, 0.12-3.29; I2 = 0) (Supplementary Fig. 5B) or postsphincterotomy bleeding (OR, 0.82; 95% CI, 0.40-1.65; I2 = 0) (Supplementary Fig. 6B). There was a statistically nonsignificant trend toward reduction in the odds of moderately severe/severe post-ERCP pancreatitis (OR, 0.53; 95% CI, 0.27-1.05; P = .035; I2 = 10.7%) (Supplementary Fig. 6C). Exclusion of the studies that used a lower dose did not have an impact on the results (Supplementary Table 3, Supplementary Fig. 7A, available online at www.giejournal.org). Similarly, exclusion of the 1 study that was published only as an abstract did not alter the findings (Supplementary Fig. 7B). There was a trend (not statistically significant) toward protection whether given before or after ERCP (Supplementary Fig. 7C and D). Whereas subanalyses restricted to indomethacin demonstrated significant protection in high-risk patients, a statistically significant protective effect was not found in studies restricted to diclofenac (Supplementary Fig. 7E and F). The randomized trials used to inform this question used random sequence generation and concealed allocation (Supplementary Fig. 8, available online at www.giejournal.org). Funnel plots were symmetric, and the trials appeared to be low risk for detection and attrition bias (Supplementary Fig. 5C and D). Certainty for the main outcome of PEP was rated down to moderate for imprecision, given an I2 = 59% (Table 4). For the outcome of moderately severe/severe pancreatitis, postsphincterotomy bleeding, and renal failure, the certainty was also rated as moderate, given the imprecision suggested by wide confidence intervals.Table 4Evidence profile for population, intervention, comparator, outcomes 2: rectal NSAIDs versus placebo to prevent PEP in high-risk patientsCertainty assessmentNo. of patientsEffectCertaintyImportanceNo. of studiesStudy designRisk of biasInconsistencyIndirectnessImprecisionOther considerationsRectal NSAIDsNoneRelative (95% CI)Absolute (95% CI)Overall PEP10Randomized trialsNot seriousSerious∗High I2.Not seriousNot seriousNone80/1008 (7.9%)152/1022 (14.9%)OR 0.50 (0.