Falk Gastro-Info 11/2021

Dunkel- bis hellblaue Grafik einer Tonspur-Frequenz auf orangem Hintergund.



Lancet Gastroenterol Hepatol. 2021;6(6):429–37

Kobayashi T, Motoya S, Nakamura S, Yamamoto T, Nagahori M, Tanaka S, Hisamatsu T, Hirai F, Nakase H, Watanabe K, Matsumoto T, Tanaka M, Abe T, Suzuki Y, Watanabe M, Hibi T; HAYABUSA Study Group

Discontinuation of infliximab in patients with ulcerative colitis in remission (HAYABUSA): A multicenter, open-label, randomized controlled trial

Background: Anti-tumor necrosis factor (TNF) agents are the mainstay of long-term treatment for refractory ulcerative colitis. However, long-term use of anti-TNF therapy might lead to an increased risk of malignancy or infection. To date, no randomized controlled trial has evaluated whether anti-TNF agents can be safely discontinued in patients with ulcerative colitis in remission. The authors therefore aimed to compare outcomes in these patients who continued infliximab (IFX) with those who discontinued IFX.
Methods: They did a multicenter, open-label randomized controlled trial at 24 specialist centers in Japan, and enrolled patients with ulcerative colitis who were in remission, had been treated with intravenous IFX (5 mg/kg) every 8 weeks, and had started IFX at least 14 weeks before study enrolment. No restrictions regarding age and comorbidities were used to exclude participation. Patients who were confirmed to be in remission for > 6 months, to be corticosteroid-free, and to have a Mayo Endoscopic Subscore (MES) of 0 or 1 were centrally randomized. An independent organization randomly assigned patients (1:1) into either the IFX-continued group or IFX-discontinued group, using a computer-generated stratified randomization procedure. The stratified factors were the use of immunomodulators (yes or no) and MES (0 or 1). Neither patients nor health-care providers were masked to the randomization. The primary end point was the remission rate at week 48 in the full analysis set, which was based on the intention-to-treat principle and excluded participants with no efficacy data after randomization.
Findings: Between June 16, 2014, and July 28, 2017, 122 patients were eligible for screening and a total of 95 patients were randomly assigned to the IFX-continued group (n = 48) or the IFX-discontinued group (n = 47). 92 patients (n = 46 for both groups) were included in the full analysis set: 37 (80.4%; 95% confidence interval [CI]: 66.1–90.6) of 46 patients in the IFX-continued group and 25 (54.3%; 95% CI: 39.0–69.1) of 46 patients in the IFX-discontinued group were in remission at week 48. The between-group difference was 26.1% (95% CI: 7.7–44.5; p = 0.0076) before adjustment and 27.3% (95% CI: 8.0–44.1; p = 0.0059) after adjustment for stratification factors. Eight (17%) of 48 patients in the IFX-continued group and 6 (13%) of 47 in the IFX-discontinued group developed adverse events (between-group difference 3.9%; 95% CI: -10.3–18.1; p = 0.59). In the IFX-continued group, 1 patient had an infusion reaction and 2 patients had psoriatic skin lesions. Eight (66.7%; 95% CI: 34.9–90.1) of the 12 patients in the IFX-discontinuation group who were re-treated with IFX after relapsing were in remission within 8 weeks of re-treatment; none had infusion reactions.

Interpretation: Maintenance of remission was significantly more common in patients who continued infliximab (IFX) than in those who discontinued. Discontinuing IFX should therefore be discussed with caution, taking both risk of relapse and efficacy of re-treatment into account.

Prof. Dr. T. Hibi, Center for Advanced IBD Research and Treatment, Kitasato University Kitasato Institute Hospital, Tokyo 108-8642, Japan,

E-Mail: thibi@insti.kitasato-u.ac.jp



Gastroenterology. 2021;161(3):827–36

Khan N, Mahmud N

Effectiveness of SARS-CoV-2 vaccination in a Veterans Affairs cohort of patients with inflammatory bowel disease with diverse exposure to immunosuppressive medications

Background and aims: Vaccination against severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2) has rapidly expanded; however, clinical trials excluded patients taking immunosuppressive medications such as those with inflammatory bowel disease (IBD). Therefore, the authors explored real-world effectiveness of Coronavirus Disease 2019 (COVID-19) vaccination on subsequent infection in patients with IBD with diverse exposure to immunosuppressive medications.
Methods: This was a retrospective cohort study of patients in the Veterans Health Administration with IBD diagnosed before December 18, 2020, the start date of the Veterans Health Administration patient vaccination program. IBD medication exposures included mesalamine, thiopurines, anti-tumor necrosis factor biologic agents, vedolizumab, ustekinumab, tofacitinib, methotrexate, and corticosteroid use. The authors used inverse probability weighting and Cox's regression with vaccination status as a time-updating exposure and computed vaccine effectiveness from incidence rates.
Results: The cohort comprised 14,697 patients, 7321 of whom received at least 1 vaccine dose (45.2% Pfizer, 54.8% Moderna). The cohort had median age 68 years, 92.2% were men, 80.4% were White, and 61.8% had ulcerative colitis. In follow-up data through April 20, 2021, unvaccinated individuals had the highest raw proportion of SARS-CoV-2 infection (197 [1.34%] vs. 7 [0.11%] fully vaccinated). Full vaccination status, but not partial vaccination status, was associated with a 69% reduced hazard of infection relative to an unvaccinated status (hazard ratio = 0.31, 95% confidence interval: 0.17–0.56; p < 0.001), corresponding to an 80.4% effectiveness.

Conclusions: Full vaccination (> 7 days after the second dose) against SARS-CoV-2 infection has an approximately 80.4% effectiveness in a broad inflammatory bowel disease cohort with diverse exposure to immunosuppressive medications. These results may serve to increase patient and provider willingness to pursue vaccination in these settings.

N. Khan, M.D., Associate Professor of Clinical Medicine, Corporal Michael J. Crescenz VA Medical Center, 3900 Woodland Avenue, Philadelphia, PA 19104, USA,

E-Mail: nabeel.khan@va.gov



J Crohns Colitis. 2021;15(7):1174–83

Verhaegh BPM, Münch A, Guagnozzi D, Wildt S, Cebula W, Diac AR, Fernández-Bañares F, Al-Khalaf MAR, Pedersen N, Kupcinskas J, Bohr J, Macaigne G, Lucendo AJ, Lyutakov I, Tontini GE, Pigò F, Russo E, Hjortswang H, Miehlke S, Munck LK

Course of disease in patients with microscopic colitis: A European prospective incident cohort study

Background and aims: The disease course of microscopic colitis (MC) is considered chronic but benign. However, this assumption is based on mainly retrospective studies, reporting on incomplete follow-up of selective cohorts. Systematic, prospective and unbiased data to inform patients and healthcare professionals on the expected course of the disease and real-life response to therapy are warranted.
Methods: A prospective, pan-European, multicenter, web-based registry was established. Incident cases of MC were included. Data on patient characteristics, symptoms, treatment and quality of life were systematically registered at baseline and during real-time follow-up. Four disease course phenotypes were discriminated and described.
Results: Among 381 cases with complete 1-year follow-up, 49% had a chronic active or relapsing disease course, 40% achieved sustained remission after treatment and 11% had a quiescent course. In general, symptoms and quality of life improved after 3 months of follow-up. A relapsing or chronic active disease course was associated with significantly more symptoms and impaired quality of life after 1 year.

Conclusions: A minority of patients with microscopic colitis follow a quiescent disease course with spontaneous clinical improvement, whereas the majority suffer a chronic active or relapsing disease course during the first year after diagnosis, with persisting symptoms accompanied by a significantly impaired quality of life.

Dr. Dr. B.P.M. Verhaegh, Department of Gastroenterology-Hepatology, Maastricht University Medical Center, P. Debyelaan 25, 6229 HX Maastricht, The Netherlands,

E-Mail: bas.verhaegh@mumc.nl



J Hepatol. 2021;75(4):786–94

Younes R, Caviglia GP, Govaere O, Rosso C, Armandi A, Sanavia T, Pennisi G, Liguori A, Francione P, Gallego-Durán R, Ampuero J, Garcia Blanco MJ, Aller R, Tiniakos D, Burt A, David E, Vecchio FM, Maggioni M, Cabibi D, Pareja MJ, Zaki MYW, Grieco A, Fracanzani AL, Valenti L, Miele L, Fariselli P, Petta S, Romero-Gomez M, Anstee QM, Bugianesi E

Long-term outcomes and predictive ability of non-invasive scoring systems in patients with non-alcoholic fatty liver disease

Background and aims: Non-invasive scoring systems (NSS) are used to identify patients with non-alcoholic fatty liver disease (NAFLD) who are at risk of advanced fibrosis, but their reliability in predicting long-term outcomes for hepatic/extrahepatic complications or death and their concordance in cross-sectional and longitudinal risk stratification remain uncertain.
Methods: The most common NSS (NAFLD fibrosis score [NFS], fibrosis-4 [FIB-4], BMI, aspartate/alanine aminotransferase ratio, diabetes [BARD], aspartate aminotransferase to platelet ratio index [APRI]) and the Hepamet fibrosis score (HFS) were assessed in 1173 European patients with NAFLD from tertiary centers. Performance for fibrosis risk stratification and for the prediction of long-term hepatic/extrahepatic events, hepatocarcinoma (HCC) and overall mortality were evaluated in terms of area under the curve (AUC) and Harrell's c-index. For longitudinal data, NSS-based Cox proportional hazard models were trained on the whole cohort with repeated 5-fold cross-validation, sampling for testing from the 607 patients with all NSS available.
Results: Cross-sectional analysis revealed HFS as the best performer for the identification of significant (F0–1 vs. F2–4, AUC = 0.758) and advanced (F0–2 vs. F3–4, AUC = 0.805) fibrosis, while NFS and FIB-4 showed the best performance for detecting histological cirrhosis (range AUCs 0.85–0.88). Considering longitudinal data (follow-up between 62 and 110 months), NFS and FIB-4 were the best at predicting liver-related events (c-indices > 0.7), NFS for HCC (c-index = 0.9 on average), and FIB-4 and HFS for overall mortality (c-indices > 0.8). All NSS showed limited performance (c-indices < 0.7) for extrahepatic events.

Conclusions: Overall, NFS, HFS and FIB-4 outperformed APRI and BARD for both cross-sectional identification of fibrosis and prediction of long-term outcomes, confirming that they are useful tools for the clinical management of patients with non-alcoholic fatty liver disease at increased risk of fibrosis and liver-related complications or death.

Prof. Dr. E. Bugianesi, Department of Medical Sciences, Division of Gastroenterology and Hepatology, A.O. Città della Salute e della Scienza di Torino, University of Turin, Corso Dogliotti 14, 10126 Turin, Italy,


Prof. Dr. Q.M. Anstee, Translational & Clinical Research Institute, The Medical School, Newcastle University, 4th Floor, William Leech Building, Framlington Place, Newcastle upon Tyne, NE2 4HH, UK,

E-Mail: elisabetta.bugianesi@unito.it

E-Mail: quentin.anstee@ncl.ac.uk



Hepatology. 2021;74(3):1496–508

Cristoferi L, Calvaruso V, Overi D, Viganò M, Rigamonti C, Degasperi E, Cardinale V, Labanca S, Zucchini N, Fichera A, Di Marco V, Leutner M, Venere R, Picciotto A, Lucà M, Mulinacci G, Palermo A, Gerussi A, D'Amato D, Elisabeth O'Donnell S, Cerini F, De Benedittis C, Malinverno F, Ronca V, Mancuso C, Cazzagon N, Ciaccio A, Barisani D, Marzioni M, Floreani A, Alvaro D, Gaudio E, Invernizzi P, Carpino G, Nardi A, Carbone M; Italian PBC Registry

Accuracy of transient elastography in assessing fibrosis at diagnosis in naive patients with primary biliary cholangitis: A dual cut-off approach

Background and aims: Liver fibrosis holds a relevant prognostic meaning in primary biliary cholangitis (PBC). Non-invasive fibrosis evaluation using vibration-controlled transient elastography (VCTE) is routinely performed. However, there is limited evidence on its accuracy at diagnosis in PBC. The aim of this study was to estimate the diagnostic accuracy of VCTE in assessing advanced fibrosis (AF) at disease presentation in PBC.
Approach and results: The authors collected data from 167 consecutive treatment-naive PBC patients who underwent liver biopsy (LB) at diagnosis at 6 Italian centers. VCTE examinations were completed within 12 weeks of LB. Biopsies were scored by 2 blinded expert pathologists, according to the Ludwig system. Diagnostic accuracy was estimated using the area under the receiver operating characteristic curves (AUROCs) for AF (Ludwig stage ? III). Effects of biochemical and clinical parameters on liver stiffness measurement (LSM) were appraised. The derivation cohort consisted of 126 patients with valid LSM and LB; VCTE identified patients with AF with an AUROC of 0.89. LSM cut-offs ? 6.5 and > 11.0 kPa enabled to exclude and confirm, respectively, AF (negative predictive value [NPV] = 0.94; positive predictive value [PPV] = 0.89; error rate = 5.6%). These values were externally validated in an independent cohort of 91 PBC patients (NPV = 0.93; PPV = 0.89; error rate = 8.6%). Multivariable analysis found that the only parameter affecting LSM was fibrosis stage. No association was found with BMI and liver biochemistry.

Conclusions: In a multicenter study of treatment-naive primary biliary cholangitis (PBC) patients, the authors identified 2 cut-offs (LSM ? 6.5 and > 11.0 kPa) able to discriminate at diagnosis the absence or presence, respectively, of advanced fibrosis in PBC patients, with external validation. In patients with liver stiffness measurement (LSM) between these 2 cut-offs, vibration-controlled transient elastography is not reliable and liver biopsy should be evaluated for accurate disease staging. Body mass index and liver biochemistry did not affect LSMs.

Dr. Dr. M. Carbone, Division of Gastroenterology, Center for Autoimmune Liver Diseases, Department of Medicine and Surgery, University of Milano-Bicocca, Via Cadore, 48, 20900 Monza, Italy,

E-Mail: marco.carbone@unimib.it



J Hepatol. 2021;75(4):848–55

Mallet V, Beeker N, Bouam S, Sogni P, Pol S; Demosthenes research group

Prognosis of French COVID-19 patients with chronic liver disease: A national retrospective cohort study for 2020

Background and aims: The impact of chronic liver disease on outcomes in patients with COVID-19 is uncertain. Hence, the authors aimed to explore this association.
Methods: They explored the outcomes of all adult inpatients with COVID-19 in France, in 2020. They computed adjusted odds ratios to measure the associations between chronic liver disease, alcohol use disorders, mechanical ventilation and day-30 in-hospital mortality.
Results: The sample comprised 259,110 patients (median age 70 [interquartile range, 54–83] years; 52% men), including 15,476 (6.0%) and 10,006 (3.9%) patients with chronic liver disease and alcohol use disorders, respectively. Death occurred in 38,203 (15%) patients, including 7475 (28%) after mechanical ventilation, and 2941 (19%) with chronic liver disease. The adjusted odds ratios for mechanical ventilation and day-30 mortality were 1.54 (95% CI: 1.44–1.64, p < 0.001) and 1.79 (95% CI: 1.71–1.87, p < 0.001) for chronic liver disease; 0.55 (95% CI: 0.47–0.64, p < 0.001) and 0.54 (95% CI: 0.48–0.61, p < 0.001) for mild liver disease; 0.64 (95% CI: 0.53–0.76; p < 0.001) and 0.71 (95% CI: 0.63–0.80, p < 0.001) for compensated cirrhosis; 0.65 (95% CI: 0.52–0.81, p < 0.001) and 2.21 (95% CI: 1.94–2.51, p < 0.001) for decompensated cirrhosis; 0.34 (95% CI: 0.24–0.50; p < 0.001) and 1.38 (95% CI: 1.17–1.62, p < 0.001) for primary liver cancer; and 0.82 (95% CI: 0.76–0.89; p < 0.001) and 1.11 (95% CI: 1.05–1.17; p < 0.001) for alcohol use disorders. Chronic viral hepatitis, non-viral, non-alcoholic chronic hepatitis, organ, including liver, transplantation, and acquired immunodeficiency syndrome were not associated with COVID-19-related death.

Conclusion: Chronic liver disease increased the risk of COVID-19-related death in France in 2020. Therapeutic effort limitation may have contributed to COVID-19-related death in French residents with a liver-related complication or an alcohol use disorder.

Prof. Dr. V. Mallet, Université de Paris, AP-HP Centre, Groupe Hospitalier Cochin Port Royal, DMU Cancérologie et Spécialités Médico-Cirurgicales, Service d'Hépatologie, 27, rue du Faubourg Saint Jacques, 75014 Paris, France,

E-Mail: vincent.mallet@aphp.fr



Gut. 2021;70(10):1815–22

Mégraud F, Bruyndonckx R, Coenen S, Wittkop L, Huang TD, Hoebeke M, Bénéjat L, Lehours P, Goossens H, Glupczynski Y; European Helicobacter pylori Antimicrobial Susceptibility Testing Working Group

Helicobacter pylori resistance to antibiotics in Europe in 2018 and its relationship to antibiotic consumption in the community

Objective: The aim of the present study was to prospectively assess the antibiotic resistance rates in Helicobacter pylori strains in Europe in 2018 and to study the link between antibiotic consumption in the community and H. pylori resistance levels in the different countries.
Design: The proportion of primary antibiotic resistance cases of H. pylori and their corresponding risk factors were investigated in 24 centers from 18 European countries according to a standardized protocol. Data on antibiotic consumption in the community were collected for the period 2008–2017. The link between antibiotic consumption and resistance data was assessed using generalized linear mixed models. The model with the best fit was selected by means of the Akaike Information Criterion.
Results: H. pylori resistance rates for the 1211 adult patients included were 21.4% for clarithromycin, 15.8% for levofloxacin and 38.9% for metronidazole and were significantly higher in Central/Western and Southern than in the Northern European countries. The best model fit was obtained for the Poisson distribution using 2013 consumption data. A signi?cant association was found between H. pylori clarithromycin resistance and consumption in the community of macrolides (p = 0.0003) and intermediate-acting macrolides (p = 0.005), and between levo?oxacin resistance and consumption of quinolones (p = 0.0002) and second-generation quinolones (p = 0.0003).

Conclusion: This study confirms the positive correlation between macrolide and quinolone consumption in the community and corresponding Helicobacter pylori resistance in European countries. Hence, H. pylori treatment with clarithromycin and levofloxacin should not be started without susceptibility testing in most European countries.

Prof. Dr. F. Mégraud, UMR BaRITOn, INSERM U1053, University of Bordeaux, 33076 Bordeaux, France,


Prof. Dr. Y. Glupczynski, Laboratory of Medical Microbiology, Vaccine & Infectious Disease Institute (VAXINFECTIO), University of Antwerp, Prinsstraat 13, 2000 Antwerp, Belgium,

E-Mail: francis.megraud@chu-bordeaux.fr

E-Mail: gyglupczynski@gmail.com



Endoscopy. 2021;53(9):886–92

Eluri S, Corder SR, Kim E, Tappata M, Reed CC, Shaheen NJ, Dellon ES

Clinical features and time trends associated with an endoscopically normal esophagus in active eosinophilic esophagitis

Background: A proportion of patients with active eosinophilic esophagitis (EoE) have a normal-appearing esophagus on esophagogastroduodenoscopy (EGD). The authors aimed to determine the associations between the baseline clinical features and the endoscopically normal esophagus in EoE, as well as time trends in reporting.
Methods: In this retrospective study of active EoE cases from 2002–2018, patients with and without esophageal endoscopic abnormalities were compared. Multivariable logistic regression identified the independent predictors of a normal EGD. The proportion of patients with a normal EGD was determined per year, and before and after the introduction of the first EoE guidelines and the EoE Endoscopic Reference Score (EREFS).
Results: Of 878 EoE patients, 101 (11.5%) had an endoscopically normal esophagus; they were younger (8.3 vs. 25.4 years), had shorter median symptom duration before diagnosis (2.8 vs. 5.0 years), were less likely to have dysphagia (40% vs. 76%) or food impaction (8% vs. 33%), and more likely to have abdominal pain (37% vs. 19%; p < 0.01 for all). On multivariable logistic regression, independent predictors of a normal esophagus were younger age (odds ratio [OR] = 0.96, 95% confidence interval [CI]: 0.94–0.98), abdominal pain (OR = 2.03, 95% CI: 1.13–3.67), and lack of dysphagia (OR = 0.49, 95% CI: 0.26–0.93). The proportion of patients with a normal esophagus decreased from 21% before the first EoE guidelines to 7% (p < 0.01) after introduction of the EREFS.

Conclusions: An endoscopically normal esophagus is seen in approximately 10% of patients with active eosinophilic esophagitis and should not preclude biopsies; younger age, abdominal pain, and lack of dysphagia are independent predictors. The proportion of normal esophagogastroduodenoscopies decreased over time, suggesting improved recognition of endoscopic findings.

S. Eluri, M.D., Assistant Professor of Medicine, University of North Carolina, CB #7080, Bioinformatics Bldg., 130 Mason Farm Road, Chapel Hill, NC 27599-7080, USA,

E-Mail: swathi@med.unc.edu



Gut. 2021;70(9):1632–41

Smyth EC, Vlachogiannis G, Hedayat S, Harbery A, Hulkki-Wilson S, Salati M, Kouvelakis K, Fernandez-Mateos J, Cresswell GD, Fontana E, Seidlitz T, Peckitt C, Hahne JC, Lampis A, Begum R, Watkins D, Rao S, Starling N, Waddell T, Okines A, Crosby T, Mansoor W, Wadsley J, Middleton G, Fassan M, Wotherspoon A, Braconi C, Chau I, Vivanco I, Sottoriva A, Stange DE, Cunningham D, Valeri N

EGFR amplification and outcome in a randomized phase 3 trial of chemotherapy alone or chemotherapy plus panitumumab for advanced gastroesophageal cancers

Objective: Epidermal growth factor receptor (EGFR) inhibition may be effective in biomarker-selected populations of advanced gastroesophageal adenocarcinoma (aGEA) patients. Here, the authors tested the association between outcome and EGFR copy number (CN) in pretreatment tissue and plasma cell-free DNA (cfDNA) of patients enrolled in a randomized first-line phase 3 clinical trial of chemotherapy or chemotherapy plus the anti-EGFR monoclonal antibody panitumumab in aGEA.
Design: EGFR CN by either fluorescence in situ hybridization (n = 114) or digital-droplet PCR in tissues (n = 250) and plasma cfDNAs (n = 354) was available for 474 (86%) patients in the intention-to-treat (ITT) population. Tissue and plasma low-pass whole-genome sequencing was used to screen for coamplifications in receptor tyrosine kinases. Interaction between chemotherapy and EGFR inhibitors was modeled in patient-derived organoids (PDOs) from aGEA patients.
Results: EGFR amplification in cfDNA correlated with poor survival in the ITT population and similar trends were observed when the analysis was conducted in tissue and plasma by treatment arm. EGFR inhibition in combination with chemotherapy did not correlate with improved survival, even in patients with significant EGFR CN gains. Addition of anti-EGFR inhibitors to the chemotherapy agent epirubicin in PDOs, resulted in a paradoxical increase in viability and accelerated progression through the cell cycle, associated with p21 and cyclin B1 downregulation and cyclin E1 upregulation, selectively in organoids from EGFR-amplified aGEA.

Conclusion: The epidermal growth factor receptor copy number (EGFR CN) can be accurately measured in tissue and liquid biopsies and may be used for the selection of patients with advanced gastroesophageal adenocarcinoma. EGFR inhibitors may antagonize the antitumor effect of anthracyclines with important implications for the design of future combinatorial trials.

Dr. N. Valeri, Division of Molecular Pathology, The Institute of Cancer Research, 15 Cotswold Road, Sutton, SM2 5NG, UK,

E-Mail: nicola.valeri@icr.ac.uk



Lancet Gastroenterol Hepatol. 2021;6(9):733–42

Akshintala VS, Sperna Weiland CJ, Bhullar FA, Kamal A, Kanthasamy K, Kuo A, Tomasetti C, Gurakar M, Drenth JPH, Yadav D, Elmunzer BJ, Reddy DN, Goenka MK, Kochhar R, Kalloo AN, Khashab MA, van Geenen EJM, Singh VK

Non-steroidal anti-inflammatory drugs, intravenous fluids, pancreatic stents, or their combinations for the prevention of post-endoscopic retrograde cholangiopancreatography pancreatitis: A systematic review and network meta-analysis

Background: Non-steroidal anti-inflammatory drugs (NSAIDs), intravenous fluid, pancreatic stents, or combinations of these have been evaluated in randomized controlled trials (RCTs) for the prevention of post-endoscopic retrograde cholangiopancreatography (ERCP) pancreatitis (PEP), but the comparative efficacy of these treatments remains unclear. The aim of the present study was to do an exploratory network meta-analysis of previous RCTs to systematically compare the direct and indirect evidence and rank NSAIDs, intravenous fluids, pancreatic stents, or combinations of these to determine the most efficacious method of prophylaxis for PEP.
Methods: The authors searched PubMed, Embase, and the Cochrane Central Register from inception to November 15, 2020, for full-text RCTs that evaluated the efficacy of NSAIDs, pancreatic stents, intravenous fluids, or combinations of these for PEP prevention in adult (aged ? 18 years) patients undergoing ERCP. Summary data from intention-to-treat analyses were extracted from published reports. Incidence of PEP was analyzed across studies using network meta-analysis under the frequentist framework, obtaining pairwise odds ratios (ORs) and 95% confidence intervals [CIs]. The Grading of Recommendations Assessment, Development, and Evaluation (GRADE) system was used for the confidence rating.
Findings: 1503 studies were identified, of which 55 RCTs evaluating 20 interventions in 17,062 patients were included in the network meta-analysis. The mean incidence of PEP in the placebo or active control group was 12.2% (95% CI: 11.4–13.0). Normal saline plus rectal indometacin (OR = 0.02, 95% CI: 0.00–0.40), intramuscular diclofenac 75 mg (OR = 0.24, 95% CI: 0.09–0.69), intravenous high-volume Ringer's lactate plus rectal diclofenac 100 mg (OR = 0.30, 95% CI: 0.16–0.55), intravenous high-volume Ringer's lactate (OR = 0.31, 95% CI: 0.12–0.78), 5–7 Fr pancreatic stents (OR = 0.35, 95% CI: 0.26–0.48), rectal diclofenac 100 mg (OR = 0.36, 95% CI: 0.25–0.52), 3 Fr pancreatic stents (OR = 0.47, 95% CI: 0.26–0.87), and rectal indometacin 100 mg (OR = 0.60, 95% CI: 0.50–0.73) were all more efficacious than placebo for preventing PEP in pairwise comparisons. 5–7 Fr pancreatic stents (OR = 0.59, 95% CI: 0.41–0.84), intravenous high-volume Ringer's lactate plus rectal diclofenac 100 mg (OR = 0.49, 95% CI: 0.26–0.94), intravenous standard-volume normal saline plus rectal indometacin 100 mg (OR = 0.04, 95% CI: 0.00–0.66), and rectal diclofenac 100 mg (OR = 0.59, 95% CI: 0.40–0.89) were more efficacious than rectal indometacin 100 mg. The GRADE confidence rating was low to moderate for 98.3% of the pairwise comparisons.

Interpretation: This systematic review and network meta-analysis summarizes the available literature on non-steroidal anti-inflammatory drugs (NSAIDs), pancreatic stents, intravenous fluids, or combinations of these for prophylaxis of post-ERCP pancreatitis (PEP). Rectal diclofenac 100 mg is the best performing rectal NSAID in this network meta-analysis. Combinations of prophylaxis might be more effective, but there is little evidence. These findings help to establish prophylaxis of PEP for future research and practice, and could reduce costs and increase adoption of prophylaxis.

V.S. Akshintala, M.D., Division of Gastroenterology, Johns Hopkins Medical Institutions, Baltimore, MD 21205, USA,

E-Mail: vakshin1@jhmi.edu