Indomethacin with or without prophylactic pancreatic stent placement to prevent pancreatitis after ERCP: a randomised non-inferiority trial.

Rebecca L Spitzer, Richard S Kwon, Jose Serrano, Amitabh Chak, Steven A Edmundowicz, Georgios I Papachristou, James M Scheiman, Shyam Varadarajulu, Field F Willingham, Gregory A Coté, Nauzer Forbes, Cathie Spino, Lydia D Foster, Adam Slivka, Steven A Keilin, Rajesh Keswani, Joanna Law, Bret Petersen, Collins Ordiah, B Joseph Elmunzer, Valerie Durkalski-Mauldin, Zachary L Smith, Vladimir Kushnir, James Buxbaum, Mouen Khashab, Patrick Yachimski, Amit Rastogi, Daniel Mullady, John R Saltzman, Ji Young Bang, Yen-I Chen, Timothy B Gardner, Andrew Ross, Andrew Y Wang, Alan Barkun, Sachin Wani, Raj Shah, Vikesh K Singh

Journal: Lancet (London, England) 2024;403(10425):450-458

PMID: 38219767

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Abstract

BACKGROUND

The combination of rectally administered indomethacin and placement of a prophylactic pancreatic stent is recommended to prevent pancreatitis after endoscopic retrograde cholangiopancreatography (ERCP) in high-risk patients. Preliminary evidence suggests that the use of indomethacin might eliminate or substantially reduce the need for stent placement, a technically complex, costly, and potentially harmful intervention.

METHODS

In this randomised, non-inferiority trial conducted at 20 referral centres in the USA and Canada, patients (aged ≥18 years) at high risk for post-ERCP pancreatitis were randomly assigned (1:1) to receive rectal indomethacin alone or the combination of indomethacin plus a prophylactic pancreatic stent. Patients, treating clinicians, and outcomes assessors were masked to study group assignment. The primary outcome was post-ERCP pancreatitis. To declare non-inferiority, the upper bound of the two-sided 95% CI for the difference in post-ERCP pancreatitis (indomethacin alone minus indomethacin plus stent) would have to be less than 5% (non-inferiority margin) in both the intention-to-treat and per-protocol populations. This trial is registered with ClinicalTrials.gov (NCT02476279), and is complete.

FINDINGS

Between Sept 17, 2015, and Jan 25, 2023, a total of 1950 patients were randomly assigned. Post-ERCP pancreatitis occurred in 145 (14·9%) of 975 patients in the indomethacin alone group and in 110 (11·3%) of 975 in the indomethacin plus stent group (risk difference 3·6%; 95% CI 0·6-6·6; p=0·18 for non-inferiority). A post-hoc intention-to-treat analysis of the risk difference between groups showed that indomethacin alone was inferior to the combination of indomethacin plus prophylactic stent (p=0·011). The relative benefit of stent placement was generally consistent across study subgroups but appeared more prominent among patients at highest risk for pancreatitis. Safety outcomes (serious adverse events, intensive care unit admission, and hospital length of stay) did not differ between groups.

INTERPRETATION

For preventing post-ERCP pancreatitis in high-risk patients, a strategy of indomethacin alone was not as effective as a strategy of indomethacin plus prophylactic pancreatic stent placement. These results support prophylactic pancreatic stent placement in addition to rectal indomethacin administration in high-risk patients, in accordance with clinical practice guidelines.

FUNDING

US National Institutes of Health.

Address: Division of Gastroenterology & Hepatology, Medical University of South Carolina, Charleston, SC, USA. Electronic address: [email protected].; Data Coordination Unit, Department of Public Health Sciences, Medical University of South Carolina, Charleston, SC, USA.; National Institute of Diabetes and Digestive and Kidney Diseases, National Institutes of Health, Bethesda, MD, USA.; Division of Gastroenterology & Hepatology, Oregon Health & Science University, Portland, OR, USA.; Division of Gastroenterology and Hepatology, University of Colorado Anschutz Medical Campus, Aurora, CO, USA.; Orlando Health Digestive Health Institute, Orlando Health, Orlando, FL, USA.; Division of Gastroenterology, Johns Hopkins Medical Institutions, Baltimore, MD, USA.; Division of Gastroenterology, University of Michigan Medical Center, Ann Arbor, MI, USA.; Division of Digestive Diseases, Emory University School of Medicine, Atlanta, GA, USA.; Division of Gastroenterology, Hepatology, and Nutrition, The Ohio State University Wexner Medical Center, Columbus, OH, USA.; Division of Gastroenterology, University Hospitals Cleveland Medical Center, Cleveland, OH, USA.; Division of Gastroenterology, Hepatology, and Nutrition, University of Pittsburgh Medical Center, Pittsburgh, PA, USA.; Division of Gastroenterology, Washington University School of Medicine, St Louis, MO, USA.; Division of Gastroenterology, University of Southern California, Los Angeles, CA, USA.; Division of Gastroenterology, Northwestern University Feinberg School of Medicine, Chicago, IL, USA.; Section of Gastroenterology and Hepatology, Dartmouth-Hitchcock Health, Lebanon, NH, USA.; Division of Gastroenterology, University of Calgary, Calgary, AB, Canada.; Division of Gastroenterology and Hepatology, University of Kansas Medical Center, Kansas City, KS, USA.; Division of Gastroenterology, Virginia Mason Medical Center, Seattle, WA, USA.; Division of Gastroenterology, Hepatology, and Nutrition, Vanderbilt University Medical Center, Nashville, TN, USA.; Division of Gastroenterology, McGill University, Montreal, QC, Canada.; Division of Gastroenterology, Medical College of Wisconsin, Milwaukee, WI, USA.; Department of Gastroenterology, Mayo Clinic, Rochester, MN, USA.; Division of Gastroenterology, University of Virginia, Charlottesville, VA, USA.; Division of Gastroenterology, Hepatology and Endoscopy, Brigham and Women's Hospital, Boston, MA, USA.; Division of Gastroenterology & Hepatology, Medical University of South Carolina, Charleston, SC, USA.; Department of Public Health, University of Michigan, Ann Arbor, MI, USA.

DOI: 10.1016/S0140-6736(23)02356-5

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MeSH Terms: Adolescent, Adult, Humans, Administration, Rectal, Anti-Inflammatory Agents, Non-Steroidal, Cholangiopancreatography, Endoscopic Retrograde, Indomethacin, Pancreatitis, Risk Factors, Stents