Supplementary Material for: Rectal Indomethacin in Preventing Post-Endoscopic Retrograde Cholangiopancreatography Pancreatitis: An Updated Meta-Analysis with Trial Sequential Analysis

Background: Acute pancreatitis is a significant complication of endoscopic retrograde Cholangiopancreatography (ERCP) with no established prevention strategy. Recent studies suggest that rectal indomethacin may reduce the incidence of post-ERCP pancreatitis (PEP), but its effectiveness varies with patient risk levels and the concurrent use of pancreatic stenting. This updated meta-analysis evaluates the efficacy of rectal indomethacin in preventing PEP.
Methods: A systematic search of PubMed, Embase, and Scopus up to April 2025 identified randomized controlled trials (RCTs) comparing rectal indomethacin with placebo for PEP prevention. Random-effects meta-analysis, metaregression, and subgroup analysis were conducted using the R Meta package v8.0- 2. Cochrane's ROB2 and Egger's regression test are used to assess the risk of bias.
Results: The analysis included 15 RCTs representing a total of 4962 patients. Rectal indomethacin significantly reduced the incidence of PEP compared to placebo (RR: 0.58; 95% CI, 0.45–0.73; P < 0.01) with no increased risk for bleeding complications (RR: 0.95, 95% CI: 0.64–1.41, P = 0.76). Subgroup analysis showed that indomethacin was effective, especially when given concurrently with a pancreatic stent (RR: 0.4539, 95% CI: 0.26–0.79). However, a high risk of bias was observed in nearly 25% of the overall assessment; there was evidence of a small study effect, as suggested by Egger's regression test (P < 0.01).
Conclusion: Prophylactic rectal indomethacin appears to be effective in preventing PEP, with no increased risk for bleeding. Future studies should focus on combining other prophylactic options to achieve better prevention of PEP.