For pancreatitis prophylaxis following endoscopic retrograde cholangiopancreatography (ERCP) in elevated-risk individuals, it is recommended to administer rectal Indomethacin along with placing a prophylactic pancreatic stent. This non-inferiority trial was carried out to explore whether using Indomethacin alone could potentially obviate or considerably diminish the necessity for stent placement, a procedure known for its technical complexity, expense, and potential risks.

In this randomized study, 1950 volunteers aged 18 years or older, deemed at high risk for post-ERCP pancreatitis, were randomized in a 1:1 ratio to get either rectal Indomethacin alone or Indomethacin combined with prophylactic pancreatic stent. Participants, treating physicians, and endpoint assessors were blinded to the allocated study group.

The occurrence of post-ERCP pancreatitis was the key endpoint ascertained. In both the intention-to-treat (ITT) and per-protocol (PP) population, the upper limit of the two-sided 95% confidence interval (CI) for the difference in post-ERCP pancreatitis (Indomethacin alone minus Indomethacin plus stent) had to be less than 5% (the non-inferiority margin) for establishing non-inferiority.

In 145 (14.9%) of 975 subjects in the Indomethacin alone group and 110 (11.3%) of 975 in the Indomethacin + stent group (risk difference 3.6%; 95% CI 0.6-6.6; p=0.18 for non-inferiority), post-ERCP pancreatitis occurred. According to the findings of the post-hoc ITT analysis, Indomethacin alone was inferior to Indomethacin combined with prophylactic stent (p=0.011).

Across various study subgroups, the relative benefit of stent placement was consistent. But, it seemed more pronounced among those at the greatest susceptibility for pancreatitis. Safety outcomes (hospitalization, intensive care unit admission, and severe adverse events) did not vary between the study groups.

In high-risk individuals undergoing ERCP, a strategy of using Indomethacin alone appears to be less efficient compared to combining Indomethacin with stent placement. These findings support the practice of adding prophylactic pancreatic stent placement to rectal Indomethacin administration in high-risk patients, aligning with existing clinical practice guidelines.