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

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.

Figure 1:

Enrollment.

Figure 2:

Risk difference in post-ERCP pancreatitis between indomethacin alone and indomethacin plus a prophylactic stent.* *Because the upper bound of the 95% confidence interval around the risk difference in post-ERCP pancreatitis between the groups was more than 5%, non-inferiority was not demonstrated. Since the lower bound of the risk difference favoring the combination group was >0, indomethacin alone was found to be inferior to indomethacin plus a prophylactic stent. *Pi-Pi+s represents the difference in the primary outcome (the proportion of patients with post-ERCP pancreatitis) between patients assigned to indomethacin alone and those assigned to indomethacin plus stent; CI denotes confidence interval.

Figure 3:

Exploratory subgroup analyses. 3a. The primary outcome was generally consistent across the prespecified subgroups. *The following subgroups had a statistically significant interaction with indomethacin + stent: biliary sphincterotomy (p=0.01), pancreatic sphincterotomy (p=0.006), double wire technique (p=0.004), and prior post-ERCP pancreatitis (p=0.04). 3b. The relative benefit of indomethacin plus stent increased with rising pretreatment risk score categories. The absolute risk reduction associated with indomethacin plus stent ranged from a number needed to treat (NNT) to prevent one case of ERCP-related pancreatitis of 44 when the risk score was 1–1.5, to 38 when the risk score was 2–2.5, to 7 when the risk score was 3+. *Individual patient risk scores were determined by assigning 1.0 point for each major inclusion criterion and 0.5 points for each minor inclusion criterion, as outlined in the Methods section.