A randomized trial of rectal indomethacin to prevent post-ERCP pancreatitis

Abstract

Background: Preliminary research suggests that rectally administered nonsteroidal antiinflammatory drugs may reduce the incidence of pancreatitis after endoscopic retrograde cholangiopancreatography (ERCP).

Methods: In this multicenter, randomized, placebo-controlled, double-blind clinical trial, we assigned patients at elevated risk for post-ERCP pancreatitis to receive a single dose of rectal indomethacin or placebo immediately after ERCP. Patients were determined to be at high risk on the basis of validated patient- and procedure-related risk factors. The primary outcome was post-ERCP pancreatitis, which was defined as new upper abdominal pain, an elevation in pancreatic enzymes to at least three times the upper limit of the normal range 24 hours after the procedure, and hospitalization for at least 2 nights.

Results: A total of 602 patients were enrolled and completed follow-up. The majority of patients (82%) had a clinical suspicion of sphincter of Oddi dysfunction. Post-ERCP pancreatitis developed in 27 of 295 patients (9.2%) in the indomethacin group and in 52 of 307 patients (16.9%) in the placebo group (P=0.005). Moderate-to-severe pancreatitis developed in 13 patients (4.4%) in the indomethacin group and in 27 patients (8.8%) in the placebo group (P=0.03).

Conclusions: Among patients at high risk for post-ERCP pancreatitis, rectal indomethacin significantly reduced the incidence of the condition. (Funded by the National Institutes of Health; ClinicalTrials.gov number, NCT00820612.).

Figure 1

Enrollment and Outcomes.

Figure 2. Incidence of the Primary and Secondary End Points and Adverse Events

Panel A shows that post-ERCP pancreatitis developed in 27 of 295 patients (9.2%) in the indomethacin group and in 52 of 307 patients (16.9%) in the placebo group (P = 0.005). Moderate or severe post-ERCP pancreatitis developed in 13 patients in the indomethacin group (4.4%) and in 27 patients in the placebo group (8.8%). Panel B shows that clinically significant bleeding events occurred in 4 patients in the indomethacin group and 7 patients in the placebo group (P = 0.72). Two cases of acute renal failure occurred, both in the placebo group.

Figure 3. Analysis of the Heterogeneity in Treatment Effects

The relative protective effect of indomethacin was consistent across subgroups of patients who were stratified according to the risk of post-ERCP pancreatitis (PEP). 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. Although the risk score is divided into two categories for ease of presentation, it was also evaluated as a continuous risk factor (range, 1.0 to 5.5) with the use of multiple logistic regression. In that analysis, there was no evidence that the relative risk reduction associated with indomethacin varied across risk groups (P = 0.52). On the basis of the full risk score, the number of patients who would need to be treated (NNT) to prevent one case of ERCP-related pancreatitis was 21 when the risk score was 1, 11 when the risk score was 3, and 6 when the risk score was 5. The between-group difference in the relative risk reduction was not significant (P = 0.82 for the Mantel–Haenszel test for homogeneity). The red vertical line indicates the overall risk reduction, and the dashed vertical line indicates no relative risk reduction.

Figure 4 (facing page). Exploratory Subgroup Analyses

The primary outcome was consistent across the pre-specified and post hoc subgroups. There were no significant interaction terms between indomethacin and any of these subgroups. A corresponding figure presenting these data in terms of absolute risk difference and the definitions of types 1, 2, and 3 sphincter of Oddi dysfunction are provided in the Supplementary Appendix.