Our findings showed that one dose of rectal indomethacin given immediately after ERCP significantly reduced the incidence of post-ERCP pancreatitis in patients at elevated risk for this complication. Moreover, we found that prophylactic indomethacin decreased the severity of post-ERCP pancreatitis and was associated with a shorter hospital stay. In this trial, the number of high-risk ERCP patients who would need to be treated to prevent one episode of pancreatitis was 13.
The majority of patients in this study had a clinical suspicion of sphincter of Oddi dysfunction, and more than half had sphincter hypertension, as documented on manometry, which suggests that the results are particularly applicable to this challenging patient population. However, among patients who received indomethacin, there was a trend toward benefit with respect to rates of post-ERCP pancreatitis for those who did not have a clinical suspicion of sphincter of Oddi dysfunction (8.5% vs. 20.0%, P = 0.11). Moreover, in a subgroup analysis, the relative treatment effect of indomethacin was consistent across the spectrum of patients’ risk of post-ERCP pancreatitis. Additional studies will be necessary to reproduce our results in different patient populations and to determine whether indomethacin is effective in low- risk patients, as suggested by our previous meta-analysis.13
Although more than 80% of the patients in this clinical trial underwent pancreatic stenting on the basis of their elevated risk of post-ERCP pancreatitis, certain patients did not receive stents, either because the endoscopist did not deem it indicated (e.g., difficult cannulation not requiring a precut sphincterotomy) or because placement was not technically feasible (failed pancreatic access). Among patients who received a pancreatic stent, indomethacin reduced the risk of post-ERCP pancreatitis from 16.1% to 9.7% (P = 0.04). Indomethacin conferred similar benefit in patients who did not receive a pancreatic stent, reducing the risk of post-ERCP pancreatitis from 20.6% to 6.3% (P = 0.049).
Congruent with previous clinical trials evaluating NSAIDs in the prevention of post-ERCP pancreatitis, the risk of adverse events that were potentially attributable to indomethacin in this study was similar in the two study groups. Specifically, there was no significant between-group difference in the frequency or severity of bleeding events. This finding is consistent with previously published data suggesting that NSAIDs in standard doses do not increase the risk of bleeding after biliary sphincterotomy.2,22
Of note, patients with contraindications to NSAIDs, such as renal failure and active peptic-ulcer disease, were excluded from this study.
The rate of post-ERCP pancreatitis in the placebo group (16.9%) exceeded that revealed by the internal audit of high-risk ERCP patients at participating institutions (16.9% vs. 10%). (These audit results had been used to calculate the sample size.) This difference may be due to the increased capture of complications that occurs in randomized, controlled trials. Nevertheless, the incidence of post-ERCP pancreatitis in the placebo group of this trial was similar to that in previous studies of NSAID pharmacoprevention in high-risk subjects, in which the mean rate of post-ERCP pancreatitis was 18.8%.13
In summary, prophylactic rectal indomethacin significantly reduced the incidence and severity of post-ERCP pancreatitis in patients at elevated risk for this complication, particularly in those with a clinical suspicion of sphincter of Oddi dysfunction.