Rectal Indomethacin Prevents Post-ERCP Pancreatitis

Caroline Helwick

May 24, 2012

May 24, 2012 (San Diego, California) — Rectal indomethacin, an inexpensive and safe intervention, can prevent pancreatitis after endoscopic retrograde cholangiopancreatography (ERCP) in patients at increased risk for the condition, according to a multicenter study that was terminated early because of the positive prophylactic effect.

The study, by the US Cooperative for Outcomes Research in Endoscopy, was reported here at Digestive Disease Week (DDW) 2012 by B. Joseph Elmunzer, MD, from the University of Michigan in Ann Arbor. The results were published in the April 12 issue of the New England Journal of Medicine.

"Rectal indomethacin is effective in preventing post-ERCP pancreatitis [PEP] in patients at elevated risk for this complication, particularly in those with a clinical suspicion of sphincter of Oddi dysfunction [SOD]. Given its apparent benefit in non-SOD patients, as well as its favorable safety and cost profile, prophylactic indomethacin is reasonable to consider for all high-risk patients undergoing ERCP," Dr. Elmunzer said.

The study determined that 13 patients need to be treated for 1 to derive benefit, at a cost of only about $2 per patient.

"Pancreatitis is the most frequent complication of ERCP, accounting for substantial morbidity, occasional mortality, and considerable healthcare expenditures," he said.

Preliminary research suggested that rectally administered nonsteroidal anti-inflammatory drugs substantially reduces the incidence of PEP. This led to the multicenter, randomized, placebo-controlled, double-blinded clinical trial of patients deemed to be at elevated risk for the condition.

Subjects were included on the basis of validated patient and procedure-related risk factors, such as clinical suspicion of SOD, history of PEP, difficult cannulation, precut (access) sphincterotomy, and pancreatic sphincterotomy. Patients were randomized to receive 2 indomethacin 50 mg suppositories or 2 identical-appearing placebo suppositories immediately after ERCP, and were followed for 30 days.

Mean patient age was 45; 79% of the cohort was female, 82% had clinical suspicion of SOD, 85% underwent pancreatography, 57% underwent pancreatic sphincterotomy, and 82% received a pancreatic stent. Distribution of the covariates was similar between the study groups.

Investigators had randomized 602 of an intended 948 patients before the Data Safety and Monitoring Board halted enrolment because of the overwhelming benefit of indomethacin.

In the placebo group, 52 (16.9%) of 307 patients developed PEP, as did 27 (9.2%) of 295 patients in the indomethacin group, corresponding to a relative risk reduction of 46% (P = .005) and an absolute risk reduction of 7.7%. Moderate to severe PEP developed in 27 patients (8.8%) in the placebo group and in 13 patients (4.4%) in the indomethacin group (P = .034).

"Indomethacin was protective across the entire range of pancreatitis risk," Dr. Elmunzer reported.

By PEP risk score, the relative risk reduction with indomethacin was 46% overall, 49% for patients scoring 1 or 2, and 44% for those scoring more than 2. Indomethacin appeared to be equally protective in patients with and without clinical suspicion of SOD and in patients who received a pancreatic ductal stent and in those who did not.

Also similar between the indomethacin and placebo groups were adverse events potentially attributable to indomethacin, such as gastrointestinal bleeding (4% of vs 7%) and renal failure (0% vs 2%).

The presentation was included in the Best of DDW session, during which Steven A. Edmundowicz, MD, chief of endoscopy and professor of medicine at Washington University in St. Louis, Missouri, said that the study is "the largest, best-designed, randomized controlled trial" to address a problem that can occur in more than 10% of women with normal bilirubin and SOD, and reach 40% in the setting of a difficult cannulation.

Although the study was conducted in tertiary referral centers, he believes the findings are generalizable to clinical practice, especially those that treat SOD.

However, because 82% of patients had clinical suspicion of SOD, it is not completely clear that indomethacin will be preventive in people with other risk factors for PEP, he said. He noted that the incidence of PEP in the study was much higher than expected, compared with data from previous studies (16.9% vs ~10.0%).

In addition, most patients received a pancreatic duct stent, which might have enhanced the success of the intervention, he said.

"I congratulate Dr. Elmunzer and his colleagues," he concluded, "for a well-done randomized controlled trial" of an intervention that is "inexpensive and safe," and one that will probably "change clinical practice."

Dr. Elmunzer reports a relationship with Olympus America. Dr. Edmundowicz has disclosed no relevant financial relationships.

N Engl J Med. 2012;366:1414-1422. Abstract

Digestive Disease Week (DDW) 2012. Abstract 720. Presented May 21, 2012.


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