Safety of rectal indomethacin (100 mg) for the prevention of post-ERCP pancreatitis in the Japanese population: A single-center prospective pilot study

Kotro Tkeshit Stoshi Asi Noki Fujimoto Tkumi Ichinon Eisuke Akmine Mmoru Tkenk

a Department of Gastroenterology, Tane General Hospital, Osaka 550-0025, Japan

b Department of Gastroenterology and Hepatology, Kindai University Faculty of Medicine, Osaka-Sayama 589-8511, Japan

TotheEditor:

Endoscopic retrograde cholangiopancreatography (ERCP) causes adverse events; post-ERCP pancreatitis (PEP) is one of the frequent adverse events.Recently, the efficacy of rectal administration of non-steroidal anti-inflammatory drugs (NSAIDs) before or after ERCP for PEP prevention has been reported [1].The European Society of Gastrointestinal Endoscopy and American Society for Gastrointestinal Endoscopy recommend routine rectal administration of 100 mg NSAIDs immediately before or after ERCP for patients without any contraindication [ 2 , 3 ].However, the use of rectal administration of 100 mg NSAIDs is uncommon in Japan and not covered by health insurance policies.The feasibility and safety of NSAID use at low doses (25–50 mg) for PEP prevention have been certainly obtained only from single-center randomized and retrospective studies [ 4 , 5 ].The clinical trial in China indicated that the rectal administration of 100 mg indomethacin does not cause drugrelated severe adverse events and its PEP-reducing effect is obvious [6].It demonstrates the safety and efficacy of rectal administration of 100 mg indomethacin for PEP prophylaxis in an Asian population.Moreover, recently the ineffectiveness of low-dose indomethacin in terms of PEP prevention was reported [7].As there is no report on the safety of rectal administration of 100 mg indomethacin in Japanese individuals, we conducted this single-arm,prospective, pilot study.The protocol of this trial was approved by the Institutional Review Board of Tane General Hospital and registered in the University Hospital Medical Information Network Clinical Trials Registry (Registration number: UMIN0 0 0 02890 0 0).This study was performed in compliance with the Ethical Principles for Medical Research Involving Human Subjects outlined in theDeclarationofHelsinkiin 1975 (revised in 2013).

Patients older than 18 years but younger than 80 years who had ERCP for therapeutic purposes in our institution from September 2017 to February 2019 were enrolled.Written informed consent was obtained from all patients.The exclusion criteria were as follows: patients with gastrointestinal ulcers, severe hematopathy, severe liver dysfunction (liver cirrhosis Child-Pugh grade C),chronic kidney dysfunction (estimated glomerular filtration rate of<15 mL/min/1.73 m2), chronic heart failure, and a history of allergy to salicylic acid-based compounds or aspirin-exacerbated asthma; those who required a continuous supply of oxygen; and pregnant women.In case an enrolled patient required more than one ERCP session during the study period, only the first one was considered for analysis.

Before insertion of an endoscope, the patients were administered rectal indomethacin (100 mg as two suppositories of 50 mg each) at the same time with sedation.Blood pressure was measured 15 min before ERCP; immediately after endoscope insertion; 30 and 60 min after rectal indomethacin administration; immediately after endoscope withdrawal; and 15, 30, and 60 min after ERCP.Body temperature was measured 15 min before and 15 min after ERCP.To assess aspartate aminotransferase, alanine aminotransferase, and serum amylase activities; blood urea nitrogen, serum creatinine, and hemoglobin levels; and white blood cell, red blood cell, and platelet counts, blood analysis was performed the next day.A physical examination and additional blood tests were appropriately performed until discharge, and then at outpatient units 1 or 2 week(s) after discharge.The primary outcome was the rate of severe or moderate adverse events related to indomethacin.The secondary outcomes were the rate of mild adverse events potentially due to indomethacin, rate of PEP, and other adverse events due to ERCP.

PEP and its severity were assessed based on Cotton’s criteria [8].Other adverse events were diagnosed, and their severity was assessed based on the National Cancer Institute Common Terminology Criteria for Adverse Events [9].Delayed adverse events were followed-up until discharge and investigated at outpatient units 1 or 2 week(s) later.Physicians who had performed more than 200 ERCP procedures without supervision for more than 3 years were considered non-trainees and the others as trainees.

For selective biliary cannulation, wire-guided cannulation was attempted first.If it was difficult for a trainee within 10 min, a non-trainee was referred to.If wire-guided cannulation was unsuc-cessful, other methods such as cannulation assisted by pancreatic guidewire (PGW) and the rendezvous technique were attempted.

Fig.1.Flowchart of this study.ERCP: endoscopic retrograde cholangiopancreatography; NSAIDs: non-steroidal anti-inflammatory drugs.

ERCP procedures were performed on 423 patients, 116 were administered rectal indomethacin, and 16 were excluded due to missing data or ERCP failure ( Fig.1 ).Finally, 100 patients were analyzed, 76 men and 24 women with an average age of 68.0 ±11.4 years.Among them, 78% had naive papillae, and 79% were treated by trainees.Cannulation was successful in all cases, with an average cannulation time of 10.3 ±11.7 min; the average total procedure time was 38.0 ±20.0 min.PGW and rendezvous techniques were used in 20% and 1% of patients, respectively.Pancreatic duct stenting was performed in 13% of the patients, and pancreatic duct contrast injection (including unintentional injection) was performed in 10% of the patients ( Table 1 ).

The main outcome of severe or moderate adverse events related to indomethacin administration was 0%.The rate of mild adverse events was 24%.None of the patients experienced a decrease in body temperature, allergy to indomethacin, or any other adverse events due to the drug.

PEP and hyperamylasemia were detected in 9 (9%) and 8 (8%)patients, respectively.Mild PEP was observed in 5 (5%) and moderate PEP in 4 (4%) patients.Other adverse events, including post-ERCP cholangitis (1%), hemorrhage of the papilla (2%), and minor perforation of the biliary duct (1%), were observed in 4% of patients.All 4 patients were improved conservatively or by endoscopic procedures without surgery ( Table 2 ).

Table 1Patients characteristics ( n = 100).

Table 2Adverse events.

The results revealed that none of the patients experienced severe or moderate adverse events owing to 100 mg indomethacin in this study.Even in cases where mild adverse events were noticed, additional invasive therapy or prolonged hospitalization was not necessary and the consequences of organ dysfunction were not observed.The rate of PEP was 9%.It was recently reported 10.2% in regional hospital in Japan [10].Direct comparison was not appropriate because the backgrounds were different.However, the rate of PEP in this study was not observed to be high considering that 78% had naive papillae and 79% were treated by trainees.

This study has some limitations.The sample size was relatively small; some eligible patients had to be excluded because of missing data.It was unclear whether the observed mild adverse events were due to indomethacin or ERCP procedures.The efficacy of 100 mg indomethacin in PEP prevention was not assessed.

Nevertheless, our results suggest that the use of rectal administration of 100 mg indomethacin could be safe in the Japanese population.The next step is to conduct a large-scale multicenter randomized trial to show the feasibility of 100 mg indomethacin for PEP prevention in Japanese patients aged ≤80 years.

Acknowledgments

None.

CRediT authorship contribution statement

Kotaro Takeshita:Conceptualization, Project administration,Writing - original draft.Satoshi Asai:Methodology, Writing - review & editing.Naoki Fujimoto:Data curation.Takumi Ichinona:Software.Eisuke Akamine:Formal analysis.Mamoru Takenaka:Supervision.

Funding

None.

Ethical approval

This study was approved by the Ethics Committee of Tane General Hospital.Written informed consent was obtained from all participants.

Competing interest

No benefits in any form have been received or will be received from a commercial party related directly or indirectly to the subject of this article.