Comparative Effectiveness Between Indomethacin and Pancreatic Stenting in the Prevention of Post ERCP Pancreatitis
Comparative Effectiveness Between Indomethacin and Pancreatic Stenting in the Prevention of Post ERCP Pancreatitis
Post ERCP pancreatitis (PEP) occurs in 4 to 5% of patients and is associated with significant
 morbidities and occasional mortalities. The use of rectall administered indomethacin and
 pancreatic duct stent (PDS) placement have independently been proven to reduce PEP. The
 comparative effectiveness of the two methods has however not been studied. It is argued that
 in the context of indomethacin, the placement of a PDS is unnecessary. Advocates for PDS
 insertion however believe that mechanical decompression of the pancreatic duct is critical in
 the prevention of pancreatitis. The investigators propose a multi-centre randomised
 controlled trial to compare the use of rectal indomethacin to PDS insertion in high risk
 patients in the prevention of PEP.
Background of research

 Pancreatitis is the most common complication after Endoscopic retrograde
 cholangiopancreatography (ERCP). It occurs in approximately 5% of patients. The risk can
 approach 20 to 30% in those with known pre- and intra-procedural risk factors. Three in 100
 patients with post ERCP pancreatitis (PEP) consequently die. The placement of pancreatic duct
 stent and the use of rectal administered indomethacin have both been independently shown to
 reduce PEP. The placement of a pancreatic duct stent has been for a long time considered the
 gold standard in the prophylaxis against PEP. In a meta-analysis of 8 RCTs that compared the
 use of pancreatic duct stents to no treatment, pancreatic duct stenting in high risk patients
 reduces incidence of PEP by approximately 5 fold. In a landmark study by Elmunzer et al.,
 rectal administered indomethacin was shown to reduce PEP (52 of 307 patients,16.9% to 27 of
 295 patients, 9.2%, P=0.005). In the trial, >80% received pancreatic duct stents in addition
 to rectal indomethacin. Overall there have been 7 RCTs on the use of rectal indomethacin all
 showing benefits with its use, 3 with PDS and 4 without. In the literature, there has been no
 direct comparison between the use of rectal indomethacin alone and insertion of PDS. In a
 secondary analysis of the trial by Elmunzer et al., PEP following the use of rectal
 indomethacin alone was less compared with the placement of PDS. In a meta-analysis by Akbar
 et al. pooling 29 studies (22 PDS and 7 indomethacin), the use of rectal indomethacin alone
 was associated with fewer PEP when compared to insertion of PDS on an indirect comparison
 using network metaanalysis (OR 0.48, 95%CI 0.26-0.87). The more favorable results with rectal
 indomethacin alone raised the question if PDS insertion is necessary. Furthermore, in another
 secondary analysis, patients after failed PDS insertion had a 34.7% rate of pancreatitis. In
 contrary, the rate of pancreatitis was 16.4% in those after successful PDS and 12.1% after no
 attempt at PDS insertion. The SVI (stent versus indomethacin) trial (NCT024762279) by the US
 cooperative for Outcomes Research in Endoscopy (USCORE) group is an ongoing non-inferiority
 trial that compares indomethacin alone to the combination of indomethacin and PDS in 1430
 high risk patients with the primary outcome of pancreatitis. The trial tests the hypothesis
 that PDS is no longer necessary in the context of rectal indomethacin.

 The rationale for the trial has been based on the secondary analysis of the Elmunzer trial
 and the network analysis aforementioned.

 The investigators argue that the relative merits of rectal indomethacin and PDS placement
 have not been established. There may have been substantial difference in the baseline risks
 between the trials using either rectal indomethacin and PDS placement alone. The small number
 of RCTs over the use of rectal indomethacin may have overestimated its beneficial effect
 especially among patients at lower risk of PEP. A direct comparison in the form of a RCT to
 compare effectiveness of both treatment modalities is required. The insertion of PDS may
 continue to be important in patients contraindicated for the use of NSAIDs.

 Research plan and methodology The investigators hypothesize that rectal administration of
 indomethacin is not inferior to placement of a pancreatic duct stent in the prevention of
 pancreatitis after ERCP in high risk patients. In patients randomised to receive pancreatic
 duct stents, the investigators sought to determine the success rate with PDS insertion and
 outcomes following successful or unsuccessful PDS insertion. In addition, the investigators
 analyse possible factors to PEP in both cohorts of patients on either indomethacin or PDS.
Inclusion Criteria:

 presence of one of the following risk factors for Post ERCP Pancreatitis

 1. sphincter of Oddi dysfunction

 2. history of PEP, pancreatic instrumentation or sphincterotomy, precut sphincterotomy,

 3. difficult cannulation defined by >5 cannulation attempts

 4. the use of double wire technique in bile duct access

 5. at least 2 of the followings including i) female age<50 ii) 3 pancreatograms iii)
 acinarization (contrast injection to tail fo pancreas). iv） normal bilirubin；
 v）guidewire to the tail of pancreas or secondary branches.

 Exclusion Criteria:

 -  patients intended for pancreatic stenting e.g. those with pancreatic duct strictures,
 ampullectomy,

 -  without informed consents from patient or next of kin

 -  age <18

 -  pregnant or lactating women

 -  patients with altered anatomy except except Billroth I and II gastrectomy

 -  contraindications to the use of NSAIDs such as those with active gastrointestinal
 bleeding, renal failure (serum creatinine > 140)

 -  known NSAID allergy

 -  incipient heart failure.