Does Glyceryl Nitrate Prevent Post-Endoscopic Retrograde Cholangiopancreaticography (ERCP) Pancreatitis?
Does Glyceryl Nitrate Prevent Post-Endoscopic Retrograde Cholangiopancreaticography (ERCP) Pancreatitis?
Post-ERCP pancreatitis can be a serious complication to ERCP. Two studies have shown a
 promising preventive effect of glyceryl nitrate. This study should provide a final answer to
 the clinical question: Does glyceryl nitrate prevent post-ERCP pancreatitis? The study is a
 prospective, randomized, double blind, placebo-controlled multicenter trial. The
 investigators intend to include 1600 patients from Norway, Sweden, Denmark, and France.

 The patients will receive either placebo or a glyceryl nitrate patch (15 mg/24 hours).
 Follow-up will occur after 7 days. The primary outcome measure will be post-ERCP
 pancreatitis, and secondary outcome measures will be mild, moderate and severe pancreatitis;
 post procedure pancreatitis-related mortality; and adverse events.
Project:

 This study will compare glyceryl nitrate (GN) treatment to non-active treatment for the
 prevention of post-ERCP acute pancreatitis, which is an inflammation of the pancreas that can
 occur after a procedure known as ERCP.

 Background:

 ERCP (endoscopic retrograde cholangiopancreaticography) is an examination of the pancreas by
 which it is possible to perform therapeutic measures such as stone removal from the common
 bile duct and visualisation of the pancreas. Inflammation of the pancreas after the ERCP
 procedure (called: post-ERCP pancreatitis) is the most feared and common complication of the
 ERCP. It occurs in 1-40% of patients, with rates of 5% or more being more typical. Currently,
 the background of post-ERCP pancreatitis is poorly known.

 Attempts at preventing post-ERCP pancreatitis have been carried out through a change to
 low-risk techniques, by avoiding high-risk patients, and by use of pharmacological
 prophylaxis.

 Glyceryl Nitrate:

 Glyceryl nitrate is a well-known medicine used for many years in other diseases. Possible
 side effects are headache and low blood pressure. Other side effects such as dizziness,
 tiredness, nausea, local redness at the application site and allergic reactions of the skin
 are rare.

 Aim:

 The purpose of this study is to document that pre-treatment with GN is effective in
 preventing post-ERCP pancreatitis. In two earlier GN studies, sample sizes were relatively
 small (less than one hundred) and the rates of post-ERCP pancreatitis in the control group
 were quite high (15-17%). Therefore, further studies are needed to confirm the promising
 effect of GN in the prophylaxis of post-ERCP pancreatitis.

 Participants:

 The study includes every patient undergoing ERCP above the age of 18 years. Patients are
 excluded if they have active acute pancreatitis, previous sphincterotomy (cut in the
 sphincter at the end of the biliary and pancreatic ducts in the duodenum) or chronic
 pancreatitis with calcifications. Also, patients may not take sildenafil (Viagra) as GN
 should not be taken together with sildenafil. Patients allergic to glyceryl nitrate or glue
 should not be included. Patients with constrictive pericarditis (inflammation and fibrosis in
 the sack around the heart); pericardial tamponade (blood or liquor in the sack around the
 heart); low blood pressure; aortic stenosis (stenosis of the aortic valve); hypertrophic
 obstructive cardiomyopathy (a special disease with thickness of the heart); mitral stenosis
 (stenosis of the mitral valve); anemia (low hemoglobin); and untreated hypothyroidism
 (thyroid disease) are excluded because these are other diseases to which glyceryl nitrate
 should not be used. Pregnant women are excluded. Patients can only be included once.

 Practical:

 Patients have been preparing for the study as if it was a normal procedure. Prior to the
 procedure, patients will be asked to participate in the study. If the patients accept, after
 oral and written consent, they will receive either a GN patch or non-active patch on the
 chestwall 40-60 minutes prior to the ERCP procedure.

 A canula is inserted in a cubital vein for medication. The ERCP is initiated, and patients
 are observed afterwards according to local practice, which is typically 3 hours. Patients are
 asked to fill out a letter with questions related to symptoms of pancreatitis (pain, fever,
 nausea, vomiting, hospitalization) to send to the investigating center after 7 days. If
 patients do not send the letter they will be contacted by phone within 14 days.

 Interim analysis:

 An interim analysis will be made, when 800 patients have been included. The study will stop,
 if 1) the interim analysis shows a significant higher mortality in one group than in the
 other or 2) if the study has proceeded more than 2 years.

 Economy:

 The project is a multicenter trial of the European Post-ERCP Pancreatitis Preventing Study
 Group. This local project is located at XX-department. No commercial interests are involved.
 The investigators/authors work for free against authorship. Finances are sought through funds
 for research.

 References:

 1. Freeman M. Post-ERCP pancreatitis: patient and technique-related risk factors. JOP
 2002;3(6):169-176.

 2. Demols A, Deviere J. New frontiers in the pharmacological prevention of post-ERCP
 pancreatitis: the cytokines. JOP 2003; 4(1):49-57.

 3. Testoni P. Preventing post-ERCP pancreatitis: where are we?. JOP 2003; 4(1):22-32.

 4. Mariani A. Pharmacological prevention of post-ERCP pancreatitis:which therapy is best?.
 JOP 2003; 4(1):68-74.

 5. Murray B, Carter R et al. Diclofenac reduces the incidence of acute pancreatitis after
 endoscopic retrograde cholangiopancreatography. Gastroenterology 2003; 124:1786-1791.

 6. Sand J, Nordback I. Prospective randomized trial of the effect of nifedipine on
 pancreatic irritation after endoscopic retrograde cholangiopancreatography. Digestion
 1993; 54:105-11.

 7. Sudhindran S, Bromwich E et al. Prospective randomized double-blind placebo-controlled
 trial of glyceryl trinitrate in endoscopic retrograde cholangiopancreaticography-induced
 pancreatitis. British J of Surg 2001; 88:1178-1182.

 8. Moreto M, Zaballa M. et al. Transdermal glyceryl trinitrate for prevention of post-ERCP
 pancreatitis: a randomized double-blind trial. Gastrointest Endoscopy 2003;57:1-7.

 9. Harrison et al. Bioequivalence comparison of two drug-in-adhesive transdermal
 nitroglycerine patches. Am J Ther 1996;3:580-585.

 10. Pande H, Thuluvath PJ. Pharmacological prevention of post-endoscopic retrograde
 cholangiopancreatography pancreatitis. Drugs 2003;63(17):1799-1812.

 11. Freeman ML. Prevention of post-ERCP pancreatitis: Pharmacologic solution or patient
 selection and pancreatic stents? Gastroenterology 2003;124(7):1977-1980.

 12. Cotton PB, Lehman G, Vennes J, Geenen JE, et al. Endoscopic sphincterotomy complications
 and their management: an attempt at consensus. Gastrointest Endosc 1991;37:383-393.
Inclusion Criteria:

 -  All patients (men and women) more than 18 years old who are going to have an ERCP
 procedure performed at the different centers from September 1, 2004 to about January
 31, 2005 will be included.

 Exclusion Criteria:

 -  Before the study: active acute pancreatitis (defined as: acute upper abdominal pain
 and S-amylases x 3 upper normal limit OR upper abdominal pain + radiological findings
 [CAT-/MR-scan] consistent with acute pancreatitis OR pathoanatomical findings
 consistent with acute pancreatitis by surgery)

 -  Known previous sphincterotomy

 -  Chronic pancreatitis with known calcifications

 -  Hypotension (definition: systolic blood pressure < 100 mmHg)

 -  Anemia, men/women (hemoglobin < 6 mmol/l or <9.7 g/dl)

 -  Constrictive pericarditis

 -  Pericardial tamponade

 -  Hypertrophic obstructive cardiomyopathy, aortic stenosis

 -  Mitral stenosis sildenafil within 24 hours before the ERCP procedure and 24 hours
 after the procedure

 -  Hypersensibility to nitroglycerine

 -  Hypersensibility to the applied glue on the patch

 -  Known untreated hypothyroidism

 -  Pregnancy or a potential to become pregnant, i.e. those who are not using safe
 contraception (intrauterine device [IUD] or oral contraception)

 -  Included earlier in the study

 -  Exchange of stent