Clinical Trial Finds that ERCP with Minor Papillotomy Does Not Benefit Patients with Acute Recurrent Pancreatitis and Pancreas Divisum

Endoscopic retrograde cholangiopancreatography (ERCP) with minor papillotomy is not associated with a reduced risk of future acute pancreatitis episodes for individuals with idiopathic acute recurrent pancreatitis and pancreas divisum, according to a recent study published in JAMA, Minor Papillotomy for Treatment of Idiopathic Acute Pancreatitis With Pancreas Divisum: A Randomized Clinical Trial.

The findings from the multicenter, randomized, sham-controlled, double-masked clinical trial, challenge current treatment guidelines for patients with unexplained acute recurrent pancreatitis.

The study was co-led by Dhiraj Yadav, MD, MPH, vice chair for clinical research, Department of Medicine at the University of Pittsburgh School of Medicine, along with Gregory A. Cote, MD, M Sc., professor of medicine at Oregon Health and Science University, Portland, OR and Valerie Durkalski-Mauldin, PhD, professor of biostatistics at Medical University of South Carolina, Charlston, SC. Study coauthors included UPMC and University of Pittsburgh researcher Adam Slivka, MD, PhD, associate chief of clinical affairs, Division of Gastroenterology, Hepatology and Nutrition at the University of Pittsburgh School of Medicine.

Acute Pancreatitis

Acute pancreatitis is a painful inflammatory condition that is increasing in worldwide incidence. In the U.S. specifically, acute pancreatitis contributes to approximately a quarter of a million hospitalizations per year, leading to high financial costs for both health care systems and individual patients. Acute pancreatitis also increases the patient’s risk of developing other conditions, such as chronic pancreatitis, diabetes mellitus, and exocrine pancreatic dysfunction.

Common causes of acute pancreatitis include gallstones, alcohol use, high serum triglycerides, and certain medications. However, sometimes a specific cause cannot be determined, limiting opportunities to prevent future acute pancreatitis episodes and complications of acute pancreatitis. In these cases, anatomical variations in the pancreas, such as pancreas divisum, are viewed as potential opportunities for intervention.

Pancreas Divisum

Pancreas divisum is a congenital condition in which the pancreas’ ventral and dorsal ducts have not fused into one main pancreatic duct. In individuals with pancreas divisum, exocrine secretions drain into the duodenum through the minor, rather than the major, papilla. The smaller size of the minor papilla is thought to result in inadequate drainage of pancreas secretions into the duodenum. Due to this, pancreas divisum has been considered a cause of pancreas duct obstruction that could be corrected through an endoscopic retrograde cholangiopancreatography (ERCP) with minor papillotomy.

However, pancreas divisum is common in the general population, present in up to 7-10% individuals.

ERCP with Minor Papillotomy

In the ERCP with minor papillotomy procedure, the clinician uses a sphincterotome to make an incision and widen the opening of the minor papilla. The clinician also places a temporary stent to keep the minor papilla open. This intervention has been thought to prevent future pancreatitis episodes by enabling freer flow of pancreatic secretions to the duodenum.

However, there are potential risks associated with the ERCP procedure, such as post-ERCP pancreatitis (PEP) and stenosis of the minor papilla orifice requiring reintervention.

Current clinical guidelines for patients with idiopathic acute recurrent pancreatitis weigh the potential risks of the ERCP procedure against a potentially reduced risk of future acute pancreatitis episodes. However, the potential benefit of ERCP with minor papillotomy for patients with unexplained acute recurrent pancreatitis has only been explored through retrospective cohort studies with limited follow-up durations. This randomized clinical trial’s strengths include the reduction of potential bias through double-masking and a lengthier participant follow-up duration.

Study Set Up

Researchers enrolled 148 participants at 21 study sites in U.S. and Canada.

• 75 participants were randomly assigned to receive an ERCP with minor papillotomy.
• 73 participants were randomly assigned to receive a sham ERCP.

The primary outcome of the trial was the development of acute pancreatitis more than 30 days after randomization. Study coauthors specified the greater than 30 days’ timeframe to avoid the potential confounding factor of post-ERCP pancreatitis, which typically occurs during the first few days after the procedure.

Secondary outcomes included the frequency of acute pancreatitis episodes, and development of complications associated with acute pancreatitis, such as chronic calcific pancreatitis, diabetes mellitus, and exocrine pancreatic dysfunction.

Participants in the ERCP with minor papillotomy arm were followed for a median duration of 33.4 months (IQR, 19.4-45.6 months). Participants in the sham ERCP arm were followed for a median duration of 34.0 months (IQR, 22.8-45.8 months)

Participants

Study participants were adult individuals who had at least two documented episodes of unexplained acute pancreatitis before enrollment. At least one of the two pancreatitis episodes must have occurred within two years of randomization.

Participants must also have pancreas divisum, as determined through magnetic resonance cholangiopancreatography (MRCP).

Individuals who had any of the following characteristics were excluded from the study:

• Prior ERCP with minor papillotomy.
• Documented pancreatic tumors or pancreatic calcifications.
• Main pancreatic duct strictures.
• Self-reported regular opioid use in the past 3 months.
• High probability of alcohol misuse, as measured by the Tolerance, Worried, Eye-opener, Amnesia, Kut down (TWEAK) screening tool.

Minor Papillotomy Arm

Participants in the ERCP with minor papillotomy arm received a minor papillotomy with cannulation.

The clinician also used standard techniques to lower the risk of post-ERCP pancreatitis, including the placement of a pancreatic duct stent and the use of rectal indomethacin, a nonsteroidal anti-inflammatory drug (NSAID) delivered via suppository.

Sham ERCP Arm

Participants in the sham ERCP arm did not receive a minor papillotomy or cannulation. Instead, during the sham ERCP, the clinician photographed the minor papilla and dropped a pancreatic duct stent in the duodenal lumen. The stent placement was intended to preserve the mask in case imaging was performed within days of the procedure. Participants in the sham ERCP arm did not receive rectal indomethacin.

Results

Participants who underwent an ERCP with minor papillotomy and cannulation did not have a lower risk of acute pancreatitis recurrence compared to patients who underwent a sham ERCP.

Development of Acute Pancreatitis More than 30 Days After Randomization

There was no significant between-group difference in the development of acute pancreatitis more than 30 days after randomization.

• 26/75 (34.7%) of participants randomized to receive a minor papillotomy developed acute pancreatitis more than 30 days after randomization.
• 32/73 (43.8%) of participants randomized to receive a sham ERCP developed acute pancreatitis more than 30 days after randomization.

Development of Acute Pancreatitis at Any Time After Randomization

There was no significant between-group difference in the development of acute pancreatitis at any time after randomization.

• 37/75 (49.3%) of participants randomized to receive a minor papillotomy developed acute pancreatitis at any time after randomization.
• 38/73 (52.1%) of participants randomized to receive a sham ERCP developed acute pancreatitis at any time after randomization.

Frequency of Acute Pancreatitis Episodes Before and After Randomization

There was no between-group difference in the frequency of acute pancreatitis episodes before and after randomization.

• Minor Papillotomy Arm:
  • 187 acute pancreatitis episodes reported before randomization
  • 46 acute pancreatitis episodes reported after randomization
• Sham ERCP Arm
  • 184 acute pancreatitis episodes reported before randomization
  • 56 acute pancreatitis episodes reported after randomization

Frequency and Incidence of Acute Pancreatitis Sequelae During Follow-Up Period

There was also no between-group difference in the frequency and incidence of sequelae related to acute pancreatitis, including chronic calcific pancreatitis, diabetes, and exocrine pancreatic dysfunction:

• Chronic calcific pancreatitis
  • Minor Papillotomy Arm: 3/75 (4%) participants
  • Sham ERCP Arm: 2/73 (2.7%) participants
• Diabetes
  • Minor Papillotomy Arm: 6/38** (15.8%) participants
  • Sham ERCP Arm: 5/39** (12.8%) participants
    **The denominator reflects the number of patients with no diabetes at enrollment who were tested for diabetes during the follow-up period.
• Exocrine pancreatic dysfunction
  • Minor Papillotomy Arm: 2/26** (7.7%) participants
  • Sham ERCP Arm: 5/29** (12.8%) participants
    **The denominator reflects the number of patients with no exocrine pancreatic dysfunction at enrollment who were tested for exocrine pancreatic dysfunction during the follow-up period.

Takeaways

Results of the study suggest that ERCP with minor papillotomy does not prevent future episodes of acute pancreatitis and may lead to a cycle of interventions, pancreatitis symptoms and pain, and more interventions. Finding of pancreas divisum in a patient with recurrent acute pancreatitis is not an automatic indication for ERCP with minor papillotomy. These patients should be referred to an expert center where the etiology of their recurrent pancreatitis can be thoroughly investigated.

Ongoing work in the SHARP study is evaluating the relationship of genetic factors, such as mutations in the cystic fibrosis transmembrane conductance regulator (CFTR) gene, with minor papilla sphincterotomy on the risk of acute pancreatitis in these patients.

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