Nafamostat mesylate in the prevention of post-ERCP pancreatitis and risk factors for post-ERCP pancreatitis
Abstract
Background: Pancreatitis is a significant complication associated with endoscopic retrograde cholangiopancreatography (ERCP).
Objective: This study aimed to evaluate whether prophylactic administration of nafamostat mesylate can reduce the incidence of post-ERCP pancreatitis (PEP).
Design: The research was conducted as a single-center, randomized, double-blinded, controlled trial.
Setting: The study took place at a large tertiary-referral medical center.
Patients: From January 2005 to December 2007, a total of 704 patients who underwent ERCP were included in the analysis.
Intervention: Participants were administered a continuous infusion of 500 mL of 5% dextrose solution containing either 20 mg of nafamostat mesylate (354 patients) or no nafamostat mesylate (350 patients). Serum amylase and lipase levels were measured prior to ERCP, as well as 4 and 24 hours after the procedure, and at additional times as clinically necessary.
Main Outcome Measurements: The primary outcome was the incidence of PEP, along with the identification of risk factors associated with its development.
Results: The overall incidence of acute pancreatitis was found to be 5.4%. A statistically significant difference was observed in the incidence of PEP between the groups receiving nafamostat mesylate and the control group (3.3% vs 7.4%, respectively; P = 0.018). Univariate analysis revealed several significant risk factors for PEP, including a history of acute pancreatitis (P < 0.001), difficult cannulation (P = 0.023), presence of a periampullary diverticulum (P = 0.004), age younger than 40 years (P = 0.009), and multiple pancreatic-duct contrast injections (odds ratio [OR] 2.736, P = 0.012). Limitations: This study was conducted at a single center, which may limit the generalizability of the findings. Conclusions: Prophylaxis with nafamostat mesylate demonstrates partial effectiveness in preventing post-ERCP pancreatitis. Identified independent risk factors for PEP include a history of acute pancreatitis and multiple pancreatic-duct contrast injections. Introduction Acute pancreatitis is recognized as the most common and severe complication following ERCP. The incidence of post-ERCP pancreatitis (PEP) has been reported to vary between 2% and 9%. Despite advancements in ERCP techniques and increased clinical experience, the rate of post-procedural pancreatitis has not significantly decreased. Recent meta-analyses indicate that pancreatic-duct stents can lower the incidence of PEP in patients deemed high-risk. The exact pathophysiology underlying PEP remains incompletely understood; however, several contributing factors such as hydrostatic injury, obstruction of pancreatic juice outflow, thermal injury from electrocautery, and chemical or allergic reactions can lead to PEP, either independently or in combination. Ultimately, the premature activation of proteolytic enzymes within acinar cells leads to cellular injury and autodigestion of the pancreas. Significant efforts have been directed toward minimizing both the incidence and severity of PEP through pharmaceutical interventions. Additionally, various studies have focused on identifying risk factors for PEP to better recognize patients at heightened risk of developing post-procedural pancreatitis. When ERCP is necessary for high-risk patients, it is advisable to consider protective endoscopic techniques or pharmacological agents. Several pharmacological agents, including gabexate mesylate, somatostatin, prednisone, low-dose heparin, nonsteroidal anti-inflammatory drugs (NSAIDs), and allopurinol, have been assessed for their potential to reduce the incidence and severity of PEP, though many results remain controversial. Gabexate mesylate has been shown to be effective in preventing PEP in numerous studies; however, a recent meta-analysis suggested it may not be effective. Nafamostat mesylate, a low molecular weight serine protease inhibitor with a longer half-life and greater potency than gabexate, has demonstrated efficacy against pancreatitis in experimental studies and case reports. To our knowledge, no large controlled human studies have been conducted to evaluate the effectiveness of nafamostat mesylate in preventing PEP. Therefore, this study aims to determine whether prophylactic nafamostat mesylate can reduce the incidence of PEP and to analyze patient and clinical characteristics to identify independent risk factors for PEP. Patients and Methods This research was designed as a prospective, randomized, double-blinded, single-center trial. Informed consent was obtained from all participants, and the study received approval from the ethics committee of the internal review board of Pusan National University. All diagnostic and therapeutic ERCP procedures were performed by highly experienced endoscopists. Patients Between January 2005 and December 2007, patients over the age of 18 scheduled to undergo ERCP for suspected or diagnosed pancreatobiliary diseases were assessed for eligibility. Exclusion criteria included prior biliary sphincterotomy or pre-cut sphincterotomy, exchange of biliary endoprosthesis or repeated ERCP, active pancreatitis prior to the procedure, pregnancy, mental disabilities, and refusal to participate. Data were collected to identify risk factors for PEP, and patients meeting inclusion criteria were randomized into a study group. Study Design A total of 723 patients were recruited and randomized into two groups using a computer-generated list to ensure blinding. All participants began fasting at midnight the day before the endoscopic retrograde cholangiopancreatography (ERCP). Patients received either a 500 mL infusion of 5% dextrose solution containing 20 mg of nafamostat mesylate (test group) or a similar solution without nafamostat mesylate (control group) within one hour prior to the procedure, with the infusion continuing for 24 hours. ERCP was performed under conscious sedation using side-viewing endoscopes, and iopamidol was utilized as the contrast medium for all participants. All procedures, including both diagnostic and therapeutic interventions, as well as factors influencing post-ERCP pancreatitis (PEP), were recorded. Serum amylase and lipase levels were obtained before the procedure, 4 hours and 24 hours post-ERCP, and at other clinically indicated times. All patients were monitored in the hospital for a minimum of 24 hours following ERCP, and clinical parameters, including abdominal pain, were documented for the same duration. Pancreatic duct stents were not employed as a preventive measure against pancreatitis. Definitions Difficult cannulation is defined by the number of attempts made to cannulate the ampulla of Vater using a cannulation instrument. Cannulation is categorized as easy if it requires between 1 and 9 attempts and as difficult if more than 10 attempts are necessary. The total number of pancreatic duct injections refers to the frequency with which any volume of contrast medium is injected into the pancreatic duct during the procedure. The bile duct diameter is assessed by measuring the maximum duct diameter within 2 centimeters of the ampulla, with adjustments made for radiographic magnification. Post-ERCP pancreatitis (PEP) is defined as a threefold or greater increase in serum amylase levels at 24 hours following ERCP, accompanied by significant pain and symptoms that necessitate hospital admission or an extension of an existing admission. Post-ERCP hyperamylasemia is defined similarly but occurs without the presence of accompanying symptoms. The severity of PEP is categorized based on the duration of hospitalization: mild if the stay lasts between 2 and 3 days, moderate if it extends from 4 to 9 days, and severe if the hospitalization exceeds 10 days or if complications arise, such as hemorrhagic pancreatitis, pancreatic necrosis, pancreatic pseudocyst formation, or the necessity for percutaneous drainage or surgical intervention. Body mass index (BMI) is calculated as body weight in kilograms divided by the square of height in meters. The classification of BMI follows the criteria established by the World Health Organization for the Western Pacific region: normal weight is defined as a BMI of less than 23 kg/m2, overweight is classified as a BMI equal to or greater than 23 kg/m2 but less than 25 kg/m2, and obesity is defined as a BMI of 25 kg/m2 or greater. After undergoing ERCP, patients are categorized as high risk if they have a history of acute pancreatitis, suspected sphincter of Oddi dysfunction, difficult cannulation, pre-cut sphincterotomy, transpapillary balloon dilation, or multiple pancreatic duct injections; all other patients are classified as low risk. Statistical Analysis The primary outcome of interest in this study is the development of post-ERCP pancreatitis. Risk factors associated with pancreatitis are evaluated through univariate analysis using the chi-squared test or Fisher's exact test for categorical variables, while the Student's t-test is employed for continuous variables. Variables demonstrating a P-value of less than 0.05 in univariate analysis are included in a forward, stepwise multiple logistic regression model to identify independent risk factors for pancreatitis. A P-value of less than 0.05 is considered statistically significant. Statistical calculations are performed using SPSS software version 12.0 for Windows. Results A total of 723 patients were recruited for this study; 19 were excluded because ERCP was not performed due to pyloric stenosis, distorted duodenum, or previous Billroth II gastrectomy. Ten patients failed selective bile duct cannulation and were categorized into the difficult cannulation group. Ultimately, data from 704 patients were analyzed, with 350 in the control group and 354 in the nafamostat mesylate group. There were no significant differences in baseline characteristics, therapeutic procedures, or endoscopic findings between the two groups. The most common indication for ERCP was choledocholithiasis, accounting for 59.0% of the cases. The overall incidence of post-ERCP hyperamylasemia was 9.0%. There was no significant difference in the rate of post-ERCP hyperamylasemia between the nafamostat mesylate and control groups. The overall incidence of PEP was 5.4%, with a significant difference in the rate of PEP between the nafamostat mesylate and control groups. Subgroup analysis indicated that in low-risk patients, the rate of PEP was significantly lower in the nafamostat mesylate group compared to the control group. In high-risk patients, although there was no significant difference in PEP rates between the two groups, a reduced rate of pancreatitis was noted in the nafamostat mesylate group. All patients diagnosed with PEP exhibited mild to moderate symptoms and received conservative treatment. There were no severe or fatal events reported, and no adverse events related to the administration of the study drug were observed. Risk Factors for Post-ERCP Pancreatitis The investigation into potential patient-related and procedure-related risk factors for post-ERCP pancreatitis (PEP) revealed several significant findings. Univariate analysis highlighted important patient-related risk factors, including a history of acute pancreatitis, the presence of a periampullary diverticulum, and being younger than 40 years. In addition, it was found that not receiving nafamostat mesylate premedication and having multiple pancreatic duct contrast injections were significant procedure-related risk factors. These identified risk factors were subsequently utilized to develop a multivariate model. The results of the multivariate analysis confirmed that a history of acute pancreatitis, multiple pancreatic duct contrast injections, and the absence of nafamostat mesylate premedication were statistically significant risk factors for the development of post-ERCP pancreatitis. Discussion Endoscopic retrograde cholangiopancreatography (ERCP) and sphincterotomy are critical procedures for addressing biliary and pancreatic diseases. Among the various complications associated with ERCP, post-ERCP pancreatitis is the most common and challenging complication. The estimated incidence of PEP varies, ranging from 2% to 9%. The discrepancies in these estimates may arise from differences in patient characteristics, the skill level of the endoscopist, and the complexity of the procedures performed. Most instances of PEP are classified as mild or moderate; however, severe pancreatitis, which can lead to fatal outcomes, occurs in only 0.4% to 0.6% of cases. Furthermore, a silent rise in serum amylase levels is observed more frequently than PEP, occurring in up to 70% of cases. Recent meta-analyses have indicated that pancreatic duct stenting can reduce the occurrence of PEP. Many endoscopists agree that the placement of prophylactic pancreatic duct stents is effective in preventing PEP in high-risk patients. However, clear guidelines on which patients should receive pancreatic duct stenting are lacking. There are also potential downsides to stent placement, including the endoscopist's unfamiliarity with the procedure, challenges in inserting stents in patients with small or tortuous ducts, the risk of pancreatic duct injury, and the need for follow-up ERCP to remove the stent. In our study, the focus was on assessing the efficacy of nafamostat mesylate for the prevention of PEP, which is why pancreatic duct stenting was not employed. Researchers have explored various pharmacologic agents aimed at preventing or mitigating the severity of pancreatitis, with several different agents being evaluated, including steroids, nonsteroidal anti-inflammatory drugs (NSAIDs), allopurinol, low-dose heparin, and interleukin-10. The outcomes of these studies have often been disappointing. Although prophylactic NSAIDs have been shown to be effective in preventing PEP in recent meta-analyses, further multicenter studies are necessary to confirm these findings before they can be widely adopted. Somatostatin has been shown to suppress pancreatic secretion and reduce intrapancreatic duct pressure by inhibiting sphincter of Oddi motility. Despite some studies indicating that somatostatin reduces the frequency of PEP, conflicting results have also been reported. Similarly, octreotide treatment has produced mixed results, and its lack of efficacy may be partly attributed to its stimulating effect on sphincter of Oddi contraction, which hinders pancreatic duct outflow and counteracts the inhibitory effect of octreotide on pancreatic secretion. Gabexate mesylate, a commonly used protease inhibitor, has demonstrated effectiveness in preventing PEP. However, due to its short half-life, gabexate must be administered continuously for 12 to 24 hours after the procedure, requiring relatively high doses. Nafamostat mesylate is a low molecular weight protease inhibitor that inhibits serine proteases such as trypsin, kallikrein, C1r and C1s, thrombin, and plasmin. It is widely used in Asia for treating conditions such as acute pancreatitis, disseminated intravascular coagulation, and in extracorporeal circulation; however, it is not available in many countries. Nafamostat mesylate has several advantages over gabexate, including a longer plasma half-life and a more potent inhibitory profile. The cost of nafamostat mesylate is also more favorable compared to other alternatives. In our study, we found that nafamostat mesylate significantly reduced the incidence of PEP, with rates of 3.3% compared to 7.4% in the control group. Importantly, there were no severe cases of PEP observed, and all patients made a full recovery under supportive management. The multivariate analysis indicated that pretreatment with nafamostat mesylate was associated with a significantly reduced risk of developing PEP. Given that the rate of PEP can reach as high as 20% in high-risk patients, it is crucial to focus on reducing the risk of PEP in this population. However, identifying high-risk patients prior to ERCP remains challenging, as some risk factors can only be determined during the procedure. In our study, most patients required therapeutic interventions, which included procedures such as sphincterotomy or infundibulotomy. These patients were admitted through the emergency department due to acute cholangitis or severe abdominal pain. Consequently, ERCP was performed on an inpatient basis, enabling the continuous intravenous infusion of nafamostat mesylate to commence prior to the procedure and continue for 24 hours afterward. This practice may limit the practicality of using nafamostat mesylate in outpatient settings. Future research should investigate whether administering a bolus injection of nafamostat mesylate prior to ERCP is effective in preventing post-ERCP pancreatitis. Post-ERCP pancreatitis is influenced by a combination of patient-related, procedure-related, and operator-related factors. Recent studies have identified several significant patient-related risk factors, including younger age, female sex, sphincter of Oddi dysfunction, prior episodes of acute pancreatitis or recurrent pancreatitis, normal serum bilirubin levels, and the absence of bile duct stones. Procedure-related factors encompass pancreatic duct injection, pancreatic sphincterotomy, balloon dilation of an intact biliary sphincter, difficult cannulation, and pre-cut sphincterotomy. The diverse nature of these risk factors may arise from heterogeneous patient populations, varying levels of endoscopic expertise, different cannulation techniques, and inconsistent definitions of post-ERCP pancreatitis. In our study, we evaluated all the aforementioned risk factors, and our results were consistent with previous findings. Although there are conflicting data regarding the significance of the endoscopist's level of expertise as a risk factor for post-ERCP pancreatitis, all procedures in our study were performed by two highly skilled endoscopists. Therefore, operator-related risk factors were deemed negligible. We found that a history of acute pancreatitis and multiple injections of contrast into the pancreatic duct were significant independent risk factors for post-ERCP pancreatitis, aligning with earlier research. The injection of contrast medium into the pancreatic duct is independently associated with an increased risk for post-ERCP pancreatitis. Our findings did not indicate pancreatic acinarization, underscoring the importance of intrapancreatic duct pressure and contrast-induced pancreatitis as pathophysiological events in post-ERCP pancreatitis. While difficult bile cannulation was not significant on multivariate analysis, it was identified as a significant risk factor on univariate analysis. Difficult bile duct cannulation and pancreatic duct injection are interconnected, as repeated attempts at bile duct cannulation often lead to pancreatic duct injections. Difficult bile duct cannulation can also provoke spasms of the sphincter of Oddi and edema of the papilla, potentially obstructing the pancreatic duct and resulting in pancreatitis. It is likely that the frequency of post-ERCP pancreatitis could be minimized by avoiding repeated attempts at challenging cannulations; we typically perform infundibulotomy using a needle-knife in cases of difficult cannulation. Additionally, although periampullary diverticulum was not significant on multivariate analysis, it was a notable risk factor on univariate analysis. This condition is associated with difficult cannulation and multiple pancreatic duct injections due to the challenging location of the papillary orifice. Age under 40 years was identified as a significant risk factor on univariate analysis but not on multivariate analysis. This may suggest that the progressive decline in pancreatic exocrine function with age could protect older patients from pancreatic injury. To prevent post-ERCP pancreatitis, several strategies are necessary, with careful patient selection being the most crucial. In high-risk patients, alternative imaging modalities such as magnetic resonance cholangiopancreatography (MRCP) or endoscopic ultrasound (EUS) should be considered first. After these alternative imaging studies, diagnostic or empiric biliary therapeutic ERCP should not be performed in patients with a low probability of biliary disease. If ERCP is deemed necessary, meticulous technical maneuvers, such as minimizing pancreatic injections, placing pancreatic plastic stents, and employing efficient cannulation techniques, along with pharmacologic prophylaxis using nafamostat mesylate, should be considered. In conclusion, the prophylactic use of nafamostat mesylate demonstrates partial effectiveness in preventing post-ERCP pancreatitis. A history of acute pancreatitis and multiple pancreatic duct injections are identified as independent risk factors for post-ERCP pancreatitis. The identification of these risk factors, along with the prophylactic use of nafamostat mesylate, will aid endoscopists in developing better strategies for managing high-risk patients. Further large-scale multicenter studies are needed to validate these findings.