ORIGINAL ARTICLE
Randomized Controlled Trial for Efficacy of Nafamostat Mesilate in Preventing Post–Endoscopic Retrograde Cholangiopancreatography Pancreatitis Jiro Ohuchida, MD, Kazuo Chijiiwa, MD, PhD, FACS, AGAF, Naoya Imamura, MD, Motoaki Nagano, MD, and Masahide Hiyoshi, MD
ndoscopic retrograde cholangiopancreatography (ERCP) is a procedure performed for the diagnosis and treatment of cholangiopancreatic diseases, but with advances in less-invasive diagnostic imaging modalities such as multi–detector-row computed tomography and magnetic resonance cholangiopancreatography, the importance of ERCP as a diagnostic technique has been decreasing. However, because radical surgery for cholangiopancreatic diseases is among the most highly invasive of abdominal procedures, ERCP is still an important technique when performing preoperative intraductal ultrasonography (IDUS) to precisely determine the proper area of resection in cases of surgical resection and when performing cytological examination or biopsy to obtain a definitive diagnosis preoperatively or prior to chemotherapy in nonresection patients. The frequency of incidental performance of ERCP is much higher than with other procedures of endoscopy, and there is a particularly high incidental occurrence, about 1.3% to 15.1%, in pancreatitis.1–8 Moreover, because severe pancreatitis can be fatal,
conducting diagnosis and treatment while avoiding the occurrence of post-ERCP pancreatitis (PEP) is a perpetual challenge for doctors who specialize in this procedure, and various attempts to prevent PEP have been reported. Although a range of methods to prevent this outcome has been reported, no reliable means of prevention are available. The most frequently reported procedures and methods presently used with the aim of avoiding PEP include preventive pancreatic duct stenting,9–14 wire-guided cannulation,15–19 and prophylactic medication. In particular, there have been many reports on various medications, including gabexate mesilate,20–28 ulinastatin,28–33 and somatostatin,22,24,26,34 but the efficacies of these agents remain controversial, and in most institutions, they are used in a vague hope that administration might lower the incidence of PEP compared with the nonuse of medication. Recent reports have occasionally appeared on the efficacy of nonsteroidal anti-inflammatory drugs.35–40 However, the doses for the prevention of PEP exceed the clinical dosages generally used for fever and pain, and for that reason, NSAIDs are not usually used. A meta-analysis reported that local epinephrine administration to the papilla is effective, but this also is not used as a general procedure.40 We carried out a randomized controlled trial to investigate whether prophylactic administration of nafamostat mesilate, a protease inhibitor that has been the subject of an increasing number of reports in recent years,41–44 that the main outcome of the study was to evaluate the prophylactic benefit of nafamostat mesilate in reducing PEP. Nafamostat mesilate (Futhan), like gabexate mesilate, is a synthetic low-molecular-weight serine protease inhibitor developed by Fujii et al.45 Nafamostat mesilate was developed with the aim of offering a more powerful drug than gabexate mesilate. The pharmacological properties of nafamostat mesilate include a powerful serine protease inhibiting effect and a powerful inhibitory effect against trypsin, shown to be a trigger for the onset of acute pancreatitis in an and in vitro experiment, and plasmin, kallikrein, and the complement components C1r and C1s.45,46 In Japan, the administration of nafamostat mesilate for acute pancreatitis following pancreatography is covered under the national health insurance system. Nafamostat mesilate also has the pharmacokinetic property of not being readily metabolized by esterase in the blood. The serum half-life of nafamostat mesilate is 23.1 minutes, about 20 times greater than that of gabexate mesilate. The action of nafamostat mesilate is also 10 to 100 times more powerful than that of gabexate mesilate,47 and it is used not only for acute pancreatitis but also can be applied clinically as an anticoagulant during extracorporeal circulation.48–50
From the Department of Surgical Oncology and Regulation of Organ Function, Miyazaki University School of Medicine, Miyazaki, Japan. Received for publication December 3, 2013; accepted August 18, 2014. Reprints: Kazuo Chijiiwa, MD, PhD, FACS, AGAF, Department of Surgical Oncology and Regulation of Organ Function, Miyazaki University School of Medicine, Miyazaki 889-1692, Japan (e‐mail: [email protected]). The authors declare no conflict of interest. Copyright © 2014 Wolters Kluwer Health, Inc. All rights reserved.
This study was a prospective, randomized, double-blind clinical trial. The trial protocols were approved by the ethics committee at Miyazaki University and registered with a national clinical database (UMIN Clinical Trials Registry as UMIN 000002762). Informed consent was obtained from all patients. Exclusion
Objective: The objective of this study was to investigate whether prophylactic administration of nafamostat mesilate reduces the incidence of post– endoscopic retrograde cholangiopancreatography (ERCP) pancreatitis (PEP), its efficacy, and risk factors for PEP. Methods: Potential subjects comprised 876 patients who underwent ERCP between September 2008 and February 2011. Of these, 58 patients were excluded after meeting exclusion criteria, and 818 patients were randomized. Patients in the nafamostat mesilate group were administered 20 mg of nafamostat mesilate dissolved in 500 mL of 5% glucose solution, whereas the control group received 500 mL of 5% glucose solution alone, over 2 hours from the start of ERCP. Results: Post-ERCP pancreatitis occurred in 5.1% (41 patients) overall, with a significantly lower frequency in the nafamostat mesilate group (3.5%) than in the control group (6.7%; P = 0.0349). Analysis of the 322 patients who had undergone ERCP for the first time (n = 158 in the nafamostat mesilate group; n = 164 in the control group) found that PEP again significantly less frequently occurred in the nafamostat mesilate group (5.7%) than in the control group (13.4%; P = 0.0172). Conclusions: Our randomized controlled study suggested that shortterm administration of nafamostat mesilate 20 mg may reduce the incidence of PEP. Key Words: ERCP, post-ERCP pancreatitis, nafamostat mesilate, prevention (Pancreas 2015;44: 415–421)
E
Pancreas • Volume 44, Number 3, April 2015
MATERIALS AND METHODS
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Copyright © 2015 Wolters Kluwer Health, Inc. All rights reserved.
415
Pancreas • Volume 44, Number 3, April 2015
Ohuchida et al
criteria comprised patients with acute pancreatitis or receiving treatment for this condition; patients with severe heart failure, renal failure, or diabetes; patients scheduled to undergo pancreatic duct stenting; patients with metal stents placed in such a way as to expose the duodenum; patients who had undergone Billroth II or Roux-en-Y reconstruction after gastrectomy; children younger than 15 years; and patients who did not consent to participate in the study.
Patients The potential subjects were 876 patients who had undergone ERCP for cholangiopancreatic disease between September 2008 and February 2011. Fifty-eight patients who met the exclusion criteria (13 patients receiving pancreatic enzyme inhibitors for the treatment of pancreatitis, 13 patients with pancreatic duct stent, 10 patients with Billroth II reconstruction, 9 patients with a stent exposing the duodenum, 7 patients with heart failure, 3 patients with renal dysfunction, and 3 patients with severe diabetes) were excluded. The remaining 818 patients were randomized with the envelope method into 2 groups: a group of 410 patients who received nafamostat mesilate and a group of 408 patients (the control group). Of them, 9 patients with complete separation of the orifices were excluded; therefore, comparisons were made with 405 patients in the nafamostat mesilate group and 404 patients in the control group (Fig. 1).
Study Design A solution of 20 mg nafamostat mesilate dissolved in 500 mL of 5% glucose solution was used in the nafamostat mesilate group, whereas 500 mL of 5% glucose solution only
was used in the control group. These solutions were administered over 2 hours simultaneously with the start of ERCP. Endoscopic retrograde cholangiopancreatography was conducted with sedation by intravenous injection of midazolam and the use of posterior oblique-viewing endoscopes (JF-260 V or TJF-240; Olympus Optical, Co Ltd, Tokyo, Japan). The examiners were 4 specialists who practice ERCP (endoscopist A had performed >2000 ERCPs, endoscopist B had performed 1000, endoscopist C had performed 500, and endoscopist D had performed 200 ERCPs). The decision of which endoscopist would perform the examinations was also randomized. The endoscopists recorded the diagnostic procedures, therapeutic procedures, examination time, and factors that would affect PEP. After the examination, the patients did not eat or drink, and serum amylase and lipase were measured before and at 4 and 24 hours after the examination. Clinical findings such as abdominal and back pain were assessed over 24 hours.
Definitions Post-ERCP pancreatitis was defined as serum amylase 3 times or more above the normal value at 24 hours after ERCP with accompanying abdominal or back pain. Patients without symptoms were considered to have hyperamylasemia.51 The level of severity was classed as mild when the fasting duration was 2 to 3 days, moderate when it was 4 to 9 days, and severe when it was 10 or more days or there was pancreatic necrosis, pseudocyst or need for percutaneous drainage or surgery. Cannulation difficulty was defined as the requirement of 15 minutes or more to achieve target contrast enhancement. The number of injections to the pancreatic duct was taken to be the number of contrast agent
FIGURE 1. Study flowchart. The potential subjects were 876 patients who had undergone ERCP. Fifty-eight patients who met the exclusion criteria were excluded. The remaining 818 patients were randomized with the envelope method into 2 groups. Of them, 9 patients with completely separation of the orifices were excluded; therefore, comparisons were made with 405 patients in the nafamostat mesilate group and 404 patients in the control group.
416
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© 2014 Wolters Kluwer Health, Inc. All rights reserved.
Copyright © 2015 Wolters Kluwer Health, Inc. All rights reserved.
Pancreas • Volume 44, Number 3, April 2015
Efficacy of Nafamostat Mesilate in Preventing PEP
TABLE 1. Patient Characteristics in Nafamostat Mesylate and Control Groups Nafamostat Group (n = 405), n (%)
Control Group (n = 404), n (%)
P
Male 258 (63.7) 244 (60.4) 0.3324 Age, y 68.4 ± 12.1 69.3 ± 11.2 0.2810 Aged ≥40 y 390 (96.3) 395 (97.8) 0.2160 High-risk patients 128 (31.6) 115 (28.5) 0.3301 Initial ERCP 158 (39.0) 164 (40.1) 0.6458 Biliary disease 299 (73.8) 310 (76.7) 0.3381 Malignant disease 253 (62.5) 242 (59.9) 0.4536 Therapeutic procedure 247 (61.0) 253 (62.6) 0.6320 Difficult cannulation 60 (14.8) 66 (16.3) 0.5506 History of acute 48 (11.9) 27 (6.7) 0.0113 pancreatitis Periampullary diverticulum 95 (23.5) 93 (23.0) 0.8830 Endoscopist 99/107/90/109 105/97/110/92 0.2505 (A/B/C/D) Procedure time, min 31.4 ± 20.1 34.3 ± 23.2 0.0585 Pancreatic duct 1.18 ± 1.74 1.18 ± 1.70 0.9540 injection, no. times PEP 14 (3.5) 27 (6.7) 0.0349 Mild/moderate/severe 11/3/0 25/1/1 0.1308 Post-ERCP 57 (14.1) 48 (11.9) 0.3534 hyperamylasemia Submucosal injection 7 (1.7) 11 (2.7) 0.3377 Double guide-wire 35 (8.6) 32 (7.9) 0.7098 technique
injections plus the number of deep cannulations at the time of catheter exchange when performing IDUS or cytological examination. Patients in whom there was a history of acute pancreatitis, suspected sphincter of Oddi dysfunction, cannulation difficulty, precut endoscopic sphincterotomy, or papillary sphincter balloon dilation or patients younger than 40 years were classified into a high-risk group and into a low-risk group for all others.
Statistical Analysis The primary outcome was occurrence of PEP. Risk factors for PEP were assessed and analyzed with the χ2 test and Student t test. Multivariate analysis was conducted with logistic regression analysis, with P < 0.05 taken to indicate a statistically significant difference. JMP 9.0 for Mac (SAS Institute, Inc, Cary, NC) was used in the statistical analysis.
RESULTS There were no significant differences between the nafamostat mesilate group and control group in the patient characteristics of age, sex, disease, and diagnostic and therapeutic procedures, other than a significantly higher rate of history of pancreatitis in the nafamostat mesilate group (Tables 1, 2). There were no significant differences between the groups in incidental occurrence of ERCP except for PEP. The overall frequency of PEP was 5.1% (41 patients), with severity designated as mild in 36 patients, moderate in 4, and severe in 1. There were no deaths and no significant differences in severity between the nafamostat mesilate and control groups. The incidence of PEP in the 2 groups was 3.5% © 2014 Wolters Kluwer Health, Inc. All rights reserved.
(14 patients) in the nafamostat mesilate group and 6.7% (27 patients) in the control group, which was significantly lower in the nafamostat mesilate group (P = 0.0349) (Table 1). Univariate analysis of risk factors for PEP revealed significant differences in 15 factors. Multivariate analysis of these factors identified pancreatography and no administration of nafamostat mesilate as independent risk factors for PEP (Table 3). Next, of all the 809 study patients, the same analyses were conducted in 322 patients who had undergone ERCP for the first time (nafamostat mesilate group, 158 patients; control group, 164 patients) (Tables 4, 5). Among the characteristics of the first-time ERCP patients, age was significantly higher in the control group, but there were no differences in other factors. The incidence of PEP was 5.7% (9 patients) in the nafamostat mesilate group and 13.4% (22 patients) in the control group, significantly lower in the nafamostat mesilate group (P = 0.0172). Univariate analysis of risk factors for PEP revealed significant differences in 8 factors. Multivariate analysis identified female sex, pancreatography, and no administration of nafamostat mesilate as independent risk factors for PEP (Table 6). In a subgroup analysis, the incidence of PEP was significantly lower in the nafamostat mesilate group in all patients and first-time ERCP patients in the low-risk group (all patients: P = 0.0466; first-time ERCP patients, P = 0.0430). In the high-risk group, there was no significant difference in the incidence of PEP, although the incidence tended to be lower in the nafamostat mesilate group (Table 7).
DISCUSSION Since the late 1990s, numerous reports have described the frequent use of gabexate mesilate and ulinastatin as medications for preventing PEP. However, no recent large-scale comparative
TABLE 2. Procedures in Nafamostat Mesylate and Control Groups Nafamostat Group (n = 405), n (%)
Control Group (n = 404), n (%)
P
373 (92.1) 201 (49.6) 104 (25.7) 32 (7.9) 134 (33.1) 23 (5.7) 15 (3.7) 20 (4.9)
360 (89.1) 193 (47.8) 116 (28.7) 39 (9.7) 137 (33.9) 32 (7.9) 19 (4.7) 21 (5.2)
0.1450 0.5972 0.3322 0.3785 0.8038 0.2053 0.4788 0.8663
99 (24.4) 86 (21.2)
112 (27.7) 66 (16.3)
0.2882 0.0746
49 (12.1) 9 (2.2) 84 (20.7) 33 (8.1)
48 (11.9) 18 (4.5) 90 (22.3) 32 (7.9)
0.9241 0.0770 0.5949 0.9053
9 (2.0)
8 (2.0)
0.8104
Cholangiography Pancreatography Balloon cholangiography Balloon pancreatography IDUS of BD IDUS of MPD Biliary sphincterotomy Papillary balloon dilatation Biliary plastic stent Endoscopic nasobiliary drainage Biliary metallic stent Mechanical lithotripsy Brushing cytology of BD Brushing cytology of MPD Peroral cholangiopancreatoscopy
BD indicates bile duct; MPD, main pancreatic duct.
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TABLE 3. Univariate and Multivariate Analyses of Risk Factors for PEP
Univariate analysis High-risk group Initial ERCP No nafamostat mesylate Diagnostic ERCP Difficult cannulation Prior pancreatography Untreated papilla of Vater Pancreatography Balloon pancreatography IDUS of BD Brushing of BD Procedure time ≥28 min Pancreatic duct injection ≥2 times Submucosal injection Double guide-wire technique Multivariate analysis No nafamostat mesylate Pancreatography
OR
95% CI
P
3.942 5.081 2.000 3.324 5.335 3.405 6.386 10.649 3.203 2.176 3.070 2.888 5.332
2.083–7.669 2.540–11.06 1.049–3.978 1.742–6.618 2.772–10.19 1.775–6.804 2.712–18.74 4.220–35.82 1.386–6.761 1.155–4.112 1.598–5.815 1.468–6.103 2.785–10.65
Randomized Controlled Trial for Efficacy of Nafamostat Mesilate in Preventing Post–Endoscopic Retrograde Cholangiopancreatography Pancreatitis Jiro Ohuchida, MD, Kazuo Chijiiwa, MD, PhD, FACS, AGAF, Naoya Imamura, MD, Motoaki Nagano, MD, and Masahide Hiyoshi, MD
ndoscopic retrograde cholangiopancreatography (ERCP) is a procedure performed for the diagnosis and treatment of cholangiopancreatic diseases, but with advances in less-invasive diagnostic imaging modalities such as multi–detector-row computed tomography and magnetic resonance cholangiopancreatography, the importance of ERCP as a diagnostic technique has been decreasing. However, because radical surgery for cholangiopancreatic diseases is among the most highly invasive of abdominal procedures, ERCP is still an important technique when performing preoperative intraductal ultrasonography (IDUS) to precisely determine the proper area of resection in cases of surgical resection and when performing cytological examination or biopsy to obtain a definitive diagnosis preoperatively or prior to chemotherapy in nonresection patients. The frequency of incidental performance of ERCP is much higher than with other procedures of endoscopy, and there is a particularly high incidental occurrence, about 1.3% to 15.1%, in pancreatitis.1–8 Moreover, because severe pancreatitis can be fatal,
conducting diagnosis and treatment while avoiding the occurrence of post-ERCP pancreatitis (PEP) is a perpetual challenge for doctors who specialize in this procedure, and various attempts to prevent PEP have been reported. Although a range of methods to prevent this outcome has been reported, no reliable means of prevention are available. The most frequently reported procedures and methods presently used with the aim of avoiding PEP include preventive pancreatic duct stenting,9–14 wire-guided cannulation,15–19 and prophylactic medication. In particular, there have been many reports on various medications, including gabexate mesilate,20–28 ulinastatin,28–33 and somatostatin,22,24,26,34 but the efficacies of these agents remain controversial, and in most institutions, they are used in a vague hope that administration might lower the incidence of PEP compared with the nonuse of medication. Recent reports have occasionally appeared on the efficacy of nonsteroidal anti-inflammatory drugs.35–40 However, the doses for the prevention of PEP exceed the clinical dosages generally used for fever and pain, and for that reason, NSAIDs are not usually used. A meta-analysis reported that local epinephrine administration to the papilla is effective, but this also is not used as a general procedure.40 We carried out a randomized controlled trial to investigate whether prophylactic administration of nafamostat mesilate, a protease inhibitor that has been the subject of an increasing number of reports in recent years,41–44 that the main outcome of the study was to evaluate the prophylactic benefit of nafamostat mesilate in reducing PEP. Nafamostat mesilate (Futhan), like gabexate mesilate, is a synthetic low-molecular-weight serine protease inhibitor developed by Fujii et al.45 Nafamostat mesilate was developed with the aim of offering a more powerful drug than gabexate mesilate. The pharmacological properties of nafamostat mesilate include a powerful serine protease inhibiting effect and a powerful inhibitory effect against trypsin, shown to be a trigger for the onset of acute pancreatitis in an and in vitro experiment, and plasmin, kallikrein, and the complement components C1r and C1s.45,46 In Japan, the administration of nafamostat mesilate for acute pancreatitis following pancreatography is covered under the national health insurance system. Nafamostat mesilate also has the pharmacokinetic property of not being readily metabolized by esterase in the blood. The serum half-life of nafamostat mesilate is 23.1 minutes, about 20 times greater than that of gabexate mesilate. The action of nafamostat mesilate is also 10 to 100 times more powerful than that of gabexate mesilate,47 and it is used not only for acute pancreatitis but also can be applied clinically as an anticoagulant during extracorporeal circulation.48–50
From the Department of Surgical Oncology and Regulation of Organ Function, Miyazaki University School of Medicine, Miyazaki, Japan. Received for publication December 3, 2013; accepted August 18, 2014. Reprints: Kazuo Chijiiwa, MD, PhD, FACS, AGAF, Department of Surgical Oncology and Regulation of Organ Function, Miyazaki University School of Medicine, Miyazaki 889-1692, Japan (e‐mail: [email protected]). The authors declare no conflict of interest. Copyright © 2014 Wolters Kluwer Health, Inc. All rights reserved.
This study was a prospective, randomized, double-blind clinical trial. The trial protocols were approved by the ethics committee at Miyazaki University and registered with a national clinical database (UMIN Clinical Trials Registry as UMIN 000002762). Informed consent was obtained from all patients. Exclusion
Objective: The objective of this study was to investigate whether prophylactic administration of nafamostat mesilate reduces the incidence of post– endoscopic retrograde cholangiopancreatography (ERCP) pancreatitis (PEP), its efficacy, and risk factors for PEP. Methods: Potential subjects comprised 876 patients who underwent ERCP between September 2008 and February 2011. Of these, 58 patients were excluded after meeting exclusion criteria, and 818 patients were randomized. Patients in the nafamostat mesilate group were administered 20 mg of nafamostat mesilate dissolved in 500 mL of 5% glucose solution, whereas the control group received 500 mL of 5% glucose solution alone, over 2 hours from the start of ERCP. Results: Post-ERCP pancreatitis occurred in 5.1% (41 patients) overall, with a significantly lower frequency in the nafamostat mesilate group (3.5%) than in the control group (6.7%; P = 0.0349). Analysis of the 322 patients who had undergone ERCP for the first time (n = 158 in the nafamostat mesilate group; n = 164 in the control group) found that PEP again significantly less frequently occurred in the nafamostat mesilate group (5.7%) than in the control group (13.4%; P = 0.0172). Conclusions: Our randomized controlled study suggested that shortterm administration of nafamostat mesilate 20 mg may reduce the incidence of PEP. Key Words: ERCP, post-ERCP pancreatitis, nafamostat mesilate, prevention (Pancreas 2015;44: 415–421)
E
Pancreas • Volume 44, Number 3, April 2015
MATERIALS AND METHODS
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Copyright © 2015 Wolters Kluwer Health, Inc. All rights reserved.
415
Pancreas • Volume 44, Number 3, April 2015
Ohuchida et al
criteria comprised patients with acute pancreatitis or receiving treatment for this condition; patients with severe heart failure, renal failure, or diabetes; patients scheduled to undergo pancreatic duct stenting; patients with metal stents placed in such a way as to expose the duodenum; patients who had undergone Billroth II or Roux-en-Y reconstruction after gastrectomy; children younger than 15 years; and patients who did not consent to participate in the study.
Patients The potential subjects were 876 patients who had undergone ERCP for cholangiopancreatic disease between September 2008 and February 2011. Fifty-eight patients who met the exclusion criteria (13 patients receiving pancreatic enzyme inhibitors for the treatment of pancreatitis, 13 patients with pancreatic duct stent, 10 patients with Billroth II reconstruction, 9 patients with a stent exposing the duodenum, 7 patients with heart failure, 3 patients with renal dysfunction, and 3 patients with severe diabetes) were excluded. The remaining 818 patients were randomized with the envelope method into 2 groups: a group of 410 patients who received nafamostat mesilate and a group of 408 patients (the control group). Of them, 9 patients with complete separation of the orifices were excluded; therefore, comparisons were made with 405 patients in the nafamostat mesilate group and 404 patients in the control group (Fig. 1).
Study Design A solution of 20 mg nafamostat mesilate dissolved in 500 mL of 5% glucose solution was used in the nafamostat mesilate group, whereas 500 mL of 5% glucose solution only
was used in the control group. These solutions were administered over 2 hours simultaneously with the start of ERCP. Endoscopic retrograde cholangiopancreatography was conducted with sedation by intravenous injection of midazolam and the use of posterior oblique-viewing endoscopes (JF-260 V or TJF-240; Olympus Optical, Co Ltd, Tokyo, Japan). The examiners were 4 specialists who practice ERCP (endoscopist A had performed >2000 ERCPs, endoscopist B had performed 1000, endoscopist C had performed 500, and endoscopist D had performed 200 ERCPs). The decision of which endoscopist would perform the examinations was also randomized. The endoscopists recorded the diagnostic procedures, therapeutic procedures, examination time, and factors that would affect PEP. After the examination, the patients did not eat or drink, and serum amylase and lipase were measured before and at 4 and 24 hours after the examination. Clinical findings such as abdominal and back pain were assessed over 24 hours.
Definitions Post-ERCP pancreatitis was defined as serum amylase 3 times or more above the normal value at 24 hours after ERCP with accompanying abdominal or back pain. Patients without symptoms were considered to have hyperamylasemia.51 The level of severity was classed as mild when the fasting duration was 2 to 3 days, moderate when it was 4 to 9 days, and severe when it was 10 or more days or there was pancreatic necrosis, pseudocyst or need for percutaneous drainage or surgery. Cannulation difficulty was defined as the requirement of 15 minutes or more to achieve target contrast enhancement. The number of injections to the pancreatic duct was taken to be the number of contrast agent
FIGURE 1. Study flowchart. The potential subjects were 876 patients who had undergone ERCP. Fifty-eight patients who met the exclusion criteria were excluded. The remaining 818 patients were randomized with the envelope method into 2 groups. Of them, 9 patients with completely separation of the orifices were excluded; therefore, comparisons were made with 405 patients in the nafamostat mesilate group and 404 patients in the control group.
416
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© 2014 Wolters Kluwer Health, Inc. All rights reserved.
Copyright © 2015 Wolters Kluwer Health, Inc. All rights reserved.
Pancreas • Volume 44, Number 3, April 2015
Efficacy of Nafamostat Mesilate in Preventing PEP
TABLE 1. Patient Characteristics in Nafamostat Mesylate and Control Groups Nafamostat Group (n = 405), n (%)
Control Group (n = 404), n (%)
P
Male 258 (63.7) 244 (60.4) 0.3324 Age, y 68.4 ± 12.1 69.3 ± 11.2 0.2810 Aged ≥40 y 390 (96.3) 395 (97.8) 0.2160 High-risk patients 128 (31.6) 115 (28.5) 0.3301 Initial ERCP 158 (39.0) 164 (40.1) 0.6458 Biliary disease 299 (73.8) 310 (76.7) 0.3381 Malignant disease 253 (62.5) 242 (59.9) 0.4536 Therapeutic procedure 247 (61.0) 253 (62.6) 0.6320 Difficult cannulation 60 (14.8) 66 (16.3) 0.5506 History of acute 48 (11.9) 27 (6.7) 0.0113 pancreatitis Periampullary diverticulum 95 (23.5) 93 (23.0) 0.8830 Endoscopist 99/107/90/109 105/97/110/92 0.2505 (A/B/C/D) Procedure time, min 31.4 ± 20.1 34.3 ± 23.2 0.0585 Pancreatic duct 1.18 ± 1.74 1.18 ± 1.70 0.9540 injection, no. times PEP 14 (3.5) 27 (6.7) 0.0349 Mild/moderate/severe 11/3/0 25/1/1 0.1308 Post-ERCP 57 (14.1) 48 (11.9) 0.3534 hyperamylasemia Submucosal injection 7 (1.7) 11 (2.7) 0.3377 Double guide-wire 35 (8.6) 32 (7.9) 0.7098 technique
injections plus the number of deep cannulations at the time of catheter exchange when performing IDUS or cytological examination. Patients in whom there was a history of acute pancreatitis, suspected sphincter of Oddi dysfunction, cannulation difficulty, precut endoscopic sphincterotomy, or papillary sphincter balloon dilation or patients younger than 40 years were classified into a high-risk group and into a low-risk group for all others.
Statistical Analysis The primary outcome was occurrence of PEP. Risk factors for PEP were assessed and analyzed with the χ2 test and Student t test. Multivariate analysis was conducted with logistic regression analysis, with P < 0.05 taken to indicate a statistically significant difference. JMP 9.0 for Mac (SAS Institute, Inc, Cary, NC) was used in the statistical analysis.
RESULTS There were no significant differences between the nafamostat mesilate group and control group in the patient characteristics of age, sex, disease, and diagnostic and therapeutic procedures, other than a significantly higher rate of history of pancreatitis in the nafamostat mesilate group (Tables 1, 2). There were no significant differences between the groups in incidental occurrence of ERCP except for PEP. The overall frequency of PEP was 5.1% (41 patients), with severity designated as mild in 36 patients, moderate in 4, and severe in 1. There were no deaths and no significant differences in severity between the nafamostat mesilate and control groups. The incidence of PEP in the 2 groups was 3.5% © 2014 Wolters Kluwer Health, Inc. All rights reserved.
(14 patients) in the nafamostat mesilate group and 6.7% (27 patients) in the control group, which was significantly lower in the nafamostat mesilate group (P = 0.0349) (Table 1). Univariate analysis of risk factors for PEP revealed significant differences in 15 factors. Multivariate analysis of these factors identified pancreatography and no administration of nafamostat mesilate as independent risk factors for PEP (Table 3). Next, of all the 809 study patients, the same analyses were conducted in 322 patients who had undergone ERCP for the first time (nafamostat mesilate group, 158 patients; control group, 164 patients) (Tables 4, 5). Among the characteristics of the first-time ERCP patients, age was significantly higher in the control group, but there were no differences in other factors. The incidence of PEP was 5.7% (9 patients) in the nafamostat mesilate group and 13.4% (22 patients) in the control group, significantly lower in the nafamostat mesilate group (P = 0.0172). Univariate analysis of risk factors for PEP revealed significant differences in 8 factors. Multivariate analysis identified female sex, pancreatography, and no administration of nafamostat mesilate as independent risk factors for PEP (Table 6). In a subgroup analysis, the incidence of PEP was significantly lower in the nafamostat mesilate group in all patients and first-time ERCP patients in the low-risk group (all patients: P = 0.0466; first-time ERCP patients, P = 0.0430). In the high-risk group, there was no significant difference in the incidence of PEP, although the incidence tended to be lower in the nafamostat mesilate group (Table 7).
DISCUSSION Since the late 1990s, numerous reports have described the frequent use of gabexate mesilate and ulinastatin as medications for preventing PEP. However, no recent large-scale comparative
TABLE 2. Procedures in Nafamostat Mesylate and Control Groups Nafamostat Group (n = 405), n (%)
Control Group (n = 404), n (%)
P
373 (92.1) 201 (49.6) 104 (25.7) 32 (7.9) 134 (33.1) 23 (5.7) 15 (3.7) 20 (4.9)
360 (89.1) 193 (47.8) 116 (28.7) 39 (9.7) 137 (33.9) 32 (7.9) 19 (4.7) 21 (5.2)
0.1450 0.5972 0.3322 0.3785 0.8038 0.2053 0.4788 0.8663
99 (24.4) 86 (21.2)
112 (27.7) 66 (16.3)
0.2882 0.0746
49 (12.1) 9 (2.2) 84 (20.7) 33 (8.1)
48 (11.9) 18 (4.5) 90 (22.3) 32 (7.9)
0.9241 0.0770 0.5949 0.9053
9 (2.0)
8 (2.0)
0.8104
Cholangiography Pancreatography Balloon cholangiography Balloon pancreatography IDUS of BD IDUS of MPD Biliary sphincterotomy Papillary balloon dilatation Biliary plastic stent Endoscopic nasobiliary drainage Biliary metallic stent Mechanical lithotripsy Brushing cytology of BD Brushing cytology of MPD Peroral cholangiopancreatoscopy
BD indicates bile duct; MPD, main pancreatic duct.
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Pancreas • Volume 44, Number 3, April 2015
Ohuchida et al
TABLE 3. Univariate and Multivariate Analyses of Risk Factors for PEP
Univariate analysis High-risk group Initial ERCP No nafamostat mesylate Diagnostic ERCP Difficult cannulation Prior pancreatography Untreated papilla of Vater Pancreatography Balloon pancreatography IDUS of BD Brushing of BD Procedure time ≥28 min Pancreatic duct injection ≥2 times Submucosal injection Double guide-wire technique Multivariate analysis No nafamostat mesylate Pancreatography
OR
95% CI
P
3.942 5.081 2.000 3.324 5.335 3.405 6.386 10.649 3.203 2.176 3.070 2.888 5.332
2.083–7.669 2.540–11.06 1.049–3.978 1.742–6.618 2.772–10.19 1.775–6.804 2.712–18.74 4.220–35.82 1.386–6.761 1.155–4.112 1.598–5.815 1.468–6.103 2.785–10.65
