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Mo1463 Incidence, Severity and Mortality of Post-ERCP Pancreatitis: a Systematic Review of Randomized Controlled Trials
Abstracts
period, 245 were considered high risk [Table 1]. There was no significant difference in ketorolac use between those who developed acute pancreatitis (AP) (7/28, 25%) and those who did not (52/217, 24%) (p⫽0.9). Recurrent AP, female gender, age ⬍50 years old and performance of a pancreatogram were significantly associated with PEP. Pancreatic stent placement was not associated with PEP. Even after adjusting for these variables and exploring other models, no associations were found between ketorolac and PEP. Conclusion: Intravenous ketorolac was not found to be protective of post-ERCP pancreatitis in high-risk patients. Further randomized studies using intravenous NSAIDs in high risk patients may be appropriate. Table 1. Univariable analysis
Factor Female Current Age Alcohol use Smoking . Never . Ex-smoker . Current smoker Risk factors (non-exclusive) Suspected Sphincter of Oddi Dysfunction Recurrent AP Pancreatic sphincterotomy Balloon dilation Precut sphincterotomy Female ⬍ 50 years Prior post-ERCP pancreatitis Ampullectomy Pancreatogram Pancreatic duct brush cytology Cannulation for 30⫹min/MD gave up Pancreatic stent Ketorolac Timing of ketorolac administration (min) Dexamethasone Medications . None . Ketorolac only . Dexamethasone only . Ketorolac ⫹ Dexamethasone
No Post-ERCP Pancreatitis (Nⴝ217)
Post-ERCP Pancreatitis (Nⴝ28) 22 (78.6) 57.7⫾18.9 1 (3.6) 19 (67.9) 4 (14.3) 5 (17.9) 9 (32.1)
0.03 0.58 0.56 0.37
245
124 (57.1) 59.6⫾16.4 4 (1.9) 122 (56.5) 57 (26.4) 37 (17.1) 50 (23.0)
245 245 245 245 245 245 245 245 245 245
20 (9.2) 81 (37.3) 7 (3.2) 109 (50.2) 32 (14.7) 3 (1.4) 8 (3.7) 3 (1.4) 5 (2.3) 18 (8.3)
7 (25.0) 11 (39.3) 0 (0.0) 11 (39.3) 10 (35.7) 0 (0.0) 2 (7.1) 3 (10.7) 0 (0.0) 3 (10.7)
0.012 0.84 0.33 0.28 0.006 0.53 0.38 0.003 0.42 0.67
244 245 59
118 (54.6) 52 (24.0) 0.00 [0.00,20.0]
18 (64.3) 7 (25.0) 0.00 [0.00,15.0]
0.33 0.9 0.77
245 245
88 (40.6)
14 (50.0)
0.34 0.62
109 (50.2) 20 (9.2) 56 (25.8) 32 (14.7)
13 (46.4) 1 (3.6) 8 (28.6) 6 (21.4)
N 245 245 238
as mild, moderate and severe in 7.9%, 3.9% and 0.9% respectively. The cumulative mortality among high risk patients was 0.17%. Among high risk patients, 27% of cases were performed for suspected sphincter of Oddi dysfunction (SOD) versus 15.7% in the total cohort. The incidence of PEP was 12.3% in North American centers compared to 8.7% in European or 8.3% in Asian centers. The proportion of ERCPs performed in North America for SOD was 38.2% compared to 6% in Europe and 2.5% in Asia. Conclusion: Based on the placebo arm of 101 RCTs evaluating pharmacologic agents and pancreatic stents for the prevention of PEP, the cumulative incidence of PEP was 9.5% with severe disease in 0.7% and 0.18% mortality. Among high risk patients, the cumulative incidence of PEP was 12.5% with severe disease in 0.9% and 0.17% mortality. The higher rates of PEP in North America versus Europe and Asia are likely due to higher proportion of ERCPs being performed for patients with suspected SOD. Incidence, Severity and Mortality for Post ERCP Pancreatitis (PEP)
p-value
0.29
Values presented as Mean ⫾ SD with t-test; Median [P25, P75] with Wilcoxon rank sum test, or N (%) with Pearson’s chi-square test
Mo1463 Incidence, Severity and Mortality of Post-ERCP Pancreatitis: a Systematic Review of Randomized Controlled Trials Bharati Kochar*, Venkata S. Akshintala, Susan Hutfless, Katherine Kim, Elham Afghani, Anne Marie Lennon, Mouen Khashab, Anthony N. Kalloo, Vikesh K. Singh Medicine, The Johns Hopkins Hospital, Baltimore, MD Background: Data regarding the incidence, severity and mortality of post-ERCP pancreatitis (PEP) have largely come from retrospective observational studies as opposed to randomized control trials (RCTs) Aim: To determine the incidence, severity and mortality of PEP in consecutive and high risk patients based on a systemic review of the placebo arms of RCTs. Methods: The MEDLINE, EMBASE and Cochrane databases were searched from the inception of each database to June 2012 to identify RCTs evaluating the efficacy of drugs and pancreatic duct stents in preventing PEP. Only full text publications which reported the incidence of PEP were chosen for analysis. The incidence, severity and mortality of PEP from the placebo or no intervention arms of RCTs were extracted for consecutive and high risk patients to avoid the influence of an intervention on the development of PEP. The severity of PEP was defined according to the Cotton criteria. Results: There were a total of 101 RCTs with 12,921 patients in the placebo or no stent groups. The cumulative incidence of PEP was 9.5%. There were 54 RCTs with 8,791 patients which reported the severity of PEP, in which 5.8%, 3.3% and 0.7% of cases were mild, moderate and severe, respectively. The cumulative mortality was 0.18%. There were 20 RCTs with 2,216 patients at high risk of PEP. The cumulative incidence of PEP among high risk patients was 12.5%. The severity of PEP in high risk patients was classified
Cumulative Incidence Mild PEP Moderate PEP Severe PEP Mortality ERCPs for suspected SOD
TOTAL
High Risk
Asia
Europe
North America
9.5% 5.8% 3.3% 0.7% 0.18% 15.7%
12.5% 7.9% 3.9% 0.9% 0.17% 27.0%
8.3% 5.9% 2.7% 0.19% 0% 2.5%
8.7% 5.2% 3.0% 0.8% 0.20% 6.0%
12.3% 6.7% 4.5% 1.0% 0.10% 38.2%
Mo1464 The Results of the Tokyo Trial of Prevention of Post-ERCP Pancreatitis With Risperidone-2 (Tokyo P3R-2): a Multicenter, Randomized, Placebo-Controlled, Double-Blind Clinical Trial Rie Uchino1, Hiroyuki Isayama*1, Takeshi Tsujino1,2, Yukiko Ito2, Saburo Matsubara3, Naminatsu Takahara4, Toshihiko Arizumi5, Nobuo Toda5, Dai Mohri6, Osamu Togawa6, Hiroshi Yagioka7, Dai Akiyama2, Tsuyoshi Hamada1, Koji Miyabayashi1, Suguru Mizuno1, Kazumichi Kawakubo1, Hirofumi Kogure1, Takashi Sasaki1, Natsuyo Yamamoto1, Yousuke Nakai1, Naoki Sasahira1, Kenji Hirano1, Minoru Tada1, Kazuhiko Koike1 1 Department of Gastroenterology, Graduate School of Medicine, University of Tokyo, Tokyo, Japan; 2Department of Gastroenterology, Japanese Red Cross Medical Center, Tokyo, Japan; 3Department of Gastroenterology, Tokyo Metropolitan Police Hospital, Tokyo, Japan; 4 Department of Gastroenterology, Kanto Central Hospital, Tokyo, Japan; 5Department of Gastroenterology, Mitsui Memorial Hospital, Tokyo, Japan; 6Saitama Medical University International Medical Center, Saitama, Japan; 7Department of Gastroenterology, JR Tokyo General Hospital, Tokyo, Japan Background and Aims: Post-endoscopic retrograde cholangiography (ERCP) pancreatitis (PEP) is the most common and severe complication that needs to be resolved. Our previous study suggested that infusion of ulinastatin before ERCP significantly reduced the incidence of PEP in a multicenter, randomized, controlled trial (Tsujino, CGH 2005; 3: 376-383). Serotonin [5-hydroxytryptamine (5-HA)] activates pancreatic enzyme secretion and is associated with the development and aggravation of acute pancreatitis. Risperidone, a 5-HA2A antagonist, ameliorated pancreatitis in experimental models. In a previous multicenter, randomized, phase II, non-placebo-controlled study, we demonstrated that a combination of ulinastatin and risperidone might reduce the incidence of PEP (Tokyo P3R; Tsujino, JG 2012, in press). The incidence of PEP did not differ significantly between the risperidone ⫹ ulinastatin group and the ulinastatin alone group, but post-ERCP levels of amylase were significantly lower in the risperidone ⫹ ulinastatin group. This pilot study demonstrated that risperidone might have a beneficial effect with regard to PEP prevention. The aim of this study was to evaluate the efficacy of risperidone alone for the prevention of PEP. Methods: In this multicenter, randomized, placebo-controlled, double-blinded clinical trial, 500 patients undergoing invasive diagnostic or therapeutic ERCP were randomized to receive 2 mg of oral risperidone (risperidone group, n ⫽ 250) or placebo (placebo group, n ⫽ 250) at 0.5-2 h before ERCP; however, 17 patients (11 in the risperidone group and 6 in the placebo group) were excluded after randomization. The primary outcome was the incidence of PEP; other outcomes included the incidence of hyperenzymemia with increased levels of amylase, pancreatic amylase, and lipase and a risk factor of PEP. Results: Twenty-four patients (10.0%) in the risperidone group and 21 (8.6%) in the placebo group (p ⫽ 0.587) developed PEP. Serum amylase and p-amylase levels at 3 h after ERCP were significantly lower in the risperidone group than in the placebo group, unlike those at 18 h after ERCP. Univariate analysis revealed “small papilla of Vater,” “cannulation time ⱖ10 min,” “acinarization,” “stenosis of the intrahepatic bile duct,” and “total
AB392 GASTROINTESTINAL ENDOSCOPY Volume 77, No. 5S : 2013
www.giejournal.org
period, 245 were considered high risk [Table 1]. There was no significant difference in ketorolac use between those who developed acute pancreatitis (AP) (7/28, 25%) and those who did not (52/217, 24%) (p⫽0.9). Recurrent AP, female gender, age ⬍50 years old and performance of a pancreatogram were significantly associated with PEP. Pancreatic stent placement was not associated with PEP. Even after adjusting for these variables and exploring other models, no associations were found between ketorolac and PEP. Conclusion: Intravenous ketorolac was not found to be protective of post-ERCP pancreatitis in high-risk patients. Further randomized studies using intravenous NSAIDs in high risk patients may be appropriate. Table 1. Univariable analysis
Factor Female Current Age Alcohol use Smoking . Never . Ex-smoker . Current smoker Risk factors (non-exclusive) Suspected Sphincter of Oddi Dysfunction Recurrent AP Pancreatic sphincterotomy Balloon dilation Precut sphincterotomy Female ⬍ 50 years Prior post-ERCP pancreatitis Ampullectomy Pancreatogram Pancreatic duct brush cytology Cannulation for 30⫹min/MD gave up Pancreatic stent Ketorolac Timing of ketorolac administration (min) Dexamethasone Medications . None . Ketorolac only . Dexamethasone only . Ketorolac ⫹ Dexamethasone
No Post-ERCP Pancreatitis (Nⴝ217)
Post-ERCP Pancreatitis (Nⴝ28) 22 (78.6) 57.7⫾18.9 1 (3.6) 19 (67.9) 4 (14.3) 5 (17.9) 9 (32.1)
0.03 0.58 0.56 0.37
245
124 (57.1) 59.6⫾16.4 4 (1.9) 122 (56.5) 57 (26.4) 37 (17.1) 50 (23.0)
245 245 245 245 245 245 245 245 245 245
20 (9.2) 81 (37.3) 7 (3.2) 109 (50.2) 32 (14.7) 3 (1.4) 8 (3.7) 3 (1.4) 5 (2.3) 18 (8.3)
7 (25.0) 11 (39.3) 0 (0.0) 11 (39.3) 10 (35.7) 0 (0.0) 2 (7.1) 3 (10.7) 0 (0.0) 3 (10.7)
0.012 0.84 0.33 0.28 0.006 0.53 0.38 0.003 0.42 0.67
244 245 59
118 (54.6) 52 (24.0) 0.00 [0.00,20.0]
18 (64.3) 7 (25.0) 0.00 [0.00,15.0]
0.33 0.9 0.77
245 245
88 (40.6)
14 (50.0)
0.34 0.62
109 (50.2) 20 (9.2) 56 (25.8) 32 (14.7)
13 (46.4) 1 (3.6) 8 (28.6) 6 (21.4)
N 245 245 238
as mild, moderate and severe in 7.9%, 3.9% and 0.9% respectively. The cumulative mortality among high risk patients was 0.17%. Among high risk patients, 27% of cases were performed for suspected sphincter of Oddi dysfunction (SOD) versus 15.7% in the total cohort. The incidence of PEP was 12.3% in North American centers compared to 8.7% in European or 8.3% in Asian centers. The proportion of ERCPs performed in North America for SOD was 38.2% compared to 6% in Europe and 2.5% in Asia. Conclusion: Based on the placebo arm of 101 RCTs evaluating pharmacologic agents and pancreatic stents for the prevention of PEP, the cumulative incidence of PEP was 9.5% with severe disease in 0.7% and 0.18% mortality. Among high risk patients, the cumulative incidence of PEP was 12.5% with severe disease in 0.9% and 0.17% mortality. The higher rates of PEP in North America versus Europe and Asia are likely due to higher proportion of ERCPs being performed for patients with suspected SOD. Incidence, Severity and Mortality for Post ERCP Pancreatitis (PEP)
p-value
0.29
Values presented as Mean ⫾ SD with t-test; Median [P25, P75] with Wilcoxon rank sum test, or N (%) with Pearson’s chi-square test
Mo1463 Incidence, Severity and Mortality of Post-ERCP Pancreatitis: a Systematic Review of Randomized Controlled Trials Bharati Kochar*, Venkata S. Akshintala, Susan Hutfless, Katherine Kim, Elham Afghani, Anne Marie Lennon, Mouen Khashab, Anthony N. Kalloo, Vikesh K. Singh Medicine, The Johns Hopkins Hospital, Baltimore, MD Background: Data regarding the incidence, severity and mortality of post-ERCP pancreatitis (PEP) have largely come from retrospective observational studies as opposed to randomized control trials (RCTs) Aim: To determine the incidence, severity and mortality of PEP in consecutive and high risk patients based on a systemic review of the placebo arms of RCTs. Methods: The MEDLINE, EMBASE and Cochrane databases were searched from the inception of each database to June 2012 to identify RCTs evaluating the efficacy of drugs and pancreatic duct stents in preventing PEP. Only full text publications which reported the incidence of PEP were chosen for analysis. The incidence, severity and mortality of PEP from the placebo or no intervention arms of RCTs were extracted for consecutive and high risk patients to avoid the influence of an intervention on the development of PEP. The severity of PEP was defined according to the Cotton criteria. Results: There were a total of 101 RCTs with 12,921 patients in the placebo or no stent groups. The cumulative incidence of PEP was 9.5%. There were 54 RCTs with 8,791 patients which reported the severity of PEP, in which 5.8%, 3.3% and 0.7% of cases were mild, moderate and severe, respectively. The cumulative mortality was 0.18%. There were 20 RCTs with 2,216 patients at high risk of PEP. The cumulative incidence of PEP among high risk patients was 12.5%. The severity of PEP in high risk patients was classified
Cumulative Incidence Mild PEP Moderate PEP Severe PEP Mortality ERCPs for suspected SOD
TOTAL
High Risk
Asia
Europe
North America
9.5% 5.8% 3.3% 0.7% 0.18% 15.7%
12.5% 7.9% 3.9% 0.9% 0.17% 27.0%
8.3% 5.9% 2.7% 0.19% 0% 2.5%
8.7% 5.2% 3.0% 0.8% 0.20% 6.0%
12.3% 6.7% 4.5% 1.0% 0.10% 38.2%
Mo1464 The Results of the Tokyo Trial of Prevention of Post-ERCP Pancreatitis With Risperidone-2 (Tokyo P3R-2): a Multicenter, Randomized, Placebo-Controlled, Double-Blind Clinical Trial Rie Uchino1, Hiroyuki Isayama*1, Takeshi Tsujino1,2, Yukiko Ito2, Saburo Matsubara3, Naminatsu Takahara4, Toshihiko Arizumi5, Nobuo Toda5, Dai Mohri6, Osamu Togawa6, Hiroshi Yagioka7, Dai Akiyama2, Tsuyoshi Hamada1, Koji Miyabayashi1, Suguru Mizuno1, Kazumichi Kawakubo1, Hirofumi Kogure1, Takashi Sasaki1, Natsuyo Yamamoto1, Yousuke Nakai1, Naoki Sasahira1, Kenji Hirano1, Minoru Tada1, Kazuhiko Koike1 1 Department of Gastroenterology, Graduate School of Medicine, University of Tokyo, Tokyo, Japan; 2Department of Gastroenterology, Japanese Red Cross Medical Center, Tokyo, Japan; 3Department of Gastroenterology, Tokyo Metropolitan Police Hospital, Tokyo, Japan; 4 Department of Gastroenterology, Kanto Central Hospital, Tokyo, Japan; 5Department of Gastroenterology, Mitsui Memorial Hospital, Tokyo, Japan; 6Saitama Medical University International Medical Center, Saitama, Japan; 7Department of Gastroenterology, JR Tokyo General Hospital, Tokyo, Japan Background and Aims: Post-endoscopic retrograde cholangiography (ERCP) pancreatitis (PEP) is the most common and severe complication that needs to be resolved. Our previous study suggested that infusion of ulinastatin before ERCP significantly reduced the incidence of PEP in a multicenter, randomized, controlled trial (Tsujino, CGH 2005; 3: 376-383). Serotonin [5-hydroxytryptamine (5-HA)] activates pancreatic enzyme secretion and is associated with the development and aggravation of acute pancreatitis. Risperidone, a 5-HA2A antagonist, ameliorated pancreatitis in experimental models. In a previous multicenter, randomized, phase II, non-placebo-controlled study, we demonstrated that a combination of ulinastatin and risperidone might reduce the incidence of PEP (Tokyo P3R; Tsujino, JG 2012, in press). The incidence of PEP did not differ significantly between the risperidone ⫹ ulinastatin group and the ulinastatin alone group, but post-ERCP levels of amylase were significantly lower in the risperidone ⫹ ulinastatin group. This pilot study demonstrated that risperidone might have a beneficial effect with regard to PEP prevention. The aim of this study was to evaluate the efficacy of risperidone alone for the prevention of PEP. Methods: In this multicenter, randomized, placebo-controlled, double-blinded clinical trial, 500 patients undergoing invasive diagnostic or therapeutic ERCP were randomized to receive 2 mg of oral risperidone (risperidone group, n ⫽ 250) or placebo (placebo group, n ⫽ 250) at 0.5-2 h before ERCP; however, 17 patients (11 in the risperidone group and 6 in the placebo group) were excluded after randomization. The primary outcome was the incidence of PEP; other outcomes included the incidence of hyperenzymemia with increased levels of amylase, pancreatic amylase, and lipase and a risk factor of PEP. Results: Twenty-four patients (10.0%) in the risperidone group and 21 (8.6%) in the placebo group (p ⫽ 0.587) developed PEP. Serum amylase and p-amylase levels at 3 h after ERCP were significantly lower in the risperidone group than in the placebo group, unlike those at 18 h after ERCP. Univariate analysis revealed “small papilla of Vater,” “cannulation time ⱖ10 min,” “acinarization,” “stenosis of the intrahepatic bile duct,” and “total
AB392 GASTROINTESTINAL ENDOSCOPY Volume 77, No. 5S : 2013
www.giejournal.org