Original article
415
Authors
Yu Bai1, *, Xu Ren2, **, Xiao-Feng Zhang3, *, Nong-Hua Lv4, **, Xue-Gang Guo5, *, Xin-Jian Wan6, Zhan-Guo Nie7, Shu-Tang Han8, Ping Bie9, De-An Tian10, Ming Ji11, Zhao-Shen Li1, **
Institutions
Institutions are listed at the end of article.
submitted 18. June 2014 accepted after revision 27. October 2014
Background and study aim: Post-endoscopic retrograde cholangiopancreatography (ERCP) pancreatitis (PEP) remains the most common complication of ERCP. Somatostatin may inhibit pancreatic secretion and has been tested for PEP prophylaxis. However, the results of previous studies are inconsistent. The aim of the current study was to investigate whether somatostatin can reduce the incidence of PEP. Patients and methods: The study was a multicenter, open-label, randomized controlled trial. A total of 908 patients with normal amylase levels who were undergoing ERCP were randomized to receive somatostatin 250 μg bolus injection before ERCP and 250 μg/hour intravenous infusion for 11 hours after ERCP (somatostatin group) or no somatostatin treatments (control group). The
incidences of PEP and hyperamylasemia were compared in the two groups. Results: The full analysis set included 900 patients (445 in the somatostatin group, 455 in the control group). PEP developed in 34 patients (7.5 %) in the control group (95 % confidence interval [CI] 5.4 % – 10.3 %) and in 18 patients (4.0 %) in the somatostatin group (95 %CI 2.6 % – 6.3 %; P = 0.03). Hyperamylasemia occurred in 46 patients (10.1 %) in the control group (95 %CI 7.7 % – 13.2 %) and in 27 patients (6.1 %) in the somatostatin group (95 %CI 4.2 % – 8.7 %; P = 0.03). No perforation or death occurred during the study. Conclusions: This study showed that somatostatin was effective and safe for the prevention of PEP and hyperamylasemia in ERCP patients. (ClinicalTrials.gov number, NCT01431781).
Introduction
also indicated that PEP was the most frequent (54.5 %) complication after ERCP [3]. In an effort to reduce the incidence of PEP, a number of pharmacological agents have been studied, and many agents (e. g. allopurinol, corticosteroids, octreotide [4 – 6]) showed promising results in pilot studies but failed to show a benefit in largescale, randomized studies and meta-analyses. Recently, a large-scale, multicenter, randomized, placebo-controlled study by Elmunzer et al. [7] demonstrated that rectal indomethacin significantly decreased the rate of PEP from 16.9 % to 9.2 % (P = 0.005). However, as prophylactic pancreatic stents, which have been shown to significantly reduce the incidence of ERCP-induced pancreatitis in high-risk patients [8, 9], were placed in more than 80 % of the studied population, the true efficacy of nonsteroidal anti-inflammatory drugs needs to be confirmed in further, sufficiently powered, randomized trials without pancreatic stent placement. Somatostatin may potently inhibit pancreatic secretion and has been investigated for PEP prophylaxis; however, clinical trials have produced in-
Bibliography DOI http://dx.doi.org/ 10.1055/s-0034-1391227 Published online: 15.1.2015 Endoscopy 2015; 47: 415–420 © Georg Thieme Verlag KG Stuttgart · New York ISSN 0013-726X Corresponding author Zhao-Shen Li, MD, PhD Department of Gastroenterology Changhai Hospital Second Military Medical University 168 Changhai Road Shanghai, 200433 China Fax: +86-021-55621735 [email protected]
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Since its introduction in 1968, endoscopic retrograde cholangiopancreatography (ERCP) has become a common endoscopic procedure for diagnosing and treating biliary and pancreatic diseases. However, ERCP is a highly specialized procedure, and, compared with other endoscopic procedures, it is associated with a higher risk of severe complications, including acute pancreatitis, bleeding, infection, and perforation [1]. Among these complications, the most frequently reported is post-ERCP pancreatitis (PEP). Andriulli et al. summarized the data of 21 prospective studies involving 16 855 patients, and 1154 ERCP-related complications were reported, of which more than half were pancreatitis (585/ 1154) [2]. A previous prospective, multicenter study of ERCP-related complications by our group
* These authors are joint first authors. ** These authors are joint corresponding authors.
Bai Yu et al. Prophylactic somatostatin prevents post-ERCP pancreatitis … Endoscopy 2015; 47: 415–420
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Prophylactic somatostatin can reduce incidence of post-ERCP pancreatitis: multicenter randomized controlled trial
Original article
consistent results on its prophylactic effect [10 – 13]. Bordas et al. [10] and Lee et al. [11] showed that PEP occurred significantly less often in patients receiving somatostatin compared with those receiving placebo. In contrast, in the study by Andriulli et al. [12], no significant difference in the incidence of PEP was observed between the somatostatin and placebo groups. Another study by Andriulli et al. [13] suggested that 6.5 hours’ administration of somatostatin was ineffective for the prevention of PEP. Subsequent systematic reviews and meta-analyses have yielded inconsistent recommendations [14, 15]. Omata et al. [14] showed that somatostatin can effectively prevent PEP, whereas Andriulli et al. [15] found a nonsignificant effect of somatostatin on the prevention of pancreatitis. Therefore, currently available data are inconclusive and it remains unclear whether somatostatin should be administrated before ERCP to prevent pancreatitis. In view of this controversy, a large-scale, multicenter, randomized controlled trial (RCT) was undertaken to determine the prophylactic effect of somatostatin on PEP.
Methods !
This multicenter RCT was conducted between September 2011 and September 2012 at 11 tertiary hospitals in China. The study was approved by the individual institutional review board at each hospital.
Patients Patients were eligible if they were aged > 18 years and had normal serum amylase levels prior to ERCP. The exclusion criteria were: pregnancy, history of allergy to somatostatin, renal insufficiency (serum creatinine > 177 μmol/L), attack of acute myocardial infarction within 3 months, history of subtotal gastrectomy (Billroth II), signs and symptoms of shock before ERCP, including hypotension (systolic blood pressure < 90 mmHg) or tachycardia (heart rate > 120 bpm), any medical or psychological condition that would prevent patients from completing the study or signing the informed consent form, involvement in other studies in the 2 months prior to the current study, or contraindication to somatostatin.
Post-procedure management After ERCP, all patients were monitored in the inpatient unit. Serum amylase was measured before ERCP (baseline) and at 3 and 24 hours after ERCP, and subsequently at the discretion of the physician. Clinical symptoms, including abdominal pain, tenderness, nausea and vomiting, gastrointestinal bleeding, and requirement for treatment, were documented during the 24 hour period after ERCP by physicians in the inpatient unit. For patients who developed PEP, the management of pancreatitis was at the clinical discretion of the physician. As most PEP develops within 48 hours after the procedure, patients were discharged if no complication occurred within this period. In addition to PEP, other ERCP-related complications were defined as described previously [16]. Any case of ERCP complication (e. g. gastrointestinal bleeding, perforation, infection), and adverse events that were potentially attributable to somatostatin were reported to the local institutional review board.
Outcomes The primary outcome was the incidence of PEP. According to international consensus [16], the diagnosis of PEP was made when there was new onset of epigastric pain, an increase in pancreatic enzymes of at least three times the upper limit of the normal range within 24 hours after ERCP, and hospitalization for at least 2 nights. The severity of PEP was categorized as mild if the length of stay was < 3 nights, moderate if hospital stay was 4 – 10 nights, and severe if hospital stay was > 10 days or if intensive care unit admission or surgery was required for pancreatitis. Secondary outcomes were the incidence of PEP in high-risk patients and the incidence of post-ERCP hyperamylasemia. High risk was defined according to previous large-scale epidemiological studies [3, 17, 18]: young age (< 60 years old), female, normal bilirubin, history of acute pancreatitis, history of PEP, allergy to contrast media, failed cannulation, cannulation time > 10 minutes, at least one pancreatic deep wire pass, needle-knife precut, two or more injections of contrast agent into the pancreatic duct, major papilla sphincterotomy, difficult cannulation, suspected sphincter of Oddi dysfunction, pancreatic divisum, chronic pancreatitis. Post-ERCP hyperamylasemia was defined as serum amylase level at least three times the upper limit of the normal range (normal range defined as < 120 U/L), without clinical symptoms.
Procedure All patients fasted for at least 8 hours before ERCP. Sedation was provided by meperidine and midazolam. All ERCP procedures were performed by well-trained endoscopists who were experts with at least 5 years’ experience in ERCP; there was no trainee involvement in the study. The endoscopist and the assistant nurse were blinded to the treatment allocation, but the patient was not blinded. Therapeutic procedures included biliary and/or pancreatic sphincterotomy, pre-cut papillotomy, biliary and/or pancreatic stenting, biliary and/or pancreatic stone extraction, or balloon dilation of the common bile duct. The procedure time was defined as the time from endoscope insertion to the complete withdrawal of the endoscope. Eligible patients were randomized to receive either routine treatment (fasted for at least 6 hours after ERCP, adequate fluid intake, etc) + somatostatin 250 μg intravenous bolus before ERCP and 250 μg/hour continuous infusion for 11 hours after ERCP, or routine treatment alone.
Statistical analysis Sample size calculation Based on the reported incidences of PEP in previous studies [19 – 21], sample size calculations showed that 870 patients would provide power of at least 90 % to detect a decrease in the incidence of PEP from 8 % in the control group to 3 % in the somatostatin group.
Randomization The randomization list, which was stratified according to individual center, was computer generated at the Center for Clinical Epidemiology and Evidence-Based Medicine (Second Military Medical University, Shanghai, China). The person who generated the randomization list was not involved in the ERCP procedure or patient care.
Bai Yu et al. Prophylactic somatostatin prevents post-ERCP pancreatitis … Endoscopy 2015; 47: 415–420
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416
Original article
Data analysis
417
Potentially eligible patients screened at 11 centers (n = 908)
Categorical data were analyzed using the chi-squared test. Continuous variables were expressed as mean (SD) and ranges, and were compared using the Student’s t test. P values of < 0.05 were considered to be statistically significant and all tests were two sided. All statistical analyses were performed using SAS software (version 9.1.3; SAS Institute Inc., Cary, North Carolina, USA).
Randomized
Somatostatin group (n = 452)
Control group (n = 456)
Failed to complete study (n = 6) Excluded for various reasons (n = 2)
Results !
Control group (n = 455)
900 patients included in full analysis set (445 in Somatostatin group; 455 in control group)
Fig. 1
Flow diagram of patient enrollment.
ERCP procedures The indication for ERCP was suspected biliary disease in 820 cases and pancreatic pathologies in 73; 7 patients had both biliary and pancreatic disorders. The majority of the ERCP procedures (817; 90.8 %) were therapeutic, with only 83 patients undergoing diagnostic ERCP (9.2 %). The cannulation techniques were not standardized and were at the discretion of the endoscopist. Single- or multiple-lumen sphincterotome, catheters, needle-knife sphincterotomy as well as guidewire cannulation were used for biliary access. There was no statistically significant difference between the groups in terms of the mean procedure " Table 2). Overall, time for ERCP and the time for cannulation (● ERCP was unsuccessful in 14 patients (6 in the control group and 8 in the somatostatin group). In cases of failed ERCP, a repeat ERCP by the same endoscopist or another expert was scheduled
Study group (n = 445)
P value
Age, median (range), years
63 (22 – 93)
60 (19 – 96)
0.02
Weight, mean ± SD, kg
60.7 ± 11.7
60.2 ± 11.0
0.54
1.64 ± 0.1
0.34
Height, mean ± SD, m BMI, mean ± SD, kg/m 2
1.65 ± 0.1 22.1 ± 3.3
22.2 ± 3.2
Sex, n (%) 237 (52.1)
197 (44.3)
Female
218 (47.9)
248 (55.7)
Yes
91 (20.0)
74 (16.6)
No
364 (80.0)
371 (83.4)
46 (10.1)
54 (12.1)
Smoking, n (%)
0.19
Alcohol, n (%) No History of surgery, n (%) Gastrectomy (Billroth-I) Choledochojejunostomy
0.33 409 (89.9)
391 (87.9)
236 (51.9)
218 (49.0)
5 1
1 143
CBD exploration + T Tube placement
19
16
ERCP
23
20
Others
97
85
Co-morbidities, n (%)
224 (49.2)
195 (43.8)
Cardiovascular
121 (54.0)
102 (52.3)
Hypertension
101 (45.1)
97 (49.7)
Respiratory
21 (9.4)
16 (8.2)
Genitourinary
11 (4.9)
13 (6.7)
Liver
22 (9.8)
29 (14.9)
6 (2.7)
7 (3.6)
Immunosuppressive
0.39
6
157
Cholecystectomy
0.89 0.02
Male
Yes
Table 1 Demographic information of the study population.
0.10
BMI, body mass index; CBD, common bile duct; ERCP, endoscopic retrograde cholangiopancreatography.
Bai Yu et al. Prophylactic somatostatin prevents post-ERCP pancreatitis … Endoscopy 2015; 47: 415–420
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During the study period, a total of 908 consecutive patients from 11 centers were screened and randomized. Six patients were lost or failed to complete the study, and two patients were excluded because they did not meet the inclusion criteria. Therefore, 900 patients were included in the full analysis set and 897 patients " Fig. 1 shows the flow were included in the per-protocol set. ● diagram of patient enrollment. The mean age of patients was similar in both groups. The body mass index of the two groups was also comparable. There were more male patients in the control group than in the somatostatin group (52.1 % vs. 44.3 %) and more patients who smoked (20.0 % vs. 16.6 %, respectively). Alcohol use was similar between the groups (10.1 % and 12.1 %, respectively). The percentage of patients with a history of surgery was comparable (51.9 % vs. 49.0 %), and approximately one-third of patients in each group had undergone previous cholecystectomy. In all, 224 patients in the control group and 195 patients in the somatostatin group were diagnosed with co-morbidities, mainly cardiovascular comorbidities. The demographic details of the study groups are " Table 1. summarized in ●
Original article
Control group (n = 455) Procedure time for ERCP, mean ± SD, minutes Time for cannulation, mean ± SD, minutes
Study group (n = 445)
P value
31.1 ± 15.0
31.4 ± 14.2
0.4
6.1 ± 6.8
5.8 ± 6.2
0.6 0.8
Table 2 Details of endoscopic retrograde cholangiopancreatography procedures.
Diagnosis after ERCP, n (%) CBD stone
299 (65.7)
289 (64.9)
Malignant biliary stricture
63 (13.9)
55 (12.4)
0.5
Benign biliary stricture
33 (7.3)
36 (8.1)
0.6
Chronic pancreatitis
16 (3.5)
18 (4.0)
0.7
Pancreatic divisum
0 (0.0)
3 (0.7)
0.2
SOD
9 (2.0)
17 (3.8)
0.1
35 (7.7)
27 (6.1)
0.3
Others
ERCP, endoscopic retrograde cholangiopancreatography; CBD, common bile duct; SOD, sphincter of Oddi dysfunction.
several days after the index ERCP. If the second ERCP also failed, alternative procedures such as percutaneous transhepatic cholangial drainage would be performed.
P = 0.0276
10 %
Primary outcome Overall, PEP developed in 52 patients (5.8 %): 34/455 (7.5 %; 95 % CI 5.4 % – 10.3 %) occurred in the control group and 18/445 (4.0 %; 95 %CI 2.6 % – 6.3 %) occurred in the somatostatin group (P = 0.03) " Fig. 2), which indicates an absolute risk reduction of 3.5 % (● points (95 % confidence interval [CI] 2.0 % – 6.2 %) (number needed to treat to prevent one episode of PEP, 29 [95 %CI 16 – 636]). A logistical regression analysis, adjusted for possible confounders, showed that the prophylactic effect of somatostatin was not changed (P = 0.026). All of the cases of PEP were of mild or moderate severity. A total of 27 patients in the control group and 17 patients in the somatostatin group had mild PEP, and 7 patients in the control group and 1 patient in the somatostatin group had moderate pancreatitis. The patients with pancreatitis were supportively managed with close observation. None of them required surgical treatment, and all of them recovered without sequelae.
16 %
Secondary outcomes
14%
8%
7.47 %
6% 4.04 % 4%
2%
0%
The secondary outcome of hyperamylasemia occurred in 73 patients (8.1 %): 46 (10.1 %; 95 %CI 7.7 % – 13.2 %) in the control group and 27 (6.1 %; 95 %CI 4.2 % – 8.7 %) in the somatostatin group, and " Fig. 3). Among all pathe difference was significant (P = 0.03) (● tients, 88.2 % were considered to be at high risk for PEP, and among these patients, 28/386 patients (7.3 %) in the control group and 17/408 patients (4.2 %) in the somatostatin group developed PEP (P = 0.06).
Control
Somatostatin
Fig. 3 Incidence of hyperamylasemia. P = 0.0264
12 % 10 %
10.11 %
8% 6.07 %
6% 4%
Adverse events The total adverse event incidence rate was 15.9 % (143/900) (16.7 % [76/455] in the control group and 15.1 % [67/445] in the treatment group, with no significant difference between groups). Two adverse events were related to the ERCP procedure. Upper gastrointestinal bleeding occurred in two patients (one from each group), and both patients recovered uneventfully with medical treatment. None of the bleeding events required radiological or surgical treatment. No perforation or death occurred during the study. In the somatostatin group, five patients complained of minor discomfort, including dizziness (n = 1), numbness (n = 1), palpitation (n = 1), desaturation (n = 1), abdominal pain and vomiting (n = 1). All of the symptoms resolved spontaneously within 24 hours after withdrawal of somatostatin.
Fig. 2 Incidence of post-endoscopic retrograde cholangiopancreatography pancreatitis.
12 %
2% 0%
Control
Somatostatin
Discussion !
Based on the findings of this large-scale, multicenter, RCT, somatostatin 250 μg intravenous bolus before ERCP plus 250 μg/hour continuous infusions for 11 hours after ERCP significantly reduced the incidence of PEP and hyperamylasemia (P = 0.03). The number of ERCP patients who needed to be treated to prevent one episode of PEP was 29. These results are similar to those reported in a meta-analysis [22], which showed that 12-hour ad-
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Original article
closer reflection of the true effect of somatostatin for PEP prevention. In summary, these study results showed that somatostatin was effective and safe in the prevention of PEP and hyperamylasemia in patients undergoing ERCP. Competing interests: The study was supported by Merck Serono Co., Ltd. Institutions 1 Department of Gastroenterology, Changhai Hospital, Second Military Medical University, Shanghai, China 2 Department of Gastroenterology, Heilongjiang Province Hospital, Harbin, China 3 Department of Gastroenterology, First People’s Hospital of Hangzhou, Hangzhou, Zhejiang, China 4 Department of Gastroenterology, First Affiliated Hospital, Nan Chang University, Jiangxi, China 5 Department of Gastroenterology, Xijing Hospital of Digestive Diseases, Fourth Military Medical University, Xi’an, China 6 Department of Gastroenterology, First People’s Hospital, School of Medicine, Shanghai Jiaotong University, Shanghai, China 7 Department of Gastroenterology, Urumchi General Hospital, Lanzhou Command, PLA, China 8 Gastrointestinal Endoscopy Center, Jiangsu Provincial Hospital of Traditional Chinese Medicine, Nanjing, Jiangsu, China 9 Department of Gastroenterology, Southwest Hospital, Third Military Medical University, Chongqing, China 10 Department of Gastroenterology, Tongji Hospital, Tongji Medical College, Huazhong University of Science and Technology, Wuhan, China 11 Department of Gastroenterology, Beijing Friendship Hospital, Capital Medical University, Beijing, China
Acknowledgment !
Dr. Bai was supported by the 2014 Shanghai Rising-Star Program (A type, No. 14QA1404800) and Outstanding Young Scholars Fund of Second Military Medical University and the Foundation for the Author of National Excellent Doctoral Dissertation of PR China. The study was also supported by Merck Serono Co., Ltd.
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ministration of somatostatin was associated with a 7.7 % decrease in PEP (95 %CI 3.4 % – 12.0 %; P < 0.0001), and somatostatin was also found to be effective in reducing the incidence of hyperamylasemia (P = 0.02). Another RCT [11] of 391 patients in whom therapeutic ERCP was undertaken showed that the incidence of PEP was significantly lower in the group in which somatostatin administration was continued for 12 hours starting from 30 minutes before ERCP (3.6 % in the treatment group vs. 9.6 % in the placebo group; P = 0.02). This result is closer to that in the current study. The meta-analysis reported by Omata et al. [14] draws the same conclusion. The current study suffers from some limitations. First, the study was not a placebo-controlled study and was not double blinded. Second, unlike a previous trial [23], this study only investigated one method of somatostatin administration (250 μg bolus before plus 250 μg/hour for 11 hours after ERCP). This approach was chosen because it is relatively easy to apply in clinical practice. Efforts to reduce PEP have taken the form of strict patient selection, improved ERCP techniques, and medication prophylaxis, but much controversy remains over the role of pharmacological prevention. The efficacy of somatostatin for PEP prevention has been studied extensively during the past 3 decades; however, the conclusions of these individual studies and meta-analyses are contradictory [10 – 15]. After a thorough review of available evidence, we suggest that the possible reasons for previous controversy concerning the effect of somatostatin on PEP prevention could be that more than half of the 16 published randomized trials [10 – 13, 19, 20, 23 – 32] included small sample sizes and some had methodological drawbacks. In addition, the average incidence of PEP in the placebo group in previous studies [10 – 13, 19, 20, 23 – 32] was about 8 %. To detect a reduced incidence to 3 % with 80 % power using a cutoff for statistical significance of 0.05, the required sample size would be at least 652 patients [33]. It is clear that few trials could fulfill this criterion, which may be the reason why the majority of randomized trials showed a nonstatistically significant decrease in the incidence of PEP in the somatostatin group. Therefore, it is plausible that the inconsistency shown in previous results has been due to a type II error, which did not allow detection of the true effect of somatostatin on PEP reduction. As simple randomization was used in the current study, age and sex were different between the two groups despite the randomization. The mean age of the patient population was 60 years, about half of them reported a history of abdominal surgery, and more than 45 % of them had co-morbidities. All of these patientrelated factors, combined with procedure-related factors, contributed to the large proportion of high-risk patients (88.2 %). However, the incidence of PEP (7.5 %) was lower than that of a recent trial (9.2 %) [7]. We suggest that the reason for this difference may be that in this previous study [7], more than 80 % of patients had clinical suspicion of sphincter of Oddi dysfunction, and therapeutic pancreatic ERCP were performed, whereas in the current study, the majority of enrolled patients had biliary diseases and required therapeutic biliary procedures. In addition, the endoscopy centers that participated in the current study were all high-volume centers, which performed between 1000 and 2500 ERCP procedures per year. Therefore, the incidence of pancreatitis may be lower than what might be expected in nonreferral centers. Moreover, in the current study, only 35 patients (3.9 %) underwent placement of a prophylactic pancreatic stent, which was much lower than the rate of stent placement (> 80 %) in the Elmunzer et al. study [7]. Therefore, the current results may be a
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Authors
Yu Bai1, *, Xu Ren2, **, Xiao-Feng Zhang3, *, Nong-Hua Lv4, **, Xue-Gang Guo5, *, Xin-Jian Wan6, Zhan-Guo Nie7, Shu-Tang Han8, Ping Bie9, De-An Tian10, Ming Ji11, Zhao-Shen Li1, **
Institutions
Institutions are listed at the end of article.
submitted 18. June 2014 accepted after revision 27. October 2014
Background and study aim: Post-endoscopic retrograde cholangiopancreatography (ERCP) pancreatitis (PEP) remains the most common complication of ERCP. Somatostatin may inhibit pancreatic secretion and has been tested for PEP prophylaxis. However, the results of previous studies are inconsistent. The aim of the current study was to investigate whether somatostatin can reduce the incidence of PEP. Patients and methods: The study was a multicenter, open-label, randomized controlled trial. A total of 908 patients with normal amylase levels who were undergoing ERCP were randomized to receive somatostatin 250 μg bolus injection before ERCP and 250 μg/hour intravenous infusion for 11 hours after ERCP (somatostatin group) or no somatostatin treatments (control group). The
incidences of PEP and hyperamylasemia were compared in the two groups. Results: The full analysis set included 900 patients (445 in the somatostatin group, 455 in the control group). PEP developed in 34 patients (7.5 %) in the control group (95 % confidence interval [CI] 5.4 % – 10.3 %) and in 18 patients (4.0 %) in the somatostatin group (95 %CI 2.6 % – 6.3 %; P = 0.03). Hyperamylasemia occurred in 46 patients (10.1 %) in the control group (95 %CI 7.7 % – 13.2 %) and in 27 patients (6.1 %) in the somatostatin group (95 %CI 4.2 % – 8.7 %; P = 0.03). No perforation or death occurred during the study. Conclusions: This study showed that somatostatin was effective and safe for the prevention of PEP and hyperamylasemia in ERCP patients. (ClinicalTrials.gov number, NCT01431781).
Introduction
also indicated that PEP was the most frequent (54.5 %) complication after ERCP [3]. In an effort to reduce the incidence of PEP, a number of pharmacological agents have been studied, and many agents (e. g. allopurinol, corticosteroids, octreotide [4 – 6]) showed promising results in pilot studies but failed to show a benefit in largescale, randomized studies and meta-analyses. Recently, a large-scale, multicenter, randomized, placebo-controlled study by Elmunzer et al. [7] demonstrated that rectal indomethacin significantly decreased the rate of PEP from 16.9 % to 9.2 % (P = 0.005). However, as prophylactic pancreatic stents, which have been shown to significantly reduce the incidence of ERCP-induced pancreatitis in high-risk patients [8, 9], were placed in more than 80 % of the studied population, the true efficacy of nonsteroidal anti-inflammatory drugs needs to be confirmed in further, sufficiently powered, randomized trials without pancreatic stent placement. Somatostatin may potently inhibit pancreatic secretion and has been investigated for PEP prophylaxis; however, clinical trials have produced in-
Bibliography DOI http://dx.doi.org/ 10.1055/s-0034-1391227 Published online: 15.1.2015 Endoscopy 2015; 47: 415–420 © Georg Thieme Verlag KG Stuttgart · New York ISSN 0013-726X Corresponding author Zhao-Shen Li, MD, PhD Department of Gastroenterology Changhai Hospital Second Military Medical University 168 Changhai Road Shanghai, 200433 China Fax: +86-021-55621735 [email protected]
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Since its introduction in 1968, endoscopic retrograde cholangiopancreatography (ERCP) has become a common endoscopic procedure for diagnosing and treating biliary and pancreatic diseases. However, ERCP is a highly specialized procedure, and, compared with other endoscopic procedures, it is associated with a higher risk of severe complications, including acute pancreatitis, bleeding, infection, and perforation [1]. Among these complications, the most frequently reported is post-ERCP pancreatitis (PEP). Andriulli et al. summarized the data of 21 prospective studies involving 16 855 patients, and 1154 ERCP-related complications were reported, of which more than half were pancreatitis (585/ 1154) [2]. A previous prospective, multicenter study of ERCP-related complications by our group
* These authors are joint first authors. ** These authors are joint corresponding authors.
Bai Yu et al. Prophylactic somatostatin prevents post-ERCP pancreatitis … Endoscopy 2015; 47: 415–420
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Prophylactic somatostatin can reduce incidence of post-ERCP pancreatitis: multicenter randomized controlled trial
Original article
consistent results on its prophylactic effect [10 – 13]. Bordas et al. [10] and Lee et al. [11] showed that PEP occurred significantly less often in patients receiving somatostatin compared with those receiving placebo. In contrast, in the study by Andriulli et al. [12], no significant difference in the incidence of PEP was observed between the somatostatin and placebo groups. Another study by Andriulli et al. [13] suggested that 6.5 hours’ administration of somatostatin was ineffective for the prevention of PEP. Subsequent systematic reviews and meta-analyses have yielded inconsistent recommendations [14, 15]. Omata et al. [14] showed that somatostatin can effectively prevent PEP, whereas Andriulli et al. [15] found a nonsignificant effect of somatostatin on the prevention of pancreatitis. Therefore, currently available data are inconclusive and it remains unclear whether somatostatin should be administrated before ERCP to prevent pancreatitis. In view of this controversy, a large-scale, multicenter, randomized controlled trial (RCT) was undertaken to determine the prophylactic effect of somatostatin on PEP.
Methods !
This multicenter RCT was conducted between September 2011 and September 2012 at 11 tertiary hospitals in China. The study was approved by the individual institutional review board at each hospital.
Patients Patients were eligible if they were aged > 18 years and had normal serum amylase levels prior to ERCP. The exclusion criteria were: pregnancy, history of allergy to somatostatin, renal insufficiency (serum creatinine > 177 μmol/L), attack of acute myocardial infarction within 3 months, history of subtotal gastrectomy (Billroth II), signs and symptoms of shock before ERCP, including hypotension (systolic blood pressure < 90 mmHg) or tachycardia (heart rate > 120 bpm), any medical or psychological condition that would prevent patients from completing the study or signing the informed consent form, involvement in other studies in the 2 months prior to the current study, or contraindication to somatostatin.
Post-procedure management After ERCP, all patients were monitored in the inpatient unit. Serum amylase was measured before ERCP (baseline) and at 3 and 24 hours after ERCP, and subsequently at the discretion of the physician. Clinical symptoms, including abdominal pain, tenderness, nausea and vomiting, gastrointestinal bleeding, and requirement for treatment, were documented during the 24 hour period after ERCP by physicians in the inpatient unit. For patients who developed PEP, the management of pancreatitis was at the clinical discretion of the physician. As most PEP develops within 48 hours after the procedure, patients were discharged if no complication occurred within this period. In addition to PEP, other ERCP-related complications were defined as described previously [16]. Any case of ERCP complication (e. g. gastrointestinal bleeding, perforation, infection), and adverse events that were potentially attributable to somatostatin were reported to the local institutional review board.
Outcomes The primary outcome was the incidence of PEP. According to international consensus [16], the diagnosis of PEP was made when there was new onset of epigastric pain, an increase in pancreatic enzymes of at least three times the upper limit of the normal range within 24 hours after ERCP, and hospitalization for at least 2 nights. The severity of PEP was categorized as mild if the length of stay was < 3 nights, moderate if hospital stay was 4 – 10 nights, and severe if hospital stay was > 10 days or if intensive care unit admission or surgery was required for pancreatitis. Secondary outcomes were the incidence of PEP in high-risk patients and the incidence of post-ERCP hyperamylasemia. High risk was defined according to previous large-scale epidemiological studies [3, 17, 18]: young age (< 60 years old), female, normal bilirubin, history of acute pancreatitis, history of PEP, allergy to contrast media, failed cannulation, cannulation time > 10 minutes, at least one pancreatic deep wire pass, needle-knife precut, two or more injections of contrast agent into the pancreatic duct, major papilla sphincterotomy, difficult cannulation, suspected sphincter of Oddi dysfunction, pancreatic divisum, chronic pancreatitis. Post-ERCP hyperamylasemia was defined as serum amylase level at least three times the upper limit of the normal range (normal range defined as < 120 U/L), without clinical symptoms.
Procedure All patients fasted for at least 8 hours before ERCP. Sedation was provided by meperidine and midazolam. All ERCP procedures were performed by well-trained endoscopists who were experts with at least 5 years’ experience in ERCP; there was no trainee involvement in the study. The endoscopist and the assistant nurse were blinded to the treatment allocation, but the patient was not blinded. Therapeutic procedures included biliary and/or pancreatic sphincterotomy, pre-cut papillotomy, biliary and/or pancreatic stenting, biliary and/or pancreatic stone extraction, or balloon dilation of the common bile duct. The procedure time was defined as the time from endoscope insertion to the complete withdrawal of the endoscope. Eligible patients were randomized to receive either routine treatment (fasted for at least 6 hours after ERCP, adequate fluid intake, etc) + somatostatin 250 μg intravenous bolus before ERCP and 250 μg/hour continuous infusion for 11 hours after ERCP, or routine treatment alone.
Statistical analysis Sample size calculation Based on the reported incidences of PEP in previous studies [19 – 21], sample size calculations showed that 870 patients would provide power of at least 90 % to detect a decrease in the incidence of PEP from 8 % in the control group to 3 % in the somatostatin group.
Randomization The randomization list, which was stratified according to individual center, was computer generated at the Center for Clinical Epidemiology and Evidence-Based Medicine (Second Military Medical University, Shanghai, China). The person who generated the randomization list was not involved in the ERCP procedure or patient care.
Bai Yu et al. Prophylactic somatostatin prevents post-ERCP pancreatitis … Endoscopy 2015; 47: 415–420
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Original article
Data analysis
417
Potentially eligible patients screened at 11 centers (n = 908)
Categorical data were analyzed using the chi-squared test. Continuous variables were expressed as mean (SD) and ranges, and were compared using the Student’s t test. P values of < 0.05 were considered to be statistically significant and all tests were two sided. All statistical analyses were performed using SAS software (version 9.1.3; SAS Institute Inc., Cary, North Carolina, USA).
Randomized
Somatostatin group (n = 452)
Control group (n = 456)
Failed to complete study (n = 6) Excluded for various reasons (n = 2)
Results !
Control group (n = 455)
900 patients included in full analysis set (445 in Somatostatin group; 455 in control group)
Fig. 1
Flow diagram of patient enrollment.
ERCP procedures The indication for ERCP was suspected biliary disease in 820 cases and pancreatic pathologies in 73; 7 patients had both biliary and pancreatic disorders. The majority of the ERCP procedures (817; 90.8 %) were therapeutic, with only 83 patients undergoing diagnostic ERCP (9.2 %). The cannulation techniques were not standardized and were at the discretion of the endoscopist. Single- or multiple-lumen sphincterotome, catheters, needle-knife sphincterotomy as well as guidewire cannulation were used for biliary access. There was no statistically significant difference between the groups in terms of the mean procedure " Table 2). Overall, time for ERCP and the time for cannulation (● ERCP was unsuccessful in 14 patients (6 in the control group and 8 in the somatostatin group). In cases of failed ERCP, a repeat ERCP by the same endoscopist or another expert was scheduled
Study group (n = 445)
P value
Age, median (range), years
63 (22 – 93)
60 (19 – 96)
0.02
Weight, mean ± SD, kg
60.7 ± 11.7
60.2 ± 11.0
0.54
1.64 ± 0.1
0.34
Height, mean ± SD, m BMI, mean ± SD, kg/m 2
1.65 ± 0.1 22.1 ± 3.3
22.2 ± 3.2
Sex, n (%) 237 (52.1)
197 (44.3)
Female
218 (47.9)
248 (55.7)
Yes
91 (20.0)
74 (16.6)
No
364 (80.0)
371 (83.4)
46 (10.1)
54 (12.1)
Smoking, n (%)
0.19
Alcohol, n (%) No History of surgery, n (%) Gastrectomy (Billroth-I) Choledochojejunostomy
0.33 409 (89.9)
391 (87.9)
236 (51.9)
218 (49.0)
5 1
1 143
CBD exploration + T Tube placement
19
16
ERCP
23
20
Others
97
85
Co-morbidities, n (%)
224 (49.2)
195 (43.8)
Cardiovascular
121 (54.0)
102 (52.3)
Hypertension
101 (45.1)
97 (49.7)
Respiratory
21 (9.4)
16 (8.2)
Genitourinary
11 (4.9)
13 (6.7)
Liver
22 (9.8)
29 (14.9)
6 (2.7)
7 (3.6)
Immunosuppressive
0.39
6
157
Cholecystectomy
0.89 0.02
Male
Yes
Table 1 Demographic information of the study population.
0.10
BMI, body mass index; CBD, common bile duct; ERCP, endoscopic retrograde cholangiopancreatography.
Bai Yu et al. Prophylactic somatostatin prevents post-ERCP pancreatitis … Endoscopy 2015; 47: 415–420
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During the study period, a total of 908 consecutive patients from 11 centers were screened and randomized. Six patients were lost or failed to complete the study, and two patients were excluded because they did not meet the inclusion criteria. Therefore, 900 patients were included in the full analysis set and 897 patients " Fig. 1 shows the flow were included in the per-protocol set. ● diagram of patient enrollment. The mean age of patients was similar in both groups. The body mass index of the two groups was also comparable. There were more male patients in the control group than in the somatostatin group (52.1 % vs. 44.3 %) and more patients who smoked (20.0 % vs. 16.6 %, respectively). Alcohol use was similar between the groups (10.1 % and 12.1 %, respectively). The percentage of patients with a history of surgery was comparable (51.9 % vs. 49.0 %), and approximately one-third of patients in each group had undergone previous cholecystectomy. In all, 224 patients in the control group and 195 patients in the somatostatin group were diagnosed with co-morbidities, mainly cardiovascular comorbidities. The demographic details of the study groups are " Table 1. summarized in ●
Original article
Control group (n = 455) Procedure time for ERCP, mean ± SD, minutes Time for cannulation, mean ± SD, minutes
Study group (n = 445)
P value
31.1 ± 15.0
31.4 ± 14.2
0.4
6.1 ± 6.8
5.8 ± 6.2
0.6 0.8
Table 2 Details of endoscopic retrograde cholangiopancreatography procedures.
Diagnosis after ERCP, n (%) CBD stone
299 (65.7)
289 (64.9)
Malignant biliary stricture
63 (13.9)
55 (12.4)
0.5
Benign biliary stricture
33 (7.3)
36 (8.1)
0.6
Chronic pancreatitis
16 (3.5)
18 (4.0)
0.7
Pancreatic divisum
0 (0.0)
3 (0.7)
0.2
SOD
9 (2.0)
17 (3.8)
0.1
35 (7.7)
27 (6.1)
0.3
Others
ERCP, endoscopic retrograde cholangiopancreatography; CBD, common bile duct; SOD, sphincter of Oddi dysfunction.
several days after the index ERCP. If the second ERCP also failed, alternative procedures such as percutaneous transhepatic cholangial drainage would be performed.
P = 0.0276
10 %
Primary outcome Overall, PEP developed in 52 patients (5.8 %): 34/455 (7.5 %; 95 % CI 5.4 % – 10.3 %) occurred in the control group and 18/445 (4.0 %; 95 %CI 2.6 % – 6.3 %) occurred in the somatostatin group (P = 0.03) " Fig. 2), which indicates an absolute risk reduction of 3.5 % (● points (95 % confidence interval [CI] 2.0 % – 6.2 %) (number needed to treat to prevent one episode of PEP, 29 [95 %CI 16 – 636]). A logistical regression analysis, adjusted for possible confounders, showed that the prophylactic effect of somatostatin was not changed (P = 0.026). All of the cases of PEP were of mild or moderate severity. A total of 27 patients in the control group and 17 patients in the somatostatin group had mild PEP, and 7 patients in the control group and 1 patient in the somatostatin group had moderate pancreatitis. The patients with pancreatitis were supportively managed with close observation. None of them required surgical treatment, and all of them recovered without sequelae.
16 %
Secondary outcomes
14%
8%
7.47 %
6% 4.04 % 4%
2%
0%
The secondary outcome of hyperamylasemia occurred in 73 patients (8.1 %): 46 (10.1 %; 95 %CI 7.7 % – 13.2 %) in the control group and 27 (6.1 %; 95 %CI 4.2 % – 8.7 %) in the somatostatin group, and " Fig. 3). Among all pathe difference was significant (P = 0.03) (● tients, 88.2 % were considered to be at high risk for PEP, and among these patients, 28/386 patients (7.3 %) in the control group and 17/408 patients (4.2 %) in the somatostatin group developed PEP (P = 0.06).
Control
Somatostatin
Fig. 3 Incidence of hyperamylasemia. P = 0.0264
12 % 10 %
10.11 %
8% 6.07 %
6% 4%
Adverse events The total adverse event incidence rate was 15.9 % (143/900) (16.7 % [76/455] in the control group and 15.1 % [67/445] in the treatment group, with no significant difference between groups). Two adverse events were related to the ERCP procedure. Upper gastrointestinal bleeding occurred in two patients (one from each group), and both patients recovered uneventfully with medical treatment. None of the bleeding events required radiological or surgical treatment. No perforation or death occurred during the study. In the somatostatin group, five patients complained of minor discomfort, including dizziness (n = 1), numbness (n = 1), palpitation (n = 1), desaturation (n = 1), abdominal pain and vomiting (n = 1). All of the symptoms resolved spontaneously within 24 hours after withdrawal of somatostatin.
Fig. 2 Incidence of post-endoscopic retrograde cholangiopancreatography pancreatitis.
12 %
2% 0%
Control
Somatostatin
Discussion !
Based on the findings of this large-scale, multicenter, RCT, somatostatin 250 μg intravenous bolus before ERCP plus 250 μg/hour continuous infusions for 11 hours after ERCP significantly reduced the incidence of PEP and hyperamylasemia (P = 0.03). The number of ERCP patients who needed to be treated to prevent one episode of PEP was 29. These results are similar to those reported in a meta-analysis [22], which showed that 12-hour ad-
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418
Original article
closer reflection of the true effect of somatostatin for PEP prevention. In summary, these study results showed that somatostatin was effective and safe in the prevention of PEP and hyperamylasemia in patients undergoing ERCP. Competing interests: The study was supported by Merck Serono Co., Ltd. Institutions 1 Department of Gastroenterology, Changhai Hospital, Second Military Medical University, Shanghai, China 2 Department of Gastroenterology, Heilongjiang Province Hospital, Harbin, China 3 Department of Gastroenterology, First People’s Hospital of Hangzhou, Hangzhou, Zhejiang, China 4 Department of Gastroenterology, First Affiliated Hospital, Nan Chang University, Jiangxi, China 5 Department of Gastroenterology, Xijing Hospital of Digestive Diseases, Fourth Military Medical University, Xi’an, China 6 Department of Gastroenterology, First People’s Hospital, School of Medicine, Shanghai Jiaotong University, Shanghai, China 7 Department of Gastroenterology, Urumchi General Hospital, Lanzhou Command, PLA, China 8 Gastrointestinal Endoscopy Center, Jiangsu Provincial Hospital of Traditional Chinese Medicine, Nanjing, Jiangsu, China 9 Department of Gastroenterology, Southwest Hospital, Third Military Medical University, Chongqing, China 10 Department of Gastroenterology, Tongji Hospital, Tongji Medical College, Huazhong University of Science and Technology, Wuhan, China 11 Department of Gastroenterology, Beijing Friendship Hospital, Capital Medical University, Beijing, China
Acknowledgment !
Dr. Bai was supported by the 2014 Shanghai Rising-Star Program (A type, No. 14QA1404800) and Outstanding Young Scholars Fund of Second Military Medical University and the Foundation for the Author of National Excellent Doctoral Dissertation of PR China. The study was also supported by Merck Serono Co., Ltd.
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ministration of somatostatin was associated with a 7.7 % decrease in PEP (95 %CI 3.4 % – 12.0 %; P < 0.0001), and somatostatin was also found to be effective in reducing the incidence of hyperamylasemia (P = 0.02). Another RCT [11] of 391 patients in whom therapeutic ERCP was undertaken showed that the incidence of PEP was significantly lower in the group in which somatostatin administration was continued for 12 hours starting from 30 minutes before ERCP (3.6 % in the treatment group vs. 9.6 % in the placebo group; P = 0.02). This result is closer to that in the current study. The meta-analysis reported by Omata et al. [14] draws the same conclusion. The current study suffers from some limitations. First, the study was not a placebo-controlled study and was not double blinded. Second, unlike a previous trial [23], this study only investigated one method of somatostatin administration (250 μg bolus before plus 250 μg/hour for 11 hours after ERCP). This approach was chosen because it is relatively easy to apply in clinical practice. Efforts to reduce PEP have taken the form of strict patient selection, improved ERCP techniques, and medication prophylaxis, but much controversy remains over the role of pharmacological prevention. The efficacy of somatostatin for PEP prevention has been studied extensively during the past 3 decades; however, the conclusions of these individual studies and meta-analyses are contradictory [10 – 15]. After a thorough review of available evidence, we suggest that the possible reasons for previous controversy concerning the effect of somatostatin on PEP prevention could be that more than half of the 16 published randomized trials [10 – 13, 19, 20, 23 – 32] included small sample sizes and some had methodological drawbacks. In addition, the average incidence of PEP in the placebo group in previous studies [10 – 13, 19, 20, 23 – 32] was about 8 %. To detect a reduced incidence to 3 % with 80 % power using a cutoff for statistical significance of 0.05, the required sample size would be at least 652 patients [33]. It is clear that few trials could fulfill this criterion, which may be the reason why the majority of randomized trials showed a nonstatistically significant decrease in the incidence of PEP in the somatostatin group. Therefore, it is plausible that the inconsistency shown in previous results has been due to a type II error, which did not allow detection of the true effect of somatostatin on PEP reduction. As simple randomization was used in the current study, age and sex were different between the two groups despite the randomization. The mean age of the patient population was 60 years, about half of them reported a history of abdominal surgery, and more than 45 % of them had co-morbidities. All of these patientrelated factors, combined with procedure-related factors, contributed to the large proportion of high-risk patients (88.2 %). However, the incidence of PEP (7.5 %) was lower than that of a recent trial (9.2 %) [7]. We suggest that the reason for this difference may be that in this previous study [7], more than 80 % of patients had clinical suspicion of sphincter of Oddi dysfunction, and therapeutic pancreatic ERCP were performed, whereas in the current study, the majority of enrolled patients had biliary diseases and required therapeutic biliary procedures. In addition, the endoscopy centers that participated in the current study were all high-volume centers, which performed between 1000 and 2500 ERCP procedures per year. Therefore, the incidence of pancreatitis may be lower than what might be expected in nonreferral centers. Moreover, in the current study, only 35 patients (3.9 %) underwent placement of a prophylactic pancreatic stent, which was much lower than the rate of stent placement (> 80 %) in the Elmunzer et al. study [7]. Therefore, the current results may be a
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