Meta-Analysis of Early Endoscopic Retrograde Cholangiopancreatography (ERCP) ± Endoscopic Sphincterotomy (ES) Versus Conservative Management for Gallstone Pancreatitis (GSP).

REVIEW ARTICLE

Meta-Analysis of Early Endoscopic Retrograde Cholangiopancreatography (ERCP) ± Endoscopic Sphincterotomy (ES) Versus Conservative Management for Gallstone Pancreatitis (GSP) Matthew J. Burstow, BSc, BMed, FRACS,* Rossita M. Yunus, PhD,wz Md Belal Hossain, PhD,wy Shahjahan Khan, PhD,w Breda Memon, RN, LLB, PGC Ed, Dip Prac Mgt,8 and Muhammed A. Memon, MBBS, MA, DCH, FRACS, FRCSI, FRCSEd, FRCSEng, AFACS8z#**

Context: The utility of early endoscopic retrograde cholangiopancreatography (ERCP) ± endoscopic sphincterotomy (ES) in the treatment of gallstone pancreatitis (GSP) is still contentious. Objectives: The aim was to conduct a meta-analysis of randomized controlled trials (RCTs) investigating the treatment of GSP by early ERCP ± ES versus conservative management and analyzing the patient outcomes. Data Sources: A search of Medline, Embase, Science Citation Index, Current Contents, PubMed, and the Cochrane Database of Systematic Reviews identified all RCTs comparing early ERCP to conservative management in GSP published between January 1970 and January 2014. Search terms included “Endoscopic retrograde cholangiopancreatography (ERCP)”; “Endoscopic sphincterotomy”; “Gallstones”; “Bile duct stones”; “Gallstone pancreatitis”; “Biliary pancreatitis”; “Randomize/Randomised controlled trials”; “Conservative management/treatment”; “Human”; “English.” Study Eligibility Criteria, Participants, and Interventions: Only prospective RCTs comparing early intervention (ie, between 24 and 72 h) with ERCP ± ES versus conservative management in GSP were included. Study Appraisal and Synthesis Methods: Data extraction and critical appraisal was carried out independently by 2 authors (M.J.B. and M.A.M.) using predefined data fields. Variables analyzed included severity of pancreatitis (mild or severe), overall mortality, overall complications which included pseudocyst formation, organ failure (renal, respiratory, and cardiac), abnormal coagulation, biliary sepsis, and development of pancreatic abscess/phlegmon.

The quality of RCTs was assessed using Jadad’s scoring system. Random-effects model was used to calculate the outcomes of both binary and continuous data. Heterogeneity among the outcome variables of these trials was determined by the Cochran Q statistic and I2 index. The meta-analysis was prepared in accordance with PRISMA (Preferred Reporting Items for Systematic Reviews and Meta-analyses) guidelines. Results: Eleven RCTs consisting of 1314 patients (conservative management = 662, ERCP = 652) were analyzed. There was a near significant decrease in mortality for ERCP group compared with conservatively managed patients with severe pancreatitis [odds ratio (OR) 0.45; 95% confidence interval (CI), 0.19, 1.09; P = 0.08]. In patients with mild pancreatitis, mortality results were comparable for both groups (OR 0.66; 95% CI, 0.02, 28.75; P = 0.83). Overall complications were significantly reduced in the ERCP group in severe pancreatic patients (OR 0.32; 95% CI, 0.17, 0.61; P = 0.00). In those with mild disease, a strong trend to decreased complications in the ERCP group was seen, however, this was not significant (OR 0.67; 95% CI, 0.43, 1.03; P = 0.06). Conclusions: This meta-analysis demonstrates a significant decrease in complications in patients with severe GSP managed with early ERCP/ES compared with conservative management. As far as the mortality is concerned, no significant decrease was observed in mortality even in severe GSP patients treated with early ERCP/ES. Key Words: endoscopic retrograde cholangiopancreatography (ERCP), endoscopic sphincterotomy (ES), meta-analysis, randomized controlled trials (RCT), gallstone pancreatitis (GSP), biliary pancreatitis, conservative management/treatment, human, English

(Surg Laparosc Endosc Percutan Tech 2015;25:185–203) Received for publication October 16, 2014; accepted January 22, 2015. From the *Department of Surgery, Royal Brisbane and Women’s Hospital; wSchool of Agricultural, Computing and Environmental Sciences, Australian Centre for Sustainable Catchments, University of Southern Queensland, Toowoomba; 8Sunnybank Obesity Centre and SEQS, McCullough Centre, Sunnybank; zDepartment of Surgery, Mayne Medical School, University of Queensland, Herston; #Faculty of Health Sciences and Medicine, Bond University, Gold Coast, QLD, Australia; zInstitute of Mathematical Sciences, University of Malaya, Kuala Lumpur, Malaysia; yDepartment of Statistics, Biostatistics & Informatics, Dhaka University, Dhaka, Bangladesh; and **Faculty of Health and Social Science, Bolton University, Bolton, Lancashire, UK. The authors declare no conflicts of interest. Reprints: Muhammed A. Memon, MBBS, MA, DCH, FRACS, FRCSI, FRCSEd, FRCSEng, AFACS, Sunnybank Obesity Centre and SEQS, Suite 9, McCullough Centre, 259 McCullough Street, Sunnybank, QLD 4109, Australia (e-mail: [email protected]). Copyright r 2015 Wolters Kluwer Health, Inc. All rights reserved.

Surg Laparosc Endosc Percutan Tech

RATIONALE Acute pancreatitis is a condition that is responsible for around 220,000 hospital admissions annually in the United States and 14,500 in Australia (2009 to 2010). The estimated cost of hospitalization for these patients to the US health system is around $2.6 billion dollars annually.1–3 The incidence of acute pancreatitis varies between 4.9 and 73.4 cases per 100,000 worldwide.4 The National Hospital Discharge Survey from the US showed increase in hospital admission for acute pancreatitis from 40 per 100,000 in 1988 to 70 per 100,000 in 2002.4 There are many and varying causes that lead to this common pathologic endpoint, however, the vast majority of cases are caused by either gallstones or alcohol; in Australia this is 45% and

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35%, respectively.5 Similar trend has been observed in the United States and European countries.6,7 The spectrum of disease severity seen in acute pancreatitis also varies, 80% of individuals will have mild pathology with a relatively benign course, 20% suffer a severe attack, and 5% die.1,5–8 Pancreatic inflammation caused by gallstones is likely related to biliary “hypertension” from obstruction and inappropriate activation of pancreatic enzymes, but the exact cause is not fully understood.1,2,8–10 Relieving biliary obstruction in gallstone pancreatitis (GSP) by endoscopic retrograde cholangiopancreatography (ERCP) ± endoscopic sphincterotomy (ES) has been practiced since 1973 and advocated as an early intervention in an attempt to mitigate the complications and mortality of this condition.11–23 Randomized controlled trials (RCTs) have been conducted comparing conservative (supportive) management of GSP with early ERCP ± ES (usually within 24 to 72 h of presentation) to prevent complications and mortality especially in severe GSP. However, the results have been conflicting.13–23 Meta-analyses performed on these trials have also delivered conflicting results contributing to the uncertainty surrounding the optimum management of these patients.24–30 One of these meta-analyses has been withdrawn25; the most recent meta-analysis was that by Tse and Yuan30 in the Cochrane Database of Systematic reviews, however, since this study a further RCT has been published.


Study Selection Standardized data extraction31 forms were used by the authors to independently and blindly summarize the RCTs meeting the eligibility criteria. The authors were not blinded to the source of the document or authorship for the purpose of data extraction. The data were compared and discrepancies were resolved by consensus.

Data Collection Process Data extraction and critical appraisal were carried out by 2 authors (M.J.B. and M.A.M.). The original authors of 2 RCTs were contacted to obtain clarification of data and to acquire unpublished, missing, or additional information on various outcome measures to facilitate further data analysis. However, only 1 author responded with additional information (Dr Nowak).16 Perusal of previously published meta-analyses24–30 on this subject yielded additional information for 2 studies which were also included in the analysis.

Data Items The variables that were considered the most objective to analyze were severity of pancreatitis (mild or severe), overall mortality, and overall complications such as pseudocyst formation, organ failure (renal, respiratory, and cardiac), abnormal coagulation, biliary sepsis, and development of pancreatic abscess/phlegmon.

Risk of Bias in Individual Studies

Objectives Specific questions evaluated include the utility of early ERCP ± ES versus conservative management in GSP with respect to complications and mortality, both overall and when stratified for severity.

Summary Measures, Synthesis of Results, Risk of Bias Across Studies

METHODS Eligibility Criteria RCTs that compared early ERCP ± ES with conservative management, and were published both in full peer-reviewed journals and abstract forms between January 1970 and January 2014, were included for analysis. Unpublished studies and abstracts presented at national and international meetings were also evaluated and included if deemed suitable. Manual search of the bibliographies of relevant papers was also carried out to identify trials for possible inclusion. Published studies that contained insufficient information were excluded only after multiple attempts had failed to obtain unpublished or missing data from the original authors. Also excluded were the previously presented abstracts of full peer-reviewed published articles and duplicate publications.

Information Sources/Search RCTs were identified by conducting a comprehensive search of Medline, Embase, Science Citation Index, Current Contents, bibliographies of systematic reviews, PubMed, and the Cochrane Database of Systematic Reviews, using medical subject headings “Endoscopic retrograde cholangiopancreatography (ERCP)”; “Endoscopic sphincterotomy”; “Gallstones”; “Bile duct stones”; “Gallstone pancreatitis”; “Biliary pancreatitis”; “Randomized/Randomised controlled trials”; “Conservative management/treatment; “Human”; and “English.”

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The quality of the RCTs was assessed using Jadad’s scoring system (Table 1) and the meta-analysis prepared in accordance with the PRISMA (Preferred Reporting Items for Systematic Reviews and Meta-analyses) statement.32,33

Meta-analyses were performed using odds ratios (ORs) for binary outcome and weighted mean differences for continuous outcome measures. The slightly amended estimator of OR was used to avoid the computation of reciprocal of zeros among observed values in the calculation of the original OR.34 Random-effects model based on the inverse variance-weighted method approach, was used to combine the data.35 Heterogeneity among studies was assessed using the Q statistic proposed by Cochran and I2 index introduced by Higgins and Thompson.35–39 If the observed value of Q was larger than the associated x2 critical value at a given significant level, in this case 0.05, we conclude the presence of statistically significant betweenstudies variation. To pool continuous data, mean and SD are required. However, some of the published clinical trials did not report the mean and SD, but rather reported the size of the trial, the median, and range. Using these available statistics, estimates of the mean and SD were obtained using formulas proposed by Hozo et al.40 Funnel plots were created to determine the presence of publication bias in the present meta-analysis (Fig. 1). Both total sample size and precision (reciprocal of SE) were plotted against the treatment effects (OR for dichotomous variables and weighted mean difference for continuous variables).35,41–43 All estimates were obtained using a computer program written in R.44 All plots were obtained using the meta-package.45 In the case of tests of hypotheses, the paper reports P-values for different statistical tests on the study variables. In general, the effect is considered to be statistically significant if

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Meta-Analysis of Early ERCP ± ES

TABLE 1. Study Details and Methodology Neoptolemos et al13

Study Methods

Generation of allocation sequences: unclear. Study duration: 1983-1987. Blinding: patient-not stated, provider-not stated, assessor-not stated. Intent to treat: no. Characteristics Single center (Leicester, UK): 121 adults, Age range: 20-96; Sex: 52 males, 69 females. Included: suspected GSP stratified according to modified Glasgow criteria. Excluded after randomization: 10 patients (6 experimental arm; 4 control arm) due to alternative diagnosis. Interventions Randomization: ERCP ± ES within 72 h of admission (experimental arm) or conservative management including withheld ERCP for initial 5 d of admission (control arm). Outcomes Primary: mortality. Secondary: complications. Jadad Score 2 Fan et al14

Study Methods

Generation of allocation sequences: unclear. Study duration: September 1988-December 1991. Blinding: patient-not stated, provider-not stated, assessor-not stated. Intent to treat: yes. Characteristics Single center (Hong Kong): 195 adults; Age range: 17-94; Sex: 80 males, 115 females. Included: suspected GSP stratified into mild and severe according to Ranson’s criteria. Interventions Randomization: ERCP ± ES within 24 h of admission (experimental arm) or conservative management including urgent ERCP if acute cholangitis developed (control arm). Outcomes Primary: in-hospital mortality. Secondary: complications Jadad Score 2 Fo¨lsch et al15

Study Methods

Generation of allocation sequences: stratified block procedure. Study duration: November 1989-February 1994. Blinding: patient-not stated, provider-not stated, assessor-no. Intent to treat: yes. Characteristics 22 centers (Germany): 238 adults; Age range: 15-93; Sex: 96 males, 142 females. Included: suspected GSP stratified into mild and severe according to modified Glasgow criteria. Excluded after randomization: 32 patients (16 each group) had incomplete data. Interventions Randomization: ERCP ± ES within 72 h of admission (experimental arm) or conservative management including urgent ERCP if acute cholangitis developed (control arm). Outcomes Primary: mortality within 3 mo of admission. Secondary: complications. Jaad score 2 Nowak et al16

Study Methods

Generation of allocation sequences: not stated. Study duration: not stated. Blinding/provider/assessor: not stated. Intention to treat: yes. Characteristics Single center (Poland): 280 adults, aged matched. Stratified for severity, but methodology and results not provided. Interventions Randomization: duodenoscopy within 24 h, stone impacted at papilla—immediate ES (75), no impacted stone—immediate ES (103), no stone—conservative management (102). Outcomes Primary: mortality. Secondary: complications Jadad Score 1 Zhou et al17

Study Methods

Generation of allocation sequences: not stated. Study duration: not stated. Blinding: patient-not stated, provider-not stated, assessor-not stated. Intent to treat: yes. Characteristics 1 center (Shanghai, China): 45 adults; Age range: 36-82; Sex: 25 females, 20 males. Included: patients with GSP stratified by severity according to APACHE II score. Excluded: not stated. Interventions Randomization: ERCP ± ES within 24 h if obstruction. Persisted, conservative management, no ERCP performed. Outcomes Primary: complications, length of hospital stay, and cost. Secondary: none. Jadad Score 1

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TABLE 1. (continued) Study

Acosta et al18

Methods

Generation of allocation sequences: computer-generated list, sealed envelopes. Study duration: May 21, 2001-May 20, 2002. Blinding: patient-not stated, provider-not stated, assessor-not stated. Intent to treat: yes. Characteristics 2 centers (Southern California): 61 adults; Age range: 19-87; Sex: 46 females, 15 males. Included: patients with GSP stratified by severity according to Glasgow score. Excluded: severe cholangitis (immediate ERCP). Interventions Randomization: initial conservative management and ERCP ± ES within 48 h if obstruction. Persisted for 24 h or longer (study group), conservative management ± selective ERCP ± ES after 48 h (control group). Outcomes Primary: mortality up to 30 d postdischarge. Secondary: complications up to 30 d postdischarge. Jadad Score 3 Study

Oria et al19

Methods

Generation of allocation sequences: stratified block procedure. Study duration: May 1, 2000-September 3, 2005. Blinding: patient-not stated, provider-not stated, assessor-not stated. Intent to treat: yes. Characteristics Single center (Buenos Aires, Argentina). Included: patients with distal CBDZ8 mm on admission ultrasound scan + total serum bilirubin >1.20 mg/dL (20 mmol/ L), stratified by APACHE II score, Z6 = severe, SOFA (organ severity score). Excluded: cholangitis, unable to perform ERCP within 72 h. Interventions Supportive care, 7/7 abs, ERCP + ES (experienced endoscopist, ES if >1 biliary stone, insufficient drainage or edema), stent if incomplete stone removal + repeat ERCP in 24 h. Outcomes Primary—if treatment leads to reduction in organ failure scores in first week and limits extension of peri/pancreatic lesions. Secondary—local complications and mortality. Jadad Score 3 Study

Chen et al20

Methods

Generation of allocation sequences: randomized by computer-generated list into 2 groups. Study duration: unclear. Blinding: patient-not stated, provider-not stated, assessor-not stated. Intent to treat: no. Characteristics Single center (China). Included: patients with acute severe GSP on admission (ultrasound scan proven gallstones), APACHE II score, Z11, obstructed biliary tract >12 h (total serum bilirubin >50 mmoL/L, severe ongoing epigastric pain with bile-free gastric aspirate), admitted to ICU < 72 h of the onset of Sx. Patients with cholangitis. Excluded: patients with pancreatitis from other causes. Interventions Supportive care (NBM, NGT, IVF, TPN, antibiotics, analgesia, octreotide, assisted ventilation), ERCP + ES without fluoroscopy within 72 h of admission (with or without ENBD) performed by a team of 3 experienced endoscopists, further ERCP as required, supportive care. Outcomes Days for sign/symptom relief, normalization of biochemical parameters, APACHE II score at day 10, complications, death. Jadad Score 2 Study

Tang et al21

Methods

Generation of allocation sequences: drawing a ballot. Study duration: January 2005-January 2010. Blinding: patient-not stated, provider-not stated, assessor-not stated. Intent to treat: yes. Characteristics Single center (China). Included: patients with severe GSP (Atlanta classification), diagnosis by history, symptoms, amylase level, liver enzyme abnormalities, CT confirmation of pancreatic, gallstone disease or biliary dilatation on imaging. Cholangitis, biliary obstruction. Excluded: patients with a history of elevated calcium, lipids, or excessive alcohol intake. Interventions Supportive care (NBM, NGT, IVF, nutritional support, antibiotics, analgesia, protease inhibitor, ERCP < 48 h of admission with ES and stone extraction or ENBD in unstable patients, subsequent ERCP as required, surgery after 1 wk of conservative therapy. Outcomes In hospital mortality, local and systemic complications, normalization of biochemical parameters, time to sign/symptom relief, length of hospital stay. Jadad Score 2 Study

Zhou et al22

Methods

Generation of allocation sequences: random numbers table. Study duration: January 2004-July 2009. Blinding: patient-not stated, provider-not stated, assessor-not stated. Intent to treat: yes.


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TABLE 1. (continued) Characteristics Single center (China). Included: patients with acute severe GSP (diagnostic criteria based on proposal of the Pancreatic Disease Group of the Chinese Society of Surgery 2007). Excluded: not stated. Interventions Supportive care, (NBM, NGT, IVF, gastric acid suppression, antibiotics, analgesia, somatostatin with TPN gradually replaced by EN via NJT), ERCP (ES with stone removal and ENBD if required 3 the normal value, value of serum total bilirubin > 36 mmoL/L, cholelithiasis, or obstruction in the lower segment of the common bile duct and the diameter of common bile duct larger than 8 mm as confirmed by type-B ultrasonic and magnetic resonance cholangiopancreatography, APACHE II score Z8 points, or Balthazar CT grading is D or E; body temperature equals Z38.51C, signing of medical informed consent. Excluded: patients not fit for ERCP, pregnancy, blood coagulation disorder, cirrhosis, Billroth II surgery; having performed ERCP intervention outside the treating institution. Interventions Supportive care (NBM, NGT, IVF, gastric acid and enzyme suppression, antibiotics, nutritional support, ICU and invasive ventilator support), ERCP (within 72 h, ES, ENBD, stone extraction as indicated), with subsequent procedures as required. Outcomes Primary—mortality, complication rate, hospital stay, cost. Secondary—normalization of temperature, time to resolution of abdominal pain. Jadad Score 3 APACHE indicates Acute Physiology and Chronic Health Evaluation; CT, computed tomography; ENBD, endoscopic nasobiliary drainage; ERCP, endoscopic retrograde cholangiopancreatography; ES, endoscopic sphincterotomy; GSP, gallstone pancreatitis; ICU, intensive care unit; IVF, intravenous fluid; NBM, nil by mouth; NGT, nasogastric tube; NJT, nasojejunal tube; TPN, total parenteral nutrition.

the P-value is small. If one uses a 5% significance level then the effect is significant only if the associated P-value is r5%.

RESULTS Study Selection/Characteristics Eleven prospective RCTs were identified by the authors as meeting the eligibility criteria for this metaanalysis13–23 (Fig. 2). The studies include 1314 patients (662 treated conservatively and 652 ERCP ± ES), the largest body of information so far available for the comparison in patients with GSP in the international literature. Patient demographics and selection methods were detailed in all of the available studies (Table 1). The design of each RCT was slightly different, namely timing of ERCP in the treatment group (varying from 24 to 72 h), and in the specific aspects of systemic complications (renal, cardiac, respiratory, coagulation abnormalities and biliary sepsis, and local complications—pseudocyst and pancreatic abscess formation) reported; the primary and secondary endpoints for each study as well as study methodology are listed in Table 1.

P = 0.00) (Fig. 4). A subgroup analysis of mortality and complications based on severity of GSP (mild vs. severe) was performed on 11 and 10 studies, respectively. There was no significant decrease in mortality even in severe GSP patients treated with early ERCP ± ES compared with the group treated conservatively (OR 0.45; 95% CI, 0.19, 1.09; P = 0.08) (Fig. 3). Complications were significantly decreased in patients with severe GSP (OR 0.32; 95% CI, 0.17, 0.61; P = 0.00), but not in mild GSP cohort who underwent ERCP (OR 0.67; 95% CI, 0.43, 1.03; P = 0.06). (Fig. 4) (Table 2). Systemic complications (renal, cardiac, respiratory, coagulation abnormalities, and biliary sepsis) were not significantly reduced with early intervention (Figs. 5–9) (Table 3). Likewise, there was no significant reduction in local complications (pseudocyst and pancreatic abscess formation) through early ERCP (Figs. 10, 11) (Table 3). Only 1 funnel plot, that is, that of complications showed asymmetry suggesting the existence of publication bias. However, the number of studies included in the funnel plots for all the variables (number of plotted points) are too few for the detection of study bias.41–43

DISCUSSION

Synthesis of Results Statistical analysis revealed no significant decrease in mortality between the ERCP ± ES and conservative management groups in the studies included [OR 0.47; 95% confidence interval (CI), 0.20, 1.09; P = 0.08] (Fig. 3), however, overall complications were significantly reduced in the ERCP ± ES group (OR 0.43; 95% CI, 0.27, 0.68; Copyright

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Summary of Evidence In the hospital setting, acute pancreatitis is categorized according to etiology (with gallstones contributing in 40% to 45% of cases), and severity with the 2 scoring systems most commonly used to predict severity being Ranson’s criteria and the Acute Physiology and Chronic Health



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FIGURE 1. Funnel plots for complications and mortality for mild and severe gallstones pancreatitis.

Evaluation (APACHE II) score.1,2,5,8–10 A Ranson’s score Z3 or an APACHE II score Z8 indicates severe acute pancreatitis, and in these individuals more intensive monitoring is crucial as, although the overall mortality in acute pancreatitis is 5%, 10% to 30% of individuals suffering a

severe episode will die, rising to 30% to 50% with intensive care unit admission.1,8,46–48 The high complication rate and mortality associated with early surgical intervention in patients with GSP lead to the first successful ERCP and ES for biliary ductal stone

FIGURE 2. Flow chart providing information through the different phases of meta-analysis. RCT indicates randomized controlled trial.


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FIGURE 3. Death (mortality). CI indicates confidence interval; ERCP, endoscopic retrograde cholangiopancreatography; ES, endoscopic sphincterotomy; OR, odds ratio. Forest plots: interpretation of forest plots: values in the left panel of the forest plots are authors’ names with year of publication, and observed counts for ERCP ± ES and Cons Mx. In the right panel of the plot there are effect sizes, and their 95% confidence intervals. In the forest plot, square shapes indicate point estimates of treatment effect (effect size for ERCP ± ES over Cons Mx groups) of individual studies with the size of the squares representing the weight attributed to each study. The horizontal lines represent 95% confidence interval for effect size of individual studies. The pooled estimate for the pancreatitis rate is the pooled effect size, obtained by combining all effect size of the listed studies using the inverse variance weighting method. The 95% confidence interval for the pooled estimate is represented by the diamond shape and the length of the diamond depicts the width of the confidence interval. Values to the left of the vertical line at one favor ERCP.

extraction in 1968 and 1970, respectively.49–51 The utility of ERCP in relieving biliary obstruction in GSP is undoubted, despite this, there is still much controversy as to which patients benefit from this intervention. Both the American Gastroenterology Association (AGA) and the American College of Gastroenterologists (ACG) guidelines agree that patients with GSP plus cholangitis should undergo immediate ERCP.52–54 The former ACG guidelines (2006) added that patients with severe GSP should also undergo early ERCP, however, the updated guidelines released in 2013 no longer support this position sighting the RCT by Fo¨lsch and colleagues and the meta-analysis by Moretti and colleagues despite more recent evidence being available.52,53 AGA guidelines view early ERCP in patients with GSP in the absence of cholangitis controversial, sighting the conflicting data, whereas the British Society of Gastroenterology recommends that in addition to those patients with cholangitis, patients with acute pancreatitis of suspected or proven gallstone etiology who satisfy the criteria for predicted or actual severe pancreatitis, should also be considered for ERCP, mudding the waters further.54,55 Although the severity of GSP is a continuum of the same process, evidence points towards mild and severe disease being treated as almost separate entities, with the greatest benefit from early ERCP + ES likely to favor those Copyright

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with severe disease.8,9,48,56 Seven previous meta-analyses24–30 have all produced conflicting evidence which may be due to (a) search strategy and selection criteria of the eligible studies; (b) quality of included studies; (c) models used to analyze the data (random-effects or fixed-effects models); and (d) not addressing the issue of publication bias to name but a few (Table 4). The first analysis performed on 4 RCTs13–16 including 834 (ERCP = 460, conservative management = 374) patients.24 This trial only searched Medline database, did not analyze the quality of any included studies, and did not describe the type of analysis used (eg, random-effect model or fixed-effect model). The primary endpoints for this analysis were mortality rates and rates of overall complication rate. The analysis revealed that early ERCP (24 to 72 h) significantly decreased complications and mortality in the ERCP + ES group (regardless of severity).24 The second study25 focused on only 3 RCTs13–15 with 554 patients, but stratified for severity, and demonstrated that a significant reduction in complications was found only in patients with severe biliary pancreatitis This meta-analysis has been withdrawn from the Cochrane database since its initial publication. A third meta-analysis by Moretti et al26 included 5 RCTs13–15,17–19 analyzing 702 patients (ERCP = 353, conservative management = 349). There was significant decrease in



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FIGURE 4. Overall complications by severity. CI indicates confidence interval; ERCP, endoscopic retrograde cholangiopancreatography; ES, endoscopic sphincterotomy; OR, odds ratio. Forest plots: interpretation of forest plots: values in the left panel of the forest plots are authors’ names with year of publication, and observed counts for ERCP ± ES and Cons Mx. In the right panel of the plot there are effect sizes, and their 95% confidence intervals. In the forest plot, square shapes indicate point estimates of treatment effect (effect size for ERCP ± ES over Cons Mx groups) of individual studies with the size of the squares representing the weight attributed to each study. The horizontal lines represent 95% confidence interval for effect size of individual studies. The pooled estimate for the pancreatitis rate is the pooled effect size, obtained by combining all effect size of the listed studies using the inverse variance weighting method. The 95% confidence interval for the pooled estimate is represented by the diamond shape and the length of the diamond depicts the width of the confidence interval. Values to the left of the vertical line at one favor ERCP.

complication rate in the early ERCP group compared with conservative management group in patients with predicted severe biliary pancreatitis. There was no difference in the mortality rate among the 2 groups. In predicted mild biliary pancreatitis, ERCP did not confer any advantage over conservative management. Unfortunately all the abovementioned meta-analyses suffered from an error in analysis by including patients from the RCT by Fan et al14 which

includes patients who had pancreatitis from causes other than gallstones. The results of these studies should therefore be approached with a level of caution due to the inherent bias within the meta-analyses. The fourth meta-analysis by Petrov et al27 focused on early ERCP versus conservative management in acute biliary pancreatitis without cholangitis. The authors focused on 3 RCTs13,15,19 with 450 patients (ERCP = 230;

TABLE 2. Summary of Pooled Data Comparing Conservative Management and ERCP + ES for Death and Complications of GSP Stratified by Severity

Outcome Variables Death

Severity of Studies Patients GSP n n

Mild Severe Both Complications Mild Severe Both

7 11 6 10

656 658 1314 547 597 1144

Test for Overall Effect Pooled OR 0.66 0.45 0.47 0.67 0.32 0.43

(0.02, (0.19, (0.20, (0.43, (0.17, (0.27,

28.7) 1.09) 1.09) 1.03) 0.61) 0.68)

z

P

0.21 1.77 1.75 1.82 3.47 3.59

0.83 0.08 0.08 0.06 0.00 0.00

Test for Heterogeneity Q

df

P

3.2 1 0.07 11.69 8 0.16 14.92 10 0.13 3.49 4 0.48 18.22 9 0.03 26.6 14 0.02

I2 [CI] 68.5% 31.6% [0%, 68.4%] 33% [0%, 67.1%] 0% [0%, 76.2%] 50.6% [0%, 76%] 47.5% [4.3%, 71.1%]

CI indicates confidence interval; ERCP, endoscopic retrograde cholangiopancreatography; ES, endoscopic sphincterotomy; GSP, gallstone pancreatitis; OR, odds ratio.


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FIGURE 5. Renal failure. CI indicates confidence interval; ERCP, endoscopic retrograde cholangiopancreatography; ES, endoscopic sphincterotomy; OR, odds ratio. Forest plots: interpretation of forest plots: values in the left panel of the forest plots are authors’ names with year of publication, and observed counts for ERCP ± ES and Cons Mx. In the right panel of the plot there are effect sizes, and their 95% confidence intervals. In the forest plot, square shapes indicate point estimates of treatment effect (effect size for ERCP ± ES over Cons Mx groups) of individual studies with the size of the squares representing the weight attributed to each study. The horizontal lines represent 95% confidence interval for effect size of individual studies. The pooled estimate for the pancreatitis rate is the pooled effect size, obtained by combining all effect size of the listed studies using the inverse variance weighting method. The 95% confidence interval for the pooled estimate is represented by the diamond shape and the length of the diamond depicts the width of the confidence interval. Values to the left of the vertical line at one favor ERCP.

conservative management = 220) who satisfied these criteria. Early ERCP was associated with a nonsignificant reduction in overall complications and nonsignificant increase in mortality. Subgroup analysis based on predicted severity did not affect these outcomes. The fifth meta-analysis, again by Petrov et al28 was concerned with the question of whether ERCP reduced local pancreatic complications. Five RCTs13–15,18,19 were

included in the review (n = 717 patients), analysis found there was no statistically significant difference in the incidence of pancreatic complications with early ERCP compared with conservative management. Subgroup analyses of patients with mild versus severe acute pancreatitis showed similar results. Similarly, a sixth meta-analysis by Uy et al29 continued in a similar vein to that of Petrov et al,28 analyzing only those

FIGURE 6. Cardiac failure. CI indicates confidence interval; ERCP, endoscopic retrograde cholangiopancreatography; ES, endoscopic sphincterotomy; OR, odds ratio. Forest plots: interpretation of forest plots: values in the left panel of the forest plots are authors’ names with year of publication, and observed counts for ERCP ± ES and Cons Mx. In the right panel of the plot there are effect sizes, and their 95% confidence intervals. In the forest plot, square shapes indicate point estimates of treatment effect (effect size for ERCP ± ES over Cons Mx groups) of individual studies with the size of the squares representing the weight attributed to each study. The horizontal lines represent 95% confidence interval for effect size of individual studies. The pooled estimate for the pancreatitis rate is the pooled effect size, obtained by combining all effect size of the listed studies using the inverse variance weighting method. The 95% confidence interval for the pooled estimate is represented by the diamond shape and the length of the diamond depicts the width of the confidence interval. Values to the left of the vertical line at one favor ERCP.

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FIGURE 7. Respiratory failure. CI indicates confidence interval; ERCP, endoscopic retrograde cholangiopancreatography; ES, endoscopic sphincterotomy; OR, odds ratio. Forest plots: interpretation of forest plots: values in the left panel of the forest plots are authors’ names with year of publication, and observed counts for ERCP ± ES and Cons Mx. In the right panel of the plot there are effect sizes, and their 95% confidence intervals. In the forest plot, square shapes indicate point estimates of treatment effect (effect size for ERCP ± ES over Cons Mx groups) of individual studies with the size of the squares representing the weight attributed to each study. The horizontal lines represent 95% confidence interval for effect size of individual studies. The pooled estimate for the pancreatitis rate is the pooled effect size, obtained by combining all effect size of the listed studies using the inverse variance weighting method. The 95% confidence interval for the pooled estimate is represented by the diamond shape and the length of the diamond depicts the width of the confidence interval. Values to the left of the vertical line at one favor ERCP.

RCTs that excluded patients with GSP and concomitant cholangitis. Initially, the same 3 RCTs13,15,19 analyzed by Petrov and colleagues were included, eventually Neoptolemos et al13 was excluded due to concerns over methodological quality and difference in study design which contributed to a heterogeneous meta-analysis. Two RCTs15,19 involving 340 (177 = ERCP, 163 = control) patients demonstrated a trend

towards more mortality from early ERCP with or without sphincterotomy in the setting of acute GSP without cholangitis. The authors did indicate the need for more studies to make a more robust conclusion; this is underlined by the fact that this analysis delivered essentially the opposite result to that of Petrov and colleagues with the exclusion of only 1 study (110 patients).

FIGURE 8. Coagulation/disseminated intravascular coagulopathy. CI indicates confidence interval; ERCP, endoscopic retrograde cholangiopancreatography; ES, endoscopic sphincterotomy; OR, odds ratio. Forest plots: interpretation of forest plots: values in the left panel of the forest plots are authors’ names with year of publication, and observed counts for ERCP ± ES and Cons Mx. In the right panel of the plot there are effect sizes, and their 95% confidence intervals. In the forest plot, square shapes indicate point estimates of treatment effect (effect size for ERCP ± ES over Cons Mx groups) of individual studies with the size of the squares representing the weight attributed to each study. The horizontal lines represent 95% confidence interval for effect size of individual studies. The pooled estimate for the pancreatitis rate is the pooled effect size, obtained by combining all effect size of the listed studies using the inverse variance weighting method. The 95% confidence interval for the pooled estimate is represented by the diamond shape and the length of the diamond depicts the width of the confidence interval. Values to the left of the vertical line at one favor ERCP.


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FIGURE 9. Biliary sepsis. CI indicates confidence interval; ERCP, endoscopic retrograde cholangiopancreatography; ES, endoscopic sphincterotomy; OR, odds ratio. Forest plots: interpretation of forest plots: values in the left panel of the forest plots are authors’ names with year of publication, and observed counts for ERCP ± ES and Cons Mx. In the right panel of the plot there are effect sizes, and their 95% confidence intervals. In the forest plot, square shapes indicate point estimates of treatment effect (effect size for ERCP ± ES over Cons Mx groups) of individual studies with the size of the squares representing the weight attributed to each study. The horizontal lines represent 95% confidence interval for effect size of individual studies. The pooled estimate for the pancreatitis rate is the pooled effect size, obtained by combining all effect size of the listed studies using the inverse variance weighting method. The 95% confidence interval for the pooled estimate is represented by the diamond shape and the length of the diamond depicts the width of the confidence interval. Values to the left of the vertical line at one favor ERCP.

conservative treatment in mortality or local and systemic complications in unselected patients. The severity of pancreatitis was not a significant factor, however, patients with cholangitis showed a statistically significant decrease in mortality and local and systemic complications; in patients with biliary obstruction there was a nonsignificant trend toward decreased mortality and complications with early ERCP. This meta-analysis does not provided a definitive answer in regards to optimum treatment for GSP, but it does raise a number of interesting points that require further investigation. To begin with, there is this issue of which patients benefit from early ERCP + ES. There is little doubt that those suffering acute GSP with severe cholangitis should undergo urgent ERCP + ES, as studies and consensus statements attest.52–55,57,58 Analyses before Petrov et al27 seemed to support the argument for performing early ERCP + ES in those with severe GSP sighting

The final and most recent meta-analysis is the second Cochrane review by Tse et al,30 this review included 5 studies comprising 644 (326 = ERCP, 318 = early conservative)13–15,19,17 in the main analysis and 2 further studies with a further 113 (51 = ERCP, 62 = conservative)20,21 patients in a subgroup analysis. Analyses include early routine ERCP versus early conservative management with or without delayed or selected ERCP, ERCP-related complications, ERCP versus conservative management according to predicted severity of pancreatitis, inclusion or exclusion of patients with cholangitis and biliary obstruction, time to ERCP intervention, use of selective ERCP in early conservative management, ERCP compared with early conservative treatment according to risk of bias, and an analysis according to the geographical location of trials (Asian vs. non-Asian).30 There was no statistically significant difference between intervention and

TABLE 3. Summary Statistics of Pooled Data Comparing Conservative Management and ERCP for Various Complications

Test for Overall Effect

Studies Patients Outcome Variables

n

n

Renal failure Cardiac failure Respiratory failure Biliary sepsis Pseudocyst Pancreatic sbscess/phlegmon Coagulation/disseminated intravascular coagulopathy

6 5 6 6 7 8 5

806 701 806 764 882 919 701

z

Pooled OR 0.84 0.77 0.75 0.37 0.55 0.70 1.15

(0.35, (0.35, (0.32, (0.07, (0.29, (0.34, (0.40,

2.05) 1.71) 1.75) 2.04) 1.04) 1.45) 3.30)

0.38 0.61 0.65 1.14 1.84 0.96 0.26

P

Test for Heterogeneity Q

P

I2 [CI]

0.71 6.18 0.29 19.1% [0%, 63.8%] 0.54 3.15 0.53 0% [0%, 73.6%] 0.51 10.58 0.06 52.7% [0%, 81.1%] 0.25 6.34 0.09 52.7% [0%, 84.3%] 0.06 3.55 0.74 0% [0%, 50.6%] 0.33 7.5 0.37 6.6% [0%, 69.7%] 0.79 1.63 0.80 0% [0%, 49.1%]

CI indicates confidence interval; ERCP, endoscopic retrograde cholangiopancreatography; OR, odds ratio.

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FIGURE 10. Pseudocyst. CI indicates confidence interval; ERCP, endoscopic retrograde cholangiopancreatography; ES, endoscopic sphincterotomy; OR, odds ratio. Forest plots: interpretation of forest plots: values in the left panel of the forest plots are authors’ names with year of publication, and observed counts for ERCP ± ES and Cons Mx. In the right panel of the plot there are effect sizes, and their 95% confidence intervals. In the forest plot, square shapes indicate point estimates of treatment effect (effect size for ERCP ± ES over Cons Mx groups) of individual studies with the size of the squares representing the weight attributed to each study. The horizontal lines represent 95% confidence interval for effect size of individual studies. The pooled estimate for the pancreatitis rate is the pooled effect size, obtained by combining all effect size of the listed studies using the inverse variance weighting method. The 95% confidence interval for the pooled estimate is represented by the diamond shape and the length of the diamond depicts the width of the confidence interval. Values to the left of the vertical line at one favor ERCP.

FIGURE 11. Pancreas abscess and phelgmon. CI indicates confidence interval; ERCP, endoscopic retrograde cholangiopancreatography; ES, endoscopic sphincterotomy; OR, odds ratio. Forest plots: interpretation of forest plots: values in the left panel of the forest plots are authors’ names with year of publication, and observed counts for ERCP ± ES and Cons Mx. In the right panel of the plot there are effect sizes, and their 95% confidence intervals. In the forest plot, square shapes indicate point estimates of treatment effect (effect size for ERCP ± ES over Cons Mx groups) of individual studies with the size of the squares representing the weight attributed to each study. The horizontal lines represent 95% confidence interval for effect size of individual studies. The pooled estimate for the pancreatitis rate is the pooled effect size, obtained by combining all effect size of the listed studies using the inverse variance weighting method. The 95% confidence interval for the pooled estimate is represented by the diamond shape and the length of the diamond depicts the width of the confidence interval. Values to the left of the vertical line at one favor ERCP.


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TABLE 4. Characteristics of Previous Meta-Analyses Sharma and Howden24

Study

Identify the report as a systematic review, meta-analysis, or both | Provide a structured summary including, as applicable: background; objectives; data sources; study eligibility criteria, participants, and interventions; study appraisal and synthesis methods; results; limitations; conclusions and implications of key findings; systematic review registration number | Introduction Rationale | Objectives | Methods Protocol and registration ¾ Eligibility criteria | Information sources| Search | (no flow diagram) Study selection | Data collection process | Data items ¾ Risk of bias in individual studies ¾ Summary measures ¾ Synthesis of results | Risk of bias across studies ¾ Additional analyses NA Results Study selection | Study characteristics | Risk of bias within studies ¾ Results of individual studies | Synthesis of results | Risk of bias across studies ¾ Additional analysis NA Discussion Summary of evidence | Limitations | Conclusions | Funding Funding ¾ Key Findings: ERC + ES reduces complications and mortality in patients with acute biliary pancreatitis. Treating 26 such patients with ERC + ES is predicted to save 1 life. Title Abstract

Ayub et al25

Study

Identify the report as a systematic review, meta-analysis, or both | Provide a structured summary including, as applicable: background; objectives; data sources; study eligibility criteria, participants, and interventions; study appraisal and synthesis methods; results; limitations; conclusions and implications of key findings; systematic review registration number | Introduction Rationale | Objectives | Methods Protocol and registration | Eligibility criteria | Information sources | Search | Study selection | Data collection process | Data items | Risk of bias in individual studies | Summary measures | Synthesis of results | Risk of bias across studies | Additional analyses NA Results Study selection | Study characteristics | Risk of bias within studies | Results of individual studies | Synthesis of results | Risk of bias across studies | Additional analysis NA | Discussion Summary of evidence | Limitations | Conclusions | Funding Funding | Key Findings: Odds of having complications are reduced in predicted severe disease by early ERCP ± ES. This effect was, however, nonsignificant in predicted mild disease and for reduction of mortality in either predicted mild or severe disease. These results are controlled for confounding due to associated acute cholangitis and are robust for clinical and statistical heterogeneity. Title Abstract

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Moretti et al26

Title Abstract

Identify the report as a systematic review, meta-analysis, or both Provide a structured summary including, as applicable: background; objectives; data sources; study eligibility criteria, participants, and interventions; study appraisal and synthesis methods; results; limitations; conclusions and implications of key findings; systematic review registration number Introduction Rationale | Objectives | Methods Protocol and registration ¾ Eligibility criteria | Information sources | Search | (no flow diagram) Study selection | Data collection process | Data items | Risk of bias in individual studies ¾ Summary measures | Synthesis of results | Risk of bias across studies | Additional analyses NA Results Study selection | Study characteristics | Risk of bias within studies ¾ Results of individual studies | Synthesis of results | Risk of bias across studies | Additional analysis NA Discussion Summary of evidence | Limitations ¾ (minimal discussion) Conclusions | Funding Funding | Key Findings: Early endoscopic retrograde cholangiopancreatography reduces pancreatits-related complications in patients with predicted severe pancreatitis although mortality rate is not affected. In predicted mild pancreatitis early endoscopic retrograde cholangiopancreatography has no advantage compared with conservative management. Study

Petrov et al27

Identify the report as a systematic review, meta-analysis, or both | Provide a structured summary including, as applicable: background; objectives; data sources; study eligibility criteria, participants, and interventions; study appraisal and synthesis methods; results; limitations; conclusions and implications of key findings; systematic review registration number | Introduction Rationale | Objectives | Methods Protocol and registration ¾ Eligibility criteria | Information sources | Search | Study selection | (authors did not state how papers were selected) Data collection process | Data items | Risk of bias in individual studies | Summary measures | Synthesis of results | Risk of bias across studies | Additional analyses NA Results Study selection | Study characteristics | Risk of bias within studies | Results of individual studies | Synthesis of results | Risk of bias across studies | Additional analysis NA Discussion Summary of evidence | Limitations | Conclusions | Funding Funding ¾ Key Findings: In this meta-analysis, early ERCP in patients with predicted mild and predicted severe ABP without acute cholangitis did not lead to a significant reduction in the risk of overall complications and mortality. Title Abstract


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TABLE 4. (continued) Petrov et al28

Study

Identify the report as a systematic review, meta-analysis, or both | Provide a structured summary including, as applicable: background; objectives; data sources; study eligibility criteria, participants, and interventions; study appraisal and synthesis methods; results; limitations; conclusions and implications of key findings; systematic review registration number| Introduction Rationale | Objectives | Methods Protocol and registration ¾ Eligibility criteria | Information sources | Search | Study selection | Data collection process | Data items | Risk of bias in individual studies | Summary measures | Synthesis of results | Risk of bias across studies | Additional analyses NA Results Study selection | Study characteristics | Risk of bias within studies | Results of individual studies | Synthesis of results | Risk of bias across studies | Additional analysis NA Discussion Summary of evidence | Limitations | Conclusions | Funding Funding ¾ (not explicitly stated) Key Findings: The early use of ERCP did not result in a significantly reduced risk of local pancreatic complications for either patients with mild acute pancreatitis or those with severe form of the disease. Title Abstract

Uy et al29

Study

Identify the report as a systematic review, meta-analysis, or both | Provide a structured summary including, as applicable: background; objectives; data sources; study eligibility criteria, participants, and interventions; study appraisal and synthesis methods; results; limitations; conclusions and implications of key findings; systematic review registration number | Introduction Rationale | Objectives | Methods Protocol and registration ¾ Eligibility criteria | Information sources | Search | (no flow diagram) Study selection | Data collection process | Data items | Risk of bias in individual studies | (Jadad score included but detailed risk of bias not completed) Summary measures | Synthesis of results | Risk of bias across studies | Additional analyses NA Results Study selection | Study characteristics | Risk of bias within studies | Results of individual studies | Synthesis of results | Risk of bias across studies | Additional analysis NA Discussion Summary of evidence | Limitations | Conclusions | Funding Funding | Key Findings: There is a trend towards more mortality from early ERCP with or without sphincterotomy in the setting of acute gallstone pancreatitis without cholangitis. However, more studies are needed. In the meantime, early ERCP should not be carried out unless there is at least a slight suspicion of cholangitis or persistent ampullary obstruction. Title Abstract

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Tse and Yuan30

Identify the report as a systematic review, meta-analysis, or both | Provide a structured summary including, as applicable: background; objectives; data sources; study eligibility criteria, participants, and interventions; study appraisal and synthesis methods; results; limitations; conclusions and implications of key findings; systematic review registration number | Introduction Rationale | Objectives | Methods Protocol and registration | Eligibility criteria | Information sources | Search | Study selection | Data collection process | Data items | Risk of bias in individual studies | Summary measures | Synthesis of results | Risk of bias across studies | Additional analyses | Results Study selection | Study characteristics | Risk of bias within studies | Results of individual studies | Synthesis of results | Risk of bias across studies | Additional analysis | Discussion Summary of evidence | Limitations | Conclusions | Funding Funding | Key Findings: No statistically significant difference in complications and mortality in unselected patients with GSP treated conservatively or with ERCP, results not dependent on severity of pancreatitis. In patients with cholangitis, complications and mortality were significantly reduced with early ERCP. Patients with biliary obstruction demonstrated a significant reduction in local complications (by primary study) and a trend towards decreased local and systemic complications (Atlanta criteria). Title Abstract

ERCP indicates endoscopic retrograde cholangiopancreatography; ES, endoscopic sphincterotomy.

reduced complications, but subsequent analyses have indicated that the benefit may be confined to those with associated cholangitis. A notable source of potential confounding is the heterogeneity of the studies included for analysis. As previously mentioned, the study by Fan et al14 included individuals with pancreatitis from all causes and although providing data for those with GSP only, incorrect data has been incorporated into 3 previous meta-analyses.24–26 Furthermore, Fan et al14 stratified severity of GSP by urea and glucose levels and mentions that similar results were seen when Ranson’s criteria was applied and this may also alter results. Fo¨lsch et al15 excluded patients with cholangitis as well as those with obvious obstruction (> 90 mmol/L), which may lessen the impact of ERCP + ES in this study as strong evidence exists that persisting obstruction (> 48 h) increases the risk of complications.59 The study by Fo¨lsch et al,15 was stopped early due to poorer patient outcomes in the ERCP group both for mortality (in mild and severe GSP) and complications (again in both groups), although this was not statistically significant. Neoptolemos et al13 excluded those with cholangitis and GSP in a subgroup analysis and the results nevertheless demonstrated the superiority of early ERCP + ES with respect to complications (overall P = 0.02, severe GSP P = 0.003). Six patients in the study by Neoptolemos et al13 had severe pancreatitis with cholangitis treated with early ERCP + ES and in fact these patients had the highest complication rate (66.7%),


contrary to what would be expected.10 The abstract by Nowak et al16 was included for analysis as further data were obtained through correspondence with the author (Table 1), however, significant detail is lacking. Oria et al19 excluded cholangitis but patients with biliary obstruction were included. In contrast to other studies, there were increased complications in the group with severe GSP and early ERCP + ES as opposed to those with mild disease who also underwent early intervention. Acosta et al18 excluded severe cholangitis but still showed significantly reduced complications when ERCP was performed

Commentary Re: Meta-Analysis of Early Endoscopic Retrograde Cholangiopancreatography (ERCP) ± Endoscopic Sphincterotomy (ES) Versus Conservative Management for Gallstone Pancreatitis (GSP).

Endoscopic retrograde cholangiopancreatography (ERCP)-related adverse events: post-ERCP pancreatitis.

Endoscopic retrograde cholangiopancreatography (ERCP): radiographic technique.

ERCP- and endoscopic sphincterotomy-induced pancreatitis.

Endoscopic retrograde cholangiopancreatography (ERCP) performed in children.

Endoscopic prevention of post-endoscopic retrograde cholangiopancreatography pancreatitis.

Early endoscopic sphincterotomy in the management of acute gallstone pancreatitis in elderly patients.

Endoscopic retrograde cholangiography, sphincterotomy, and gallstone extraction via gastrostomy.

How often does bacteraemia occur following endoscopic retrograde cholangiopancreatography (ERCP)?

Endoscopic retrograde cholangiopancreatography for cholangiocarcinoma.

[Conservative treatment of duodenal perforation after therapeutic endoscopic retrograde cholangiopancreatography].

Prevention of postendoscopic retrograde cholangiopancreatography pancreatitis: the endoscopic technique.

Endoscopic retrograde cholangiopancreatography.

Endoscopic retrograde cholangiopancreatography.

Nonradiation, Endoscopic Ultrasound-Based Endoscopic Retrograde Cholangiopancreatography.

The role of endoscopic retrograde cholangiopancreatography in acute pancreatitis.

Preventing post-endoscopic retrograde cholangiopancreatography pancreatitis: what can be done?

Endoscopic retrograde cholangiopancreatography.

Difficult endoscopic retrograde cholangiopancreatography.

Diagnosis of cytomegalovirus pancreatitis in AIDS by endoscopic retrograde cholangiopancreatography.

Conscious sedation for endoscopic retrograde cholangiopancreatography: dexmedetomidine versus midazolam.

Characteristic findings of endoscopic retrograde cholangiopancreatography in autoimmune pancreatitis.

Proton pump inhibitors impact on post-endoscopic retrograde cholangiopancreatography pancreatitis.

ERCP for gallstone pancreatitis.