Rectal Indomethacin Prevents Moderate to Severe Post-ERCP Pancreatitis and Death and Should Be Used Before the Procedure: A Meta-Analysis of Aggregate Subgroup Data

Rectal Indomethacin Prevents Moderate to Severe Post-ERCP Pancreatitis and Death and Should Be... Background: Despite overall evidence in the literature favoring rectal indomethacin in preventing post-endoscopic retrograde cholangiopancreatography (ERCP) pancreatitis (PEP), its role in prevent- ing potentially fatal complications is not well explored. Method: A comprehensive electronic literature search was done to select randomized controlled tri- als (RCTs) comparing rectal indomethacin and placebo in preventing PEP. Methodological quality was assessed using the Cochrane risk of bias tool. Statistical heterogeneity was characterized. Random effect model meta-analysis was used. Several subgroup, sensitivity and aggregate subgroup data analy - ses were completed based on specific risk factors or patient characteristics to identify patient popula - tions who may benefit most from rectal indomethacin. Results: A total of eight out of 336 trials published between 2007 and 2016 (n=3324) were included. Analysis showed administering rectal indomethacin before rather than during or ae ft r ERCP signifi - cantly reduced PEP rates (odds ratio (OR): 0.56 [0.40–079]). Rectal indomethacin also significantly decreased the rate of moderate to severe PEP and death amongst all patients (OR: 0.53 [0.31–0.89] and 0.10 [0.02–0.65], respectively). Rectal indomethacin significantly prevented PEP in patients with sphincter of Oddi dysfunction (SOD) (OR: 0.49 [0.30–0.78]) and those undergoing biliary sphinc- terotomy (OR: 0.63 [0.42–0.95]), but not in those undergoing precut or pancreatic sphincterotomy or prophylactic pancreatic stent placement. Sensitivity analysis showed that the effect remained signif - icant ae ft r two studies with high risk of bias were excluded. Conclusion: Rectal indomethacin significantly decreases the occurrence of moderate to severe PEP and death in all patients, only if given before the procedure. Key words: Meta-analysis; Post-ERCP pancreatitis; Prevention; Rectal indomethacin. Acute pancreatitis is the most common major post-endoscopic ret- Risk factors include patient-related factors such as young age, female rograde cholangiopancreatography (ERCP) complication. It ranges gender, pancreas divisum, sphincter of Oddi dysfunction (SOD), from 1% to 10% and as high as 25% to 30% in high-risk patients. prior post-ERCP pancreatitis (PEP), and procedure-related factors © The Author(s) 2018. Published by Oxford University Press on behalf of the Canadian Association of Gastroenterology. 67 This is an Open Access article distributed under the terms of the Creative Commons Attribution Non-Commercial License (http:// creativecommons.org/licenses/by-nc/4.0/), which permits non-commercial re-use, distribution, and reproduction in any medium, provided the original work is properly cited. For commercial re-use, please contact journals.permissions@oup.com Downloaded from https://academic.oup.com/jcag/article-abstract/1/2/67/4955217 by guest on 20 June 2018 68 Journal of the Canadian Association of Gastroenterology, 2018, Vol. 1, No. 2 such as difficult cannulation and pancreatic duct injection (1–3). EMBASE (1980 to May 2016), Cochrane library, clinical trials Multiple modalities have been proposed to decrease the rate of PEP, database (www.clinicaltrials.gov), and ISI Web of knowledge including technical improvement, prophylactic pancreatic stent and from 1980 to May 2016. Other available sources (grey litera- pharmacoprevention (4, 5). The list of pharmacological agents that ture) were also searched through cross-referencing. Articles have been proposed and tested for this purpose is long and varied (1, were selected using a highly sensitive search strategy to iden- 6). Among all these, rectal indomethacin has gained universal ae tt n- tify reports of RCTs, with a combination of MeSH headings tion ae ft r a large US-based multicentre double-blinded randomized and text words that included 1) Pancreatitis, 2) Indomethacin controlled trial (RCT) in high-risk patients (7). The trial showed and 3)  ERCP. Recursive searches and cross-referencing were a significant risk reduction of 46% in those who received it. Later, carried out using a ‘similar articles’ function; bibliographies of in a meta-analysis of four randomized controlled trials, our group the articles identified ae ft r an initial search were also manually showed that rectal indomethacin significantly reduced the rate of reviewed. Non-randomized trials, studies with insufficient data PEP, including moderate to severe pancreatitis to half in both high- on clinical response, abstracts, any study on rescue therapy, risk and low-risk patients (8). The latest recommendation from the pediatric studies and duplicate publications were excluded. European Society of Gastrointestinal Endoscopy advocates routine Data extraction and quality control were independently done by use of rectally administered diclofenac or indomethacin imme- two reviewers (MY and MAA). A third reviewer ( JM or ANB) diately before or ae ft r ERCP to prevent PEP (9 ). In the absence was involved if conflict occurred. We first tried to extract the of direct comparison, a network meta-analysis showed that rectal raw data from available published information. Corresponding nonsteroidal anti-inflammatory drugs  (NSAIDs) were superior to authors were then contacted to obtain missing data, where pancreatic duct stenting and was not inferior to the combination of appropriate. If missing data could not be obtained then the trial rectal indomethacin and prophylactic pancreatic stent placement was excluded and the reason was described. for the prevention of PEP (10). Several other meta-analyses showed The risk of bias of the included studies was evaluated using that rectal indomethacin or diclofenac reduced the overall rate of the Cochrane Collaboration tool for assessing the risk of bias PEP and decreased both mild and moderate to severe PEP in both recommendations by the Cochrane Collaboration (22, 23). high-risk and unselected patients (8,11–18). However, more recent The study was registered (CRD42016038397) in PROSPERO studies did not support previous findings especially in unselected (International prospective register of systematic reviews). patients (19, 20). Specifically, in the most recent double-blinded Outcome measures single centre RCT on 449 consecutive patients, rectal indometh- acin had no significant effect on preventing PEP as compared to The main outcome of interest was the incidence of PEP within placebo (7.2% versus 4.9%; p=0.33) (20). In the largest published a 7-day period following the ERCP. Secondary outcomes were RCT, pre-procedure rectal indomethacin was shown to be superior set to compare incidence of moderate to severe post-ERCP pan- to risk-stratified post-procedural administration in high-risk patients creatitis in the 7-day period following ERCP as well as death. (21). Subgroup analyses and analyses of aggregate subgroup data Despite the significant number of studies including RCTs were planned beforehand according to different patient char - and systematic reviews, the effect of the intervention on major acteristics that included high-risk versus average-risk for PEP; adverse events such as moderate to severe PEP and death is not sphincter of Oddi dyskinesia; those undergoing pancreatic, well scrutinized. Therefore, we aimed to complete a more con- biliary, or precut sphincterotomy or prophylactic pancreatic temporary meta-analysis of aggregate subgroup data, including stent placement; and according to differing doses and timing RCTs comparing rectal indomethacin and placebo in prevent- of administration of rectal indomethacin. The analysis was ing more severe PEP and mortality. also planned for the rate of moderate to severe pancreatitis and death. We respected authors’ definition of high-risk and aver - age-risk population as mentioned previously. MATERIAL AND METHODS Trial selection criteria Statistical analysis Only RCTs were included. For inclusion, we required that Summary outcomes are described as proportions and 95% patients undergoing ERCP in the trial have been randomized confidence intervals (CI ).  Pooled proportionate rates of PEP to rectal indomethacin or placebo. No studies were excluded were calculated separately for rectal indomethacin and placebo based on the language of publication, quality of study, duration and were reported as proportions and confidence intervals. of follow-up or country of origin. A  meta-analysis of intention-to-treat study-level or aggregate subgroup data was done using the random effect model Mantel- Search strategy Haenszel method for each risk factor (24). Peto method was Comprehensive computerized medical literature searches used when the rate of events was under 1% (24). The signifi - were conducted using OVID MEDLINE (1946 to May 2016), cance and extent of statistical heterogeneity were calculated Downloaded from https://academic.oup.com/jcag/article-abstract/1/2/67/4955217 by guest on 20 June 2018 Journal of the Canadian Association of Gastroenterology, 2018, Vol. 1, No. 2 69 using the Q test and I index, respectively (23). Odds ratios (OR) were calculated for each analysis with the correspond- ing 95% confidence intervals. Number needed to treat (NNT) was calculated using the reciprocal of absolute risk difference rather than treat-as-one-trial method to avoid Simpson’s para- dox (25, 26). Funnel plots, Begg adjusted rank correlation test and the Egger regression asymmetry test were planned to detect the possibility of publication bias in meta-analyses including more than 10 studies (23, 27, 28). We also planned to perform meta-regression and sensitivity analyses based on the quality and weight of the trials (23). Sensitivity analyses were planned, excluding studies with high risk of bias and by excluding the largest trial. All statistical analyses were done using RevMan (Version 5.3, Copenhagen: The Nordic Cochrane Centre, The Cochrane Collaboration, 2008) and R (version 2.13.0, R Foundation for  Statistical Computing, Vienna, Austria, 2008). The PRISMA statement outline for reporting systematic reviews and meta-analyses was used to report on this work (29). RESULTS Characteristics of included trials A total of eight out of 336 identified studies (N=3324 patients, including 1684 in treatment group and 1640 in placebo group) were included; all were performed between 2007 and 2016. All studies were published in English. There was no missed data, and the authors provided all required raw data not previ- ously presented in published manuscript. Figure  1 depicts the PRISMA flow diagram. Table 1 shows the methodological and clinical details for each trial. Clinical heterogeneity All trials used relatively similar criteria to define PEP as depicted in Table 1. Two studies included only high-risk patients (7, 30) while the rest included unselected patients (19, 20, 31–34). All included studies used 100 mg of rectal indomethacin. Five Figure 1. PRISMA flow diagram of included and excluded trials. studies administered pre-procedure rectal indomethacin (19, 31–34), one intra-procedure (20) and two post-procedure (7, tests is considered too low to distinguish chance from real 30). Three studies allowed prophylactic pancreatic stent (7, 20, asymmetry according to recommendation by the Cochrane 34) but three did not (19,30,31) and two studies were unclear Collaboration (23). in regard to this possible co-intervention (32, 33). Analysis of main outcome Risk of bias All included studies reported the primary outcome. The pooled Figure 2 presents the consensus risk of bias assessments of the proportion estimates of PEP were 5.6 (95% CI: 4.5–11.5) with included studies. Risk of bias was low in all but two studies rectal indomethacin and 8.8 (95% CI: 7.5–14.4) with placebo. (33,34). This rate was significantly lower with rectal indomethacin as compared to placebo (OR=0.56 [0.39–0.82]). Statistical Publication bias heterogeneity was significant (p: 0.07, I : 46%). The number A funnel plot was not provided since the number of included needed to treat was 20. We were unable to perform a separate studies was fewer than 10, and in this case, the power of the meta-regression analysis since the number of included studies Downloaded from https://academic.oup.com/jcag/article-abstract/1/2/67/4955217 by guest on 20 June 2018 70 Journal of the Canadian Association of Gastroenterology, 2018, Vol. 1, No. 2 Table 1. Characteristics of included studies. PEP: Post-ERCP pancreatitis Study Year Country Number of Number of Intervention Definition of PEP patients post-ERCP (Indomethacin pancreatitis 100 mg per rectum) Andrade-Dávila (30) 2015 Mexico 166 21 Ae ft r ERCP Pain, lipase or amylase> x3, positive imaging Dobronte et al (33) 2012 Hungary 228 22 10 Minutes before Clinical/Amylase> x3/ ERCP prolonged hospital admission Dobronte et al (19) 2014 Hungary 686 22 10–15 minutes before Clinical/Amylase 24h ERCP Elmunzer et al (7) 2012 USA 602 79 Immediately ae ft r Pain, Amylase> x3, ERCP admission for at least 2 nights Levenick et al (20) 2016 USA 449 27 during ERCP Pain, lipase> x3, admission >2 nights Montaño Loza et al 2007 Mexico 150 16 2 hours before ERCP Clinical, amylase level (34) Patai et al (32) 2015 Hungary 574 55 Within one hour before Pain, amylase> x3, ERCP admission >2 nights Sotoudehmanesh et al 2007 Iran 490 22 right before ERCP Pain, Amylase> x3, (31) admission>2 days was less than 10 (23). Figure  3 depicts the Forest plots of the regardless of the risk for post-ERCP pancreatitis. There was selected study analyses. no statistically significant heterogeneity in this analysis (I : 0%). Rectal indomethacin was not statistically superior to pla- Subgroup analyses cebo when analyzing three studies (n=1217) using intra- or Meta-analysis of aggregate subgroup data on risk factors post-procedure dosing (OR: 0.56 [0.21–1.49], p=0.25] (7, Table 2 represents the detail of these analyses. In summary, rec- 20, 30). There was statistically significant heterogeneity in this tal indomethacin significantly decreased the rate of moderate to analysis (p: 0.009, I : 79%). severe PEP. Death happened only and more significantly with placebo (five out of 177 events) and not with indomethacin High-risk versus unselected patients (zero out of 107 events). The effect remained statistically signifi - Ae ft r excluding the two studies on high-risk populations (7, 30), cant in sensitivity analysis ae ft r using the total number of patients the PEP rates were no longer statistically different (OR: 0.65 instead of the ones with PEP as denominator. It also significantly [0.42–1.00]). There was statistically significant heterogeneity decreased the rate of PEP amongst subgroup of patients with in this analysis (p: 0.12, I : 43%). The OR for the rate of PEP sphincter of Oddi dysfunction  (SOD). The effect remained was 0.37 (0.16–0.84) and significant for rectal indomethacin robust in sensitivity analysis ae ft r excluding the largest SOD amongst the two studies (n=768) exclusively done in high-risk population from one study (7). Rectal indomethacin was also patients. Number needed to treat was 10. There was no statisti - significantly effective in preventing PEP in those patients under - cally significant heterogeneity in this analysis (p: 0.16, I : 50%). going biliary sphincterotomy. This effect was not significant ae ft r Sensitivity analyses excluding two studies on high-risk population (OR :0.69 [0.42– 1.15]). It did not significantly decrease the rate of PEP amongst The effect remained significant when two studies with high risk subgroup of patients who received a pancreatic sphincterotomy, of bias (33, 34) were excluded (OR : 0.57 [0.37–0.89]) or ae ft r precut sphincterotomy, or prophylactic pancreatic stent. excluding the largest included trial (7) (OR : 0.52 [0.35–0.79]). Timing of dosing Discussion Amongst five studies (n=2107) administering pre-procedure To our knowledge, this is the first meta-analysis of aggregate suppositories (19, 31–34), the difference remained statisti - subgroup data on the role of rectal indomethacin in preventing cally significant (OR: 0.56 [0.40–0.79], p=0.0008), favoring moderate to severe post-ERCP pancreatitis and mortality. We rectal indomethacin. All included patients were randomized Downloaded from https://academic.oup.com/jcag/article-abstract/1/2/67/4955217 by guest on 20 June 2018 Journal of the Canadian Association of Gastroenterology, 2018, Vol. 1, No. 2 71 Figure 2. Consensus risk of bias assessments of the included studies. Green: Low risk, Yellow: Unclear, Red: High risk. used aggregate data from the different trials and performed a that also benefit from this approach, mainly in patients with meta-analysis in each subgroup according to PEP-risk cate- sphincter of Oddi dyskinesia. The intervention effectively gory. Our study tried to answer important questions that have decreases the rate of moderate to severe post-ERCP pancreati- remained unanswered despite multiple clinical and meta-ana- tis and fatality in all patients, regardless of patient risk category. lytical studies on this topic using the additional statistical power Also, pre-procedure dosing appears to be significantly more brought about by summary analyses of clinically pertinent effective than post-procedure administration of rectal indo - patient subgroups. Our study identifies population subgroups methacin in preventing PEP. Downloaded from https://academic.oup.com/jcag/article-abstract/1/2/67/4955217 by guest on 20 June 2018 72 Journal of the Canadian Association of Gastroenterology, 2018, Vol. 1, No. 2 Figure 3. Forest plot of selected Mantel-Haenszel meta-analysis of the post-ERCP pancreatitis with rectal indomethacin versus placebo. CI, confidence interval; M-H , Mantel-Haenszel. Our sensitivity analyses show results that remain unchanged subgroup meta-analyses, there was no more heterogeneity when excluding the study with high risk of bias or with the when we stratified the data based on those factors. largest sample size. All but one of the included studies demon- We showed rectal indomethacin is effective in preventing strated at least an arithmetical trend favoring rectal indometh- PEP in patients at high-risk for it. This is consistent with the acin. Despite the observed statistical heterogeneity in some of results of the two large RCTs performed exclusively on high- the analyses, the designs of the included RCTs were very similar, risk patients. Our meta-analysis of aggregate subgroup data thereby resulting in low clinical heterogeneity, not measurable from five studies showed that SOD patients particularly bene- by statistical means, which might further enhance the validity fited from the intervention. Minimal heterogeneity was found of the findings. Some of the possible reason for heterogeneity in this analysis. A  large US study (7), which mainly included in subgroup analyses might be the timing of administration of SOD patients, concluded that rectal indomethacin significantly rectal indomethacin, difference in patient population regarding decreased the rate of PEP in included patients with a NNT of the risk for PEP and considering cumulative outcome by com- 12, which was close to the NNT achieved for SOD patients bining mild, moderate and severe PEP. Based on our aggregate in our study, as depicted in Table  2. Based on the grade of the Downloaded from https://academic.oup.com/jcag/article-abstract/1/2/67/4955217 by guest on 20 June 2018 Journal of the Canadian Association of Gastroenterology, 2018, Vol. 1, No. 2 73 Table 2. Meta-analysis of aggregate subgroup data in each risk category. OR : Odds Ratio; CI: Confidence Interval; NNT: Number Needed to Treat; NA: Non-applicable Subgroup analyses Number of patients OR CI 95% Heterogeneity NNT (I2) Preventing moderate to severe PEP (7, 19, 20, 3324 0.53 0.31–0.89 0% 100 30–34) Sphincter of Oddi Dyskinesia (7, 19, 20, 694 0.49 0.30–0.78 0% 10 30–34) Death 284 with post-ERCP 0.10 0.02–0.65 0% NA pancreatitis 3324 randomized patients 0.13 0.02–0.77 0% NA Biliary sphincterotomy (7, 19, 20, 31–34) 2062 0.63 0.42–0.95 53% 33 Pancreatic sphincterotomy (7, 19, 20, 30–34) 492 0.81 0.36–1.83 34% NA Precut sphincterotomy (7, 19, 20, 30–34) 436 0.50 0.14–1.82 72% NA Prophylactic pancreatic stent (7, 19, 20, 30–34) 572 0.98 0.26–3.62 72% NA evidence, we strongly recommend administering rectal indo- and mortality due to PEP occurs in patients with moderate to methacin in all patients suspected of SOD undergoing ERCP. severe cases (41). Stent placement in the pancreatic duct has been one of the We have shown that pre-procedural administration of rectal proven effective interventions for post-ERCP pancreatitis pro - indomethacin appears to be superior to intra- or post-procedure phylaxis associated with a protective OR of 0.44 (0.24–0.81) administration, a result no doubt driven statistically by the find - (35–37); however, more than 20% of endoscopists do not ings of a very recent large RCT from China on 2600 unselected perform prophylactic pancreatic stenting (37). The combi - patients undergoing ERCP. In this trial, patients were random- nation of rectal indomethacin and prophylactic pancreatic ized to either pre-procedure rectal indomethacin or risk-strati- stent placement in the current meta-analysis does not signifi - fied post-procedural administration in high-risk patients (21). cantly alter the rate of PEP compared to rectal indomethacin Post-ERCP pancreatitis occurred significantly less in patients alone. This is the first meta-analytic evidence showing lack of who universally received pre-procedural rectal indomethacin synergistic protection of rectal indomethacin and pancreatic (4% versus 8% respectively, p<0.0001). There might exist a stenting. A post-hoc analysis by Elmunzer et al. has previously biologically plausible explanation for this effect. Indeed, peak shown a higher PEP rate following this combination compared plasma concentrations are achieved in 30 minutes following to rectal indomethacin alone (9.7% versus 6.3%, respectively) rectal administration of indomethacin (42). Therefore, post- (38). Moreover, their economic model demonstrated rectal ERCP dosing may theoretically render the NSAID not availa- indomethacin alone is more cost-effective than placebo, pro - ble at the time of the initial injury to the pancreas and thus less phylactic pancreatic duct stent placement, or a combination able to prevent the inflammatory cascade. It may be prudent of rectal indomethacin and stent placement (38). A  network to administer rectal indomethacin, when indicated, before the meta-analysis, based on indirect comparisons, has concluded procedure rather than during or ae ft r ERCP in patients without that rectal NSAIDs are superior to prophylactic pancreatic stent a contraindication. placement (OR: 0.48 [0.26–0.87]), and a combination of rec- Although meta-analyses have been described to provide high tal NSAIDs and prophylactic pancreatic stent placement is not quality evidence for clinical use, they are not free of risk of bias. superior to rectal NSAIDs (OR:1.46 [0.79–2.69]) (39). Only The possibility of missed trials cannot be completely ruled out. the advent of true head-to-head data will provide more defini - We tried to minimize this possibility by including several types tive clarity on this issue, and we await the results from at least of publications, search methods and all languages. However, two ongoing RCTs (40). However, to date, there is insufficient the number of included studies was not sufficient to perform proof to recommend the combination of these two modalities a meta-regression analysis in a search for causes of statistical over performing either. heterogeneity. In our meta-analysis of aggregate subgroup data, rectal indo- In conclusion, this meta-analysis suggests rectal indometha- methacin significantly decreases the rate of moderate to severe cin is effective in preventing post-ERCP pancreatitis and that PEP, as well as the rate of death from ERCP or post-ERCP pan- this protective effect is true for high-risk patients, specifically creatitis in all patients. This alone may be an indication for uni - in those with sphincter of Oddi dyskinesia. It also signifi - versal routine administration since the majority of morbidity cantly decreases the rate of moderate to severe PEP and death Downloaded from https://academic.oup.com/jcag/article-abstract/1/2/67/4955217 by guest on 20 June 2018 74 Journal of the Canadian Association of Gastroenterology, 2018, Vol. 1, No. 2 in unselected patients, and this should be given to all patients retrograde cholangiopancreatography: a network meta-analysis. Clin Gastroenterol Hepatol. 2013;11(7):778–83. without a contraindication prior to the ERCP. 11. Elmunzer BJ, Waljee AK, Elta GH, et  al. A meta-analysis of rec- Registration & Funding tal NSAIDs in the prevention of post-ERCP pancreatitis. Gut. This study was registered (CRD42016038397) in PROSPERO 2008;57(9):1262–7. doi: 10.1136/gut.2007.140756. (International prospective register of systematic reviews). The authors 12. Dai HF, Wang XW, Zhao K. Role of nonsteroidal anti-inflam- received no funding to support this study. matory drugs in the prevention of post-ERCP pancreatitis: a meta-analysis. Hepatobiliary Pancreat Dis Int. 2009;8(1):11–6. ACKNOWLEDGEMENTS 13. Ding X, Chen M, Huang S, et al. Nonsteroidal anti-inflammatory drugs for prevention of post-ERCP pancreatitis: a meta-analysis. The authors would like to thank the authors of the included trials Gastrointest Endosc. 2012;76(6):1152–9. including Dr. Zoltán Döbrönte, Dr Alejandro Gonzalez Ojeda, Dr 14. Sethi S, Sethi N, Wadhwa V, Garud S, Brown A . A meta-analysis on Rasoul Sotoudehmanesh, and Dr Arpad Patai for providing additional the role of rectal diclofenac and indomethacin in the prevention of subgroup data and Dr Frances Tse for intellectual contribution. post-endoscopic retrograde cholangiopancreatography pancreati- Conflicts of Interest tis. Pancreas. 2014;43(2):190–7. Dr Yaghoobi is supported by an Internal Medicine Career Award by 15. 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Gastrointest Effect of the administration of rectal indomethacin on amylase Endosc. 1991;37(3):383–93. serum levels ae ft r endoscopic retrograde cholangiopancreatogra - 42. Van Der Marel C, Anderson B, Romsing J, et  al. Diclofenac phy, and its impact on the development of secondary pancreatitis and metabolite pharmacokinetics in children. Paediatr Anesth episodes. Rev Esp Enferm Dig. 2007;99(6):330–6. 2004;14:443–51. Downloaded from https://academic.oup.com/jcag/article-abstract/1/2/67/4955217 by guest on 20 June 2018 http://www.deepdyve.com/assets/images/DeepDyve-Logo-lg.png Journal of the Canadian Association of Gastroenterology Oxford University Press

Rectal Indomethacin Prevents Moderate to Severe Post-ERCP Pancreatitis and Death and Should Be Used Before the Procedure: A Meta-Analysis of Aggregate Subgroup Data

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Canadian Association of Gastroenterology
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© The Author(s) 2018. Published by Oxford University Press on behalf of the Canadian Association of Gastroenterology.
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2515-2084
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Abstract

Background: Despite overall evidence in the literature favoring rectal indomethacin in preventing post-endoscopic retrograde cholangiopancreatography (ERCP) pancreatitis (PEP), its role in prevent- ing potentially fatal complications is not well explored. Method: A comprehensive electronic literature search was done to select randomized controlled tri- als (RCTs) comparing rectal indomethacin and placebo in preventing PEP. Methodological quality was assessed using the Cochrane risk of bias tool. Statistical heterogeneity was characterized. Random effect model meta-analysis was used. Several subgroup, sensitivity and aggregate subgroup data analy - ses were completed based on specific risk factors or patient characteristics to identify patient popula - tions who may benefit most from rectal indomethacin. Results: A total of eight out of 336 trials published between 2007 and 2016 (n=3324) were included. Analysis showed administering rectal indomethacin before rather than during or ae ft r ERCP signifi - cantly reduced PEP rates (odds ratio (OR): 0.56 [0.40–079]). Rectal indomethacin also significantly decreased the rate of moderate to severe PEP and death amongst all patients (OR: 0.53 [0.31–0.89] and 0.10 [0.02–0.65], respectively). Rectal indomethacin significantly prevented PEP in patients with sphincter of Oddi dysfunction (SOD) (OR: 0.49 [0.30–0.78]) and those undergoing biliary sphinc- terotomy (OR: 0.63 [0.42–0.95]), but not in those undergoing precut or pancreatic sphincterotomy or prophylactic pancreatic stent placement. Sensitivity analysis showed that the effect remained signif - icant ae ft r two studies with high risk of bias were excluded. Conclusion: Rectal indomethacin significantly decreases the occurrence of moderate to severe PEP and death in all patients, only if given before the procedure. Key words: Meta-analysis; Post-ERCP pancreatitis; Prevention; Rectal indomethacin. Acute pancreatitis is the most common major post-endoscopic ret- Risk factors include patient-related factors such as young age, female rograde cholangiopancreatography (ERCP) complication. It ranges gender, pancreas divisum, sphincter of Oddi dysfunction (SOD), from 1% to 10% and as high as 25% to 30% in high-risk patients. prior post-ERCP pancreatitis (PEP), and procedure-related factors © The Author(s) 2018. Published by Oxford University Press on behalf of the Canadian Association of Gastroenterology. 67 This is an Open Access article distributed under the terms of the Creative Commons Attribution Non-Commercial License (http:// creativecommons.org/licenses/by-nc/4.0/), which permits non-commercial re-use, distribution, and reproduction in any medium, provided the original work is properly cited. For commercial re-use, please contact journals.permissions@oup.com Downloaded from https://academic.oup.com/jcag/article-abstract/1/2/67/4955217 by guest on 20 June 2018 68 Journal of the Canadian Association of Gastroenterology, 2018, Vol. 1, No. 2 such as difficult cannulation and pancreatic duct injection (1–3). EMBASE (1980 to May 2016), Cochrane library, clinical trials Multiple modalities have been proposed to decrease the rate of PEP, database (www.clinicaltrials.gov), and ISI Web of knowledge including technical improvement, prophylactic pancreatic stent and from 1980 to May 2016. Other available sources (grey litera- pharmacoprevention (4, 5). The list of pharmacological agents that ture) were also searched through cross-referencing. Articles have been proposed and tested for this purpose is long and varied (1, were selected using a highly sensitive search strategy to iden- 6). Among all these, rectal indomethacin has gained universal ae tt n- tify reports of RCTs, with a combination of MeSH headings tion ae ft r a large US-based multicentre double-blinded randomized and text words that included 1) Pancreatitis, 2) Indomethacin controlled trial (RCT) in high-risk patients (7). The trial showed and 3)  ERCP. Recursive searches and cross-referencing were a significant risk reduction of 46% in those who received it. Later, carried out using a ‘similar articles’ function; bibliographies of in a meta-analysis of four randomized controlled trials, our group the articles identified ae ft r an initial search were also manually showed that rectal indomethacin significantly reduced the rate of reviewed. Non-randomized trials, studies with insufficient data PEP, including moderate to severe pancreatitis to half in both high- on clinical response, abstracts, any study on rescue therapy, risk and low-risk patients (8). The latest recommendation from the pediatric studies and duplicate publications were excluded. European Society of Gastrointestinal Endoscopy advocates routine Data extraction and quality control were independently done by use of rectally administered diclofenac or indomethacin imme- two reviewers (MY and MAA). A third reviewer ( JM or ANB) diately before or ae ft r ERCP to prevent PEP (9 ). In the absence was involved if conflict occurred. We first tried to extract the of direct comparison, a network meta-analysis showed that rectal raw data from available published information. Corresponding nonsteroidal anti-inflammatory drugs  (NSAIDs) were superior to authors were then contacted to obtain missing data, where pancreatic duct stenting and was not inferior to the combination of appropriate. If missing data could not be obtained then the trial rectal indomethacin and prophylactic pancreatic stent placement was excluded and the reason was described. for the prevention of PEP (10). Several other meta-analyses showed The risk of bias of the included studies was evaluated using that rectal indomethacin or diclofenac reduced the overall rate of the Cochrane Collaboration tool for assessing the risk of bias PEP and decreased both mild and moderate to severe PEP in both recommendations by the Cochrane Collaboration (22, 23). high-risk and unselected patients (8,11–18). However, more recent The study was registered (CRD42016038397) in PROSPERO studies did not support previous findings especially in unselected (International prospective register of systematic reviews). patients (19, 20). Specifically, in the most recent double-blinded Outcome measures single centre RCT on 449 consecutive patients, rectal indometh- acin had no significant effect on preventing PEP as compared to The main outcome of interest was the incidence of PEP within placebo (7.2% versus 4.9%; p=0.33) (20). In the largest published a 7-day period following the ERCP. Secondary outcomes were RCT, pre-procedure rectal indomethacin was shown to be superior set to compare incidence of moderate to severe post-ERCP pan- to risk-stratified post-procedural administration in high-risk patients creatitis in the 7-day period following ERCP as well as death. (21). Subgroup analyses and analyses of aggregate subgroup data Despite the significant number of studies including RCTs were planned beforehand according to different patient char - and systematic reviews, the effect of the intervention on major acteristics that included high-risk versus average-risk for PEP; adverse events such as moderate to severe PEP and death is not sphincter of Oddi dyskinesia; those undergoing pancreatic, well scrutinized. Therefore, we aimed to complete a more con- biliary, or precut sphincterotomy or prophylactic pancreatic temporary meta-analysis of aggregate subgroup data, including stent placement; and according to differing doses and timing RCTs comparing rectal indomethacin and placebo in prevent- of administration of rectal indomethacin. The analysis was ing more severe PEP and mortality. also planned for the rate of moderate to severe pancreatitis and death. We respected authors’ definition of high-risk and aver - age-risk population as mentioned previously. MATERIAL AND METHODS Trial selection criteria Statistical analysis Only RCTs were included. For inclusion, we required that Summary outcomes are described as proportions and 95% patients undergoing ERCP in the trial have been randomized confidence intervals (CI ).  Pooled proportionate rates of PEP to rectal indomethacin or placebo. No studies were excluded were calculated separately for rectal indomethacin and placebo based on the language of publication, quality of study, duration and were reported as proportions and confidence intervals. of follow-up or country of origin. A  meta-analysis of intention-to-treat study-level or aggregate subgroup data was done using the random effect model Mantel- Search strategy Haenszel method for each risk factor (24). Peto method was Comprehensive computerized medical literature searches used when the rate of events was under 1% (24). The signifi - were conducted using OVID MEDLINE (1946 to May 2016), cance and extent of statistical heterogeneity were calculated Downloaded from https://academic.oup.com/jcag/article-abstract/1/2/67/4955217 by guest on 20 June 2018 Journal of the Canadian Association of Gastroenterology, 2018, Vol. 1, No. 2 69 using the Q test and I index, respectively (23). Odds ratios (OR) were calculated for each analysis with the correspond- ing 95% confidence intervals. Number needed to treat (NNT) was calculated using the reciprocal of absolute risk difference rather than treat-as-one-trial method to avoid Simpson’s para- dox (25, 26). Funnel plots, Begg adjusted rank correlation test and the Egger regression asymmetry test were planned to detect the possibility of publication bias in meta-analyses including more than 10 studies (23, 27, 28). We also planned to perform meta-regression and sensitivity analyses based on the quality and weight of the trials (23). Sensitivity analyses were planned, excluding studies with high risk of bias and by excluding the largest trial. All statistical analyses were done using RevMan (Version 5.3, Copenhagen: The Nordic Cochrane Centre, The Cochrane Collaboration, 2008) and R (version 2.13.0, R Foundation for  Statistical Computing, Vienna, Austria, 2008). The PRISMA statement outline for reporting systematic reviews and meta-analyses was used to report on this work (29). RESULTS Characteristics of included trials A total of eight out of 336 identified studies (N=3324 patients, including 1684 in treatment group and 1640 in placebo group) were included; all were performed between 2007 and 2016. All studies were published in English. There was no missed data, and the authors provided all required raw data not previ- ously presented in published manuscript. Figure  1 depicts the PRISMA flow diagram. Table 1 shows the methodological and clinical details for each trial. Clinical heterogeneity All trials used relatively similar criteria to define PEP as depicted in Table 1. Two studies included only high-risk patients (7, 30) while the rest included unselected patients (19, 20, 31–34). All included studies used 100 mg of rectal indomethacin. Five Figure 1. PRISMA flow diagram of included and excluded trials. studies administered pre-procedure rectal indomethacin (19, 31–34), one intra-procedure (20) and two post-procedure (7, tests is considered too low to distinguish chance from real 30). Three studies allowed prophylactic pancreatic stent (7, 20, asymmetry according to recommendation by the Cochrane 34) but three did not (19,30,31) and two studies were unclear Collaboration (23). in regard to this possible co-intervention (32, 33). Analysis of main outcome Risk of bias All included studies reported the primary outcome. The pooled Figure 2 presents the consensus risk of bias assessments of the proportion estimates of PEP were 5.6 (95% CI: 4.5–11.5) with included studies. Risk of bias was low in all but two studies rectal indomethacin and 8.8 (95% CI: 7.5–14.4) with placebo. (33,34). This rate was significantly lower with rectal indomethacin as compared to placebo (OR=0.56 [0.39–0.82]). Statistical Publication bias heterogeneity was significant (p: 0.07, I : 46%). The number A funnel plot was not provided since the number of included needed to treat was 20. We were unable to perform a separate studies was fewer than 10, and in this case, the power of the meta-regression analysis since the number of included studies Downloaded from https://academic.oup.com/jcag/article-abstract/1/2/67/4955217 by guest on 20 June 2018 70 Journal of the Canadian Association of Gastroenterology, 2018, Vol. 1, No. 2 Table 1. Characteristics of included studies. PEP: Post-ERCP pancreatitis Study Year Country Number of Number of Intervention Definition of PEP patients post-ERCP (Indomethacin pancreatitis 100 mg per rectum) Andrade-Dávila (30) 2015 Mexico 166 21 Ae ft r ERCP Pain, lipase or amylase> x3, positive imaging Dobronte et al (33) 2012 Hungary 228 22 10 Minutes before Clinical/Amylase> x3/ ERCP prolonged hospital admission Dobronte et al (19) 2014 Hungary 686 22 10–15 minutes before Clinical/Amylase 24h ERCP Elmunzer et al (7) 2012 USA 602 79 Immediately ae ft r Pain, Amylase> x3, ERCP admission for at least 2 nights Levenick et al (20) 2016 USA 449 27 during ERCP Pain, lipase> x3, admission >2 nights Montaño Loza et al 2007 Mexico 150 16 2 hours before ERCP Clinical, amylase level (34) Patai et al (32) 2015 Hungary 574 55 Within one hour before Pain, amylase> x3, ERCP admission >2 nights Sotoudehmanesh et al 2007 Iran 490 22 right before ERCP Pain, Amylase> x3, (31) admission>2 days was less than 10 (23). Figure  3 depicts the Forest plots of the regardless of the risk for post-ERCP pancreatitis. There was selected study analyses. no statistically significant heterogeneity in this analysis (I : 0%). Rectal indomethacin was not statistically superior to pla- Subgroup analyses cebo when analyzing three studies (n=1217) using intra- or Meta-analysis of aggregate subgroup data on risk factors post-procedure dosing (OR: 0.56 [0.21–1.49], p=0.25] (7, Table 2 represents the detail of these analyses. In summary, rec- 20, 30). There was statistically significant heterogeneity in this tal indomethacin significantly decreased the rate of moderate to analysis (p: 0.009, I : 79%). severe PEP. Death happened only and more significantly with placebo (five out of 177 events) and not with indomethacin High-risk versus unselected patients (zero out of 107 events). The effect remained statistically signifi - Ae ft r excluding the two studies on high-risk populations (7, 30), cant in sensitivity analysis ae ft r using the total number of patients the PEP rates were no longer statistically different (OR: 0.65 instead of the ones with PEP as denominator. It also significantly [0.42–1.00]). There was statistically significant heterogeneity decreased the rate of PEP amongst subgroup of patients with in this analysis (p: 0.12, I : 43%). The OR for the rate of PEP sphincter of Oddi dysfunction  (SOD). The effect remained was 0.37 (0.16–0.84) and significant for rectal indomethacin robust in sensitivity analysis ae ft r excluding the largest SOD amongst the two studies (n=768) exclusively done in high-risk population from one study (7). Rectal indomethacin was also patients. Number needed to treat was 10. There was no statisti - significantly effective in preventing PEP in those patients under - cally significant heterogeneity in this analysis (p: 0.16, I : 50%). going biliary sphincterotomy. This effect was not significant ae ft r Sensitivity analyses excluding two studies on high-risk population (OR :0.69 [0.42– 1.15]). It did not significantly decrease the rate of PEP amongst The effect remained significant when two studies with high risk subgroup of patients who received a pancreatic sphincterotomy, of bias (33, 34) were excluded (OR : 0.57 [0.37–0.89]) or ae ft r precut sphincterotomy, or prophylactic pancreatic stent. excluding the largest included trial (7) (OR : 0.52 [0.35–0.79]). Timing of dosing Discussion Amongst five studies (n=2107) administering pre-procedure To our knowledge, this is the first meta-analysis of aggregate suppositories (19, 31–34), the difference remained statisti - subgroup data on the role of rectal indomethacin in preventing cally significant (OR: 0.56 [0.40–0.79], p=0.0008), favoring moderate to severe post-ERCP pancreatitis and mortality. We rectal indomethacin. All included patients were randomized Downloaded from https://academic.oup.com/jcag/article-abstract/1/2/67/4955217 by guest on 20 June 2018 Journal of the Canadian Association of Gastroenterology, 2018, Vol. 1, No. 2 71 Figure 2. Consensus risk of bias assessments of the included studies. Green: Low risk, Yellow: Unclear, Red: High risk. used aggregate data from the different trials and performed a that also benefit from this approach, mainly in patients with meta-analysis in each subgroup according to PEP-risk cate- sphincter of Oddi dyskinesia. The intervention effectively gory. Our study tried to answer important questions that have decreases the rate of moderate to severe post-ERCP pancreati- remained unanswered despite multiple clinical and meta-ana- tis and fatality in all patients, regardless of patient risk category. lytical studies on this topic using the additional statistical power Also, pre-procedure dosing appears to be significantly more brought about by summary analyses of clinically pertinent effective than post-procedure administration of rectal indo - patient subgroups. Our study identifies population subgroups methacin in preventing PEP. Downloaded from https://academic.oup.com/jcag/article-abstract/1/2/67/4955217 by guest on 20 June 2018 72 Journal of the Canadian Association of Gastroenterology, 2018, Vol. 1, No. 2 Figure 3. Forest plot of selected Mantel-Haenszel meta-analysis of the post-ERCP pancreatitis with rectal indomethacin versus placebo. CI, confidence interval; M-H , Mantel-Haenszel. Our sensitivity analyses show results that remain unchanged subgroup meta-analyses, there was no more heterogeneity when excluding the study with high risk of bias or with the when we stratified the data based on those factors. largest sample size. All but one of the included studies demon- We showed rectal indomethacin is effective in preventing strated at least an arithmetical trend favoring rectal indometh- PEP in patients at high-risk for it. This is consistent with the acin. Despite the observed statistical heterogeneity in some of results of the two large RCTs performed exclusively on high- the analyses, the designs of the included RCTs were very similar, risk patients. Our meta-analysis of aggregate subgroup data thereby resulting in low clinical heterogeneity, not measurable from five studies showed that SOD patients particularly bene- by statistical means, which might further enhance the validity fited from the intervention. Minimal heterogeneity was found of the findings. Some of the possible reason for heterogeneity in this analysis. A  large US study (7), which mainly included in subgroup analyses might be the timing of administration of SOD patients, concluded that rectal indomethacin significantly rectal indomethacin, difference in patient population regarding decreased the rate of PEP in included patients with a NNT of the risk for PEP and considering cumulative outcome by com- 12, which was close to the NNT achieved for SOD patients bining mild, moderate and severe PEP. Based on our aggregate in our study, as depicted in Table  2. Based on the grade of the Downloaded from https://academic.oup.com/jcag/article-abstract/1/2/67/4955217 by guest on 20 June 2018 Journal of the Canadian Association of Gastroenterology, 2018, Vol. 1, No. 2 73 Table 2. Meta-analysis of aggregate subgroup data in each risk category. OR : Odds Ratio; CI: Confidence Interval; NNT: Number Needed to Treat; NA: Non-applicable Subgroup analyses Number of patients OR CI 95% Heterogeneity NNT (I2) Preventing moderate to severe PEP (7, 19, 20, 3324 0.53 0.31–0.89 0% 100 30–34) Sphincter of Oddi Dyskinesia (7, 19, 20, 694 0.49 0.30–0.78 0% 10 30–34) Death 284 with post-ERCP 0.10 0.02–0.65 0% NA pancreatitis 3324 randomized patients 0.13 0.02–0.77 0% NA Biliary sphincterotomy (7, 19, 20, 31–34) 2062 0.63 0.42–0.95 53% 33 Pancreatic sphincterotomy (7, 19, 20, 30–34) 492 0.81 0.36–1.83 34% NA Precut sphincterotomy (7, 19, 20, 30–34) 436 0.50 0.14–1.82 72% NA Prophylactic pancreatic stent (7, 19, 20, 30–34) 572 0.98 0.26–3.62 72% NA evidence, we strongly recommend administering rectal indo- and mortality due to PEP occurs in patients with moderate to methacin in all patients suspected of SOD undergoing ERCP. severe cases (41). Stent placement in the pancreatic duct has been one of the We have shown that pre-procedural administration of rectal proven effective interventions for post-ERCP pancreatitis pro - indomethacin appears to be superior to intra- or post-procedure phylaxis associated with a protective OR of 0.44 (0.24–0.81) administration, a result no doubt driven statistically by the find - (35–37); however, more than 20% of endoscopists do not ings of a very recent large RCT from China on 2600 unselected perform prophylactic pancreatic stenting (37). The combi - patients undergoing ERCP. In this trial, patients were random- nation of rectal indomethacin and prophylactic pancreatic ized to either pre-procedure rectal indomethacin or risk-strati- stent placement in the current meta-analysis does not signifi - fied post-procedural administration in high-risk patients (21). cantly alter the rate of PEP compared to rectal indomethacin Post-ERCP pancreatitis occurred significantly less in patients alone. This is the first meta-analytic evidence showing lack of who universally received pre-procedural rectal indomethacin synergistic protection of rectal indomethacin and pancreatic (4% versus 8% respectively, p<0.0001). There might exist a stenting. A post-hoc analysis by Elmunzer et al. has previously biologically plausible explanation for this effect. Indeed, peak shown a higher PEP rate following this combination compared plasma concentrations are achieved in 30 minutes following to rectal indomethacin alone (9.7% versus 6.3%, respectively) rectal administration of indomethacin (42). Therefore, post- (38). Moreover, their economic model demonstrated rectal ERCP dosing may theoretically render the NSAID not availa- indomethacin alone is more cost-effective than placebo, pro - ble at the time of the initial injury to the pancreas and thus less phylactic pancreatic duct stent placement, or a combination able to prevent the inflammatory cascade. It may be prudent of rectal indomethacin and stent placement (38). A  network to administer rectal indomethacin, when indicated, before the meta-analysis, based on indirect comparisons, has concluded procedure rather than during or ae ft r ERCP in patients without that rectal NSAIDs are superior to prophylactic pancreatic stent a contraindication. placement (OR: 0.48 [0.26–0.87]), and a combination of rec- Although meta-analyses have been described to provide high tal NSAIDs and prophylactic pancreatic stent placement is not quality evidence for clinical use, they are not free of risk of bias. superior to rectal NSAIDs (OR:1.46 [0.79–2.69]) (39). Only The possibility of missed trials cannot be completely ruled out. the advent of true head-to-head data will provide more defini - We tried to minimize this possibility by including several types tive clarity on this issue, and we await the results from at least of publications, search methods and all languages. However, two ongoing RCTs (40). However, to date, there is insufficient the number of included studies was not sufficient to perform proof to recommend the combination of these two modalities a meta-regression analysis in a search for causes of statistical over performing either. heterogeneity. In our meta-analysis of aggregate subgroup data, rectal indo- In conclusion, this meta-analysis suggests rectal indometha- methacin significantly decreases the rate of moderate to severe cin is effective in preventing post-ERCP pancreatitis and that PEP, as well as the rate of death from ERCP or post-ERCP pan- this protective effect is true for high-risk patients, specifically creatitis in all patients. This alone may be an indication for uni - in those with sphincter of Oddi dyskinesia. It also signifi - versal routine administration since the majority of morbidity cantly decreases the rate of moderate to severe PEP and death Downloaded from https://academic.oup.com/jcag/article-abstract/1/2/67/4955217 by guest on 20 June 2018 74 Journal of the Canadian Association of Gastroenterology, 2018, Vol. 1, No. 2 in unselected patients, and this should be given to all patients retrograde cholangiopancreatography: a network meta-analysis. Clin Gastroenterol Hepatol. 2013;11(7):778–83. without a contraindication prior to the ERCP. 11. Elmunzer BJ, Waljee AK, Elta GH, et  al. A meta-analysis of rec- Registration & Funding tal NSAIDs in the prevention of post-ERCP pancreatitis. Gut. This study was registered (CRD42016038397) in PROSPERO 2008;57(9):1262–7. doi: 10.1136/gut.2007.140756. (International prospective register of systematic reviews). The authors 12. Dai HF, Wang XW, Zhao K. Role of nonsteroidal anti-inflam- received no funding to support this study. matory drugs in the prevention of post-ERCP pancreatitis: a meta-analysis. Hepatobiliary Pancreat Dis Int. 2009;8(1):11–6. ACKNOWLEDGEMENTS 13. Ding X, Chen M, Huang S, et al. Nonsteroidal anti-inflammatory drugs for prevention of post-ERCP pancreatitis: a meta-analysis. The authors would like to thank the authors of the included trials Gastrointest Endosc. 2012;76(6):1152–9. including Dr. Zoltán Döbrönte, Dr Alejandro Gonzalez Ojeda, Dr 14. Sethi S, Sethi N, Wadhwa V, Garud S, Brown A . A meta-analysis on Rasoul Sotoudehmanesh, and Dr Arpad Patai for providing additional the role of rectal diclofenac and indomethacin in the prevention of subgroup data and Dr Frances Tse for intellectual contribution. post-endoscopic retrograde cholangiopancreatography pancreati- Conflicts of Interest tis. Pancreas. 2014;43(2):190–7. Dr Yaghoobi is supported by an Internal Medicine Career Award by 15. 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