MISS CHONGRONG SHEN (Orcid ID : 0000-0001-7164-3888)

Accepted Article
Received Date : 04-Oct-2016

Revised Date : 11-Jan-2017

Accepted Date : 18-Jan-2017

Article type : Review

Rectal NSAIDs in the prevention of post-ERCP pancreatitis in

unselected patients: A systematic review and meta-analysis

Chongrong Shen a , 1; Yanqiang Shi a , 1; Tianyu Liang a; Peizhu Su b,*

a
The Second Clinical Medical School, Southern Medical University, 510282, Guangzhou

City, Guangdong Province, People's Republic of China.

b
Department of Gastroenterology, First People's Hospital of Foshan Affiliated to Sun Yat-sen

University, 528000, Foshan City, Guangdong Province, People's Republic of China.

1
These authors (Chongrong Shen and Yanqiang Shi) contributed equally to this study and

should be considered as co-first authors.

This article has been accepted for publication and undergone full peer review but has not been
through the copyediting, typesetting, pagination and proofreading process, which may lead to
differences between this version and the Version of Record. Please cite this article as doi:
10.1111/den.12816

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 * Correspondence:
Accepted Article
Peizhu Su

Department of Gastroenterology, First People's Hospital of Foshan Affiliated to Sun Yat-sen

University, 81 Lingnan Street North, Foshan, 528000, Guangdong, People's Republic of China

E-mail: supeizhu1986@163.com.

Telephone number: +86 15521287895

Abstract

Background

The efficacy of rectal nonsteroidal anti-inflammatory drugs (NSAIDs) for post-endoscopic retrograde

cholangiopancreatography (ERCP) pancreatitis (PEP) prophylaxis in unselected patients is

controversial.

Aim

To evaluate the efficacy of rectal NSAIDs in the prevention of PEP in unselected patients.

Methods

An electronic literature search in the Cochrane library, Embase, and PubMed was performed for

randomized controlled trials comparing rectal indomethacin or diclofenac with placebo in the

prevention of PEP in unselected patients. Cochrane risk of bias tool was used to evaluate

methodological quality. The data were performed in a forest plot using fixed-effect methods, and

random-effect methods were used when heterogeneity was significant.

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 Results
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A total of 9 trials were included in our final analysis. Rectal NSAIDs were effective to reduce the

incidence of PEP in unselected patients (RR, 0.61; 95% CI, 0.460.79), especially for

moderate-to-severe PEP (RR, 0.40; 95% CI, 0.190.84). Both indomethacin (RR, 0.67; 95% CI,

0.500.88) and diclofenac (RR, 0.29; 95% CI, 0.120.69) were significantly efficacious. Rectal

NSAIDs administrated pre-ERCP showed significant efficacy (RR, 0.53; 95% CI, 0.390.71),

whether when administrated within 30 minutes pre-ERCP (RR, 0.58; 95% CI, 0.400.83) or not (RR,

0.46; 95% CI, 0.280.74).

Conclusions

Rectal NSAIDs are effective in the prevention of PEP in unselected patients.

Key Words: ERCP, pancreatitis, indomethacin, diclofenac, meta-analysis.

Introduction

The most common complication of endoscopic retrograde cholangiopancreatography (ERCP) is

pancreatitis, with an incidence of 7.5%1, 3.8%2, 4.3%3, and 13.3%4 in unselected prospective series, as

reported by four randomized controlled trials (RCT), respectively. The outcome of post-ERCP

pancreatitis (PEP) can be devastating, leading to considerable morbidity5, long hospitalization and

rare mortality6. Consequently, masses of pharmacological and mechanical interventions have been

assessed for PEP prophylaxis. As for mechanical interventions, pancreatic stent placement now

remains to be the standard alternative in the prevention of PEP in high-risk patients.7, 8 When it comes

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 to pharmacological interventions, a few recent studies have showed that nonsteroidal

anti-inflammatory drugs (NSAIDs) were effective in the prevention of PEP, especially in high-risk
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patients.9

Recently, European Society for Gastrointestinal Endoscopy (ESGE) guidelines recommended rectal

diclofenac or indomethacin of 100mg immediately after or before ERCP in all patients without

contraindication.10 However, a very recent RCT by Levenick et al11 countered the guidelines that

rectal indomethacin of 100 mg was not effective in the prevention of PEP in unselected patients. In

addition, the recent meta-analysis by Inamdar et al12 concluded that rectal indomethacin was not

effective in the prevention of PEP in average-risk patients. At the same time, although multiple

previous meta-analyses have confirmed the efficacy of NSAIDs in the prevention of PEP, most of

them included both RCTs involving unselected patients and RCTs involving only high risk patients,

such as the meta-analyses by Puig et al13, by Sethi et al14, and by Ding et al15. All of these reflect the

controversy of the efficacy of rectal NSAIDs for PEP prophylaxis in unselected patients. In addition,

although strong evidence has been given to support prophylactic rectal NSAIDs among high-risk

patients for PEP9, studies involving only low-risk patients were rare. The only existing large study to

evaluate the efficacy of rectal indomethacin in the primarily low-risk patient population was reported

by Thiruvengadam et al16. This large retrospective cohort study of 4017 individuals concluded that

prophylactic rectal indomethacin was effective among both low-risk and high-risk patients for PEP

prophylaxis.16 However, more studies are required to investigate the efficacy of rectal NSAIDs among

low-risk patients, and a meta-analysis investigating the efficacy of the agents in unselected patients

may give an indirect evidence to support the use of the agents in low-risk patients. Therefore, we

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 perform a meta-analysis evaluating the existing evidence of PEP prophylaxis of rectal diclofenac or

indomethacin in unselected patients.

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Methods

Search Strategy

Comprehensive searches were performed in the Cochrane library, Embase and PubMed. Abstracts

from the conference abstracts of Embase were searched. Key terms with free terms included

indomethacin, diclofenac, nonsteroidal anti-inflammatory drugs, pancreatitis and ERCP. The manual

searching of included studies and relevant reviews was also conducted. Any restriction including

study design, publication date, publication status, and language was not allowed. The latest search

was performed in Sept, 2016, and there was no limit to the publish time of studies included in the

meta-analysis.

Inclusion and Exclusion Criteria

Two investigators independently screened the studies and discussed to reach a consensus in the

process. The inclusion criteria were as follows: ( ) RCTs examining the effect of rectal

administration of indomethacin or diclofenac on the incidence of PEP; ( ) Studies aiming at

unselected patients. The exclusion criteria were: () nonhuman studies; () studies including only

high-risk patients; () insufficient or unspecific data of PEP; () other study types like letters,

editorials, reviews, case series and case reports.

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 Data extraction
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Two authors extracted the data independently from a total of 551 identified studies by searching of

Cochrane library (n = 63), Embase (n = 328), PubMed (n = 160), and manual searching (n = 0). The

variables included: authors, publication year, country of the population studied, total size of patients,

inclusion criteria, type of medication, dose and administration time, definition of PEP and primary

outcome reported.

Risk of Bias Assessment

The quality of the studies was assessed independently by two authors through the Cochrane

Collaboration tool.17 The assessing items included: selection bias, performance bias, detection bias,

attrition bias, reporting bias, and other bias.

Statistical Analysis

The statistical analysis was performed by Review Manager Version 5.5 software. The binary

outcomes were reported as relative risk (RR) with 95% confidence intervals (CIs). The data were

performed in a forest plot using fixed-effect methods, and random-effect methods were used when

heterogeneity was significant. The difference in the risk reduction between indomethacin and

diclofenac compared with placebo was calculated by z score. P-values <0.05 were considered

significant. Heterogeneity was assessed by Cochran Q test and I2 test. P < 0.1 or I2 >50% indicates the

presence of heterogeneity.18, 19

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 The Begg adjusted rank correlation test20 and the Egger regression asymmetry test21 were used to

evaluate the possibility of publication bias (P-values <0.05 indicated a significant publication bias). In
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addition, we conduct a sensitivity analysis for every study. One set of study data was moved

systematically and the results for the remaining studies were checked to see the change in test

performance. The calculations of the Beggs test and Eggers test were performed using Stata/SE 12.0

software.

Results

Characteristics of Included Studies

As was shown in Figure 1, 9 of 551 identified studies were involved, including 8 full text11, 22-28 and 1

abstract29. Table 1 showed the characteristics of each study. All the trials were published between

2007 and 2016, and most of them were published after 2012. A total of 2791 individuals were

included in the nine RCTs , including 15022, 44223, 22824, 66525, 52926, 44911, 10427, 10028 and 4229

patients, respectively. Of these trials, 6 evaluated rectal indomethacin (a total number of 2473

patients)11, 22-26 and 3 evaluated rectal diclofenac (a total number of 246 patients) for the prophylaxis of

PEP27-29. Five studies investigated the efficacy of indomethacin administrated before ERCP22-26 and one

in the procedure of ERCP11. Pre-ERCP use of diclofenac was in the three studies27-29. Assessments of

risk of bias of the included studies were presented in Figure 2.

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 Analysis of Outcomes
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Analysis of main outcome

The incidence of PEP was reported in nine studies.11, 22-29 Heterogeneity between these studies was not

significant (I2 = 39%, P = 0.11). The incidence of PEP was significantly lower in the experimental

group (82/1388, 5.9%) than that in the placebo group (129/1331, 9.7%) (RR, 0.61; 95% CI,

0.460.79; p = 0.0003) (Figure 3 A).

Seven studies measured moderate to severe PEP incidence.11, 22, 23, 25-28 Among these trials, five

evaluated rectal indomethacin11, 22, 23, 25, 26 and two evaluated rectal diclofenac27, 28. No statistically

significant heterogeneity was found (I2 = 0%, P = 0.56). The incidence of PEP was significantly lower

in the experimental group (8/1237, 0.6%) than that in the placebo group (22/1212, 1.8%) (RR, 0.40;

95% CI, 0.190.84; p = 0.02) (Figure 3 B).

Subgroup analyses

Indomethacin vs. diclofenac

Six studies compared PEP incidence between indomethacin and placebo groups.11, 22-26 Heterogeneity

between these studies was not significant (I2 = 42%, P = 0.13). The incidence of PEP was significantly

lower in the experimental group (76/1266, 6.0%) than that in the placebo group (108/1207, 8.9%)

(RR, 0.67; 95% CI, 0.500.88; p = 0.005) (Figure 4 A).

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 Three studies compared PEP incidence between diclofenac and placebo groups.27-29 Heterogeneity

between these trials was low (I2 = 20%, P = 0.29). The incidence of PEP was significantly lower in the
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experimental group (6/122, 4.9%) than that in the placebo group (21/124, 16.9%) (RR, 0.29; 95% CI,

0.120.69; p = 0.005) (Figure 4 A).

Administration time of rectal NSAIDs

There were eight studies investigating rectal NSAIDs administrated before ERCP22-29 and one in the

procedure of ERCP11. Heterogeneity between the studies investigating rectal NSAIDs administrated

before ERCP was low (I2 = 4%, P = 0.40). The incidence of PEP was significantly lower in the

experimental group (66/1165, 5.7%) than that in the placebo group (118/1105, 10.7%) (RR, 0.53;

95% CI, 0.390.71; p < 0.0001) (Figure 4 B).

Five studies compared PEP incidence between rectal NSAIDs administrated within 30 minutes

pre-ERCP and placebo groups.22-25, 27 Heterogeneity between these studies was not significant (I2 =

20%, P = 0.29). The incidence of PEP was significantly lower in the experimental group (44/824,

5.3%) than that in the placebo group (70/765, 9.1%) (RR, 0.58; 95% CI, 0.400.83; p = 0.003) (Figure

4 B).

Three studies compared PEP incidence between NSAIDs administrated more than 30 minutes

pre-ERCP and placebo groups.26, 28, 29 Heterogeneity between these trials was low (I2 = 0%, P = 0.41).

The incidence of PEP was significantly lower in the experimental group (22/341, 6.5%) than that in

the placebo group (48/340, 14.1%) (RR, 0.46; 95% CI, 0.280.74; p = 0.001) (Figure 4 B).

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 Procedure-related and patient-related factors affecting the efficacy of rectal NSAIDs in the

prevention of PEP
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Few of the included studies showed PEP incidence according to each procedure-related or

patient-related factor. The analysis of procedure-related and patient-related factors affecting the

efficacy of rectal indomethacin or diclofenac in the prevention of PEP was presented in Table 2. None

of the results showed significant efficacy of rectal NSAIDs in the subgroups. Data on other factors

affecting the efficacy of rectal NSAIDs in the prevention of PEP were inadequate to perform a

meta-analysis.

Publication Bias

Both Beggs tests (P =0.076) and Eggers tests (P =0.207) indicated no significant publication bias.

Sensitivity Analysis

It was found in the sensitivity analysis that the trial by Levenick et al11 was the source of

heterogeneity through excluding each trial in turn. Be that as it may, the prophylactic efficacy of

rectal indomethacin or diclofenac in unselected patients was not affected significantly when excluding

the trial (RR, 0.53; 95% CI, 0.390.71; p<0.0001). Similar outcomes were found in other analyses

that involved this trial.

Discussion

It was shown in our meta-analysis that rectal NSAIDs were effective in reducing the incidence of PEP

in unselected patients. The drugs showed a significant benefit in the prevention of moderate-to-severe

PEP. Both indomethacin and diclofenac were significantly efficacious. The analyses in the

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 administration time showed that rectal indomethacin or diclofenac in unselected patients were

beneficial when adminitrated before ERCP, whether when administrated within 30 minutes before
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ERCP or not.

Our findings resemble several previous meta-analyses on this topic. Among the previous

meta-analysis, the analyses by Rustagi et al30, by Puig et al13, by Muhammad et al31, and by Ding et

al15, all reported that NSAIDs seemed to have advantage of reducing the incidence of PEP. However,

all of the analyses13, 15, 30, 31 involved the studies which were heterogeneous concerning the route of

administration32-35. The trials assessing orally32, intraduodenally33, intravenously34, and

intramuscularly35 administered NSAIDs were not significantly associated with the decreased risk of

PEP. In addition, the analyses by Rustagi et al30 and by Ding et al15 involved the study34 evaluating

the efficacy of valdecoxib, which was reported not to be effective in the prevention of PEP. The

recent analysis by Sethi et al14, including seven trials9, 22, 23, 27, 36-38, involved studies assessing rectal

indomethacin and diclofenac. Compared with other analyses, which concluded the efficacy of

NSAIDs in general13, 15, 30, 31, the analysis by Sethi et al14 concluded that rectal NSAIDs were effective.

However, the analysis included the studies only involving high-risk patients9, 36, 37. Actually, most of

the previous meta-analyses tended to include both RCTs involving unselected patients and RCTs

involving only high-risk patients when making analysis.13-15, 30, 31 The most recent meta-analysis by

Inamdar et al12 concluded that rectal indomethacin was effective in the prevention of PEP in high-risk

patients but not in average-risk patients. However, the result must be interpreted with great caution

because of the conflicts between the definition of average-risk patients and the data extraction.

Inamdar et al12 defined average-risk patients as patients not meeting the criteria for high-risk

patients for PEP. However, five of the RCTs11, 22-25 in the analysis of average-risk patients included a

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 proportion of high-risk patients. In another RCT involved in the analysis of average-risk patients26,

the authors extracted the patients undergoing successful ERCP within five attempts of cannulation12.
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However, the patients with some of patient-related risk factors for PEP such as suspected sphincter of

Oddi dysfunction could not be separated totally. Therefore, the objection to the ESGE guidelines10 by

the meta-analysis12 was not convincing. Actually, the RCTs involving only low-risk patients or

average-risk patients were relatively rare, which may be caused by the difficulty to accurately

definite low-risk patients or average-risk patients for PEP. More studies are required on the risk

factors for PEP to give a more accurate definition of patients at different risks for PEP. In our

meta-analysis, a very strict selection in the trials involving unselected patients was made and the two

most recent RCTs11, 28 were included. We investigated the role of rectal indomethacin or diclofenac in

the prevention of PEP in unselected patients. In this way, our meta-analysis may give more conclusive

supporting evidence to recommendations by ESGE10 that rectal diclofenac or indomethacin of 100mg

immediately after or before ERCP in all patients without contraindication, thus countering the

objection to the ESGE guidelines10 from the meta-analysis by Inamdar et al12 and the RCT by

Levenick et al11 and further expanding the indication of rectal NSAIDs for PEP prophylaxis.

Two agents, diclofenac and indomethacin, were included in our meta-analysis. The efficacy of

rectal diclofenac of 100 mg administrated immediately post-ERCP among high-risk patients was

reported successively by the RCTs by Murray et al36 and by Khoshbaten et al37. Then low-dose rectal

diclofenac of either 25mg or 50mg among patients weighing <50kg or 50kg was compared with

placebo in a RCT from Japan.27 In the same year, Katsinelos et al38 confirmed the efficacy of

diclofenac plus somatostatin for PEP prophylaxis. Through analyzing the four RCTs above27, 36-38,

meta-analysis by Sethi et al14 revealed benefits of rectal diclofenac for PEP prophylaxis. In our

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 subgroup analysis of diclofenac, RCTs for only high-risk patients36, 37 and the RCT evaluating

diclofenac plus somatostatin38 were excluded, and we added the recent RCTs by Arain29 and by
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UAR et al28. Similar to the results of meta-analysis by Sethi et al14, our result revealed the beneficial

effects of rectal diclofenac among unselected patients for PEP prophylaxis.

The beneficial effects of 100 mg rectal indomethacin given immediately pre-ERCP among

unselected patients were reported by the RCTs by Sotoudehmanesh et al23 and Montano et al22 in the

same year. Then a multicenter RCT by Elmunzer et al9, including 602 individuals, compared 100 mg

indomethacin administrated immediately post-ERCP with placebo, strongly supporting the

effectiveness of rectal indomethacin among high-risk patients. Recently, the RCT by Levenick et al11

questioned the efficacy of rectal indomethacin in unselected patients. In our subgroup analysis of

indomethacin, all of the existing RCTs administrating rectal indomethacin for unselected patients

were involved11, 22-26. In contrast to the result of the RCT by Levenick et al11, our result confirmed the

efficacy of rectal indomethacin among unselected patients.

Interestingly, the RCT by Levenick et al11 was virtually the main source of heterogeneity of our

overall analysis, which was found in the sensitivity analysis. The study concluded that rectal

indomethacin administrated during ERCP was not effective in the prevention of PEP in unselected

patients.11 Through comparing, it was found that the main characteristic of the study different from

other included studies22-29 was administration time, which was also a departure from the

recommendations by ESGE10. In our analysis, the included trials other than the study by Levenick et

al11 chose the administration before ERCP22-29, while the study by Levenick et al11 chose

administration during the procedure of ERCP. Another departure of the study by Levenick et al11 from

other included studies22-29 was that approximately 18% of the patients underwent fine needle

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 aspiration/concomitant endoscopic ultrasound. In addition, the early termination of the trial might

have prevented the findings from becoming significant. Although the RCT by Levenick et al11
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reported that NSAIDs did not have advantage of reducing the incidence of PEP, the result of our

meta-analysis suggested no significant heterogeneity, confirming the conclusion of our analysis.

As we can see in the ESGE guideline10, only administration immediately after or before ERCP was

recommended. However, the optimal timing for administration stayed controversial. The time for

administration of the dugs varied among different trials, from pre-procedure or during the ERCP to

post-procedure. A very recent RCT by Hui Luo et al39, comparing the efficacy for PEP prophylaxis of

rectal indometacin administrated within 30 mins before ERCP in unselected patients with rectal

indometacin administrated immediately after ERCP in high risk patients, recommended rectal

indometacin in unselected patients without contraindications before ERCP. The recent meta-analysis

by Rustagi et al13 also gave the similar recommendation. In our findings, when we analyzed the 8

RCTs22-29 assessing rectal NSAIDs administrated before ERCP, we found a significant benefit shown

whether when the drugs were administrated within 30 minutes pre-ERCP or not. A possible

explanation for the advantage of administration before ERCP might be the more suitable peak serum

concentration attained in prevention of the inflammation cascade of pancreatitis. Consequently, the

efficacy of NSAIDs administrated before ERCP can be approved but the optimal administration time

before ERCP required more studies. As for administration during ERCP, we only found one RCT,

exactly the study we mentioned above by Levenick et al11, administrated rectal indometacin during

ERCP in unselected patients and showed no significant benefit of the drug. However, the data were

inadequate to perform a meta-analysis and we also failed to find a similar meta-analysis investigating

the efficacy in the prevention of PEP of rectal NSAIDs administrated during ERCP. Therefore, the

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 efficacy of rectal NSAIDs administrated during ERCP in unselected patitents required more studies.

When it comes to the administration after ERCP, the meta-analyses by Puig et al13 and by Sethi et al14
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reported that both rectal indometacin and diclofenac post-ERCP were significantly beneficial in the

prevention of PEP. Furthermore, the meta-analysis by Sethi et al14 recommended rectal NSAIDs

administrated post-ERCP because in this way, the patients failing to undergo ERCP due to any

unforeseen circumstances such as endoscope insertion (perforation, bleeding) or complications from

anesthesia (cardiopulmonary distress) would not receive NSAIDs unnecessarily, thus preventing the

unnecessary health care costs. However, no RCT assessing rectal NSAIDs administrated post-ERCP

in unselected patients were found and the efficacy of post-procedure rectal NSAIDs in unselected

patitents required more studies.

Although we have concluded the efficacy of rectal indomethacin or diclofenac for PEP prophylaxis

in unselected patients, some limitations have to be acknowledged. Firstly, some characteristics such as

countries, doses and administration time varied in the included studies, which may lead to some

heterogeneity. However, the variation increased the external validity of our results at the same time.

Secondly, some of our subgroup analyses, such as the analysis on the factors affecting the efficacy of

the drugs in the prevention of PEP, have to be interpreted with great caution due to the low number of

patients and included studies. Thirdly, only aggregate data were included in our meta-analysis and

individual data, which can improve the quality and produce more reliable results, were unavailable for

analysis.

In conclusion, our meta-analysis suggests that rectal indomethacin and diclofenac are efficacious

for PEP prophylaxis in unselected patients. The results are significant with low heterogeneity and

should be regarded as part of the current proof in preparing clinical practice guidelines. There are

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 three suggestions for the future researches: more studies are required on the risk factors for PEP to

give a more accurate definition of patients at different risks for PEP; more trials comparing the
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efficacy of the drugs administrated in different times are required; more studies are needed on the

factors affecting the efficacy of the drugs in the prevention of PEP.

Acknowledgments

None.

Conflict of interests

Authors declare no Conflict of Interests for this article.

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Supporting Information

None.

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 Figure legends
Accepted Article
Figure 1. Flow diagram.

Figure 2. A: Risk of bias graph. B: Risk of bias summary.

Figure 3. A: Meta-analysis comparing rectal NSAIDs vs. placebo in post-ERCP pancreatitis

incidence. B: Meta-analysis comparing rectal NSAIDs vs. placebo in moderate-to-severe post-ERCP

pancreatitis incidence. NSAIDs: nonsteroidal anti-inflammatory drugs; ERCP: endoscopic retrograde

cholangiopancreatography.

Figure 4. A: Meta-analysis showing the difference in post-ERCP pancreatitis prophylaxis between

indomethacin and diclofenac. B: Meta-analysis showing the difference in post-ERCP pancreatitis

prophylaxis between NSAIDs administrated within 30 minutes before ERCP and NSAIDs

administrated more than 30 minutes before ERCP. ERCP: endoscopic retrograde

cholangiopancreatography; NSAIDs: nonsteroidal anti-inflammatory drugs.

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 Table 1 Characteristics of Included Studies
Accepted Article
Authors, year, Total Inclusion criteria Intervention Definition of PEP

country size

Montao Loza et al.22, 150 Unselected patients with 100 mg indomethacin given Amylase >x3 ULN and sharp

2007, Mexico suspected bile duct rectally immediately before pain radiating to back and
obstruction ERCP nausea or vomiting

Sotoudehmanesh et al.23, 442 Unselected patients 100 mg indomethacin given Amylase >x3 ULN and

2007, Iran rectally immediately before epigastric or back pain

ERCP
and epigastric tenderness

Dbrnte et al.24, 2012, 228 Unselected patients 100 mg indomethacin given Amylase >x3 ULN, new

rectally10 mins before abdominal pancreatic pain

Hungary
within 24h post-ERCP and
ERCP
prolongation of admission

Dbrnte et al.25, 2014, 665 Unselected patients 100 mg indomethacin given Amylase and/or lipase level >x3
rectally10-15 mins before ULN, new abdominal pancreatic
Hungary
ERCP pain within 24h post-ERCP and
prolongation of admission

and/or CT/MRI findings

consistent with the diagnosis

Patai et al.26, 2015, 529 Unselected patients 100 mg indomethacin given Amylase >x3 ULN, new
Hungary with intact papilla rectally 1 h before ERCP abdominal pancreatic pain and

prolongation of admission

Levenick et al.11, 2016, 449 Unselected patients with 100 mg indomethacin given Amylase >x3 ULN, new
United States or without endoscopic rectally during the ERCP abdominal pancreatic pain and

ultrasound hospitalization following ERCP

for at least two consecutive

nights

Otsuka et al.27, 2012, 104 Unselected patients 50 mg diclofenac given Amylase>x3 ULN and new
rectally 30 mins before abdominal pain within 24 h
Japan
ERCP post-ERCP

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 UAR et al.28, 2016, 100 Unselected patients 100 mg diclofenac given Amylase>x3 ULN within 24 h
Turkey rectally 30-90 mins before
after ERCP
ERCP
Accepted Article
Arain29, 2013, India 42 Unselected patients 100 mg diclofenac given Amylase >x3 ULN, new
abdominal pancreatic pain
rectally 60 mins before
within 24h after ERCP and
ERCP
hospitalization for at least two

nights

ERCP: endoscopic retrograde cholangiopancreatography; PEP: post-ERCP pancreatitis; ULN: upper limit of normal.

Subgroup Studies Patients RR (95% CI) I2, P

Age

Older Patients 3 937 0.73 (0.421.26) 0%, 0.68

Young Patients 3 398 0.67 (0.351.25) 0%, 0.61

Gender

Males 3 517 0.64 (0.251.64) 0%, 0.44

Females 3 818 0.75 (0.471.18) 0%, 0.82

Pancreatic Sphincterotomy

Yes 3 94 1.25 (0.582.71) 68%, 0.04

No 3 1248 0.89 (0.571.39) 64%, 0.06

ERCP: endoscopic retrograde cholangiopancreatography; RR: relative risk; 95% IC: 95% confidence interval.

Older and young patients were separated by two different cutoff values (2 studies used 60 years and 2 studies used
50 years).

Table 2 Analyses in Procedure-related and Patient-related Factors: indomethacin or diclofenac

Versus Placebo in Reducing the Incidence of Post-ERCP Pancreatitis

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Accepted Article

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Accepted Article

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Accepted Article

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Accepted Article

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