Rectal Nonsteroidal Anti-inflammatory Drugs Are Superior to Pancreatic Duct Stents in Preventing Pancreatitis After Endoscopic Retrograde Cholangiopancreatography: A Network Meta-analysis

doi:10.1016/j.cgh.2012.12.043

Clinical Gastroenterology and Hepatology

Volume 11, Issue 7, July 2013, Pages 778-783

https://doi.org/10.1016/j.cgh.2012.12.043 Get rights and content

Background & Aims

Placement of pancreatic duct (PD) stents prevents pancreatitis after endoscopic retrograde cholangiopancreatography (ERCP). There is evidence that rectal administration of nonsteroidal anti-inflammatory drugs (NSAIDs) also prevents post-ERCP pancreatitis, but the 2 approaches alone have not been compared directly. We conducted a network meta-analysis to indirectly compare the efficacies of these procedures.

Methods

PubMed and Embase were searched by 2 independent reviewers to identify full-length clinical studies, published in English, investigating use of PD stent placement and rectal NSAIDs to prevent post-ERCP pancreatitis. We identified 29 studies (22 of PD stents and 7 of NSAIDs). We used network meta-analysis to compare rates of post-ERCP pancreatitis among patients who received only rectal NSAIDs, only PD stents, or both.

Results

Placement of PD stents and rectal administration of NSAIDs were each superior to placebo in preventing post-ERCP pancreatitis. The combination of rectal NSAIDs and stents was not superior to either approach alone. Pooled results showed that rectal NSAIDs alone were superior to PD stents alone in preventing post-ERCP pancreatitis (odds ratio, 0.48; 95% confidence interval, 0.26–0.87).

Conclusions

Based on a network meta-analysis, rectal NSAIDs alone are superior to PD stents alone in preventing post-ERCP pancreatitis, and should be considered first-line therapy for selected patients. However, these findings were limited by the small number of studies assessed (only 29 studies), potential publication bias, and the indirect nature of the comparison. High-quality, randomized, controlled trials are needed to compare these 2 interventions and confirm these findings.

Section snippets

Methods

This was a protocol-driven, systematic review of the literature. The methodology and reporting of this systematic review complies with the Preferred Reporting Items for Systematic reviews and Meta-Analyses statement.¹⁰

We performed a computer-assisted literature search of PubMed and Embase to identify studies published up until July 2012 that addressed interventions to reduce the risk of PEP. We used the following search terms, stent and pancreatitis, diclofenac and pancreatitis, indomethacin

Studies and Quality

A total of 6371 articles were identified; 6289 were excluded based on title review and 53 were excluded based on abstract review (Figure 1). Twenty-nine studies comparing the risk of PEP after PD stent placement or rectally administered NSAIDs to a control group were included (Table 1, Table 2). Previous meta-analyses were reviewed and a manual search of the reference section of identified articles was performed and no additional relevant studies were identified. Of the 29 included studies, 22

Discussion

PEP is the most common adverse event after ERCP and is associated with significant morbidity and health care costs.¹⁸ The mechanism of pancreatic injury that leads to PEP has not been well delineated and is an evolving area of research; however, similar to other causes of acute pancreatitis, the common pathway seems to involve a localized or systemic inflammatory reaction resulting in a common spectrum of clinical manifestations.¹⁹

Over the past decade, placement of a main PD stent has evolved

Acknowledgment

A.A. and B.K.A.D. contributed equally to this study.

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Cited by (95)

Indomethacin with or without prophylactic pancreatic stent placement to prevent pancreatitis after ERCP: a randomised non-inferiority trial
2024, The Lancet
The combination of rectally administered indomethacin and placement of a prophylactic pancreatic stent is recommended to prevent pancreatitis after endoscopic retrograde cholangiopancreatography (ERCP) in high-risk patients. Preliminary evidence suggests that the use of indomethacin might eliminate or substantially reduce the need for stent placement, a technically complex, costly, and potentially harmful intervention.
In this randomised, non-inferiority trial conducted at 20 referral centres in the USA and Canada, patients (aged ≥18 years) at high risk for post-ERCP pancreatitis were randomly assigned (1:1) to receive rectal indomethacin alone or the combination of indomethacin plus a prophylactic pancreatic stent. Patients, treating clinicians, and outcomes assessors were masked to study group assignment. The primary outcome was post-ERCP pancreatitis. To declare non-inferiority, the upper bound of the two-sided 95% CI for the difference in post-ERCP pancreatitis (indomethacin alone minus indomethacin plus stent) would have to be less than 5% (non-inferiority margin) in both the intention-to-treat and per-protocol populations. This trial is registered with ClinicalTrials.gov (NCT02476279), and is complete.
Between Sept 17, 2015, and Jan 25, 2023, a total of 1950 patients were randomly assigned. Post-ERCP pancreatitis occurred in 145 (14·9%) of 975 patients in the indomethacin alone group and in 110 (11·3%) of 975 in the indomethacin plus stent group (risk difference 3·6%; 95% CI 0·6–6·6; p=0·18 for non-inferiority). A post-hoc intention-to-treat analysis of the risk difference between groups showed that indomethacin alone was inferior to the combination of indomethacin plus prophylactic stent (p=0·011). The relative benefit of stent placement was generally consistent across study subgroups but appeared more prominent among patients at highest risk for pancreatitis. Safety outcomes (serious adverse events, intensive care unit admission, and hospital length of stay) did not differ between groups.
For preventing post-ERCP pancreatitis in high-risk patients, a strategy of indomethacin alone was not as effective as a strategy of indomethacin plus prophylactic pancreatic stent placement. These results support prophylactic pancreatic stent placement in addition to rectal indomethacin administration in high-risk patients, in accordance with clinical practice guidelines.
US National Institutes of Health.
Interventions to improve the performance of ERCP and EUS quality indicators
2023, Gastrointestinal Endoscopy
A Cost-Effectiveness Analysis for Post-Endoscopic Retrograde Cholangiopancreatography Pancreatitis Prophylaxis in the United States
2022, Clinical Gastroenterology and Hepatology
Post–endoscopic retrograde cholangiopancreatography pancreatitis (PEP) is the most common adverse event after endoscopic retrograde cholangiopancreatography, and is responsible for substantial morbidity and health care expenditures of at least $200 million. Therapies for PEP prevention include pancreatic stent placement (PSP), rectal indomethacin, sublingual nitrates, and aggressive lactated Ringer’s hydration. Our objective was to determine which PEP prophylactic strategies are cost effective.
We developed 2 separate decision trees to evaluate PEP prophylactic strategies. The first, in high-risk patients, compared rectal indomethacin, PSP, PSP with indomethacin, sublingual nitrates, aggressive hydration with lactated Ringer’s, and no prophylaxis. The second, in average-risk patients, compared rectal indomethacin, sublingual nitrates, aggressive hydration, and no prophylaxis. We used incidence rates, transition probabilities, and costs from publications and public data sources. Outcome measures were reported as incremental cost-effectiveness ratios, with a willingness-to-pay (WTP) threshold of $100,000/quality-adjusted life years (QALYs).
Compared with no prophylaxis, all strategies were cost effective at a WTP of $100,000 in preventing PEP in high-risk patients. When directly compared with each other, rectal indomethacin was the cost-effective strategy in high-risk patients ($31,589/QALYs). In average-risk patients, indomethacin and sublingual nitrates were cost effective at a WTP of $100,000/QALYs compared with no prophylaxis. When directly compared with each other, rectal indomethacin was the cost-effective strategy ($53,016/QALYs).
Rectal indomethacin was the cost-effective strategy for preventing PEP in both average-risk and high-risk patients undergoing endoscopic retrograde cholangiopancreatography. All strategies were cost effective when compared with no prophylaxis in high-risk patients, whereas all strategies except for aggressive hydration with lactated Ringer’s were cost effective in average-risk patients. Further studies are needed to improve the utilization of PEP prevention strategies.
Non-steroidal anti-inflammatory drugs, intravenous fluids, pancreatic stents, or their combinations for the prevention of post-endoscopic retrograde cholangiopancreatography pancreatitis: a systematic review and network meta-analysis
2021, The Lancet Gastroenterology and Hepatology
Non-steroidal anti-inflammatory drugs (NSAIDs), intravenous fluid, pancreatic stents, or combinations of these have been evaluated in randomised controlled trials (RCTs) for the prevention of post-endoscopic retrograde cholangiopancreatography (ERCP) pancreatitis, but the comparative efficacy of these treatments remains unclear. Our aim was to do an exploratory network meta-analysis of previous RCTs to systematically compare the direct and indirect evidence and rank NSAIDs, intravenous fluids, pancreatic stents, or combinations of these to determine the most efficacious method of prophylaxis for post-ERCP pancreatitis.
We searched PubMed, Embase, and the Cochrane Central Register from inception to Nov 15, 2020, for full-text RCTs that evaluated the efficacy of NSAIDs, pancreatic stents, intravenous fluids, or combinations of these for post-ERCP pancreatitis prevention in adult (aged ≥18 years) patients undergoing ERCP. Summary data from intention-to-treat analyses were extracted from published reports. We analysed incidence of post-ERCP pancreatitis across studies using network meta-analysis under the frequentist framework, obtaining pairwise odds ratios (ORs) and 95% CIs. We used the Grading of Recommendations Assessment, Development, and Evaluation (GRADE) system for the confidence rating. This study is registered with PROSPERO, CRD42020172606.
We identified 1503 studies, of which 55 RCTs evaluating 20 interventions in 17 062 patients were included in the network meta-analysis. The mean incidence of post-ERCP pancreatitis in the placebo or active control group was 12·2% (95% CI 11·4–13·0). Normal saline plus rectal indometacin (OR 0·02, 95% CI 0·00–0·40), intramuscular diclofenac 75 mg (0·24, 0·09–0·69), intravenous high-volume Ringer's lactate plus rectal diclofenac 100 mg (0·30, 0·16–0·55), intravenous high-volume Ringer's lactate (0·31, 0·12–0·78), 5–7 Fr pancreatic stents (0·35, 0·26–0·48), rectal diclofenac 100 mg (0·36, 0·25–0·52), 3 Fr pancreatic stents (0·47, 0·26–0·87), and rectal indometacin 100 mg (0·60, 0·50–0·73) were all more efficacious than placebo for preventing post-ERCP pancreatitis in pairwise comparisons. 5–7 Fr pancreatic stents (0·59, 0·41–0·84), intravenous high-volume Ringer's lactate plus rectal diclofenac 100 mg (0·49, 0·26–0·94), intravenous standard-volume normal saline plus rectal indometacin 100 mg (0·04, 0·00–0·66), and rectal diclofenac 100 mg (0·59, 0·40–0·89) were more efficacious than rectal indometacin 100 mg. The GRADE confidence rating was low to moderate for 98·3% of the pairwise comparisons.
This systematic review and network meta-analysis summarises the available literature on NSAIDs, pancreatic stents, intravenous fluids, or combinations of these for prophylaxis of post-ERCP pancreatitis. Rectal diclofenac 100 mg is the best performing rectal NSAID in this network meta-analysis. Combinations of prophylaxis might be more effective, but there is little evidence. These findings help to establish prophylaxis of post-ERCP pancreatitis for future research and practice, and could reduce costs and increase adoption of prophylaxis.
None.
Network meta-analysis of prophylactic pancreatic stents and non-steroidal anti-inflammatory drugs in the prevention of moderate-to-severe post-ERCP pancreatitis
2021, Pancreatology
There is an ongoing debate that non-steroidal anti-inflammatory drugs (NSAID) or prophylactic pancreatic stents (PPS) are more beneficial in preventing post-endoscopic retrograde cholangiopancreatography (ERCP) pancreatitis (PEP). In our present network meta-analysis, we aimed to compare PPSs to rectal NSAIDs in the prevention of moderate and severe PEP in average- and high-risk patients.
We performed a systematic search for randomized controlled trials (RCT) from MEDLINE (via PubMed), Embase and Cochrane Central databases. RCTs using prophylactic rectal NSAIDs or PPSs in patients subjected to ERCP at average- and high-risk population were included. The main outcome was moderate and severe PEP defined by the Cotton criteria. Pairwise Bayesian network meta-analysis was performed, and interventions were ranked based on surface under cumulative ranking (SUCRA) values.
Seven NSAID RCTs (2593 patients), and 2 PPS RCTs (265 patients) in the average-risk, while 5 NSAID RCTs (1703 patients), and 8 PPS RCTs (974 patients) in the high-risk group were included in the final analysis. Compared to placebo, only PPS placement reduced the risk of moderate and severe PEP in both patient groups (average-risk: RR = 0.07, 95% CI [0.002–0.58], high-risk: RR = 0.20, 95% CI [0.051–0.56]) significantly. Rectal NSAID also reduced the risk, but this effect was not significant (average-risk: RR = 0.58, 95% CI [0.22–1.3], high-risk: RR = 0.58, 95% CI [0.18–2.3]). Based on SUCRA, PPS placement was ranked as the best preventive method.
Prophylactic pancreatic stent placement but not rectal NSAID seems to prevent moderate-to-severe PEP better both, in average- and high-risk patients.
Aggressive fluid hydration plus non-steroidal anti-inflammatory drugs versus non-steroidal anti-inflammatory drugs alone for post-endoscopic retrograde cholangiopancreatography pancreatitis (FLUYT): a multicentre, open-label, randomised, controlled trial
2021, The Lancet Gastroenterology and Hepatology
Citation Excerpt :
This potentially complicates our patient selection and sample size generation. However, the risk profile of our study population is similar to the populations of the studies that were the basis of our sample size calculation: patients with moderate to high risk who receive rectal NSAIDs.34,35 The meta-analyses mention a post-ERCP pancreatitis incidence of 8·0% and 5·7%, which is similar to that in the control group (rectal NSAIDs alone) of our study (9%).
Pancreatitis is the most common complication of endoscopic retrograde cholangiopancreatography (ERCP). Prophylactic rectal administration of non-steroidal anti-inflammatory drugs (NSAIDs) is considered as standard of care to reduce the risk of post-ERCP pancreatitis. It has been suggested that aggressive hydration might further reduce this risk. Guidelines already recommend aggressive hydration in patients who are unable to receive rectal NSAIDs, although it is laborious and time consuming. We aimed to evaluate the added value of aggressive hydration in patients receiving prophylactic rectal NSAIDs.
FLUYT, a multicentre, open-label, randomised, controlled trial done across 22 Dutch hospitals, included patients aged between 18 and 85 years with moderate to high risk of post-ERCP pancreatitis. Patients were randomly assigned (1:1) by a web-based module with varying block sizes to a combination of aggressive hydration and rectal NSAIDs (100 mg diclofenac or indomethacin; aggressive hydration group) or rectal NSAIDs (100 mg diclofenac or indomethacin) alone (control group). Randomisation was stratified according to treatment centre. Aggressive hydration comprised 20 mL/kg intravenous Ringer's lactate solution within 60 min from the start of ERCP, followed by 3 mL/kg per h for 8 h. The control group received normal intravenous saline with a maximum of 1·5 mL/kg per h and 3 L per 24 h. The primary endpoint was post-ERCP pancreatitis and was analysed on a modified intention-to-treat basis (including all patients who underwent randomisation and an ERCP and for whom data regarding the primary outcome were available). The trial is registered with the ISRCTN registry, ISRCTN13659155.
Between June 5, 2015, and June 6, 2019, 826 patients were randomly assigned, of whom 388 in the aggressive hydration group and 425 in the control group were included in the modified intention-to-treat analysis. Post-ERCP pancreatitis occurred in 30 (8%) patients in the aggressive hydration group and in 39 (9%) patients in the control group (relative risk 0·84, 95% CI 0·53–1·33, p=0·53). There were no differences in serious adverse events, including hydration-related complications (relative risk 0·99, 95% CI 0·59–1·64; p=1·00), ERCP-related complications (0·90, 0·62–1·31; p=0·62), intensive care unit admission (0·37, 0·07–1·80; p=0·22), and 30-day mortality (0·95, 0·50–1·83; p=1·00).
Aggressive periprocedural hydration did not reduce the incidence of post-ERCP pancreatitis in patients with moderate to high risk of developing this complication who routinely received prophylactic rectal NSAIDs. Therefore, the burden of laborious and time-consuming aggressive periprocedural hydration to further reduce the risk of post-ERCP pancreatitis is not justified.
Netherlands Organisation for Health Research and Development and Radboud University Medical Center.

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: Conflicts of interest The authors disclose no conflicts.

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Original articleSystematic reviews and meta-analysesRectal Nonsteroidal Anti-inflammatory Drugs Are Superior to Pancreatic Duct Stents in Preventing Pancreatitis After Endoscopic Retrograde Cholangiopancreatography: A Network Meta-analysis

Background & Aims

Methods

Results

Conclusions

Section snippets

Methods

Studies and Quality

Discussion

Acknowledgment

Gastrointest Endosc

Gastrointest Endosc

Gastrointest Endosc

Clin Gastroenterol Hepatol

Gastroenterology

Control Clin Trials

Gastrointest Endosc

Gastrointest Endosc

Gastrointest Endosc

Gastroenterology

Gastrointest Endosc

Gastrointest Endosc

Gastrointest Endosc

Gastrointest Endosc

Gastrointest Endosc

Gastrointest Endosc

Gastrointest Endosc

Clin Gastroenterol Hepatol

Gastrointest Endosc

Pancreatology

Gastrointest Endosc

Gastroenterology

Complications of endoscopic biliary sphincterotomy

N Engl J Med

Sphincter of Oddi dysfunction: pancreaticobiliary sphincterotomy with pancreatic stent placement has a lower rate of pancreatitis than biliary sphincterotomy alone

Endoscopy

Original article
Systematic reviews and meta-analyses
Rectal Nonsteroidal Anti-inflammatory Drugs Are Superior to Pancreatic Duct Stents in Preventing Pancreatitis After Endoscopic Retrograde Cholangiopancreatography: A Network Meta-analysis