Evaluation of Pharmacologic Prevention of Pancreatitis After Endoscopic Retrograde Cholangiopancreatography

A Systematic Review

Nisa M. Kubiliun; Megan A. Adams; Venkata S. Akshintala; Marisa L. Conte; Gregory A. Cote; Peter B. Cotton; Jean-Marc Dumonceau; Grace H. Elta; Evan L. Fogel; Martin L. Freeman; Glen A. Lehman; Mariam Naveed; Joseph Romagnuolo; James M. Scheiman; Stuart Sherman; Vikesh K. Singh; B. Joseph Elmunzer

Disclosures

Clin Gastroenterol Hepatol. 2015;13(7):1231-1239. 

In This Article

Abstract and Introduction

Abstract

Background & Aims: There is controversy over the efficacy of pharmacologic agents for preventing pancreatitis after endoscopic retrograde cholangiopancreatography (PEP). We performed a systematic review of PEP pharmacoprevention to evaluate safety and efficacy.

Methods: We performed a systematic search of the literature for randomized controlled trials (RCTs) and meta-analyses of PEP pharmacoprevention through February 2014. After identifying relevant studies, 2 reviewers each extracted information on study characteristics, clinical outcomes, and risk of bias. A research classification scale was developed to identify pharmacologic agents ready for clinical use, agents for which a confirmatory RCT should be considered a high priority, agents for which exploratory studies are still necessary, and agents for which additional research should be of low priority. Clinical and research recommendations for each agent were made by consensus after considering research classification results and other important factors such as magnitude of benefit, safety, availability, and cost.

Results: After screening 851 citations and 263 potentially relevant articles, 2 reviewers identified 85 RCTs and 28 meta-analyses that were eligible. On the basis of these studies, rectal nonsteroidal anti-inflammatory drugs were found to be appropriate for clinical use, especially for high-risk cases. Sublingual nitroglycerin, bolus-administered somatostatin, and nafamostat were found to be promising agents for which confirmatory research is warranted. Additional research was found to be required to justify confirmatory RCTs for topical epinephrine, aggressive intravenous fluids, gabexate, ulinastatin, secretin, and antibiotics.

Conclusions: On the basis of a systematic review, NSAIDs are appropriate for use in prevention of PEP, especially for high-risk cases. Additional research is necessary to clarify the role of other pharmacologic agents. These findings could inform future research and guide clinical decision-making and policy.

Introduction

Pharmacoprevention of post–endoscopic retrograde cholangiopancreatography (ERCP) pancreatitis (PEP) has been a major research priority for the last 3 decades. However, randomized controlled trials (RCTs) in this area have traditionally suffered from low methodological quality, inadequate sample sizes, and negative, conflicting, or inconclusive results. Furthermore, studies have failed to consistently use the consensus definition of PEP that requires (1) evidence of clinical pancreatitis, (2) serum amylase or lipase ≥3 times the upper limit of normal 24 hours after the procedure, and (3) hospitalization (or prolongation of existing hospitalization) of at least 2 days.[1] Therefore, until recently, no pharmacologic agent had been adopted into routine clinical use.

Within the last decade, research focusing on the prophylactic effect of rectally administered nonsteroidal anti-inflammatory drugs (NSAIDs) has provided renewed hope for PEP pharmacoprevention. Positive meta-analyses[2,3] of exploratory trials of rectal diclofenac and indomethacin led to a grade A recommendation for the use of these medications by the European Society for Gastrointestinal Endoscopy,[4] and a subsequent large-scale, methodologically rigorous RCT[5] has prompted increased acceptance of rectal NSAIDs in clinical practice.[6]

Despite the administration of rectal NSAIDs and the placement of prophylactic pancreatic stents,[7,8] PEP continues to affect 10%–15% of patients at increased risk. Because of the substantial morbidity, occasional mortality, and high costs associated with PEP,[9–11] additional research is necessary to further reduce the incidence of this complication. To this end, there are currently at least 9 ongoing, registered PEP pharmacoprevention RCTs.[12–20]

Adequately powered, methodologically rigorous clinical trials in this area require large sample sizes and substantial resources, incurring high economic and opportunity costs. Therefore, in this era of diminishing research funding, a responsible approach to the selection, design, and conduct of PEP pharmacoprevention trials is necessary to maximize limited resources and efficiently identify beneficial agents. Moreover, an informed appraisal of the existing literature is necessary to help guide clinical decision-making and policy.

To provide clinical guidance and a framework for future research in this important area, we performed a systematic review of the global literature on PEP pharmacoprevention. On the basis of existing RCT and meta-analytic data, we aimed to identify (1) pharmacologic agents that are ready for clinical use, (2) agents for which a confirmatory RCT should be considered a high priority, (3) agents for which exploratory studies are still necessary, and (4) agents for which additional research should be of low priority at this time. In addition, we aimed to construct a comprehensive catalogue of the existing literature on PEP pharmacoprevention for future reference by interested investigators.

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