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Postendoscopic retrograde cholangiopancreatography (ERCP) pancreatitis (PEP) is one of the most common complications after ERCP. The optimal drugs for reducing the risk of PEP are still unclear. This study aimed to compare the efficacy of 9 major drugs used worldwide for the prevention of PEP through a network meta-analysis.We conducted a systematic search of the literature up to October 2018 on PubMed, Embase, Web of Science, the Cochrane Central Library, and ClinicalTrials.gov. Randomized controlled trials (RCTs) comparing allopurinol, diclofenac, gabexate (GAB), glyceryl trinitrate (GTN), indomethacin, nafamostat, octreotide, somatostatin, and ulinastatin for protection against PEP were included.Eighty-six randomized controlled trials involving 25,246 patients were included in this network meta-analysis. Results indicated that diclofenac, GAB, GTN, indomethacin, somatostatin, and ulinastatin were more effective than placebo with odds ratios ranging between 0.48 (95% credible interval, 0.26-0.86) for GAB and 0.61 (0.39-0.94) for somatostatin. However, allopurinol, nafamostat, and octreotide showed similar efficacy as placebo in reducing the risk of PEP. No significant differences were found in the efficacy between diclofenac, GAB, GTN, indomethacin, somatostatin, and ulinastatin. In terms of prognosis, GAB may be the most effective treatment (surface under the cumulative ranking curve=70.6%) and the least effective was octreotide (surface under the cumulative ranking curve=28%).Although our analysis suggests that GAB may be the most effective drug in preventing PEP, the limitations of our study warrants more high-quality head-to-head trials of these clinical drugs in the future.