Evidence-Based Strategies for Mitigating Pancreatic Fistula After Distal Pancreatectomy: A Systematic Review of Randomized Clinical Trials

<b>Background:</b> Postoperative pancreatic fistula remains a frequent complication after distal pancreatectomy and represents the first cause for major morbidity and mortality. Multiple strategies have been proposed to mitigate the severity of pancreatic fistula, but their real benefits remain inconclusive. This study aimed to identify effective mitigation strategies for clinically relevant pancreatic fistula (CR-POPF) through a systematic review of randomized clinical trials. <b>Methods:</b> A systematic search of the Medline and Web of Science databases was conducted for studies published between 2006 and February 2025. Eligible studies included randomized clinical trials evaluating strategies to mitigate clinically relevant postoperative pancreatic fistula following distal pancreatectomy. Only studies in English and involving human subjects were included. <b>Results:</b> Twenty-seven studies were found eligible, comprising 4062 patients, treated with 22 different strategies classified in 8 categories: tissue coverage, sealants and glues, systemic corticoids, analogues of somatostatin, anastomosis of the stump, drain usage, closure of the stump and transpapillary stent. Only 6 studies demonstrated a significant reduction in CR-POPF, strategies applied include systemic corticoids, selective use of drains, polyglycolic acid mesh, reinforced staplers, and collagen enhanced thrombin sealant. <b>Conclusions:</b> Studies reporting successful strategies show considerable heterogeneity in both the included populations and the way the strategies were applied. A personalized approach based on the risk of developing fistula and specific pancreatic features may be beneficial and should be further explored in future randomized clinical trials.