Elucidating the Optimal Use of Mitigation Strategies for Improving Pancreatic Fistula Rates after Pancreatoduodenectomy

Objective: To identify optimal approaches to fistula mitigation for pancreatoduodenectomy. Background: Postoperative Pancreatic Fistula (POPF) is the most consequential complication following pancreatoduodenectomy (PD). To date, the various POPF prevention methods have been investigated predominantly in isolation; however, the complexity of PD demands studying the interplay between approaches. Methods: 7128 PDs with complete POPF, Fistula Risk Score (FRS), and mitigation data were performed from 2000-2024 between 18 international institutions. Techniques analyzed were: drains, stents, octreotide, pancreatogastrostomy, and sealants. POPF was tabulated for strategy combinations, accounting for FRS. The additive effect of early drain removal (EDR; POD≤4) was assessed. Results: The fistula rate was 15.1%. Mitigation application rates were drains=94.0%; stents=37.4%; octreotide=21.2%; pancreatogastrostomy=3.5%; and sealants=3.3%. Analyzed individually, drains were not associated with POPF, while stents, octreotide, pancreatogastrostomy, and sealants were associated with increased POPF. Risk adjustment revealed nuance among the 27 observed mitigation combinations. For Negligible and Low FRS patients, no approach improved upon omission. Drain-alone was best for Moderate FRS patients (POPF: 13.1% vs. 19.8%, P <0.001). Best outcomes for High FRS patients were achieved by employing Drain+Stent (23.7% vs. 38.5%, P <0.001). These results inform a “playbook” of optimal management. Increased adherence to these tenets was associated with improved surgeon practice-level fistula rates ( P =0.034). Universal adoption of optimal fistula mitigation projects to eliminate from one-third of fistulas, up to one-half when incorporating EDR. Conclusion: This robust experience indicates that many frequently employed fistula mitigation tactics are actually ineffective. Conversely, the optimal approaches identified herein are underutilized—in just 32% of patients. Simplified, tailored application can drive down stubborn fistula rates, enhance care, and move toward personalized medicine for fistula prevention.