Delayed bleeding is a major adverse event of endoscopic papillectomy (EP). However, established preventive strategies and clear risk stratification remain ill-defined due to the rarity of the disease. We aimed to identify independent risk factors for delayed bleeding after EP using a large-scale multicenter dataset, specifically evaluating the impact of procedural interventions and pharmacological prophylaxis.

We conducted a retrospective cohort study across 22 Japanese academic and community hospitals (2009–2020). Patients undergoing EP for ampullary tumors were included. To ensure homogeneity, patients requiring nasobiliary/nasopancreatic drainage or metallic biliary stents were excluded. We identified independent risk factors for delayed bleeding using multivariable logistic regression.

A total of 875 candidates were screened, and 848 patients were included in the final analysis. The overall incidence of delayed bleeding was 19.2% (163/848). Severity was mild in 15.6%, moderate in 2.4%, and severe in 1.3% of cases. Multivariable analysis identified prophylactic clipping (>50% closure of the mucosal defect) as a significant independent preventive factor (Odds Ratio [OR] 0.49; 95% Confidence Interval [CI] 0.28–0.81; p=0.007). Conversely, independent risk factors included male sex (OR 1.82; p=0.002), younger age (65 years; OR 2.82;0.001), and pancreatic stent placement (OR 2.60; p=0.041). Acid-suppressing agents (PPIs or H2RAs) showed no significant association with delayed bleeding.

Prophylactic clipping significantly reduced the risk of delayed bleeding, whereas younger age, male sex, and pancreatic stent placement were identified as significant risk factors. Notably, acid-suppressing agents did not affect bleeding risk. The novel finding that pancreatic stent placement is a risk factor suggests that constant exposure of the ulcer bed to pancreatic juice via the stent may induce bleeding, warranting further investigation.