Distal pancreatectomy (DP) is the standard surgical treatment for both benign and malignant body-tail pancreatic neoplasms. Despite advances in surgical technique and perioperative care, morbidity after DP remains substantial. The clinically relevant postoperative pancreatic fistula (POPF)¹ is the most frequent complication, occurring in 20%–40% of cases in high-volume series. ^2–3 However, POPF is detrimental not only to itself, but also because it precipitates other complications such as hemorrhage and sepsis. Among these, postpancreatectomy hemorrhage (PPH) is one of the most feared, with reported mortality rates up to 50% in severe cases. ^4–5 PPH is often secondary to POPF-induced vascular erosion or pseudoaneurysm formation, and its management frequently requires complex interventional radiology or reoperation, thereby prolonging hospitalization and increasing costs. ^6–7 Several strategies have been proposed to reduce the risk of PPH after pancreaticoduodenectomy (PD) ⁸, while the event is underestimated in DP. Some years ago, an Italian multicenter randomized controlled trial (RCT) by Montorsi et al. ⁷ was conducted to investigate the benefit of an absorbable fibrin sealant patch (TachoSil®) in addition to standard pancreatic stump closure. This study failed to demonstrate the reduction of the POPF rate.

However, at the time of the study, no standardized definition of PPH was available, precluding systematic assessment of this outcome across studies and potentially leading to underreporting. Since then, the ISGPS has provided a consensus definition for PPH, enabling consistent classification and comparison across studies.⁴ This has opened the door to re-evaluating interventions not merely for their ability to reduce POPF incidence, but for their impact on preventing high-risk, clinically meaningful complications such as PPH.

In this context, this is an explorative study that aims to evaluate the effect of TachoSil® following DP, with a specific emphasis on its potential role in mitigating PPH, using standardized contemporary definitions and robust adjustment for confounding. For this purpose, we applied the inverse probability of treatment weighting (IPTW) to emulate the balance of a randomized trial while preserving the granularity of real-world surgical practice.

This was a single-center, retrospective analysis of a prospectively maintained pancreatic surgery database at the IRCCS Azienda Ospedaliero–Universitaria di Bologna, Sant’Orsola–Malpighi Hospital. All consecutive adult patients undergoing distal pancreatectomy between January 2015 and December 2024 were considered. The study protocol was approved by the local Ethics Committee (Comitato Etico di Area Vasta Emilia Centro, PANBO 064/2017/U/Oss), and informed consent for data collection and analysis was obtained from all participants.

A total of 224 patients underwent distal pancreatectomy, of whom 56 (25.0%) received TachoSil® and 168 (75.0%) did not.

Table 1 shows the patients before and after IPTW adjustment. Several covariates have baseline imbalance with standardized mean difference (SMD) values above the non-small threshold (> 0.2). These included surgical approach (laparoscopic vs open, SMD = 0.385), splenectomy (yes vs no, SMD = 0.279), and preoperative symptoms (yes vs no, SMD = 0.273). The use of other hemostatic agents (SMD = 0.197) and sex distribution (male vs female, SMD = 0.166) were close to the small-to-moderate range. After IPTW adjustment, all covariates had SMD values < 0.2, with the majority ≤ 0.1, indicating adequate balance between treatment groups (Fig. 1).

In the weighted analysis (Table 2), the risk difference (RD) for postpancreatectomy hemorrhage (PPH) was − 0.065 (95% CI − 0.121 to − 0.009; p = 0.015), with a number needed to treat (NNT) of 15 (95% CI 8–110) and an E-value of 6.7. The RD for clinically relevant POPF was 0.115 (95% CI − 0.045 to 0.276; p = 0.115). The mean difference (MD) for the Comprehensive Complication Index (CCI) was 3.517 (95% CI − 1.559 to 8.593; p = 0.096). The RD for reoperation was − 0.016 (95% CI − 0.067 to 0.035; p = 0.487), for 90-day mortality 0.013 (95% CI − 0.026 to 0.051; p = 0.489), and the MD for length of stay (LOS) was − 0.238 days (95% CI − 2.623 to 2.148; p = 0.856).

Table 3 shows the stratified analysis for POPF. In patients without clinically relevant POPF, the RD for PPH was − 0.013 (95% CI − 0.062 to 0.035; p = 0.370; E-value 2.7), the MD for CCI was 6.008 (95% CI − 1.422 to 13.437; p = 0.061), the RD for reoperation was − 0.018 (95% CI − 0.044 to 0.007; p = 0.152; E-value not estimable), for 90-day mortality 0.033 (95% CI − 0.031 to 0.098; p = 0.568; E-value not estimable), and the MD for LOS was − 0.178 days (95% CI − 1.822 to 1.467; p = 0.772). In patients with clinically relevant POPF, the RD for PPH was − 0.180 (95% CI − 0.311 to − 0.048; p = 0.003; E-value 12.7), the MD for CCI was − 4.473 (95% CI − 10.293 to 1.348; p = 0.087), the RD for reoperation was − 0.029 (95% CI − 0.149 to 0.089; p = 0.505; E-value 2.5), for 90-day mortality − 0.018 (95% CI − 0.055 to 0.018; p = 0.082; E-value not estimable), and the MD for LOS was − 2.081 days (95% CI − 6.993 to 2.830; p = 0.621). Figure 2 shows the distribution of PPH incidence across groups in the overall population and by POPF status.

In this IPTW-adjusted observational study, the use of TachoSil® after DP was associated with a statistically significant reduction in postpancreatectomy hemorrhage (PPH) in the overall population and, more markedly, among patients who developed clinically relevant postoperative pancreatic fistula (POPF). No significant differences were observed for the incidence of POPF itself, the Comprehensive Complication Index (CCI), reoperation rate, 90-day mortality, or postoperative length of stay (LOS). These findings suggested that TachoSil® may not influence the occurrence of POPF, but it could mitigate one of its most severe and clinically impactful sequelae, such as PPH. Our results align partially with those of the pivotal randomized controlled trial by Montorsi et al.⁸, which found no significant reduction in overall POPF rates with TachoSil® use after DP.

That trial, conducted before the International Study Group of Pancreatic Surgery (ISGPS) definition for PPH was established ⁴, did not systematically assess bleeding events as a primary outcome. As a result, the potential benefit of TachoSil® in preventing PPH, particularly in the presence of POPF, may have been underappreciated. The present study, applying standardized ISGPS criteria for PPH and contemporary analytic methods, provides evidence supporting a targeted protective effect in high-risk patients. The observed NNT of 15 for PPH prevention in the overall cohort, and of only 5 in the POPF subgroup, represents a clinically relevant magnitude of effect, particularly given the high morbidity and mortality associated with post-pancreatectomy bleeding. ^7,8 From a pathophysiological standpoint, the mechanism underlying the observed benefit may relate to the capacity of TachoSil® to provide immediate hemostatic sealing of the pancreatic stump¹⁴, potentially reducing early exposure of adjacent vascular structures to proteolytic pancreatic juice. Indeed, the breakdown of tissue planes and persistent enzymatic exposure increase the risk of vascular erosion and pseudoaneurysm formation, which are common precursors to delayed hemorrhage.⁶ The interaction between POPF and PPH is well known⁶ and confirmed by e-values. E-value increased moving from the entire cohort (6.7) to the POPF subgroup (12.7). In other words, considering POPF as the main covariate related to PPH, the benefit effect of TachoSil® is more evident and more robust.

The selective use of TachoSil® in patients with a significant risk of POPF could be one part of a multilevel strategy in preventing the detrimental effects of POPF. Indeed, with the D-FRS, it is now possible at the time of surgery to identify patients at significant risk for postoperative pancreatic fistula. ¹⁵

The present study has strengths and limitations. It is based on a prospectively maintained, single-center database from a high-volume pancreatic surgery unit, ensuring detailed and consistent perioperative data collection. The use of IPTW allowed robust adjustment for measured confounders and achieved excellent post-weighting covariate balance, reducing selection bias inherent to observational designs. Endpoints were defined according to standardized ISGPS criteria, enabling comparability with contemporary literature. Nevertheless, limitations must be acknowledged. The observational design precludes definitive causal inference, and residual confounding from unmeasured variables cannot be excluded despite the robustness suggested by E-values. The single-center nature of the study may limit generalizability to settings with different case mixes, surgical techniques, or postoperative care protocols. Additionally, the relatively small number of PPH events, particularly within subgroups, may have reduced the precision of some estimates, as reflected in wide confidence intervals. Future research should aim to validate these findings in larger, multicenter cohorts and ideally through randomized trials incorporating standardized PPH definitions as the primary endpoint. By randomizing only patients at high risk according to the D-FRS (> 25% predicted POPF incidence), and assuming a control group PPH rate of 20%, a superiority trial powered to detect an absolute risk reduction of 15% (α = 0.05, 90% power) would require 99 patients per arm ( near 198 total), whereas an effect size consistent with our pilot data (absolute reduction of 18%) would require 62 patients per arm (124 total). In conclusion, this study suggests that TachoSil use in distal pancreatectomy is associated with a significant reduction in PPH, particularly in patients with clinically relevant POPF, without affecting POPF incidence itself. These findings support a paradigm in which adjunctive measures are evaluated not only for their effect on leak rates but also for their ability to prevent severe, downstream complications. Incorporating PPH prevention into surgical decision-making and trial design could enhance patient safety and improve outcomes after distal pancreatectomy.