Andexanet Alfa Versus Four-Factor Prothrombin Complex Concentrate for Factor Xa Inhibitor–Related Major Bleeding: A Real-World Observational Study

Background and aims: The optimal strategy for reversing factor Xa inhibitor-associated major bleeding remains uncertain. Andexanet alfa (AA), the only specific reversal agent, is recommended for life-threatening bleeding but its use is limited by high cost, availability, and potential thrombotic risk. Four-factor prothrombin complex concentrate (4F-PCC) is widely used as an off-label alternative, but comparative real-world evidence remains limited. We aimed to compare hemostatic efficacy, mortality, thrombotic events, functional outcomes, length of stay, and treatment costs in patients with factor Xa inhibitor-associated major bleeding treated with AA or 4F-PCC. Materials and Methods: We conducted a single-center retrospective observational study of consecutive adults with factor Xa inhibitor-associated major bleeding treated with AA or 4F-PCC at the Emergency Department of the Azienda Ospedale–Università di Padova between November 2021 and December 2025. The primary endpoint was hemostatic effectiveness, defined according to bleeding site as ≤35% hematoma expansion in intracranial hemorrhage (ICH) or hemoglobin stabilization without further hemostatic intervention or red blood cell transfusion within 48 hours in non-ICH bleeding. Secondary endpoints included 30-day mortality, functional disability (Modified Rankin Scale ≥3), thrombotic events, hospital length of stay, and treatment costs. Multivariable logistic regression assessed the association between reversal strategy and hemostatic effectiveness, adjusting for age, bleeding site, DOAC dose, time to reversal, and time since last DOAC intake. Results: A total of 150 patients were included: 56 (37.3%) received AA and 94 (62.7%) 4F-PCC. Patients were elderly, with a median age of 81.5 years (IQR 76–86) in the AA group and 82 years (IQR 76–87) in the 4F-PCC group. Apixaban was the most frequently used factor Xa inhibitor (53% vs 42%), while atrial fibrillation was the predominant indication for anticoagulation (91% vs 92%). ICH was the most common bleeding presentation, particularly among patients receiving AA. Baseline clinical and laboratory characteristics were otherwise broadly comparable between groups, including time to treatment. Additional invasive procedures were performed in 13 patients receiving AA and 29 (31%) receiving 4F-PCC. Hemostatic effectiveness was evaluable in 147 patients and was achieved in 45 (83.3%) patients treated with AA versus 62 (66.7%) treated with 4F-PCC (p=0.035). In-hospital mortality did not differ significantly between groups (28.6% vs 24.5%; p=0.701), nor did permanent functional disability (48.6% vs 38.5%; p=0.482). Hospital length of stay was slightly longer with AA, without reaching statistical significance (p=0.096). Thirty-day thrombotic events occurred at similar rates with AA and 4F-PCC (3.6% vs 4.3%; p=1.000), whereas treatment costs were significantly higher with AA (p<0.001). After multivariable adjustment, AA was independently associated with higher odds of effective hemostasis compared with 4F-PCC (adjusted OR, 2.73; 95% CI, 1.01–7.34; p=0.047). This association remained consistent in sensitivity analysis (adjusted OR, 2.61; 95% CI, 1.03–6.63; p=0.044). In exploratory analyses, hemostatic effectiveness was numerically higher with AA than with 4F-PCC in both ICH (81.8% vs 64.9%) and non-ICH bleeding (85.7% vs 67.9%), with no evidence of effect modification by bleeding site (p for interaction=0.863).Conclusion: In this real-world cohort, AA was associated with a significantly higher likelihood of effective hemostasis than 4F-PCC. However, this advantage did not translate into significant differences in mortality, functional disability, hospital length of stay, or thrombotic events. AA was associated with substantially higher treatment costs. These findings suggest that greater hemostatic efficacy may not necessarily result in improved patient-centered outcomes.