Real-world bleeding risk and molecular interaction profiles of direct oral anticoagulants: a comparative study integrating clinical outcomes and in silico docking

Background Differences in bleeding risk among direct oral anticoagulants (DOACs) may reflect not only exposure-related factors but also molecule-specific drug–target interaction characteristics. This study aimed to evaluate real-world bleeding outcomes and to complement these findings with molecular docking analyses as supportive, hypothesis-generating mechanistic context for safety differences among factor Xa inhibitors and a direct thrombin inhibitor. Methods A retrospective cohort of 5,721 patients treated with apixaban, rivaroxaban, edoxaban, or dabigatran was analyzed using real-world clinical data. Demographic characteristics, comorbidities, non–life-threatening complications, life-threatening hemorrhagic events, and overall bleeding outcomes were systematically compared. Multivariable logistic regression modeling was used to identify independent predictors of bleeding, with apixaban as the reference agent. Molecular docking analyses were performed using AutoDock 4.2.6 to assess comparative binding energy profiles, hydrogen bond interactions, and root-mean-square deviation values between each DOAC and factor Xa or thrombin. Results Life-threatening bleeding occurred in 3.1% of patients, while any bleeding event was observed in 13.5% of the cohort. Compared with apixaban, rivaroxaban (OR 1.52), dabigatran (OR 1.29), and edoxaban (OR 1.44) were independently associated with higher odds of bleeding. Advanced age and renal dysfunction were identified as additional independent predictors. Docking analyses indicated that apixaban exhibited the lowest docking-derived binding energy toward factor Xa (ΔG = −14.46 kcal/mol), whereas dabigatran showed selective interaction with thrombin (ΔG = −11.91 kcal/mol). These molecular findings are exploratory and hypothesis-generating and should be interpreted as supportive mechanistic context rather than direct predictors of clinical outcomes. Conclusion In this retrospective cohort, apixaban was associated with a comparatively lower observed bleeding risk compared with other DOAC agents. Docking findings provide exploratory, hypothesis-generating mechanistic context that may help to contextualize observed clinical patterns.