Montero-Balosa, Mª CarmenLimón-Mora, Juan A.Leal-Atienza, AnaGarcía-Robredo, BeatrizSanchez-Villegas, PabloIsabel-Gómez, RebecaAguado-Romeo, Mª JoséLuque-Romero, Luis GabrielMolina-López, Mª Teresa2025-10-012025-10-012025-08-01Montero-Balosa MC, Limón-Mora JA, Leal-Atienza A, García-Robredo B, Sánchez-Villegas P, Isabel-Gómez R, et al. Comparative clinical outcomes of acenocoumarol versus direct oral anticoagulants (DOACs) and warfarin in patients with atrial fibrillation: real-world-evidence (SIESTA-A study). Front Pharmacol. 2025 Aug 1;16:1548298.1663-9812https://hdl.handle.net/10668/28555The study protocol was submitted to the Spanish Agency of Medicines and Medical Devices (AEMPS, Spanish acronym) and classified as an observational study (AEMPS reference number: 0004–2022-OBS; 12 January 2022). The author(s) declare that financial support was received for the research and/or publication of this article. This work was supported by the Andalusian Public Foundation for Health Research Management in Seville (FISEVI) of the Andalusian Ministry of Health (AP-0222-2019 and AP-0379-2023-C4-F2) and by the Instituto de Salud Carlos III (PI20/01281), Spanish Ministry of Health (co-financed by the European Regional Development Funds).Objective: The aim of this study was to evaluate the effectiveness and safety of direct oral anticoagulants (DOACs: dabigatran, rivaroxaban, apixaban and edoxaban) and warfarin versus acenocoumarol in patients with atrial fibrillation under real-world clinical practice conditions. Methods: This was a retrospective, real-world data-based study. The data source was the Andalusian Population Health Database. The study covered the period from January 2012 to December 2020. Effectiveness outcomes were defined as the identification of a first occurrence of ischaemic or bleeding events, or all-cause mortality. The statistical analysis included crude incidence analysis, survival models: Kaplan-Meier curves, propensity score matched pairs analysis, Fine-Gray model, and Cox regression analysis adjusted for possible confounding. Results: A total of 150,949 patients were included. The mean age of the cohort was 74 years (48.2% female). The mean follow-up time was 3.3 years. The combined effectiveness endpoint of ischaemic events (transient ischaemic attack, systemic embolism, pulmonary embolism, or ischaemic stroke) showed the following results compared to acenocoumarol: warfarin (RR:1.06; 95%CI 0.93–1.22); dabigatran (RR:1.17; 95%CI 1.02–1.33); rivaroxaban (RR:1.15; 95%CI 1.05–1.26); apixaban (RR: 0.96; 95%CI 0.87–1.07) and edoxaban (RR: 1.10; 95%CI 0.79–1.51). Compared to acenocoumarol, the risk of all-cause mortality was lower for dabigatran, rivaroxaban and apixaban (RR:0.77; 95%CI 0.72–0.82; RR:0.79; 95%CI 0.76–0.83; RR:0.85; 95%CI 0.81–0.89, respectively) and higher for warfarin (RR:1.12; 95%CI 1.05–1.20). An increased risk of gastrointestinal bleeding was observed with dabigatran (RR:1.36; 95%CI 1.09–1.70) and a lower risk with rivaroxaban (RR:0.84; 95%CI 0.72–0.98). All 4 DOACs showed a lower risk of intracranial bleeding compared to acenocoumarol. Warfarin carried a higher risk of both gastrointestinal bleeding (RR:1.64; 95%CI 1.31–2.06) and intracranial bleeding (RR:1.61; 95%CI 1.22–2.13) compared to acenocoumarol. An unadjusted analysis of matched groups in a multivariate Cox regression analysis yielded similar results for combined effectiveness and safety outcomes compared to acenocoumarol. Conclusion: Although DOACs were clearly associated with a lower risk of intracranial bleeding compared to acenocoumarol, our data did not reveal a significant reduction in thromboembolic events. Warfarin was found to be both less effective and less safe than acenocoumarol.enAttribution 4.0 Internationalhttp://creativecommons.org/licenses/by/4.0/EffectivenessHealth outcomesOral anticoagulant agentsOral direct anticoagulantsSafetyRed Andaluza de Medicina Transfusional de Tejidos y CélulasÁrea de Evaluación de Tecnologías Sanitarias de Andalucía (AETSA)Administration, OralAnticoagulantsAtrial FibrillationBrain IschemiaStrokeresearch article40822463open accessAnticoagulantes orales directos (DOACs)AcenocumarolFibrilación auricularSeguridad y efectividad clínicaEstudios en práctica clínica real10.3389/fphar.2025.1548298PMC12354484