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Objective To analyze the temporal trends of atrial fibrillation (AF)-related ischemic stroke (IS) and their relationship with the prescription patterns of antithrombotic treatment from 2013 to 2019 in the Health Assistance Area of a regional hospital. Methods First, a retrospective ecological study of aggregate data to analyze the annual incidence of IS between 2013 and 2019 was performed. Second, we selected those patients diagnosed with AF between 2013 and 2019 and performed a retrospective longitudinal study to assess the role of antithrombotic therapy in the development of AF-related IS. Results During this period, whereas the annual incidence of IS remained stable (from 1.3 in 2013 to 1.2 cases per 1000 inhabitants in 2019; adjusted P for trend .829), the annual incidence of AF-related IS decreased over time (from 23.8 to 18.8 cases per 1000 inhabitants, respectively; adjusted P for trend .001). Among AF patients, the use of direct oral anticoagulants increased from 5.5% to 46.8%, while the prescription of antiplatelets and vitamin K antagonists decreased from 21.9% to 6.0% and from 63.8% to 36.1%, respectively. Overall, the use of oral anticoagulants increased from 69.3% to 82.9%; p < .001. Patients under antiplatelet agents had a higher probability of presenting IS than those patients taking oral anticoagulants, either vitamin K antagonists or direct oral anticoagulants (adjusted OR 1.89; 95% CI 1.52-2.37; p < .001). Conclusions The prescription of oral anticoagulants, particularly direct oral anticoagulants, has increased from 2013 to 2019 in our Health Assistance Area. This increase might partially explain the reduction in AF-related IS.