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Background: In non-valvular-associated atrial fibrillation (AF), direct oral anticoagulants (DOAC) are as effective as vitamin K antagonists (VKA) for the prevention of acute ischemic stroke (AIS). DOAC are associated with decreased risk and severity of intracranial hemorrhage. It is unknown if different pre-admission anticoagulants impact the prognosis of AF related AIS (AF-AIS). We sought to analyze the literature to assess the association between pre-admission anticoagulation (VKA or DOAC) and admission severity of AF-AIS. Methods: A Systematic literature search (PubMed and ScienceDirect) between January 2011 to April 2021 was undertaken to identify studies describing the outcome of AF-AIS. Results: A total of 128 articles were identified. Of 9493 patients, 1767 were on DOAC, 919 were on therapeutical VKA, 792 were on non-therapeutical VKA and 6015 were not anticoagulated. In comparison to patients without anticoagulation, patients with therapeutical VKA and under DOAC presented with less severe stroke (MD −1.69; 95% CI [−2.71, −0.66], p = 0.001 and MD −2.96; 95% Cl [−3.75, −2.18], p < 0.00001, respectively). Patients with non-therapeutical VKA presented with more severe stroke (MD 1.28; 95% Cl [0.45, 2.12], p = 0.003). Conclusions: In AF-AIS, patients under therapeutical VKA or DOAC have reduced stroke severity on admission in comparison to patients without any anticoagulation, with higher magnitude of protection for DOAC. Peter Sporns