Philippe Lyrer, MD, and Nils Peters, MD, University Hospital and University of Basel, Basel, Switzerland, discuss unresolved questions regarding the use of anticoagulation for secondary prevention after stroke in patients with atrial fibrillation. Novel oral anticoagulants are now the standard of care preventative treatment option for patients with atrial fibrillation, as they are easier to take and associated with lower rates of intracerebral hemorrhage (ICH), compared to vitamin K antagonists. The benefits of anticoagulation for prevention of recurrent thrombotic events must be carefully balanced against the risk of bleeding, particularly when deciding whether to restart anticoagulation after an ICH. Ongoing efforts are looking for ways to better predict individual risk of ischemic stroke versus rebleeding, such as markers of small vessel disease or atherosclerosis. Timing of initiation or re-initiation is another unresolved question. The ELAN (NCT03148457) randomized, controlled trial is one study aiming to shed light on this, assessing early versus late initiation of direct oral anticoagulants in patients with ischemic stroke related to atrial fibrillation. Prof. Lyrer and Prof. Peters also discuss the use of reversal agents and the importance of determining the underlying stroke mechanisms in patients with atrial fibrillation who have had a stroke despite anticoagulation. This interview took place at the ESOC 2022 congress in Lyon, France.