Background: Optimal secondary prevention after embolic stroke of undetermined source (ESUS) is not established. ESUS is caused by thromboembolism and is associated with high risk of recurrent ischemic stroke and clinically silent ischemic lesions (IL). Current standard in ESUS patients is acetylsalicylic acid (ASA), despite high prevalence of occult atrial fibrillation (AF).

Objective: ATTICUS will determine whether the direct oral factor Xa inhibitor apixaban started within 28 days after index stroke is superior to ASA for prevention of new IL on follow-up brain magnetic resonance imaging at 12 months in an AF-at-risk-enriched ESUS population, i.e. in patients with a dilated left atrium, a reduced flow or spontaneous echo contrast in the left atrial appendage on transesophageal echocardiogram, atrial runs on 24-hour Holter ECG, or an CHA2DS2-VASc score of at least four.

Design: Prospective, randomized (1:1), open, blinded endpoint (PROBE), multicenter phase III trial aiming at enrolling approx. 500 ESUS patients undergoing cardiac remote monitoring (mandatory). Event-driven trial with core-lab adjudicated primary outcome, i.e. occurrence of at least one new IL at 12 months compared to baseline. Key secondary outcomes are the combination of recurrent ischemic/hemorrhagic strokes and systemic embolism, combination of MACE including recurrent stroke, myocardial infarction and cardiovascular death, combination of major and clinically relevant non-major bleeding, and the change of cognitive function (Montreal Cognitive Assessment) and quality of life (EuroQol-5D, Stroke Impact Scale).

CONCLUSIONS: In contrast to the recently published NAVIGATE and RESPECT ESUS, patients enrolled in ATTICUS need to exhibit additional AF predicting factors. Furthermore, mandatory cardiac remote monitoring will help to elucidate the impact of AF and the effects of early oral anticoagulation with apixaban compared to antiplatelet therapy with ASA on the incidence of new IL after ESUS.