title: Apixaban for treatment of embolic stroke of undetermined source (ATTICUS randomized trial): Rationale and study design.
abstract: Rationale Optimal secondary prevention of embolic stroke of undetermined source is not established. The current standard in these patients is acetylsalicylic acid, despite high prevalence of yet undetected paroxysmal atrial fibrillation. Aim The ATTICUS randomized trial is designed to determine whether the factor Xa inhibitor apixaban administered within 7 days after embolic stroke of undetermined source, is superior to acetylsalicylic acid for prevention of new ischemic lesions documented by brain magnetic resonance imaging within 12 months after index stroke. Design Prospective, randomized, blinded, parallel-group, open-label, German multicenter phase III trial in approximately 500 patients with embolic stroke of undetermined source. A key inclusion criterion is the presence or the planned implantation of an insertable cardiac monitor. Patients are 1:1 randomized to apixaban or acetylsalicylic acid and treated for a 12-month period. It is an event-driven trial aiming for core-lab adjudicated primary outcome events. Study outcomes The primary outcome is the occurrence of at least one new ischemic lesion identified by axial T2-weighted FLAIR magnetic resonance imaging and/or axial DWI magnetic resonance imaging at 12 months when compared with the baseline magnetic resonance imaging. Key secondary outcomes are the combination of recurrent ischemic strokes, hemorrhagic strokes, systemic embolism; combination of MACE including recurrent stroke, myocardial infarction, and cardiovascular death and combination of major and clinically relevant non-major bleeding defined according to ISTH, and change of cognitive function and quality of life (EQ-5D, Stroke Impact Scale). Discussion Embolic stroke of undetermined source is caused by embolic disease and associated with a high risk of recurrent ischemic strokes and clinically silent cerebral ischemic lesions. ATTICUS will investigate the impact of atrial fibrillation detected by insertable cardiac monitor and the effects of early anticoagulation with apixaban compared with antiplatelet therapy with acetylsalicylic acid on the incidence of new ischemic lesion after embolic stroke of undetermined source.
authors.affiliation: 1 Department of Cardiology, German Heart Competence Centre, Tübingen, Germany.
authors.forename: Tobias
authors.initials: T
authors.lastname: Geisler
authors.affiliation: 2 Department of Neurology and Stroke, Tübingen Center of Neurovascular Diseases, Tübingen, Germany.
authors.forename: Sven
authors.initials: S
authors.lastname: Poli
authors.affiliation: 3 Eberhard-Karl University of Tübingen, Institute for Clinical Epidemiology and Applied Biometry, Tübingen, Germany.
authors.forename: Christoph
authors.initials: C
authors.lastname: Meisner
authors.affiliation: 1 Department of Cardiology, German Heart Competence Centre, Tübingen, Germany.
authors.forename: Juergen
authors.initials: J
authors.lastname: Schreieck
authors.affiliation: 1 Department of Cardiology, German Heart Competence Centre, Tübingen, Germany.
authors.forename: Christine S
authors.initials: CS
authors.lastname: Zuern
authors.affiliation: 4 Department of Neuroradiology, University of Tübingen, Tübingen, Germany.
authors.forename: Thomas
authors.initials: T
authors.lastname: Nägele
authors.affiliation: 5 Department of Internal Medicine II, Cardiology, Angiology and Pneumology, Klinikum Coburg GmbH, Coburg, Germany.
authors.forename: Johannes
authors.initials: J
authors.lastname: Brachmann
authors.affiliation: 6 Department of Internal Medicine III, Schwarzwald-Baar Klinikum, Villingen-Schwenningen, Germany.
authors.forename: Werner
authors.initials: W
authors.lastname: Jung
authors.affiliation: 7 Department Neurologie, Klinikum Karlsruhe, Karlsruhe, Germany.
authors.forename: Georg
authors.initials: G
authors.lastname: Gahn
authors.affiliation: 8 Department of Neurology, Klinikum Stuttgart, Stuttgart, Germany.
authors.forename: Elisabeth
authors.initials: E
authors.lastname: Schmid
authors.affiliation: 8 Department of Neurology, Klinikum Stuttgart, Stuttgart, Germany.
authors.forename: Hansjörg
authors.initials: H
authors.lastname: Bäezner
authors.affiliation: 1 Department of Cardiology, German Heart Competence Centre, Tübingen, Germany.
authors.forename: Timea
authors.initials: T
authors.lastname: Keller
authors.affiliation: 9 Department of Neurology, University Hospital Bonn, Bonn, Germany.|10 German Center for Neurodegenerative Diseases (DZNE), Bonn, Germany.
authors.forename: Gabor C
authors.initials: GC
authors.lastname: Petzold
authors.affiliation: 11 Department of Medicine-Cardiology, University Hospital Bonn, Bonn, Germany.
authors.forename: Jan-Wilko
authors.initials: JW
authors.lastname: Schrickel
authors.affiliation: 12 Department of Neurology, University of Göttingen, Göttingen, Germany.
authors.forename: Jan
authors.initials: J
authors.lastname: Liman
authors.affiliation: 13 Department of Cardiology and Pneumology, Göttingen University Medical Center, German Cardiovascular Research Center (DZHK), partner site Göttingen, Germany.
authors.forename: Rolf
authors.initials: R
authors.lastname: Wachter
authors.affiliation: 14 Department of Neurology, Klinikum Ludwigsburg, Ludwigsburg, Germany.
authors.forename: Frauke
authors.initials: F
authors.lastname: Schön
authors.affiliation: 14 Department of Neurology, Klinikum Ludwigsburg, Ludwigsburg, Germany.
authors.forename: Martin
authors.initials: M
authors.lastname: Schabet
authors.affiliation: 15 Department of Neurology, Marienhospital Stuttgart, Stuttgart, Germany.
authors.forename: Alfred
authors.initials: A
authors.lastname: Lindner
authors.affiliation: 16 Department of Neurology, University of Ulm, Ulm, Germany.
authors.forename: Albert C
authors.initials: AC
authors.lastname: Ludolph
authors.affiliation: 17 Clinic of Neurology, Schwarzwald-Baar Klinikum, Villingen-Schwenningen, Germany.|18 Department of Neurology, University Freiburg, Freiburg, Germany.
authors.forename: Hubert
authors.initials: H
authors.lastname: Kimmig
authors.affiliation: 19 Department of Neurology, Heinrich-Heine-University, Düsseldorf, Germany.
authors.forename: Sebastian
authors.initials: S
authors.lastname: Jander
authors.affiliation: 20 Department of Neurology, Knappschaftskrankenhaus, Klinikum der Ruhr-Universität Bochum, Bochum, Germany.
authors.forename: Uwe
authors.initials: U
authors.lastname: Schlegel
authors.affiliation: 1 Department of Cardiology, German Heart Competence Centre, Tübingen, Germany.
authors.forename: Meinrad
authors.initials: M
authors.lastname: Gawaz
authors.affiliation: 2 Department of Neurology and Stroke, Tübingen Center of Neurovascular Diseases, Tübingen, Germany.
authors.forename: Ulf
authors.initials: U
authors.lastname: Ziemann
mesh_terms: D001241:Aspirin / Q000627:therapeutic use; D001921:Brain / Q000000981:diagnostic imaging / Q000187:drug effects; D004617:Embolism / Q000000981:diagnostic imaging / Q000188:drug therapy*; D065427:Factor Xa Inhibitors / Q000627:therapeutic use*; D005343:Fibrinolytic Agents / Q000627:therapeutic use; D006801:Humans; D011720:Pyrazoles / Q000627:therapeutic use*; D011728:Pyridones / Q000627:therapeutic use*; D012107:Research Design; D055502:Secondary Prevention; D020521:Stroke / Q000000981:diagnostic imaging / Q000188:drug therapy*
chemical_list: D065427:Factor Xa Inhibitors; D005343:Fibrinolytic Agents; D011720:Pyrazoles; D011728:Pyridones; C522181:apixaban; D001241:Aspirin
keywords: ESUS; NOAC; apixaban; aspirin; atrial fibrillation; intracardiac monitor; stroke