BACKGROUND: Embolic strokes of undetermined source comprise up to 20% of ischemic strokes. The stroke recurrence rate is substantial with aspirin, widely used for secondary prevention. The New Approach riVaroxaban Inhibition of Factor Xa in a Global trial versus ASA to prevenT Embolism in Embolic Stroke of Undetermined Source international trial will compare the efficacy and safety of rivaroxaban, an oral factor Xa inhibitor, versus aspirin for secondary prevention in patients with recent embolic strokes of undetermined source. MAIN HYPOTHESIS: In patients with recent embolic strokes of undetermined source, rivaroxaban 15 mg once daily will reduce the risk of recurrent stroke (both ischemic and hemorrhagic) and systemic embolism (primary efficacy outcome) compared with aspirin 100 mg once daily. DESIGN: Double-blind, randomized trial in patients with embolic strokes of undetermined source, defined as nonlacunar cryptogenic ischemic stroke, enrolled between seven days and six months from the qualifying stroke. The planned sample size of 7000 participants will be recruited from approximately 480 sites in 31 countries between 2014 and 2017 and followed for a mean of about two years until at least 450 primary efficacy outcome events have occurred. The primary safety outcome is major bleeding. Two substudies assess (1) the relative effect of treatments on MRI-determined covert brain infarcts and (2) the biological underpinnings of embolic strokes of undetermined source using genomic and biomarker approaches. SUMMARY: The New Approach riVaroxaban Inhibition of Factor Xa in a Global trial versus ASA to prevenT Embolism in Embolic Stroke of Undetermined Source trial is evaluating the benefits and risks of rivaroxaban for secondary stroke prevention in embolic strokes of undetermined source patients. Main results are anticipated in 2018.

2nd Department of Neurology Institute of Psychiatry and Neurology Medical University of Warsaw Warsaw Poland

Bayer Healthcare Pharmaceuticals Parsippany USA

Bayer Pharma AG Berlin Germany

Bayer Pharma AG Wuppertal Germany

Bayer Vital Leverkusen Germany

Baylor College of Medicine Houston USA

Centro Hospitalar e Universitário de Coimbra Coimbra Portugal

Clinica Alemana de Santiago Universidad del Desarrollo Universidad de Chile Santiago Chile

Department of Clinical Epidemiology and Biostatistics Department of Medicine Population Health Research Institute McMaster University Hamilton Health Sciences Hamilton Canada

Department of Clinical Sciences Department of Neurology and Rehabilitation Medicine Skane University Hospital Lund University Lund Sweden

Department of Innere Medizin Universitätsspital Basel Basel Switzerland

Department of Medicine Population Health Research Institute McMaster University Hamilton Health Sciences Hamilton Canada

Department of Medicine University of Thessaly Larissa Greece

Department of Neurology and Psychiatry Sapienza University of Rome Rome Italy

Department of Neurology Beijing Tiantan Hospital Capital Medical University Beijing China

Department of Neurology Bichat Hospital Paris France

Department of Neurology Helsinki University Central Hospital Helsinki Finland

Department of Neurology Selcuk University Konya Turkey

Department of Neurology Semmelweis University Budapest Hungary

Department of Neurology Seoul National University Hospital Seoul Korea

Department of Neurology University of Pennsylvania Philadelphia USA

Department of Neurosciences Hospital Universitari Germans Trias i Pujol Barcelona Spain

Groote Schuur Hospital University of Cape Town Cape Town South Africa

Hospital St John of God Medical Faculty Sigmund Freud University Vienna Austria

Imperial College London London UK

Institute for Neurological Research Fundacion para la Lucha contra las Enfermedades Neurologicas de la Infancia Buenos Aires Argentina

Institute of Neuroscience and Psychology University of Glasgow Queen Elizabeth University Hospital Glasgow UK

Instituto Nacional de Neurologia y Neurocirugia Mexico D F Mexico

International Clinical Research Center and Neurology Department St Anne's University Hospital Brno Czech Republic

Irmandade da Santa Casa de Misericórdia de São Paulo Sao Paulo Brazil

Janssen Research and Development LLC Spring House Pennsylvania USA

Klinik und Hochschulambulanz für Neurologie Center for Stroke Research Berlin Charité Universitätsmedizin Berlin Germany

National University of Ireland Galway Ireland

Pirogov Russian National Research Medical University Moscow Russia

Population Health Research Institute Hamilton Canada

Sanno Hospital and Sanno Medical Center Tokyo Japan

School of Medicine and Pharmacology University of Western Australia Sir Charles Gairdner Hospital Perth Australia

Tel Aviv Medical Center Tel Aviv Israel

Thrombosis and Atherosclerosis Research Institute McMaster University Hamilton Canada

Universitair Ziekenhuis Brussel Brussels Belgium

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Rivaroxaban versus aspirin for prevention of covert brain infarcts in patients with embolic stroke of undetermined source: NAVIGATE ESUS MRI substudy

Microbleeds and the Effect of Anticoagulation in Patients With Embolic Stroke of Undetermined Source: An Exploratory Analysis of the NAVIGATE ESUS Randomized Clinical Trial

Characterization of Patients with Embolic Strokes of Undetermined Source in the NAVIGATE ESUS Randomized Trial