BACKGROUND: Covert brain infarcts are associated with important neurological morbidity. Their incidence in patients with embolic stroke of undetermined source (ESUS) is unknown. AIMS: To assess the incidence of covert brain infarcts and cerebral microbleeds using MRI in a prospective substudy of the NAVIGATE ESUS randomized trial and to evaluate the effects of antithrombotic therapies. METHODS: At 87 sites in 15 countries, substudy participants were randomly assigned to receive rivaroxaban 15 mg daily or aspirin 100 mg daily and underwent brain MRI near randomization and after study termination. The primary outcome was incident brain infarct (clinical ischemic stroke or covert brain infarct). Brain infarcts and microbleeds were ascertained centrally by readers unaware of treatment. Treatment effects were estimated using logistic regression. RESULTS: Among the 718 substudy participants with interpretable, paired MRIs, the mean age was 67 years and 61% were men with a median of 52 days between the qualifying ischemic stroke and randomization and a median of seven days between randomization and baseline MRI. During the median (IQR) 11 (12) month interval between scans, clinical ischemic strokes occurred in 27 (4%) participants, while 60 (9%) of the remaining participants had an incident covert brain infarct detected by MRI. Assignment to rivaroxaban was not associated with reduction in the incidence of brain infarct (OR 0.77, 95% CI 0.49, 1.2) or of covert brain infarct among those without clinical stroke (OR 0.85, 95% CI 0.50, 1.4). New microbleeds were observed in 7% and did not differ among those assigned rivaroxaban vs. aspirin (HR 0.95, 95% CI 0.52-1.7). CONCLUSIONS: Incident covert brain infarcts occurred in twice as many ESUS patients as a clinical ischemic stroke. Treatment with rivaroxaban compared with aspirin did not significantly reduce the incidence of covert brain infarcts or increase the incidence of microbleeds, but the confidence intervals for treatment effects were wide.Registration: https://www.clinicaltrials.gov. Unique identifier: NCT02313909.

Bayer AG Wuppertal Germany

Center for Stroke Research Charite Universitatsmedizin Berlin Berlin Germany

Department of Brain Sciences 4615Imperial College London London UK

Department of Clinical Neurosciences 2129University of Calgary Calgary AB Canada

Department of Human Neurosciences Sapienza University of Rome Rome Italy

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

Department of Neurology Aarhus University Hospital Aarhus Denmark

Department of Neurology Semmelweis University Budapest Hungary

Department of Neurology Seoul National University Hospital Seoul Korea

Department of Neurology University of Pennsylvania Philadelphia PA USA

Department of Radiology Girona Biomedical Research Institute Hospital Dr Josep Trueta Girona Spain

Division de Neurologia Vascular Departmento de Neurologia Institute for Neurological Research FLENI Cuidad Autonoma Buenos Aires Argentina

Federal Center of Brain Research and Neurotechnology Federal Medical Biological Agency Moscow Russia

HRB Clinical Research Facility National University Ireland Galway Ireland

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

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

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

Pharmaceuticals Clinical Development Thrombosis Bayer U S LLC Whippany NJ USA

Population Health Research Institute Hamilton Health Sciences Hamilton ON Canada

St Catharines Ontario Canada

University Department of Geriatic Medicine Felix Platter Department of Neurology University of Basel University Hospital Basel Basel Switzerland

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Smith EE, Saposnik G, Biessels GJ, et al. Prevention of stroke in patients with silent cerebrovascular disease: a scientific statement for Healthcare Professionals from the American Heart Association/American Stroke Association. Stroke 2017; 48: e44–e71. PubMed

Vermeer SE, Longstreth WT, Jr, Koudstaal PJ. Silent brain infarcts: a systematic review. Lancet Neurol 2007; 6: 611–619. PubMed

Hart RG, Diener HC, Coutts SB, et al. on behalf of the Cryptogenic Stroke/ESUS International Working Group. Embolic strokes of undetermined source: the case for a new clinical construct. Lancet Neurol 2014; 13: 429–438. PubMed

Hart RG, Sharma M, Mundl H, et al. for the NAVIGATE ESUS Steering Committee. Rivaroxaban for secondary stroke prevention in patients with embolic strokes of undetermined source: design of the NAVIGATE ESUS randomized trial. Euro Stroke J 2016; 1: 146–154. PubMed PMC

Hart RG, Sharma M, Mundl H, for the NAVIGATE ESUS, Investigators. Rivaroxaban for stroke prevention after embolic stroke of undetermined source. N Engl J Med 2018; 378: 2191–2201. PubMed

Wardlaw JM, Smith EE, Biessels GJ, et al. Neuroimaging standards for research into small vessel disease and its contribution to ageing and neurodegeneration. Lancet Neurol 2013; 12: 822–838. PubMed PMC

Sharma M, Hart RG, Smith EE, et al. Rivaroxaban for prevention of covert brain infarcts and cognitive decline. Stroke 2020; 51: 2901–2909. PubMed

Butcher K, Ng K, Sheridan P, et al. Dabigatran treatment of acute non-cardioembolic ischemic stroke. Stroke 2020; 51: 1190–1198. PubMed

Sondergaard L, Kasner SE, Rhodes JF, for the Gore REDUCE Clinical Study Investigators. Patent foramen ovale closure or antiplatelet therapy for cryptogenic stroke. N Engl J Med 2017; 377: 1033–1042. PubMed

Pinter D, Gattringer T, Enzinger C, et al. Longitudinal MRI dynamics of recent small subcortical infarcts and possible predictors. J Cerebral Blood Flow Met 2019; 39: 1669–1677. PubMed PMC

Hilal S, Baaij LGA, de Groot M, et al. Prevalence and clinical relevance of diffusion weighted imaging lesions. Neurol 2019; 93: e1058–e1067. PubMed

O’Donnell MJ, Eikelboom JW, Yusuf S, et al. Effect of apixaban on brain infarction and microbleeds: AVERROES-MRI assessment study. Am Heart J 2016; 178: 145–150. PubMed

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ClinicalTrials.gov
NCT02313909