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Original Investigation
October 19, 2020

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

Author Affiliations
  • 1Division of Neurology, McMaster University / Population Health Research Institute, Hamilton, Ontario, Canada
  • 2Department of Neurology, University of Pennsylvania, Philadelphia
  • 3Department of Clinical Neurosciences, University of Calgary, Calgary, Alberta, Canada
  • 4Hospital de la Santa Creu i Sant Pau, Barcelona, Spain
  • 5Department of Statistics, Population Health Research Institute, Hamilton, Ontario, Canada
  • 6Department of Neurology, Clinical Research Center for Medicine, International University of Health and Welfare, Tokyo, Japan
  • 7International Clinical Research Center and Department of Neurology, St. Anne’s University Hospital and Masaryk University, Brno, Czech Republic
  • 8Department of Neurology, Imperial College Healthcare NHS Trust, London, United Kingdom
  • 9Department of Medicine, National University of Ireland Galway, Galway, Ireland
  • 10Department of Internal Medicine, University of Thessaly, Larissa, Greece
  • 11Institute of Neuroscience & Psychology, University of Glasgow, Glasgow, Scotland
  • 12Division of Neurology, University of British Columbia, Vancouver, Canada
  • 13Department of Neurology, Hospitais da Universidade de Coimbra, Coimbra, Portugal
  • 14Department of Neurology and Psychiatry, Clínica Alemana de Santiago, Facultad de Medicina, Clínica Alemana Universidad del Desarrollo, Santiago, Chile
  • 15Pharmaceuticals Development, TA Cardiovascular, Bayer Pharma AG, Wuppertal, Germany
  • 16Department of Neurology, Oregon Health and Science University, Portland
  • 17Thrombosis Group, Pharmaceuticals Research and Development, Bayer, Whippany, New Jersey
JAMA Neurol. 2021;78(1):11-20. doi:10.1001/jamaneurol.2020.3836
Key Points

Question  Does the presence of cerebral microbleeds (CMBs) modify the effect of rivaroxaban, 15 mg, compared with aspirin, 100 mg, daily in patients with embolic stroke of undetermined source (ESUS)?

Findings  In this analysis of a randomized clinical trial that included 3699 patients with ESUS, those with CMBs had higher rates of recurrent stroke, ischemic stroke, intracerebral hemorrhage, and mortality during 11 months of follow-up. There was, however, no treatment effect modification observed with CMBs for these outcomes.

Meaning  In this study, CMBs marked an increased risk of adverse clinical outcomes in ESUS but did not appear to influence the effects of rivaroxaban.


Importance  The reported associations of cerebral microbleeds with recurrent stroke and intracerebral hemorrhage have raised concerns regarding antithrombotic treatment in patients with a history of stroke and microbleeds on magnetic resonance imaging.

Objective  To characterize microbleeds in embolic strokes of undetermined source (ESUS) and report interactions between microbleeds and the effects of random assignment to anticoagulant vs antiplatelet therapy.

Design, Setting, and Participants  Subgroup analyses of the New Approach Rivaroxaban Inhibition of Factor Xa in a Global Trial vs Aspirin to Prevent Embolism in ESUS (NAVIGATE ESUS) international, double-blind, randomized, event-driven phase 3 clinical trial. Participants were enrolled between December 2014 and September 2017 and followed up for a median of 11 months. The study setting included 459 stroke recruitment centers in 31 countries. Patients aged 50 years or older who had neuroimaging-confirmed ESUS between 7 days and 6 months before screening were eligible. Of these 7213 NAVIGATE ESUS participants, 3699 (51%) had information on cerebral microbleeds reported on their baseline clinical magnetic resonance imaging and were eligible for these analyses. Patients with a prior history of symptomatic intracerebral hemorrhage were excluded from the NAVIGATE ESUS trial.

Interventions  Rivaroxaban, 15 mg, compared with aspirin, 100 mg, daily.

Main Outcomes and Measures  The primary outcome was recurrent stroke. Secondary outcomes were ischemic stroke, intracerebral hemorrhage, and all-cause mortality.

Results  Microbleeds were present in 395 of 3699 participants (11%). Of patients with cerebral microbleeds, mean (SD) age was 69.5 (9.4) years, 241 were men (61%), and 201 were White (51%). Advancing age (odds ratio [OR] per year, 1.03; 95% CI, 1.01-1.04), East Asian race/ethnicity (OR, 1.57; 95% CI, 1.04-2.37), hypertension (OR, 2.20; 95% CI, 1.54-3.15), multiterritorial infarcts (OR, 1.95; 95% CI, 1.42-2.67), chronic infarcts (OR, 1.78; 95% CI, 1.42-2.23), and occult intracerebral hemorrhage (OR, 5.23; 95% CI, 2.76-9.90) were independently associated with microbleeds. The presence of microbleeds was associated with a 1.5-fold increased risk of recurrent stroke (hazard ratio [HR], 1.5; 95% CI, 1.0-2.3), a 4-fold risk of intracerebral hemorrhage (HR, 4.2; 95% CI, 1.3-13.9), a 2-fold risk of all-cause mortality (HR, 2.1; 95% CI, 1.1-4.3), and strictly lobar microbleeds with an approximately 2.5-fold risk of ischemic stroke (HR, 2.3; 95% CI, 1.3-4.3). There were no interactions between microbleeds and treatment assignments for recurrent stroke, ischemic stroke, or all-cause mortality. The HR of intracerebral hemorrhage on rivaroxaban was similar between persons with microbleeds (HR, 3.1; 95% CI, 0.3-30.0) and persons without microbleeds (HR, 3.0; 95% CI, 0.6-14.7; interaction P = .97).

Conclusions and Relevance  Microbleeds mark an increased risk of recurrent stroke, ischemic stroke, intracerebral hemorrhage, and mortality in ESUS but do not appear to influence effects of rivaroxaban on clinical outcomes.

Trial Registration  ClinicalTrials.gov Identifier: NCT02313909

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