[Skip to Navigation]
Access to paid content on this site is currently suspended due to excessive activity being detected from your IP address Please contact the publisher to request reinstatement.
Original Investigation
July 6, 2020

Characteristics of Recurrent Ischemic Stroke After Embolic Stroke of Undetermined Source: Secondary Analysis of a Randomized Clinical Trial

Author Affiliations
  • 1Division of Brain Sciences, Imperial College London, London, United Kingdom
  • 2Department of Neurology, Alfried Krupp Krankenhaus, Essen, Germany
  • 3currently a biostatistics consultant, St Catharines, Ontario, Canada
  • 4Department of Clinical Therapeutics, National and Kapodistrian University of Athens, Athens, Greece
  • 5Population Health Research Institute, Department of Medicine, McMaster University, Hamilton, Ontario, Canada
  • 6Department of Neurology, University of Pennsylvania, Philadelphia
  • 7Department of Human Neurosciences, Sapienza University of Rome, Rome, Italy
  • 8Departamento de Neurología, Fleni, Buenos Aires, Argentina
  • 9Bayer AG, Wuppertal, Germany
  • 10Department of Clinical Neuroscience, Institute of Neurosciences and Physiology, Sahlgrenska Academy at University of Gothenburg, Gothenburg, Sweden
  • 11Department of Neurology, Sahlgrenska University Hospital, Gothenburg, Sweden
  • 12Faculty of Health and Medical Sciences, Medical School, University of Western Australia, Perth, Australia
  • 13Department of Clinical Sciences and Neurology, Lund University, Lund, Sweden
  • 14Department of Neurology, Skåne University Hospital, Lund, Sweden
  • 15Bayer, LLC, Whippany, New Jersey
  • 16Instituto Nacional de Neurologia y Neurocirugia Manual Velasco Suarez, Mexico City, Mexico
  • 17Department of Neurology, Faculty of Medicine, Selcuk University, Konya, Turkey
  • 18Institute of Neuroscience and Psychology, University of Glasgow, Queen Elizabeth University Hospital, Glasgow, United Kingdom
  • 19Department of Neuroscience, Hospital Clinic of Barcelona, Institute Reçerca Biomèdica August Pi i Sunyer, University of Barcelona, Barcelona, Spain
  • 20Department of Medicine, University of Alberta, Edmonton, Canada
JAMA Neurol. 2020;77(10):1233-1240. doi:10.1001/jamaneurol.2020.1995
Key Points

Question  What are the characteristics and the etiology of recurrent strokes after embolic strokes of undetermined source?

Findings  In this secondary analysis of a randomized clinical trial, recurrent ischemic stroke occurred in 309 of 7213 patients undergoing randomization. Among 270 classifiable recurrent strokes, 156 (58%) were embolic strokes of undetermined source, and 114 (42%) were not. Atrial fibrillation was found in 27 recurrent strokes (9%) and was associated with higher mortality and disability compared with other causes.

Meaning  This trial analysis found that most stroke recurrences after embolic strokes of undetermined source were embolic and often of undetermined source; few were associated with atrial fibrillation, and these had worse outcomes.


Importance  The concept of embolic stroke of undetermined source (ESUS) unifies a subgroup of cryptogenic strokes based on neuroimaging, a defined minimum set of diagnostic tests, and exclusion of certain causes. Despite an annual stroke recurrence rate of 5%, little is known about the etiology underlying recurrent stroke after ESUS.

Objective  To identify the stroke subtype of recurrent ischemic strokes after ESUS, to explore the interaction with treatment assignment in each category, and to examine the consistency of cerebral location of qualifying ESUS and recurrent ischemic stroke.

Design, Setting, and Participants  The NAVIGATE-ESUS trial was a randomized clinical trial conducted from December 23, 2014, to October 5, 2017. The trial compared the efficacy and safety of rivaroxaban and aspirin in patients with recent ESUS (n = 7213). Ischemic stroke was validated in 309 of the 7213 patients by adjudicators blinded to treatment assignment and classified by local investigators into the categories ESUS or non-ESUS (ie, cardioembolic, atherosclerotic, lacunar, other determined cause, or insufficient testing). Five patients with recurrent strokes that could not be defined as ischemic or hemorrhagic in absence of neuroimaging or autopsy were excluded. Data for this secondary post hoc analysis were analyzed from March to June 2019.

Interventions  Patients were randomly assigned to receive rivaroxaban, 15 mg/d, or aspirin, 100 mg/d.

Main Outcomes and Measures  Association of recurrent ESUS with stroke characteristics.

Results  A total of 309 patients (205 men [66%]; mean [SD] age, 68 [10] years) had ischemic stroke identified during the median follow-up of 11 (interquartile range [IQR], 12) months (annualized rate, 4.6%). Diagnostic testing was insufficient for etiological classification in 39 patients (13%). Of 270 classifiable ischemic strokes, 156 (58%) were ESUS and 114 (42%) were non-ESUS (37 [32%] cardioembolic, 26 [23%] atherosclerotic, 35 [31%] lacunar, and 16 [14%] other determined cause). Atrial fibrillation was found in 27 patients (9%) with recurrent ischemic stroke and was associated with higher morbidity (median change in modified Rankin scale score 2 [IQR, 3] vs 0 (IQR, 1]) and mortality (15% vs 1%) than other causes. Risk of recurrence did not differ significantly by subtype between treatment groups. For both the qualifying and recurrent strokes, location of infarct was more often in the left (46% and 54%, respectively) than right hemisphere (40% and 37%, respectively) or brainstem or cerebellum (14% and 9%, respectively).

Conclusions and Relevance  In this secondary analysis of randomized clinical trial data, most recurrent strokes after ESUS were embolic and of undetermined source. Recurrences associated with atrial fibrillation were a minority but were more often disabling and fatal. More extensive investigation to identify the embolic source is important toward an effective antithrombotic strategy.

Trial Registration  ClinicalTrials.gov Identifier: NCT02313909

Limit 200 characters
Limit 25 characters
Conflicts of Interest Disclosure

Identify all potential conflicts of interest that might be relevant to your comment.

Conflicts of interest comprise financial interests, activities, and relationships within the past 3 years including but not limited to employment, affiliation, grants or funding, consultancies, honoraria or payment, speaker's bureaus, stock ownership or options, expert testimony, royalties, donation of medical equipment, or patents planned, pending, or issued.

Err on the side of full disclosure.

If you have no conflicts of interest, check "No potential conflicts of interest" in the box below. The information will be posted with your response.

Not all submitted comments are published. Please see our commenting policy for details.

Limit 140 characters
Limit 3600 characters or approximately 600 words