Abstract
Ischaemic strokes have traditionally been classified according to the TOAST criteria, in which strokes with unclear aetiology are classified as cryptogenic strokes. However, the definition of cryptogenic stroke did not meet the operational criteria necessary to define patient populations for randomized treatment trials. To address this problem, the concept of embolic stroke of undetermined source (ESUS) was developed and published in 2014. A hypothesis that underpinned this concept was that most strokes in patients with ESUS are caused by embolic events, perhaps many cardioembolic, and that anticoagulation would prevent secondary ischaemic events. On this basis, two large randomized trials were conducted to compare the non-vitamin K antagonist oral anticoagulants (NOACs) dabigatran and rivaroxaban with aspirin. Neither NOAC was superior to aspirin in these trials, although subgroups of patients with ESUS seemed to benefit specifically from anticoagulation or antiplatelet therapy. The neutral results of the trials of anticoagulation and insights into ESUS from research conducted since the concept was introduced warrant reassessment of the ESUS construct as a research concept and a treatment target. In this Review, we discuss the evidence produced since the concept of ESUS was introduced, and propose updates to the criteria and diagnostic algorithm in light of the latest knowledge.
Key points
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Embolic stroke of undetermined source (ESUS) is a subtype of cryptogenic ischaemic stroke and accounts for ~20% of all ischaemic strokes; its diagnosis requires a specified evaluation.
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Non-stenotic atherosclerotic plaques are a major contributor to ESUS.
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Neutral results in randomized trials that compared dabigatran and rivaroxaban (non-vitamin K oral anticoagulants) with aspirin mean that anticoagulation cannot be recommended for secondary prevention of ischaemic stroke in unselected patients with ESUS.
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Patients aged <60 years with an otherwise unexplained ischaemic stroke and a patent foramen ovale (PFO) with high-risk clinical and/or anatomical features should be diagnosed with PFO-associated stroke rather than ESUS.
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Studies to identify subgroups of patients with ESUS who could benefit from anticoagulation (for example, patients with atrial cardiopathy) are underway.
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H.-C.D. has received honoraria for participation in clinical trials, contribution to advisory boards or oral presentations from Abbott, BMS, Boehringer Ingelheim, Daiichi-Sankyo, Medtronic, Novo-Nordisk, Pfizer, Portola and WebMD Global. He has received financial support for research projects from Boehringer Ingelheim. He has received research grants from the German Research Council (DFG), German Ministry of Education and Research (BMBF), European Union, NIH, Bertelsmann Foundation and Heinz-Nixdorf Foundation. He serves as editor of Neurologie up2date, Info Neurologie & Psychiatrie and Arzneimitteltherapie. J.D.E. has received research grant support from AstraZeneca for the planning and conduct of the SOCRATES trial (NCT01994720), research grant support as a consultant from Boehringer Ingelheim for the planning and conduct of the RE-SPECT ESUS trial (NCT02239120), and research grant support from NIH/NINDS as Co-Principal Investigator on the POINT trial (NCT00991029); POINT received free study drug and placebo from Sanofi. He has also received an honorarium for participating in a consultant/advisory board meeting for Sanofi in May 2019. R.G.H. led the NAVIGATE ESUS trial sponsored by Bayer and received research support and a stipend from Bayer. He currently receives research support and a stipend from Bayer for co-ordination of the PACIFIC-Stroke trial. S.K. has received grant support from Medtronic and WL Gore & Associates; consulting fees from Abbott, Abbvie, Bayer, Boehringer Ingelheim, Bristol-Myers Squibb and Medtronic; and royalties from UpToDate. H.K. serves as a principal investigator for the NIH-funded ARCADIA trial (NINDS U01NS095869), which receives in-kind study drug from the BMS-Pfizer Alliance for Eliquis and ancillary study support from Roche Diagnostics. He serves as Deputy Editor for JAMA Neurology, serves as a steering committee member of Medtronic’s Stroke AF trial, serves on a trial executive committee for Janssen, and serves on an end point adjudication committee for a trial of empagliflozin for Boehringer Ingelheim. G.N. has received honoraria for participation in clinical trials, contribution to advisory boards or oral presentations from Abbott, Amgen, AstraZeneca, Bayer, Bristol Myers Squibb, Elpen, Pfizer and Sanofi. He has received financial support for research projects from Amgen, the EU and Pfizer.
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Nature Reviews Neurology thanks N. Akoum; M. Koga; F. Nahab, who co-reviewed with G. Mohamed; and J. Putaala for their contribution to the peer review of this work.
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Glossary
- NAVIGATE ESUS
-
New approach rivaroxaban inhibition of factor Xa in a global trial versus ASA to prevent embolism in embolic stroke of undetermined source.
- RE-SPECT ESUS
-
Randomized, double-blind evaluation in secondary stroke prevention comparing the efficacy and safety of the oral thrombin inhibitor dabigatran etexilate versus acetylsalicylic acid in patients with embolic stroke of undetermined source.
- ATTICUS
-
Apixaban for treatment of embolic stroke of undetermined source.
- CLOSURE
-
Evaluation of the STARFlex Septal Closure System in patients with a stroke and/or transient ischemic attack due to presumed paradoxical embolism through a patent foramen ovale.
- RESPECT
-
Randomized evaluation of recurrent stroke comparing PFO closure to established current standard of care treatment.
- PC
-
Percutaneous closure of patent foramen ovale in cryptogenic embolism.
- CLOSE
-
Patent foramen ovale closure or anticoagulants versus antiplatelet therapy to prevent stroke recurrence.
- REDUCE
-
GORE HELEX Septal Occluder/GORE CARDIOFORM Septal Occluder and antiplatelet medical management for reduction of recurrent stroke or imaging-confirmed TIA in patients with patent foramen ovale (PFO).
- DEFENSE-PFO
-
Device closure versus medical therapy for cryptogenic stroke patients with high-risk patent foramen ovale.
- PICSS
-
Patent foramen ovale in cryptogenic stroke study.
- ARCADIA
-
Atrial cardiopathy and antithrombotic drugs in prevention after cryptogenic stroke.
- MOSES
-
Midregional proatrial natriuretic peptide to guide secondary stroke prevention.
- AVERROES
-
Apixaban versus acetylsalicylic acid (ASA) to prevent stroke in atrial fibrillation patients who have failed or are unsuitable for vitamin K antagonist treatment.
- TEACH2
-
Trial of apixaban versus aspirin in cancer patients with cryptogenic ischemic stroke.
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Diener, HC., Easton, J.D., Hart, R.G. et al. Review and update of the concept of embolic stroke of undetermined source. Nat Rev Neurol 18, 455–465 (2022). https://doi.org/10.1038/s41582-022-00663-4
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DOI: https://doi.org/10.1038/s41582-022-00663-4
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