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Multicenter Study
. 2022 May 1;79(5):450-458.
doi: 10.1001/jamaneurol.2022.0048.

Evaluating Rates of Recurrent Ischemic Stroke Among Young Adults With Embolic Stroke of Undetermined Source: The Young ESUS Longitudinal Cohort Study

Kanjana S Perera  1   2 , Danielle de Sa Boasquevisque  1   2 , Purnima Rao-Melacini  1   3 , Amanda Taylor  2 , Anna Cheng  2 , Graeme J Hankey  4   5 , Sarah Lee  6   7 , Joan Marti Fabregas  8 , Sebastian F Ameriso  9 , Thalia S Field  10 , Antonio Arauz  11 , Shelagh B Coutts  12 , Marcel Arnold  13 , Robert Mikulik  14   15 , Danilo Toni  16 , Jennifer Mandzia  17 , Roland C Veltkamp  18 , Elena Meseguer  19 , Karl Georg Haeusler  20 , Robert G Hart  2 ; Young ESUS Investigators
Collaborators, Affiliations
Multicenter Study

Evaluating Rates of Recurrent Ischemic Stroke Among Young Adults With Embolic Stroke of Undetermined Source: The Young ESUS Longitudinal Cohort Study

Kanjana S Perera et al. JAMA Neurol. .

Abstract

Importance: Cryptogenic strokes constitute approximately 40% of ischemic strokes in young adults, and most meet criteria for the embolic stroke of undetermined source (ESUS). Two randomized clinical trials, NAVIGATE ESUS and RESPECT ESUS, showed a high rate of stroke recurrence in older adults with ESUS but the prognosis and prognostic factors among younger individuals with ESUS is uncertain.

Objective: To determine rates of and factors associated with recurrent ischemic stroke and death and new-onset atrial fibrillation (AF) among young adults.

Design, setting, and participants: This multicenter longitudinal cohort study with enrollment from October 2017 to October 2019 and a mean follow-up period of 12 months ending in October 2020 included 41 stroke research centers in 13 countries. Consecutive patients 50 years and younger with a diagnosis of ESUS were included. Of 576 screened, 535 participants were enrolled after 1 withdrew consent, 41 were found to be ineligible, and 2 were excluded for other reasons. The final follow-up visit was completed by 520 patients.

Main outcomes and measures: Recurrent ischemic stroke and/or death, recurrent ischemic stroke, and prevalence of patent foramen ovale (PFO).

Results: The mean (SD) age of participants was 40.4 (7.3) years, and 297 (56%) participants were male. The most frequent vascular risk factors were tobacco use (240 patients [45%]), hypertension (118 patients [22%]), and dyslipidemia (109 patients [20%]). PFO was detected in 177 participants (50%) who had transthoracic echocardiograms with bubble studies. Following initial ESUS, 468 participants (88%) were receiving antiplatelet therapy, and 52 (10%) received anticoagulation. The recurrent ischemic stroke and death rate was 2.19 per 100 patient-years, and the ischemic stroke recurrence rate was 1.9 per 100 patient-years. Of the recurrent strokes, 9 (64%) were ESUS, 2 (14%) were cardioembolic, and 3 (21%) were of other determined cause. AF was detected in 15 participants (2.8%; 95% CI, 1.6-4.6). In multivariate analysis, the following were associated with recurrent ischemic stroke: history of stroke or transient ischemic attack (hazard ratio, 5.3; 95% CI, 1.8-15), presence of diabetes (hazard ratio, 4.4; 95% CI, 1.5-13), and history of coronary artery disease (hazard ratio, 10; 95% CI, 4.8-22).

Conclusions and relevance: In this large cohort of young adult patients with ESUS, there was a relatively low rate of subsequent ischemic stroke and a low frequency of new-onset AF. Most recurrent strokes also met the criteria for ESUS, suggesting the need for future studies to improve our understanding of the underlying stroke mechanism in this population.

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Conflict of interest statement

Conflict of Interest Disclosures: Dr Perera reported grants from Bayer during the conduct of the study and personal fees from Abbott and nonfinancial support from Bayer outside the submitted work. Dr Hankey reported personal fees from Bayer for consulting about stroke prevention in atrial fibrillation, from Bristol Myers Squibb for serving as a member of the Steering Committee of A Study on BMS-986177 for the Prevention of a Stroke in Patients Receiving Aspirin and Clopidogrel (AXIOMATIC-SSP) trial of milvexian, and from the American Heart Association for serving as an Associate Editor of Circulation outside the submitted work; Dr Hankey was also a member of the steering committee of the Rivaroxaban Versus Aspirin in Secondary Prevention of Stroke and Prevention of Systemic Embolism in Patients With Recent Embolic Stroke of Undetermined Source (NAVIGATE ESUS) trial comparing rivaroxaban vs aspirin in patients with Embolic Stroke of Undetermined Source (ESUS). Dr Ameriso reported grants from Bayer during the conduct of the study and grants from Boehringer Ingelheim and personal fees from Abbott outside the submitted work. Dr Field reported personal fees from Servier Canada Speaker’s Bureau outside the submitted work. Dr Arnold reported personal fees from Amgen, Bayer, Bristol Myers Squibb, Daiichi Sankyo, Medtronic, Novartis, and Pfizer Honoraria for scientific advisory boards and from AstraZeneca, Bayer, Covidien, Medtronic, and Sanofi Honoraria for lectures during the conduct of the study as well as grants from the Swiss National Science Foundation and the Swiss Heart Foundation outside the submitted work. Dr Mikulik reported grants from the COST Association, the Ministry of Education, Youth and Sports of the Czech Republic INTER-EXCELLENCE INTER-COST; the Ministry of Education, Youth and Sports of the Czech Republic National Program of Sustainability II; and the state budget of the Czech Republic outside the submitted work. Dr Toni reported personal fees from Abbott, Bayer, Boehringer Ingelheim, Daiichi Sankyo, Medtronic, and Pfizer outside the submitted work. Dr Mandzia reported personal fees from Bayer outside the submitted work. Dr Veltkamp reported grants from Imperial College London RV, is an investigator of the Imperial BRC, and is partially funded by the European Union’s Horizon 2020 research and innovation program under grant agreement No. 754517 during the conduct of the study; Dr Veltkamp also reports grants from Bayer, Boehringer, Bristol Myers Squibb, Pfizer, Biogen, and Daiichi Sankyo and nonfinancial support from Medtronic, personal fees from Javelin, Alexion, Bayer, and AstraZeneca outside the submitted work; and is the coordinating investigator of the European Union’s Horizon 2020 research and innovation program. Dr Haeusler reported personal fees from Bayer during the conduct of the study and personal fees from Abbott, Amarin, AstraZeneca, Bayer, Biotronik, Boehringer Ingelheim, Bristol Myers Squibb, Daiichi Sankyo, Edwards Lifesciences, Medtronic, Pfizer, Premier Research, Sun Pharma, and W. L. Gore & Associates outside the submitted work. Dr Hart reported grants from Bayer during the conduct of the study. No other disclosures were reported.

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