Comprehensive Diagnostic Evaluation and Risk of Recurrent Stroke After Embolic Stroke of Undetermined Source: Introducing the Concept of ESUS 2.0

BACKGROUND: Although the embolic stroke of undetermined source (ESUS) construct was proposed as a unifying concept for embolic-appearing strokes without an identified cause, it includes patients with diverse and often unrecognized underlying mechanisms. This study investigates the differential rate of recurrent stroke according to the completeness of neurodiagnostic testing in a diverse multicenter cohort. METHODS: This was a retrospective analysis of a multicenter observational cohort study (n=27 sites). ESUS was categorized into 3 groups: (1) established mechanism after further workup (ESUS-E), (2) comprehensive diagnostic workup without an identified cause (ESUS 2.0), and (3) no advanced workup. The primary outcome of recurrent ischemic stroke was compared between ESUS with established mechanism and ESUS 2.0 versus ESUS with no advanced workup and was assessed using adjusted Cox proportional hazards models. RESULTS: Among 2281 patients, the mean age was 65 years, and 50.1% were men. 694 (30.4%) classified as ESUS-E, 1,243 (54.5%) classified as ESUS-NAW, and 344 (15.1%) as ESUS 2.0. The ESUS 2.0 group had a significantly lower risk of recurrent stroke than both the group with ESUS with no advanced workup (adjusted hazard ratio [aHR], 0.31 [95% CI, 0.13-0.76]) and the group with ESUS with established mechanism (aHR, 0.35 [95% CI, 0.15-0.85]). Within the group with ESUS with established mechanism, cancer (aHR, 5.33 [95% CI, 2.09-13.63]) and nonstenosing atherosclerotic disease or arch atheroma (aHR, 3.40 [95% CI, 1.18-9.83]) were associated with significantly increased risk of recurrence when compared with the group with ESUS 2.0. CONCLUSIONS: These findings demonstrate a lower risk of recurrent stroke in patients classified as ESUS 2.0 than reported in prior ESUS trials and highlight the importance of age-appropriate advanced diagnostic evaluation. REGISTRATION: URL: https://www.clinicaltrials.gov. Identifier: NCT06398366.

Authors

Institutions

Publication Details

Journal
Journal of the American Heart Association
Published
2026-09-09
DOI
https://doi.org/10.1161/jaha.126.050182
Primary Topic
Aortic Thrombus and Embolism
Type
article
Field-Weighted Citation Impact
0.00
Controls
|||
ALL TIME
JAN
FEB
MAR
APR
MAY
JUN
JUL
AUG
SEP
article

Comprehensive Diagnostic Evaluation and Risk of Recurrent Stroke After Embolic Stroke of Undetermined Source: Introducing the Concept of ESUS 2.0

Wayneho Kam, Jennifer Ro, Hamid Ali, Dalia Chahien et al.
Journal of the American Heart Association
Aortic Thrombus and Embolism
article

Comprehensive Diagnostic Evaluation and Risk of Recurrent Stroke After Embolic Stroke of Undetermined Source: Introducing the Concept of ESUS 2.0

Wayneho Kam, Jennifer Ro, Hamid Ali, Dalia Chahien, Mudassir Farooqui, Alicia Zha, Christoph Stretz, Emiliya Melkumova, Brian Stamm, Setareh Salehi Omran, Franziska Herpich, Simona Nedelcu, David S. Liebeskind, Shadi Yaghi, Deborah Kerrigan, Adeel Zubair, Patrick Glover, Mahan Shahrivari, Mary Penckofer, Sean Thompson, Hassan Aboul Nour, Dinesh Jillella, Yasmin Aziz, James E. Siegler, Collin Culbertson, Fadi Nahab, Sami Al Kasab, Adam de Havenon, Guillermo Linares, S Sehgal, Thanh N. Nguyen, Kelsey Eklund, Eric Goldstein, Eesha Singh, Marissa D’Souza, Richa Sharma, James R. Brorson, Farid Khasiyev, Anna Bowman, Jesse Thon, Kelly L. Sloane, Shani Peter, Russell J. Van Coevering, Farhan Khan, Vivek Patel, Oana M. Dumitrascu, A. M. Abdel-Wahab, Ahmad Abu Qdais, Skylar Lewis, Christina M. Lineback, Lucia Chen, Fawad Talat, Camelia Valhuerdi Porto, Wenzheng Yu, Frank G. Conyers, Jieun Kang, Neeharika Thottempudi, Diana Rojas‐Soto
article en

Abstract

BACKGROUND: Although the embolic stroke of undetermined source (ESUS) construct was proposed as a unifying concept for embolic-appearing strokes without an identified cause, it includes patients with diverse and often unrecognized underlying mechanisms. This study investigates the differential rate of recurrent stroke according to the completeness of neurodiagnostic testing in a diverse multicenter cohort. METHODS: This was a retrospective analysis of a multicenter observational cohort study (n=27 sites). ESUS was categorized into 3 groups: (1) established mechanism after further workup (ESUS-E), (2) comprehensive diagnostic workup without an identified cause (ESUS 2.0), and (3) no advanced workup. The primary outcome of recurrent ischemic stroke was compared between ESUS with established mechanism and ESUS 2.0 versus ESUS with no advanced workup and was assessed using adjusted Cox proportional hazards models. RESULTS: Among 2281 patients, the mean age was 65 years, and 50.1% were men. 694 (30.4%) classified as ESUS-E, 1,243 (54.5%) classified as ESUS-NAW, and 344 (15.1%) as ESUS 2.0. The ESUS 2.0 group had a significantly lower risk of recurrent stroke than both the group with ESUS with no advanced workup (adjusted hazard ratio [aHR], 0.31 [95% CI, 0.13-0.76]) and the group with ESUS with established mechanism (aHR, 0.35 [95% CI, 0.15-0.85]). Within the group with ESUS with established mechanism, cancer (aHR, 5.33 [95% CI, 2.09-13.63]) and nonstenosing atherosclerotic disease or arch atheroma (aHR, 3.40 [95% CI, 1.18-9.83]) were associated with significantly increased risk of recurrence when compared with the group with ESUS 2.0. CONCLUSIONS: These findings demonstrate a lower risk of recurrent stroke in patients classified as ESUS 2.0 than reported in prior ESUS trials and highlight the importance of age-appropriate advanced diagnostic evaluation. REGISTRATION: URL: https://www.clinicaltrials.gov. Identifier: NCT06398366.

Journal of the American Heart Association
Tufts University (US), University of Iowa (US), Christiana Care Health System (US), Dartmouth–Hitchcock Medical Center (US), Harvard University (US), Emory University (US), Medical University of South Carolina (US), University of California, Los Angeles (US), Duke University (US), Vanderbilt University (US), Brown University (US), University of Michigan (US), University of Minnesota System (US), Cooper University Hospital (US), University of Colorado System (US), The Ohio State University Wexner Medical Center (US), Henry Ford Hospital (US), Yale University (US), California University of Pennsylvania (US), University of Chicago (US), VA Ann Arbor Healthcare System (US), Lahey Medical Center (US), Mayo Clinic Hospital (US), Hackensack Meridian Health (US), Meridian Medical Systems (United States) (US), The Ohio State University (US), University of Cincinnati (US), The University of Texas Health Science Center at Houston (US)
Good health and well-being
Openalex Percentile: Top 11%
Aortic Thrombus and Embolism
DOIOpen Access PDFOpenAlex
AI Navigator

Ask Laika to Summarize, Analyze, and Connect papers live on the map.

Summarize Papers & Methodologies

Extract key findings, datasets, and comparative methods across publications.

Benchmark Rankings & Visual Analytics

Rank top research institutions, authors, funders, topics, and journals by Field-Weighted Citation Impact (FWCI) and paper volume with instant charts.

Connect Distant Disciplines

Bridge topological clusters on the map to find hidden collaborative intersections.