Patients with embolic stroke of undetermined source who underwent comprehensive diagnostic workup without an identified cause (ESUS 2.0) had a significantly lower risk of recurrent stroke than those with no advanced workup or those with an established mechanism identified after workup.
Key Findings
Results
ESUS 2.0 patients (comprehensive workup without identified cause) had significantly lower recurrent stroke risk than those with no advanced workup.
Adjusted hazard ratio for recurrent ischemic stroke in ESUS 2.0 vs. ESUS with no advanced workup was 0.31 (95% CI, 0.13–0.76)
344 patients (15.1%) were classified as ESUS 2.0
1,243 patients (54.5%) were classified as ESUS with no advanced workup (ESUS-NAW)
Analysis used adjusted Cox proportional hazards models
Study included 2,281 patients across 27 sites
Results
ESUS 2.0 patients also had significantly lower recurrent stroke risk compared to patients in whom an established mechanism was identified after further workup.
Adjusted hazard ratio for recurrent stroke in ESUS 2.0 vs. ESUS with established mechanism (ESUS-E) was 0.35 (95% CI, 0.15–0.85)
694 patients (30.4%) were classified as ESUS-E
This comparison suggests that identifying a mechanism does not itself confer protection and may reflect higher-risk underlying etiologies
Results
Among patients with an established mechanism, cancer was associated with the highest risk of recurrent stroke compared to ESUS 2.0.
Cancer was associated with an adjusted hazard ratio of 5.33 (95% CI, 2.09–13.63) for recurrent stroke compared to ESUS 2.0
This was the strongest individual mechanism-specific risk identified within the ESUS-E group
Findings highlight cancer as a particularly high-risk etiology within the ESUS framework
Results
Nonstenosing atherosclerotic disease or arch atheroma was associated with significantly increased recurrent stroke risk within the established mechanism group.
Adjusted hazard ratio for nonstenosing atherosclerotic disease or arch atheroma vs. ESUS 2.0 was 3.40 (95% CI, 1.18–9.83)
This etiology represented a distinct high-risk subgroup within ESUS-E
The finding underscores the importance of vascular imaging as part of advanced diagnostic evaluation
Methods
The study cohort was multicenter, diverse, and predominantly middle-aged, with roughly equal sex distribution.
Total cohort: n=2,281 patients across 27 sites
Mean age was 65 years
50.1% were men
This was a retrospective analysis of a multicenter observational cohort study (NCT06398366)
The three ESUS subgroups were: ESUS-E (30.4%), ESUS-NAW (54.5%), and ESUS 2.0 (15.1%)
Results
The majority of ESUS patients in clinical practice did not receive advanced diagnostic workup.
54.5% of patients (n=1,243) were classified as ESUS with no advanced workup (ESUS-NAW), the largest single subgroup
Only 15.1% (n=344) achieved the comprehensive evaluation needed for ESUS 2.0 classification
This distribution highlights a gap between the proposed ESUS construct and real-world diagnostic practice
Background
The ESUS 2.0 concept is introduced as a refined subcategory representing truly cryptogenic embolic stroke after exhaustive evaluation.
ESUS 2.0 is defined as comprehensive diagnostic workup completed without an identified cause
The concept distinguishes true cryptogenic stroke from ESUS cases where workup is incomplete or a mechanism is subsequently found
The authors propose that prior ESUS trial results may have been confounded by inclusion of patients with incomplete workup or unrecognized mechanisms
Findings suggest ESUS 2.0 patients may have a lower baseline recurrence risk than historically reported for ESUS overall
What This Means
This research suggests that not all 'cryptogenic' or unexplained strokes carry the same risk of happening again. The study introduced the concept of 'ESUS 2.0' — a label for patients who had a thorough, comprehensive diagnostic evaluation after their stroke and still had no cause identified. Across 2,281 patients at 27 hospitals, patients who met the ESUS 2.0 criteria had a 69% lower risk of having another stroke compared to patients who received no advanced testing, and a 65% lower risk compared to patients in whom a cause was eventually found. This suggests that truly exhaustive evaluation — not just a standard workup — may help identify which patients are at genuinely low risk for stroke recurrence.
The study also found that among patients where a cause was identified, certain conditions were particularly dangerous: patients whose stroke was linked to cancer had more than five times the risk of another stroke compared to ESUS 2.0 patients, and those with arterial plaque or atherosclerosis had more than three times the risk. These findings highlight that the 'embolic stroke of undetermined source' label currently groups together patients with very different underlying risks, which may explain why large clinical trials testing treatments for this group have had mixed results.
This research suggests that the quality and completeness of the diagnostic workup matters greatly for understanding a patient's true stroke recurrence risk. Most patients in this real-world cohort — over half — did not receive a comprehensive evaluation. The authors propose that future research and clinical care should aim to clearly distinguish between patients who have had thorough testing and those who have not, as these groups appear to have meaningfully different prognoses.
Khan F, Stretz C, Lewis S, Chahien D, Goldstein E, Siegler J, et al.. (2026). Comprehensive Diagnostic Evaluation and Risk of Recurrent Stroke After Embolic Stroke of Undetermined Source: Introducing the Concept of ESUS 2.0.. Journal of the American Heart Association. https://doi.org/10.1161/JAHA.126.050182