Symptomatic Non-stenotic Carotid Disease in Embolic Stroke of Undetermined Source: Analysis of the ESCAPE-NA1 Trial

Purpose: Non-stenotic (< 50%) carotid disease may play an important etiological role in ischemic stroke classified as embolic stroke of undetermined source (ESUS). We aimed to assess the prevalence of non-stenotic carotid disease and its association with ipsilateral ischemic stroke. Methods: Data are from ESCAPE-NA1, a randomized controlled trial investigating the neuroprotectant nerinetide in patients with acute ischemic stroke and large vessel occlusion (LVO). The degree of stenosis of the extracranial internal carotid artery (ICA) and high-risk plaque features were assessed on baseline computed tomography (CT) angiography. We evaluated the association of non-stenotic carotid disease and ipsilateral stroke by age-adjusted and sex-adjusted logistic regression and calculated the attributable risk of ipsilateral stroke caused by non-stenotic carotid disease. Results: After excluding patients with non-assessable imaging, symptomatic > 50% carotid stenosis and extracranial dissection, 799/1105 (72.1%) patients enrolled in ESCAPE-NA1 remained for this analysis. Of these, 127 (15.9%) were classified as ESUS. Non-stenotic carotid disease occurred in 34/127 ESUS patients (26.8%) and was associated with the presence of ipsilateral ischemic stroke (odds ratio, OR 1.6, 95% confidence interval, CI 1.0–2.6, p = 0.049). The risk of ipsilateral ischemic stroke attributable to non-stenotic carotid disease in ESUS was estimated to be 19.7% (95% CI −5.7% to 39%), the population attributable risk was calculated as 4.3%. Imaging features such as plaque thickness, plaque irregularity or plaque ulceration were not different between non-stenotic carotids with vs. without ipsilateral stroke. Conclusion: Non-stenotic carotid disease frequently occurs in patients classified as ESUS and is associated with ipsilateral ischemic stroke. Our findings support the role of non-stenotic carotid disease as stroke etiology in ESUS, but further prospective research is needed to prove a causal relationship.