In a population of adults younger than 50 years with embolic stroke of undetermined source, despite repeated diagnostic workup at the time of recurrent stroke, no source of embolus was identified for two-thirds of participants with recurrent ischemic strokes.
Newly published data from the Young ESUS longitudinal cohort study suggest that young adults 50 years and younger with embolic stroke of undetermined source (ESUS) have a relatively low rate of subsequent ischemic stroke and new-onset atrial fibrillation (AFib) compared with older adults.1
Led by Kanjara S. Perera, MD, MBBS, associate professor of medicine, McMaster University, a multivariate analysis identified several factors, including history of stroke or transient ischemic attack (HR, 5.3 [95% CI, 1.8-15.0), presence of diabetes (HR, 4.4; 95% CI, 1.5-13), and history of coronary artery disease (HR, 10; 95% CI, 4.8-22) that were associated with recurrent ischemic stroke. Additionally, investigators found that most of the recurrent ischemic strokes met the criteria for ESUS, and that two-thirds of the participants had no source of embolus identified despite repeated diagnostic workup at the time of recurrent stroke.
Across 41 stroke research centers in 13 countries, the cohort included 535 patients, 520 of which completed their final follow-up visit. Although previous notable studies NAVIGATE ESUS (NCT02313909) and RESPECT ESUS (NCT02239120) showed a high rate of stroke recurrence in older adults with ESUS, this analysis specifically looked at consecutive patients 50 years and younger, the largest such registry according to Perera et al.
At baseline, the most common vascular risk factors included current or former tobacco use (45%), hypertension (22%), and dyslipidemia (20%), with median National Institutes of Health Stroke Scale score of 2 (IQR, 1-6) at the time of enrollment. The primary outcome, a composite of ischemic stroke or death, occurred in 3% (n = 16; 95% CI, 1.7-4.8) of the cohort or 2.19 events per 100 patient-years. Stroke recurrence was 2.6% (n = 14; 95% CI, 1.4-4.4), or 1.9 events per 100 patient-years.
Patent foramen ovale (PFO), one of the main outcomes was found in 50% (n = 177) of those who had transthoracic echocardiograms with bubble studies (n = 354). Overall, the PFO status was unknown in 148 patients (28%). Of those who underwent transesophageal echocardiography (n = 226), 50% (n = 113) had a PFO identified, and 3% (n = 14) had aortic arch atheroma identified.
In a related editorial, George Ntaios, MD, MSc, PhD, and Setareh S. Omran, MD, write that the findings by Perera et al are “an important addition to the literature." They added, "When the ESUS concept was introduced, AFib was presumed to be the main underlying etiology. However, accumulating evidence offers support to the argument that the etiologic role of AFib in ESUS is less important than initially perceived."2
Aspirin monotherapy, accounting for 56% of participants, was the most used treatment at enrollment, followed by clopidogrel monotherapy (11%), dual antiplatelet therapy (21%), and ticagrelor alone (0.2%). Statins were used in 66% of the cohort as well. At 6 months following ESUS, treatment use changed, still led by aspirin monotherapy (54%), followed by clopidogrel (20%) and dual antiplatelet therapy (8%), along with 11% that were taking anticoagulation, usually a direct oral anticoagulant therapy.1
Of the 14 recurrent strokes, 2 were classified as cardioembolic; 2 were secondary to the diagnosis of dissection; 1 was diagnosed with mitochondrial encephalomyopathy, lactic acidosis, and stroke-like episodes; and the remaining 9 (64%) met the criteria for ESUS.
Ntaios and Omran concluded that while the understanding of ESUS has improved since its introduction, there are still far more questions than answers, writing, "We need to operationalize the definitions of evolving concepts, such as atrial cardiopathy and the vulnerable atheromatous plaque; enhance our ability to understand whether the presence of a particular embolic source in a given patient with ESUS is causally associated or only an innocent bystander; and optimize our secondary preventive strategies, both in the overall ESUS population and specific subgroups like the young."2