ANA Investigates: Embolic Stroke of Unknown Source (ESUS) Clinical Trials & Advances in Research

Accurate identification of the cause of an ischemic stroke is an essential step preceding the initiation of appropriate secondary prevention measures. However, there are challenges implicit in the diagnosis of etiologic subtypes. For example, common risk factors, such as hypertension, can overlap between different types of strokes and causation can be difficult to determine in the absence of a gold-standard test.

Embolic Stroke of Unknown Source (ESUS) was first coined in 2014 in an editorial which began to distinguish a group of patients that were currently included in the category of cryptogenic strokes, but may in fact represent a more specific entity.¹ Understanding this concept is particularly imperative when a stroke appears embolic on imaging, but the patient does not manifest atrial fibrillation (AF), despite prolonged monitoring, or evidence of carotid artery disease.

In this podcast, ANA investigates ESUS clinical trials and advances in research, by interviewing Dr. Hooman Kamel, the head of Neurocritical care in the Department of Neurology at Weill Cornell Medicine, and an expert and research leader in this field. In the introduction of the podcast, Dr. Johansen, an Assistant Professor in the cerebrovascular division at the Johns Hopkins School of Medicine, and Dr. Kamel define ESUS, and set this concept in light of the history of stroke adjudication, specifically contrasting this entity with cryptogenic stroke and cardioembolic stroke.

They begin by discussing that cryptogenic stroke classically has included patients who either never had testing, did not undergo a complete investigation of possible causes of the stroke, or have two competing possible etiologies for their stroke. ESUS, on the other hand better, defines a subset of cryptogenic stroke by requiring a minimal threshold of testing, and refers to a non-lacunar stroke where the source of the embolism is unknown. ESUS occurs in one out of every six ischemic strokes, usually the patients are younger with fewer traditional risk factors, and the recurrence rate is not negligible (>4% per year).²

When considering the work-up of a stroke patient with possible ESUS, Dr. Kamel suggests that a 12 lead electrocardiogram, a minimum of 24 hours of telemetry to search for AF, vascular imaging of the head and neck and an echocardiogram should all be considered. He adds that other tests for rarer causes of emboli might be considered in specific patient populations, such as the younger adult. Drs. Johansen and Kamel discuss the current standard of care of treatment for ESUS patients, antiplatelet medications, and that risk factor modification is always a best evidence-based approach in stroke patients, regardless of etiology. ³

An important question that is discussed in the podcast is whether or not there are either other treatments that can be beneficial when applied to all ESUS patients, or whether, after more appropriately defining subgroups of ESUS, there might be tailored treatment algorithms for ESUS patients. It may be that some ESUS patients will respond to anticoagulants, similarly to a cardioembolic patient with diagnosed AF. Dr. Kamel offers experience and insight on the many exciting, ongoing research efforts that are helping to answer this question, such as the ARCADIA trial (AtRial Cardiopathy and Antithrombotic Drugs In Prevention After Cryptogenic Stroke)⁴ and the ATTICUS (Apixaban for Treatment of Embolic Stroke of Undetermined Source) trial.⁵

As a principal investigator for the ARCADIA trial, Dr. Kamel explains that the underlying premise of this study is that some of the ESUS patients have experienced a stroke because of a thrombus that arises from the left atrium, in the absence of AF. Dr. Johansen highlights for the listener that research supports that there is a paradox regarding the relationship of the timing and presence of AF and stroke, suggesting that tachyarrhythmia is not the only mechanism by which an embolism can form in the heart.⁶ They transition to a rapid review of the concept of atrial myopathy and new ways in which left atrial dysfunction is being defined. Dr. Kamel explains that the investigators of ARCADIA and other groups have used different markers of left atrial structure and function to identify patients and randomize them to different stroke secondary prevention therapies.^5,7,8 ARCADIA specifically is using P-wave terminal force in lead V1, serum NT-proBNP and left atrial diameter on echocardiogram to define a state of atrial myopathy.

When asked to summarize three main points of the podcast, Dr. Kamel emphasizes that ESUS stroke is not uncommon with a high risk of recurrence, the current standard of care is a single antiplatelet agent and blood pressure and LDL lowering as appropriate, and the hope is in the future, a more effective personalized treatment based on a better understanding of the underlying mechanisms of ESUS will be available. The discussants agree that the next decade will continue to be an exciting time for both diagnosing and treating ischemic stroke patients as other empiric and tailored strategies for secondary prevention are tested in the ESUS population.