Potential Contributors to ESUS Explored in New Consensus Statement

When it comes to handling patients with an embolic stroke of undetermined source (ESUS), which comes with high cardiovascular risk, it’s important to take a more holistic view of the situation rather than focusing on just one specific potential etiology, according to a European consensus statement.

The main message is to “treat the patient, not the disease,” stressed George Ntaios, MD, PhD (University of Thessaly, Larissa University Hospital, Greece), lead author of the document, which was published online recently in the European Heart Journal.

About 10 years ago, the ESUS concept grew out of the more general idea of cryptogenic stroke, which incorporated three types of patients who had a stroke of unknown etiology: those with an incomplete diagnostic workup, those with multiple potential embolic sources, and those without a definitive cause despite a comprehensive workup.

ESUS encompasses this last subset of patients, and it was initially believed that much of the risk observed in this group was driven by undetected atrial fibrillation (AF) and that treatment with oral anticoagulation would help, Ntaios said. However, he noted, the failure of multiple trials of direct oral anticoagulants in the setting of ESUS—including NAVIGATE ESUS, RE-SPECT ESUS, ARCADIA, and ATTICUS—indicates that there are other issues at play.

This new consensus statement, from the European Society of Cardiology (ESC) Council on Stroke, the European Association of Cardiovascular Imaging, and the European Heart Rhythm Association, represents some collective brainstorming on the various potential conditions that could be contributing to risk of recurrent events following ESUS and thus will impact subsequent treatment, Ntaios said.

For the document, the writers—a multidisciplinary group of clinicians and researchers from cardiology, internal medicine, neurology, radiology, and vascular surgery—discuss six main features that can influence thromboembolic risk in patients with ESUS:

• Supracardiac atherosclerosis
• Cancer
• Left ventricular disease
• Left atrial disease
• Patent foramen ovale (PFO) and other right-to-left shunts
• Valvular heart disease

Within each of those categories, the authors provide specific findings that indicate either a slightly or moderately increased thromboembolic risk. In patients with supracardiac atherosclerosis, for example, an acute or recent intra-plaque hemorrhage signals a moderately increased risk, whereas irregular plaque morphology points to a slightly elevated risk.

The key message, Ntaios said, is to consider all potential sources of risk when deciding on strategies to prevent recurrent events in patients with ESUS. “What we are doing wrongly, all of us, is that we’re trying to treat the disease, not the patients,” he said.

He pointed out that even if a specific source of stroke has been identified, it doesn’t mean treating it will fully protect the patient from having another event, noting that prior research has shown that in about half of patients who have a recurrent stroke, the etiology differs from what caused the first one. The takeaway is to “treat the patient holistically, and not the specific disease which you and I think might have been the specific cause of stroke,” Ntaios said.

The categories identified in the consensus statement can help clinicians and researchers focus on more specific subgroups under the ESUS umbrella when searching for effective therapies to mitigate their thromboembolic risks, say the authors.

They provide a list of key areas for future research based on the specific contributor to risk. For patients with supracardiac atherosclerosis, there is a need for studies evaluating the impact of treatments that lower lipids and lipoprotein(a), antithrombotic and anti-inflammatory therapies, and endarterectomy or stenting. In patients with a PFO who are older than 60, the effect of percutaneous PFO closure is unknown. And there remain questions about whether oral anticoagulation still has a role to play in various subsets of patients with ESUS.

“The big idea is to focus on these subgroups of ESUS patients and try to have a more individualized approach compared to what we had 10 years ago when we put all ESUS patients together into a single basket,” Ntaios said.

He also defended the concept of ESUS, despite the lack of successful trials in this space, citing the fact that those studies were designed when it was thought that AF was a major contributor to thromboembolic risk in this population.

The failure of those prior trials “doesn’t mean that the ESUS concept is invalid,” he said. “It means that the hypothesis that oral anticoagulation is helpful in ESUS patients is invalid.”