Victor J. Del Brutto, MD

Ntaios G, Pearce LA, Meseguer E, Endres M, Amarenco P, Ozturk S, et al. Aortic Arch Atherosclerosis in Patients With Embolic Stroke of Undetermined Source: An Exploratory Analysis of the NAVIGATE ESUS Trial. Stroke. 2019

When it comes to establishing the mechanism of injury in a stroke victim, the label “unknown/undetermined” deprives the patient of receiving the appropriate prognosis and strategy for secondary prevention. One-fourth of ischemic strokes are identified as cryptogenic without a definite understanding of the cause, and a sizable proportion of them will fit into the concept of embolic stroke of undetermined source (ESUS). The cause of ESUS could be an under-recognized cardiac source or a non-stenosing arterial lesion. Despite seminal studies in the 1990s that have identified a causal association between protruding plaques in the aortic arch and ischemic stroke, aortic arch atherosclerosis (AAA) is often overlooked during routine stroke work-up, thus falling into the category of stroke of undetermined etiology.

The current manuscript published by Ntaios and colleagues reports the exploratory analysis of the subgroup of individuals who participated in the New Approach Rivaroxaban Inhibition of Factor Xa in a Global Trial Versus ASA to Prevent Embolism in Embolic Stroke of Undetermined Source (NAVIGATE-ESUS) trial and underwent transesophageal echocardiogram (TEE) for evaluation of AAA. The authors found a prevalence of 19% of AAA among patients with ESUS, from which one-third (8% of the total cohort) were considered to have high-risk complex plaques as defined by the presence of ulceration, thickness greater than 4 mm, or presence of a mobile thrombus. As noticed by the authors, the prevalence of AAA might be underestimated due to lower atherosclerotic risk factors in those who underwent TEE. Increasing age, diabetes mellitus and aortic valve disease, as well as geographic region (east Asia and eastern Europe), were significant determinants of AAA in the multivariable analysis. In addition, chronic infarcts and multi-territorial infarcts were associated with AAA, arguing against the common belief that multifocal strokes are exclusively cardioembolic. There was a non-significant trend for higher rate of stroke recurrence in patients with complex AAA (7.2% annualized rate) when compared to those without AAA (5.6% annualized rate). Data from this analysis was merged with two other randomized controlled trials to construct a meta-analysis of anticoagulation versus antiplatelet therapy in patients with cryptogenic stroke and AAA. The meta-analysis found no significant difference in the rate of stroke recurrence between the two antithrombotic approaches.

The results of this exploratory analysis align with previous reports: (1) AAA identified by TEE is frequent among patients initially diagnosed with ESUS, and (2) complex plaque features are important markers of stroke risk in patients with AAA. It is, therefore, that routine screening for AAA in stroke patients is advised. TEE is the most common diagnostic method used in the literature to identify AAA plaque characteristics. However, it implies an invasive procedure and need for sedation, and may prolong length of hospitalization based on cardiology service availability. Moreover, as therapeutic interventions for AAA remain uncertain, justifying the need for TEE in certain clinical settings could be challenging. CT-angiography is a suitable alternative for AAA diagnosis and is increasingly being used in the acute setting for identification of large vessel occlusion. Adding a CT-angiogram protocol that includes the aortic arch seems to be a practical approach for routine screening of AAA in patients with stroke. Nevertheless, further research is required to establish the best diagnostic method for AAA screening.

Compared to other stroke mechanisms, there has been relatively scarce data on medical treatment for secondary stroke prevention in arch disease. Considering AAA part of the group of atherosclerotic vascular disorders responsible for causing stroke, some general approaches could be extrapolated from intracranial and cervical atherosclerotic disease. For example, maximal medical therapy commonly applied for patients with atherosclerotic plaques in other vascular beds, which incorporates antiplatelet therapy, high-dose statins, and strict target-based vascular risk factors control, is recommended for stroke patients with AAA. Furthermore, aggressive antiplatelet therapy with two agents may be reasonable in the acute phase under the assumption of an unstable plaque with high thromboembolic risk. Emerging therapies, including direct-oral anticoagulants, newer antiplatelet agents (i.e., ticagrelor), or even novel hypolipidemic medications such as PCSK9-inhibitors, are potential therapeutic strategies to prevent stroke recurrence in patients with AAA, and would be worth investigating in randomized trials. Lessons learned from post-hoc analyses of large randomized controlled trials, such as the ones presented in the article under discussion, will be fundamental to design successful trials that would provide evidence-based approaches to diagnose and prevent ischemic stroke secondary to aortoembolism.