Embolic strokes of undetermined source: theoretical construct or useful clinical tool?

Instead of being able to blithely state you had a cryptogenic stroke your doctor now has to do a complete vascular workup. It has only been out for 5 years, does your doctor and stroke hospital know about this?  Or is incompetence showing its ugly head once again?

Embolic strokes of undetermined source: theoretical construct or useful clinical tool?

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Georgios Tsivgoulis, Aristeidis H. Katsanos, Martin Köhrmann, ...

First Published May 24, 2019 Review Article

https://doi.org/10.1177/1756286419851381

Article information

Abstract

In 2014, the definition of embolic strokes of undetermined source (ESUS) emerged as a new clinical construct to characterize cryptogenic stroke (CS) patients with complete vascular workup to determine nonlacunar, nonatherosclerotic strokes of presumable embolic origin. NAVIGATE ESUS, the first phase III randomized-controlled, clinical trial (RCT) comparing rivaroxaban (15 mg daily) with aspirin (100 mg daily), was prematurely terminated for lack of efficacy after enrollment of 7213 patients. Except for the lack of efficacy in the primary outcome, rivaroxaban was associated with increased risk of major bleeding and hemorrhagic stroke compared with aspirin. RE-SPECT ESUS was the second phase III RCT that compared the efficacy and safety of dabigatran (110 or 150 mg, twice daily) to aspirin (100 mg daily). The results of this trial have been recently presented and showed similar efficacy and safety outcomes between dabigatran and aspirin. Indirect analyses of these trials suggest similar efficacy on the risk of ischemic stroke (IS) prevention, but higher intracranial hemorrhage risk in ESUS patients receiving rivaroxaban compared to those receiving dabigatran (indirect HR = 6.63, 95% CI: 1.38–31.76). ESUS constitute a heterogeneous group of patients with embolic cerebral infarction. Occult AF represents the underlying mechanism of cerebral ischemia in the minority of ESUS patients. Other embolic mechanisms (paradoxical embolism via patent foramen ovale, aortic plaque, nonstenosing unstable carotid plaque, etc.) may represent alternative mechanisms of cerebral embolism in ESUS, and may mandate different management than oral anticoagulation. The potential clinical utility of ESUS may be challenged since the concept failed to identify patients who would benefit from anticoagulation therapy. Compared with the former diagnosis of CS, ESUS patients required thorough investigations; more comprehensive diagnostic work-up than is requested in current ESUS diagnostic criteria may assist clinicians in uncovering the source of brain embolism in CS patients and individualize treatment approaches.

Keywords Cryptogenic stroke, Anticoagulation, NOACs, DOACs, Rivaroxaban, Dabigatran

Theoretical concept of embolic strokes of undetermined source

Even though no etiopathogenic mechanism can be identified in more than one-third of all ischemic strokes (IS), the definition of cryptogenic cerebral ischemia still remains very vague, given that the characterization of a cerebral ischemic event as cryptogenic depends largely on the diagnostic investigations performed, the quality of these exams, and the subjective assessment of the treating physician.^1,2 The most frequently used definition of cryptogenic stroke (CS) to date is based on the Trial of Org 10172 in Acute Stroke Treatment (TOAST) criteria, which were first published in 1993.³ TOAST criteria classify an IS as cryptogenic when no cause can be identified after baseline diagnostic work-up. However, IS with incomplete work-up or cerebral infarctions with two or more possible underlying causes are also characterized as cryptogenic. The lack of specified mandatory diagnostic testing and work-up algorithm imple-mentation of TOAST criteria results in huge variations in the reported prevalence of CS across hospital registries, as a consequence of poor agreement between physicians to classify a cerebral ischemic event as cryptogenic.^4,5
In 2007, the Causative Classification of Stroke system proposed to subdivide strokes of undetermined cause further into cryptogenic embolism, other cryptogenic, incomplete evaluation, and unclassified groups.⁶ In 2014, the definition of embolic strokes of undetermined source (ESUS) emerged as a new clinical construct to characterize nonlacunar (>1.5 cm on CT or >2 cm on MRI), nonatherosclerotic (absence of significant ipsilateral vessel stenosis ⩾50%) strokes of an undetermined embolic source, in the absence of a high-risk for embolism cardiac disease or any other specific cause.⁴ ESUS working group investigators further proposed that the minimal stroke work-up should include brain neuroimaging with CT or MRI, 12-lead ECG, transthoracic echocardiography (TTE), 24 h Holter-ECG and imaging of both extracranial and intracranial vessels with any available imaging modality (DSA, MRA, CTA, or US). Transesophageal echocardiography (TEE) and long-term ECG monitoring were not included as mandatory investigations in the diagnostic work-up of ESUS patients. Approximately 9–25% of IS patients fulfil ESUS diagnostic criteria with any variance attributed to the characteristics of the patient population.^7,8