Embolic stroke of undetermined source (ESUS)

Introduction
Histological analysis of thromboses in embolic stroke of undetermined source (ESUS) suggests that these thrombi are likely most frequently of cardioembolic origin.

Ntaios et al. ESUS Risk Score
This score was developed and externally validated.

Cardiomyopathies
In one study undiagnosed cardiomyopathies comprised 10% (7 of 70) cases of ESUS, most commonly hypertrophic cardiomyopathy but also restrictive cardiomyopathy.

Histologic analysis of thrombus after clot extraction.
Studies suggest that histologic features can differentiate cardiembolic from noncardioembolic strokes. Rarely they may show clear evidence of an alternative causes such as non-bacterial marantic endocarditis.

Direct oral anticoagulants
Trials of rivaroxaban and dabigatran compared with aspirin have shown no benefit of DOACs over aspirin for treatment of ESUS, and a slightly higher risk of bleeding. From secondary analysis of the NAVIGATE ESUS trial, there is some evidence that rivaroxaban may be of benefit in patients with a large left atrium (diameter >4.6 cm) but this result needs confirmation prior to being used in practice.

New Approach Rivaroxaban Inhibition of Factor Xa in a Global Trial versus ASA to Prevent Embolism in Embolic Stroke of Undetermined Source (NAVIGATE ESUS, 2018)
This trial randomized 7,213 patients with ESUS within the prior 6 months to receive rivaroxaban 15 mg daily plus placebo or aspirin 100 mg daily plus placebo. There was no difference in the primary outcome of any recurrent stroke or embolism, which occurred in 5.1% of the rivaroxaban group and 4.8% of the aspirin group (HR 1.07, 95% CI 0.87-1.33). Hemorrhagic stroke was more frequent in the rivaroxaban group (0.4% vs 0.1%, HR 6.50, 95% CI 1.47-28.8). Major bleeding was more common with rivaroxaban as well (1.8% vs 0.7%, HR 2.72, 95% CI 1.68-4.39). However, a secondary analysis showed that for patients with left atrial diameter of >4.6 cm, the annual risk of ischemic stroke was lower with rivaroxaban compared with aspirin (1.7% vs 6.5% per year, HR 0.26, 95% CI 0.07-0.94).

==== Randomized, Double-Blind, Evaluation in Secondary Stroke Prevention Comparing the Efficacy and Safety of the Oral Thrombin Inhibitor Dabigatran Etexilate versus Acetylsalicylic Acid in Patients with Embolic Stroke of Undetermined Source (RE-SPECT ESUS, 2019) ==== This trial randomized 5,390 patients with ESUS in the prior 3 months (6 months if over age 60 and with at least one vascular risk factor) to receive dabigatran 150 mg BID (or 110 mg BID in those 75 years old and older or who had estimated creatinine clearance of 30-50 mL/min) vs aspirin 100 mg daily, with matching placebo in each group. There was no difference in the primary outcome of first recurrent stroke, which occurred in 4.1% of the dabigatran group and 4.8% of the aspirin group (p=0.10). Disabling stroke was lower in the dabigatran group (0.6% vs 0.9%, HR 0.59, 95% CI 0.36-0.96) but this analysis was not adjusted for multiple comparisons. There was no significant different in major bleeding, but more clinically relevant nonmajor bleeding in the dabigatran group (1.6% vs 0.9%, HR 1.73, 95% CI 1.17-2.54).