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

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.