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Subclinical Atrial Fibrillation and the Risk of Recurrent Ischemic Stroke.

In 2014,Hart et al introduced the clinical construct of “embolic stroke of unknown source” (ESUS).1 In brief, it describes a subgroup of stroke patients inwhom, based on brain imaging, cardioembolism is highly suggestive to be the putative stroke mechanism. Anticoagulation should be a better choice for these patients than antiplatelet therapy and this concept was subsequently investigated in three randomized trials. TheNAVIGATE-ESUS trial randomized 7,213 patientswith a recent ESUS to either rivaroxaban 15mgor aspirin 100mg.2 The trial was stopped prematurely for futility and harm: the primary endpoint of stroke and systemic embolism was not different in both groups (5.1%/year [rivaroxaban] vs. 4.8%/ year [aspirin]), while major bleedings were nearly tripled with rivaroxaban (1.8 vs. 0.7%/year). The RESPECT-ESUS trial assigned 5,390 patients with ESUS to either dabigatran (150 or 110mg twice daily based on age and kidney function) or aspirin.3 The primary endpoint of recurrent stroke was not different between the groups (4.1%/year with dabigatran vs. 4.8%/year with aspirin). Nonmajor bleedingswere also not different between the groups, but clinically relevant nonmajor bleeding occurred more often with dabigatran (1.6%/year) than with aspirin (0.9%/year). A third trial called ATTICUS is smaller with a planned inclusion of only 500 patients and a brain imaging endpoint,4 but was stopped recently for futility (Sven Poli, personal communication). So, does the concept of ESUS belong to the “dustbin of history” (R. Hart, quote)? Yes, in terms of generally using anticoagulation in all with ESUS. No, in terms of pointing to a need to further identify a subgroup of ESUSwith cardioembolism that may benefit from anticoagulation.5 One group that without any doubt benefits from anticoagulation for stroke prevention is patients with atrial fibrillation (AF). But AF might escape routine diagnostics in stroke patients as it is often paroxysmal.5 The most sensitive method for AF detection is continuous monitoring by an implantable cardiacmonitor. This type of device-detected AF is also called subclinical AF (SCAF) or atrial high rate episodes if found in implanted cardiac devices like pacemakers with an atrial lead.5 Recent evidence suggests that SCAF is a frequent phenomenon in patients with implanted cardiac devices,6 but also in patients with cardiovascular risk factors having continuous electrocardiogram monitoring by a subcutaneous implanted cardiac monitor.7–9 It is important to note that the risk of stroke is substantially lower than in patientswith clinical AF, though structural changes of the left atrium have to be taken into account—a higher stroke risk in those with left atrial dilatation.10 The efficacy of oral anticoagulants in patients with SCAF is currently being investigated in two randomized trials: ARTESIA (NCT01938248) and NOAH-AFNET6 (NCT02618577). However, the percentage of patientswith a history of stroke is rather low (e.g., 4.5% in ARTESIA [Jeff Healey, personal communication]). The role of SCAF in stroke patients is uncertain.11,12 In this issue of Thrombosis and Haemostasis, Kitsiou et al report the 3-year follow-up data of a prospective observational study in 123 patients with ESUS,13 which extends the initial findings published in 2017.14 They report a cumulative SCAF prevalence of 41% and a stroke recurrence rate of 23%. The proportion of patients with SCAF is rather similar to studies in patients with cardiovascular risk factors or implanted devices, but the stroke recurrence rate is six to 10 times higher (►Fig 1). Therefore, the analysis of patients who