Abstract 399: Refining Embolic Stroke of Undetermined Source (ESUS) Management‐ A Systematic Synthesis of Diagnostic and Therapeutic Advances

METHOD We conducted a targeted synthesis of seven pivotal trials—NAVIGATE ESUS, RE‑SPECT ESUS, CRYSTAL AF, ARCADIA, COMPASS, ESCAPE‑NA, and AF‑ESUS—to explore diagnostic markers and therapeutic implications for optimizing individualized ESUS management. RESULTS Key ESUS sources with diagnostic and therapeutic implications may inform individualized care: 1 .Moderate LV dysfunction (LVEF 30‐40%) and regional wall motion abnormalities are common in ESUS and may increase embolic risk. An exploratory NAVIGATE ESUS analysis showed rivaroxaban (15 mg daily) reduced recurrent stroke vs. aspirin (100 mg daily) in this group. Risk stratification using Cardiac MRI, with higher LV thrombus sensitivity, alongside ECHO, may help identify patient population for anticoagulation (AC). 2 .Atrial cardiopathy markers—PTFV1, NT‐proBNP >250 pg/mL, and LA diameter >3 cm/m 2 —are prospectively linked to stroke risk, despite ARCADIA's neutral findings. PTFV1 reflects LA pathophysiology, with evidence connecting elevated PTFV1 and LA enlargement to cryptogenic stroke. NAVIGATE ESUS showed a 74% stroke reduction with rivaroxaban in patients with LA diameter >46 mm, underscoring the need to refine AC selection markers. 3. RE‐SPECT ESUS linked NT‐proBNP >505 pg/mL and older age to higher AF incidence, with patients >75 benefiting from low‐dose dabigatran. CRYSTAL AF associated older age and prolonged PR interval with AF. Extended monitoring is warranted in patients with elevated NT‐proBNP, age >75, HAVOC scores ≥3 to identify covert AF and guide anticoagulation. 4. NAVIGATE ESUS, ESCAPE NA, and RE‐SPECT ESUS identified carotid plaques ≥3 mm and 30‐50% stenosis as key ipsilateral stroke markers. AF‐ESUS showed lower Afib detection in ESUS patients with such plaques. In younger cryptogenic stroke patients, a negative plaque‐PFO association was observed, supporting non‐stenosing atherosclerosis as a stroke source. COMPASS trial secondary analyses suggest rivaroxaban plus aspirin may reduce recurrence by up to 70% in stable and possibly non‐stenotic atherosclerosis. Similar trends emerged in the AREST ESUS pilot. This approach necessitates individualized risk assessment. Conclusion Despite antiplatelets remaining the standard for secondary prevention, ESUS carries a 4‐5% annual recurrence. This review underscores a need to move beyond a uniform approach—highlighting how emerging biomarkers, imaging modalities, and targeted anticoagulation strategies could help individualize stroke prevention in specific ESUS population