MOSES - MidregiOnal proatrial natriuretic peptide to guide Secondary Stroke prevention: The MOSES Study

Background: To prevent stroke recurrence we treat our patients based on the presumed underlying etiology, but in clinical practice we are still unable to identify the underlying cause in up to 30% of patients 1. Recent evidence suggests that some cryptogenic strokes may arise from cardiac thromboembolism that goes unrecognized because it has not manifested with atrial fibrillation (AF) yet2, 3. Mid-regional atrial natriuretic peptide (MRproANP) is highly associated with AF but beyond this, it is able to independently identify cardioembolic stroke etiology even in the absence of AF (adjusted OR of 2.1 (95%CI 1.11-3.97)). Moreover MRproANP was associated with future stroke risk after adjustment of manifest cardiac disease (adjusted HR of 3.5 (95%CI 1.6-7.5))4-6. MR-proANP seems to be a subtle marker of underlying atrial thromboembolism6 which may help identifying the biological distinct group who most likely benefits from direct oral anticoagulants even when AF is (not yet) detected. Methods: We propose to perform a multicenter biomarker guided, randomized, assessor blinded, clinical trial. Five hundred patients without known atrial fibrillation and an MRproANP level above 255 pmol/L will be randomized in a 1:1 ratio either to standard treatment (aspirin 100mg/d) or treatment with a direct oral anticoagulant (DOAC)). Patients in both treatment arms will receive standardized acute medical treatment as well as risk factor management. The primary outcome measure is a composite of major bleeding, recurrent stroke and/or vascular death within 1 year after the index ischemic stroke. Specific Aim: To test the hypothesis that a direct oral anticoagulant in MRproANP selected patients is superior to standard treatment with aspirin 100mg/d for the prevention of recurrent stroke and/or vascular death within one year in acute ischemic stroke patients without known atrial fibrillation.Significance: This trial seeks to optimize secondary prevention in patients with ischemic stroke using a blood biomarker to differentiate the underlying mechanism of stroke and thereby guide therapy. On one hand given the benefit of DOACs in patients with known AF this trial may offer a similar benefit to patients with stroke due to cardiac thromboembolism without detected AF. On the other hand given the risks of bleeding associated with anticoagulant drugs, and since not all strokes without detected AF are due to atrial thromboembolism it is essential to define as precisely as possible also the groups who would not benefit from their use. Therefore, our approach adheres well with the general effort toward precision medicine.