Atrial Myopathy and Embolic Stroke (AMES) trial – Prospective Randomised Open Blinded Endpoint (PROBE) clinical trial with parallel cohort study

Patients with ischemic stroke deemed to be embolic with no clearly identified aetiology after standard evaluation (Embolic Stroke of Uncertain Source, ESUS) will be enrolled. Patients will undergo transthoracic echocardiography and be divided into two groups: impaired left atrial (LA) function (reduced 'strain', indicating atrial myopathy) and normal left atrial function. This study includes an RCT and a simultaneous prospective cohort study. The RCT will be a multi-centre ,parallel group, prospective, randomised open, blinded endpoint trial. The arms are as follow: 1. Patients with impaired left atrial function will be randomised to the intervention of Direct Acting Oral Anticoagulant (DOAC) vs. standard (guideline based) antiplatelet care (1:1 allocation ratio). 2. Patients without atrial myopathy (i.e. with normal left atrial function and thus ineligible for the RCT), will be allocated to standard care 3.Patients without atrial myopathy and as well as the patients with atrial myopathy in the RCT, who were ,randomised to standard care, will form the two parallel arms of the longitudinal cohort study. Follow-up : All participant, either , in RCT or cohort study, will have the same follow-up and observations at Baseline, at 6 months after enrolment, and at 24 months after enrolment. RCT component: Direct Acting Oral Anticoagulant (DOAC) VS standard care. Cohort Study component : Normal LA strain and Normal LA Volume participants allocated to standard care. Direct Acting Oral Anticoagulant (DOAC) VS standard care. Participants who will be randomised , to be administered one of the three DOACs as per the neurologists choice of the DOAC. Tablet will be taken orally. Rivaroxaban , apixaban and Dabigatran are administered at a fixed dose without monitoring. • Rivaroxaban: 20 mg once daily with the evening meal for 24 months following enrolment (creatinine clearance [CrCl] greater than 50 mL/minute); or 15 mg once daily with the evening meal for 24 months following enrolment (CrCl equal to 50 mL/minute). • Apixaban: 5 mg twice daily for 24 months following enrolment (CrCl greater than 50 mL/minute); or 2.5 mg twice daily ,for 24 months following enrolment ,for those with any two of the following: age is greater than or equal to 80 years, body weight is less than or equal to 60 kg, or serum creatinine is equal to 1.5 mg/dL. • Dabigatran :110 mg orally twice daily or 150 mg orally twice daily, for 24 months following enrolment (CrCl greater than 30 mL/minute). Dabigatran is generally given at a fixed dose without monitoring. Intervention Adherence will be done in the following ways : Patient Self-Report: Asking the participant directly about their medication-taking habits. Pill Counts: Have patients return unused medication, allowing site to calculate how many doses they have taken compared to what was prescribed. Pharmacy Refill Records: Review prescription refill history to see if the patient is picking up their medication as prescribed. Clinical Assessments: Monitor the participant’s clinical progress. Improvement in symptoms can indicate adherence, although it’s not definitive. Support Systems: Implement reminders or support groups (family) to encourage adherence and check in with patients regularly. COHORT STUDY PARTICIPANTS: The follow-up and observations will be exactly the same as RCT participants, at Baseline, at 6 months after enrolment, and at 24 months after enrolment. The following assessments will be attained for Cohort patients (these assessments have been widely described ) : • Baseline: Physical examination, NIHSS, MoCA, estimate of pre-stroke functioning with mRS and EQ5D, transthoracic echocardiography, ECG and digital 12-lead ECG. • 6 months: Clinician events of stroke reoccurrence, Brain MRI, mRS, MoCA, EQ5D, ECG and digital 12-lead ECG. • 24 months: Clinician events of stroke reoccurrence, Brain MRI, mRS, MoCA, EQ5D, ECG and digital 12-lead ECG Followed by adherence of standard of care treatments. • Patient Self-Report: Asking the participant directly about their medication-taking habits. • Pill Counts: Have patients return unused medication, allowing site to calculate how many doses they have taken compared to what was prescribed. • Pharmacy Refill Records: Review prescription refill history to see if the patient is picking up their medication as prescribed. • Clinical Assessments: Monitor the participant’s clinical progress. Improvement in symptoms can indicate adherence, although it’s not definitive. • Support Systems: Implement reminders or support groups (family) to encourage adherence and check in with patients regularly.