Testing a New Treatment Strategy to Improve Secondary Stroke Prevention for Older Adults: The STROKE75+ Trial

The overall aim of this research is to improve secondary stroke prevention for older patients with stroke. In current practice, patients with stroke are often prescribed antiplatelet therapy with either aspirin or clopidogrel to help prevent recurrent strokes. However, an antiplatelet medication may not be effective enough for some patients. A promising new treatment strategy to enhance stroke prevention involves a very low dose of an anticoagulant (anti-clotting medication) added to the standard antiplatelet therapy. In a previous study, this approach cut stroke risk in half among patients with heart/vascular disease, but it has not yet been formally tested in an older stroke population. The STROKE75+ trial is now being conducted to carefully evaluate the potential benefits and potential risks of this type of treatment strategy for secondary stroke prevention. The medication being tested in the STROKE75+ trial is a commonly used anticoagulant called edoxaban -- at a reduced dose of 15mg once daily (one-quarter of its full dose) to minimize the chance of bleeding. In previous research, edoxaban 15mg daily has been shown to be safe and effective for preventing strokes in patients with atrial fibrillation, but it has not been studied in stroke patients without atrial fibrillation. This trial aims to answer the following questions: 1. Does the addition of edoxaban 15mg once a day to standard antiplatelet therapy reduce the risk of recurrent strokes more than standard antiplatelet therapy alone? 2. Does the addition of edoxaban 15mg daily reduce the risk of severe (disabling) strokes, dementia, or heart attacks? 3. What is the incidence of bleeding with/without edoxaban 15mg daily? These questions will be addressed using a Randomized Clinical Trial design. Eligible participants are randomly assigned (50/50 chance) to one of two study groups. Participants in Group 1 are treated with edoxaban 15 mg once a day by mouth (tablet) in addition to their usual standard antiplatelet medication. Participants in Group 2 will continue to take their standard antiplatelet medication (aspirin or clopidogrel) without edoxaban. Participants are monitored closely for the duration of the study (approx.. 2-4 years). Every 3 months, participants will receive a phone call to check on their health status and assess if they have experienced any new strokes, bleeding, or other medical problems. Once a year, and at the start and end of the study, participants will also be asked questions about their symptoms, functioning, memory, and quality of life. At the end of the study, patient outcomes between the two groups will be compared and the results will be published. The information gained from this study will increase knowledge and help inform future stroke care for the aging population. The ultimate goal of this research is to prevent more strokes, save lives, and reduce the growing public health burden of stroke.

Inclusion Criteria: Participants must meet all of the following inclusion criteria to participate in the study: 1. Age ≥75 years on the day of informed consent. 2. Diagnosis of an acute ischemic stroke within the preceding 12 months, which was clinically symptomatic and confirmed by neuroimaging (CT or MRI), and for which the treatment plan is single antiplatelet therapy with either aspirin 81 mg daily (80 mg daily is permitted) or clopidogrel (75 mg daily) for long-term secondary stroke prevention. \[Note: The qualifying stroke event can be a clinical transient ischemic attack if there was neuroimaging evidence of acute ischemia/infarction on brain imaging. A clinically symptomatic acute intracranial vessel occlusion on angiography that recanalized without infarction is eligible for enrolment.\] 3. The patient has had ECG monitoring after the qualifying stroke event (Holter, telemetry, or other continuous ECG monitoring device) totalling at least 24 hours and with no episodes of atrial fibrillation (or atrial flutter) ≥6 minutes AND a routine 12-lead ECG within 90 days before randomization shows sinus rhythm (no atrial fibrillation or atrial flutter). 4. Written informed consent from participant or legally authorized representative. Exclusion Criteria: Patients meeting any of the following exclusion criteria at baseline are excluded from enrolment in the study: 1. Diagnosis of atrial fibrillation or atrial flutter (AF) documented in the patient's medical history or examination; any AF on a 12-lead ECG; or any episode of AF ≥6 minutes on a Holter or other continuous ECG monitor. \[Note: The following are not exclusions and are acceptable for enrolment: brief subclinical device-detected AF with a maximum episode duration \2 years ago) of transient AF that was only ever detected in the context of surgery or acute medical illness.\] 2. Any of the following 'major-risk' cardiac sources of embolism based on the patient's medical history and post-stroke echocardiography (transthoracic or transesophageal) or other cardiac imaging within the past 12 months: mechanical heart valve; intracardiac thrombus; atrial myxoma or other cardiac tumor; recent (\160 mmHg systolic or \>100 mmHg diastolic) within the past 7 days before informed consent. 10. Any of the following laboratory exclusions (must be based on the most recent available clinically acquired routine bloodwork within 90 days before randomization): * calculated creatinine clearance \