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.
Age ≥75 years on the day of informed consent.
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.
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).
Written informed consent from participant or legally authorized representative.
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.
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 (<4 weeks) myocardial infarction; or valvular vegetations or diagnosed/suspected infective endocarditis.
The patient has a medical requirement for chronic anticoagulant therapy or dual antiplatelet therapy, or dual or triple antithrombotic therapy (e.g. recent acute coronary syndrome or vascular stenting procedure, venous thromboembolism (DVT/PE), hypercoagulable state) or chronic nonsteroidal anti-inflammatory drug (NSAID) therapy.
The qualifying stroke etiology is attributed to vasculitis, arterial dissection, migraine, vasospasm, drug abuse, infective endocarditis, antiphospholipid antibody syndrome or other high-risk thrombophilia; Moya Moya; CADASIL or other genetic cause; other infectious or inflammatory cause; or an iatrogenic/procedure-related cause (e.g. post-operative stroke).
Parallel
Edoxaban 15 mg
DrugEdoxaban is a once-daily oral tablet. It can be taken with or without food. Edoxaban is widely used worldwide for the prevention of stroke in patients with atrial fibrillation, treatment of venous thromboembolism (DVT/PE), and prevention of recurrent DVT/PE. It works by inhibiting a coagulation protein called Factor Xa to reduce thrombin generation and prevent blood clots. For this trial, the dose of edoxaban chosen is 15 mg once a day (which is one-quarter of the full dose) to minimize the chance of bleeding problems. The 15 mg dose of edoxaban has been shown to be safe and effective for preventing strokes in patients with atrial fibrillation, but it has not yet been studied for stroke prevention in patients without atrial fibrillation.
Aspirin or clopidogrel
DrugStandard-care single antiplatelet therapy (either aspirin 81 mg \[or 80 mg\] po once daily or clopidogrel 75 mg po once daily; the choice of antiplatelet agent is at the discretion of the treating physician)
Rate of new strokes (fatal or non-fatal)
The primary efficacy outcome is the rate of new strokes (fatal or non-fatal) - defined as a composite of recurrent ischemic stroke, symptomatic intracerebral hemorrhage, or unknown type of stroke.
Rate of ISTH major bleeding
The primary safety outcome is the rate of ISTH major bleeding, defined as: * Fatal bleeding; and/or * Symptomatic bleeding in a critical area or organ, such as intracranial, intraspinal, intraocular (excludes conjunctival), retroperitoneal, intra-articular or pericardial, or intramuscular with compartment syndrome \[note that bleeding in a critical area or organ must be associated with a symptomatic clinical presentation related to the bleeding in order for this criterion to be met according to the ISTH definition\]; and/or * Bleeding causing a fall in hemoglobin level of 20 g/L or more, or leading to transfusion of two or more units of whole blood or red cells. Note: To qualify as a major bleed, it must be symptomatic, clinically overt bleeding (either visible bleeding or bleeding documented by imaging). Asymptomatic bleeding or a hemoglobin drop without evidence of bleeding is not classified as a major bleed.
Rates of the secondary efficacy outcomes
Rates of the following secondary efficacy outcomes: ischemic stroke; transient ischemic attack (TIA); ischemic stroke or TIA; ischemic stroke or systemic embolism; cardiovascular (CV) death; all-cause mortality; stroke or death; stroke or CV death; disabling or fatal strokes (mRS score 3-6); fatal strokes; death or total disability (mRS score 5-6); non-lacunar ischemic strokes; recurrent ischemic strokes associated with new AF; myocardial infarction (MI); stroke or MI or CV death; stroke MI, CV death or hospitalization for unstable angina or coronary revascularization procedure; deep vein thrombosis or pulmonary embolism; incident dementia; institutionalization.
Rates of the secondary safety outcomes
Rates of the following secondary safety outcomes: fatal bleeding events; bleeding leading to hospitalization; bleeding requiring transfusion of whole blood or red cells; symptomatic intracerebral hemorrhage; fatal intracerebral hemorrhage; symptomatic intracranial hemorrhage (intracerebral, intraventricular, subdural, epidural, or subarachnoid hemorrhage); fatal intracranial hemorrhage; ISTH major bleeding excluding intracranial hemorrhage; ISTH clinically relevant non-major bleeding events; Thrombolysis in Myocardial Infarction (TIMI) major bleeding; TIMI minor bleeding; Bleeding Academic Research Consortium (BARC) category 3 bleeding; gastrointestinal bleeding; category 3-4 major bleeding events
Secondary Efficacy Outcome-modified Rankin Scale (mRS)
Average score and distribution of the modified Rankin Scale (mRS) \[range 0 (normal, no symptoms) to 6 (death)\]
Secondary Efficacy Outcome- Poststroke modified Rankin Scale (mRS) score
Average 7-day and 90-day poststroke modified Rankin Scale (mRS) score
Net benefit outcome: rate of stroke or major bleeding
• rate of stroke or major bleeding
Other Outcomes-new atrial fibrillation diagnosis
Incidence of new atrial fibrillation diagnosis
Net benefit outcome: rate of stroke, MI, CV death, or major bleeding
Rate of stroke, MI, CV death, or major bleeding
Other outcomes-new cancer diagnosis
Incidence of new cancer diagnosis
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