Test of adding a very low-dose edoxaban to standard antiplatelet therapy to prevent another stroke in adults 75 and older

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.

   \[Note: The following are not exclusions and are acceptable for enrolment: brief subclinical device-detected AF with a maximum episode duration \<6 minutes on a continuous ECG recording; a remote history (\>2 years ago) of transient AF that was only ever detected in the context of surgery or acute medical illness.\]
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 (\<4 weeks) myocardial infarction; or valvular vegetations or diagnosed/suspected infective endocarditis.

   \[Note: The following are not exclusions and are acceptable for enrolment: bioprosthetic heart valve; TAVI; patent foramen ovale (PFO) with no plans for closure.\]
3. 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.
4. 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).
5. History of gastrointestinal bleeding or another major bleeding event within the past 12 months; active or recent spontaneous non-trivial bleeding (within the past 30 days); unresolved peptic ulcer; or considered by the enrolling investigator to be at high risk for serious bleeding for any reason.
6. Hepatic disease associated with coagulopathy; acute hepatitis; chronic active hepatitis; severe hepatic disease (Child-Pugh class C); or cirrhosis.
7. Receiving hemodialysis or peritoneal dialysis, or dialysis is planned within the next 12 months.
8. History of CT-detected intracranial hemorrhage (intracerebral hemorrhage, subarachnoid hemorrhage, subdural hematoma, or epidural hematoma).

   \[Note: If there was head CT evidence of hemorrhagic transformation of the qualifying ischemic stroke, or other intracranial blood on head CT following the qualifying stroke event, then a head CT documenting resolution of hemorrhage must be obtained before randomization. Presence of asymptomatic incidental MRI-detected parenchymal brain microbleeds are not an exclusion, but cortical superficial siderosis or convexity subarachnoid hemorrhage are exclusions.\]
9. Uncontrolled hypertension (BP persistently \>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 \<30 mL/min (Cockroft Gault);
    * platelet count \<100 x 109/L;
    * hemoglobin \<100 g/L;
    * INR \>1.3
11. Body weight \<45 kg.
12. The patient is receiving any of the following medications and is unable to stop or switch before randomization:

    * Any anticoagulant drug. This includes unfractionated heparin (UFH); any low molecular weight heparin (LMWH) (e.g. enoxaparin, dalteparin, nadroparin, tinzaparin), fondaparinux, argatroban, or other injectable anticoagulant; warfarin (Coumadin), acenocoumarol, DOACs e.g. apixaban (Eliquis), dabigatran (Pradaxa), non-study edoxaban (Lixiana), rivaroxaban (Xarelto), or other oral anticoagulant; or
    * Any antiplatelet medication other than aspirin 80 or 81 mg daily or clopidogrel 75 mg daily. This includes ticagrelor (Brillinta), prasugrel (Effient), dipyridamole, aspirin/extended-release dipyridamole (Aggrenox), cilostazol, Gp11b/IIIa inhibitors e.g. abciximab (ReoPro), eptifibatide (Integrilin), tirofiban (Aggrastat), and others; or
    * Dual antiplatelet therapy; or
    * Daily nonsteroidal anti-inflammatory drug (NSAID) use; or
    * Drugs expected to increase edoxaban concentration: cyclosporine, tacrolimus, quinidine, dronedarone, erythromycin, ketoconazole, itraconazole, HIV protease inhibitors (ritonavir, darunavir, atazanivir, and others), including nirmatrelvir/ritonavir (Paxlovid) which may be prescribed for COVID-19 infection; or
    * Drugs expected to decrease edoxaban concentration: carbamazepine, phenytoin, phenobarbital, primidone, valproic acid, rifampin/rifampicin, St. John's wort.
13. Total disability and dependence (modified Rankin scale score=5 at time of informed consent).
14. The patient is likely to be poorly compliant or unreliable with medication intake or study follow-up appointments, or estimated life expectancy is \<1 year due to severe stroke, concomitant disease, or terminal illness.
15. Known allergy/hypersensitivity to edoxaban or other contraindication to edoxaban.
16. Any other condition that in the opinion of the enrolling physician would not permit the addition of edoxaban 15 mg once-daily to single antiplatelet therapy.
17. Enrolment in another clinical trial involving a drug intervention, or enrolment in another clinical trial involving a non-drug intervention for stroke prevention or cardiovascular prevention.