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

This research addresses the need for better secondary stroke prevention for older adults (age 75+ years).

Worldwide, a stroke occurs every 3 seconds, making it the #2 cause of death and a leading cause of permanent disability, dementia, hospitalizations, and healthcare costs. Individuals who have had a stroke face substantial risks of recurrent strokes and cardiovascular events, and one-quarter of all strokes are recurrent events. Improved treatment strategies are needed to prevent more strokes - especially for older patients who are at greatest risk for recurrent strokes yet are also the most understudied in previous clinical trials.

In current practice, most patients after a stroke are prescribed single antiplatelet therapy (i.e. aspirin or clopidogrel), with anticoagulant therapy usually reserved for those with atrial fibrillation. However, antiplatelet therapy has only modest efficacy and may be insufficient for older, higher-risk patients. Previous trials testing standard-dose anticoagulants (without antiplatelet therapy) for post-stroke patients without atrial fibrillation have been negative or neutral but have enrolled mostly younger patients; subgroup analysis has suggested a benefit in 75+ year-olds (RE-SPECT ESUS trial) but has not changed routine clinical practice. Combination therapy involving a very low dose anticoagulant medication plus an antiplatelet medication ('dual pathway inhibition') has demonstrated greater efficacy than either agent alone in patients with coronary disease/peripheral vascular disease for whom it cut the stroke risk in half (COMPASS trial). This promising treatment strategy is now being carefully tested in a dedicated trial for older adults with stroke -- the STROKE75+ trial.

STROKE75+ is a multicentre, prospective, open-label, blinded endpoint (PROBE), phase 3 randomized controlled superiority trial. It is designed for individuals who have had an ischemic stroke, are aged 75+ years, are currently receiving single antiplatelet therapy, and do not have atrial fibrillation or other guideline-recommended indication for anticoagulation; patients at high risk of bleeding are not eligible. This trial focuses on older adults (age 75+ years) because: (1) the population is aging; (2) stroke risk increases with increasing age; (3) older patients are more likely to benefit from the combination of an anticoagulant + antiplatelet agent because they typically have multiple coexisting atherosclerotic and cardioembolic risk factors (including silent atrial fibrillation); and (4) the age 75+ group has been under-studied in previous secondary stroke prevention trials, leaving large gaps in the medical evidence and guidelines.

The main hypothesis that adding a very low dose anticoagulant on top of standard-care single antiplatelet therapy will be: 1) better than the current standard of care of single antiplatelet therapy alone for preventing recurrent strokes (primary efficacy outcome), and 2) associated with a low incidence of bleeding events that are serious (primary safety outcome). The study will also assess if this intervention reduces stroke-related disability, dementia, and heart attacks.

The anticoagulant being studied in this trial is edoxaban, which is already an approved drug in widespread use for stroke prevention in patients with atrial fibrillation. In this trial, edoxaban is being used at a reduced dose of 15 mg daily (one-quarter of its full dose) to minimize the occurrence of serious bleeding side effects. Reassuringly, in previous large trials of patients with atrial fibrillation, the 15 mg dose of edoxaban has demonstrated very good efficacy and safety, including in high-bleed-risk 80+ year-olds where it reduced strokes without a significant increase in major bleeding as compared with placebo (ENGAGE AF-TIMI 48 trial; ELDERCARE-AF trial).

Patients wishing to participate must provide informed consent for study participation and meet the study's inclusion/exclusion criteria. Eligible participants are randomly assigned by computer randomization (50/50 chance) to either the intervention group (edoxaban 15 mg once daily plus standard-care single antiplatelet therapy) or to the control group (standard-care single antiplatelet therapy without edoxaban). Participants are monitored closely throughout the duration of the study with structured follow-up assessments. Every 3 months, central blinded assessors will conduct telephone interviews with participants or their representatives to assess health status and the occurrence of any outcome events using standardized questionnaires. The primary efficacy outcome is the incidence of fatal or non-fatal strokes (defined as a recurrent ischemic stroke or symptomatic intracerebral hemorrhage or unspecified stroke type). The primary safety outcome is the incidence of major bleeding (as defined by the International Society of Thrombosis and Hemostasis). Secondary outcomes include the prevention of stroke-related disability, dementia, and cardiovascular events; rates of intracranial and fatal bleeds; and overall net clinical benefit. The study is overseen by the trial Steering Committee and an independent Data Safety Monitoring Committee.

This research is important for the large and growing aging stroke population. The study results are anticipated to have impact by contributing new knowledge to the field - with implications not only for stroke prevention but also for dementia prevention. The ultimate goal is to reduce recurrent strokes, stroke-related cognitive and physical disability, and the global economic burden of stroke.

Inclusion criteria

Participants must meet all of the following inclusion criteria to participate in the study:

• 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.

[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.]

• 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.

Exclusion criteria

Patients meeting any of the following exclusion criteria at baseline are excluded from enrolment in the study:

• 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.]

• 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.]

• 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).
• 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.
• Hepatic disease associated with coagulopathy; acute hepatitis; chronic active hepatitis; severe hepatic disease (Child-Pugh class C); or cirrhosis.
• Receiving hemodialysis or peritoneal dialysis, or dialysis is planned within the next 12 months.
• 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.]

• Uncontrolled hypertension (BP persistently >160 mmHg systolic or >100 mmHg diastolic) within the past 7 days before informed consent.
• 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
• Body weight <45 kg.
• 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.
• Total disability and dependence (modified Rankin scale score=5 at time of informed consent).
• 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.
• Known allergy/hypersensitivity to edoxaban or other contraindication to edoxaban.
• 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.
• 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.