Stroke, Ischemic
Conditions
Keywords
Stroke, Secondary Stroke Prevention, Anticoagulation, Randomized Controlled Trial
Brief summary
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.
Detailed description
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.
Interventions
DRUGEdoxaban 15 mg
Edoxaban 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.
Standard-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)
Sponsors
Sunnybrook Health Sciences Centre
Study design
Allocation
RANDOMIZED
Intervention model
PARALLEL
Primary purpose
PREVENTION
Masking
SINGLE (Outcomes Assessor)
Masking description
Central Telephone Assessors; Central Adjudication Committee; Senior Study Statistician; Principal Investigator, Co-PIs, Steering Committee
Intervention model description
Eligible male and female patients aged 75 years or older with an ischemic stroke in the past 12 months, and no established indication for anticoagulation, are randomized to receive edoxaban 15 mg po once daily added to their standard-care single antiplatelet therapy vs. standard-care single antiplatelet therapy.
Eligibility
Sex/Gender
ALL
Age
75 Years to No maximum
Healthy volunteers
No
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
Design outcomes
Primary
| Measure | Time frame | Description |
|---|---|---|
| Rate of new strokes (fatal or non-fatal) | From randomization to the end of study (approx. 2-4 years) | 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 | From randomization to the end of study (approx. 2-4 years) | 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. |
Secondary
| Measure | Time frame | Description |
|---|---|---|
| Rates of the secondary efficacy outcomes | From randomization to the end of study (approx. 2-4 years) | 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 | From randomization to the end of study (approx. 2-4 years) | 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) | From randomization to the end of study (approx. 2-4 years) | 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 | From randomization to the end of study (approx. 2-4 years)] | Average 7-day and 90-day poststroke modified Rankin Scale (mRS) score |
| Secondary Efficacy Outcome- Recurrent ischemic strokes | From randomization to the end of study (approx. 2-4 years) | % of recurrent ischemic strokes based on etiological classification |
| Secondary Safety Outcome- Post-bleed modified Rankin Scale (mRS) score | From randomization to the end of study (approx. 2-4 years) | Average 7-day and 90-day post-bleed modified Rankin Scale (mRS) score |
| Secondary Efficacy Outcome-Barthel Index | From randomization to the end of study (approx. 2-4 years) | Average score on the Barthel Index \[range 0 (fully dependent) to 100 points (fully independent functioning)\] |
| Secondary Efficacy Outcomes- EuroQoL-5D-5 (EQ-5D-5L) quality of life scale | From randomization to the end of study (approx. 2-4 years) | Average score on the EuroQoL-5D-5 (EQ-5D-5L) quality of life scale |
| Secondary Efficacy Outcomes- MoCA | From randomization to the end of study (approx. 2-4 years) | Average score on the Montreal Cognitive Assessment (MoCA) - telephone version |
| Secondary Efficacy Outcome- cognitive decline on the MoCA scale | From randomization to the end of study (approx. 2-4 years) | Proportion of participants with cognitive decline on the MoCA scale (from baseline to end-of-study) |
| Secondary Efficacy Outcome- AD8 Dementia | From randomization to the end of study (approx. 2-4 years) | Average score on the Eight-item Informant Interview to Differentiate Aging and Dementia (AD8 Dementia) scale |
| Secondary Efficacy Outcome- Lawton Brody-IADL scale | From randomization to the end of study (approx. 2-4 years) | Average score on the Lawton Instrumental Activities of Daily Living Scale (Lawton Brody-IADL scale) |
| Secondary Efficacy Outcome- adverse cognitive outcomes (MACE-cog) | From randomization to the end of study (approx. 2-4 years) | Proportion of participants with adverse cognitive outcomes (MACE-cog) |
| Secondary Efficacy Outcome- SAGEA | From randomization to the end of study (approx. 2-4 years) | Average score on the Standard Assessment of Global Everyday Activities (SAGEA) scale |
Contacts
CONTACTDavid Gladstone, BSc, MD, PhD, FRCPC
Outcome results
None listed