Randomized Trial to Evaluate the Efficacy and Safety of Very Low Dose Anticoagulant Therapy Added to Standard-Care Single Antiplatelet Therapy for Prevention of Recurrent Strokes in Patients With Ischemic Stroke Aged 75+ Years
试验速览
- 阶段
- 3 期
- 状态
- 尚未招募
- 入组人数
- 1,204
- 主要终点
- Rate of new strokes (fatal or non-fatal)
研究概览
简要总结
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:
- 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?
- Does the addition of edoxaban 15mg daily reduce the risk of severe (disabling) strokes, dementia, or heart attacks?
- 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.
详细描述
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.
研究设计
- 研究类型
- Interventional
- 分配方式
- Randomized
- 干预模型
- Parallel
- 主要目的
- Prevention
- 盲法
- Single (Outcomes Assessor)
盲法说明
Central Telephone Assessors; Central Adjudication Committee; Senior Study Statistician; Principal Investigator, Co-PIs, Steering Committee
入排标准
- 年龄范围
- 75 Years 至 —（Older Adult）
- 性别
- All
- 接受健康志愿者
- 否
入选标准
- •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.
排除标准
- •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.
研究组 & 干预措施
Intervention Group (combination therapy group)
Open-label edoxaban 15 mg po once daily added to 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)
干预措施: Edoxaban 15 mg (Drug)
Intervention Group (combination therapy group)
Open-label edoxaban 15 mg po once daily added to 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)
干预措施: Aspirin or clopidogrel (Drug)
Control Group (standard-care group)
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)
干预措施: Aspirin or clopidogrel (Drug)
结局指标
主要结局
Rate of new strokes (fatal or non-fatal)
时间窗: 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
时间窗: 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.
次要结局
- Secondary Efficacy Outcome-Barthel Index(From randomization to the end of study (approx. 2-4 years))
- Rates of the secondary efficacy outcomes(From randomization to the end of study (approx. 2-4 years))
- Rates of the secondary safety outcomes(From randomization to the end of study (approx. 2-4 years))
- Secondary Efficacy Outcome-modified Rankin Scale (mRS)(From randomization to the end of study (approx. 2-4 years))
- Secondary Efficacy Outcome- Poststroke modified Rankin Scale (mRS) score(From randomization to the end of study (approx. 2-4 years)])
- Secondary Efficacy Outcome- Recurrent ischemic strokes(From randomization to the end of study (approx. 2-4 years))
- Secondary Safety Outcome- Post-bleed modified Rankin Scale (mRS) score(From randomization to the end of study (approx. 2-4 years))
- Secondary Efficacy Outcomes- EuroQoL-5D-5 (EQ-5D-5L) quality of life scale(From randomization to the end of study (approx. 2-4 years))
- Secondary Efficacy Outcomes- MoCA(From randomization to the end of study (approx. 2-4 years))
- Secondary Efficacy Outcome- cognitive decline on the MoCA scale(From randomization to the end of study (approx. 2-4 years))
- Secondary Efficacy Outcome- AD8 Dementia(From randomization to the end of study (approx. 2-4 years))
- Secondary Efficacy Outcome- Lawton Brody-IADL scale(From randomization to the end of study (approx. 2-4 years))
- Secondary Efficacy Outcome- adverse cognitive outcomes (MACE-cog)(From randomization to the end of study (approx. 2-4 years))
- Secondary Efficacy Outcome- SAGEA(From randomization to the end of study (approx. 2-4 years))