Statin and Dual Antiplatelet Therapy to Prevent Early Neurological Deterioration in Branch Atheromatous Disease

Study Overview
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Brief Summary
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Branch atheromatous disease (BAD) has been reported to contribute to small-vessel occlusion and is associated with a higher possibility of early neurological deterioration (END). Because the pathology of BAD is due to atherosclerosis, the investigators postulate that early intensive medical treatment with dual antiplatelet therapy(DAPT) and high-intensity statin may prevent END and recurrent stroke. The investigators hypothesise that intensive medical therapy can prevent END in BAD using aspirin, clopidogrel and high-intensity statin.

Detailed Description
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The SATBRAD study is a single-centre, prospective, open-label, single-group trial with a historical control group of BAD patients treated with single antiplatelet therapy and regular statin treatment in Chang Gung Memorial Hospital in Taiwan. Eligible participants are as follows: have a clinical diagnosis of ischemic stroke; National Institute of Health Stroke Scale (NIHSS) score of 1-8; an ischemic lesion on diffuse-weighted imaging located in the middle cerebral artery(MCA) perforator, Heubner's artery or vertebrobasilar perforator territories; BAD, defined by a visible lesion in three or more axial MRI cuts in the MCA perforator territory or Heubner's artery territories or infarcts that extended from the basal surface of the brainstem. can receive intensive medical treatment within 24 hours of stroke onset. Participants in the intervention group will receive DAPT and high-intensity statin treatment. DAPT treatment is administered within 24 hours of stroke onset, with aspirin (300 mg loading and 100 mg/day) and clopidogrel (300mg and 75m/day). Participants will take aspirin and clopidogrel for 21 days and then keep aspirin or clopidogrel alone. High-intensity statin is administered, including atorvastatin 40-80mg or rosuvastatin 20 mg for 3 months. A historical control group of patients receiving single oral antiplatelet medication and regular statin treatment will be drawn from previous prospective observation studies which were executed since Jan. 2011 to Dec. 2020. The total sample sizes are 147 for intervention group and 277 for control group. The primary endpoint is the composite of END, defined as an increase of ≧2 points of NIHSS within 7 days, and recurrent ischemic stroke within 30 days.

Official Title
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Early Intensive Medical Therapy for the Prevention of Early Neurological Deterioration in Branch Atheromatous Disease

Conditions
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Acute Stroke, Dual Antiplatelet Therapy, Statin

Intervention / Treatment
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* Drug: Clopidogrel
* Drug: Aspirin
* Drug: Atorvastatin
* Drug: Rosuvastatin


Participation Criteria
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Eligibility Criteria
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Inclusion Criteria: Clinical diagnosis of ischemic stroke with National Institute of Health Stroke Scale (NIHSS) score of 1-8 An ischemic lesion on diffuse-weighted imaging located in the MCA perforator, or Heubner's artery territories or vertebro-basilar perforator territories at brain stem. Branch atheromatous disease, defined by a visible lesion in three or more axial MRI cuts in the MCA perforator or Heubner's artery territories or infarcts that extended from the basal surface of the brainstem. Ability to randomize within 24 hours of time last known free of new ischemic symptoms. Head CT or MRI ruling out hemorrhage or other pathology, such as vascular malformation, tumor, or abscess, that could explain symptoms or contraindicate therapy. Ability to tolerate high intensity medical therapy, including aspirin at a dose of 50-325 mg/day, clopidogrel with 300mg loading and 75mg after day 2 and high-intensity statin(either atorvastatin 40-80mg or rosuvastatin 20 mg/day). Pre-stroke mRS≦1 Exclusion Criteria: Age < 20 years. In the judgment of the treating physician A candidate for thrombolysis, endarterectomy or endovascular intervention. Receipt of any intravenous or intra-arterial thrombolysis within 1 week prior to index event. Patients with more than 50% stenosis of the relevant arteries on magnetic resonance angiography (MRA), including intra- or extra-cranial internal carotid artery, middle cerebral artery or basilar artery. Patients with high risk of cardioembolic source, such as atrial fibrillation, acute myocardial infarction, severe heart failure or valvular heart disease. Other determined stroke etiology, such as vasculitis, shock, antiphospholipid antibody syndrome and etc. Gastrointestinal bleed or major surgery within 3 months prior to index event. History of nontraumatic intracranial hemorrhage. Clear indication for anticoagulation during the study period (deep venous thrombosis, pulmonary embolism or hypercoagulable state). Qualifying ischemic event induced by angiography or surgery. Severe non-cardiovascular comorbidity with life expectancy <3 months. Contraindication to clopidogrel, aspirin, atorvastatin or rosuvastatin Known allergy to clopidogrel, aspirin atorvastatin or rosuvastatin Severe renal (serum creatinine >2 mg/dL) or hepatic insufficiency (INR>1.2; ALT>40 U/L or any resultant complication, such as variceal bleeding, encephalopathy, or jaundice) Hemostatic disorder or systemic bleeding in the past 3 months Current thrombocytopenia (platelet count <100 x109/L) or leukopenia (<2 x109/L) History of drug-induced hematologic or hepatic abnormalities Anticipated requirement for long-term (>7 day) non-study antiplatelet drugs (e.g., dipyridamole, ticagrelor, ticlopidine), or NSAIDs. Low-density lipoprotein<70mg/dl without prior statin treatment in recent one year or within 2 days after recruitment

Ages Eligible for Study
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Minimum Age: 20 Years

Sexes Eligible for Study
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All

Accepts Healthy Volunteers
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No

Study Plan
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How is the study designed?
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Design Details

Primary Purpose: Treatment
Allocation: Non-Randomized
Intervention Model: Parallel Assignment
Masking: None (Open Label)


Arms and Interventions

| Participant Group/Arm | Intervention/Treatment |
| --- | --- |
| Experimental: Intervention group<br>This group will receive dual antiplatelet and high-intensity statin treatment. Dual antiplatelet treatment: loading of clopidogrel 300mg plus aspirin 300mg, followed by clopidogrel 75 mg/day and aspirin 100 mg/d from day 2 to day 21, and followed by clopidogrel 75 mg/d or aspirin 100 mg/d from day 15 to day 90. High-intensity statin treatment: Atorvastatin 40-80mg/day or Rosuvastatin 20 mg/day for 90 days. | Drug: Clopidogrel<br>* 300mg loading and 75mg/day from day 2<br>Drug: Aspirin<br>* Aspirin(100-300mg/day)<br>Drug: Atorvastatin<br>* Atorvastatin 40-80mg/day<br>Drug: Rosuvastatin<br>* Rosuvastatin 20 mg/day.<br>|
| Active Comparator: Historical control<br>A historical control group of patients receiving single antiplatelet therapy but no high-intensity statin treatment will be drawn from previous prospective observation studies. Antiplatelet therapy includes aspirin(100-300mg/day) or Clopidopgrel (75mg/day). | Drug: Clopidogrel<br>* 300mg loading and 75mg/day from day 2<br>Drug: Aspirin<br>* Aspirin(100-300mg/day)<br>|

What is the study measuring?
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Primary Outcome Measures

| Outcome Measure | Measure Description | Time Frame |
| --- | --- | --- |
| The percentage of patients with early neurological deterioration within 7 days and recurrent ischemic stroke within 30 days. | The early neurological deterioration is defined as an increase of 2 points of NIHSS. The NIHSS is composed of 11 items, each of which scores a specific ability between a 0 and 4. For each item, a score of 0 typically indicates normal function in that specific ability, while a higher score is indicative of some level of impairment. The maximum possible score is 42, with the minimum score being a 0. | 30 days | 

Secondary Outcome Measures

| Outcome Measure | Measure Description | Time Frame |
| --- | --- | --- |
| Percentage of patients with favorable functional recovery defined as a mRS ≦1 | Defined as a mRS ≦1. The Modified Rankin Scale (mRS) runs from 0-6, running from perfect health without symptoms(score 0) to death(score 6). | 90 days | 
| Percentage of patients with new clinical vascular events | ischemic stroke/hemorrhagic stroke/TIA/myocardial infarction/vascular death | 90 days | 
| Changes of atherosclerotic plaque | The changes of atherosclerotic plaque was measured by high-resolution MRI initially and 6 months later. | 6 months | 
| Numbers of moderate to severe bleeding events |  | 90 days | 
| Total mortality |  | 90 days | 

 Terms related to the study
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Keywords Provided by Centre Hospitalier Valida
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Branch Atheromatous Disease, Early neurological deterioration, Dual antiplatelet therapy, Statin