Apixaban Versus Dual-antiplatelet Therapy (Clopidogrel and Aspirin) in Acute Non-disabling Cerebrovascular Events

Study Overview
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Brief Summary
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Nondisabling cerebrovascular events represent the largest group of cerebrovascular disease with a high risk of recurrent stroke. A recent trial indicated that clopidogrel and aspirin treatment reduced the risk of recurrent stroke and was not associated with increased hemorrhage events, compared with aspirin monotherapy. Apixaban, a new oral anticoagulant, is proved to be as effective as traditional anticoagulants with less risk of bleeding events. To estimate whether apixaban is beneficial for acute TIA or minor stroke, a randomized, double-blind, multicenter, controlled clinical trial has been designed. The investigators will assess the hypothesis that a 21-days apixaban regimen is superior to clopidogrel and aspirin dual-therapy for the treatment of high-risk patients with acute nondisabling cerebrovascular event.

Detailed Description
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The ADANCE study is a randomized, double-blind clinical trial with a target enrollment of 3,000 Chinese patients. Two subtypes of patients will be enrolled: I, acute disabling ischemic stroke (<24 hours of symptoms onset); II, acute TIA (<24 hours of symptoms onset). Patients will be randomized into 3 groups: Ⅰ Receiving a 75 mg dose of clopidogrel and 75mg dose of aspirin from day 1 to day 21, with placebo apixaban twice daily. Ⅱ Receiving a 2.5-mg twice daily of apixaban, with placebo clopidogrel and placebo aspirin from day 1 to day 21. Ⅲ Receiving a 5-mg twice daily of apixaban, with placebo clopidogrel and placebo aspirin from day 1 to day 21. From day 22 to 3 months, all patients will receive 75-mg dose of clopidogrel long-term antiplatelet therapy. The primary efficacy end point is percentage of patients with new stroke (ischemic or hemorrhage) at 90 days.

Official Title
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Apixaban Versus Dual-antiplatelet Therapy (Clopidogrel and Aspirin) in High-risk Patients With Acute Non-disabling Cerebrovascular Events (ADANCE): Rationale, Objectives, and Design

Conditions
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Ischemic Stroke, TIA

Intervention / Treatment
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* Drug: Apixaban
* Drug: Clopidogrel
* Drug: Aspirin
* Drug: placebo


Participation Criteria
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Eligibility Criteria
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Inclusion Criteria: Adult subjects (male or female ≥18 years old) Acute nondisabling ischemic stroke (NIHSS ≤3 at the time of randomization) that can be treated with study drug within 24 hours of symptoms onset. Symptom onset is defined by the last see normal principle TIA (neurologic deficit attributed to focal brain ischemia, with resolution of the deficit within 24 hours of symptom onset), that can be treated with investigational medication within 24 hours of symptoms onset. Symptom onset is defined by the last see normal principle Informed consent signed Exclusion Criteria: Diagnosis of hemorrhage or other pathology, such as vascular malformation, tumor, abscess or other major nonischemic brain disease, on baseline head CT or MRI scan mRS score >2 at randomization (premorbid historical assessment) NIHSS ≥4 at randomization Clear indication for anticoagulation (atrial fibrillation, mechanical cardiac valves, deep venous thrombosis, pulmonary embolism or known hypercoagulable state) Contraindication to investigational medications Thrombolysis for ischemic stroke within preceding 7 days History of intracranial hemorrhage Current treatment (last dose given within 10 days before randomization) with heparin therapy or oral anticoagulation Gastrointestinal bleed or major surgery within 3 months Planned or likely revascularization (any angioplasty or vascular surgery) within the next 3 months TIA or minor stroke induced by angiography or surgery Severe noncardiovascular comorbidity with life expectancy <3 months Women of childbearing age not practicing reliable contraception who do not have a documented negative pregnancy test result Severe renal failure, defined as Glomerular Filtration Rate (GFR) <30 ml/min Severe hepatic insufficiency (Child-Pugh score B to C)

Ages Eligible for Study
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Minimum Age: 18 Years
Maximum Age: 80 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: Randomized
Intervention Model: Parallel Assignment
Masking: Triple


Arms and Interventions

| Participant Group/Arm | Intervention/Treatment |
| --- | --- |
| Active Comparator: Dual-antiplatelet Therapy<br>Receiving a 75 mg dose of clopidogrel and 75mg dose of aspirin from day 1 to day 21, with placebo apixaban twice daily | Drug: Clopidogrel<br>* an irreversible inhibitor of the P2Y12 adenosine diphosphate receptor<br>* Other names: Clopivid;Drug: Aspirin<br>* a non-steroidal anti-inflammatory drug<br>* Other names: Acetylsalicylic acid;Drug: placebo<br> <br> |
| Experimental: Apixaban 2.5mg<br>Receiving a 2.5-mg twice daily of apixaban, with placebo clopidogrel and placebo aspirin from day 1 to day 21 | Drug: Apixaban<br>* orally active direct factor Xa inhibitor<br>* Other names: BMS-562247-01;Drug: placebo<br> <br> |
| Experimental: Apixaban 5mg<br>Receiving a 5-mg twice daily of apixaban, with placebo clopidogrel and placebo aspirin from day 1 to day 21 | Drug: Apixaban<br>* orally active direct factor Xa inhibitor<br>* Other names: BMS-562247-01;Drug: placebo<br> <br> |

What is the study measuring?
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Primary Outcome Measures

| Outcome Measure | Measure Description | Time Frame |
| --- | --- | --- |
| percentage of patients with new stroke (ischemic or hemorrhage) |  | 90 days | 

Secondary Outcome Measures

| Outcome Measure | Measure Description | Time Frame |
| --- | --- | --- |
| Percentage of patients with new clinical vascular events (ischemic stroke/hemorrhagic stroke/TIA/myocardial infarction/vascular death) |  | 30 days | 
| Percentage of patients with new clinical vascular events (ischemic stroke/hemorrhagic stroke/TIA/myocardial infarction/vascular death) |  | 30 days and 90 days | 
| Changes in NIHSS scores |  | 90 days | 
| moderate to severe bleeding events |  | 90 days | 
| Total mortality |  | 90 days | 
| Adverse events/severe adverse events reported by the investigators |  | 90 days | 

 Terms related to the study
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Keywords Provided by Centre Hospitalier Valida
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apixaban, clopidogrel, aspirin, new oral anticoagulant, TIA, acute minor ischemic stroke