Large-artery stenosis plays an important role in the occurrence of ischemic stroke. The primary purpose of this study is to evaluate the efficacy and safety of intensive antiplatelet therapy versus standard antiplatelet therapy and immediate high-intensity statin therapy (80mg atorvastatin) versus delayed high-intensity statin therapy (40mg atorvastatin) and intensive antiplatelet combined with immediate high-intensity statin therapy (80mg atorvastatin) versus standard antiplatelet combined with delayed high-intensity statin therapy (40mg atorvastatin) in reducing the risk of stroke at 90 days in patients with acute and high-risk symptomatic extracranial or intracranial arterial stenosis.

Large-artery atherosclerotic stenosis is the main cause of ischemic stroke, especially in Asian population. However, targeted treatment evidence for large-artery atherosclerotic stenosis is limited according to the current guidelines. And also, randomized trial for statin therapy in patients with acute large arterial stenosis at early stage is still limited. The primary purpose of this study is to evaluate the efficacy and safety of intensive antiplatelet therapy versus standard antiplatelet therapy in reducing the risk of stroke at 90 days in patients with acute and high-risk symptomatic extracranial or intracranial arterial stenosis; the efficacy and safety of immediate high-intensity statin therapy (80mg atorvastatin) versus delayed high-intensity statin therapy (40mg atorvastatin) in reducing the risk of stroke at 90 days in patients with acute and high-risk symptomatic extracranial or intracranial arterial stenosis; and the efficacy and safety of intensive antiplatelet combined with immediate high-intensity statin therapy (80mg atorvastatin) versus standard antiplatelet combined with delayed high-intensity statin therapy (40mg atorvastatin) in reducing the risk of stroke at 90 days in patients with acute and high-risk symptomatic extracranial or intracranial arterial stenosis.

This trial is a randomized, double-blind, placebo-controlled, multicenter, 2×2 factorial designed clinical trial. 6100 patients in 250 centers in China will be enrolled with one of the following situations (1) Mild ischemic stroke (NIHSS 4~5) within 24 hours of onset meets any of the following imaging conditions: a) Acute single cerebral infarction with criminal intracranial and extracranial atherosclerotic stenosis (stenosis rate ≥50%),b) Acute multiple cerebral infarction (considered to be caused by large artery atherosclerosis, including non-stenotic vulnerable plaque);Or (2) Moderate-to-high-risk TIA (ABCD2≥4) or mild ischemic stroke (NIHSS≤5) within 24 to 72 hours of onset meets any of the following imaging conditions: a) Medium and high risk TIA with criminal intracranial and extracranial atherosclerotic stenosis (stenosis rate ≥50%),b) Acute single cerebral infarction with criminal intracranial and extracranial atherosclerotic stenosis (stenosis rate ≥50%),c) Acute multiple cerebral infarction (considered to be caused by large artery atherosclerosis, including non-stenotic vulnerable plaque) . Patients will be randomly assigned into 4 groups according to the ratio of 1:1:1:1:

1. Intensive antiplatelet therapy + immediate high-intensity statin therapy (80mg atorvastatin)
2. Intensive antiplatelet therapy + delayed high-intensity statin therapy (40mg atorvastatin)
3. Standard antiplatelet therapy + immediate high-intensity statin therapy (80mg atorvastatin)
4. Standard antiplatelet therapy + delayed high-intensity statin therapy (40mg atorvastatin)

Face to face interviews will be made at baseline, 7, 14 (or hospital discharge), 90 ± 7 days and 12th month ± 14 days after randomization.

Survival curves will be estimated for the primary outcome using the Kaplan-Meier procedure and compared using a Cox regression model Wald test, stratified by the opposite arm of the factorial design. Safety outcomes will be calculated using the Kaplan-Meier curve to simulate the 3-month cumulative risk, and the Cox proportional hazards model to calculate the HR and 95% confidence interval.

Primary outcome is defined as stroke (including hemorrhagic and ischemic stroke). Secondary outcomes include composite vascular events (stroke, myocardial infarction, and cardiovascular death); ischemic stroke; transient ischemic attack; myocardial infarction; vascular death; all-cause death; poor functional outcome (mRS 2-6); and quality of life (EQ-5D scale). Safety outcomes, relating to antiplatelet therapy (i.e. bleeding, intracranial hemorrhage, and adverse events) and statin therapy (i.e. hepatotoxicity, muscle toxicity and adverse events) will be investigated.

Inclusion Criteria:

1. Age :35-80 years old , male or female;
2. Any of the following three two situations:

(1) Mild ischemic stroke (NIHSS 4 to 5 points) within 24 hours of onset meets any of the following imaging conditions:

1. Acute single cerebral infarction with criminal intracranial and extracranial atherosclerotic stenosis (stenosis rate ≥50%)
2. Acute multiple cerebral infarction (considered to be caused by large artery atherosclerosis, including non-stenotic vulnerable plaque)

Or (2) Moderate-to-high-risk TIA (ABCD2≥4 points) or mild ischemic stroke (NIHSS≤5 points) within 24 to 72 hours of onset meets any of the following imaging conditions:

1. Medium and high risk TIA with criminal intracranial and extracranial atherosclerotic stenosis (stenosis rate ≥50%)
2. Acute single cerebral infarction with criminal intracranial and extracranial atherosclerotic stenosis (stenosis rate ≥50%)
3. Acute multiple cerebral infarction (considered to be caused by large artery atherosclerosis, including non-stenotic vulnerable plaque)

The rate of intracranial artery stenosis is assessed by MRA, CTA, or DSA according to WASID standards; the rate of extracranial artery stenosis is assessed by carotid ultrasound, CEMRA, CTA or DSA, according to NASCET standards; 3. Signed informed consent

Exclusion Criteria:

1. Specific cardiogenic ischemic cerebrovascular diseases(eg. combined with atrial fibrillation, heart valve prosthesis, atrial myxoma, endocarditis, etc.)

2. Other ischemic cerebrovascular diseases with specific causes (eg. aortic dissection, vasculitis, vascular malformation, etc.)

3. Non-cerebral vascular disease (eg. intracranial tumors, multiple sclerosis)

4. Cerebral infarction of large area (infarct size greater than half the single lobe area)

5. CT indicating hemorrhagic transformation of cerebral infarction before randomization

6. Patients with pre-existing contraindications of using clopidogrel, aspirin or statin drugs:

   Known history of allergy ; Severe heart failure and asthma ; Coagulant disorders and systemic bleeding ; Pre-existing drug - induced blood system disease or abnormal liver function ; Leukopenia (< 2×109/l) or thrombocytopenia (<100×109/l) ; active liver disease ; pregnancy or lactation period ; Severe heart failure：New York Heart Association (NYHA) Functional Classification III and IV

7. MRS > 2 before the onset

8. Use of intravenous or arterial thrombolysis intravascular therapy or bridge therapy after onset

9. Use of defibrinating therapy like snake venom, defibrase, lumbrokinase, etc. or use of anticoagulant therapy like argatroban, or use of antiplatelet therapy except clopidogrel and aspirin, such as tirofiban, ticagrelor, ozagrel, and so on after onset.

10. Creatine Kinase(CK) more than 5 times of the upper limit of normal value after onset

11. Use of drugs affecting the metabolism of statins such as immune-suppressive drugs, antifungal agents, or fibrates drugs and so on, within 14 days before randomization.

12. Severe hepatic or renal insufficiency (Note: Severe hepatic insufficiency refers to the ALT value > 2 times the upper limit of normal value or AST times > 2 times the upper limit of normal value; Severe hepatic insufficiency is refers to creatinine values > 1.5 times he upper limit of normal value or GFR < 40 ml/min/1.73 m2)

13. Usage of dual antiplatelet therapy with aspirin plus clopidogrel within 14 days before randomization. (patients who received dual antiplatelet therapy (aspirin combined with clopidogrel) but did not use clopidogrel with loading dose after onset were excluded)

14. Use of Intensive statin therapy within 14 days before randomization（atorvastatin ≥40mg/d or rosuvastatin ≥ 20mg/d）.

15. Pre-existing intracranial hemorrhage（eg. ICH, SAH）

16. Gastrointestinal bleeding or major surgery occurred within 90 days before randomization.

17. Pre-existing extracranial angioplasty or vascular surgery

18. Anticipated requirement for long-term non-study antiplatelet drugs, or non-steroid anti-inflammatory drugs.

19. Experimental drugs need to stop due to angioplasty or vascular surgery, which was planned or likely to perform within 90 days after randomization

20. Patients with severe disease expected to live for less than 90 days

21. Pregnant or childbearing-age women who have no effective contraceptives or positive pregnancy test records

22. Patients who are undergoing experimental drugs or device tests

23. Unable to finish the follow-up of 90 days due to geographical factor or other reasons（eg. dementia, alcoholism, substance abuse, severe mental disease, etc.）

Two nearly identical tablet forms of Clopidogrel (75mg Clopidogrel and matching placebo) with almost the same size, color and smell will be used in this research.

Two nearly identical tablet forms of Aspirin (100mg Aspirin and matching placebo) with almost the same size, color and smell will be used in this research.

Two nearly identical tablet forms of Atorvastatin (20mg Atorvastatin and matching placebo) with almost the same size, color and smell will be used in this research.

Centers are not able to apply unblinding with biological experiment in this study. Researchers shall never unblind the code unless special situations occur such as Serious Adverse Events (SAE), which is essential for treatment. Clinical outcomes of efficacy and safety are submitted to Adjudication Committee, who should be blinded to randomization, for final determination.