Intensive Medical Therapy for High-risk Intracranial or Extracranial Arterial Stenosis
Intensive Medical Therapy for High-risk Intracranial or Extracranial Arterial Stenosis
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.）