Treat Stroke to Target

The aim of this study is the evaluation of two usual care strategies after stroke or TIA : achieved target LDL-C of 100 mg/dL (+/-10 mg/dL) or less than 70 mg/dL. Investigators will use the statin and titrate the dosage to achieve the target assigned by randomization in monotherapy or in combination with ezetimibe or other drugs.

The primary end-point is the occurrence of recurrent non fatal stroke, non fatal MI, and vascular death in each group.

3760 patients will be recruited and followed for eight and a half years maximum.

The aim of this study is the evaluation of two usual care strategies after stroke or TIA : achieved target LDL-C of 100 mg/dL (+/-10 mg/dL) or less than 70 mg/dL. Investigators will use the statin and titrate the dosage to achieve the target assigned by randomization in monotherapy or in combination with ezetimibe or other drugs.

Inclusion criteria:

* Recent (less than 3 months) ischemic stroke As soon as possible after the event, once the neurologic deficit is stabilized (investigator judgment). These ischemic strokes include TIA with ischemic lesion documented by CT or MRI.
* Or recent TIA (less than 15 days) without documentation of ischemic lesion on CT/MR imaging. Must be limb weakness or aphasia lasting more than 10 min.
* And documented atherosclerotic stenosis in carotid artery (investigator judgment) (based on the results of Duplex echography, CTA, MRA or X ray- angiography), Or in the aortic arch (investigator judgment) (based on TEE or CTA), Or in other brain artery: vertebral, basilar or other intracranial artery (based on CTA, MRA, XRA), Or in coronary arteries (past history of acute coronary syndrome, coronary revascularization or positive coronary angiography)
* And statin treatment is indicated, following ANSM guidelines (French drug agency), age \>18 years, rankin score ≤ 4, patient or a legal representative signs consent, patient is affiliated to social security system

Exclusion criteria :

* Ischemic stroke/TIA du to arterial dissection (investigator judgment)
* Cardiac source of embolism (e.g., mitral stenosis, endomyocardial fibrosis) without documented atherosclerotic stenosis : a patient with atrial fibrillation or a past history of recent myocardial infarction or calcified aortic stenosis can be randomized if he otherwise fulfils inclusion criteria
* Symptomatic hemorrhagic stroke : Presence of microbleeds on gradient echo imaging (T2\*) is not an exclusion criteria. Hemorrhagic transformation of an ischemic stroke is not an exclusion criteria
* Uncontrolled hypertension (investigator judgment)
* LDL-C \<100 mg/dL or patients for whom treatment intensification is impossible
* F/U impossible or bad observance anticipated.
* Co-morbid condition that may interfere with the F/U or with the evaluation of primary endpoint
* Participation to another clinical trial

The primary end-point is:

Recurrent ischemic stroke or stroke of undetermined origin, myocardial infarction, urgent coronary or carotid revascularization following new symptoms requiring hospitalization, and vascular death.

Secondary endpoints:

* Recurrent nonfatal ischemic stroke
* Nonfatal myocardial infarction
* Recurrent ischemic stroke, fatal or non
* Recurrent ischemic stroke or TIA
* Intracranial hemorrhage (intracerebral hemorrhage, subarachnoid hemorrhage, subdural hematoma)
* All stroke (ischemic or hemorrhagic)
* Any major coronary events (including fatal and nonfatal myocardial infarction)
* Any coronary heart disease end-point (myocardial infarction, hospitalization for acute corornary symptoms, coronary revascularization procedure)
* Any revascularisation procedure (coronary, carotid, or peripheral artery))
* Carotid artery revascularization procedure (urgent following new symptoms or elective)
* Vascular death (ischemic stroke or undetermined stroke, fatal myocardial infarction, other vascular deaths, sudden death, death of undetermined cause, i.e., without other cause documented such as cancer, infection, accident, suicide, etc...)
* All causes deaths
* Primary endpoint plus intracranial hemorrhage
* New onset diabetes

Hypothesis :

* Follow-up of three years
* Risk of primary end-point in the control group (Target LDL \<100 mg/dL) : 4% per year (12 % at 36 months)
* 5% Alpha, 80% power, total number of subject is :
* 3068 patients with a RRR 25%
* 20% drop-out: 3760 patients (385 primary EP)

Study specifications Follow-up : eight and a half years Follow-up visit : every 6 months Number of centers (French Stroke Units, under the auspice of the French Neurovascular Society) : 60-100

Ancillary study As an ancillary study, 800 patients (400 in each arm in 4 centers) will participate in the TST-PLUS (Plaque Ultrasound Study), in which they will have three ultrasound examination (baseline, 1 year and 3 years) and baseline blood sampling. The primary endpoint of this substudy will be the rate of occurrence of new carotid plaque, with the hypothesis that Rate of plaque occurrence in the \<100 mg/dL group will be 25% after 3 years (45% in EVA when atherosclerosis was present at baseline) RRR of plaque of 25% in the \<70 mg/dL group Alpha 5%, power 80%

As an ancillary study, 1000 patients will participate in the TST-PGS (Pharmacogenetics) Study, in which they will have 1 blood sampling either at baseline or during one of the follow-up visits of TST. The aim of this study is to show that the benefit (risk of ischemic stroke, myocardial infarction, and vascular death) observed with a strategy of LDL-C \<0.7 g / l compared to a strategy of LDL-C to 1 ± 0.1 g / l is higher in carriers of polymorphism 719Arg of the gene KIF-6 than non-carriers of this polymorphism.

Eligibility Criteria:
Inclusion Criteria:

* • Recent (less than 3 months) ischemic stroke
* As soon as possible after the event, once the neurologic deficit is stabilized (investigator judgment)
* These ischemic strokes include TIA with ischemic lesion documented by CT or MRI

  • Or recent TIA (less than 15 days)
* without documentation of ischemic lesion on CT/MR imaging
* Must be limb weakness or aphasia lasting more than 10 min

  • And documented atherosclerotic stenosis
* In carotid artery (investigator judgment) (based on the results of Duplex echography, CTA, MRA or X ray- angiography)
* Or in the aortic arch (investigator judgment) (based on TEE or CTA)
* Or in other brain artery: vertebral, basilar or other intracranial artery (based on CTA, MRA, XRA)
* Or in coronary arteries (past history of acute coronary syndrome, coronary revascularization or positive coronary angiography)

  • And
* Statin treatment is indicated, following ANSM guidelines (French drug agency)
* age \>18 years
* rankin score ≤ 4
* patient or a legal representative signs consent
* Patient is affiliated to social security system

Exclusion Criteria:

* • Ischemic stroke/TIA du to
* arterial dissection (investigator judgment)
* Cardiac source of embolism (e.g., mitral stenosis, endomyocardial fibrosis) without documented atherosclerotic stenosis : a patient with atrial fibrillation or a past history of recent myocardial infarction or calcified aortic stenosis can be randomized if he otherwise fulfils inclusion criteria

  • Symptomatic hemorrhagic stroke
* Presence of microbleeds on gradient echo imaging (T2\*) is not an exclusion criteria.
* Hemorrhagic transformation of an ischemic stroke is not an exclusion criteria

  * Uncontrolled hypertension (investigator judgment)
  * LDL-C \<100 mg/dL or patients for whom treatment intensification is impossible
  * F/U impossible or bad observance anticipated.
  * Co-morbid condition that may interfere with the F/U or with the evaluation of primary endpoint
  * Participation to another clinical trial