Antiplatelet Therapy and Endothelial-stabilizing Agents in Cerebral Small Vessel Diseases

Prior treatment

• Major surgery (including open femoral, aortic, cardiac or carotid surgery) within previous 30 days or planned in the 1 year after enrollment.

Other illness

• Intracranial aneurysms that need surgical treatment. Other significant active neurological illness e.g seizures, multiple sclerosis, intracranial tumor (except meningioma) or any intracranial vascular malformation.
• Active cardiac disease (atrial fibrillation, myocardial infarct in last six months, active angina, symptomatic cardiac failure).
• History of any intracranial hemorrhage (parenchymal, subarachnoid, subdural, epidural).
• Known allergy or contraindication to aspirin, clopidogrel, cilostazol, isosorbide mononitrate or statin.
• Dementia or psychiatric problem that prevents the patient from relevant evaluation or follow-up reliably.
• Co-morbid conditions that may limit survival to less than 1 year.

Lab values

• Active peptic ulcer disease, major systemic hemorrhage within 30 days, active bleeding diathesis, platelets \< 100,000, hematocrit \< 30, international normalized ratio (INR) \> 1.5, clotting factor abnormality that increases the risk of bleeding, current alcohol or substance abuse, uncontrolled severe hypertension (systolic pressure \> 180 mm Hg or diastolic pressure \> 115 mm Hg), severe liver impairment (aspartate transaminase \[AST\] or alanine transaminase \[ALT\] \> 3 x normal, cirrhosis), creatine kinase \> 5 times the upper limit of normal (ULN) at final screening, severe renal dysfunction, defined as an estimated glomerular filtration rate (eGFR) \< 20mL/min/1.73 square meter at final screening.

Other

• Currently breastfeeding, pregnancy, planning to become pregnant and unwilling to use contraception for the duration of this study
• Unable to tolerate, or contraindication to, MRI.
• Enrollment in another study that would conflict with the current study.

• Age ≥ 30 years and ≤ 79 years.
• A recent small subcortical infarct that occurred within 3 weeks prior to randomization; or patient with whiter matter hyperintensities with a 2-3 grading on Fazekas scale.
• Absence of signs or symptoms of cortical dysfunction, such as aphasia, apraxia, agnosia, agraphia, homonymous visual field defect.
• Modified Rankin score of ≤ 4.
• In the absence of any other pathology in the parent artery at the site of the origin of the penetrating artery (focal atheroma, parent vessel dissection, vasculitis, vasospasm, and so on).
  • 7\. No ipsilateral cervical carotid stenosis (≥30%) by brain high resolution magnetic resonance imaging (HRMRI) or computed tomography angioplasty (CTA) or (magnetic resonance angioplasty) MRA and cervical artery ultrasound, if qualifying event is hemispheric. No vertebra artery stenosis (≥30%) by brain HRMRI or CTA or MRA and cervical artery ultrasound, if the lesion is in the territory of posterior circulation.
  • 8\. No major-risk cardioembolic sources requiring anticoagulation or other specific therapy.
  • 9\. Patient agrees with follow-up visits and is available by phone. 10. Patient understands the purpose and requirements of the study, can make him/herself understood, and has signed informed consent.