This prospective, randomized, single-center clinical trial is designed to figure out the most optimal algorithm of remote ischemic conditioning on patients with chronic cerebral ischemia.

Chronic cerebral ischemia (CCI) refers to a prevalent pathophysiological condition in which cerebral hypoperfusion is caused by a reduction in cerebral blood flow over a long period of time. CCI, as a consequence of intracranial atherosclerotic stenosis (ICAS) has been identified as one of the major culprits that are responsible for occurrence/recurrence of acute cerebrovascular accidents such as ischemic stroke and transient ischemic attack, as well as vascular cognitive dysfunction. The prevalence of ICAS related CCI among stroke patients is remarkably higher in the Chinese population than in the whites, and there are no quite effective therapies for the general patient population with ICAS up to now. Endovascular intervention appears to be a promising option for a group of patients with severe ICAS, but may not be applicable for those with certain vascular risk features that are supposed to increase the rate of complications or result in unsatisfactory clinical outcomes. In addition, high cost and adverse effects of medications pose huge burdens to patients, their families and even the whole society as well.

RIC is a novel therapeutic approach whereby repetitive, transient, non-lethal ischemia intervened by reperfusion employed on a distant organ or tissue confers protection to targeted organs against subsequent major ischemic attack. Preclinical experimental studies have demonstrated the neuroprotective effects of RIC in ischemic stroke models. Meanwhile, small-scale, proof of concept clinical trials revealed that long-term RIC was able to lower the stroke recurrence and enhance the cerebral reperfusion, without inducing adverse events in patients with ICAS. Nevertheless, current protocol of RIC utilited in this scenario was mainly based on previous animal studies or cardiovascular clinical trials. Whether modifying the ischemic pressure, numbers of cycles, duration of ischemia as well as the method for application can lead to different outcomes remain to be settled. In this study, 600 patients satisfied with the inclusion criteria will be recruited and randomly allocated into four substudies to receive RIC treatment (Doctormate®) under different algorithms. The most optimal algorithm of RIC on patients with ICAS related CCI would be determined according to clinical endpoints. Other medical managements are guaranteed based on the best medical judgment from clinical practitioners.

Inclusion Criteria:

• 1. Age ranging from 45 to 80 years of age, both genders;

  2. Patients diagnosed with an ischemic stroke or TIA before admission and the following requirements should be satisfied as well:

  1. The occurrence of an ischemic stroke within 30 days and with a baseline modified Rankin Scale (mRS) score≤4.
  2. The occurrence of an TIA within 15 days and with a baseline Oxfordshire Community Stroke Project on the basis of age, blood pressure (BP), clinical features, and duration of TIA symptoms (ABCD2) score≥4.

  3. Patients with symptomatic intracranial atherosclerotic stenosis (sIAS) that is attributed to at least 50% stenosis of the diameter of a major intracranial artery (carotid artery, or middle cerebral artery (M1)) verified by magnetic resonance angiography (MRA) or computed tomographic angiography (CTA).

  4. Informed consent obtained patients or health care proxy, as appropriate, able to cooperate and participate follow-up visits.

Exclusion Criteria:

• 1. Received intravenous or intraarterial thrombolytic therapy such as recombinant tissue plasminogen activator (rtPA) within 24 hours prior to inclusion.

  2. Progressive deterioration of neurological manifestations within 24 hours prior to inclusion.

  3. Intracranial arterial stenosis due to any of the following non-atherosclerotic etiologies, for instance, moyamoya disease, artery dissection, any known vasculitic disease, any intracranial infection, radiation induced vasculopathy, cerebrospinal fluid (CSF) pleocytosis associated intraarterial stenosis, genetic or developmental abnormalities such as fibromuscular dysplasia, neurofibromatosis, sickle cell disease, and mitochondrial encephalopathy, intracranial granulomatous arteritis, postpartum angiopathy, suspected vasospasm or embolism, iatrogenic trauma.

  4. Intracranial abnormalities such as tumor, abscess, vascular malformation, cerebral venous sinus stenosis or thrombosis.

  5. Any hemorrhagic transformation or large area of cerebral infarction (more than 1/3 of middle cerebral artery perfusion territory).

  6. Any type of intracranial hemorrhage within 90 days prior to inclusion.

  7. Potential cardiac source of embolism such as rheumatic mitral and or aortic stenosis, prosthetic heart valves, atrial flutter, atrial fibrillation, left atrial myxoma, sick sinus syndrome, patent foramen ovale, left ventricular mural thrombus or valvular vegetation, congestive heart failure, and bacterial endocarditis.

  8. Previous stent, angioplasty, or other mechanical device in the target lesion, or plan to receive any of the above procedures within 12 months after inclusion.

  9. Refractory hypertension (systolic blood pressure (SBP) >180 mmHg; diastolic blood pressure (DBP) >110 mmHg) that cannot be controlled by medical intervention.

  10. Above 50% stenosis of extracranial artery (carotid artery or vertebral artery).

  11. Above 50% stenosis of subclavian artery or subclavian steal syndrome.

  12. Retinal hemorrhage or visceral bleeding within 30 days prior to inclusion.

  13. Myocardial infarction within previous 30 days prior to inclusion.

  14. Previous history of major surgery within 30 days prior to inclusion, or arranged for any of the procedure within 12 months after inclusion.

  15. Severe hemostatic or coagulation disorders (Haemoglobin <10 g/dL, blood platelet count < 100 × 109/L).

  16. Hepatic or renal dysfunctions (aspartate transaminase (AST) and/or alanine transaminase (ALT) >3×upper limit of normal range, creatinine clearance <0.6 ml/s and/or serum creatinine >265 μmol/l (>3.0 mg/dl)).

  17. Current or having a history of chronic physical diseases or mental disorders.

  18. Life expectancy < 3 years due to concomitant life-threatening illness.

  19. Contraindications for remote ischemic conditioning: significant peripheral arterial disease, soft tissue or vascular injury, wounds, and fracture affecting the upper limbs.

  20. Pregnant or lactating women.

  21. Patients unlikely to be compliant with intervention or return for follow-up visits.

  22. No consent obtained from the patient or available legally authorized representatives.

  23. Patients recruited into another clinical investigation with medication or device, which is likely to impact the outcome of this study.