Table 2 Included studies on treatment of intracranial atherosclerosis [63, 64]

Comparison of Warfarin versus Aspirin for symptomatic ICAS (WASID) [12]

1999–2003

Randomized-Controlled Clinical Trial

50-99%

Aspirin 650 mg twice a day versus Warfarin (target INR:2–3)

Warfarin non superior for stroke prevention and with a higher rate of major hemorrhages and all-caused death compared to aspirin

Death: 4.3% in the aspirin group versus 9.7% in the warfarin group;

major hemorrhage: 3.2% versus 8.3%, respectively; myocardial infarction or sudden death: 2.9% versus 7.3%, respectively

Comparison of stenting versus aggressive medical management for severe ICAS (SAMMPRIS) [70]

2008–2011 (enrollment was stopped because of safety concerns regarding the risk of periprocedural stroke or death in the PTAS group)

Randomized-Controlled Clinical Trial

70-99%

Aspirin 325 mg per day combined with clopidogrel 75 mg per day for 90 days and management of risk factors (blood pressure, low density lipoprotein cholesterol, diabetes, smoking, obesity, exercise) versus percutaneous transluminal angioplasty and stenting (PTAS) with the use of Wingspan stent system

Aggressive medical management (combination antiplatelet therapy and intensive management of risk factors) is superior to PTAS with the use of the Wingspan stent system

30-day rate of stroke or death was 14.7% in the PTAS group (nonfatal stroke: 12.5%; fatal stroke: 2.2%) versus 5.8% in the medical-management group (nonfatal stroke: 5.3%; non-stroke-related death: 0.4%)

Comparison of clopidogrel plus aspirin versus aspirin alone for reducing embolization in patients with acute symptomatic cerebral or carotid artery stenosis (CLAIR study) [88]

2003–2008

Randomized-Controlled Clinical Trial

50-99%

Dual therapy of clopidogrel

300 mg for the first day and then 75 mg daily plus

75–160 mg aspirin daily for 7 days versus monotherapy

75–160 mg aspirin once daily for 7 days

Combination therapy with clopidogrel and aspirin is more effective than aspirin alone in reducing microembolic signals in patients with predominantly intracranial symptomatic stenosis

On day 2, 14 of 45 patients in

the dual therapy group and 27 of 50 in the monotherapy

group had microembolic signals. At day 7, ten of

43 patients in the dual therapy group and 26 of 51 in the

monotherapy group had microembolic signals. The number of adverse events was similar between the

two groups.

Comparison of balloon-expandable stent plus medical therapy versus medical therapy alone; the Vitesse Intracranial Stent Study for Ischemic Stroke Therapy (VISSIT) trial [71]

2009–2012

Randomized-Controlled Clinical Trial

70-99%

Medical therapy consisted of clopidogrel (75 mg daily) for the first 3 months after enrollment plus aspirin (81–325 mg daily) for the study duration, and management of risk factors compared to balloon-expandable stent placement

Among patients with symptomatic ICAS, the use of a balloon-expandable stent compared with medical therapy resulted in an increased 12-month risk of added stroke or TIA in the same territory, and increased 30-day risk of any stroke or TIA

Intracranial hemorrhage within 30 days occurred in 8.6% of the patients in the stenting group versus none in the medical group, the 1-year primary outcome of stroke or hard TIA occurred in 36.2% of the patients in the stenting group versus 15.1% of the patients in the medical group; worsening of baseline disability score (modified Rankin Scale) occurred in 24.1% of the patients in the stent group versus 11.3% of the patients in the medical group.

Comparison of stenting versus medical treatment in patients with ICAS; the Vertebral Artery Stenting Trial (VAST) [72]

2008–2013

Randomized-Controlled Clinical Trial

50-99%

Patients randomized to stenting received clopidogrel 75 mg daily starting at least five days before the procedure and continued for 30 days after the procedure. Patients not on clopidogrel the day before the procedure were loaded with 300 mg clopidogrel at least six hours before stenting

Stenting of symptomatic vertebral artery stenosis did not lower the risk of

stroke and presented more adverse events

Three patients in the stenting group had vascular death, myocardial infarction, or any stroke within 30 days after the start of treatment (5%) versus one patient in the medical treatment group (2%). During a median follow-up of 3 years, seven (12%) patients in the stenting group and four (7%) in the medical treatment group had a stroke in the territory of the symptomatic vertebral artery; 11 (19%) patients in the stenting group and ten (17%) in the medical treatment group had vascular death, myocardial infarction, or any stroke.

Αssessment of safety and effectiveness for percutaneous transluminal angioplasty and stenting (PTAS) in patients with symptomatic ICAS; systematic review and

meta-analysis [73]

2016

Meta-analysis

50-99%

Meta-analysis of three studies: SAMMPRIS, VAST and VISSIT

PTAS is associated with adverse early and long-term outcomes and should not

be recommended in patients with symptomatic ICAS

PTAS was associated with a higher risk of recurrent ischemic stroke in the territory of qualifying artery both within 30 days [risk ratio (RR) = 2.21] and 1 year (RR = 1.92). PTAS was also related to a higher risk of any ischemic stroke within 30 days from the index event (RR = 2.08). The risk for intracranial hemorrhage was found to be higher in PTAS patients both within 30 days (RR = 10.60) and 1 year (RR = 8.15). The composite outcome of any stroke or death within 1 year (RR = 2.29) and 2 years (RR = 1.52) was higher in PTAS than in medical therapy. PTAS was associated with a higher risk of any stroke or death within 2 years in the symptomatic ICAS subgroup located in posterior circulation (RR = 2.37)

The Wingspan Stent System Post Market Surveillance (WEAVE) trial assessed the periprocedural safety of the Wingspan Stent system in the treatment of symptomatic patients with ICAS and specific criteria [75]

2012–2018

Postmarketing Surveillance Trial

70-99%

Patients aged 22 to 80 years, with symptomatic ICAS of 70–99%, baseline modified Rankin Scale score ≤ 3, ≥2 strokes in the vascular territory of the stenotic lesion with at least 1 stroke while on medical therapy, and stenting of the lesion ≥ 8 days after the last stroke, underwent angioplasty and stenting with the Wingspan stent

With experienced interventionalists, and proper patient selection following the on-label usage guidelines, the use of the Wingspan stent for ICAS demonstrated a low periprocedural complication rate and excellent safety profile

A total of 97.4% (148/152) patients were event-free at 72 h, 1.3% (2/152) had nonfatal strokes, and 1.3% (2/152) of patients died.

Comparison of Drug-Eluting Stent (DES) With Bare-Metal Stent (BMS)

in patients with symptomatic high-grade ICAS [79]

2015–2018

Randomized-Controlled Wingspan Clinical Trial

70-99%

Patients were randomly assigned to receive DES (NOVA intracranial

sirolimus-eluting stent system) or BMS (Apollo intracranial stent system) treatment in a 1:1

ratio

Compared with BMS, DES reduced the

risks of in-stent restenosis and ischemic stroke recurrence in patients with symptomatic high-grade ICAS

The 1-year in-stent restenosis rate was lower in the DES group than in the BMS group (10 [9.5%] versus 32 [30.2%]). The DES group also had a significantly lower ischemic stroke recurrence rate from day 31 to 1 year (1 [0.8%] versus 9 [6.9%]). No significant difference in the rate of any stroke or death within 30 days was observed between the DES and BMS groups (10 [7.6%] versus 7 [5.3%]).

Comparison of stenting plus medical therapy versus medical therapy alone in patients with symptomatic severe ICAS; the China Angioplasty and Stenting for Symptomatic

Intracranial Severe Stenosis (CASSISS) trial [74]

2014–2019

Randomized-Controlled Clinical Trial

70-99%

Medical therapy (dual antiplatelet therapy with aspirin 100 mg and clopidogrel 75 mg daily for 90 days followed by aspirin or clopidogrel alone daily, and stroke risk factor control) plus stenting compared to medical therapy alone

Among patients with transient ischemic attack or ischemic stroke due to symptomatic severe ICAS, the addition of percutaneous transluminal angioplasty and stenting to medical therapy, compared with medical therapy alone, resulted in no significant difference in the risk of stroke or death within 30 days or stroke in the qualifying artery territory beyond 30 days through 1 year

For the stenting plus medical therapy group versus medical therapy alone, no significant difference was found for the primary outcome of risk of stroke or death (8.0% [14/176] versus 7.2% [13/181]). Of the 5 prespecified secondary end points, none showed a significant difference including stroke in the qualifying artery territory at 2 years (9.9% [17/171] versus 9.0% [16/178]) and 3 years (11.3% [19/168] versus 11.2% [19/170]). Mortality at 3 years was 4.4% (7/160) in the stenting plus medical therapy group versus 1.3% (2/159) in the medical therapy alone group.

Comparison of extracranial-intracranial arterial bypass plus medical treatment versus medical treatment alone, in patients with atherosclerotic narrowing or occlusion of the ipsilateral internal carotid or middle cerebral artery; the International Cooperative Study of

Extracranial/Intracranial Arterial Anastomosis (EC/IC Bypass study) [82]

1977–1982

Randomized-Controlled Clinical Trial

Narrowing or occlusion of the ipsilateral internal carotid or middle cerebral artery

714 patients were randomly assigned to the best medical care (acetylsalicylic acid 325 mg four times a day), and 663 to the same regimen with the addition of bypass surgery joining the superficial temporal artery and the middle cerebral artery

Extracranial-intracranial anastomosis is not effective in preventing cerebral ischemia in patients ICAD in the carotid and middle cerebral arteries

30-day surgical mortality and major stroke morbidity rates were 0.6% and 2.5%, respectively. Nonfatal and fatal stroke occurred both more frequently and earlier in the patients operated on. Secondary survival analyses comparing the two groups for major strokes and all deaths, for all strokes and all deaths, and for ipsilateral ischemic strokes demonstrated a similar lack of benefit from surgery. Separate analyses in patients with different angiographic lesions did not identify a subgroup with any benefit from surgery.