Endovascular therapy versus medical treatment for symptomatic intracranial artery stenosis

Abstract

Background

Intracranial artery stenosis (ICAS) is an arterial narrowing in the brain that can cause stroke. Endovascular therapy (ET) and conventional medical treatment (CMT) may prevent recurrent ischaemic stroke caused by ICAS. However, there is no consensus on the best treatment for people with ICAS.

Objectives

To evaluate the safety and efficacy of endovascular therapy plus conventional medical treatment compared with conventional medical treatment alone for the management of symptomatic intracranial artery stenosis.

Search methods

We searched the Cochrane Stroke Group Trials Register, CENTRAL, MEDLINE, Embase, four other databases, and three trials registries on 16 August 2022. We contacted study authors and researchers when we required additional information.

Selection criteria

We included randomised controlled trials (RCTs) comparing ET plus CMT with CMT alone for the treatment of symptomatic ICAS. ET modalities included angioplasty alone, balloon‐mounted stent, and angioplasty followed by placement of a self‐expanding stent. CMT included antiplatelet therapy in addition to control of risk factors such as hypertension, hyperlipidaemia, and diabetes.

Data collection and analysis

Two review authors independently screened the records to select eligible RCTs, then extracted data from them. We resolved any disagreements through discussion, reaching consensus decisions among the full team. We assessed risk of bias and applied the GRADE approach to assess the certainty of the evidence. The primary outcome was death by any cause or non‐fatal stroke of any type within three months of randomisation. Secondary outcomes included all‐cause death or non‐fatal stroke of any type occurring more than three months after randomisation, ipsilateral stroke, transient ischaemic attack, ischaemic stroke, haemorrhagic stroke, death, restenosis, dependency, and health‐related quality of life.

Main results

We included four RCTs with 989 participants who had symptomatic ICAS, with an age range of 18 to 85 years. We identified two ongoing RTCs. All trials had high risk of performance bias, as it was impossible to blind participants and personnel to the intervention. Three trials were terminated early. One trial was at high risk of attrition bias because of substantial loss to follow‐up after one year and a high proportion of participants transferring from ET to CMT. The certainty of evidence ranged from low to moderate; we downgraded for imprecision.

Compared to CMT alone, ET plus CMT probably increases the risk of short‐term death or stroke (risk ratio (RR) 2.93, 95% confidence interval (CI) 1.81 to 4.75; 4 RCTs, 989 participants; moderate certainty), short‐term ipsilateral stroke (RR 3.26, 95% CI 1.94 to 5.48; 4 RCTs, 989 participants; moderate certainty), short‐term ischaemic stroke (RR 2.24, 95% CI 1.30 to 3.87; 4 RCTs, 989 participants; moderate certainty), and long‐term death or stroke (RR 1.49, 95% CI 1.12 to 1.99; 4 RCTs, 970 participants; moderate certainty). Compared to CMT alone, ET plus CMT may increase the risk of short‐term haemorrhagic stroke (RR 13.49, 95% CI 2.59 to 70.15; 4 RCTs, 989 participants; low certainty), short‐term death (RR 5.43, 95% CI 1.21 to 24.40; 4 RCTs, 989 participants; low certainty), and long‐term haemorrhagic stroke (RR 7.81, 95% CI 1.43 to 42.59; 3 RCTs, 879 participants; low certainty). It is unclear if ET plus CMT compared with CMT alone has an effect on the risk of short‐term transient ischaemic attack (RR 0.79, 95% CI 0.30 to 2.07; 3 RCTs, 344 participants; moderate certainty), long‐term transient ischaemic attack (RR 1.05, 95% CI 0.50 to 2.19; 3 RCTs, 335 participants; moderate certainty), long‐term ipsilateral stroke (RR 1.78, 95% CI 1.00 to 3.17; 4 RCTs, 970 participants; moderate certainty), long‐term ischaemic stroke (RR 1.56, 95% CI 0.77 to 3.16; 4 RCTs, 970 participants; moderate certainty), long‐term death (RR 1.61, 95% CI 0.77 to 3.38; 4 RCTs, 951 participants; moderate certainty), and long‐term dependency (RR 1.51, 95% CI 0.93 to 2.45; 4 RCTs, 947 participants; moderate certainty). No subgroup analyses significantly modified the effect of ET plus CMT versus CMT alone. The trials included no data on restenosis or health‐related quality of life.

Authors' conclusions

This review provides moderate‐certainty evidence that ET plus CMT compared with CMT alone increases the risk of short‐term stroke and death in people with recent symptomatic severe ICAS. This effect was still apparent at long‐term follow‐up but appeared to be due to the early risks of ET; therefore, there may be no clear difference between the interventions in terms of their effects on long‐term stroke and death. The impact of delayed ET intervention (more than three weeks after a qualifying event) warrants further study.

Plain language summary

Endovascular therapy versus conventional medical treatment for symptomatic intracranial artery stenosis

What is intracranial artery stenosis?

Intracranial artery stenosis (ICAS) is the narrowing of the blood vessels in the brain caused by buildup of plaque (fatty deposits). It is a common cause of stroke worldwide. When this condition causes stroke symptoms, it is known as symptomatic ICAS.

How can intracranial artery stenosis be treated?

ICAS can be treated with endovascular therapy or conventional medical treatment, but it is unclear which approach works best. In endovascular therapy, the surgeon inserts a thin tube called a catheter into an artery in the arm or groin of the person being treated and guides it to the affected artery in the brain. The surgeon can then expand the narrowed artery with a small balloon or place a small mesh tube inside the narrowed artery to hold it open, or perform both techniques in the same procedure. Conventional medical treatment includes taking antiplatelets (medicines that stop platelets in the blood from sticking together) and trying to control factors that increase the risk of stroke (high blood pressure, high cholesterol, and diabetes) with medicines and lifestyle changes.

What did we want to find out?

We wanted to find out whether endovascular therapy in addition to conventional medical treatment was more effective than conventional medical treatment alone for preventing stroke and death in people with symptomatic ICAS.

What did we do?

We searched for randomised controlled trials (studies that assign participants to one of two or more treatment groups using a random method) that compared the two treatments in people with symptomatic ICAS. We compared and summarised the results of the studies and rated our confidence in the evidence, based on factors such as study methods and sizes.

What did we find?

We included four trials with a total of 989 participants who had recent symptoms of ICAS. Three trials were carried out across multiple centres and compared endovascular therapy involving stents with conventional medical treatment. Two trials took place in Chinese centres and compared different types of endovascular therapy with conventional medical treatment in Chinese participants.

Main results

People who received endovascular therapy as well as conventional medical treatment were more likely to die or have a stroke in the short term and in the long term. There were no major differences in the rates of ischaemic stroke and death or dependency in the long term.

What are the limitations of the evidence?

We are moderately confident in some results and have little confidence in others, because the studies enroled few people.

How up to date is the evidence?

The evidence is up to date to 16 August 2022.

Summary of findings

Summary of findings 1. Endovascular therapy plus conventional medical treatment compared to conventional medical treatment alone for symptomatic intracranial artery stenosis.

Endovascular therapy plus conventional medical treatment compared to conventional medical treatment alone for symptomatic intracranial artery stenosis
Patient or population: people with symptomatic intracranial artery stenosis Setting: hospital Intervention: endovascular therapy Comparison: conventional medical treatment
Outcomes			Anticipated absolute effects* (95% CI)		Relative effect (95% CI)	No. of participants (studies)	Certainty of the evidence (GRADE)	Comments
			Risk with CMT alone	Risk with ET plus CMT
Death or stroke		Short‐term follow‐up: mean 30 days (primary outcome)	Study population		RR 2.93 (1.81 to 4.75)	989 (4 RCTs)	⊕⊕⊕⊝ Moderatea	—
			40 per 1000	114 per 1000 (72 to 178)
		Long‐term follow‐up: mean 12 months	Study population		RR 1.49 (1.12 to 1.99)	970 (4 RCTs)	⊕⊕⊕⊝ Moderatea	—
			132 per 1000	190 per 1000 (147 to 246)
Ipsilateral stroke		Short‐term follow‐up: mean 30 days	Study population		RR 3.26 (1.94 to 5.48)	989 (4 RCTs)	⊕⊕⊕⊝ Moderatea	—
			34 per 1000	108 per 1000 (66 to 174)
		Long‐term follow‐up: mean 12 months	Study population		RR 1.78 (1.00 to 3.17)	970 (4 RCTs)	⊕⊕⊕⊝ Moderatea	—
			99 per 1000	170 per 1000 (125 to 228)
Type of recurrent event	Transient ischaemic attack	Short‐term follow‐up: mean 30 days	Study population		RR 0.79 (0.30 to 2.07)	344 (3 RCTs)	⊕⊕⊕⊝ Moderatea	—
			49 per 1000	39 1000 (15 to 99)
		Long‐term follow‐up: mean 12 months	Study population		RR 1.05 (0.50 to 2.19)	335 (3 RCTs)	⊕⊕⊕⊝ Moderatea	—
			76 per 1000	80 per 1000 (39 to 159)
	Ischaemic stroke	Short‐term follow‐up: mean 30 days	Study population		RR 2.24 (1.30 to 3.87)	989 (4 RCTs)	⊕⊕⊕⊝ Moderatea	—
			34 per 1000	75 per 1000 (44 to 126)
		Long‐term follow‐up: mean 12 months	Study population		RR 1.56 (0.77 to 3.16)	978 (4 RCTs)	⊕⊕⊕⊝ Moderatea	—
			99 per 1000	149 per 1000 (109 to 204)
	Haemorrhagic stroke	Short‐term follow‐up: mean 30 days	Study population		RR 13.49 (2.59 to 70.15)	989 (4 RCTs)	⊕⊕⊝⊝ Lowa,b	—
			0 per 1000	0 per 1000 (0 to 0)
		Long‐term follow‐up: mean 12 months	Study population		RR 7.81 (1.43 to 42.59)	879 (3 RCTs)	⊕⊕⊝⊝ Lowa,b	—
			2 per 1000	17 per 1000 (3 to 92)
Death		Short‐term follow‐up: mean 30 days	Study population		RR 5.43 (1.21 to 24.40)	989 (4 RCTs)	⊕⊕⊝⊝ Lowa,b	—
			2 per 1000	11 per 1000 (2 to 48)
		Long‐term follow‐up: mean 12 months	Study population		RR 1.61 (0.77 to 3.38)	951 (4 RCTs)	⊕⊕⊕⊝ Moderatea	—
			23 per 1000	37 per 1000 (18 to 76)
Dependency		Long‐term follow‐up: mean 12 months	Study population		RR 1.51 (0.93 to 2.45)	947 (4 RCTs)	⊕⊕⊕⊝ Moderatea	—
			53 per 1000	79 per 1000 (50 to 126)
Restenosis (≥ 50%)			—	—	—	—	—	No data for analysis
Health‐related quality of life			—	—	—	—	—	No data for analysis
*The risk in the intervention group (and its 95% confidence interval) is based on the assumed risk in the comparison group and the relative effect of the intervention (and its 95% CI). CI: confidence interval; CMT: conventional medical treatment; ET: endovascular therapy; RCT: randomised controlled trial; RR: risk ratio.
GRADE Working Group grades of evidence High certainty: we are very confident that the true effect lies close to that of the estimate of the effect. Moderate certainty: we are moderately confident in the effect estimate; the true effect is likely to be close to the estimate of the effect, but there is a possibility that it is substantially different. Low certainty: our confidence in the effect estimate is limited; the true effect may be substantially different from the estimate of the effect. Very low certainty: we have very little confidence in the effect estimate; the true effect is likely to be substantially different from the estimate of effect.

^a Downgraded one level for imprecision (few events and small sample size).
^b Downgraded one level for imprecision (wide confidence interval).

Background

Description of the condition

Stroke, encompassing ischaemic and haemorrhagic stroke, is the second leading cause of disability and death worldwide. It places a considerable economic burden on families and healthcare systems (Banerjee 2017; Benjamin 2017; Saini 2021; WHO 2017). Intracranial artery stenosis (ICAS) represents an advanced stage of intracranial atherosclerotic disease (ICAD), with narrowing of vessel lumen by 50% to 90% (Qureshi 2009). ICAS is thought to be the most common cause of stroke worldwide (Arenillas 2011; Bang 2014; Chatterjee 2015; Gorelick 2008; Holmstedt 2013; Qureshi 2014). The most common site for ICAS is the middle cerebral arteries, followed by the basilar artery and the internal carotid arteries. The vertebral arteries, posterior cerebral arteries, and anterior cerebral arteries are less commonly affected, while the cerebellar and communicating arteries are rarely involved (Resch 1970; Van der Kolk 2015; Wityk 1996). ICAD often occurs concomitantly with systemic atherosclerosis, involving extracranial, coronary, or peripheral arteries (Manzano 2012).

ICAS is more prevalent in Asia, Africa, South America, and the Middle East than in Europe or North America (Gorelick 2008; Liu 1996; Sacco 1995; Wang 2014; White 2005). It causes 30% to 50% of ischaemic strokes in Asia, compared with 8% to 10% of ischaemic strokes in North America (Feldmann 1990; Leung 1993; Solberg 1972; White 2005; Wong 2006; Wong 2007). The precise reason for this is unknown; however, genetic susceptibility and environmental factors are thought to play an important role. The high prevalence of ICAS among African Americans may be partly attributable to the disproportionately high rate of specific risk factors for atherosclerotic disease in this population, including hypertension, diabetes mellitus, and hyperlipidaemia (Carson 2011; Ritz 2014; Waddy 2009). On the other hand, the white population in the USA and Europe has a higher rate of extracranial atherosclerotic disease (Stevens 2008). Based on clinical manifestation, ICAS can be classified into asymptomatic and symptomatic types; symptomatic ICAS correlates with a high clinical recurrence rate of stroke (Chimowitz 2005).

Physicians can diagnosis ICAS using invasive neuroimaging, namely catheter angiography, which is the gold standard for accurately measuring the degree of stenosis, differentiating occlusion from severe stenosis, and evaluating collateral flow. Non‐invasive modalities include transcranial Doppler (TCD), magnetic resonance angiography (MRA), and computed tomographic angiography (CTA). These offer safer, accessible, and less expensive methods of evaluating intracranial circulation (Feldmann 2007; Hirai 2002; Hou 2009; Sloan 2004). Moreover, high‐resolution magnetic resonance imaging (MRI), intravascular ultrasonography, and optical coherence tomography (OCT) have enabled visualisation of the submillimetric structure of the intracranial arterial wall. These modalities help physicians to characterise plaque morphology and identify high‐risk plaque components, such as intraplaque haemorrhage, thin or ruptured fibrous cap, and high lipid core scores (Aoki 1995; Chu 2004; Hatsukami 2000; Patel 2013; Saam 2005; Turan 2015).

Description of the intervention

Contemporary treatment for ICAS consists of conventional medical treatment (CMT), endovascular treatment (ET), and, in rare cases, open surgery. CMT includes antiplatelet therapy, glycaemic and blood pressure control, statin therapy, and lifestyle modifications. Despite advances in CMT, the risk of recurrent stroke remains quite high. In the Warfarin‐Aspirin Symptomatic Intracranial Disease (WASID) trial, the risk of recurrent stroke was 20.4% in the aspirin group and 17% in the warfarin group over the average follow‐up time of 1.8 years (Kasner 2006). Since the mid 2000s, the preference for aggressive medical management (i.e. dual antiplatelet therapy with aspirin and clopidogrel combined with intensive risk factor management) in people with symptomatic ICAS has increased, in view of the relatively lower complication rates reported in several trials (Chimowitz 2015; Kasner 2006; Turan 2010). Open surgery is rarely used for ICAS management. The most common open surgical procedure is extracranial‐to‐intracranial bypass surgery (EC‐IC bypass; Ma 2013). However, the EC‐IC trial found no benefit of this intervention over medical management; in fact, EC‐IC bypass surgery was associated with worse outcomes for middle cerebral artery stenosis (EC/IC Bypass Study Group 1985).

ET, namely percutaneous transluminal angioplasty and stenting (PTAS), has been proposed for ICAS management since the 1980s (Derdeyn 2007). The middle cerebral arteries, basilar artery, internal carotid arteries, and intracranial vertebral arteries are the major target vessels for this minimally invasive approach (Derdeyn 2014; Zaidat 2015). Initial studies suggested that PTAS had potential efficacy for preventing recurrent ischaemia in people with symptomatic ICAS, and an acceptable periprocedural morbidity rate (Aoki 1995; Derdeyn 1998; Feldmann 2007; Zacharatos 2010). However, the results of the first randomised controlled trial (RCT) on this intervention, the Stenting versus Aggressive Medical Therapy for Intracranial Arterial Stenosis (SAMMPRIS) trial, did not favour PTAS over medical treatment for ICAS management (Chimowitz 2011). Use of ET for ICAS has since decreased (Chimowitz 2015; Derdeyn 1999). Practice guidelines allow for the investigational use of angioplasty, with or without stenting, for severe ICAS (70% to 99% stenosis) of a major intracranial artery with actively progressing symptoms despite aggressive medical management (An 2002; Kernan 2014; Kleindorfer 2021). However, studies from Asia have shown promising outcomes for ET (Derdeyn 2014; Hankey 2002). The safety and efficacy of ET compared with CMT for ICAS therefore remains unclear.

How the intervention might work

ET can be broadly categorised into angioplasty alone, balloon‐mounted stenting, and angioplasty followed by placement of a self‐expanding stent. Each method has its own technical advantages and disadvantages. Angioplasty alone is the simplest method for achieving revascularisation by dilating the stenotic vascular lumen with an endovascular balloon. The advantages of angioplasty alone include the low procedural risk and the potential for the lesion to remodel after angioplasty (Chatterjee 2015). The major disadvantage is the risk of vessel recoil and flow‐limiting dissection of the plaque and vessel, which stenting can overcome (Connors 2014). In balloon‐mounted stenting, the surgeon navigates the stent delivery balloon over a microguidewire to the stenosis, then inflates the balloon to dilate and deploy the stent (Berkefeld 2009). Balloon‐mounted stents were originally designed for coronary arteries; delivering these devices through the tortuous intracranial vasculature can be challenging, and this procedure carries a risk of regional anatomy distortion and even vascular trauma. Delayed in‐stent restenosis is a notable complication of balloon‐mounted bare metal stents that could be reduced by drug‐eluting stents (Gupta 2006; Natarajan 2010). Stenting with balloon‐expandable stents, as opposed to self‐expanding stents, has the advantage of being a rapid‐exchange single‐step system that does not require the more complex exchange‐length guidewires (Jiang 2007; Kurre 2012). Moreover, when using balloon‐mounted stents, the surgeon navigates to the lesion only once, which reduces the risk of embolic stroke and haemorrhagic (wire perforation) complications (Chimowitz 2011; Derdeyn 2013; Marks 2012). With self‐expanding stents, the surgeon must first perform balloon angioplasty, then position and deploy the self‐expanding stent across the lesion. However, compared to balloon‐mounted stents, angioplasty balloons and stents are less rigid and are associated with reduced distortion of anatomy and traumatic injuries, and greater technical success (Chatterjee 2015).

Why it is important to do this review

Stroke is the second leading cause of disability and death worldwide after ischaemic heart disease (Saini 2021). ICAS is a leading cause of stroke (Bang 2014; Holmstedt 2013; Qureshi 2014), particularly symptomatic high‐grade ICAS (generally defined as 70% or greater; Benjamin 2017; Huang 2014). The results of the SAMMPRIS trial showed no advantages of ET over CMT for ICAS management (Chimowitz 2011). Many researchers criticised this trial on its design, including the lack of a lead‐in phase, inexperience of the operators, and poor participant selection (Abou‐Chebl 2012; Gao 2016; Luo 2018; Tsivgoulis 2016). Since the 2010s, several studies have shown favourable outcomes for stenting versus CMT. One prospective study from Hong Kong of 65 participants with ICAS treated with the Wingspan stent reported a 30‐day periprocedural stroke or death rate of 6.1%, with no stroke up to one year. There is a decreased likelihood of recurrent stroke following Wingspan stenting among Asians compared to the white population (Yu 2014). In addition, the Wingspan Stent System Post Market Surveillance (WEAVE) trial, a US Food and Drug Administration (FDA)‐mandated study, reported a 2.6% rate of perioperative stroke and death and an 8.5% rate of one‐year stroke and death in people who underwent on‐label PTAS for ICAS; these rates are significantly lower than those of the PTAS group in the SAMMPRIS trial (Alexander 2019; Alexander 2021).

This is an update of a Cochrane Review first published in 2020 (Wang 2020). The previous review included three RCTs and found that CMT was superior to ET for ICAS. One revised RCT published in 2022 found that ET was not inferior to CMT for symptomatic severe ICAS (Gao 2022). Therefore, we decided to update this review to determine the safety and efficacy of ET versus CMT for management of symptomatic ICAS. The conclusions may help clinicians make more informed decisions and help researchers to develop more targeted and localised study designs.

Objectives

To evaluate the safety and efficacy of endovascular therapy plus conventional medical treatment compared with conventional medical treatment alone for the management of symptomatic intracranial artery stenosis.

Methods

Criteria for considering studies for this review

Types of studies

RCTs that compared ET plus CMT with CMT alone for managing symptomatic ICAS.

Types of participants

Adults (aged 18 and over) with symptomatic ICAS (at least 50%, measured by digital subtraction angiography) related to atherosclerotic factors, where the stenosis was located in at least one major intracranial artery (internal carotid artery, vertebral artery, middle cerebral artery, or basilar artery). We defined symptomatic as being associated with a transient ischaemic attack (TIA) or stroke attributable to the territory of the stenotic artery. We defined TIA as a transient episode (lasting between 10 minutes and 24 hours) of neurological dysfunction (focal weakness or language disturbance, transient monocular blindness, or required assistance in walking) caused by focal brain or retinal ischaemia (Easton 2009). We accepted diagnoses of TIA and stroke by experienced researchers.

Types of interventions

We compared ET plus CMT with CMT alone. The following ET modalities were acceptable: angioplasty alone, balloon‐mounted stent, and angioplasty followed by placement of a self‐expanding stent. CMT included antiplatelet therapy in addition to control of risk factors such as hypertension, hyperlipidaemia, and diabetes.

Types of outcome measures

Primary outcomes

• Short‐term death or stroke

We defined short‐term as the periprocedural period, or mean follow‐up of less than or equal to three months after randomisation. We defined stroke as sudden onset of new neurological deficits that persist over 24 hours, with new cerebral infarction detected by diffusion‐weighted MRI or computed tomography (CT), including ischaemic or haemorrhagic stroke (Sacco 2013).

 We defined death or stroke as a composite of all‐cause death and non‐fatal stroke of any type in any territory.

Secondary outcomes

• Long‐term death or stroke

• Ipsilateral stroke (same territory as the index stenosis)

• TIA

• Ischaemic stroke

• Haemorrhagic stroke

• Death

• Dependency: modified Rankin Scale or equivalent

• Restenosis (50% or greater) of the involved vessel documented by conventional cerebral angiography

• Health‐related quality of life

We defined long‐term as mean follow‐up of more than three months after randomisation. We evaluated all secondary outcomes (except long‐term death and stroke) at both short‐ and long‐term follow‐up. Ipsilateral stroke was identified in the vascular territory of the stenosed vessel.

Search methods for identification of studies

We searched for trials in all languages and arranged for the translation of relevant articles where necessary.

Electronic searches

We searched the Cochrane Stroke Group Trials Register (16 August 2022) and the following electronic databases.

• Cochrane Central Register of Controlled Trials (CENTRAL) in the Cochrane Library (to 16 August 2022; Appendix 1)

• MEDLINE Ovid (1946 to 16 August 2022; Appendix 2)

• Embase Ovid (1974 to 16 August 2022; Appendix 3)

• Science Citation Index Web of Science (1900 to 16 August 2022; Appendix 4)

• Scopus (1960 to 16 August 2022; Appendix 5)

• Academic Source Complete EBSCO (ASC; from 1982 to 16 August 2022; Appendix 6)

• China Biological Medicine Database (CBM; from 1978 to 16 August 2022; Appendix 7)

We developed the MEDLINE search strategy with the help of the Cochrane Stroke Information Specialist, and adapted it for searching the other databases. We combined the search strategies deployed with adaptations of the Highly Sensitive Search Strategy designed by Cochrane for identifying RCTs and controlled clinical trials, as described in Chapter 4 of Cochrane Handbook for Systematic Reviews of Interventions (Higgins 2022).

We searched the following ongoing trials registers.

• US National Institutes of Health Ongoing Trials Register ClinicalTrials.gov (www.clinicaltrials.gov/; searched 16 August 2022; Appendix 8)

• World Health Organization (WHO) International Clinical Trials Registry Platform (ICTRP; who.int/ictrp/en/; searched 16 August 2022; Appendix 9)

We contacted study authors and researchers where we required additional information.

Searching other resources

In an effort to identify further published, unpublished, and ongoing trials, we: checked the bibliographies of included studies and any relevant systematic reviews for further references to relevant trials (16 August 2022); contacted experts/trialists/organisations in the field to obtain additional information on relevant trials; and conducted a search of the grey literature through the Canadian Coordinating Office for Health Technology Assessment (CCOHTA; 16 August 2022).

Data collection and analysis

We conducted this update according to Cochrane guidelines without deviating from the planned protocol Wang 2019.

Selection of studies

Two review authors (TW and XW) independently screened the titles and abstracts of the references identified as a result of the search and excluded obviously irrelevant reports. We retrieved the full‐text articles for the remaining references and the same two review authors (TW and XW) independently read through them, identifying studies for inclusion and recording the reasons for exclusion of the ineligible studies. We resolved any disagreements by discussion, reaching consensus among all members of the review team. We collated multiple reports of the same study so that each study, not each reference, was the unit of interest in the review. We recorded the selection process and completed a PRISMA flow diagram (Page 2021).

Data extraction and management

Two review authors (KY and PG) independently extracted data and recorded details from the included studies using a standardised data extraction form. We extracted all relevant data related to methods, participant characteristics, interventions, outcomes, and reporting time points. We resolved any disagreements between the two review authors by discussion, reaching consensus among all members of the review team. We contacted study authors to request any key information that was missing from the full text. For dichotomous data, we extracted the number of participants who experienced the event and the total number of participants in each arm of the trial. For continuous data, we extracted the mean value and standard deviation (SD) in each arm of the trial, along with the total number in each group.

Assessment of risk of bias in included studies

Two review authors (JL and TW) independently assessed the risk of bias for each included study using the criteria outlined in Chapter 8 of the Cochrane Handbook for Systematic Reviews of Interventions (Higgins 2011). We resolved any disagreements between the two review authors through discussion with the full review team. We assessed risk of bias according to the following seven domains.

• Random sequence generation

• Allocation concealment

• Blinding of participants and personnel

• Blinding of outcome assessment

• Incomplete outcome data

• Selective outcome reporting

• Other possible bias

We rated the risk of bias for each domain as high, low, or unclear, and provided information from the study report together with a justification for our judgement in the risk of bias tables.

Measures of treatment effect

For dichotomous data (e.g. ischaemic stroke, haemorrhagic stroke, death), we calculated effect sizes as risk ratios (RRs) with 95% confidence intervals (CIs), as recommended by Boissel 1999. We had planned to convert continuous data to standardised mean differences (SMDs) with 95% CIs in the likely event that study authors had used different measurement scales, or mean differences (MDs) with 95% CIs if the authors of different studies had recorded continuous outcome data on the same measurement scale. If key data (e.g. SDs) had been missing from any studies, we would have imputed them using the calculations presented in Chapter 6 of the Cochrane Handbook for Systematic Reviews of Interventions (Higgins 2022). We would have extracted both change scores (i.e. change from baseline) and final values. We had planned to incorporate studies with change‐from‐baseline outcomes and studies with final measurement outcomes into the same meta‐analysis using the (unstandardised) MD method in Review Manager 5.4.1 (Review Manager 2020). However, the included studies reported no continuous outcomes of interest for this review. 

Unit of analysis issues

If we had included any studies with non‐standard designs (e.g. cluster‐randomised trials, multiple‐arm studies), we would have managed the data according to the recommendations in Chapter 6 of the Cochrane Handbook for Systematic Reviews of Interventions (Higgins 2022).

Dealing with missing data

We conducted a complete‐case analysis as far as possible on an intention‐to‐treat basis for all outcomes, following the methods for dealing with missing data described in Chapter 6 of the Cochrane Handbook for Systematic Reviews of Interventions (Higgins 2022). We planned to contact study authors or sponsors to request any missing data for dropouts, withdrawals or outcome measures, where appropriate. If this were not possible, we planned to perform best‐case and worst‐case sensitivity analyses for dichotomous data (e.g. ischaemic stroke, intracranial haemorrhage, death).

Assessment of heterogeneity

We used the I² statistic to measure heterogeneity among the trials in each analysis. We considered an I² value of 60% or greater as evidence of moderate to substantial levels of heterogeneity (Higgins 2022). Where we identified heterogeneity, we attempted to explore potential causes through subgroup analyses.

Assessment of reporting biases

Funnel plots are useful for measuring reporting bias, but are of limited power when the meta‐analysis includes fewer than 10 studies. Had we included 10 or more studies in this systematic review, we would have used funnel plots to assess the potential existence of small‐study effects and reporting bias. Because we included fewer than 10 studies, we assessed reporting bias qualitatively on the basis of study characteristics

Data synthesis

When at least two studies that were sufficiently similar provided data for the same outcome, we meta‐analysed the results. Otherwise, we provided a narrative description of the results. We used a random‐effects model to analyse outcomes, or a fixed‐effect model if there was little evidence of heterogeneity.

Subgroup analysis and investigation of heterogeneity

We planned the following subgroup analyses for the main outcome.

• Type of ET (i.e. angioplasty alone versus balloon‐mounted stent versus self‐expandable stent)

• Ethnicity (e.g. Asian versus white versus African versus Hispanic)

• Timing from qualifying event to randomisation (e.g. less than three weeks versus more than three weeks)

• Lesion location (internal carotid artery versus middle cerebral artery versus basilar artery versus intracranial vertebral artery).

We evaluated differences between subgroups using the test for subgroup differences.

Sensitivity analysis

Where we found heterogeneity, we performed sensitivity analyses on the primary outcome to explore the causes. This process involved repeating the meta‐analysis after excluding studies affected by the following issues.

• Inadequate allocation concealment

• Unblinded outcome assessment

• Unpublished studies

• Loss to follow‐up not reported or greater than 10%

• Role of funder potentially affected primary outcome

Summary of findings and assessment of the certainty of the evidence

We created a summary of findings table including the following outcomes.

• Death or stroke (short term: less than three months follow‐up; long term: more than three months follow‐up)

• Ipsilateral stroke (same territory as the index stenosis)

• TIA

• Ischaemic stroke

• Haemorrhagic stroke

• Death

• Dependency (modified Rankin Scale),

• Restenosis (50% or greater) of the involved vessel documented by cerebral angiography

• Health‐related quality of life

We used the five GRADE considerations (study limitations, consistency of effect, imprecision, indirectness, and publication bias) to assess the certainty of a body of evidence as it related to the studies that contributed data to the prespecified outcomes (Atkins 2004). We followed the methods and recommendations described in Chapter 14 of the Cochrane Handbook for Systematic Reviews of Interventions (Higgins 2022), employing GRADEpro GDT software (GRADEpro GDT). We justified all decisions to downgrade the certainty of evidence using footnotes, and made comments to aid the reader's understanding of the review where necessary.

Results

Description of studies

See Characteristics of included studies, Characteristics of excluded studies, and Characteristics of ongoing studies.

Results of the search

The searches for this update retrieved 29,140 references. After removing 7325 duplicates, we screened the titles and abstracts of 21,815 references, of which we excluded 21,806. We retrieved and reviewed the full‐text articles of the nine remaining studies. Two were ongoing studies (Cui 2016; Yang 2018), three studies were ineligible because they enroled mostly people with extracranial atherosclerotic stenosis (Compter 2015; Coward 2007; Markus 2017), and three studies had been included in the previous version of this review (Chimowitz 2011; Miao 2012; Zaidat 2015). In addition to these three previous studies, we included one new study in this update (Gao 2022). Figure 1 shows the flow of studies.

1.

Study flow diagram. 
ECAS: extracranial artery stenosis.

Included studies

All participants had intracranial atherosclerosis with more than 70% stenosis. The age of participants was 18 to 85 years; the average age ranged from 53.4 to 61.8 years across the four trials. Most participants were men (66.4%). In total, 494 participants were randomised to ET plus CMT and 495 participants to CMT alone.

Miao 2012 was a single‐centre RCT comparing ET plus CMT versus CMT alone for symptomatic severe middle cerebral artery stenosis (70% or greater). Chimowitz 2011 (Stenting and Aggressive Medical Management for Preventing Recurrent Stroke in Intracranial Stenosis (SAMMPRIS) trial), Gao 2022 (the China Angioplasty and Stenting for Symptomatic Intracranial Severe Stenosis (CASSISS) trial), and Zaidat 2015 (the Vitesse Intracranial Stent Study for Ischemic Stroke Therapy (VISSIT)) were multicentre RCTs comparing ET plus aggressive medical treatment with aggressive medical treatment alone for symptomatic ICAS (70% or greater) involving the internal carotid artery, middle cerebral artery, intracranial vertebral artery, or basilar artery.

There were some key differences between studies, as follows.

• Types of ET: participants in the ET group of Chimowitz 2011 and Gao 2022 were treated with a self‐expandable intracranial stent (Wingspan). Participants in the ET group of Zaidat 2015 were treated with a balloon‐expandable intracranial stent (PHAROS Vitesse). Participants in the ET group of Miao 2012 received various types of ET, including primary angioplasty, coronary balloon‐expandable stent (Coroflex or Coroflex Blue), or the Wingspan stent.

• Time interval between qualifying event and intervention: Gao 2022 and Miao 2012 performed ET more than three weeks after the qualifying event, while Chimowitz 2011 and Zaidat 2015 performed ET less than three weeks after the qualifying event.

• Ethnicity of participants: Gao 2022 and Miao 2012 were both conducted in China and recruited only Chinese people (428 in total), whereas 71.4% of the combined population of Chimowitz 2011 and Zaidat 2015 (401/562) was white.

The study endpoints were similar in the four studies. We were able to extract and analyse detailed data for any stroke or death, ischaemic stroke caused by ICAS, intracranial haemorrhage, TIA, disabling or fatal stroke, and all‐cause death, at 30 days and one year.

Excluded studies

We excluded three studies that investigated both extra‐ and intracranial artery stenosis and did not provide separate data for ICAS (Compter 2015; Coward 2007; Markus 2017).

Ongoing studies

Two studies are ongoing (Cui 2016; Yang 2018). The only publications from these studies were protocols, and we were unable to obtain more information for analysis.

Risk of bias in included studies

Information related to risk of bias is presented in Characteristics of included studies, Figure 2, and Figure 3.

2.

Risk of bias graph: review authors' judgements about each risk of bias item presented as percentages across all included studies.

3.

Risk of bias summary: review authors' judgements about each risk of bias item for each included study.

Allocation

We deemed allocation concealment for all trials to be adequate, with a low risk of bias.

Blinding

Due to the nature of ET, blinding of participants and personnel was not possible. Risk of performance bias was thus high in all four RCTs. Risk of bias related to blinding of outcome assessment was low for all studies because the investigators were unaware of the allocated groups when detecting and reporting outcome events.

Incomplete outcome data

Risk of attrition bias was low in Chimowitz 2011, Gao 2022, and Zaidat 2015. Miao 2012 reported a 30% (49/70) loss in one‐year follow‐up, and 19.4% of participants in the ET group transferred to the CMT group, which resulted in a high risk of attrition bias despite the intention‐to‐treat analysis.

Selective reporting

We considered all studies at low risk of selective reporting. Chimowitz 2011, Gao 2022 and Zaidat 2015 reported the outcomes that had been prespecified in their published protocols. Although there was no published protocol for Miao 2012, we obtained the registered information from the Chinese Clinical Trial Registration (ChiCTR‐TRC‐12001989) website, and found that the reported outcomes matched the prespecified outcomes.

Other potential sources of bias

Only Gao 2022 recruited the planned sample size. Chimowitz 2011, Miao 2012, and Zaidat 2015 were terminated early. The final results would not have changed in Chimowitz 2011 and Zaidat 2015, because the interim analysis revealed that CMT alone was superior to ET plus CMT. However, in Miao 2012, the final results may have been different if recruitment had continued, because the interim analysis showed equipoise between the interventions in terms of safety and efficacy. The industry funding source may be a source of bias in Zaidat 2015 and Gao 2022.

We therefore assessed risk of other bias as low in Chimowitz 2011, but high in Miao 2012, Zaidat 2015, and Gao 2022.

Effects of interventions

See: Table 1

See Table 1 for the main comparison: ET plus CMT versus CMT alone for symptomatic ICAS in adults.

 For this review, we considered the 30‐day outcomes as short‐term outcomes, and one‐year outcomes as long‐term outcomes.

Primary outcome: short‐term death or stroke

Four RCTs reported short‐term death or stroke (Chimowitz 2011; Gao 2022; Miao 2012; Zaidat 2015). ET plus CMT compared with CMT alone probably increases the risk of short‐term death or stroke (RR 2.93, 95% CI 1.81 to 4.75; P < 0.001, I² = 0%; 989 participants; moderate‐certainty evidence; Analysis 1.1).

1.1. Analysis.

Comparison 1: Primary outcome: short‐term death or stroke, Outcome 1: Short‐term death or stroke

Subgroup analysis: types of endovascular therapy

We included three RCTs with 919 participants in the subgroup analysis of types of ET: Chimowitz 2011 and Gao 2022 treated participants in the ET group (total n = 400) with a self‐expandable stent (Wingspan), and Zaidat 2015 treated participants in the ET group (n = 58) with a balloon‐mounted stent (PHAROS Vitesse). We excluded Miao 2012 from this subgroup analysis because it used various types of ET without providing separate data for each. There was no statistically significant subgroup effect (P = 0.27), which suggests type of ET did not modify the effect of ET plus CMT in comparison to CMT alone on short‐term death or stroke. However, there were fewer trials and participants in the balloon‐mounted stent subgroup than in the self‐expandable stent subgroup, and detecting differences within these subgroups may be difficult. ET plus CMT compared to CMT alone was associated with a higher risk of short‐term death or stroke in the self‐expandable stent subgroup (RR 2.51, 95% CI 1.46 to 4.32; P < 0.001; 2 RCTs, 808 participants; Analysis 1.2) and in the balloon‐mounted stent subgroup (RR 5.18, 95% CI 1.61 to 16.68; P = 0.006; 1 RCT, 111 participants; Analysis 1.2).

1.2. Analysis.

Comparison 1: Primary outcome: short‐term death or stroke, Outcome 2: Subgroup analysis: types of endovascular therapy

Subgroup analysis: ethnicity

Miao 2012 and Gao 2022 enroled only Chinese people. Neither study found a significant difference in short‐term death or stroke between the ET plus CMT group and the CMT alone group. We did not perform the subgroup analysis of short‐term death or stroke in different ethnicities owing to a lack of data from other ethnic groups. Chimowitz 2011 and Zaidat 2015 enroled people from multiple ethnicities including white, Asian, Black, and Hispanic; however, they did not report outcomes by ethnicity in both treatment arms. We requested individual participant data from the study authors, but these data were unavailable.

Subgroup analysis: time intervals from qualifying event to intervention

Data from all four RCTs were available. Chimowitz 2011 and Zaidat 2015 performed ET within three weeks of the qualifying event (562 participants); the mean time interval was seven days in Chimowitz 2011 and nine days in Zaidat 2015. Gao 2022 and Miao 2012 performed ET more than three weeks after symptom onset (427 participants); the mean time interval was 34.5 days in Gao 2022 and 261.95 days in Miao 2012. There was no significant subgroup difference (P = 0.67), suggesting that the time interval between the qualifying event and the intervention did not alter the effect of ET plus CMT relative to CMT alone on short‐term death or stroke. However, fewer participants contributed to the subgroup with more than a three‐week delay from symptom onset to treatment, meaning that more research is necessary to detect this phenomenon. The pooled effect estimate for the subgroup with more than three weeks between symptom onset and treatment indicated no clear difference between ET plus CMT and CMT alone (RR 2.37, 95% CI 0.80 to 7.05; P = 0.91; 2 RCTs, 427 participants; Analysis 1.3). In contrast, the pooled effect estimate for the subgroup with a delay of less than three weeks favoured CMT (RR 3.08, 95% CI 1.80 to 5.29; P = 0.001; 2 RCTs, 562 participants; Analysis 1.3).

1.3. Analysis.

Comparison 1: Primary outcome: short‐term death or stroke, Outcome 3: Subgroup analysis: time interval from qualifying event to intervention

Subgroup analysis: location of lesion

There were insufficient data for subgroup analysis by lesion location. Chimowitz 2011, Gao 2022, and Zaidat 2015 enroled people with lesions in several territories, including internal carotid artery, middle cerebral artery, basilar artery, and vertebral artery (intracranial segment). None of these three studies reported outcomes by lesion location. Miao 2012 enroled people with middle cerebral artery stenosis, and found no clear difference between ET plus CMT and CMT alone (RR 2.84, 95% CI 0.12 to 67.36; P = 0.52; 1 RCT, 70 participants).

Secondary outcomes

Short‐term outcomes

We obtained sufficient data for analysing five short‐term outcomes: ipsilateral stroke, TIA, ischaemic stroke, haemorrhagic stroke, and death. Chimowitz 2011 did not report TIA, but all four studies reported the remaining four outcomes. ET plus CMT compared with CMT alone probably increases the short‐term risk of ipsilateral stroke (RR 3.26, 95% CI 1.94 to 5.48; P < 0.001; 4 RCTs, 989 participants; moderate‐certainty evidence; Analysis 2.1) and ischaemic stroke (RR 2.24, 95% CI 1.30 to 3.87; P = 0.004; 4 RCTs, 989 participants; moderate‐certainty evidence; Analysis 2.2). ET plus CMT compared with CMT alone may increase the short‐term risk of haemorrhagic stroke (RR 13.49, 95% CI 2.59 to 70.15; P = 0.002; 4 RCTs, 989 participants; low‐certainty evidence; Analysis 2.3) and death (RR 5.43, 95% CI 1.21 to 24.40; P = 0.03; 4 RCTs, 989 participants; low‐certainty evidence; Analysis 2.5). It is unclear if ET plus CMT compared with CMT alone affects short‐term risk of TIA (RR 0.79, 95% CI 0.30 to 2.07; P = 0.63; 3 RCTs, 344 participants; moderate‐certainty evidence; Analysis 2.4). There was no heterogeneity among studies in these 30‐day outcomes.

2.1. Analysis.

Comparison 2: Other outcomes, Outcome 1: Short‐term ipsilateral stroke

2.2. Analysis.

Comparison 2: Other outcomes, Outcome 2: Short‐term ischaemic stroke

2.3. Analysis.

Comparison 2: Other outcomes, Outcome 3: Short‐term haemorrhagic stroke

2.5. Analysis.

Comparison 2: Other outcomes, Outcome 5: Short‐term death

2.4. Analysis.

Comparison 2: Other outcomes, Outcome 4: Short‐term TIA

Long‐term outcomes

We obtained sufficient data for analysing seven one‐year outcomes: death or stroke, ipsilateral stroke, TIA, ischaemic stroke, haemorrhage stroke, death, and dependency. Chimowitz 2011 did not report TIA, but all four studies reported the remaining six outcomes. We defined dependency as a modified Rankin Scale of 4 or more points.

ET plus CMT compared with CMT alone probably increases the long‐term risk of death or stroke (RR 1.49, 95% CI 1.12 to 1.99; P <0.001; 4 RCTs, 970 participants; moderate‐certainty evidence; Analysis 2.6). ET plus CMT compared with CMT alone may increase the long‐term risk of haemorrhagic stroke (RR 7.81, 95% CI 1.43 to 42.59; P = 0.02; 3 RCTs, 879 participants; low‐certainty evidence; Analysis 2.9). It is unclear if ET plus CMT compared with CMT alone affects long‐term risk of ipsilateral stroke (RR 1.78, 95% CI 1.00 to 3.17; P = 0.05; 4 RCTs, 970 participants; moderate‐certainty evidence; Analysis 2.7); ischaemic stroke (RR 1.56, 95% CI 0.77 to 3.16; P = 0.21; 4 RCTs, 970 participants; moderate‐certainty evidence; Analysis 2.8); TIA (RR 1.05, 95% CI 0.50 to 2.19; P = 0.89; 3 RCTs, 335 participants; moderate‐certainty evidence; Analysis 2.10); death (RR 1.61, 95% CI 0.77 to 3.38; P = 0.20; 4 RCTs, 951 participants; moderate‐certainty evidence; Analysis 2.11); or dependency (RR 1.51, 95% CI 0.93 to 2.45; P = 0.09; 4 RCTs, 947 participants; moderate‐certainty evidence; Analysis 2.12). For the above analysis, most I² values were 0%; only the analysis of one‐year ischaemic stroke showed moderate heterogeneity (I² = 65%). Through sensitivity analysis, we found that the heterogeneity was due to Gao 2022: excluding this trial reduced the I² value to 12%, but also pushed the effect measure above the line of no effect to favour CMT (RR 2.07, 95% CI 1.37 to 3.13; P < 0.001; 3 RCTs, 632 participants). 

2.6. Analysis.

Comparison 2: Other outcomes, Outcome 6: Long‐term death or stroke

2.9. Analysis.

Comparison 2: Other outcomes, Outcome 9: Long‐term haemorrhagic stroke

2.7. Analysis.

Comparison 2: Other outcomes, Outcome 7: Long‐term ipsilateral stroke

2.8. Analysis.

Comparison 2: Other outcomes, Outcome 8: Long‐term ischaemic stroke

2.10. Analysis.

Comparison 2: Other outcomes, Outcome 10: Long‐term TIA

2.11. Analysis.

Comparison 2: Other outcomes, Outcome 11: Long‐term death

2.12. Analysis.

Comparison 2: Other outcomes, Outcome 12: Long‐term dependency

We did not perform a meta‐analysis for restenosis of the involved vessel owing to lack of relevant data in the CMT group. Only Zaidat 2015 reported restenosis in people treated with a stent, finding that 26.5% had least 50% restenosis and 2.9% had at least 70% restenosis at one year of follow‐up. We did not assess health‐related quality of life because the studies provided no relevant data.

Discussion

Summary of main results

This review update included four RCTs with 989 participants. These studies provided moderate‐certainty evidence that CMT was superior to ET in participants with symptomatic ICAS of 70% or greater in terms of short‐ and long‐term death or stroke, short‐term ipsilateral stroke, and short‐term ischaemic stroke. There was low‐certainty evidence favouring CMT over ET for reducing short‐ and long‐term haemorrhagic stroke and short‐term death. However, there were no clear differences between the interventions for long‐term ipsilateral stroke, long‐term ischaemic stroke, short‐ and long‐term TIA, long‐term death, and long‐term dependency. The main reasons for downgrading the certainty of the evidence were early termination of the trials and small sample sizes. One Cochrane Review on angioplasty for ICAS calculated that 950 participants per group would be necessary under alpha of 0.05, power of 80%, expected relative risk reduction of 25%, and less than 7% perioperative risk of death or stroke (Cruz‐Flores 2006). In view of this estimation, the sample size of our review may have been insufficient.

Overall completeness and applicability of evidence

The certainty of evidence for major outcomes ranged from low to moderate, which partially limits the application of our findings to clinical decision‐making. Nonetheless, this review provides the highest level of current evidence. Furthermore, investigators applied different participant selection criteria for ET in the post‐SAMMPRIS trials. Trials with modified inclusion criteria reported a promising perioperative risk of 2% and 4.3%, respectively (Gao 2016; Miao 2015). The ongoing RCTs we identified have adopted the revised inclusion criteria (Cui 2016; Yang 2018). Future studies should clarify the safety and efficacy of ET for selected participants. One major limitation of this review is the small number of trials contributing evidence to the meta‐analysis. Consequently, the tests of heterogeneity have a very low power and do not provide reliable results. Substantial heterogeneity may exist although the tests are negative.

The time interval from the qualifying event to intervention may be a factor affecting the outcomes of ET. According to the subgroup analysis of this review, it may be safer to perform ET more than three weeks after the qualifying event versus less than three weeks after. The rates of short‐term death or stroke were low in studies that performed ET more than three weeks after the qualifying event (Gao 2016; Miao 2015). The cause of the increased risk of death or stroke in people who undergo ET in the early period may relate to instability of plaque and intracranial microcirculation leading to the 'snowploughing' effect (displacement of plaque to perforating arteries) and reperfusion haemorrhage (Luo 2018). Future studies are needed to confirm this speculation.

Quality of the evidence

The certainty of evidence in the included RCTs was low or moderate. The included trials had a high risk of performance bias because they could not blind participants or operators to the intervention. Moreover, three trials were terminated early after interim analysis (Chimowitz 2011; Miao 2012; Zaidat 2015). Miao 2012 had a high risk of attrition bias because the rate of loss to one‐year follow‐up was 30%, and 19.4% of participants transferred from ET to CMT.

Potential biases in the review process

We tried to minimise bias at every stage of the review's development; however, we could not avoid all bias during our review. Because we searched only English and Chinese databases, we may have missed articles in other languages without English abstracts. In addition, we only analysed data from published RCTs, and the lack of data from unpublished articles may have contributed to bias. Moreover, the number of studies related to the topic and the overall sample size were small, which may result in biased analysis results due to low statistical power.

Agreements and disagreements with other studies or reviews

The 2020 version of this review did not favour ET plus CMT over CMT alone (Wang 2020). We included updated data from randomised trials, and reached the same conclusion. Our results are similar to those of Zhang 2017, which meta‐analysed data from two randomised trials and two retrospective cohort studies, finding that ET plus CMT and CMT alone had comparable risks of event‐free survival and recurrent TIA, but that ET was associated with a higher risk of short‐term stroke.

However, two studies published in the late 2010s suggested that ET would benefit selected people with symptomatic intracranial atherosclerosis and cerebral hypoperfusion and people with at least two failures of best medical management (Abualhasan 2019; Padalia 2018). The WEAVE (Wingspan Stent System Post Market Surveillance) trial was an FDA‐authorised post‐market surveillance trial that aimed to reassess the perioperative safety of the Wingspan stent in on‐label patients who had symptomatic intracranial atherosclerosis with 70% to 90% stenosis, a baseline modified Rankin score of less than 3, and at least two failures of best medical management. The result was favourable for ET (in all cases performed more than eight days after the latest event), with a 2.6% rate of perioperative stroke and death and an 8.5% rate of one‐year stroke and death (Alexander 2019; Alexander 2021).

Authors' conclusions

Implications for practice.

This systematic review provides moderate‐certainty evidence that endovascular therapy plus conventional medical treatment compared to conventional medical treatment alone carries a higher risk of short‐term and long‐term stroke and death, short‐term ipsilateral stroke, and short‐term ischaemic stroke in people with recently symptomatic severe intracranial artery stenosis. Further information on treatment decisions is limited by the relatively small sample size.

Implications for research.

There are ongoing debates about whether specific subgroups, for example those treated after a certain delay, may benefit from ET more than those treated acutely, but more high‐certainty evidence is needed to unpick this.

What's new

Date	Event	Description
30 January 2023	New search has been performed	New search for studies and content updated. We included one new study since the previous version, bringing the total number of includes studies to four, involving 989 participants
30 January 2023	New citation required but conclusions have not changed	New search for studies and content updated (no change to conclusions)

History

Protocol first published: Issue 2, 2019
Review first published: Issue 8, 2020

Appendices

Appendix 1. CENTRAL search strategy

1. MeSH descriptor: [Vascular Surgical Procedures] this term only
2. MeSH descriptor: [Endovascular Procedures] this term only
3. MeSH descriptor: [Angioplasty] this term only
4. MeSH descriptor: [Angioplasty, Balloon] this term only
5. MeSH descriptor: [Angioplasty, Balloon, Laser‐Assisted] this term only
6. MeSH descriptor: [Cerebral Revascularization] this term only
7. MeSH descriptor: [Blood Vessel Prosthesis] this term only
8. MeSH descriptor: [Blood Vessel Prosthesis Implantation] this term only
9. MeSH descriptor: [Stents] this term only
10. MeSH descriptor: [Dilatation] this term only
11. MeSH descriptor: [Catheterization] this term only
12. (angioplasty or stent* or pta or revasculari?ation or recanali?ation or catheter* or dilatation):ti,ab,kw
13. #1 or #2 or #3 or #4 or #5 or #6 or #7 or #8 or #9 or #10 or #11 or #12
14. MeSH descriptor: [Intracranial Arterial Diseases] explode all trees
15. MeSH descriptor: [Intracranial Arteriosclerosis] this term only
16. MeSH descriptor: [Vertebrobasilar Insufficiency] this term only
17. MeSH descriptor: [Cerebral Arteries] explode all trees
18. MeSH descriptor: [Basilar Artery] this term only
19. MeSH descriptor: [Vertebral Artery Dissection] this term only
20. #17 or #18 or #19
21. MeSH descriptor: [Arterial Occlusive Diseases] explode all trees
22. MeSH descriptor: [Arteriosclerosis] this term only
23. MeSH descriptor: [Constriction, Pathologic] this term only
24. #21 or #22 or #23
25. #20 and #24
26. ((intracranial or intra‐cranial or cerebral arter* or basilar arter* or vertebral arter* or vertebrobasilar or vertebro basilar) near/5 (stenos?s or isch?emia or insufficien* or arteriosclerosis or atherosclerosis or occlus* or obstruct* or plaque*)):ti,ab,kw
27. #14 or #15 or #16 or #25 or #26
28. #13 AND #27
29. MeSH descriptor: [Carotid Artery Diseases] this term only and with qualifier(s): [surgery ‐ SU, therapy ‐ TH]
30. MeSH descriptor: [Carotid Stenosis] this term only and with qualifier(s): [surgery ‐ SU, therapy ‐ TH]
31. MeSH descriptor: [Vertebrobasilar Insufficiency] this term only and with qualifier(s): [surgery ‐ SU, therapy ‐ TH]
32. MeSH descriptor: [Brain Ischemia] this term only and with qualifier(s): [surgery ‐ SU, therapy ‐ TH]
33. MeSH descriptor: [Cerebral Arteries] this term only and with qualifier(s): [surgery ‐ SU]
34. MeSH descriptor: [Basilar Artery] this term only and with qualifier(s): [surgery ‐ SU]
35. MeSH descriptor: [Vertebral Artery] this term only and with qualifier(s): [surgery ‐ SU]
36. #29 or #30 or #31 or #32 or #33 or #34 or #35
37. #28 or #36 in Trials

Appendix 2. MEDLINE Ovid search strategy

1. vascular surgical procedures/
2. endovascular procedures/ or angioplasty/ or angioplasty, balloon/ or angioplasty, balloon, laser‐assisted/
3. cerebral revascularization/ or Blood Vessel Prosthesis/ or Blood Vessel Prosthesis Implantation/
4. stents/ or dilatation/ or catheterization/
5. (angioplasty or stent$ or pta or revasculari?ation or recanali?ation or catheter$ or dilatation).tw.
6. or/1‐5
7. exp intracranial arterial diseases/ or intracranial arteriosclerosis/ or vertebrobasilar insufficiency/
8. exp cerebral arteries/ or basilar artery/ or vertebral artery/
9. exp arterial occlusive diseases/ or arteriosclerosis/ or constriction, pathologic/
10. 8 and 9
11. ((intracranial or intra‐cranial or cerebral arter$ or basilar arter$ or vertebral arter$ or vertebrobasilar or vertebro basilar) adj5 (stenos?s or isch?emia or insufficien$ or arteriosclerosis or atherosclerosis or occlus$ or obstruct$ or plaque$)).tw.
12. 7 or 10 or 11
13. 6 and 12
14. *Carotid Artery Diseases/su, th [Surgery, Therapy]
15. *Carotid Stenosis/su, th [Surgery, Therapy]
16. *Vertebrobasilar Insufficiency/su, th [Surgery, Therapy]
17. *Brain Ischemia/su, th [Surgery, Therapy]
18. *Cerebral Arteries/su [Surgery]
19. *Basilar Artery/su [Surgery]
20. *Vertebral Artery/su [Surgery]
21. or/14‐20
22. 13 or 21
23. randomized controlled trial.pt.
24. controlled clinical trial.pt.
25. randomized.ab.
26. placebo.ab.
27. randomly.ab.
28. trial.ab.
29. groups.ab.
30. 23 or 24 or 25 or 26 or 27 or 28 or 29
31. 22 and 30

Appendix 3. Embase Ovid search strategy

1. endovascular surgery/ or vascular surgery/
2. angioplasty/ or bare metal stenting/ or carotid angioplasty/ or carotid artery stenting/ or patch angioplasty/
3. cerebral revascularization/
4. blood vessel prosthesis/ or artery prosthesis/
5. balloon dilatation/ or stent/ or exp metal stent/ or exp self expanding stent/
6. (angioplasty or stent$ or pta or revasculari?ation or recanali?ation or catheter$ or dilatation).tw.
7. or/1‐6
8. cerebral artery disease/ or brain atherosclerosis/ or vertebrobasilar insufficiency/
9. exp brain artery/ or vertebral artery/
10. peripheral occlusive artery disease/ or atherosclerosis/ or arteriosclerosis/ or atherosclerotic plaque/ or brain atherosclerosis/ or carotid atherosclerosis/
11. 9 and 10
12. ((intracranial or intra‐cranial or cerebral arter$ or basilar arter$ or vertebral arter$ or vertebrobasilar or vertebro basilar) adj5 (stenos? s or isch?emia or insufficien$ or arteriosclerosis or atherosclerosis or occlus$ or obstruct$ or plaque$)).tw.
13. 8 or 11 or 12
14. 7 and 13
15. carotid artery disease/su, th [Surgery, Therapy]
16. carotid artery obstruction/su, th [Surgery, Therapy]
17. vertebrobasilar insufficiency/su, th [Surgery, Therapy]
18. brain ischemia/su, th [Surgery, Therapy]
19. brain artery/su [Surgery]
20. basilar artery/su [Surgery]
21. vertebral artery/su [Surgery]
22. or/15‐21
23. 14 or 22
24. Randomized Controlled Trial/ or "randomized controlled trial (topic)"/
25. randomisation/
26. Controlled clinical trial/ or "controlled clinical trial (topic)"/
27. control group/ or controlled study/
28. clinical trial/ or "clinical trial (topic)"/ or phase 1 clinical trial/ or phase 2 clinical trial/ or phase 3 clinical trial/ or phase 4 clinical trial/
29. Crossover Procedure/
30. Double Blind Procedure/
31. Single Blind Procedure/ or triple blind procedure/
32. placebo/ or placebo effect/
33. (random$ or RCT or RCTs).tw.
34. controlled adj5 (trial$ or stud$)).tw.
35. (clinical$ adj5 trial$).tw.
36. ((control or treatment or experiment$ or intervention) adj5 (group$ or subject$ or patient$)).tw.
37. (quasi‐random$ or quasi random$ or pseudo‐random$ or pseudo random$).tw.
38. ((control or experiment$ or conservative) adj5 (treatment or therapy or procedure or manage$)).tw.
39. ((singl$ or doubl$ or tripl$ or trebl$) adj5 (blind$ or mask$)).tw.
40. (cross‐over or cross over or crossover).tw.
41. (placebo$ or sham).tw.
42. trial.ti.
43. (assign$ or allocat$).tw.
44. controls.tw.
45. or/24‐44
46. 23 and 45

Appendix 4. Science Citation Index Web of Science search strategy

1. TS=(angioplasty OR stent* OR pta OR revascularization OR revascularisation OR recanalisation OR recanalization OR recanaliation OR catheter* OR dilatation)
2. TS=(intracranial OR intra‐cranial OR cerebral arter* OR basilar arter* OR vertebral arter* OR vertebrobasilar OR vertebro basilar) AND TS=(stenosis OR stenosis OR ischemia OR ischaemia OR insufficien* OR arteriosclerosis OR atherosclerosis OR occlus* OR obstruct* OR plaque*)
3. #1 AND #2
4. TS=(randomized OR placebo OR randomly OR trial OR groups)
5. #3 AND #4

Appendix 5. Scopus search strategy

1. INDEXTERMS("endovascular procedures" OR angioplasty OR "vascular surgical procedures" OR "cerebral revascularization" OR "Blood Vessel Prosthesis" OR "Blood Vessel Prosthesis Implantation" OR "balloon dilatation" OR "stents" OR "dilatation" OR "catheterization" )
2. TITLE‐ABS ( angioplasty OR stent* OR pta OR revasculari?ation OR recanali?ation OR catheter* OR dilatation )
3. #1 OR #2
4. INDEXTERMS("intracranial arterial diseases" OR "intracranial arteriosclerosis" OR "vertebrobasilar insufficiency")
5. INDEXTERMS("cerebral arteries" OR "basilar artery" OR "vertebral artery" )
6. INDEXTERMS("arterial occlusive diseases" OR arteriosclerosis OR "constriction, pathologic")
7. #5 AND #6
8. TITLE‐ABS ( intracranial OR intra‐cranial OR "cerebral arter*" OR "basilar arter*" OR "vertebral arter*" OR vertebrobasilar OR "vertebro basilar" ) W/5 ( stenos?s OR isch?emia OR insufficien* OR arteriosclerosis OR atherosclerosis OR occlus* OR obstruct* OR plaque* )
9. #4 OR #7 OR #8
10. #3 AND #9
11. TITLE‐ABS ( randomized OR placebo OR randomly OR trial OR groups )
12. INDEXTERMS ( "randomized controlled trial" OR "controlled clinical trial" )
13. #11 OR #12
14. #10 AND #13

Appendix 6. Academic Source Complete EBSCO search strategy

1. SU endovascular procedures OR SU angioplasty OR SU vascular surgical procedures OR SU cerebral revascularization OR SU Blood Vessel Prosthesis OR SU Blood Vessel Prosthesis Implantation OR SU balloon dilatation OR SU stents OR SU dilatation OR SU catheterization
2. angioplasty OR stent* OR pta OR revascularization OR revascularisation OR recanalisation OR recanalization OR recanaliation OR catheter* OR dilatation
3. #1 OR #2
4. SU intracranial arterial diseases OR SU intracranial arteriosclerosis OR SU vertebrobasilar insufficiency
5. SU cerebral arteries OR SU basilar artery OR SU vertebral artery
6. SU arterial occlusive diseases OR SU arteriosclerosis OR SU constriction, pathologic
7. #5 AND #6
8. (intracranial OR intra‐cranial OR cerebral arter* OR basilar arter* OR vertebral arter* OR vertebrobasilar OR vertebro basilar) AND (stenosis OR stenosis OR ischemia OR ischaemia OR insufficien* OR arteriosclerosis OR atherosclerosis OR occlus* OR obstruct* OR plaque*)
9. #4 OR #7 OR #8
10. #3 AND #9
11. SU randomized controlled trial OR SU controlled clinical trial OR AB randomized OR AB placebo OR AB randomly OR AB trial OR AB groups
12. #10 AND #11

Appendix 7. China Biological Medicine Database search strategy

1. ((((((((("血管内操作"[不加权:不扩展]) OR "血管成形术"[不加权:扩展]) OR "血管外科手术"[不加权:不扩展]) OR "脑血管重建术"[不加权:不扩展]) OR "人工血管"[不加权:不扩展]) OR "血管假体植入"[不加权:不扩展]) OR "血管成形术, 气囊"[不加权:不扩展]) OR "支架"[不加权:不扩展]) OR "扩张术"[不加权:不扩展]) OR "导管插入术"[不加权:不扩展]
2. 血管 OR 血运
3. 重建 OR 再建 OR 再生 OR 再造 OR 重造 OR 重生 OR 成形
4. (#3) AND (#2)
5. 导管 OR 扩张 OR 膨胀 OR 支架 OR PTA
6. (#5) OR (#4) OR (#1)
7. (("颅内动脉疾病"[不加权:扩展]) OR "颅内动脉硬化"[不加权:不扩展]) OR "椎底动脉供血不足"[不加权:不扩展]
8. (("脑动脉"[不加权:扩展]) OR "基底动脉"[不加权:不扩展]) OR "椎动脉"[不加权:不扩展]
9. (("动脉闭塞性疾病"[不加权:扩展]) OR "动脉硬化"[不加权:不扩展]) OR "缩窄, 病理性"[不加权:不扩展]
10. (#9) AND (#8)
11. 颅内动脉 OR 脑动脉 OR 基底动脉 OR 椎动脉 OR 椎基底动脉
12. 狭窄 OR 缺血 OR 供血不足 OR 动脉粥样硬化 OR 动脉硬化 OR 粥样硬化 OR 阻塞 OR 闭塞 OR 梗阻 OR 斑块
13. (#12) AND (#11)
14. (#13) OR (#10) OR (#7)
15. (#14) AND (#6)
16. (((((("颈动脉疾病/外科学"[加权:不扩展]) OR "颈动脉狭窄/外科学"[加权:不扩展]) OR "椎底动脉供血不足/外科学"[加权:不扩展]) OR "脑缺血/外科学"[加权:不扩展]) OR "脑动脉/外科学"[加权:不扩展]) OR "基底动脉/外科学"[加权:不扩展]) OR "椎动脉/外科学"[加权:不扩展]
17. ("随机对照试验"[不加权:扩展]) OR "临床对照试验"[不加权:扩展]
18. (((("随机"[摘要:智能]) OR "安慰剂"[摘要:智能]) OR "试验"[摘要:智能]) OR "分组"[摘要:智能]) OR "对照"[摘要:智能]
19. (#18) OR (#17)
20. (#16) OR (#15)
21. (#20) AND (#19)
22. ((#30) AND (#19)) AND ( 随机对照试验[文献类型])
23. 动物[特征词] NOT 人类[特征词]
24. #22 NOT #23

Appendix 8. ClinicalTrials.gov search strategy

1. (angioplasty OR stent OR surgery OR revascular* OR recanal* OR catheter* OR dilatation ) | Interventional Studies | intracranial artery OR cerebral artery OR vertebral OR basilar OR vertebrobasilar

Appendix 9. WHO ICTRP search strategy

1. intracranial AND angioplasty OR intracranial AND stent OR intracranial AND PTA OR intracranial AND revascularization OR intracranial AND revascularisation OR intracranial AND recanalisation OR intracranial AND recanalization OR intracranial AND recanaliation OR intracranial AND catheterisation OR intracranial AND dilatation OR intracranial AND endovascular procedures OR intracranial AND surgical OR intracranial AND blood vessel prosthesis
2. cerebral arteries AND angioplasty OR cerebral arteries AND stent OR cerebral arteries AND PTA OR cerebral arteries AND revascularization OR cerebral arteries AND revascularisation OR cerebral arteries AND recanalisation OR cerebral arteries AND recanalization OR cerebral arteries AND recanaliation OR cerebral arteries AND catheterisation OR cerebral arteries AND dilatation OR cerebral arteries AND endovascular procedures OR cerebral arteries AND surgical OR cerebral arteries AND blood vessel prosthesis
3. vertebral AND angioplasty OR vertebral AND stent OR vertebral AND PTA OR vertebral AND revascularization OR vertebral AND revascularisation OR vertebral AND recanalisation OR vertebral AND recanalization OR vertebral AND recanaliation OR vertebral AND catheterisation OR vertebral AND dilatation OR vertebral AND endovascular procedures OR vertebral AND surgical OR vertebral AND blood vessel prosthesis
4. basilar AND angioplasty OR basilar AND stent OR basilar AND PTA OR basilar AND revascularization OR basilar AND revascularisation OR basilar AND recanalisation OR basilar AND recanalization OR basilar AND recanaliation OR basilar AND catheterisation OR basilar AND dilatation OR basilar AND endovascular procedures OR basilar AND vascular surgical procedures OR basilar AND blood vessel prosthesis

Data and analyses

Comparison 1. Primary outcome: short‐term death or stroke.

Outcome or subgroup title	No. of studies	No. of participants	Statistical method	Effect size
1.1 Short‐term death or stroke	4	989	Risk Ratio (M‐H, Fixed, 95% CI)	2.93 [1.81, 4.75]
1.2 Subgroup analysis: types of endovascular therapy	3	919	Risk Ratio (M‐H, Fixed, 95% CI)	2.93 [1.80, 4.78]
1.2.1 Self‐expandable stent plus CMT vs CMT alone	2	808	Risk Ratio (M‐H, Fixed, 95% CI)	2.51 [1.46, 4.32]
1.2.2 Balloon‐mounted stent plus CMT vs CMT alone	1	111	Risk Ratio (M‐H, Fixed, 95% CI)	5.18 [1.61, 16.68]
1.3 Subgroup analysis: time interval from qualifying event to intervention	4	989	Risk Ratio (M‐H, Fixed, 95% CI)	2.93 [1.81, 4.75]
1.3.1 3 weeks or less	2	562	Risk Ratio (M‐H, Fixed, 95% CI)	3.08 [1.80, 5.29]
1.3.2 More than 3 weeks	2	427	Risk Ratio (M‐H, Fixed, 95% CI)	2.37 [0.80, 7.05]

Comparison 2. Other outcomes.

Outcome or subgroup title	No. of studies	No. of participants	Statistical method	Effect size
2.1 Short‐term ipsilateral stroke	4	989	Risk Ratio (M‐H, Fixed, 95% CI)	3.26 [1.94, 5.48]
2.2 Short‐term ischaemic stroke	4	989	Risk Ratio (M‐H, Fixed, 95% CI)	2.24 [1.30, 3.87]
2.3 Short‐term haemorrhagic stroke	4	989	Risk Ratio (M‐H, Fixed, 95% CI)	13.49 [2.59, 70.15]
2.4 Short‐term TIA	3	344	Risk Ratio (M‐H, Fixed, 95% CI)	0.79 [0.30, 2.07]
2.5 Short‐term death	4	989	Risk Ratio (M‐H, Fixed, 95% CI)	5.43 [1.21, 24.40]
2.6 Long‐term death or stroke	4	970	Risk Ratio (M‐H, Fixed, 95% CI)	1.49 [1.12, 1.99]
2.7 Long‐term ipsilateral stroke	4	970	Risk Ratio (M‐H, Random, 95% CI)	1.78 [1.00, 3.17]
2.8 Long‐term ischaemic stroke	4	978	Risk Ratio (M‐H, Random, 95% CI)	1.56 [0.77, 3.16]
2.9 Long‐term haemorrhagic stroke	3	879	Risk Ratio (M‐H, Fixed, 95% CI)	7.81 [1.43, 42.59]
2.10 Long‐term TIA	3	335	Risk Ratio (M‐H, Fixed, 95% CI)	1.05 [0.50, 2.19]
2.11 Long‐term death	4	951	Risk Ratio (M‐H, Fixed, 95% CI)	1.61 [0.77, 3.38]
2.12 Long‐term dependency	4	947	Risk Ratio (M‐H, Fixed, 95% CI)	1.51 [0.93, 2.45]

Characteristics of studies

Characteristics of included studies [ordered by study ID]

Chimowitz 2011.

Study characteristics
Methods	Multicentre open‐label RCT with 3‐year follow‐up
Participants	Estimated sample size: 764 Number randomised: 451 Inclusion criteria Age 30–80 years TIA or non‐disabling ischaemic stroke (score on mRS ≤ 3) within 30 days Intracranial stenosis (70%–99%) in internal carotid artery, middle cerebral artery, vertebral artery, or basilar artery Target area of stenosis in an intracranial artery of normal diameter (2.00 mm–4.50 mm) and length < 14 mm Exclusion criteria Tandem extracranial or intracranial stenosis (70%–99%) or occlusion that is proximal or distal to the target intracranial lesion Bilateral intracranial vertebral artery stenosis of 70%–99% and uncertainty about which artery is symptomatic Endovascular therapy or endarterectomy of an extracranial or intracranial artery within 30 days Previous treatment of target lesion with a stent or other mechanical device Presence of intraluminal thrombus proximal to or at the target lesion Plan to perform concomitant angioplasty or stenting of an extracranial vessel tandem to an intracranial stenosis Presence of intraluminal thrombus proximal to or at the target lesion Any aneurysm proximal to or distal to stenotic intracranial artery Intracranial tumour (except meningioma) or any intracranial vascular malformation CT or angiographic evidence of severe calcification at target lesion Thrombolytic therapy within 24 hours prior to enrolment Progressive neurological signs within 24 hours prior to enrolment Brain infarct within previous 30 days of enrolment that is of sufficient size (> 5 cm) to be at risk of hemorrhagic conversion during or after stenting Any hemorrhagic infarct within 14 days prior to enrolment Any hemorrhagic infarct within 15–30 days that is associated with mass effect Any history of a primary intracerebral (parenchymal) haemorrhage (ICH) Any other intracranial haemorrhage (subarachnoid, subdural, epidural) within 30 days Any untreated chronic subdural haematoma > 5 mm in thickness Non‐athersclerotic stenosis
Interventions	ET plus CMT versus CMT alone
Outcomes	Primary outcomes Any stroke or death within 30 days after enrolment Any stroke or death within 30 days after a revascularisation procedure of the qualifying lesion during follow‐up Ischaemic stroke in the territory of the qualifying artery beyond 30 days Secondary outcomes Disabling stroke Any stroke or death Myocardial infarction Major non‐stroke haemorrhage (i.e. major systemic haemorrhage, subdural haemorrhage, epidural haemorrhage) Functional outcome at the end of follow‐up measured by Rankin Scale and BI Cognitive outcome at end of follow‐up measured by MoCA
Funding source	US National Institute of Neurological Disorders and Stroke
Notes	ClinicalTrials.gov identifier: NCT00576693
Risk of bias
Bias	Authors' judgement	Support for judgement
Random sequence generation (selection bias)	Low risk	Quote: "The sequence of treatment assignments are stratified by centre and produced at the Statistical Coordinating centre using a pseudo‐random number generator with randomly permuted block sizes."
Allocation concealment (selection bias)	Low risk	Quote: "Patients are randomized (1:1) to aggressive medical management alone or to PTAS plus aggressive medical management."  Comment: the study used software that carried out allocations in a closed environment, and nobody knew the allocation until after enrolment had been confirmed.
Blinding of participants and personnel (performance bias) All outcomes	High risk	As the 2 treatments were very different, blinding of participants and personnel was not possible.
Blinding of outcome assessment (detection bias) All outcomes	Low risk	Quote: "All potential endpoints are adjudicated by independent panels of neurologists and cardiologists who are unaware of treatment assignments."
Incomplete outcome data (attrition bias) All outcomes	Low risk	Incomplete outcome data adequately resolved and unlikely to seriously alter the results with ITT analysis.
Selective reporting (reporting bias)	Low risk	All study outcomes were prespecified in the published protocol.
Other bias	Low risk	Although the study was stopped early, the interim analysis already showed superiority of CMT over ET, and this result was unlikely to change.

Gao 2022.

Study characteristics
Methods	Multicentre, randomised, open‐label, outcome assessor‐blinded trial with 3‐year follow‐up
Participants	Estimated sample size: 380 Number randomised: 380 Inclusion criteria: Age 30–80 years TIA or non‐disabling ischaemic stroke (mRS < 3) within past 12 months Target vessel reference diameter 2.00 mm–4.50 mm; target stenosis < 14 mm in length. Intracranial stenosis (70%–99%) of a major intracranial artery supplying the territory of the ischaemic event.  Exclusion criteria Brainstem or basal ganglia perforator stroke (identified by DWI) < 3 weeks from latest ischaemic symptom onset Tandem extracranial or intracranial stenosis (70%–99%) or occlusion that is proximal or distal to the target intracranial lesion Bilateral intracranial vertebral artery stenosis of 70%–99% and uncertainty about which lesion is symptomatic Presence of a previously placed intravascular stent or graft in the ipsilateral distribution within 30 days Plan to perform concomitant angioplasty or stenting of an extracranial vessel tandem to an ipsilateral intracranial stenosis Presence of intraluminal thrombus proximal to or at the target lesion Intracranial tumours or any intracranial vascular malformations Any aneurysm proximal to or distal to intracranial stenotic artery CT or angiographic evidence of severe calcification at target lesion Thrombolytic therapy within 24 hours before enrolment Thrombolytic therapy within 24 hours before enrolment Stroke of sufficient size (> 5 cm on CT or MRI) to place patient at risk of hemorrhagic transformation during the procedure; hemorrhagic transformation of an ischaemic stroke within previous 15 days Previous spontaneous intracerebral (parenchymal) or other intracranial (subarachnoid, subdural, or epidural) haemorrhage within previous 30 days Untreated chronic subdural haematoma > 5 mm in thickness Myocardial infarction within previous 30 days
Interventions	ET plus CMT versus CMT alone
Outcomes	Primary endpoints Stroke and death within 30 days after enrolment Stroke in the territory of qualifying artery beyond 30 days through 1 year Secondary endpoints Disabling stroke or death after enrolment within 3 years Stroke in the qualifying artery territory within 2 years Stroke in the qualifying artery territory within 3 years Any stroke, TIA, or cardiovascular events within 3 years Death within 3 years
Funding source	Funded by a research grant (2011BAI08B04) from the National Health Commission of the People's Republic of China. Stryker Neurovascular provided supplemental funding for third‐party site monitoring and auditing.
Notes	ClinicalTrials.gov Identifier: NCT01763320
Risk of bias
Bias	Authors' judgement	Support for judgement
Random sequence generation (selection bias)	Low risk	Quote: "IVRS (Interactive Voice Response System, Clinicalsoft Company Limited) will be used for patient randomization."
Allocation concealment (selection bias)	Low risk	Quote: "Patients meeting the inclusion criteria will be randomized (1:1) to medical therapy alone or medical therapy plus stenting using Wingspan." Comment: the study used software that carried out allocations in a closed environment, and nobody knew the allocation until after enrolment had been confirmed.
Blinding of participants and personnel (performance bias) All outcomes	High risk	As the 2 treatments were very different, blinding of participants and personnel was not possible.
Blinding of outcome assessment (detection bias) All outcomes	Low risk	Quote: "An imaging database was established to facilitate central reading by an independent imaging core lab (IsCore Image Corelab)."
Incomplete outcome data (attrition bias) All outcomes	Low risk	Incomplete outcome data adequately resolved and unlikely to seriously alter the results with ITT analysis.
Selective reporting (reporting bias)	Low risk	All study outcomes were prespecified in the published protocol.
Other bias	High risk	The industry funding source may be a source of bias

Miao 2012.

Study characteristics
Methods	Single‐centre RCT with 1‐year follow‐up
Participants	Estimated sample size: 184 Number randomised: 70 Inclusion criteria Age 25–75 years TIA or stroke in the territory of unilateral MCA stenosis 70%–99% stenosis with stenotic length < 10 mm and distal vessel diameter > 2 mm.  mRS score < 3 NIHSS score < 15 Exclusion criteria Acute stroke in the target territory in previous 3 weeks Tandem ≥ 50% stenosis of target MCA Prior angioplasty or stenting at the target vessel Thrombolysis treatment within 24 hours before randomisation Non‐atherosclerotic stenosis
Interventions	ET plus CMT versus CMT alone
Outcomes	Primary outcomes  Ipsilateral stroke, TIA, or death at 30 days and 1 year Secondary outcomes None
Funding source	Funded by the Research Fund of Capital Medical Development (2007–2069).
Notes	Clinical Trial Registration URL: www.chictr.org/en/ Unique identifier: ChiCTR‐TRC‐12001989
Risk of bias
Bias	Authors' judgement	Support for judgement
Random sequence generation (selection bias)	Low risk	Quote: "The randomisation numbers were produced by Randlist software (Version 1.2 \Seed: [1497369600]; http://www.randomisation.net), 4 numbers as a block."
Allocation concealment (selection bias)	Low risk	Quote: "Patients were randomised to either the PTAS or medical group." Comment: the study used software that carried out allocations in a closed environment, and nobody knew the allocation until after enrolment had been confirmed.
Blinding of participants and personnel (performance bias) All outcomes	High risk	As the 2 treatments were very different, blinding of participants and personnel was not possible.
Blinding of outcome assessment (detection bias) All outcomes	Low risk	Quote: "Investigators who did not participate in the enrolment of the patients and were blinded to the treatment assignment..."
Incomplete outcome data (attrition bias) All outcomes	High risk	There was a high rate of loss to 1‐year follow‐up (49/70, 30%), and 19.4% of participants randomised to the ET group refused ET.
Selective reporting (reporting bias)	Low risk	All study outcomes were prespecified in the registered information.
Other bias	High risk	The study was stopped early; results of an interim analysis showed similar safety and efficacy for CMT and ET. However, the final results could have changed if recruitment had continued.

Zaidat 2015.

Study characteristics
Methods	Multicentre RCT with 1‐year follow‐up
Participants	Estimated sample size: 250 Number randomised: 112 Inclusion criteria Age 18–85 years ≥ 1 symptomatic neurovascular lesion (70%–90% stenosis) Hard TIA or stroke attributable to the territory of the lesion within the past 30 days (specific territories not reported) mRS score ≤3 Exclusion criteria Previous coil or clip placed in territory of target lesion within previous 6 months Myocardial infarction within previous 3 months Treatment with tissue plasminogen activator or other thrombolytic agent within 48 hours prior to randomisation Major surgery or trauma within 2 weeks prior to randomisation > 2 lesions with > 50% stenosis CT or MRI evidence of intracranial haemorrhage, subdural or epidural haemorrhage, or tumour Non‐atherosclerotic stenosis
Interventions	ET plus CMT versus CMT alone
Outcomes	Primary endpoints Stroke in the same territory (distal to the target lesion) as the presenting event within 12 months of randomisation Hard TIA in the same territory (distal to the target lesion) as the presenting event from day 2–month 12 postrandomisation Secondary endpoints Stent success, defined as deployment of the PHAROS Vitesse stent across the target lesion with residual stenosis of 0%–20% Percentage of stent group participants with any (symptomatic or asymptomatic) in‐stent stenosis (≥ 70%) confirmed by angiogram at 12 months Percentage of stent group participants with symptomatic in‐stent restenosis (≥ 70%) confirmed by angiogram at 12 months Percentage of medical therapy group participants with interventional procedure (e.g. angioplasty or stent) at 12 months NIHSS score mRS score
Funding source	Initiated and funded by Micrus Endovascular
Notes	ClinicalTrials.gov identifier: NCT00816166
Risk of bias
Bias	Authors' judgement	Support for judgement
Random sequence generation (selection bias)	Low risk	Quote: "Patients meeting the final enrolment criteria after angiogram were randomly assigned 1:1 to either treatment with medical therapy alone or to medical therapy and PHAROS Vitesse neurovascular stent by a telephonic interactive voice response system (BioClinica Inc, Newtown, PA, USA). Randomisation was stratified by 2 factors: enrolment site and age (18–55 versus 56–85 years)..."
Allocation concealment (selection bias)	Low risk	Quote: "Patients meeting the final enrolment criteria after angiogram were randomly assigned 1:1 to either treatment with medical therapy alone or to medical therapy and PHAROS Vitesse neurovascular stent by a telephonic interactive voice response system (BioClinica Inc, Newtown, PA, USA). Randomisation was stratified by 2 factors: enrolment site and age (18–55 versus 56–85 years)..." Comment: the study used software that carried out allocations in a closed environment, and nobody knew the allocation until after enrolment had been confirmed.
Blinding of participants and personnel (performance bias) All outcomes	High risk	Quote: "The current trial was not double‐blinded due to the lack of feasibility of masking the stent group..."
Blinding of outcome assessment (detection bias) All outcomes	Low risk	Quote: "... end point assessment by an independent neurologist who was not involved in the procedure reduced potential bias..."
Incomplete outcome data (attrition bias) All outcomes	Low risk	Incomplete outcome data adequately resolved and unlikely to seriously alter the results with ITT analysis.
Selective reporting (reporting bias)	Low risk	All study outcomes were prespecified in the published protocol.
Other bias	High risk	Although the study was stopped early, the interim analysis showed superiority of CMT over ET and this result was unlikely to change. The industry funding source may be a source of bias.

BI: Barthel Index; CMT: conventional medical treatment; CT: computed tomography; DWI: diffusion‐weighted imaging; ET: endovascular therapy; ITT: intention‐to‐treat; MCA: middle cerebral artery; MoCA: Montreal Cognitive Assessment; mRS: modified Rankin Scale; NIHSS: National Institutes of Health Stroke Scale; PTAS: percutaneous transluminal angioplasty and stenting; RCT: randomised controlled trial; TIA: transient ischaemic attack.

Characteristics of excluded studies [ordered by study ID]

Study	Reason for exclusion
Compter 2015	The trial recruited 115 people with vertebral atherosclerotic stenosis, but only 16.5% of participants had intracranial vertebral stenosis, and we were unable to obtain detailed data for these participants.
Coward 2007	The trial enroled only 16 people with vertebral atherosclerosis, including the extracranial and intracranial artery, to compare ET versus best medical treatment. We were unable to obtain detailed data for the participants with ICAS.
Markus 2017	The trial recruited 179 people with vertebral atherosclerotic stenosis, but only 17.3% of participants had intracranial vertebral stenosis, and we were unable to obtain detailed data for these participants.

ET: endovascular therapy; ICAS: intracranial artery stenosis.

Characteristics of ongoing studies [ordered by study ID]

Cui 2016.

Study name	Angioplasty and stenting for patients with symptomatic intracranial atherosclerosis
Methods	Multicentre randomised trial in 3 high‐volume centres
Participants	Estimated sample size: 539 Inclusion criteria Age 40–70 years ≥ 3 TIAs or 1 ischaemic stroke 70%–99% stenosis of intracranial carotid artery or MCA under maximal dosage of medical management Cerebral hypoperfusion in the territory of target vessels Exclusion criteria CT or MRI evidence of massive cerebral infarction Cerebral infarction caused by perforator occlusion Previous stent or angioplasty in the target lesion Progressive neurological signs within 24 hours before enrolment Haemorrhagic infarction within 14 days before enrolment Cardiac source of embolus Thrombolytic therapy within 24 hours before enrolment Intraluminal thrombus proximal to or at the target lesion Myocardial infarction within 30 days before enrolment Non‐atherosclerotic stenosis
Interventions	PTAS plus aggressive medical management after ≥ 3 weeks versus aggressive medical management alone
Outcomes	Primary outcome Incidence of ipsilateral stroke (including haemorrhagic or ischaemic stroke) or death at 30 days after randomisation Secondary outcomes Incidence of recurrent ischaemic stroke in the stenting‐involved vascular territory at 30 days, 3 months, and 12 months after randomisation Rate of participants with residual stenosis < 30% at 3 and 12 months after randomisation Incidence of in‐stent restenosis at 12 months after randomisation Incidence of cerebral parenchymal, subarachnoid, or intraventricular haemorrhage at 30 days, 3 months, and 12 months after randomisation Incidence of myocardial infarction or major non‐stroke haemorrhage (epidural or subdural haemorrhage or haemorrhage in major organs) at 30 days after randomisation C‐NIHSS: 28; mRS: 29; and CSQoL30 at 30 days, 3 months, and 12 months after randomisation
Starting date	April 2016
Contact information	ClinicalTrials.gov identifier: NCT02689037. More details in the published protocol: DOI: 10.1136/bmjopen‐2016‐012175
Notes	This study is financially supported by a Health Research Fund from People's Liberation Army (No. 12MA100). The study sponsor and funders play no role in study design, collection, management, analysis, and interpretation of data, writing of the report, or the decision to submit the report for publication.

Yang 2018.

Study name	A randomised trial of Stenting for Symptomatic Intracranial Stenosis
Methods	Multicentre randomised trial in 22 research settings
Participants	Estimated sample size: 704 Inclusion criteria Age 18–80 years TIA or ischaemic stroke in past 90 days 70%–99% ICAS Cerebral hypoperfusion in the territory of target vessels Lesion length ≤ 15 mm, target vessel diameter ≥ 2.0 mm Exclusion criteria Acute ischaemic stroke in previous 3 weeks Perforator artery stroke > 50% stenosis or occlusion of serial extracranial or intracranial vessels at the proximal or distal end of the target vessel Non‐atherosclerotic intracranial stenosis Severe calcification at target lesion Concomitant intracranial tumour, aneurysm or arteriovenous malformation Myocardial infarction within previous 30 days
Interventions	PTAS plus aggressive medical management after ≥ 3 weeks versus aggressive medical management alone
Outcomes	Primary outcomes Target vessel stroke event within 30 days TIA within 30 days Mortality rate within 30 days Secondary outcomes: Stroke event, TIA, and mortality rate within 6 and 12 months Procedural complications Stent restenosis (> 50%) within 1 year of follow‐up NIHSS score, mRS score, BI score, EQ‐5D scale score within 1 year of follow‐up Cardiovascular events related to stent or drug therapy within 1 year of follow‐up Compliance with medication within 1 year of follow‐up Incidence of non‐haemorrhagic adverse events
Starting date	May 2018
Contact information	ChiCTR1800015766 with URL www.chictr.org.cn/showproj.aspx?proj=26742
Notes	This study is self‐financed.

BI: Barthel Index; C‐NIHSS: Chinese version of National Institutes of Health Stroke Scale; EQ‐5D: EuroQol five‐dimension questionnaire; ICAS: intracranial artery stenosis; MCA: middle cerebral artery; mRS: modified Rankin Scale; NIHSS: National Institutes of Health Stroke Scale; PTAS: percutaneous transluminal angioplasty and stenting; TIA: transient ischaemic attack.

Differences between protocol and review

None (Wang 2019).

Contributions of authors

JL, TW, and KY contributed equally to this review.
JL, TW, XW, and LJ drafted the protocol.
JL, TW, and XW developed the search strategy.
JL, XW, RX, and HG searched for trials.
XZ and JW obtained copies of relevant references.
JL, TW, RY, and YM selected trials.
JL, KY, and PG extracted and entered data.
JL, TW, KY, PG, YM, and LJ analysed the data, interpreted the results, and wrote the final review.

Sources of support

Internal sources

• No sources of support provided

External sources

• No sources of support provided

Declarations of interest

JL: none
TW: none
KY: none
XW: none
RX: none
HG: none
XZ: none
JW: none
RY: none
PG: none
YM: none
LJ: none

Joint first author

New search for studies and content updated (no change to conclusions)