Global Perspectives on Endovascular Treatment of Intracranial Atherosclerotic Disease

Abstract

Intracranial atherosclerotic disease (ICAD) is one of the important causes of ischemic stroke worldwide. With advances in patient selection, perioperative management, and endovascular device technology, endovascular therapy (EVT) has become an important research focus in ICAD as a potential adjunctive treatment strategy. This review summarizes the current global status of ICAD management, with particular attention to regional differences in epidemiological characteristics, endovascular treatment strategies, and perioperative medical management. This review may help improve understanding of the evolving treatment strategies and regional differences in ICAD management and provide references for future precision-based and individualized neurointerventional therapy.

Introduction

Intracranial atherosclerotic disease (ICAD) is one of the leading causes of ischemic stroke worldwide and contributes substantially to the global cerebrovascular disease burden.^1–3) Despite contemporary standard medical therapy, the annual risk of recurrent stroke in patients with symptomatic ICAD remains as high as 15%–20% in certain high-risk populations.^4–7) Consequently, endovascular therapy (EVT) has emerged as a potential adjunctive treatment strategy for medically refractory ICAD and has become a major focus of contemporary neurointerventional research.^8,9)

Importantly, substantial regional differences exist in the epidemiology, vascular risk factor profiles, healthcare systems, and clinical management paradigms of ICAD. These disparities may significantly influence the indications, procedural strategies, and clinical outcomes of endovascular intervention. Therefore, a comprehensive global overview of ICAD epidemiology and regional therapeutic strategies is essential for optimizing individualized treatment approaches. It should be emphasized that the EVT discussed in this review refers to elective or subacute interventions for secondary prevention in symptomatic ICAD and does not include emergent mechanical thrombectomy performed for acute ICAD-related large vessel occlusion.

ICAD-related ischemic stroke can be broadly categorized into thrombotic, embolic, and hemodynamic mechanisms according to the National Institute of Neurological Disorders and Stroke classification. EVT may exert therapeutic effects by enlarging the stenotic lumen, modifying atherosclerotic plaque, reducing local thrombogenic flow disturbances, and improving distal cerebral perfusion, thereby addressing both embolic and hemodynamic components of ischemia.

This narrative review was based on a comprehensive literature search of PubMed and Web of Science databases. Relevant studies published in English were identified using combinations of the keywords “intracranial atherosclerotic disease,” “intracranial stenosis,” “endovascular therapy,” “angioplasty,” “stenting,” “drug-coated balloon,” and “stroke prevention.” Randomized controlled trials (RCTs), observational studies, registries, guidelines, and expert consensus documents were reviewed and selected according to their relevance to ICAD management and regional treatment practices in Asia, Europe, and North America. Given the narrative nature of this review, formal systematic review methodology and meta-analytic procedures were not applied.

Epidemiological Characteristics and Regional Differences of ICAD

ICAD demonstrates marked geographic and ethnic heterogeneity worldwide. In Asian populations, ICAD accounts for approximately 30%–50% of ischemic stroke etiologies. In China, the prevalence of ICAD among patients with ischemic stroke or transient ischemic attack (TIA) has been reported to reach 46.6%.¹⁰⁾ In contrast, ICAD accounts for only approximately 8%–10% of ischemic strokes in North American and European populations.^11,12) These regional disparities likely reflect a complex interplay of genetic predisposition, metabolic risk factors, environmental exposure, dietary habits, and healthcare accessibility.^13,14) Genetic susceptibility may contribute to the higher prevalence of ICAD observed in East Asian populations. Variants associated with lipid metabolism, endothelial dysfunction, vascular remodeling, and inflammatory pathways have been proposed as potential contributors to intracranial atherosclerosis, although the precise mechanisms remain incompletely understood. In particular, hypertension, metabolic syndrome, insulin resistance, and dyslipidemia appear to contribute substantially to the disproportionately high burden of ICAD observed in Asian populations.

First, the prevalence of ICAD varies considerably among different ethnic groups. Asian, African American, and Hispanic populations are recognized as high-risk groups for ICAD. Among patients with ischemic stroke, ICAD accounts for approximately 30%–50% in Asians, 15%–30% in African American and Hispanic populations, and only 5%–10% in White populations.¹⁵⁾

Second, lifestyle-related factors may also contribute significantly to these regional differences. High-salt dietary habits are more prevalent in Asian populations, whereas Western populations are more frequently affected by high-fat diets and alcohol consumption. Excessive sodium intake has been associated with an increased risk of ICAD.¹⁶⁾

Third, inadequate control of hypertension, obesity, diabetes mellitus, and metabolic syndrome in certain Asian and American populations may further increase the incidence of ICAD.¹⁷⁾

Overall, ICAD exhibits a characteristic epidemiological pattern of “high prevalence in Asia and relatively lower prevalence in Western countries.” These epidemiological differences not only influence the natural history of the disease but also largely determine regional variations in treatment paradigms and endovascular practice patterns.

Regional Differences in Endovascular Treatment Strategies for Symptomatic ICAD

Evolution of therapeutic strategies for symptomatic ICAD

The therapeutic paradigm of symptomatic ICAD has undergone a substantial shift from routine stenting toward aggressive medical management, followed more recently by a selective reappraisal of EVT in carefully selected patients. This paradigm shift has largely been driven by advances in patient selection, procedural standardization, and improved understanding of lesion-specific heterogeneity.

The Stenting and Aggressive Medical Management for Preventing Recurrent Stroke in Intracranial Stenosis (SAMMPRIS)⁵⁾ and Vitesse Intracranial Stent Study for Ischemic Therapy (VISSIT)⁶⁾ RCTs demonstrated that intracranial stenting was associated with a significantly higher risk of periprocedural stroke or death compared with aggressive medical management. Consequently, aggressive best medical treatment (BMT) has become the cornerstone of ICAD management.

However, subsequent studies incorporating stricter patient selection criteria and standardized procedural techniques have shown improved safety profiles for EVT. The China Angioplasty and Stenting for Symptomatic Intracranial Severe Stenosis (CASSISS) trial⁹⁾ demonstrated that carefully selected patients with symptomatic severe ICAD could undergo endovascular treatment with substantially reduced periprocedural complications.

Subsequently, the Balloon Angioplasty for Symptomatic Intracranial Artery Stenosis (BASIS) trial⁸⁾ showed that balloon angioplasty performed under standardized procedural protocols and strict indications achieved favorable safety and efficacy outcomes. More recently, the Drug-coated Balloon for Endovascular Treatment of Symptomatic Intracranial Stenotic Disease (DR.BEYOND) trial¹⁸⁾ suggested that drug-coated balloons (DCBs) may reduce restenosis rates compared with conventional bare-metal stents. However, further validation from larger studies is required before DCBs can be considered a standard treatment option for ICAD. The growing interest in DCB technology is also partly driven by the emerging “leave nothing behind” concept, which aims to minimize permanent intracranial implants and potentially reduce chronic inflammatory response, in-stent restenosis, and long-term thrombogenicity. A summary of the above RCTs is provided in Fig. 1.

Fig. 1. Evolution of endovascular treatment strategies for ICAD.

ICAD, intracranial atherosclerotic disease

Beyond the degree of stenosis and recurrent ischemic symptoms, cerebral hemodynamic status may also be important when selecting candidates for EVT. Similar to extracranial–intracranial bypass surgery, assessment of cerebral perfusion using CT perfusion, magnetic resonance perfusion, positron emission tomography, or cerebrovascular reserve testing may help identify patients with hemodynamically significant stenosis who remain at high risk despite aggressive medical therapy. Although routine hemodynamic assessment before EVT has not been standardized, such evaluations may provide additional information for individualized treatment decisions.

Regional variations in ICAD treatment strategies

Asian region

In Asia, EVT has been increasingly adopted in clinical practice. Japanese neurointerventional practice generally emphasizes a careful balance between procedural risk and therapeutic benefit. Aggressive medical therapy remains the cornerstone of management, while EVT is typically reserved for highly selected patients with medically refractory symptomatic ICAD despite optimized BMT.¹⁹⁾

Nevertheless, intracranial balloon angioplasty and stenting have been selectively performed in carefully chosen high-risk ICAD patients in Japan. However, according to the Japan Stroke Society Guideline 2021,²⁰⁾ the effectiveness of percutaneous transluminal angioplasty and stenting for symptomatic intracranial arterial stenosis remains not well established, and these procedures are generally reserved for medically refractory cases in experienced centers.

In China, a more proactive interventional strategy has gradually emerged. The CASSISS trial demonstrated that rigorous patient selection and procedural standardization could significantly reduce periprocedural complications and improve the safety profile of intracranial stenting. The BASIS trial further supported the safety and efficacy of balloon angioplasty for symptomatic ICAD.

In addition, the DR.BEYOND trial reported lower restenosis rates with DCB treatment compared with conventional stenting. Nevertheless, the current evidence remains limited, and further studies are required to define the role of DCBs in routine clinical practice.

European region

In Europe, aggressive BMT remains the primary treatment strategy for symptomatic ICAD. RCTs, represented by SAMMPRIS, demonstrated significantly higher periprocedural stroke and mortality rates in the stenting arm compared with aggressive medical management.

Based on these findings, the 2022 European Stroke Organisation guidelines²¹⁾ do not recommend angioplasty or stenting as first-line therapy for symptomatic intracranial arterial stenosis. Instead, EVT is considered only in highly selected patients who fail optimized medical therapy.

European practice is therefore largely guideline-driven and emphasizes procedural caution, evidence-based management, and strict patient selection.

North American region

In North America, treatment paradigms for ICAD have largely been shaped by the SAMMPRIS and VISSIT trials, both of which favored aggressive medical management over routine EVT. Current American Heart Association/American Stroke Association (AHA/ASA) guidelines⁴⁾ similarly recommend optimized medical therapy as the first-line treatment approach.

However, with advances in patient selection and procedural standardization, more recent studies have re-evaluated the role of EVT. The Wingspan Stent System Post Market Surveillance (WEAVE) trial²²⁾ demonstrated markedly reduced periprocedural complication rates with Wingspan (Stryker Neurovascular, Fremont, CA, USA) stenting when strict on-label indications and standardized techniques were applied.

Subsequently, the Wingspan One-year Vascular Events and Neurologic Outcomes (WOVEN) trial²³⁾ reported a 1-year stroke or death rate of approximately 8.5%, suggesting acceptable long-term safety and efficacy in carefully selected patients.

Overall, regional differences in ICAD intervention can be summarized in Table 1. Briefly, Asian countries emphasize technical innovation and proactive intervention, European practice is more guideline-driven and conservative, whereas North American practice is transitioning from a historically conservative approach toward more optimized and selective intervention strategies.

Table 1. Regional differences in endovascular treatment strategies for ICAD.

Characteristics	Asian region	European region	North American region
Representative countries	China, Japan	European countries under the ESO system	United States
Major supporting studies	CASSISS9), BASIS8), DR.BEYOND18)	SAMMPRIS5), ESO Guidelines21)	SAMMPRIS5), VISSIT6), WEAVE22), WOVEN23)
Preferred first-line strategy	Selective EVT + aggressive BMT	Aggressive BMT	Aggressive BMT
EVT philosophy	Proactive and innovation-oriented	Conservative and guideline-driven	Selective reappraisal of EVT
Typical candidates	Medically refractory severe ICAD	Recurrent ischemic events despite BMT	Severe symptomatic ICAD under strict indications
Representative devices	DCBs, balloon angioplasty systems, Wingspan	Conventional balloons and stents	Wingspan stent
Antiplatelet preference	DAPT ± cilostazol	Standard DAPT	Aspirin + clopidogrel
Emerging trends	DCB and “leave nothing behind” strategy	Precision patient selection	Standardized EVT protocols
Main findings	Improved safety after strict selection; lower restenosis with DCB	Aggressive medical therapy superior to routine stenting	Improved EVT safety under standardized protocols

BASIS, Balloon Angioplasty for Symptomatic Intracranial Artery Stenosis; BMT, best medical treatment; CASSISS, China Angioplasty and Stenting for Symptomatic Intracranial Severe Stenosis; DAPT, dual antiplatelet therapy; DCB, drug-coated balloon; DR.BEYOND, Drug-coated Balloon for Endovascular Treatment of Symptomatic Intracranial Stenotic Disease; ESO, European Stroke Organisation; EVT, endovascular therapy; ICAD, intracranial atherosclerotic disease; SAMMPRIS, Stenting and Aggressive Medical Management for Preventing Recurrent Stroke in Intracranial Stenosis; VISSIT, Vitesse Intracranial Stent Study for Ischemic Therapy; WEAVE, Wingspan Stent System Post Market Surveillance; Wingspan, Stryker Neurovascular, Fremont, CA, USA; WOVEN, Wingspan One-year Vascular Events and Neurologic Outcomes

Periprocedural Medical Management

Although substantial regional differences exist in interventional strategies and device selection, periprocedural medical management universally focuses on antiplatelet therapy, intensive lipid-lowering, and blood pressure control. The primary goals are to minimize thromboembolic complications, reduce restenosis risk, and avoid hemodynamic complications related to hypo- or hyperperfusion.

Antiplatelet therapy

Antiplatelet therapy remains the cornerstone of secondary stroke prevention in symptomatic ICAD. Current international guidelines generally recommend short-term dual antiplatelet therapy (DAPT) followed by long-term single antiplatelet therapy in high-risk patients with recent stroke or TIA.^24,25)

Regional differences in antiplatelet strategies are evident. Asian practice tends to favor more intensive antiplatelet regimens because of the high prevalence of ICAD. In addition to aspirin and clopidogrel, cilostazol is widely utilized in several Asian countries owing to its potentially lower hemorrhagic risk and inhibitory effect on neointimal hyperplasia.

In addition, CYP2C19 loss-of-function polymorphisms, which are more prevalent in Asian populations, may contribute to clopidogrel hyporesponsiveness and increased thromboembolic risk. This genetic background has stimulated growing interest in individualized antiplatelet strategies, including platelet function testing and alternative agents such as cilostazol or ticagrelor. Cilostazol is widely used in several Asian countries, particularly Japan and Korea.²⁰⁾ In addition to its antiplatelet effects, cilostazol may inhibit smooth muscle proliferation and may be associated with a lower risk of hemorrhagic complications compared with some alternative antiplatelet agents.

It is important to recognize that the availability of antiplatelet and antithrombotic agents varies across Asian countries. For example, in Japan, intravenous P2Y12 inhibitors such as cangrelor and glycoprotein IIb/IIIa inhibitors such as tirofiban are not approved. These regulatory differences may influence peri-procedural pharmacological strategies and contribute to a more cautious approach toward intracranial stenting.

European guidelines generally recommend aspirin plus clopidogrel for 90 days, followed by long-term monotherapy. In North America, the 2022 American Academy of Neurology (AAN) guideline²⁶⁾ recommends aspirin 325 mg/day combined with clopidogrel 75 mg/day for up to 90 days in patients with severe (70%–99%) symptomatic intracranial stenosis and low hemorrhagic risk.

Lipid-lowering therapy

High-intensity statin therapy is a fundamental component of ICAD management. Beyond low-density lipoprotein cholesterol (LDL-C) reduction, statins may stabilize atherosclerotic plaques and improve endothelial function, thereby reducing recurrent stroke risk.

In Asia, moderate- to high-intensity statin therapy is commonly initiated and subsequently individualized according to body weight, hepatic and renal function, and tolerability. A Chinese randomized study suggested that intensive statin therapy may improve cerebral perfusion and clinical outcomes in patients with intracranial arterial stenosis.²⁷⁾

European guidelines generally advocate more aggressive LDL-C targets, with some recommendations suggesting LDL-C levels below 55 mg/dL in very high-risk patients. In North America, both the AAN²⁶⁾ and AHA/ASA guidelines⁴⁾ emphasize high-intensity statin therapy with LDL-C targets below 70 mg/dL.

Blood pressure management

Blood pressure control is another essential component of comprehensive ICAD management. Although strict blood pressure reduction is generally recommended to prevent recurrent cerebrovascular events, excessive lowering may exacerbate distal hypoperfusion in patients with severe stenosis or impaired collateral circulation.

Therefore, an individualized balance between recurrent stroke prevention and maintenance of cerebral perfusion is critical.

Chinese guidelines typically recommend maintaining blood pressure below 140/90 mmHg, with stricter targets for patients with diabetes mellitus or other high-risk conditions. Japanese practice places greater emphasis on avoiding excessive blood pressure reduction in patients with severe stenosis or hemodynamic compromise.

European guidelines generally favor more aggressive targets below 130/80 mmHg during secondary stroke prevention. In North America, both the AHA/ASA and AAN guidelines^4,26) recommend long-term blood pressure control below 140/90 mmHg.

Overall, periprocedural medical management of ICAD has reached broad consensus worldwide, with short-term DAPT, intensive lipid lowering, and optimized blood pressure control serving as the core therapeutic strategies.

In addition to long-term blood pressure control, careful peri-procedural blood pressure management is essential after ICAD revascularization. Restoration of blood flow through a previously severe stenotic intracranial artery may increase the risk of cerebral hyperperfusion syndrome, particularly in patients with impaired cerebrovascular autoregulation and chronic hypoperfusion. Although the incidence of hyperperfusion syndrome after ICAD-EVT is not well established, strict postoperative blood pressure monitoring and individualized hemodynamic management are recommended, similar to the management strategies employed after carotid endarterectomy and carotid artery stenting.

Future Directions of EVT for ICAD

With the accumulation of evidence and continued advances in neurointerventional techniques, ICAD treatment paradigms are evolving from empiric intervention toward precision-based patient selection and individualized therapeutic strategies. The CASSISS,⁹⁾ BASIS,⁸⁾ and DR.BEYOND trials¹⁸⁾ collectively suggest that the critical issue is no longer simply whether intervention should be performed, but rather which patients are most likely to benefit and which endovascular modality is most appropriate.²⁸⁾ Increasing evidence suggests that ICAD is not a homogeneous disease entity but rather a spectrum of lesions with distinct hemodynamic, inflammatory, and plaque vulnerability characteristics. Therefore, future treatment strategies will likely rely more heavily on lesion-specific and patient-specific risk stratification.

Advanced multimodal imaging techniques, including high-resolution vessel wall MRI, perfusion imaging, plaque enhancement assessment, and computational hemodynamic analysis, may further facilitate precision-based patient selection for EVT. In addition, individualized antiplatelet strategies based on platelet reactivity, CYP2C19 genotype, and hemorrhagic risk may further optimize procedural safety and long-term outcomes. Future developments are also expected to focus on next-generation intracranial devices, including DCB technology, low-profile self-expanding stents, and bioresorbable scaffolds. Ultimately, large-scale multicenter studies and standardized outcome assessment systems will be essential for improving interstudy comparability and establishing more robust evidence-based treatment paradigms for symptomatic ICAD.

Conclusion

ICAD is a major cause of ischemic stroke worldwide, with substantial regional differences in epidemiology, treatment paradigms, and clinical management. With the emergence of contemporary evidence and advances in neurointerventional technology, EVT has gradually evolved from a controversial strategy to a selectively applied treatment option in carefully selected patients. Collectively, these advances indicate that ICAD management is progressively transitioning from an empiric “one-size-fits-all” approach toward a precision medicine paradigm integrating imaging biomarkers, individualized medical therapy, and tailored endovascular strategies. Further advances in evidence-based medicine, device technology, and precision neurointervention are expected to improve long-term clinical outcomes while maintaining procedural safety.

Funding Statement

This study was supported by the Laboratory for Clinical Medicine, Capital Medical University, Beijing, China (Grant No. 2024504036, Capital Medical University Document No. [2023]175).

Author Contributions

Huachen Zhang and Xiaochuan Huo contributed to the conception and design of the review.

Huachen Zhang drafted the manuscript.

Yiwen Xu contributed to the literature collection, interpretation of evidence, and critical revision of the manuscript.

Xiaochuan Huo supervised the study and critically revised the manuscript for important intellectual content.

All authors approved the final version of the manuscript.

Disclosure Statement

All authors declare that they have no conflict of interests.