Intracranial Atherosclerosis Treatment: Past, Present, and Future

Introduction

Intracranial atherosclerotic disease (ICAD) is a leading cause of ischemic stroke in the United States and the most common cause of stroke worldwide (31009344). Risk factors for symptomatic and asymptomatic ICAD include age, Asian and Black race, hypertension, diabetes mellitus, hyperlipidemia, metabolic syndrome, sedentary lifestyle, and smoking (28154100). The mechanisms of stroke in ICAD include artery to artery embolization, perforator disease, and impaired distal perfusion. (31009344) Over the years advances in diagnosis and treatment of ICAD (Figure 1) have led to a reduction in stroke rates (28154100), but it has the highest risk of recurrent stroke of any of the major ischemic stroke subtypes (21899409, 28679857) reaching as high as 12% in the first year despite optimal medical treatment (21899409). Therefore, it is imperative to improve stroke prevention strategies. This review aims to cover the evolution of past, current, and potential future treatment options based on major trials and guidelines.

Figure 1.

Timeline of major advances and trials for intracranial atherosclerotic disease.

Medical Treatments

Antithrombotic therapy

Antithrombotic therapy is an important treatment in patients with ICAD. Aspirin is the most widely used antiplatelet agent, however in patients with symptomatic ICAD, aspirin monotherapy was associated with a relatively high rate of recurrent stroke (16186524). The Warfarin-Aspirin Symptomatic Intracranial Disease (WASID) trials showed no difference in recurrent stroke or death at 2 years between warfarin and aspirin (Table 1) for patients with ICAD causing 50–99% stenosis. The rate of recurrent stroke was similar between randomization arms but the warfarin arm had a significantly higher rate of death at a median of 2 years of follow-up when compared to the aspirin arm (9.7% versus 4.3%) and significantly more major hemorrhage (8.3% versus 3.2%). (15800226) Following WASID, antiplatelet therapy has been standard of care for ICAD, although the newer, and safer, direct oral anticoagulants (DOAC) have not yet been studied in ICAD patients.

Table 1.

Completed and ongoing clinical trials testing medical and interventional treatments for ICAD.

Trial	Location	Intervention	Outcome	Sample size	Completion
International Cooperative Study of Extracranial/Intracranial Arterial Anastomosis (EC/IC Bypass)	North America, Europe, Asia	STA-MCA bypass surgery versus medical management	Surgery resulted in more strokes and adverse events	1377	1985
Comparison of Warfarin and Aspirin for Symptomatic Intracranial Atherosclerosis (WASID)	North America	Warfarin versus aspirin	Warfarin nonsuperior for stroke prevention and harmful	569	2005
Stenting versus Aggressive Medical Management for Intracranial Atherosclerosis (SAMMPRIS)	United States	Stenting versus medical management	Stenting resulted in more strokes and death	451	2011
Stenting versus Medical Treatment in Patients with Symptomatic Vertebral Artery Stenosis (VAST)	Holland	Stenting versus medical management	Stenting did not lower risk of stroke and more adverse events	115	2015
Effect of a Balloon-Expandable Intracranial Stent vs Medical Therapy on Risk of Stroke in Patients With Symptomatic Intracranial Stenosis (VISSIT)	United States. China, Europe	Stenting versus medical management	Stenting resulted in more strokes and death	112	2015
Stenting for Symptomatic Vertebral Artery Stenosis: The Vertebral Artery Ischaemia Trial (VIST)	United Kingdom	Stenting versus medical management	Stenting did not lower risk of stroke	182	2017
Surgical Indirect Revascularization For Symptomatic Intracranial Arterial Stenosis (ERSIAS)	United States	Single arm of EDAS surgery	EDAS had lower rate of recurrent stroke than historical controls	52	2018
Remote Ischemic Conditioning for Avoiding Recurrence of Symptomatic Intracranial Atherosclerotic Stenosis (sICAS)	China	Remote limb ischemic device versus sham	PENDING Ischemic stroke	3000	2019
The Effect of InTensive Statin in Ischemic Stroke With inTracranialAtherosclerotic Plaques (INSIST-HRMRI)	China	Routine dose versus high dose statin	PENDING Change in remodeling index, plaque burden, and composition	100	2021
PCSK9 Inhibition in Patients With Symptomatic Intracranial Atherosclerosis (PINNACLE)	United States	PCSK9 inhibitor versus placebo	PENDING Change in stenosis and plaque volume	40	2022

Dual antiplatelet therapy in patients with symptomatic ICAD for 90 days was used in the Stenting and Aggressive Medical Therapy for Preventing Recurrent Stroke in Intracranial Stenosis (SAMMPRIS) trial, which demonstrated a lower rate of recurrent stroke in ICAD patients with 70–99% stenosis compared to historical controls (21899409). While this effect has also been attributed to risk factor control and lifestyle modifications (28003500), there is additional evidence that suggests the dual antiplatelet reduced the risk of stroke recurrence. The Clopidogrel with Aspirin in Acute Minor Stroke or Transient Ischemic Attack (CHANCE) trial studied dual antithrombotic therapy in patients with minor stroke or transient ischemic attack. A secondary analysis of 608 patients enrolled in CHANCE with evidence of intracranial stenosis on MRA showed a trend towards fewer events with dual antithrombotic therapy versus aspirin (HR 0.79 95% CI 0.47–1.32) (26330567). In this study, however, some of the vascular lesions may have been asymptomatic and therefore the efficacy of short-term DAPT in those with symptomatic ICAD is not well established. Based on SAMMPRIS, the current AHA guideline for secondary stroke prevention specify that for patients with recent stroke or TIA (within 30 days) that is attributed to severe stenosis (70–99%) of a major intracranial artery, DAPT for 90 days might be reasonable (24788967).

Additional studies are needed to determine the optimal antithrombotic therapy and duration in ICAD patients. In particular, studies are needed to test the benefit of adding a low-dose DOAC to antiplatelet therapy, similar to studies in coronary atherosclerosis patients (29132879). Another outstanding question is if replacing clopidogrel with ticagrelor in patients with clopidogrel resistance is beneficial, or if other antiplatelet therapies, such as cilostazol or prasugrel, could have synergistic effects with aspirin.

Risk factor modification

Promotion of a healthy lifestyle is essential for primary and secondary stroke prevention including smoking cessation, adequate physical activity, and implementation of healthy dietary habits (24788967). Furthermore, hypertension, diabetes, and elevated cholesterol levels are important risk factors for ischemic stroke. Health care providers need to work with patients to achieve target levels for these risk factors. In patients with symptomatic ICAD, the effect of lifestyle modifications and risk factor control (BP goal < 140/90 mm Hg (< 130/80 if diabetic), LDL < 70 mg / dl, and diabetes control) were hypothesized to be the most effective in reducing recurrence risk highlighting the importance of these factors over antithrombotic therapy (28003500). However, a post-hic analysis of SAMMPRIS showed that in patients with ICAD, achieving target physical activity was the most important factor with a 40% reduction in stroke recurrence (28003500). Given the challenge of implementing a multimodal lifestyle and risk factor modification intervention, studies are needed to test the utility of stroke prevention clinics and health care coaches to help patients with symptomatic ICAD control risk factors and promote healthy lifestyle patterns that could lead to a reduction in recurrent stroke risk.

Lipid lowering treatments

The first evidence showing the effectiveness of statins in secondary stroke prevention comes from the Stroke Prevention by Aggressive Reduction in Cholesterol Levels (SPARCL) trial, which showed that atorvastatin 80 mg daily was superior to placebo in reducing the risk of recurrent stroke (HR 0.84, 95% CI 0.71 to 0.99) (16899775). A trend towards secondary stroke prevention was also seen in patients whose index stroke was attributed to large artery atherosclerosis (HR 0.70, 95% CI 0.49 – 1.02), although the sample size was not large enough to definitively answer this question (19228842). Nonetheless, high intensity statin therapy is the standard of care in patients with symptomatic ICAD, based off SAMMPRIS.

In addition to statins, other lipid lowering agents have been investigated though none in patients with ICAD. A randomized trial showed that in patients with elevated triglyceride levels and cardiovascular disease or diabetes, Reduction of Cardiovascular Events with Icosapent Ethyl–Intervention (REDUCE-IT) Trial icosapent ethyl was associated with a lower risk of ischemic events (HR 0.75 95% CI 0.68 – 0.83). Moreover, a recent meta-analysis showed that the use of PCSK-9 inhibition in patients with hyperlipidemia or atherosclerotic cardiovascular disease was associated with a lower risk of major adverse cardiovascular events and the effect in reducing stroke risk achieved statistical significance (RR 0.78, 95% CI 0.67–0.89, p = 0.0005). (31270529) Therefore, studies are needed to investigate the utility of these treatments in patients with symptomatic ICAD aiming to reduce recurrent and primary stroke risk.

Targeting the inflammatory cascade

Downstream biomarkers of inflammation such as high-sensitivity C-reactive protein and interleukin-6 are associated with an increased risk of cardiovascular events, independent of cholesterol levels (10733371). Interleukin-1β is a cytokine central to the inflammatory response that upregulates interleukin-6. By targeting interleukin-1β with canakinumab, a fully human monoclonal antibody, the CANTOS (Antiinflammatory Therapy with Canakinumab for Atherosclerotic Disease) trial showed that 150mg dose of canakinumab led to a significantly lower rate of recurrent cardiovascular events compared to placebo, independent of lipid-level lowering (HR 0.85 95% CI, 0.74 – 0.98; P=0.021) (28845751). However, canakinumab led to a higher rate of sepsis-related death and cardiovascular development was halted by the manufacturer. In addition, the Colchicine Cardiovascular Outcomes Trial (COLCOT) trial showed that low-dose colchicine versus placebo, in patients with recent myocardial infarction, reduced the risk of cardiovascular events (HR 0.77, 95% CI 0.61–0.96; p=0.02) as well as stroke (HR 0.26, 95% CI 0.10–0.70) (31733140). Future studies are needed to examine anti-inflammatory therapies in treatment specifically of symptomatic ICAD.

Surgical or Endovascular Treatments

Stenting

Despite medical management, symptomatic ICAD has a high risk of stroke recurrence and death, which has motivated investigators to find more effective methods of treatment, including interventional procedures. The first successful intracranial balloon angioplasty was reported in 1980, and multiple case series and retrospective studies have described the feasibility and outcomes of this technique (18838951). In 2005, the Food and Drug Administration (FDA) approved the Wingspan Stent system for patients with history of ICAD stenosis of 50–99% and TIA/stroke while on anti-platelet therapy. A Phase I trial and two registries demonstrated a 30-day rate of stroke between 4.4% and 9.6% (17290030). The promising prospective registry data opened the door for randomized clinical trials to evaluate if stenting was superior to medical management alone.

The SAMMPRIS trial (21899409) was a randomized controlled trial that investigated intracranial percutaneous transluminal angioplasty and stenting (PTAS) using the Wingspan stent system in patients with symptomatic ICAD causing 70–99% stenosis. SAMMPRIS randomized 451 patients to PTAS plus aggressive medical management (AMM) versus AMM alone. SAMMPRIS was haulted early because of increased 30-day stroke or death rates events in the stenting arm compared to AMM (14.7% vs. 5.8%, p=0.002). The superiority of medical treatment persisted up to 2 years from the index event (24168957). The Vitesse Intracranial Stent Study for Ischemic Stroke Therapy (VISSIT) trial used a different stent system, but also demonstrated superiority of medical treatment with respect to the 30-day endpoint of stroke or death (9.4% vs. 24.1%, p = 0.05) (25803346). Based on these data, current guidelines recommend against stenting as an initial treatment for patients with symptomatic ICAD. (24788967)

In 2012, the FDA updated the labeling of the Wingspan stent, limiting its use to very specific subgroups of patients. Currently, the stent is approved for patients between 22 and 80 years old who had two or more strokes despite medical treatment, had suffered the most recent stroke more than seven days prior to the planned treatment with Wingspan, had 70–99% stenosis due to ICAD which was causal of the recurrent stroke, and had made good recovery from prior strokes with a modified Rankin Scale (mRS) score of three or less prior to Wingspan treatment. The WEAVE trial (Wingspan Stent System Post Market Surveillance) was a post-market registry mandated by the FDA to assess the periprocedural safety of the Wingspan in the treatment of symptomatic ICAD. (31125298) In total, 152 patients met the FDA on-label usage, in which there was a lower than expected (2.6%) periprocedural stroke, intracranial hemorrhage, or death rate, lower than the 4% periprocedural event rate set for the interim analysis. The WEAVE data reinforce the use of the Wingspan stent in a limited sub-group of symptomatic ICAD patients who fail AMM. Furthermore, angioplasty has been suggested as a potentially safer alternative to angioplasty plus stenting but this needs further study.

Recent evidence suggests that patients with symptomatic ICAD with evidence of impaired distal perfusion or blood flow are at higher risk of recurrence with medical treatment. For instance, the Vertebrobasilar Flow Evaluation and Risk of Transient Ischaemic Attack and Stroke (VERITAS) study showed that in patients with symptomatic vertebrobasilar disease, impaired distal flow is a strong predictor of recurrent events (HR 11.55, 95% CI 1.88–71.00, p = 0.008)) (26720181). A second study demonstrated that in patients with symptomatic ICAD involving the intracranial internal carotid artery or proximal segment of the middle cerebral artery, the recurrent stroke risk was higher in those with a time to maximum (T max) > 6 second perfusion delay of ≥15 mL (vs. none) (30398302) or border-zone (vs. non-border-zone) infarct pattern (30580705). Additional studies are needed to define the optimal thresholds of impaired distal perfusion or flow to identify patients for whom stenting presents a compelling risk to benefit profile in this high-risk population.

Surgical options

Bypass surgery has been studied in patients with symptomatic atherosclerosis of the internal carotid artery (ICA) or middle cerebral artery (MCA). The EC/IC bypass study randomized 1377 patients with symptomatic ICA vs. MCA stenosis to medical treatment vs. medical treatment plus a bypass procedure that joined the superficial temporal artery and MCA. In this trial, there was no benefit of bypass over medical treatment, particularly in those with severe MCA stenosis (n = 109 patients) where the stroke recurrence risk was higher in patients receiving bypass surgery (44% vs. 23.7%, p = 0.04). (2865674).

Another surgical option is encephaloduroarteriosynangiosis (EDAS), which has been studied extensively in patients with Moya-Moya disease. Preliminary data from the EDAS Revascularization in patients with Symptomatic Intracranial Arterial Stenosis (ERSIAS) study showed that in 52 patients with severe symptomatic ICA or MCA stenosis and impaired distal perfusion, EDAS was relatively safe with a 9.6% rate of death at 30 days or recurrent ischemic stroke in the same territory at 1 year (). Therefore, patients with symptomatic ICAD and evidence of impaired distal perfusion or flow may be candidates for inclusion in trials assessing the safety and efficacy of surgical revascularization procedures such as EDAS.

Conclusion

Treatments for patients with ICAD have evolved but it remains a common cause of stroke in the world and associated with a relatively high risk of recurrence stroke. Medical therapy remains the standard of care for patients with ICAD and this includes anti-thrombotic therapy, aggressive risk factor control, and lifestyle changes. Future studies are needed to investigate novel treatments geared to optimize medical therapy, target inflammation, and identify those who may benefit from revascularization procedures. These studies should take into consideration the underlying stroke mechanism and include patients from North America, Asia, and Europe to maximize the generalizability of their findings.