Stroke

ORIGINAL CONTRIBUTION

Stenting Versus Medical Therapy for Symptomatic

Intracranial Artery Stenosis: Long-Term Follow-Up
of a Randomized Trial
Peng Gao , MD*; Xiaoxin He , MD*; Haibo Wang, PhD*; Tao Wang , MD*; Daming Wang , MD; Huaizhang Shi, MD;
Tianxiao Li , MD; Zhenwei Zhao, MD; Yiling Cai, MD; Wei Wu , MD; Weiwen He , MD; Jia Yu , MD; Bingjie Zheng, MD;
Xuebing Feng, MD; Colin P. Derdeyn , MD; Adam A. Dmytriw , MD; Yangfeng Wu , PhD; Guoguang Zhao , MD;
Liqun Jiao , MD; for the CASSISS Trial Investigators

BACKGROUND: Whether the long-term benefit of stroke prevention when stenting is added to medical therapy (MT) over MT
alone for symptomatic severe intracranial artery stenosis offsets the perioperative risks of the stenting has not been directly
evaluated in a randomized trial. We aimed to compare the long-term (>3 years) effect of stenting versus MT alone in patients
with symptomatic severe intracranial artery stenosis in a randomized trial.

METHODS: We extended the follow-up of 358 subjects enrolled in a multicenter, open-label, randomized trial conducted at 8
centers in China. Patients with transient ischemic attack or stroke attributed to severe intracranial stenosis (70% to 99%)
were recruited between March 5, 2014, and November 10, 2016. The primary outcome was a composite of stroke or death
within 30 days or stroke in the territory of the qualifying artery beyond 30 days. Other secondary outcomes included stroke
in the territory of the qualifying artery, as well as disabling stroke or death after enrollment.

RESULTS: A total of 358 patients (stenting 176 versus MT 182) were recruited from March 5, 2014, and followed up till
January 22, 2024. The median duration of follow-up was 7.4 years (interquartile range, 6.0–8.0). The primary outcome
was not significantly different (stenting 14.8% versus MT 14.3%; hazard ratio, 1.02 [95% CI, 0.58–1.77]; P=0.97). No
significant difference was found between groups for the secondary outcomes: stroke in the territory of qualifying artery
(14.8% versus 14.3%; hazard ratio, 1.02 [95% CI, 0.58–1.77]; P=0.97), disabling stroke or death (16.5% versus 14.3%;
hazard ratio, 1.12 [95% CI, 0.66–1.91]; P=0.70), and death (9.1% versus 7.1%; hazard ratio, 1.22 [95% CI, 0.58–2.58];
P=0.60).

CONCLUSIONS: This study provides compelling evidence that, even over prolonged observed periods, the addition of
stenting to MT does not confer additional benefits to MT alone in patients with symptomatic severe intracranial artery
stenosis. These results underscore the importance of MT as the cornerstone of long-term stroke prevention in this
patient population.

REGISTRATION: URL: https://www.clinicaltrials.gov; Unique identifier: NCT01763320.

GRAPHIC ABSTRACT: A graphic abstract is available for this article.

Key Words: arteries ◼ constriction, pathologic ◼ follow-up studies ◼ intracranial arteriosclerosis ◼ stroke

Correspondence to: Liqun Jiao, MD, Departments of Neurosurgery and Interventional Neuroradiology, Xuanwu Hospital, China International Neuroscience Institute,
Capital Medical University, National Center for Neurological Disorders, 45 Changchun St, Beijing 100053, China, Email [email protected]; or Guoguang Zhao, MD,
Departments of Neurosurgery and Interventional Neuroradiology, Xuanwu Hospital, China International Neuroscience Institute, Capital Medical University, National
Center for Neurological Disorders, 45 Changchun St, Beijing 100053, China, Email [email protected]
*P. Gao, X. He, H. Wang, and T. Wang contributed equally.
Supplemental Material is available at https://www.ahajournals.org/doi/suppl/10.1161/STROKEAHA.124.049602.
For Sources of Funding and Disclosures, see page XXX.
© 2025 American Heart Association, Inc.
Stroke is available at www.ahajournals.org/journal/str

Stroke. 2025;56:00–00. DOI: 10.1161/STROKEAHA.124.049602 May 2025   1

 Gao et al Long-Term Effect of Intracranial Stenting

PTAS involves navigating the balance between a height-

Original Contribution

Nonstandard Abbreviations and Acronyms ened risk of short-term perioperative complications and
a potential reduction in long-term ischemic events. This
BASIS 
Balloon Angioplasty for Symptom- trade-off was apparent in the outcomes of the SAMM-
atic Intracranial Artery Stenosis PRIS trial, where there were more disabling or fatal strokes
CASSISS-LTF CASSISS-Long Term Follow-Up within 30 days in the PTAS group than in the medical
HR hazard ratio group (7.1% versus 1.8%), but it was the opposite after
ICAS intracranial artery stenosis 30 days (2.2% versus 6.2%).5 These findings suggested
mRS modified Rankin Scale that PTAS might offer a beneficial reduction in the risk of
MT medical therapy stroke recurrence, potentially outweighing the risks associ-
PTAS 
percutaneous transluminal
ated with the perioperative period when compared with MT
angioplasty and stenting alone.12,13 Among the trials assessing this intervention, the
SAMMPRIS  Stenting and Aggressive Medical
CASSISS trial reported a notably lower 30-day periopera-
Management for Preventing Recur- tive complication rate of 5.1%,9 in contrast to the 14.7%
rent Stroke in Intracranial Stenosis observed in SAMMPRIS5 and the 24.1% in VISSIT.8 Addi-
TIA transient ischemic attack tionally, the CASSISS trial observed a consistent trend of
VISSIT 
Vitesse Intracranial Stent Study for
reduced events extending from 30 days to 3 years, with
Ischemic Stroke Therapy the PTAS group documenting a 6.2% event rate compared
with 9.0% in the medical group.9 Despite these promising
trends, the long-term effect of PTAS in fully offsetting its

S
ymptomatic intracranial artery stenosis (ICAS) is initial risks remains under-explored, highlighting the need
a significant global health concern, implicated in a for further research into the sustained clinical benefits of
considerable percentage of ischemic stroke events. PTAS over MT alone beyond a 3-year period.
It accounts for ≈10% of all ischemic strokes in the Given the potential long-term benefit of PTAS, we
United States1 and rises to as much as 50% in China.2,3 initiated the present study known as CASSISS-LTF
Despite available medical therapy (MT), the recurrence (CASSISS-Long Term Follow-up). We extended the
of stroke among patients with this condition is notably follow-up of subjects originally enrolled in CASSISS to
high, with ≈15% in randomized trials4,5 and 20% to 30% compare the long-term effect of PTAS plus MT with MT
in the real-world cohorts.6 Furthermore, ICAS–related alone over a period extended beyond 3 years.
large-vessel occlusion is identified as a primary cause
of 10% to 30% of acute ischemic stroke globally, sig-
nificantly contributing to the increased rates of morbidity METHODS
and mortality.7 Data Availability
In an effort to mitigate the high recurrence rate of The data set analyzed during this study is available from the
ICAS–related strokes, the SAMMPRIS (Stenting and corresponding author upon reasonable request.
Aggressive Medical Management for Preventing Recur-
rent Stroke in Intracranial Stenosis) and VISSIT (Vitesse
Intracranial Stent Study for Ischemic Stroke Therapy) tri-
Study Population and Design
The design of the study has been published previously.14
als were designed to critically assess the efficacy and
CASSISS was a randomized, multicenter, open-label, outcome
safety of percutaneous transluminal angioplasty and
assessor-blinded trial comparing PTAS plus MT with MT alone
stenting (PTAS) in preventing further ischemic events in in patients with symptomatic severe stenosis. CASSISS began
patients with ICAS.5,8 However, both trials failed to dem- its recruitment on March 5, 2014, and ended on November 10,
onstrate the clinical benefit of stenting over MT alone 2016. CASSISS finished the 3-year follow-up for the last enrolled
in patients with symptomatic ICAS. Similarly, the CAS- patient on November 10, 2019. Results of a planned analysis at
SISS trial (China Angioplasty and Stenting for Symp- 3 years have been published.9 For CASSIS-LTF, enrolled patients
tomatic Intracranial Severe Stenosis), which aimed to were continued to follow-up until January 22, 2024. The institu-
reduce periprocedural complications by vetting surgeons tional review board of Xuanwu Hospital reviewed and approved
and sites and refining patient selection, also concluded the study ([2013]013). The detailed protocol of CASSISS and
without showing significant improvement in outcomes a CONSORT checklist (Consolidated Standards of Reporting
Trials) have been included in the Supplemental Material.
of stenting over MT alone.9 Although the recent BASIS
trial (Balloon Angioplasty for Symptomatic Intracranial
Artery Stenosis) suggested that balloon angioplasty Credentialing of Sites and Selection of
alone (without stenting) may be an effective treatment Participants
for symptomatic ICAS,10 stenting may still be a viable Before the initiation of this trial, we conducted a lead-in phase for
treatment for ICAS in clinical practice and it is important credentialing of operators and research sites.15 The site selec-
to confirm the benefit of stenting even after BASIS.11 tion and monitoring are available in the Supplemental Material.

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Gao et al Long-Term Effect of Intracranial Stenting

Finally, 8 centers were included, which were tasked to recruit variables, and t test or Wilcoxon rank test for quantitative vari-

Original Contribution
patients aged 30 to 80 years with a transient ischemic attack (TIA) ables. Differences in the primary and secondary outcomes
or nondisabling ischemic stroke (modified Rankin Scale [mRS], between groups were determined using the log-rank test, which
0–2) and severe stenosis (70% to 99% on digital subtraction used the center information (site effect) as a stratification fac-
angiography) of a major intracranial artery supplying the territory tor. Kaplan-Meier curves were used, offering a visual repre-
of the ischemic event. We excluded the following patients: TIA or sentation of event occurrence over time. The Cox proportional
ischemic stroke within the last 3 weeks; infarction due to perfora- hazards model was utilized to generate the hazard ratios (HRs)
tors occlusion only; recent infarctions identified on magnetic reso- and their 95% CIs, adjusting for the center effect. The validity
nance imaging (indicated as high signals on diffusion-weighted of the proportional hazard assumption was examined through
imaging). Full inclusion and exclusion criteria are available in the the analysis of Schoenfeld residuals, with a significance thresh-
Supplemental Material. Each patient’s enrollment was contingent old set at P<0.05 to indicate deviations from proportionality.
upon the provision of informed consent. Enrolled patients were For specific secondary outcomes, such as stroke in the territory
randomly assigned in a 1:1 ratio to PTAS plus MT or MT alone. of the qualifying artery and any stroke, TIA, or cardiovascular
events following enrollment, a competing risk Cox proportional
hazard model was applied. This model treated death as a com-
Trial Treatment peting risk and compared the risks between groups. In survival
All participants were prescribed a regimen of aspirin and clopi- analyses, we censored patients who were lost to follow-up.
dogrel, continuing for a duration of 90 days. Management of Post hoc evaluations were performed comprising: (1) 30-day
risk factors was recommended by the 2014 American Heart rate of stroke or death, and the rate of stroke in the territory
Association/American Stroke Association guidelines.16 For of qualifying artery beyond 30 days, (2) stroke-related and
details, those included control of low-density lipoprotein choles- nonstroke-related deaths after enrollment, and (3) sensitivity analy-
terol with statins (target low-density lipoprotein cholesterol <2.58 sis of the HR utilizing a mixed-effect model by treating each center
mmol/L [100 mg/dL]), hypertension (target systolic blood pres- as a random effect. The statistical analysis within the study used a
sure <140 mm Hg and diastolic blood pressure <90 mm Hg), 2-sided test using the SAS software, version 9.4 (SAS Institute). A
glucose disorder (target hemoglobin A1c <6.5%), and lifestyle P value of <0.05 was classified as statistically significant.
modification (smoking or alcohol cessation, weight reduction,
physical activity). Those assigned to the PTAS group were treated
with the implantation of a Wingspan stent (Stryker Neurovascular,
Fremont, CA). Comprehensive details about this procedure are RESULTS
thoroughly documented in the Supplemental Material. From March 4, 2014, to November 10, 2016, 358 partic-
ipants (176 in PTAS and 182 in MT alone) were random-
Outcomes and Definitions ized and included in the full analysis set for final analysis
The primary outcome was a composite clinical outcome that (Figure 1). Prevalence of risk factors conducted at the
included stroke, death within 30 days after enrollment, or stroke baseline and throughout the follow-up period were com-
in the territory of qualifying artery beyond 30 days. Secondary parable between groups (Table 1; Table S1).
outcomes included: (1) stroke in the territory of the qualifying The median duration of follow-up was 7.4 years (inter-
artery, (2) disabling stroke or death, (3) any stroke, TIA, or car- quartile range, 6.0–8.0). At the time of 7-year, 92.0%
diovascular events, and (4) death. Adverse events included an (206/224) patients were adhering to either single or
evaluation of disabling stroke, symptomatic intracranial hemor- dual antiplatelet therapy regimes, and 85.7% (192/224)
rhage, or death within 1 year as well as evaluation of all-cause
patients were maintained on statins. Moreover, 82.6%
death after enrollment.
(185/224) of these patients had achieved their blood
pressure targets by the 7-year mark, and 68.8% had
Follow-Up and Assessment of Outcome reached the low-density lipoprotein cholesterol reduc-
Clinical follow-up for the participants was conducted via outpa- tion targets, although there was a noted decrease in the
tient visits or telephone consultations at 1 month and at annual number of participants undergoing follow-up laboratory
intervals for up to 10 years after enrollment. During these testing. About lifestyle modification, 53.1% (112/211)
follow-ups, patients were examined using a structured case
managed to engage in adequate physical activity and
reporting form, with their blood samples collected. Magnetic
resonance angiography, computed tomography angiography, or
maintained their body mass index within stable ranges.
digital subtraction angiography were used for routine imaging Cessation rates for smoking and alcohol use stood at
follow-up of the target intracranial arteries (if feasible). Study 78.0% (174/223) and 71.3% (159/223), respectively.
physicians at each site recorded any outcomes, vascular risk Comparison between groups showed no statistical dif-
factors management, medication adjustments, and lifestyle ferences in the adherence rates, nor the achievement of
modifications at each visit. An independent outcome committee medical treatment targets (Tables S2 and S3).
and imaging core laboratory, who were masked to the alloca-
tion, determined the primary and secondary outcomes.
Primary Outcome
Statistical Analysis In the PTAS group, there were 9 primary end point events
For evaluating baseline characteristics, the statistical analysis within the initial 30 days following the stenting proce-
involved the utilization of χ2 or Fisher exact test for categorical dure. Additionally, 17 ipsilateral stroke events were noted

Stroke. 2025;56:00–00. DOI: 10.1161/STROKEAHA.124.049602 May 2025   3

 Gao et al Long-Term Effect of Intracranial Stenting
Original Contribution

Figure 1. Flow diagram of the study.

beyond 30 days. In contrast, the medical group reported intention-to-treat analysis, no relevant changes were
4 primary end point events within the first 30 days and identified (16.0% [25/156] versus 14.9% [26/175]; HR,
observed 22 ipsilateral stroke events beyond 30 days. 1.05 [95% CI, 0.59–1.86]; P=0.87; Figure S1).
The analysis of the primary outcome demonstrated no
statistically significant differences between the 2 groups
(PTAS, 14.8% [26/176] versus medical, 14.3% [26/182]; Secondary Outcomes
difference, 0.49% [95% CI, −6.82% to 7.79%]; HR, 1.02 The rate of stroke in the territory of qualifying artery
[95% CI, 0.58–1.77]; P=0.97; Table 2; Figure 2). When was not statistically significant between groups (14.8%
comparing the outcomes of per-protocol analyses with [26/176] in the PTAS group versus 14.3% [26/182] in

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Gao et al Long-Term Effect of Intracranial Stenting

Table 1. Baseline Characteristics of Study Participants Table 1. Continued

Original Contribution
PTAS group Medical group PTAS group Medical group
Characteristic (N=176) (N=182) Characteristic (N=176) (N=182)
Age, mean (SD), y 56.7 (9.4) 55.9 (9.8) mRS score, median (IQR)** 0.0 (0.0, 1.0) 0.0 (0.0, 1.0)
Sex IQR indicates interquartile range; mRS, modified Rankin Scale; NIHSS,
National Institutes of Health Stroke Scale; PTAS, percutaneous transluminal
 Male 128 (72.7) 135 (74.2)
angioplasty and stenting; and TIA, transient ischemic attack.
 Female 48 (27.3) 47 (25.8) *Ethnicity was self-reported.
†Medical history was collected at the baseline visit, based on a combination of
Ethnicity*
self-reports from patients, medicated conditions, and laboratory results.
 Han 172 (97.7) 179 (98.4) ‡TIA was a clinical diagnosis without imaging.
§Isolated hemodynamic compromise refers to strokes with an arterial border
 Non-Han 4 (2.3) 3 (1.6)
zone or watershed pattern.
Medical history† ¶Stenosis was quantified on the basis of a reading of the angiogram by the
 Hypertension 117 (66.5) 125 (68.7) site interventionist on the criteria of the WASID trial (Warfarin-Aspirin Symptom-
atic Intracranial Disease).
 Diabetes 57 (32.4) 44 (24.2) #NIHSS score ranges from 0 to 42, with higher scores indicating worse neu-
 Coronary artery disease 19 (10.8) 19 (10.4) rological deficits.
**mRS score ranges from 0 to 6, with higher scores indicating worse function
 Lipid disorder 18 (10.2) 21 (11.5) deficits (0 indicates no deficit and 6 indicates death).
 Peripheral artery disease 0 (0.0) 1 (0.5)
 
Received antiplatelet therapy before 49 (27.8) 48 (26.4) the MT alone group; difference, 0.49% [95% CI, −6.82%
the latest qualifying event
to 7.79%]; HR, 1.02 [95% CI, 0.58–1.77]; P=0.97;
 
Received statin therapy before the 19 (10.8) 20 (11.0)
latest qualifying event
Table 2; Figure S2). Also, the rate of disabling stroke or
death was not statistically significant between groups
Alcohol history
(16.5% [29/176] versus 14.3% [26/182]; difference,
 Former 25 (14.2) 22 (12.1)
2.19% [95% CI, −5.28% to 9.67%]; HR, 1.12 [95% CI,
 Current 30 (17.0) 32 (17.6)
0.66–1.91]; P=0.70; Figure 3). As for the other second-
Smoking history ary outcomes, no significant difference was observed in
 Former 39 (22.2) 38 (20.9) the rate of death (9.1% [16/176] versus 7.1% [13/182];
 Current 41 (23.3) 50 (27.5) difference, 1.95% [95% CI, −3.71% to 7.61%]; HR, 1.22
Qualifying event [95% CI, 0.58–2.58]; P=0.60; Figure S3), as well as the
 TIA‡ 87 (49.4) 77 (42.3) rate of any stroke, TIA, or cardiovascular events (21.6%
 Stroke 89 (50.6) 105 (57.7) [38/176] versus 28.0% [51/182]; difference, −6.43%
  
Artery-to-artery embolism 57 (64.0) 58 (55.2)
[95% CI, −15.35% to 2.49%]; HR, 0.71 [95% CI, 0.46–
1.08]; P=0.08; Figure S4).
  Isolated hemodynamic compromise§ 18 (20.2) 22 (21.0)
  
Mixed mechanism 14 (15.7) 25 (23.8)
Time from latest ischemic event to ran- 34.5 36.0 Post Hoc Outcomes and Analyses
domization, d, median (IQR) (27.0, 65.5) (28.0, 68.0)
Sensitivity analysis of the HR utilizing a mixed-effect
 TIA, median (IQR) 33.0 33.0 model was 1.03 (95% CI, 0.60–1.77). In the PTAS group,
(25.0, 52.0) (28.0, 57.0)
the rate of stroke or death within a 30-day period pos-
 Stroke, median (IQR) 38.0 40.0
(27.0, 75.0) (29.0, 72.0)
tintervention was 5.1% (9/176), compared with a lower
rate of 2.2% (4/181) in the group that received MT
Symptomatic qualifying artery
alone.9 Further analysis showed that the rate of stroke
 Middle cerebral artery (M1) 65 (36.9) 79 (43.4)
in the territory of the qualifying artery after the initial 30
 Basilar artery 50 (28.4) 52 (28.6)
days was 9.7% (17/176) for the PTAS group and was
 Intracranial vertebral artery 46 (26.1) 34 (18.7) slightly higher at 12.1% (22/182) for the medical group
 Intracranial internal carotid artery 15 (8.5) 17 (9.3) (Figure S5). The long-term follow-up highlighted that the
Stenosis of symptomatic qualifying artery¶ rate of stroke-related death in the PTAS group was 4.0%
 % stenosis, median (IQR) 78.5 76.6 (7/176), while the medical group had a lower rate of
(74.1, 82.6) (73.2, 80.9) 1.7% (3/182). Conversely, the rate of nonstroke-related
 Distribution, % stenosis death was comparable between the 2 groups (PTAS,
  
70–79% stenosis 105 (59.7) 130 (71.4) 5.1% [9/176] versus medical, 5.5% [10/182]; Table 2).
  
80–89% stenosis 65 (36.9) 46 (25.3)
  
90–99% stenosis 6 (3.4) 6 (3.3)
Adverse Events
NIHSS score, median (IQR)# 0.0 (0.0, 1.0) 0.0 (0.0, 0.0)
In the PTAS group, the disabling stroke, symptomatic
(Continued ) intracranial hemorrhage, and death rate within 30 days

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 Gao et al Long-Term Effect of Intracranial Stenting

Table 2. Primary and Secondary Outcomes

Original Contribution

PTAS group Medical group Incidence difference, %

(n=176) n (%) (n=182) n (%) 95% CI* Hazard ratio (95% CI) P value†
Primary outcomes 26 (14.8) 26 (14.3) 0.49 (−6.82 to 7.79) 1.02 (0.58–1.77) 0.97
 Stroke or death within 30 d after enrollment‡ 9 (5.1)§ 4 (2.2)¶
 
Stroke in the territory of qualifying artery beyond 17 (9.7) 22 (12.1)
30 d
Secondary outcomes
 Stroke in the territory of qualifying artery 26 (14.8) 26 (14.3) 0.49 (−6.82 to 7.79) 1.02 (0.58–1.77) 0.97
 Disabling stroke# or death 29 (16.5) 26 (14.3) 2.19 (−5.28 to 9.67) 1.12 (0.66–1.91) 0.70
 Any stroke, TIA, cardiovascular events 38 (21.6) 51 (28.0) −6.43 (−15.35 to 2.49) 0.71 (0.46–1.08) 0.08
 Death rate 16 (9.1)** 13 (7.1)†† 1.95 (−3.71 to 7.61) 1.22 (0.58–2.58) 0.60
  
Stroke-related death 7 (4.0) 3 (1.7)
  
Non-stroke-related death 9 (5.1) 10 (5.5)
NIHSS indicates National Institutes of Health Stroke Scale; PTAS, percutaneous transluminal angioplasty and stenting; and TIA, transient ischemic attack.
*Adjusted for site effect.
†Log-rank test adjusted for site effect.
‡Post hoc analysis.
§There were 5 ischemic strokes and 4 hemorrhagic strokes. Of the 4 symptomatic hemorrhagic strokes, 1 was periprocedural subarachnoid hemorrhage immediately
after PTAS (probably related to guidewire perforation); 1 was periprocedural parenchymal and subdural brain hemorrhage evident immediately after PTAS (probably
related to guidewire perforation); 1 was cerebellar and occipital hemorrhage that occurred 3 d after PTAS (probably related to reperfusion); and 1 was subarachnoid
hemorrhage within 24 h after PTAS (probably related to reperfusion). A total of 2 of these hemorrhages were fatal (1 developed massive cerebral infarction and brain
hernia, and 1 had parenchymal brain hemorrhage), and 2 were nondisabling (1 cerebellar and occipital hemorrhage and 1 subarachnoid hemorrhage).
¶There were 4 ischemic strokes and 0 hemorrhagic strokes. Of the 4 ischemic strokes, 2 were disabling, 2 were nondisabling, and none were fatal.
#Disabling stroke was defined by any of the following: (1) an mRS score of ≥3 on a scale of 0 to 6, with higher scores indicating greater disability; (2) an increase in
at least 1 mRS category from an individual’s prestroke baseline; (3) a score on the composite NIHSS of ≥ 7 on a scale of 0 to 42, with higher scores indicating more
severe deficits; or (4) an increase of at least 4 points in the NIHSS score from prestroke baseline.
**The causes of death in the PTAS group were as follows: hemorrhagic or ischemic stroke (n=7), sudden cardiac arrest (n=4), and others (n=5).
††The causes of death in the medical management group were as follows: hemorrhagic or ischemic stroke (n=3), sudden cardiac arrest (n=3), and others (n=7).

were 2.8% (5/176), 2.3% (4/176), and 1.1% (2/176), the study, over 85% of participants consistently received
respectively. In the medical group, the disabling stroke antiplatelet agents and statins. The targets for medical
rate within 30 days was 1.1% (2/182). During a median treatment, particularly about blood pressure and low-
follow-up of 7.4 years, there were 9.1% (16/176) and density lipoprotein cholesterol levels, were effectively
7.1% (13/182) of patients died in the PTAS and medical met for a considerable number of patients.
groups, respectively (Table S4). The preplanned analysis of the CASSISS study
revealed a decreased trend for ipsilateral stroke recur-
rence in the PTAS group after the first 30 days (from
DISCUSSION 30 days to 1 year: PTAS, 2.8% versus medical 5.0%).
To the best of our understanding, the CASSISS-LTF trial Extending the observation period to 3 years,9 of the
represents the first randomized study comparing the effi- PTAS group experienced 10 (6.2%) ipsilateral strokes,
cacy of PTAS combined with MT and MT alone over a whereas the medical group reported 15 (9.0%) such
median duration of 7.4 years follow-up among patients events occurring after 30 days. These data suggested a
with TIA or nondisabling ischemic stroke due to severe potential benefit of PTAS over a longer time horizon, pro-
ICAS. The extended time-window evaluation revealed viding the rationale for CASSISS-LTF. When considering
that the long-term advantages in stroke prevention pro- follow-up periods from prior randomized trials, our study
vided by PTAS in addition to MT did not outweigh the boasts the longest duration, with a median of 7.4 years,
perioperative risk associated with the procedure. Over notably longer than the 32.4 months in SAMMPRIS and
the course of long-term follow-up, both the primary and 1 year in VISSIT.5,8 During this extended median follow-up
secondary outcomes showed no differences between in our study, the PTAS group recorded 17 stroke events,
treatments. This study, together with findings from earlier while the medical group had 27, both occurring after
studies,5,8 corroborates the guidelines by the American the initial 30 days. Over time, the efficacy gap between
Academy of Neurology,17 the American Heart Associa- groups did not widen; the cumulative ipsilateral stroke
tion/American Stroke Association,18 and the European in the PTAS group remained numerically lower than that
Stroke Organisation.19 These guidelines advocate for pri- in the medical group (from 30 days to 7.4 years: 9.7%
oritizing medical management over PTAS as the initial versus 12.1%). Taking the early and late events together,
treatment strategy for stroke prevention in patients with PTAS did not demonstrate a distinct advantage over MT
symptomatic severe ICAS. Throughout the duration of throughout the median 7.4 years of follow-up.

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Gao et al Long-Term Effect of Intracranial Stenting

Original Contribution
Figure 2. Cumulative probability of
primary outcomes (stroke or death
within 30 days or stroke in the
qualifying artery territory beyond
30 days, according to treatment
assignment).
The median time of observation was 7.4
years. P=0.97 for log-rank testing between
the percutaneous transluminal angioplasty
and stenting and medical therapy alone
groups with the center as a stratification
factor.

The long-term risk in the medical group of the present statins and antiplatelet medications, undoubtedly con-
study was comparable with the medical group of SAMM- tributed to these lower-risk results.
PRIS (14.1%) and lower than the OXVASC cohort (The The observed annual risk of ipsilateral stroke in the
Oxford Vascular Study; 22.9%).20,21 Additionally, the long- MT alone group was 2.4%, presenting a lower incidence
term risk in the PTAS group of the present study was compared with prior studies. This reduction might be
lower than the PTAS group of SAMMPRIS (20.6%).5,20 due to the effective implementation of medical therapies
This diminished risk in our trial could likely be attributed and the selection of a population with a lower-risk pro-
to the stringent patient selection that excluded individu- file.22 Notably, the CASSISS study enrolled fewer high-
als who presented with higher-risk profiles. Furthermore, risk patients than those included in the SAMMPRIS and
demographic variations such as differences in age or VISSIT trials.5,8 Key differences in patient characteris-
ethnicity among studies could also play a significant role tics included the duration since the last ischemic event,
in influencing these outcomes.9 The adherence to pre- which was longer in the CASSISS compared with those
scribed medical therapies, notably the consistent use of in SAMMPRIS and VISSIT. It was observed that most

Figure 3. Cumulative probability of a

secondary outcome (disabling stroke
or death, according to treatment
assignment).
The median time of observation was
7.4 years. P=0.70 for log-rank testing
between the percutaneous transluminal
angioplasty and stenting group and medical
therapy alone group with the center as a
stratification factor.

Stroke. 2025;56:00–00. DOI: 10.1161/STROKEAHA.124.049602 May 2025   7

 Gao et al Long-Term Effect of Intracranial Stenting

ipsilateral strokes occurred shortly after the initial onset, experiencing recurrent strokes.32 Emerging biomarkers
Original Contribution

specifically within the first 6 to 8 weeks, with no subse- linked to the risk of stroke in ICAS patients include indi-
quent ischemic episodes thereafter.23 The period follow- cators of hemodynamic impairment. These encompass
ing this initial phase is generally considered to carry a poor collateral circulation,33 reduced flow in distal regions
lower risk for recurrent strokes on medical management. as assessed by quantitative magnetic resonance angi-
Furthermore, fewer than half of the participants in this ography,25 unfavorable perfusion imaging outcomes,34
study exhibited a baseline border zone infarct pattern and a low translesional pressure ratio as calculated
indicating impaired distal perfusion. Studies like SAMM- using computational fluid dynamics models (ICAS-
PRIS24 and VERiTAS25 identified patients with hemody- MT; https://www.clinicaltrials.gov; Unique identifier:
namic compromise as having a particularly high risk of NCT05974033).35 Moreover, advancements in vessel
recurrent strokes on medical treatment alone. Addition- wall neuroimaging have shed light on plaque morphology
ally, 45.8% of the CASSISS trial participants presented as an essential determinant of stroke risk. Factors such
with TIAs only. Data from the SAMMPRIS trial indicated as plaque enhancement,36 increased plaque burden or
that patients presenting only with TIA were at a signifi- progression,36 increased plaque burden or progression,37
cantly lower risk of subsequent strokes when managed and plaque surface irregularity as revealed through high-
medically.26 resolution magnetic resonance imaging38 have been
The present study’s observation that PTAS failed to validated as significant indicators of potential stroke
exhibit a definitive advantage over MT for stroke preven- recurrence.39 Remarkably, the annual risk of stroke recur-
tion might be linked primarily to the high-rate peripro- rence was reported at 30.3% among patients exhibiting
cedural complications associated with the intervention. high-risk plaque features, compared with a mere 6.8%
To mitigate these risks, our study protocol was improved among those without such features. Looking ahead,
with revised criteria such as excluding patients who ICAS research is poised to prioritize the identification of
experienced perforator strokes only, selecting individu- patients at high risk—who could markedly benefit from
als without recent ischemic events, and ensuring that targeted treatment approaches—thereby refining inter-
only experienced interventionalists were involved in the vention strategies and enhancing patient outcomes in
procedures.1,15 Despite these precautions, developing this challenging clinical scenario.40
a consistently safe endovascular approach for treating This study presents several limitations. First, it did
ICAS remains an ongoing challenge. Recent advance- not explore the emerging treatment modalities for ICAS
ments in medical practice have shifted focus toward currently under investigation, which future research
enhancing safety measures to minimize periprocedural will address, specifically evaluating the effectiveness
risks further. Insights from the SAMMPRIS trial under- of angioplasty and drug-eluting stents against medical
scored the critical need to focus efforts on reducing the management as noted in the BASIS10 and DREAM-
occurrences of perforation infarction and wire perfora- PRIDE (Drug Eluting Stenting and Aggressive Medical
tion during procedures.27 Innovations are being made in Treatment for Preventing Recurrent Stroke in Intracranial
the field, including the adoption of newer techniques like Atherosclerotic Disease Trial) (https://www.clinicaltri-
percutaneous transluminal balloon angioplasty,28 the uti- als.gov; Unique identifier: NCT04948749). Second, the
lization of drug-coated balloons,29 drug-eluting stents,30 absence of a Questionnaire for Verifying Stroke-Free
and the introduction of next-generation self-expanding Status in this trial could have resulted in under-reported
neurovascular stents.31 However, the comparative safety cases due to subtle deficits. Additionally, with 98% of the
and efficacy of these advanced neurointerventional strat- participants being Chinese Han, the applicability of the
egies relative to traditional approaches like the Wingspan results to other ethnic groups may be limited. Despite
stent are still under investigation and warrant further these limitations, the study’s findings align with those
detailed studies to establish clearer benchmarks. Most of the US WEAVE trial (Wingspan Stent System Post
recently, the BASIS trial suggested that balloon angio- Market Surveillance),13 suggesting they could contribute
plasty plus aggressive medical management may be an to pooled analyses in a field with few randomized trials.
effective treatment for symptomatic ICAS although the Initiated in 2014, this study reflects changes in medical
risk of stroke or death within 30 days of balloon angio- management over time, yet current guidelines continue
plasty should be considered in clinical practice.10 to recommend statins and antiplatelets for secondary
In the medical group of the present study, over 85% stroke prevention.18 The median 7.4-year follow-up high-
of patients with 70% to 99% stenosis remained stroke- lighted consistent use of these medications, indicative
free during this long-term follow-up without PTAS inter- of enhanced management of risk factors over the past
vention. The finding suggests that invasive interventions decade. The approach to medical management in this
might be unnecessary for a substantial portion of this trial was less aggressive than in prior studies, requiring
patient group. Future research must focus on precisely cautious comparison due to evolving medical practices.
identifying ICAS patients who do not respond adequately The enrolled cohort had a lower risk profile than antici-
to medical therapies and are at continued high risk for pated, possibly affecting the applicability of the results to

8   May 2025 Stroke. 2025;56:00–00. DOI: 10.1161/STROKEAHA.124.049602

Gao et al Long-Term Effect of Intracranial Stenting

patients with higher risks for ICAS events. Consequently, intracranial large artery stenoses and occlusions in China: the Chinese

Original Contribution
Intracranial Atherosclerosis (CICAS) Study. Stroke. 2014;45:663–669. doi:
the external validity of the CASSISS results might be 10.1161/STROKEAHA.113.003508
questioned. 3. Wong LK. Global burden of intracranial atherosclerosis. Int J Stroke.
2006;1:158–159. doi: 10.1111/j.1747-4949.2006.00045.x
4. Chimowitz MI, Lynn MJ, Howlett-Smith H, Stern BJ, Hertzberg VS,

CONCLUSIONS Frankel MR, Levine SR, Chaturvedi S, Kasner SE, Benesch CG, et al;
Warfarin-Aspirin Symptomatic Intracranial Disease Trial Investigators. Com-
In summary, despite extending the follow-up period, parison of warfarin and aspirin for symptomatic intracranial arterial stenosis.
N Engl J Med. 2005;352:1305–1316. doi: 10.1056/NEJMoa043033
PTAS combined with MT did not demonstrate superiority 5. Chimowitz MI, Lynn MJ, Derdeyn CP, Turan TN, Fiorella D, Lane BF, Janis LS,
over MT alone in managing symptomatic severe ICAS. Lutsep HL, Barnwell SL, Waters MF, et al; SAMMPRIS Trial Investigators.
MT alone continues to be the cornerstone of secondary Stenting versus aggressive medical therapy for intracranial arterial stenosis.
N Engl J Med. 2011;365:993–1003. doi: 10.1056/NEJMoa1105335
stroke prevention for these patients. 6. Sangha RS, Naidech AM, Corado C, Ansari SA, Prabhakaran S.
Challenges in the medical management of symptomatic intracra-
nial stenosis in an urban setting. Stroke. 2017;48:2158–2163. doi:
ARTICLE INFORMATION 10.1161/STROKEAHA.116.016254
7. de Havenon A, Zaidat OO, Amin-Hanjani S, Nguyen TN, Bangad A,
Received October 09, 2024; final revision received December 21, 2024; Abbasi M, Anadani M, Almallouhi E, Chatterjee R, Mazighi M, et al. Large
accepted February 10, 2025. vessel occlusion stroke due to intracranial atherosclerotic disease: iden-
Presented in part at the European Stroke Organisation Conference, Basel, tification, medical and interventional treatment, and outcomes. Stroke.
Switzerland, May 15–17, 2024. 2023;54:1695–1705. doi: 10.1161/STROKEAHA.122.040008
8. Zaidat OO, Fitzsimmons BF, Woodward BK, Wang Z, Killer-Oberpfalzer M,
Affiliations Wakhloo A, Gupta R, Kirshner H, Megerian JT, Lesko J, et al; VISSIT Trial
Departments of Neurosurgery and Interventional Neuroradiology, Xuanwu Hospi- Investigators. Effect of a balloon-expandable intracranial stent vs medical
tal, Capital Medical University, Beijing, China (P.G., X.H., T.W., X.F., G.Z., L.J.). Clini- therapy on risk of stroke in patients with symptomatic intracranial steno-
cal Research Institute, Institute of Advanced Clinical Medicine, Peking University, sis: the VISSIT randomized clinical trial. JAMA. 2015;313:1240–1248. doi:
Beijing, China (H.W., Y.W.). Department of Neurosurgery, Beijing Hospital, National 10.1001/jama.2015.1693
Center of Gerontology, Institute of Geriatric Medicine, Chinese Academy of Medi- 9. Gao P, Wang T, Wang D, Liebeskind DS, Shi H, Li T, Zhao Z, Cai Y, Wu W,
cal Sciences, China (D.W.). Department of Neurosurgery, First Affiliated Hospital He W, et al; CASSISS Trial Investigators. Effect of stenting plus medical
of Harbin Medical University, China (H.S., B.Z.). Department of Cerebrovascular therapy vs medical therapy alone on risk of stroke and death in patients
and Neurosurgery, Henan Provincial People’s Hospital, Zhengzhou University, with symptomatic intracranial stenosis: the CASSISS randomized clinical
China (T.L.). Department of Neurosurgery, Tangdu Hospital of Air Force Medical trial. JAMA. 2022;328:534–542. doi: 10.1001/jama.2022.12000
University, Xi’an, China (Z.Z.). Department of Neurology, Strategic Support Force 10. Sun X, Deng Y, Zhang Y, Yang M, Sun D, Nguyen TN, Tong X, Peng G, Liu A,
Medical Center, Beijing, China (Y.C.). Department of Neurology, Qilu Hospital of Xu Y, et al; BASIS Investigators. Balloon angioplasty vs medical manage-
Shandong University, Ji’nan, China (W.W.). Department of Neurosurgery, Second ment for intracranial artery stenosis: the BASIS randomized clinical trial.
Affiliated Hospital of Guangzhou Medical University, China (W.H.). Department JAMA. 2024;332:1059–1069. doi: 10.1001/jama.2024.12829
of Neurology, First Affiliated Hospital of Xi’an Jiaotong University, China (J.Y.). 11. Alexander MJ, Yu W. Intracranial atherosclerosis update for neu-
Department of Radiology and Medical Imaging, University of Virginia School of rointerventionalists. J Neurointerv Surg. 2024;16:522–528. doi:
Medicine, Charlottesville (C.P.D.). Neuroendovascular Program, Massachusetts 10.1136/jnis-2022-019628
General Hospital, Harvard Medical School, Boston (A.A.D.). 12. Yu W, Jiang WJ. Stenting for intracranial stenosis: potential future for the
prevention of disabling or fatal stroke. Stroke Vasc Neurol. 2018;3:140–
Acknowledgments 146. doi: 10.1136/svn-2018-000158
The authors thank the patients and their families for participating in this trial. 13. Alexander MJ, Zauner A, Chaloupka JC, Baxter B, Callison RC, Gupta R,
Song SS, Yu W; WEAVE Trial Sites and Interventionalists. WEAVE trial:
Sources of Funding final results in 152 on-label patients. Stroke. 2019;50:889–894. doi:
This work was supported by grants from the National Health Commission of the 10.1161/STROKEAHA.118.023996
People’s Republic of China (2011BAI08B04 and SQ2016YFSF110141), the 14. Gao P, Zhao Z, Wang D, Wu J, Cai Y, Li T, Wu W, Shi H, He W, Zhu F,
National Health Commission Capacity Building and Continuing Education Center et al. China Angioplasty and Stenting for Symptomatic Intracranial Severe
Project (GWJJ2021100202), and the Beijing Municipal Science and Technology Stenosis (CASSISS): a new, prospective, multicenter, randomized
Project (Z2111000002921031). Stryker Neurovascular (Fremont, CA) provided controlled trial in China. Interv Neuroradiol. 2015;21:196–204. doi:
supplemental funding for third-party site monitoring and auditing. 10.1177/1591019915581778
15. Gao P, Wang D, Zhao Z, Cai Y, Li T, Shi H, Wu W, He W, Yin L, Huang S, et al.
Disclosures Multicenter prospective trial of stent placement in patients with symptomatic
Dr Derdeyn reports consultancy to the Penumbra, Silk Road Medical, and Euphra- high-grade intracranial stenosis. AJNR Am J Neuroradiol. 2016;37:1275–
tes Vascular. The other authors report no conflicts. 1280. doi: 10.3174/ajnr.A4698
16. Kernan WN, Ovbiagele B, Black HR, Bravata DM, Chimowitz MI,
Supplemental Material Ezekowitz MD, Fang MC, Fisher M, Furie KL, Heck DV, et al; American Heart
Supplemental Methods Association Stroke Council, Council on Cardiovascular and Stroke Nursing,
Tables S1–S4 Council on Clinical Cardiology, and Council on Peripheral Vascular Disease.
Figures S1–S5 Guidelines for the prevention of stroke in patients with stroke and transient
CONSORT Checklist ischemic attack: a guideline for healthcare professionals from the American
Previous CASSSISS Trial Protocol Heart Association/American Stroke Association. Stroke. 2014;45:2160–
2236. doi: 10.1161/STR.0000000000000024
17. Turan TN, Zaidat OO, Gronseth GS, Chimowitz MI, Culebras A, Furlan AJ,
Goldstein LB, Gonzalez NR, Latorre JG, Messe SR, et al. Stroke prevention
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10   May 2025 Stroke. 2025;56:00–00. DOI: 10.1161/STROKEAHA.124.049602