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Abstract
Objective To evaluate the clinical outcomes of early stenting (≤14 days) or late stenting (>14 days) in patients who underwent intracranial stent placement.
Methods Patients with ischemic stroke caused by 70–99% intracranial atherosclerotic stenosis combined with poor collaterals were enrolled. The early stenting group, who underwent stenting within 14 days of last ischemic symptoms, were compared with the late stenting group who underwent stenting >14 days from last ischemic symptom. The patients were treated either with a balloon-mounted stent or a self-expanding stent as determined by the operators following a guideline. The baseline characteristics and clinical outcomes were evaluated and compared.
Results One hundred and fifteen stroke patients were recruited into the study. Four patients (4/41) in the early stenting group and two patients (2/74) in the late stenting group were diagnosed with a cerebral vascular event associated with stenting within 3 days (p=0.184). In the long-term follow-up, eight patients in the early stenting group had restenosis ≥50%, which was higher than patients in the late stenting group (8/41 vs 4/74, p=0.018). The total rates of any ischemic stroke, transient ischemic attack, hemorrhagic stroke, and death in the early stenting group were higher than in the late stenting group (9/41 vs 6/74, p=0.035). The recurrence rate of ischemic stroke in the early stenting group was higher than in the late stenting group (5/41 vs 2/74, p=0.041).
Conclusions Stent placement in the setting of ischemic stroke caused by intracranial artery stenosis within 14 days may confer a higher risk of long-time cerebral vascular events and lead to a higher risk of restenosis.
Clinical trial registration NCT01968122.
- atherosclerosis
- stroke
- stenosis
- stent
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Introduction
Intracranial atherosclerotic artery stenosis is the main cause of ischemic stroke worldwide and is associated with a high risk of recurrent stroke.1–3 In Asia, nearly 33% of ischemic stroke cases were attributed to atherosclerotic intracranial artery stenosis.4 Patients with severe stenosis (70–99%) have a particularly high rate of recurrent stroke up to 23% per year despite treatment with antithrombotic agents and standard management of vascular risk factors.5 Medical therapy alone is therefore not the optimal choice for patients with severe stenosis.
In the past few years, stent placement has been shown to be a safe and effective treatment for severe intracranial atherosclerotic artery stenosis.6 7 However, recent trial results have been disappointing for supporters of intracranial stent placement, especially the Stenting and Aggressive Medical Management for Preventing Recurrent Stroke in Intracranial Stenosis (SAMMPRIS) and the Vitesse Intracranial Stent Study for Ischemic Stroke Therapy (VISSIT) trials.8 9 Both trials showed that aggressive medical therapy alone was superior to a Wingspan self-expanding stent or balloon-mounted stent placement for these patients. On the other hand, many clinical trials have shown a low risk of recurrence of stroke after stent placement in patients with intracranial atherosclerotic stenosis. In China, the trial by Miao et al showed a successful revascularization rate of 97.3% and the 30-day rate of stroke, transient ischemic attack (TIA), and death was 4.3% after intracranial stent placement, which is lower than the reports of the SAMMPRIS and VISSIT trials.10 A randomized controlled trial reported by Miao et al showed endovascular angioplasty and stent placement to be as safe and effective as medical treatment for symptomatic middle cerebral artery stenosis in a low-risk Chinese population.11 These studies suggest that a subgroup of patients may benefit from endovascular therapy more than those who benefit from medical therapy alone. Building on previous studies, we have identified many factors associated with perioperative complications for intracranial stent placement. We also draw a conclusion that patient selection and stent selection are essential to decrease this complication. For example, patients with poor collaterals and a hypoperfusion area following intracranial stenosis may continue to have symptoms despite double antiplatelet therapy, statins, and tight control of hypertension and diabetes mellitus.2 12 These patients have a higher chance of benefiting from stent placement. In addition, we also found having the choice of using either a balloon-mounted stent or a self-expanding stent will achieve a better clinical result with a low rate of complications. We believe that different lesions respond better to different devices.2 10 From our previous data, we also found that a longer time from the qualifying event to stent placement will decrease the complication rate at 30-day and long-term follow-up. In a previous trial, patients treated with carotid artery stenting within 14 days after the qualifying event were found to have a higher rate of complications than patients treated after more than 14 days.13 Extracranial-intracranial bypass in the setting of acute symptomatic stroke within 7 days may confer a higher risk of perioperative stroke and a waiting period of 3–6 weeks will result in a better outcome.14
These data suggest that the timing of stent placement may influence the clinical outcome. However, even recently published trials on the reporting standards for intracranial stent placement do not focus on this issue. We therefore aimed to identify the outcomes of early stenting (≤14 days) or late stenting (>14 days) in patients who underwent intracranial stent placement.
Methods
Study design
Details of the trial design have been published previously.2 This study was a subgroup analysis of a prospective single-arm registry study with 20 participating stroke centers in China, from September 2013 to January 2015. The study protocol was approved by the institutional review board in all the participating stroke centers. Written and oral informed consent was obtained from patients and their surrogates according to the Helsinki Declaration. The diagnosis of stenosis and treatment were confirmed by a central adjudication committee composed of designated neurologists, neurosurgeons and radiologists, blinded to the treatment choices. Early stenting was defined as stent placement performed within 14 days of most recent ischemic symptom. Late stenting was defined as stent placement performed after 14 days of most recent ischemic symptom.
Study patients
Inclusion criteria were established by the executive committee as follows. Patients were aged 18–85 years. Patients had angiographically verified stenosis of 70–99% atherosclerotic stenosis of the diameter of a major intracranial artery. The target artery had a lesion length of ≤15 mm and diameter of ≥2.0 mm. The measurements of stenosis were made by digital subtraction angiography (DSA) according to the warfarin–aspirin symptomatic intracranial disease method with normal distal vessels as the reference.15 Patients had non-disabling stroke prior to enrollment. There is a hypoperfusion area in the territory of the target lesion. Moreover, hemodynamic impairment in the territory of the artery was evaluated on imaging within 14 days before endovascular therapy, according to the following method: (1) Poor collateral circulation is determined as ≥30% decrease in cerebral blood flow at hypoperfusion area compared with the contralateral side on CT or MRI perfusion. (2) An American Society of Interventional and Therapeutic Neuroradiology/Society of Interventional Radiology Collateral Flow Grading System score of <3 on DSA. (3) Hypoperfusion by single-photon emission CT or hemodynamic ischemic lesion by MRI. (4) A peak systolic velocity of ≥200 cm/s and ≤1 collateral vessel that could be insonated on transcranial Doppler examination. The images were reviewed by at least two physicians who were allowed to resolve disagreement through discussion.
The exclusion criteria were as follows. Patients with large area brain infarction within 3 weeks, severe vessel tortuosity precluding the deployment of endovascular devices as determined by the executive committee, non-atherosclerotic lesion confirmed by high-resolution MRI, presence of Moyamoya disease, intracranial tumor, aneurysms or arteriovenous malformation, emergency arterial occlusion by embolus, or baseline modified Rankin Scale score of >3. High-resolution MRI was performed in patients without risk factors for intracranial atherosclerosis or with a lesion suspected to be non-atherosclerotic by regular CT, MRI, or DSA. All clinical and imaging data were reviewed centrally by the executive committee to decide whether the patient was eligible for enrollment in the study.
Device selection and stenting procedure
A self-expanding stent (Wingspan, Boston Scientific) and Apollo balloon-mounted stent (MicroPort Medical, Shanghai, China) were selected according to the features of the lesion and the experience of the operators. Generally speaking, the Apollo balloon-mounted stent was selected in patients with smooth arterial access and a Mori A lesion and the self-expanding stent was preferred in patients with a tortuous arterial access, or a Mori C lesion, or a lesion with a significant mismatch in the diameter between the proximal and distal segments.
Patients in our study received aspirin (100 mg/day) and clopidogrel (75 mg/day) for at least 5 days before the operation or a loading dose of 300 mg clopidogrel if the procedure was thought urgent. All angiographic procedures and angioplasty were performed by experienced neurointerventionists at all 20 stroke centers. Either general anesthesia or local anesthesia was chosen according to the operator’s experience and patient’s status. A bolus of 75 U/kg heparin was administered intravenously at the beginning of the procedure followed by half the dose 1 hour later. The 7F or 8 F guiding catheter was advanced into the internal carotid artery as high as the vessel tortuosity allowed. With the help of road mapping, stenosis in the intracranial artery was traversed with a 0.014 inch microguidewire and an angioplasty catheter was introduced across the stenosis. Recanalization was judged to be successful if the residual stenosis rate was less than 50% after stent placement. After the operation, a complete neurological examination and head CT was obtained to exclude ischemic stroke or potential hemorrhage. All patients were given a weight-based dose of low molecular weight heparin every 12 hours subcutaneously for 3 days.
Postprocedural management
Dual antiplatelet therapy with 100 mg/day aspirin and 75 mg/day clopidogrel was maintained for 3 months after stent placement, followed by platelet inhibitor monotherapy after that period. Aggressive medical therapy was implemented to achieve the following goals: systolic blood pressure <140 mm Hg, low-density lipoprotein <70 mg/dL (1.81 mmol/L) or a decrease by 50%, smoking cessation, lifestyle adjustments for obesity and sedentary state.
Patient follow-up
Outcomes were defined clinically and were confirmed radiologically by diffusion-weighted MRI in all patients with cerebrovascular complications after stenting. TIA was a focal neurological abnormality of sudden onset and brief duration (lasting <24 hours), and without cerebral infarction on the MRI scan. Ischemic stroke was defined as any sudden development of neurological deficits attributable to cerebral infarction. Hemorrhage stroke is the target blood vessel leak from CT scan. Follow-up information on clinical outcomes were collected and reviewed by at least one neurologist blindly. The information contains treatment assignment at study entry, the day of discharge, 1 month follow-up, and a face-to-face or telephone interview every 3 months. If necessary, DSA and brain imaging studies including MR angiography (MRA) and CT angiography (CTA) were obtained immediately in patients who developed neurological symptoms. DSA, CTA, or Transcranial Doppler (TCD) was recommended to all patients at long-term follow-up after the procedure.
Statistical analysis
Patients’ demographic, clinical, and stenting characteristics were presented as means (SD) for continuous variables and number or percentages for categorical data. The unpaired t-test or Mann–Whitney U test was used to identify the difference in the continuous variables. Statistical comparisons on categorical variables between the two groups were performed with χ² or Fisher’s exact tests (if the expected cell frequency was <5). The exact p value was calculated and a probability p<0.05 was considered as being of statistical significance. Statistical analysis was performed using the SPSS Version 17.0 software (SPSS, Chicago, Illinois, USA).
Result
Baseline characteristics
During a 2-year period, 115 patients with stroke were recruited into our study. A total of 41 patients (35.7%) underwent early stenting while in 74 patients (64.3%) late stenting was performed (Figure 1). All patients were confirmed by cerebral angiography to have a severe intracranial stenosis (70–99% degree of stenosis). Baseline and procedural characteristics are shown in table 1. There were no significant differences between the two groups with respect to risk factors except for diastolic blood pressure, which was higher in patients in the early stenting group than in those in the late stenting group (p=0.046). In the whole study population the median time from last ischemic event to stenting was 21 days (IQR 11–31 days), with early stenting a median of 8 days (IQR 4–12 days) and late stenting a median of 27.5 days (IQR 22–34 days). The stenosis arteries included the intracranial vertebral artery and basilar artery in 61.0% of patients in the early stenting group and in 37.8% of patients in the late stenting group (p=0.017). There were no significant differences between the early and late stenting groups in the length of stenosis, degree of arterial stenosis, Mori type, National Institutes of Health Stroke Scale (NIHSS) score, and risk factors.
Flow chart of participants.
Baseline characteristics of the patients
Procedural characteristics
Placement of the stent was successfully performed in all 115 patients and successful revascularization was achieved in all. Most patients (66/115) were treated under general anesthesia, but timing of stenting did not affect the selection of anesthesia (p=0.835). Patients in the early stenting group were more likely to be treated with the Apollo balloon mounted stent (23/41) and more patients in the late stenting group were treated with the Wingspan stent system (43/74), but the difference between the two groups was not statistically significant (p=0.144). Additionally, there was no statistical difference between the two groups in the length and diameter of the stent, operative time, or residual stenosis (table 2).
Comparison of procedural features
Complications associated with stenting within 3 days
Complications associated with stenting were identified in six patients within 3 days after the procedure. Four of these patients were in the early stenting group and experienced symptoms including weakness and numbness on one side, headache, and agitation. These patients were diagnosed as one ischemic stroke and one TIA attributed to perforator artery injury, one brain edema, and one hemorrhagic stroke induced by hyperperfusion. Two patients were in the late stenting group and were diagnosed as TIA induced by perforator artery injury. There was no statistical difference between the two groups (p=0.184). The symptoms of these patients gradually resolved after aggressive medical therapy within 3 days.
Long-term clinical follow-up after endovascular treatment
Table 3 shows the restenosis rate and major adverse events during the long-term follow-up period in each group. Our results showed that eight patients in the early stenting group and four patients in the late stenting group had a degree of restenosis ≥50%; the difference between the two groups was statistically significant (p=0.018). Two patients in the early stenting group and three in the late stenting group had a degree of restenosis ≥70% but no statistically significant difference was found between the two groups (p=0.836). The total rates of any ischemic stroke, TIA, hemorrhagic stroke, and death in the early stenting group was higher than in the late stenting group (9/41 vs 6/74, p=0.035). Furthermore, the recurrence rate of ischemic stroke in the early stenting group was higher than in the late stenting group (5/41 vs 2/74, p=0.041). No significant difference was found between the two groups in the individual rate of TIA, hemorrhagic stroke, and death (1/41 vs 3/74, p=0.651; 1/41 vs 0/74, p=0.177; 2/41 vs 1/74, p=0.256, respectively).
Comparison of long-term follow-up clinical outcomes
Discussion
To the best of our knowledge, this is the first study to demonstrate the impact of timing on clinical outcome by comparing early (≤14 days of the qualifying event) and delayed (>14 days) stenting for intracranial atherosclerotic artery stenosis. Patients with severe atherosclerotic intracranial artery stenosis within 14 days of stenting had a perioperative complications rate of 4/41 compared with just 2/74 for those who had late stenting. In addition, patients treated with delayed stenting had a relative vascular event rate of 6/74, which is lower than that in the early stenting group (9/41) on long-term follow-up. Third, patients treated within 14 days had a higher risk of in-stent restenosis than those in the delayed stenting group.
Our findings indicate that early stenting in intracranial artery stenosis may carry considerable hazards while delayed stenting seems to be relatively safe and effective. Previous studies have suggested that timing appears to be very important in minimizing perioperative complications. Patients with ischemic stroke or TIA treated with extracranial-intracranial bypass within 7 days had a higher perioperative stroke rate than those having late surgery.14 Meanwhile, patients with delayed (>14 days) carotid artery stenting had a lower 30-day stroke and death rate than those in whom the procedure was carried out <14 days of the qualifying event.13 Our previous study found that patients with symptomatic intracranial atherosclerotic stenosis treated with a stent had a rate of 4.3% of stroke, TIA, and death at 30-day follow-up, which is lower than the reports of the SAMPRRIS and VISSIT trials.10 One of the reasons for the lower rate of complications was that patients in our study had a longer time from the qualifying event to endovascular treatment than those in the SAMPRRIS and VISSIT trials (21 days vs 7 days and 12.3 days), which allowed better medical preparation of patients for the procedure, further reducing the thromboembolic events in the periprocedural period. Time from last symptom to procedure may affect the risk of perforator stroke associated with intracranial artery angioplasty and/or stenting. The time from last symptom to procedure of <18 days is a risk factor to induce perforator stroke.16 The plaques lying in the stenosis artery are unstable in the acute stage and the ‘snowplowing’ effect of intracranial stenting could result in periprocedural perforator stroke.17 In addition, the blood–brain barrier was broken down after the brain tissue suffered the ischemic injury.3 18 The artery and brain tissue have not enough time to heal in a short while, so the risks of overperfusion and cerebral hemorrhage were increased. Our study found one patient with overperfusion and one patient with hemorrhage in the early stenting group; no patient had overperfusion of intracranial hemorrhage in the later stenting group. Third, from our data we found that more lesions in the early group were in the intracranial vertebral and basilar artery, which has a higher risk of leading to perforator stroke than anterior circulation.19 With regard to our findings, we speculate that intracranial stenting on recently symptomatic, still vulnerable plaques are more likely to cause plaque dislodgement, perforator stroke, and intracranial hemorrhage. Fourth, a previous study found good collaterals were developed in the later stenting group which sustained the blood supply of the occlusion artery and reduced the risk of ischemic events.20
In our study we also found that stroke patients treated within 14 days represent a high restenosis rate and qualifying event rate on long-term follow-up. The decline in stroke risk over time may correspond with healing mechanisms at vulnerable plaques, transforming unstable plaques into more stable ones.21 More stroke was induced by plaque rupture.22 Ruptured plaque may lead to in-stent restenosis during endothelium repair if the stent is inserted within 14 days, while stenting after the endometrial repair can decrease the rate of in-stent restenosis. Moreover, delayed stenting allowed patients more time for better medical preparation including dual antiplatelet therapy and controlling the risk factors to reduce the thromboembolic events and restenosis.23 In our study, all patients in the delayed group received dual antiplatelet therapy at least 5 days before stenting and the blood pressure was well controlled. On the other hand, more patients in the early group were not treated with dual antiplatelet therapy and the diastolic pressure was not as controlled as in the delayed group. More stenosis occurred in the vertebrobasilar artery of patients in the early stenting group. A previous study suggested that patients with vertebrobasilar artery stenosis have a higher risk of restenosis than those with anterior circulation stenosis.24 25
Some limitations exist in our study. First, stroke patients with symptomatic intracranial artery stenosis carry a high risk of recurrent stroke at the acute stage and the risk seems to fall rapidly over the subsequent period.26 So, part of the qualifying event of patients in the early stenting group should be defined as recurrent stroke rather than attributed to stenting. We did not eliminate the bias in our research. Second, the percentage of patients with vertebrobasilar artery stenosis was significantly higher in the early stenting group, which resulted in a limitation and bias in our study. Third, the trial was not designed as a randomized double-blind study and a low number of patients were recruited, so it is difficult to find an accurately comparable control group. We encourage further investigation into the timing of stent placement in the subgroup of patients with symptomatic intracranial artery stenosis.
Conclusions
Stent placement in the setting of ischemic stroke caused by intracranial atherosclerotic artery stenosis within 14 days may confer a higher risk of long-term cerebral vascular events and lead to a higher risk of restenosis.
References
Footnotes
Contributors YZ: database creation, data mining, project planning, writing of first manuscript draft. YJS: literature search, database creation, data mining, project planning. XL: review of angiograms, proofreading of manuscript, met statisticians for data analysis, literature search. THL: data mining, proofreading of manuscript. PL: literature search, imaging CT and MRI review. HXW: proofreading of manuscript. JD: review of angiograms, proofreading of manuscript. ZRM: proofreading of manuscript. GWL: database creation, data mining, project planning, writing of first manuscript draft, guarantor.
Funding This work was supported by the National Natural Science Foundation of China grant number 81371290, Beijing High-level Personnel Funds grant number 2013-2-019 and Science Foundation for Young Scientists of Affiliated Hospital of Qingdao University grant number 3051.
Competing interests None declared.
Provenance and peer review Not commissioned; externally peer reviewed.
Patient consent for publication Not required.