|Year : 2016 | Volume
| Issue : 2 | Page : 64-70
Use of the Smart nitinol stent system for the treatment of severe atherosclerotic carotid stenosis: study protocol for a retrospective, non-randomized, long-term parallel controlled trial
Zhi-gang Ma, Yu-heng Sun, Xiao-xin Peng, Hong-tao Hu
Department of Neurology, Beijing Jishuitan Hospital, Beijing, China
|Date of Web Publication||7-Jul-2016|
Department of Neurology, Beijing Jishuitan Hospital, Beijing
Source of Support: This study was supported by Capital Medical Development Research Foundation, China, No. 2003-1002, Conflict of Interest: None
Background: The carotid artery should be stented in patients with 70-90% stenosis owing to the high risk of stroke. The self-expanding Smart nitinol stent system is a popular treatment for carotid artery stenosis, because it is easy to manipulate and deploy, and endothelialization is rapid.
Methods/Design: We conducted a retrospective, single-center, non-randomized, parallel controlled trial at Beijing Jishuitan Hospital, China. A cohort of 103 patients with severe atherosclerotic carotid stenosis was included in the analysis. Treatment was undertaken according to each patient's wishes after weighing the options: a Smart nitinol stent system (Cordis Corporation, Miami, FL, USA) was used in 40 patients, while 63 were managed conservatively with antiplatelet drugs. The primary outcome is the degree of disability and dependence 2 years after treatment, assessed by the modified Rankin Scale (mRS). The secondary outcomes are mRS score 90 days and 1 year after treatment, recurrence of cerebrovascular events, and severity of neurologic deficit measured using the National Institutes of Health Stroke Scale 1 and 2 years after treatment.
Discussion: Previous studies of the Smart nitinol stent system for the treatment of carotid stenosis are mostly self-controlled case series or small cohort studies with short follow-up periods. Consequently, the long-term influence of Smart nitinol stent deployment on the risk of cerebrovascular events and long-term outcomes are not known. This trial illuminates the therapeutic benefits of the Smart nitinol stent system in a 2-year follow-up study of a large cohort of patients with severe atherosclerotic carotid stenosis.
Trial registration: This trial was registered at ClinicalTrial.gov (NCT02800174).
Ethics: The study protocol was approved by the Ethics Committee of Beijing Jishuitan Hospital, China (approval number: 201605-01) and conducted in accordance with the guidelines of the Declaration of Helsinki, formulated by the World Medical Association.
Informed consent: Written informed consent was obtained from participants or their guardians.
Keywords: clinical trial; carotid artery stenosis; Smart stent; nitinol stent system; atherosclerosis; non-randomized parallel controlled trial
|How to cite this article:|
Ma Zg, Sun Yh, Peng Xx, Hu Ht. Use of the Smart nitinol stent system for the treatment of severe atherosclerotic carotid stenosis: study protocol for a retrospective, non-randomized, long-term parallel controlled trial. Clin Trials Degener Dis 2016;1:64-70
|How to cite this URL:|
Ma Zg, Sun Yh, Peng Xx, Hu Ht. Use of the Smart nitinol stent system for the treatment of severe atherosclerotic carotid stenosis: study protocol for a retrospective, non-randomized, long-term parallel controlled trial. Clin Trials Degener Dis [serial online] 2016 [cited 2019 Jun 26];1:64-70. Available from: http://www.clinicaltdd.com/text.asp?2016/1/2/64/184746
Conflicts of interest
ZGM conceived and designed the trial protocol. ZGM, YHS, and HTH recruited the patients and were responsible for data collection and analysis. XXP performed surgery. All authors approved the final version of this manuscript for publication.
This paper was screened twice using CrossCheck to verify originality before publication.
This paper was double-blinded and stringently reviewed by international expert reviewers.
| Background|| |
Atherosclerotic carotid stenosis is an independent risk factor for ischemic cerebrovascular disease (Prabhakaran et al., 2006). Stenting of carotid artery stenosis is safe, quick and minimally invasive. Stenting improves cerebral blood flow and prevents plaque rupture (Sun et al., 2005). Carotid artery stenosis of 70-90% is considered the highest risk for stroke, and is a compelling indication for stenting (Han and Ye, 2002). The Smart stent system (Cordis Corporation, Miami, FL, USA) is a nitinol self-expanding stent that is soft, elastic, has uniform radial tension and is readily endothelialized (Zhao et al., 2005).
Phatouros et al. (2000) treated four patients with carotid artery stenosis > 70% using Smart stents and < 20% residual stenosis was achieved in all cases; no transient ischemic attacks or new strokes occurred during a follow-up period of 6 months. Drescher et al. (2002) also used Smart stents in 13 patients with severe stenosis and encountered no complications during a 6-month follow-up period. Wholey et al. (2003) reported that the rates of neurologic complications and restenosis were decreased after application of either balloon-mounted or self-expanding stents in a cohort of over 500 patients. Three-year follow-up results have shown that balloon-mounted stents lead to better vessel patency than self-expanding stents, but that balloon-mounted stents are vulnerable to compression. Lownie et al. (2005) examined the efficacy of self-expanding Smart stents in 21 patients with severe symptomatic carotid artery stenosis (> 70%) without angioplasty. Patients were followed up for an average period of 19 months. Smart stents improved vascular stenosis and blood flow without the need for balloons or adjunctive protection devices.
Zhao et al. (2005) used Smart stents to treat patients with carotid artery stenosis > 65%, and found the treatment safe and effective, while observing no severe complications. Li et al. (2002) treated patients with carotid bifurcation and origin stenosis > 50% with Smart stents, and reported improved neurologic function with no strokes or transient cerebral ischemic attacks during a follow-up period of 13-14 months. Chen et al. (2003) used Smart stents to treat 48 patients with carotid artery stenosis of 75-99%, achieving favorable clinical outcomes in 43 (89.6%), with no recurrence of stenosis during a relatively short follow-up period of 1-6 months, and few postoperative complications or sequelae.
In a cohort of 38 patients with extracranial artery stenosis treated with Smart stents and followed up for an average of 18 months, satisfactory clinical outcomes were achieved in 33 (86.8%) (Sun et al., 2005). These investigators also treated another cohort of 41 patients with carotid artery stenosis with Smart stents, and concluded that stent deployment was an effective and safe treatment for carotid artery stenosis (Gao et al., 2006).
There is no long-term or randomized controlled trial evidence of the therapeutic benefits of Smart nitinol stenting in carotid stenosis. This study is a non-randomized controlled trial, in which deployment of the Smart stent system will be compared with conservative management with antiplatelet drugs in a group of patients with severe atherosclerotic carotid stenosis followed up for 2 years.
| Methods/Design|| |
A retrospective, single-center, non-randomized, parallel controlled trial.
Beijing Jishuitan Hospital, China.
Patients with severe atherosclerotic carotid stenosis were screened against our inclusion and exclusion criteria (see below). After providing informed consent and completing a baseline evaluation, 103 eligible patients with severe atherosclerotic carotid stenosis underwent either Smart stent implantation (Stent implantation group, n = 40) or conservative management with one or more antiplatelet drugs (drug group, n = 63) according to each patient's informed choice ([Figure 1]). The primary outcome is the extent of disability and dependence 2 years after treatment, assessed by the modified Rankin Scale (mRS) (Banks et al., 2007). The secondary outcomes are functional status measured by mRS 90 days and 1 year after treatment, the incidence of vascular events, and the severity of neurologic deficit measured using the National Institutes of Health Stroke Scale (NIHSS) 1 and 2 years after treatment (Kwah and Diong, 2014).
|Figure 1: Flow chart of the trial protocol.|
Note: mRS: Modified Rankin Scale; NIHSS: National Institutes of Health Stroke Scale
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The cohort comprised 103 patients with severe atherosclerotic carotid stenosis complicated by stroke or transient cerebral ischemia diagnosed in the Department of Neurology, Beijing Jishuitan Hospital, China.
Patients meeting all the following criteria were considered for admission to the trial:
- Age > 18 years
- Of either sex
- Carotid artery stenosis caused by atherosclerotic plaque
- Diagnosed with severe atherosclerotic carotid stenosis according to a previously described method (North American Symptomatic Carotid Endarterectomy Trial Collaborators, 1991)
- Severe carotid artery stenosis confirmed by transcranial Doppler and carotid duplex ultrasonography
- Provision of informed consent regarding trial procedure
Patients presenting with any of the following were excluded from the trial:
- Carotid artery stenosis caused by fibromuscular dysplasia, Takayasu's arteritis or radiation injury
- Severe central nervous system disorders, such as complete loss of cerebral function on the affected side with cerebral paralysis
- Life expectancy < 2 years because of intracranial tumors or other diseases
- Pregnant or lactating
- Renal impairment (if use of contrast agent will worsen renal function)
- Concurrent hemorrhagic disease or contraindication to antiplatelet or anticoagulant therapies for safety reasons
- Leakage of contrast agent indicative of vessel perforation
- Dilated aneurysm proximal or distal to stenotic foci
- Allergy to stent material
- Complete occlusion of the carotid artery or lesion length > 10 mm, accompanied by intravascular thrombus and multiple segments of stenosis confirmed by imaging examination
- Intracranial hemorrhage within 3 weeks or large areas of cerebral infarction within 4 weeks of treatment
- Unable to or declined to cooperate with follow-up examination
- Unable to provide informed consent because of intellectual disability or language disorder
Patients were withdrawn from the trial if one of following conditions occurred:
- Upon the request of the sponsor of medical research
- Withdrawal of informed consent and declining to continue treatment
- Loss of contact with the patient during the follow-up period
A cohort of 103 patients with severe atherosclerotic carotid stenosis underwent either carotid Smart nitinol stenting, or were managed conservatively with antiplatelet medication. Patients made an informed choice about treatment, guided by clinicians; patients were not allocated to treatment groups.
As grouping was performed according to patient choice, neither clinicians nor participants were blinded to the treatment, but results were evaluated using a blinded method.
The primary endpoint of this trial is functional prognosis 2 years after treatment, evaluated by the mRS. Sample size calculations were informed by the findings of a previous report (Wang et al., 2012). Sample size analysis was performed following the per-protocol principle for two-sample t-tests (version 11.0, Power Analysis and Sample Size, NCSS Statistical Software, Kaysville, UT, USA). The level of significance was α = 0.05 and the power was 1-β = 0.80. The final effective sample size was determined to be n = 224 per group. We identified 520 patients with extracranial artery (internal carotid artery outer segment, vertebral artery or subclavian artery) stenosis, 103 of whom had severe carotid artery stenosis.
Patients from the wards and clinics in our hospital were informed about the trial by their attending physician. Research assistants continued the enrollment process by screening eligible participants according to the inclusion/exclusion criteria. After providing written informed consent, all potential participants were screened according to the inclusion and exclusion criteria above.
Stent implantation group
Before intervention, clopidogrel (75 mg/d), aspirin (100 mg/d) and atorvastatin (40 mg/d) were prescribed. One week later, aortic arch and aortocranial angiography were performed under general anesthesia to determine the site, range and extent of the lesion and the status of the cerebral microcirculation, and consequently to inform the treatment strategy and the selection of the correct size of self-expanding nitinol stent system. After administration of 40-60 mg of heparin via the sheath, an exchange guide wire (diameter 0.0381 Fr) was introduced into the external carotid artery. A 7-Fr-long sheath was advanced into the common carotid artery on the affected side using the exchange guide wire and boluses of 0.9% saline solution under pressure. A 280-mm-long guide wire (diameter 0.035 Fr or 0.018 Fr) was advanced into the normal vessels at the narrowed distal end of the carotid artery. Under the guidance of the exchange guide wire, the Smart stent was placed across the narrowed part until it was fully covered and both ends of the Smart stent lay > 1 cm beyond it. For stenosis of the carotid bifurcation, one-third of the Smart stent was deployed in the distal narrowed part, and the remaining two-thirds lay in the proximal narrowed part. Under fluoroscopic guidance, the Smart stent was deployed in the ideal position by actuating the stent releasing system. After removal of the stent releasing system, the stent should have been stably positioned. If calcified or rigid plaques caused the stent to sit in an unsatisfactory position, a posterior dilation balloon (diameter 5-6 mm) was placed in the stent using a guidewire. The posterior dilation balloon was slowly inflated with a mixed solution of 50% contrast agent and 50% 0.9% NaCl saline solution using a 5-mL syringe, and then rapidly deflated. After one or two dilations, angiography was performed to confirm that the stent had been successfully dilated and that the vascular diameter had been restored to normal. Cerebral angiography was then performed to examine flow in the cerebrovascular circulation. In some patients, brain-protecting devices, such as an Angioguard (Cordis Corporation) or an intercepting screen, were used to prevent embolus shedding.
The Smart nitinol stent system was used (import product registration number YZB/USA 0115-2008; Nitinol stent system, trade name SMART Control). The stent system comprises a self-expanding stent and a delivery system. The self-expanding stent is composed of a nickel titanium alloy and the ends of the stent are equipped with tantalum radiopaque markers. The Smart nitinol stent system is sterilized with ethylene oxide gas and is intended for single use only.
Patients with carotid artery stenosis treated conservatively were commenced on an indefinite course of one or more oral antiplatelet drugs. The antiplatelet regimes comprised 100 mg or 300 mg aspirin before sleep with clopidogrel 125 mg or 250 mg daily; or 75 mg clopidogrel before sleep daily.
- mRS score at 2 years after treatment. Patients' disability and dependence were evaluated using the mRS. The mRS is a 7-point scale used to evaluate a patient's functional recovery. A score of 0 indicates that the patient is asymptomatic; 1, no significant disability despite symptoms, able to carry out all usual duties and activities; 2, slight disability, unable to carry out all previous activities, but able to look after own affairs without assistance; 3, moderate disability, requiring some help, but able to walk without assistance; 4, moderately severe disability, unable to walk without assistance and unable to attend to own bodily needs without assistance; 5, severe disability, bedridden, incontinent and requiring constant nursing care and attention; 6, dead.
- mRS scores at 90 days and 1 year after treatment.
- The recurrence of cerebrovascular events. The incidences of transient cerebral ischemia, cerebral infarction, cerebral hemorrhage or death from cerebrovascular diseases were recorded.
- NIHSS score at 1 and 2 years after treatment. Patient's neurologic deficits were graded with the NIHSS score. The NIHSS is a 43-point scale, with higher scores indicative of more severe neurological deficits. The NIHSS scale consists of 11 items, including (1) level of consciousness, (2) best gaze, (3) visual fields, (4) facial palsy, (5) left (right) arm motor, (6) left (right) leg motor, (7) limb ataxia, (8) sensory, (9) best language, (10) dysarthria, and (11) extinction and inattention.
Patients' baseline demographic and clinical characteristics are shown in [Table 1], and the schedule for outcome assessments is shown in [Table 2].
|Table 1: Baseline information of included patients subjected to Smart stent implantation (stent implantation group) and antiplatelet medication (drug group)|
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Possible adverse events associated with Smart stent implantation include vascular spasm, bradycardia, hypotension, luxury perfusion syndrome, intraoperative thrombosis and thrombus detachment, ischemic stroke, intraoperative hypertension, postoperative hypotension and hypoglycemia. If adverse events occur, details of the event including the date of occurrence, measures taken related to the treatment, causal relationship with the treatment and treatment of the adverse event will be reported to the principal investigator and the institutional review board within 24 hours.
Data collection, management, analysis and open access
All data will be collected in case report forms and collated. Collated data were input into an electronic database using a double-data entry strategy by trained professional staff. Information accuracy was checked when all recruited patients are followed up. The database was locked by the researcher in charge and was not be altered. All information relating to this trial was preserved by Beijing Jishuitan Hospital, China. The electronic database was fully disclosed to a professional statistician for statistical analysis. Anonymized trial data were published at http://www.figshare.com.
Statistical analysis was performed by a statistician blinded to grouping using SPSS 14.0 software. Normally distributed measurement data were expressed as the mean ± standard deviation, and numeration data as the frequency. The two sample t-test was used to compare the means of measurement data between the stent implantation and drug groups. The chi-squared test was used to compare numeration data between the groups. Multivariate regression analysis will be used to compare mRS scores 2 years after treatment. Kaplan-Meier and Cox Proportional Hazards Survival regression analysis will be used to examine survival time and survival state. A P value < 0.05 will be considered statistically significant.
Trial progression will be reported to the ethics committee of Beijing Jishuitan Hospital, China every 6-12 months and the trial's status will be updated in the registration database.
The electronic database will be preserved in a dedicated password-protected computer and managed by a data management professional. Data recorded on paper will be preserved in a secure, locked place for future viewing.
| Discussion|| |
The Smart stent used in this trial can capture shedding plaques to avoid thrombosis, and address subplaque bleeding or intimal shedding, both of which could acutely occlude the lumen. The self-expanding stent is constrained in the sheathed delivery system and is introduced into the site of stenosis. After sheath retraction, the stent opposes the vascular wall depending on the balance between the tension of the self-expanding stent and the elastic tension of the vascular wall. The Smart self-expanding stent shows favorable flexibility, which facilitates the passage of stents through tortuous vessels and calcified tissue, and conforms to the natural curve of the vascular wall. The stents are not easily deformed or compressed, even if they are placed across a mobile joint. In this study, we examined the effects of Smart stent implantation on a large cohort of patients with severe carotid artery stenosis in a non-randomized controlled long-term follow-up trial. Multivariate regression analysis was performed to examine whether stent implantation independently predicts favorable functional prognosis and/or is an independent risk factor for recurrence of cerebrovascular events.
Interventional treatment is recommended for patients with stroke or transient ischemic attack complicated by atherosclerotic carotid artery stenosis, and the indications for treatment should be adhered to strictly. After stent implantation, there is a need to take antiplatelet drugs for a long period. For patients with carotid artery stenosis and concurrent diabetes mellitus, caution should be exercised when performing intravascular stenting, as many vessels are often involved and stenosis is rapidly progressive. Also, in diabetes mellitus, atherosclerosis is often widespread, and may affect the aorta, coronary arteries, renal arteries and peripheral arteries as well as the cerebrovascular system. End organ damage caused by diabetes mellitus increases the risk of stent implantation.
There are many factors that cause restenosis after carotid artery stenting, including the site and length of stenosis, the establishment of collateral circulation, the experience and skill of the operator, the extent of patency achieved, and concurrent disease such as diabetes mellitus. Carotid artery ultrasound imaging allows plaque motion to be visualized, which helps inform an assessment of the potential risks and benefits of interventional treatment. For patients who have received interventional treatment, control of other risk factors, such as diabetes mellitus and hypercholesterolemia, reportedly reduces the incidence of in-stent restenosis (Paraskevas et al., 2007; Reid et al., 2007).
The findings of this trial should expand the evidence base for the rational use of the Smart nitinol stent system in the treatment of severe carotid artery stenosis.
This trial was completed in 2008. Related results are shown in [Table 3], [Table 4], [Table 5].
|Table 3: Modified Rankin Scale scores at different time points in each group|
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|Table 4: Multivariate regression analysis of modified Rankin Scale results 2 years after treatment in each group|
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|Table 5: Multivariate Cox regression analysis of cerebrovascular events (stroke, myocardial infarction, death from cerebrovascular diseases) in two groups|
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[Table 1], [Table 2], [Table 3], [Table 4], [Table 5]