Balloon-expandable stents for treatment of symptomatic middle cerebral artery stenosis: Clinical outcomes during long-term follow-up

Abstract

Background

Insertion of a balloon-expandable stent (BES) in patients with symptomatic intracranial atherosclerosis is a treatment option for reperfusion therapy. In this study, we retrospectively reviewed clinical outcomes during long-term follow-up after insertion of balloon-expandable stents in patients with symptomatic middle cerebral artery (MCA) stenosis.

Methods

Institutional review board approval was obtained for retrospective review of patient data. Thirty-four patients (15 men, 19 women; median age, 67.5 years) with symptomatic MCA stenosis underwent balloon-expandable stent insertion between June 2008 and December 2010. Patient records were reviewed for angiographic findings and clinical outcomes during long-term follow-up.

Results

Of these patients, 22 presented with acute ischemic stroke with underlying MCA atherosclerosis and had good clinical outcomes (modified Rankin Scale score (mRS): 0–2) after reperfusion therapy. Indications for stenting for the remaining 12 patients were recurrent transient ischemic attacks (TIAs) refractory to medical therapy and MCA stenosis greater than 70%. During the poststenting follow-up period, which ranged from 61 to 108 months (median, 67.5 months), a TIA occurred in five patients. Of these five patients, one experienced a complete reocclusion of the MCA stent, and three had symptomatic restenosis. The remaining 29 patients did not experience any further ischemic events or restenosis during the follow-up period.

Conclusions

In our study, treatment with balloon-expandable stents in patients with symptomatic MCA stenosis resulted in low recurrence rates for both ischemic events and restenosis during long-term follow-up.

Introduction

Intracranial atherosclerotic stenosis (ICAS) is considered to be a leading cause of ischemic stroke, especially in those of African descent, Asians and Hispanics.^1,2 In the United States, intracranial arterial stenosis causes 8% to 10% of all ischemic strokes, and the subsequent risk of recurrent stroke in these patients may be as high as 15% per year.^3–5

Two important trials, the Stenting and Aggressive Medical Management for Preventing Recurrent Stroke in Intracranial Stenosis (SAMMPRIS) trial and the Intracranial Stent Study for Ischemic Stroke Therapy (VISSIT) trial, both showed that angioplasty and stenting do not add any benefit to aggressive medical treatment.^6,7 However, patients with intracranial atherosclerosis that is unresponsive to optimal medical treatment may still require reperfusion therapy to improve clinical outcomes.^7–9 In addition, there may be a role for stenting in subgroups of symptomatic ICAS patients who are at increased risk of stroke despite aggressive medical treatment. Finally, our previous study showed that balloon-expandable stent (BES) deployment is effective in patients with immediate reocclusion of intracranial arteries due to underlying atherosclerotic stenosis after successful intraarterial thrombolysis (IAT).¹⁰

According to the SAMMPRIS and VISSIT trials, invasive treatments have not provided long-term benefit in recurrent cerebrovascular ischemia over medical therapy alone. The assessment of long-term outcomes for patients treated with intracranial stenting for symptomatic middle cerebral artery (MCA) stenosis is difficult. Most patient series have been limited to reporting short to midterm outcomes and lack long-term follow-up. Therefore, the purpose of our study was to review long-term clinical outcomes after stenting in patients with symptomatic severe MCA stenosis, either refractory to medical therapy or refractory to IAT, which showed instant reocclusion or recurrence of MCA stenosis.

Materials and methods

Our institutional review board had previously approved all intracranial stenting procedures for MCA stenosis, and we obtained its approval for the retrospective review of patient data as well. In addition, written informed consent was obtained from each patient or the patient’s family for review of their records.

Patients

Between June 2008 and December 2010, patients with severe (≥70%) symptomatic MCA stenosis underwent BES placement. Patient records were retrospectively analyzed from a prospectively collected database in the neuro-interventional data registry at our institution. Patients who underwent stenting were divided into two groups. The first group consisted of patients in whom transient ischemic attacks (TIAs) or stroke occurred in spite of maximum medical management, which included antiplatelet therapy (aspirin 100 mg plus clopidogrel 75 mg or ticlopidine 250 mg/daily), statin medication, and blood pressure medication, which had been controlled using one or more medications from each major class of antihypertensive agent. The second group included patients who experienced immediate reocclusion after initial successful IAT of an acute MCA obstruction.

We excluded patients who were at risk of severe bleeding, exhibiting, for example, cerebral infarction volume of more than one-third of the affected vascular territory. We also excluded patients who were noted to have severe cerebral edema, other intracranial hemorrhage, or uncontrolled hypertension. Patients with clinically significant tandem stenosis in the extracranial or intracranial internal carotid artery were also excluded. All patients were examined with noncontrast computed tomography (CT) scan for evidence of hemorrhage or evidence of early cerebral infarction before and within 24 hours after endovascular treatment. A magnetic resonance (MR) scan including MR angiography, diffusion-weighted and perfusion-weighted imaging was performed in all available patients for evaluation of infarction volume and perfusion status in target territory. Our final study group consisted of 47 patients who underwent BES placement for symptomatic MCA stenosis refractory to medical therapy.

Endovascular procedures

All angiographic procedures and angioplasty were performed by one radiologist (H.S.K.) with 13 years of experience in neurovascular interventional radiology. Patients received 300 mg of clopidogrel or 200 mg of aspirin daily for at least three days before the procedure. A bolus of 3000 U of heparin was given intravenously at the beginning of the procedure to all patients. With the patient under local anesthesia, complete diagnostic cerebral angiography was performed in each patient.

During the study period between 2008 and 2010, patients with acute ischemic stroke and underlying MCA atherosclerosis underwent IAT with urokinase and mechanical clot disruption with a microcatheter and microguidewire. If immediate reocclusion of recanalized arteries due to underlying MCA stenosis occurred during IAT, an intracranial stent was placed at the stenosis to restore MCA flow. If the patient experienced recurrent TIA or subcortical/internal border zone infarction in the MCA distribution territory that was refractory to medical therapy, an intracranial stent insertion was performed at the MCA stenosis, following diagnostic cerebral angiography.

To begin the procedure, a 7- or 8-F guiding catheter was inserted into the cervical portion of the internal carotid artery over an exchange wire. With the use of road mapping, stenosis in the MCA was traversed with a 0.014-inch microguidewire, and a balloon angioplasty catheter was introduced across the stenosis. Balloon angioplasty was performed using a balloon with a smaller diameter than the vessel and a minimum length required to cover the lesion, and was followed by stenting. The BES stent (Flexmater; Abbott, Abbott Park, MI, USA) was sized to approximate the diameter of the normal patent vessel. The stent length was selected to be equal to or exceed the length of the target stenotic lesion (2.0–2.5 mm diameter, 9–12 mm length). The proximal one-third to one-half of the stent was positioned at the point of occlusion. When indicated, stent deployment was performed with a balloon sized to 80% of the predicted vessel diameter. Postprocedural angiography was performed by means of a guiding catheter, and the degree of residual stenosis and the presence of thrombosis or dissection were recorded. Procedural success was defined as successful deployment of a stent with residual stenosis of <50%. An experienced neuroradiologist, blind to the aims of the study, analyzed the angiography results, in accordance with the methods of the Warfarin-Aspirin Symptomatic Intracranial Disease (WASID) trial,⁴ before and after stenting.

Postprocedural management

After the procedure, a complete neurologic examination was performed on each patient by neurologists. A National Institutes of Health Stroke Scale score was recorded before treatment, 24 hours after treatment, and on the day of discharge. After discharge, patients received daily doses of 100 mg of aspirin and 75 mg of clopidogrel.

Follow-up and clinical outcome

After the treatment, an immediate postprocedure angiogram was obtained, a neurological examination was performed, and a new modified Rankin Scale (mRS) score was attributed to each patient. Magnetic resonance imaging (MRI) was performed in case of clinical deterioration. The primary outcomes evaluated during the follow-up period were: (a) the occurrence of any stroke, including ischemic or hemorrhagic stroke; (b) the occurrence of TIA; and (c) death after stenting. Ischemic stroke was defined as a new focal neurological deficit of sudden onset lasting at least 24 hours, which was not associated with intracranial hemorrhage on CT or MRI. Hemorrhagic stroke was defined as a new cerebral hemorrhage, involving the cerebral parenchymal area, subarachnoid space, or intraventricular region, that was associated with a seizure or with symptoms or signs lasting 24 hours or longer. A TIA was defined as a transient episode of neurological dysfunction, caused by focal brain or retinal ischemia, that lasted for at least 10 minutes but resolved within 24 hours, regardless of any changes seen on diffusion-weighted MRI.

For patient follow-up, computed tomographic angiography or transcranial Doppler (TCD) ultrasound (US) and clinical examinations were scheduled annually, or more frequently as required by individual patient considerations. Catheter angiography follow-up was performed when in-stent restenosis was suspected clinically. In case of clinical deterioration or confirmed postprocedure stroke, a new clinical score was determined. Follow-up information was obtained from chart review and/or telephone interview by one of two authors. All symptomatic events were identified on the basis of clinical diagnoses assigned by the attending neurologists. Secondary outcomes were: (a) the occurrence of in-stent restenosis, (b) clinical changes resulting in an mRS determination, and (c) any delayed procedural complication during the follow-up period. CT angiography was used annually to determine the percentage of stenosis of a stented intracranial artery. In-stent restenosis was defined as angiographically verified stenosis of greater than 50% within the stent or at the edge of the stent. In-stent thrombus was defined as a small hypodense lesion, without stenosis, situated within the stent.

Statistical analysis

Frequencies and percentages were calculated for categorical variables. Means, standard deviations (SDs), medians, and ranges are given for continuous variables. When a patient was treated for two lesions, each lesion was analyzed separately and categorized independently. Survival rates were calculated from the date of the endovascular treatment. The cumulative occurrence of major adverse events, including restenosis, death, and stroke or TIA during the follow-up period, was analyzed by the Kaplan-Meier method. Statistical analyses were performed using SPSS software (version 18.0; IBM, Somers, NY, USA).

Results

Patient characteristics

Of 47 patients studied, procedural success was achieved in 45 (95.7%). Of the 45 patients who underwent BES due to MCA stenosis, 11 were excluded for the following reasons: (a) bypass surgery because of in-stent reocclusion that occurred within 48 hours after stent deployment (n = 2); (b) death due to aspiration pneumonia during medical management, recurrent stroke or myocardial infarction after three months (n = 3); (c) poor functional outcomes at three months after discharge (mRS > 2) (n = 4); and (d) follow-up loss during five years (n = 2). An evaluable group of 34 patients, including 15 men and 19 women (median age, 68 years), with good functional outcomes (mRS < 2) at three months after discharge, were enrolled in this study.

Of these 34 patients, 12 presented initially with acute ischemic stroke and underlying MCA stenosis and exhibited reocclusion of the MCA during IAT. Stenting indications for the remaining 22 were recurrent TIA and/or stroke, refractory to medical therapy, and MCA stenosis greater than 70%. The baseline characteristics of all patients are presented in Table 1. The most common risk factor was hypertension, which occurred in 52.9% of all the patients.

Table 1.

Patient characteristics.

	No. (%)
Total	34
Age, years
Median (IQR)	68 (57–72)
Range	40–82
Sex, male	15 (44.1)
Stenosis
% (median, IQR)	77 (73–81)
Length, mm (median, IQR)	5.2 (4.1–6.0)
Atherosclerosis risk factors
Cardiac disease	9 (26.5)
Hypertension	18 (52.9)
Smoking	13 (38.2)
Hyperlipidemia	12 (35.3)
Diabetes mellitus	9 (26.5)
Acute stroke, no. (%)	12 (35.3)
Lesion side, right, no. (%)	19 (55.9)
Follow-up period, months
Median (IQR)	69 (64–77)
Range	61–108

IQR: interquartile range.

Long-term outcomes

The median patient follow-up interval was 69 months (range 61 to 108 months). During the follow-up period, six patients underwent cerebral angiography for evaluation of possible restenosis because of recurrent symptoms of cerebral ischemia. Five patients (14.7%) had either restenosis (n = 4) or reocclusion (n = 1) (Figure 1). Of the four patients with restenosis, three had in-stent restenosis and one had stenosis of the distal margin of the MCA stent. Causes of restenosis included the presence of thrombus. Treatment of the four patients with restenosis varied. One underwent angioplasty of the stenotic lesion, and three were placed on optimal medical treatment. Of the three patients treated medically, only one experienced mild recurrent ischemic symptoms during the follow-up period. Another patient, whose stent distal margin was located at the MCA bifurcation, had reocclusion of the MCA stent after eight months but did not have any recurrence of clinical symptoms during the 68-month follow-up period (Figure 2). The remaining 29 patients (85.3%) did not experience any further ischemic events or restenosis during the follow-up period. The one-year and five-year patency rates of MCA stents in the patients with good clinical outcomes were 94.1% and 84.7%, respectively (Figure 3).

Figure 1.

A 64-year-old woman with recurrent ischemic symptoms during optimal medical treatment. (a) Initial left cerebral angiography shows severe stenosis of the left middle cerebral artery. (b) Volume-rendering imaging after balloon-expandable stent insertion shows good patency of the previous stenotic lesion. (c) Cerebral angiography after 62 months, ordered because of a focal embolic symptom, shows focal restenosis of stent distal margin.

Figure 2.

A 50-year-old man with acute right middle cerebral artery (MCA) occlusion. (a) Initial right cerebral angiography shows complete occlusion of the right MCA. (b) Cerebral angiography after mechanical thrombectomy shows underlying severe stenosis of the right MCA (arrows). (c) Cerebral angiography after balloon-expandable stent insertion shows good patency of the stenotic lesion. Note the distal margin of the stent located in the MCA bifurcation (arrow). (d) Cerebral angiography after eight months, ordered because of a mild ischemic symptom, shows the complete occlusion of the right MCA.

Figure 3.

Kaplan-Meier estimate of event-free rates of middle cerebral artery stents.

Discussion

In the present study, angioplasty and stenting were successfully performed on 45 of the 47 lesions addressed, resulting in a 95.7% technical success rate. In addition, 29 of 34 patients (85.3%) in our study group had no further cerebral ischemic events attributed to MCA treatment during a follow-up period range of 61–108 months (median, 67.5 months). On the basis of our results, we believe that insertion of intracranial BES for symptomatic MCA stenosis, refractory to medical therapy or IAT, can be a feasible treatment alternative for reducing the risk of further TIA or stroke, if it can be performed safely.

In the previous WASID study,⁴ 25% of patients presenting with 70% to 99% MCA stenosis experienced a stroke in the ipsilateral vascular distribution within two years, despite treatment with either warfarin or aspirin. Given the high failure rate of this medical therapy, patients treated in this way represent the population most likely to benefit from revascularization therapies. Recurrent TIAs, especially with a crescendo pattern, and recurrent stroke in patients undergoing antiplatelet and/or anticoagulation therapy, have led to increased use of endovascular procedures as alternative treatment, especially as the safety of those procedures has increased. There is, however, some disagreement concerning the choice between a BES or a self-expandable stent (SES). Advocates of SES claim that the balloon-mounted stents developed for cardiology are less flexible than the self-expandable stent. However, implantation of an SES is usually a two-step procedure, requiring an exchange maneuver, unlike BES. Other potential disadvantages of SES are the increased time required by the procedure and the possibility of distal vessel perforation due to movement of the guidewire during device exchange. In a previous report, a higher rate of thromboembolic complications was noted, possibly caused by unprotected balloon angioplasty and associated with the increased procedure time for SES implantation, compared with the one-step procedure used in BES placement.¹¹

The Wingspan Registry was created to evaluate the cumulative experience of five centers that used this stent initially. The previously published 12-month results of the Wingspan Registry were disappointing, with a combined rate of 13.9% for two important complications: (a) the incidence of procedural stroke or death, and (b) the occurrence of a stroke in the area of the treated artery beyond 30 days posttreatment.¹² These results are similar to those in the WASID study. However, none of our cases showed procedure-related complications, including arterial dissection or vessel perforation within 24 hours of stent placement. Only one patient had hemorrhagic transformation in the core area of a cerebral infarction, seen on an MR scan, within 72 hours of the procedure.

Yue et al.¹³ reported that the frequency of restenosis after intracranial stenting in patients with symptomatic stenosis of the MCA was higher in the SES group (34.6%) than the BES group (16.1%), but also noted that there were no differences in clinical outcomes between the two groups. In the present study, the restenosis rate during the long-term follow-up period was 14.7% (5/34). If we compare the two previous studies, which used a Wingspan SES exclusively, and our present study, their long-term results showed higher restenosis rates (20.25%¹⁴ and 23.1%,¹⁵ respectively) than our long-term results.

There have been concerns about the use of BES procedures, both because of the risk of stroke from the procedure and the difficulty of navigating the BES stent within the artery. However, a previous systematic literature review assessed 31 studies with reports of intracranial stenting.¹⁶ A total of 906 patients were treated with BES, and 271 patients were treated with SES. Although there was no statistical difference in periprocedural complications between the BES and SES groups (9.5% vs. 7.7%, respectively), the posttreatment residual stenosis was significantly lower in the BES group (11% vs. 29%). Additionally, there was a significantly higher incidence of restenosis in patients in the SES group compared with the BES-treated patients.¹⁶

In our study, the technical success rate was 95.7%. Fiorella et al.¹⁷ reported a technical success rate of 95.7% and a neurologic morbidity and mortality rate of 26.1% in a study of 44 patients. Another study, entitled Stenting of Symptomatic Atherosclerotic Lesions in the Vertebral or Intracranial Arteries (SSYLVIA), showed a 7.2% rate of periprocedural stroke.¹⁸

During the follow-up period, with a mean duration of 67.6 months, the overall incidence of restenosis or reocclusion in our patient series was 14.7% (5/34). The one-year and five-year patency rates of MCA stents were 94.1% and 84.7%, respectively. Comparing our results to those of other studies using coronary stents for BES, we noted an overall restenosis rate similar to Costalat et al.,¹⁹ Mazighi et al.²⁰ and Fiorella et al.¹⁷ and lower than Miao et al.²¹ The restenosis rates in those studies ranged from 11.9% to 20.25%. Fiorella et al.¹⁷ also reported the occurrence of additional stroke in 15% of patients, during an average 43.5-month follow-up period, a rate that was similar to our results. Marks et al. combined these data with that of other investigators and compiled a multicenter retrospective experience that included 120 patients with 124 treated lesions.²² These investigators reported that an additional 5.2% of patients experienced a recurrent stroke during the long-term follow-up period, which averaged 42.3 months.

This study had several limitations. First, it included a relatively small number of patients in a single institute even though we used historical controls from the same facility. Second, the rate of periprocedural complications in this study may not reflect the complication rate of current state-of-the-art practices, since the technology and techniques of angioplasty and stenting have evolved significantly during the past 10 years. The rate of procedure-related complications or periprocedural TIAs and stroke in this study would be lower if modern equipment and techniques had been used. In addition, few patients who were treated in the present study received a bolus of abciximab, a platelet glycoprotein IIb/IIA receptor inhibitor that is currently considered effective for preventing acute thrombosis associated with endovascular treatment. Third, our results have to be interpreted with caution because of the retrospective nature of the study, and the nonuniform modes of therapy used in addition to the placement of an intracranial stent. Fourth, we did not obtain data on patients treated with stents other than coronary stents. The Wingspan™ stent was approved in 2005, and the “learning curve” that is included in the registry might have had a negative influence on the SES treatment results. Finally, at our institution, SES could not be used because of the policies of Korean public health insurance at that time.

Conclusions

Our study showed that insertion of a BES in patients with symptomatic MCA stenosis refractory to medical treatment or in patients with MCA stenosis showing instant reocclusion refractory to IAT resulted in effective treatment with a low recurrence rate of ischemic events and low restenosis rates during long-term follow-up.

Declaration of conflicting interests

The authors declared no potential conflicts of interest with respect to the research, authorship, and/or publication of this article.

Funding

The authors disclosed receipt of the following financial support for the research, authorship, and/or publication of this article: This work was supported by Basic Science Research Program through the National Research Foundation of Korea (NRF) funded by the Ministry of Education (NRF-2017032390).