Safety of carotid artery stenting for elderly patients with cervical carotid artery stenosis

Abstract

Background

Several recent randomized controlled trials have reported that perioperative complications of carotid artery stenting increase with age, and Japan has the highest proportion of elderly in the world. We retrospectively compared clinical factors, treatment outcomes, and adverse events between younger and elderly carotid artery stenting patients at a single institution in Japan to assess carotid artery stenting safety for the aged population.

Methods

A total of 150 consecutive patients treated with carotid artery stenting using the dual protection (simultaneous flow reversal and distal filter) and blood aspiration method were enrolled. Patients were classified into an elderly (O) group ≥75 years (54/150, 36.0%) and a younger (Y) group <75 years (96/150, 64%) for comparison of demographics, clinical background, incidence of captured debris during the procedure, outcome, minor stroke, major adverse events (major stroke, myocardial infarction, or death) within 30 days, hyperintense spots on diffusion-weighted images after carotid artery stenting, and postoperative hospitalization days.

Results

The carotid artery stenting procedure was successful in all cases. No major adverse events occurred within 30 days in the Y group, and only one occurred in the O group (P = 0.348). Visible debris was captured in a significantly greater proportion of O group patients than in Y group patients (33/54 (63.5%) vs. 40/96 (42.1%), P = 0.016), but there was no significant difference in the frequency of hyperintense spots on diffusion-weighted images between Y and O groups (23/96 (24.0%) vs. 16/52 (30.8%), P = 0.435).

Conclusions

Carotid artery stenting using dual protection and blood aspiration is equally safe for younger and elderly patients.

Introduction

Cervical carotid artery stenosis is a frequent cause of atherosclerotic cerebral infarction; thus, the restoration of blood flow is critical for the prevention of stroke-related morbidity and mortality. Multiple large-scale studies conducted in the 1990s reported that carotid endarterectomy (CEA) is an effective surgical option to prevent cerebral infarction for symptomatic moderate to severe stenosis and asymptomatic severe stenosis.^1–6 Subsequently, the noninferiority of carotid artery stenting (CAS) versus CEA was reported in several comparative studies,^7–9 and revised American Heart Association (AHA)/American Stroke Association (ASA) guidelines (2014) now recommend CAS as an alternative therapy to CEA (Class IIa; Level of Evidence B).¹⁰ However, a meta-analysis of the Carotid Revascularization Endarterectomy vs. Stenting Trial (CREST),⁸ the Endarterectomy versus Angioplasty in Patients with Symptomatic Severe Carotid Stenosis study,¹¹ International Carotid Stenting Study,¹² and Stent-Protected Angioplasty versus Carotid Endarterectomy trial¹³ all reported a higher risk of ischemic complications and mortality in elderly CAS patients. In the aforementioned AHA/ASA guidelines as well, CEA is recommended instead of CAS for patients aged 70 years and older (Class IIa; Level of Evidence B).¹⁰

On the other hand, a higher incidence of heart disease complications was reported for CEA compared with CAS in elderly patients.⁸ Therefore, the optimal treatment choice for elderly patients with cervical carotid artery stenosis remains controversial. Japan is the world's most super-aged society, and the number of elderly people is expected to increase further in the coming decades. This rise is likely to be accompanied by a greater number of elderly patients with cervical carotid artery stenosis. Indeed, the mean age of patients treated with CAS continues to increase.¹⁴ It is, thus, of critical importance to establish the optimal treatment option for elderly patients with carotid artery stenosis in the cervical region.

The purpose of this study was to compare demographic factors, clinical characteristics, and treatment results between younger (<75 years) and elderly (≥75 years) cervical carotid artery stenosis patients treated by CAS at a single institution to identify factors for treatment guidance.

Materials and methods

The protocol of this study was approved by the ethics committee of Hiroshima University.

Patients

Between April 2014 and November 2018, 150 patients with carotid artery stenosis received CAS using the dual protection (simultaneous flow reversal and distal filter) and blood aspiration method. Patients were divided into an elderly (O) group and a younger (Y) group according to the definition of the Japanese Society of Geriatrics (≥75 years and <75 years, respectively).

We compared age, sex ratio, body mass index (BMI), frequencies of current smoking, regular drinking, hypertension, dyslipidemia, diabetes mellitus, cardiac disease, blood test findings (high-density lipoprotein and low-density lipoprotein cholesterols, triglyceride, hemoglobin-A1c, and estimated glomerular filtration rate), symptomatic/asymptomatic status, preoperative ipsilateral peak systolic velocity (PSV) on ultrasonography (US), rate of stenosis on cerebral angiography, surgical approach, and plaque properties (vulnerable/non-vulnerable) between Y-group and O-group patients. Cardiac disease was defined as a history of heart failure and/or percutaneous coronary intervention for myocardial infarction and/or angina. Asymptomatic status was defined as serendipitous detection of cervical carotid artery stenosis or absence of a transient ischemic attack for 180 days prior to treatment.

Preoperative US evaluation of the PSV and plaques was performed within one week before treatment. Two-dimensional B-mode and color Doppler images of the affected carotid bifurcation were obtained using the LOGIQ 7 system (GE Yokogawa Medical Systems, Tokyo, Japan) with a 3–10 MHz broadband linear array transducer. US was performed by an experienced sonographer certified by the Japan Academy of Neurosonology. We defined ulcerated plaque, jellyfish plaque,¹⁵ and floating plaque as vulnerable. Plaque properties were also assessed by magnetic resonance T1-weighted imaging (T1WI). Lesions in which the signal ratio between the plaque and the sternocleidomastoid muscle was 1.5 or more were regarded as hyperintense and a manifestation of a vulnerable plaque. The rate of stenosis was evaluated by cerebral angiography according to the North American Symptomatic Carotid Endarterectomy Trial method.

We performed cervical and body computed tomography before treatment to evaluate calcification of the vessel wall at the lesion, calcification of the aortic arch and presence of bovine arch or Type 3 arch. Calcification of more than half the stenosis circumference was defined as moderate, and 3/4 or more as severe.

Therapeutic indications

Patients with symptoms were treated with CAS if there was at least 50% stenosis on cerebrovascular angiography, PSV was 150 cm/s or more on US, or if a vulnerable plaque was detected. Asymptomatic patients were treated if stenosis was 80% on cerebrovascular angiography, PSV was 230 cm/s or more on US, there was a vulnerable plaque, or if there was progression of stenosis (defined as a change in PSV from less than 150 to 150 cm/s or more in the follow-up US observation).

CAS procedures

All procedures were performed by interventional neuroradiologists.

Multiple antiplatelet drugs (aspirin 100 mg, clopidogrel 75 mg, and/or cilostazol 200 mg) were administered for at least one week before and for one to three months after CAS. A single antiplatelet drug was then prescribed indefinitely. In the present study, almost all CAS procedures are conducted using the dual protection (simultaneous flow reversal and distal filter) and blood aspiration method.^16,17

We excluded four patients who had a bovine arch or bilateral femoral artery stenoses because these anomalies create difficulty when using the transfemoral artery approach.

The protection method was as follows. First, a 9Fr occlusion balloon-guiding catheter (OPTIMO; Tokai Medical Products, AICHI, Japan) was guided into the common carotid artery via the femoral artery. Next, a balloon wire system (Guardwire; Medtronic, Minneapolis, MN, USA) was guided into the external carotid artery. A 4Fr sheath inserted into the femoral vein was connected to the proximal end of the 9Fr occlusion balloon-guiding catheter via a blood filter. The balloon wire and 9Fr occlusion balloon-guiding catheter were extended, and as the flow was reversed, a filter wire (Filter wire EZ; Boston Scientific, Natick, MA, USA) was placed in the high cervical ICA. Predilatation and stenting was then performed under dual protection and flow reversal. After stenting, postdilatation was performed with an angioplasty balloon. After that an aspiration catheter (Export Aspiration Catheter; Medtronic) was placed between the proximal end of the stent and the filter, and blood was aspirated until no debris was observed.

A total of 142 patients were treated using a single self-expanding stent, 129 with a Carotid WALLSTENT (Boston Scientific), 7 with a PRECISE stent (Johnson & Johnson, Miami Lakes, FL, USA), and 6 with a PROTÉGÉ stent (Medtronic), while multiple stents were used in 8 patients. Argatroban anticoagulant therapy (2.5 ml/h) was continued for 12 h after CAS.

Clinical outcomes

We assessed hyperintense spots on diffusion-weighted images (DWIs) one or two days after the procedure. We counted all hyperintense spots including small one on axial DWIs. Major adverse event (MAE) was defined as a major stroke, myocardial infarction, or death within 30 days after CAS. Major stroke was defined as a cerebral infarction that remained symptomatic beyond 30 days, and minor stroke as a cerebral infarction with a complete recovery of symptoms within 30 days or as a neurological deficit improvement within 24 h. Postoperative neurological findings and postoperative magnetic resonance imaging (MRI) findings were evaluated by two or more neurointerventionists the day after treatment. We examined all debris that passed with aspirated blood or was caught in the distal filter or blood filter in the flow reversal line after CAS. Two or more neurointerventionists confirmed the presence of debris and judged its nature. We also assessed the duration of hospitalization and ratio of patients showing a modified Rankin Scale (mRS) ≥ 3 30 days after treatment.

Statistical analysis

Continuous variables are expressed as mean or median (interquartile range) depending on the normality of the data distribution and categorical variables as frequency (%). Normally distributed continuous variables were compared by Welch’s t-test, while skewed continuous variables were compared using the Wilcoxon’s rank sum test. Shapiro–Wilk test was used for normal distribution. Categorical variables were compared by the chi-square test. A P < 0.05 (two-tailed) was considered significant for all tests. All statistical analyses were performed using JMP® 13 software (SAS Institute Inc., Cary, NC, USA).

Results

Patient backgrounds

Table 1 summarizes the demographic and clinical characteristics of the 96 Y-group patients (<75 years) and the 54 O-group patients (≥75 years) (67.8 ± 5.3 vs. 78.9 ± 3.0). The sex ratio, mean BMI, hypertension rate, dyslipidemia rate, mean degree of stenosis, mean PSV, and blood chemistry metrics did not differ between the groups. Alternatively, the number of current smokers was significantly lower in the O group (30.2% vs. 9.3%, P = 0.004). Incidence of pre-existing cardiac disease was slightly higher in the O group (46.3% vs. 38.5%, P = 0.391), and severe stenosis slightly higher in the Y group (35.1% vs. 27.8%, P = 0.466), but neither difference reached significance.

Table 1.

The demographic and clinical characteristics of patients.

	Y group (n = 96)	%	O group (n = 54)	%	P-value
Left	42	43.75	22	40.74	0.735
Age	67.82 ± 5.28		78.85 ± 3.01
Female	12	12.5	5	9.26	0.604
BMI	23.8159 ± 2.98204		23.2046 ± 2.57564		0.208
Current smoker	29	30.21	5	9.26	0.004
Hypertension	68	70.83	41	77.36	0.444
Dyslipidemia	76	79.17	43	79.63	1
DM	39	40.63	22	40.74	1
Cardiac disease	37	38.54	25	46.32	0.391
T-Chol	159 ± 31 (mg/dl)		161 ± 32 (mg/dl)		0.715
HDL-Chol	53.52 ± 16.83 (mg/dl)		52.87 ± 13.01 (mg/dl)		0.806
LDL-Chol	85.84 ± 26.29 (mg/dl)		88.94 ± 28.25 (mg/dl)		0.504
TG	135 ± 68 (mg/dl)		120 ± 68 (mg/dl)		0.199
HbA1c	6.3 ± 0.69 (%)		6.48 ± 0.88 (%)		0.178
eGFR	64.81 ± 18.97 (ml/min/1.73 m2)		60.13 ± 15.42 (ml/min/1.73 m2)		0.124
Symptomatic	40	41.67	15	27.78	0.113
Severe stenosis	33	35.11	15	27.78	0.466
Stenosis rate (NASCET)	68.95 ± 23.01 (%)		72.62 ± 16.60 (%)		0.263
PSV	254 ± 147 (cm/s)		297 ± 162 (cm/s)		0.111
Arch calcification	38	39.58	47	87.04	<0.0001
Bovine arch	7	7.29	6	11.11	0.547
Type 3 arch	8	8.33	18	17.33	0.0002
US/ulcer	37	42.53	21	40.38	0.86
US/jellyfish	28	33.33	15	30	0.707
US/floating	6	7.14	4	8.16	1
Lesion calcification	72	77.42	45	86.54	0.198
Severe calcification	19	20.43	16	30.77	0.224
MRI/T1WI hyper	20	24.39	13	32.5	0.388

BMI: body mass index; DM: diabetes mellitus; T-Chol: total cholesterol; HDL-Chol: high-density lipoprotein cholesterol; LDL-Chol: low-density lipoprotein cholesterol; TG: triglyceride; HbA1c: hemoglobin A1c; eGFR: estimate glomerular filtration rate; NASCET: North American Symptomatic Carotid Endartectomy; PSV: peak systolic velocity; US: ultrasonography; MRI: magnetic resonance imaging; T1WI hyper: T1-weighted imaging hyper intensity area.

Evaluation of the approach route

Aortic arch calcification was significantly more frequent in the O group (39.6% vs. 87.0%, P < 0.0001). Incidence of a bovine arch did not differ, while the incidence of type 3 arch was significantly higher in the O group (8.3% vs. 17.3%, P = 0.0002).

Evaluation of carotid artery plaque type

Neither the incidence of vulnerable plaque nor the distribution of vulnerable plaque type (ulcerated, jellyfish, or floating) differed between groups Y and O. The frequency of hyperintense spots on MRI-T1WI (24.4% vs. 32.5%, P = 0.388), incidence of moderate calcification (77.4% vs. 86.5%, P = 0.198), and incidence of severe calcification (20.4% vs. 30.8%, P = 0.224) were all slightly higher in the O group, but none of these differences reached significance.

CAS procedure and postoperative evaluation

Table 2 summarizes the treatment results. All procedures succeeded, and all stenoses were dilated. The ratio of 100% carotid lumen restoration in the Y group and O group is 90 (93.75%) and 50 (92.59%), respectively (P = 0.747). The incidence of captured debris was significantly greater in the O group (41.7% vs. 63.5%, P = 0.016). In contrast, the frequency of hyperintense spots on DWI did not differ between groups (24.0% vs. 30.8%, P = 0.435). Incidences of minor stroke were higher (4.2% vs. 11.1%, P = 0.169) and postoperative hospital stay slightly longer (5.29 ± 0.60 vs. 6.28 ± 0.80, P = 0.328) in the O group, but the differences did not reach significance. No MAEs were encountered in the Y group, while one patient of the O group experienced an MAE within 30 days and mRS ≥ 3 within 30 days (0.0% vs. 1.9%, P = 0.360). This patient was a 79-year-old male who developed fatal arrhythmia five days after treatment and progressed to heart failure six days after treatment. On the seventh day posttreatment, transient hypotension caused by heart failure occurred concomitantly with in-stent acute occlusion, necessitating retreatment. He was transferred to a convalescent rehabilitation hospital with mRS3 43 days after treatment.

Table 2.

The treatment results.

	Y group	%	O group	%	P-value
Technical success	96	100	54	100	1
100% restoration	90	93.75	50	92.59	0.747
Captured debris	40	41.67	33	63.46	0.016
Minor stroke	4	4.17	6	11.11	0.169
MAE	0	0	1	1.85	0.36
DWI hyper	23	23.96	16	30.77	0.435
mRS ≥ 3	0	0	1	1.85	0.36
Hospitalization	5.29 ± 0.60		6.28 ± 0.80		0.328

MAE: major adverse event; DWI hyper: diffusion-weighted imaging hyperintense spots; mRS dep.: modified Rankin Scale depression.

Discussion

In this study cohort, CAS using the dual protection and blood aspiration method was as safe and effective for elderly patients (≥75 years) as for younger patients (<75 years). Alternatively, CAS in elderly patients did involve relatively more difficult surgical access due to arterial tortuosity. In addition, debris was captured more frequently in elderly patients, but hyperintense spots on DWIs and stroke events were no more frequent than in younger patients. Therefore, we conclude that CAS can be performed safely in the elderly as long as there is sufficient distal protection.

In contrast to our findings, several trials have reported increased perioperative complications of CAS in elderly patients. For instance, a meta-analysis of multiple randomized controlled trials comparing CEA to CAS concluded that combined risk of perioperative stroke and death increased with age, from 3% in patients 60 years and younger to 9% in patients 75–79 years and 11% in patients 80 years and older.¹⁸ The main reasons for this rising incidence are the increased frequencies of longer and more complicated plaques due to age-related disease progression and/or changes in vasculature, such as complex arch anatomy. Therefore, recent guidelines recommend the use of an end protection device (EPD) to prevent the complications associated with plaque rupture.^8,11–13 However, Hobson et al. found a significantly greater stroke incidence in octogenarians than nonoctogenarians following CAS (12.12% vs. 2.77%, P < 0.0001) despite a high overall rate of EPD use (88%).¹⁹ In the CREST report as well, in which the rate of EPD use was 100%, MAE frequency after CAS was higher in the over-70-year group than the under-70-year group.⁸ The elderly often have vulnerable plaques or arterial tortuosity, which increases the difficulty of using EPDs.^19–21 Therefore, prevention of perioperative ischemic complications appears to be among the most important factors for a successful CAS outcome. Even in our study, debris was captured more frequently in the elderly group. However, there was no difference in the complication rate, suggesting that the capture of debris during CAS using the dual protection and blood aspiration method contributes to the reduction of complications.

A major difference between the present study and previous reports is the method of end protection. In the CREST, end protection consisted only of distal filter protection using the RX Accunet Embolic-protection device. Distal filter protection maintains antegrade blood flow, so there is still a risk that debris may migrate to the intracranial internal carotid artery through the filter during the procedure.^22,23 On the other hand, using retrograde blood flow as proximal protection, distal embolism can be reliably prevented, and proximal embolism stopped before passing through a lesion. Indeed, proximal protection has also been reported to reduce perioperative ischemic complications.^24–29 However, analyzed meta-analysis of 18 studies comparing a distal EPD with a proximal EPD found no difference in perioperative ischemic complications and rates of MRI-DWI hyperintense spots.³⁰ While proximal protection contributes to the reduction of perioperative ischemic complications in CAS, a distal embolism may occur when deflating the proximal balloon.³¹ Therefore, there is still debate on which method is superior. Sakamoto et al. reported that adding blood aspiration to dual protection (simultaneous flow reversal and distal filter) can provide effective distal embolic protection during CAS.^16,17 Similarly, Abiko et al. reported no significant difference in perioperative complication rate or hyperintense spots on DWI between octogenarian and nonoctogenarian groups using the same dual protection plus blood aspiration method, despite more vulnerable plaques and more frequent capture of debris in the octogenarian group.³²

In the present study, there was no difference in the prevalence of vulnerable plaque on US and MRI between elderly and non-elderly groups. However, past reports have suggested that smooth muscle cell density within the plaque decreases, the fibrous cap becomes thinner, and instability increases with age,³³ and it is not always possible to determine the vulnerability of the lesion by imaging examination alone. The prevalence of vulnerable plaques, as revealed by imaging, was not high in this study, but the amount of captured debris was greater in the elderly group. It is suggested that the thinning fibrous cap could be broken during the passage of the guidewire or other devices but is captured as debris by the multi-step protection method.

Limitation

This retrospective study was conducted at a single institution, which limits generalization. Therefore, larger multicenter prospective trials are required for confirmation. We also examined vulnerable plaques by MRI-T1WI, but the diagnosis of vulnerable plaques is still controversial, and should be examined by other techniques such as time of flight magnetic resonance angiography. In addition, MRI was not performed in a small number of cases with contraindications such as cardiac pacemakers, so the diagnosis of a vulnerable plaque was based on US alone. Alternatively, calcification was too strong for a clear US image acquisition in a small number of cases. These imaging deficiencies may have influenced the overall incidence of a vulnerable plaque.

Conclusion

CAS is as safe and effective for elderly patients (≥75 years) as it is for younger patients (<75 years). While the incidence of intraoperative debris capture is higher in elderly patients, CAS can be safely implemented using dual protection and blood aspiration.

Declaration of conflicting interests

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

Ethical approval

The retrospective study was approved by the ethical committee of the Hiroshima University. (E-1758).

Funding

The authors received no financial support for the research, authorship, and/or publication of this article.

ORCID iDs

Akira Taguchi https://orcid.org/0000-0002-2450-5674

Shigeyuki Sakamoto https://orcid.org/0000-0003-3683-4771

Jumpei Oshita https://orcid.org/0000-0003-0753-0234