Predictors of Restenosis Following Carotid Angioplasty and Stenting
Background and Purpose—Restenosis after carotid angioplasty (with or without stent) is associated with increased rate of stroke and death. Our aim was to determine risk and predictive factors related to carotid restenosis post carotid angioplasty and its association to recurrent cerebrovascular events.
Methods—All consecutive patients with carotid stenosis treated with angioplasty (n=1060) in a single University Hospital were included (from 2002 to 2013). Follow-up was done prospectively evaluating restenosis, ipsilateral stroke, or death. Restenosis was defined as a narrowing of ≥70% of a previously treated vessel evaluated by ultrasonography.
Results—Of the 1060 patients treated, 9.2% (97) of patients experienced restenosis during follow up (median 12 [9–32] months). Occurrence of restenosis was associated with ipsilateral stroke during follow-up (P=0.049). After Cox regression analysis, hypertension (hazard ratio, 6.2 [1.9–19.9]; P=0.002), impaired vasoreactivity (hazard ratio, 1.7 [1.09–2.8]; P=0.019), and angioplasty without stent (hazard ratio, 2.9 [1.2–6.8]; P=0.012) were independent risk predictors of >70% restenosis.
Conclusions—Carotid restenosis after carotid angioplasty is associated with ipsilateral stroke occurrence. In our sample, hypertension, angioplasty without stent, and impaired vasoreactivity identify patients at high risk of restenosis and could help to select patients for follow-up ultrasonography imaging.
Carotid angioplasty (CA) and stenting has emerged as an alternative to carotid endarterectomy for the management of carotid stenosis.1 Clinical trial results show mixed data, with rates of restenosis after CA ranging from 1% to 21%.2–5 Differences in restenosis rates are related to study design variability. Lack of stent use in some of them increases restenosis rate. A recent study reviews clinical trials published from 1990 to 2013 comparing CA stenting and carotid endarterectomy. Carotid restenosis rate was ≥50%, or occlusion ranged around 6% four years after carotid endarterectomy or CA stenting in this study.6 This incidence is more accurate given the widespread stent use nowadays. In addition, severe carotid artery restenosis or occlusion after previous surgical or endovascular treatment is associated with an increased risk of recurrent cerebrovascular events.2–4 Recent American Heart Association/American Stroke Association guidelines state that routine long-term follow-up imaging with carotid duplex ultrasonography is not recommended after revascularization.7 Our aim was to determine the risk and predictive factors related to carotid restenosis post CA or CA stenting to identify a subset of patients who might benefit from close ultrasound monitoring during follow-up or more aggressive therapies to avoid restenosis.
We analyze a prospective database of all consecutive patients treated by CA in our center in the period 2002 to 2013. The study was approved by our institutional review committee. The patients eligible for the study were those treated with CA (with or without stent) because of symptomatic or asymptomatic carotid artery stenosis or restenosis ≥70%, regardless of cause, and with possibility of follow-up. Every patient underwent a comprehensive interview, neurological examination, carotid duplex evaluation, and brain computed tomography or magnetic resonance imaging before angioplasty. Cerebrovascular reactivity was evaluated by means of breath holding index. We considered values of breath holding index <0.69 as impaired.8
Outpatient clinical and ultrasound follow-up was scheduled for 1, 3, and 6 months and annually thereafter for all patients to evaluate recurrent events and restenosis degree. The threshold for the diagnosis of severe restenosis (≥70%) was defined by peak systolic velocities of ≥300 cm/s and hemodynamics changes. Intervention protocol is detailed in the online-only Data Supplement.
Predictors of restenosis and association of restenosis and outcome were determined by Kaplan–Meier curves with the log-rank test. Independent predictors of restenosis were assessed by Cox regression analysis by forward-stepwise method, including in the first step those baseline variables associated at a P value under 0.1 in Kaplan–Meier analysis. We used SSPS 17.0 for statistical analysis. P<0.05 was considered statistically significant.
From January 2002 to December 2013, 1196 patients underwent CA (with or without stent). There were 136 patients excluded from the study because of loss of follow-up. Final sample was 1060 patients. Baseline characteristics of patients and selected sample are shown in Table I and Figure I in the online-only Data Supplement.
Ninety-seven patients (9.2%) experienced ≥70% restenosis during follow-up. Of them, 47 restenosis patients (48.2%) underwent a new angioplasty during follow-up. Mean restenosis time was 12 months. Age older than 70 years (P=0.003) and history of hypertension (P=0.002) were the only vascular risk factors significantly related to higher rates of restenosis during follow-up (Table II in the online-only Data Supplement). Regarding angioplasty and ultrasound variables, angioplasty without stent (P<0.0001), postprocedure stenosis >30% (P<0.0001), and preprocedure impaired cerebral vasoreactivity (P=0.003) were also related to restenosis (Table III in the online-only Data Supplement).
Association of hypertension and age >70 years was related to higher restenosis rates (13.9%; P=0.003). Furthermore, patients with hypertension and impaired vasoreactivity (IVR) showed higher values of restenosis (14.8%; P=0.006; Figure 1).
After Cox regression analysis, hypertension (hazard ratio [HR], 6.2 [1.9–19.9]; P=0.002), IVR (HR, 1.7 [1.09–2.8]; P=0.019), and angioplasty without stent (HR, 2.9 [1.2–6.8]; P=0.012) were independent risk predictors of ≥70% restenosis (Table). Occurrence of restenosis was associated with ipsilateral stroke during follow-up in Kaplan–Meier analysis (9% of restenosis patients [9 patients] versus 3.1% of nonrestenosis patients [30 patients]; P=0.049), with a median modified Rankin scale score of 2 at discharge after restenosis-related stroke. Restenosis was diagnosed before ipsilateral stroke occurrence in every patient. However, we did not find a significant association with vascular death (6.7% [6 restenosis patients] versus 7.1% [68 nonrestenosis patients]; P=0.502; Figure 2).
When excluding from analysis those procedures without stent and those performed in restenosis, the final sample size was 992 patients. After Cox regression analysis, age appeared as independent risk predictors of ≥70% restenosis (HR, 1.8 [1.18–2.85]; P=0.007), together with hypertension and IVR that still were present in the final model (Tables IV–VII in the online-only Data Supplement).
Post-angioplasty restenosis is the most common late complication of this procedure. Our results provide various key findings. First, restenosis rate of our sample (9.2%) is higher than that of CREST (Carotid Revascularization Endarterectomy vs Stenting Trial) study (6%) but within the ranges reported in previous studies and still is a too frequent noncontrolled complication. Second, restenosis is independently associated with hypertension, impaired preprocedure vasoreactivity, and angioplasty without stent. Third, in our cohort, restenosis was associated with an increased risk of ipsilateral stroke. Globally, our results pointed out to a high-risk subgroup, which might benefit from a closer follow-up with carotid imaging.
Recent theories explain atherosclerotic disease as an entity based on inflammation response to endothelial dysfunction. Such dysfunction involves smooth muscle cell proliferation and neointimal hyperplasia.9 Hypertension is a known risk factor that triggers endothelial damage. The occurrence of restenosis is related to hypertension, probably because high blood pressure promotes smooth muscle cell proliferation in treated vessels.
Angioplasty alone is no longer the standard of care; however, some procedures involve technical difficulties that prevent stent use. The inclusion of some restenosis procedures and angioplasty without stent could explain, at least in part, the higher rate of restenosis detected compared with the CREST study. Nevertheless, stent use results in a more effective long-term restenosis prevention technique.
In addition, we found that hypertension and >70-year-old patients and hypertensive patients with IVR showed the highest restenosis rates during follow-up. The association of risk factors mentioned will allow us to detect patients at greater risk of restenosis. However, further validation of our results is necessary to select patients for closer monitoring in daily practice.
Cerebral vasoreactivity measures the blood flow autoregulation, and it is an essential property of brain endothelium to maintain a constant metabolism.10 Altered cerebral vasoreactivity reveals a dysfunction in vascular cerebral compensation mechanisms because of myointimal hyperplasia, which increases arterial wall stiffness. Previous studies have observed the association between impaired cerebrovascular reactivity and compromised endothelial function.10,11 IVR could be considered an ultrasonographic marker of endothelial dysfunction in small-vessel compensation mechanisms. Preprocedure IVR express endothelial dysfunction in small vessels and could suggest a common inflammatory mechanism to the large vessels with restenosis. To the best of our knowledge, this is the first description of a relation between vasoreactivity and carotid restenosis.
Finally, ipsilateral stroke was more frequent in restenosis patients. According to recent CREST analysis,3 patients who had restenosis were at greater risk for ipsilateral stroke after the periprocedural period up to the end of follow-up than were those who did not have restenosis (HR, 4.37, 95% confidence interval, 1.91–10.03; P=0.0005).
We hypothesize that high-risk restenosis patients would need early closer monitoring, given the increased rate of ipsilateral stroke detected in those patients. The identified risk factors for restenosis in this group of patients will allow us to determine the right strategy to minimize and even avoid its consequences.
The main limitation of the current study is related to the retrospective analysis of the prospectively recorded data, causing an ascertainment bias that cannot be ruled out. Another limitation is the use of ultrasound velocity threshold for detection of restenosis that is not as accurate as angiography, but it is feasible for repeated evaluation and widely accepted in guidelines.
Carotid restenosis is related to hypertension, IVR, and angioplasty without stent. Based on our data, cerebral vasoreactivity emerges as a new ultrasonographic marker of the endothelial dysfunction, which predisposes restenosis.
Sources of Funding
This project was partially funded by the Instituto de Salud Carlos III (ISCIII) project PI14/00971. The ITRIBiS project (Improving Translational Research Potential at the Institute of Biomedicine of Seville) has the registration number REGPOT-2013-1. A. Bustamante is supported by a Rio Hortega contract.
Presented in part at the European Stroke Organisation Conference, Glasgow, Scotland, April 17–19, 2015.
The online-only Data Supplement is available with this article at http://stroke.ahajournals.org/lookup/suppl/doi:10.1161/STROKEAHA.116.012650/-/DC1.
- Received February 9, 2016.
- Revision received May 5, 2016.
- Accepted May 26, 2016.
- © 2016 American Heart Association, Inc.
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