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Abstract
Background Carotid artery stenting (CAS) for symptomatic carotid artery stenosis (SCS) has been proved to be safe and effective in many randomized controlled trials, but the safety and efficacy of CAS for asymptomatic carotid artery stenosis (ACS) is not clear.
Objective To prospectively compare the outcomes of CAS between patients with ACS and SCS.
Methods 402 consecutive patients, 233 with ACS and 169 with SCS, underwent CAS. The primary outcome was a composite of death, stroke or myocardial infarction at 30 days and during the follow-up period. Procedural success and complications such as hyperperfusion, sinus-cardiac reflex, gastrointestinal hemorrhage, myocardial infarction, acute thrombosis, and vagus nerve reflex were also compared between the ACS and SCS groups.
Results CAS was successful in all patients. There were no significant differences in baseline characteristics of the patients (age, gender, hypertension, diabetes, smoking, alcohol consumption and dyslipidemia) and in 30-day or long-term follow-up outcomes between the ACS and SCS groups.
Conclusions Periprocedural and long-term follow-up outcomes of CAS appear similar for ACS and SCS.
- Angioplasty
- Atherosclerosis
- Intervention
- Stenosis
- Stent
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Introduction
Carotid artery stenosis is an important risk factor for anterior circulation ischemic stroke and is classified as either asymptomatic carotid artery stenosis (ACS) or symptomatic carotid artery stenosis (SCS) based on the absence or presence of associated retinal or cerebral ischemic symptoms.1 Patients with ACS ≥70% and SCS ≥50% often require intervention with either carotid endarterectomy or carotid artery stenting (CAS).2 The current study explored whether CAS was associated with differential periprocedural complication rates and long-term prognosis in patients with ACS ≥70% and SCS ≥50%.
Methods
Study participants
Four hundred and two patients admitted consecutively to the interventional neuroradiology department at Beijing Tian Tan Hospital to undergo CAS for carotid artery stenosis from January 2011 to December 2012 were prospectively enrolled in this controlled study according to the criteria listed below. None of the patients had previously been used for any prior study or publication.
Inclusion and exclusion criteria
Inclusion criteria were: (1) ACS ≥70% or SCS ≥50% (symptoms included retinal ischemia, transient ischemic attack (TIA), or minor or major stroke in the territory of the qualifying artery) as shown by digital subtraction angiography (DSA) or CT angiography; (2) lesions suitable for endovascular intervention as shown by angiography; (3) patient agreed to undergo endovascular intervention.
Exclusion criteria were: (1) combination with vertebral or intracranial artery stenosis requiring treatment; (2) severe and inoperable cardiopulmonary dysfunction; (3) large infarction areas as shown by imaging and neurological function (modified Rankin scale (mRS) score >3 points); (4) renal dysfunction with estimated glomerular filtration rate <80 mL/(minute 1.73 m2); (5) life expectancy <2 years; and (6) patient refused endovascular intervention.
Collection of baseline data
Baseline data included age, gender, and medical history (hypertension, diabetes, smoking, alcohol consumption, dyslipidemia and coronary artery disease) at admission.
Procedures
All patients routinely underwent MRI, ultrasonography or CT angiography (CTA) at admission, and patients with stroke underwent endovascular intervention for at least 2 weeks after stroke onset. The patients were given daily aspirin 100 mg and clopidogrel 75 mg 5 days before the operation. After the procedure, patients were given daily aspirin100 mg lifelong and clopidogrel 75 mg for 3 months.
During the periprocedural period, blood glucose and blood pressure levels were strictly controlled: fasting blood glucose level was maintained <7.1 mmol/L, insulin was preferably selected for lowering blood glucose, and biguanide drugs were prohibited; blood pressure was stabilized at 120–140/60–100 mm Hg, and ACE inhibitors or angiotensin II receptor blocker antihypertensive drugs were commonly selected. Dopamine was used to increase blood pressure and slowly discontinued until blood pressure stabilized and sinus reflex resolved for sinus-cardiac reflex and blood pressure dropping. Lifelong atorvastatin 20 mg nightly was routinely prescribed to stabilize plaque.
Carotid artery stenting (CAS)
All CAS procedures were performed under local anesthesia by surgeons with experience of at least 25 CAS cases per year. After completion of DSA using a guiding catheter, for patients with extremely severe stenosis a small balloon (2 mm) was introduced through a microguidewire for dilation. A distal protection device then was introduced and balloons with the appropriate diameter were selected for pre-dilation and stent release, as well as for post-dilation in patients with severe residual stenosis.
Outcomes and follow-up
The primary outcome was a composite of death, stroke or myocardial infarction at 30 days and during the follow-up period. Other outcomes included hyperperfusion, sinus-cardiac reflex, gastrointestinal hemorrhage, myocardial infarction, acute thrombosis, and vagus nerve reflex.
Follow-up information on clinical outcomes was collected by clinical visit and telephone interview at 3 months, 6 months, 1 year, and 2 years after the procedure.
Patients underwent long-term follow-up from 12 to 24.2 months (mean 18.3 months) primarily by clinical visit and telephone interview. All patients were followed up for at least 12 months and those requiring repeat angiography were admitted.
Statistical analysis
Data were analyzed with SPSS V.13.0 software. Postprocedural and long-term follow-up results were compared between the ACS and SCS groups. Differences between proportions were assessed by the χ2 test or the Fisher exact test. Continuous data are expressed as mean±SD (
±s) and were compared using the t test. p<0.05 was considered statistically significant. Univariate and multivariate Cox regression analysis was used to evaluate the significance of variables concerning the primary outcome occurring during the follow-up period. Statistically significant differences were considered p<0.20 in univariate Cox regression analysis and p<0.05 in multivariate Cox regression analysis.
Results
Baseline characteristics
Four hundred and two patients were prospectively registered (345 men and 57 women), 233 in the ACS group and 169 in the SCS group. There were no significant differences in distributions of age, gender, hypertension, hyperlipidemia, smoking, alcohol consumption, diabetes, coronary heart disease, and other baseline data between the two groups (table 1). Among the 169 patients with SCS, the neurological function score (mRS score) was 0 in 32 cases, 1 in 42, 2 in 76, and 3 (moderate disability) in 19 cases. The mRS score was 0 in all patients with ACS. Among the 169 patients with SCS, 32 had a TIA, 97 had a minor stroke, and 40 patients had a major stroke.
Baseline characteristics
Procedural and 30-day outcomes
CAS was successfully completed in all 402 patients (ie, the procedural success rate was 100%). Residual stenosis after stent implantation ranged from 0% to 30%. One hundred and thirty-six cases (33.8%) developed sinus-cardiac reflex during balloon angioplasty and stent placement; patients with a low heart rate had transient sinus arrest which was significantly improved after coughing or intravenous injection of atropine. Five cases received dopamine as maintenance therapy for 1–3 days because of hypotension, 17 cases developed intraoperative carotid artery spasm which resolved after intravenous administration of papaverine, and 4 cases had arterial dissection after balloon dilation which resolved after stent release.
During the 30-day follow-up period there were no deaths and 17 cases (10 (4.3%) in the ACS group and 7 (4.1%) in the SCS group) suffered complications (no significant difference), including hyperperfusion syndrome, gastrointestinal hemorrhage, myocardial infarction, acute thrombosis, vagus nerve reflex, stroke, and TIA (table 2). The probability of the primary outcome within 30 days was 1.3% (involving 3 patients) in the ACS group and 1.8% (involving 3 patients) in the SCS group. There were two myocardial infarctions which occurred at 3 and 30 days after the procedure and one major stroke related contralateral internal carotid artery (ICA) at 3 days after the procedure in the ACS group. Two patients developed minor stroke with aphasia related territory ICA and dizziness at 1 and 30 days post-procedure and one major stroke related territory ICA occurred at 3 days post-procedure in the SCS group.
Outcomes at 30 days
Long-term follow-up outcomes
Patients were followed up by telephone and clinic visit from 12 to 24.2 months (mean 18.3 months). There were four deaths (1.7%; 3 cancer and 1 pulmonary infection) in the ACS group and two deaths (1.2%; both cancer) in the SCS group with no significant differences in the incidence of TIA, minor stroke, major stroke, cerebral hemorrhage, myocardial infarction, or death (table 3). There were two major strokes (one related territory ICA and one related contralateral ICA) and one minor stroke in the ACS group. One minor stroke related territory ICA in the SCS group.
Long-term outcomes at mean 18.3 months (range 12–24.2 months)
In the ACS group, univariate Cox regression analysis identified gender, smoking, and coronary heart disease as significant independent predictors of the primary outcome (see online supplementary table S1). On multivariate Cox regression analysis, smoking and coronary heart disease were identified as significant independent predictors of the primary outcome with HR 2.332 (95% CI 1.019 to 5.337, p=0.045) and HR 6.212 (95% CI 1.563 to 24.687, p=0.009), respectively (table 4). In the SCS group, univariate Cox regression analysis identified smoking, coronary heart disease, and alcohol consumption as significant independent predictors of the primary outcome (see online supplementary table S2). On multivariate Cox regression analysis, alcohol consumption was identified as a significant independent predictor of the primary outcome with HR 3.739 (95% CI 1.052 to 13.285, p=0.041) (see online supplementary table S3).
Multivariate Cox regression analysis for smoking and coronary heart disease adjusted with primary outcome in the ACS group
Discussion
With the aging of the population, ultrasonography has shown an increasing number of patients with ACS. More than 20% of ischemic strokes are caused by carotid artery disease; however, the majority of patients with stroke secondary to carotid artery stenosis have no history of stroke or TIA. There is currently no unified opinion on whether patients with ACS need to undergo revascularization. One study estimated a 1–3% risk of ipsilateral stroke in patients with ACS.3 In a long-term study, the 10- and 15-year risks of ipsilateral stroke were 5.7% and 8.7% in patients with 0–49% degree of ACS and 9.3% and 16.6% in patients with 50–99% degree of ACS, respectively.4 The degree of stenosis may be associated with an increased risk of stroke in patients with ACS. In the European Carotid Surgery Trial (ECST), the 3-year risk of ipsilateral stroke in patients with a relative degree of stenosis of 0–29%, 30–69% and 70–99% was 1.8%, 2.1% and 5.7%, respectively.5 In the North American Symptomatic Carotid Endarterectomy Trial (NASCET), the 5-year risk of ipsilateral stroke in patients with a relative degree of stenosis of 0–49%, 50–59%, 60–74% and 75–94% was 7.8%, 12.6%, 14.8% and 18.5%, respectively.6 Three trials—namely, the Asymptomatic Carotid Atherosclerosis Study (ACAS), Medical Research Council (MRC) Asymptomatic Carotid Surgery Trial and Carotid Revascularization Endarterectomy versus Stent Trial (CREST)—confirmed that, in patients with severe ACS, the risk of periprocedural complications of revascularization and recurrent stroke in the following 5 years was 5.1%, 6.4% and 4.6%, respectively.7 The ACAS and MRC trials reported a 5-year risk of stroke in patients with severe ACS receiving simple drug treatment of 11.0% and 11.8%, respectively—that is, revascularization reduced the absolute risk of ipsilateral stroke by about 1% each year. The results of the above trials suggest that revascularization is the preferred treatment for patients with severe ACS. In the current study the risks of the 30-day outcome and primary outcome during a mean follow-up period of 18.3 months in the ACS group were 1.3% and 4.7%, respectively, which is consistent with the results of the abovementioned trials, indicating that the effect of CAS in the patients with ACS was better than that in patients with ACS in previous drug treatment groups. However, some researchers have pointed out that this can no longer reflect current reality because simple drug treatment has significantly reduced the risk of stroke in patients with ACS, and severe ACS may no longer be an indication for revascularization.8
In the Oxford Vascular Study conducted from 2002 to 2009 in which 1153 patients with stroke or TIA received antiplatelet drugs, statins, and medications for diabetes or hypertension, the risk of ipsilateral stroke in the 101 patients with severe ACS ≥50% was only 0.34%.9 In addition, a systematic review by Abbott showed that, from 1985 to 2007, the annual risk of ipsilateral stroke in patients receiving simple drug treatment was reduced from 2.5% to 1.1%.10 In fact, such risk was already equivalent to or even lower than the annual incidence of stroke in patients receiving revascularization in the ACAS, MRC, and CREST trials. Long-term results of the ACST study showed that, for patients with ACS, the rate of carotid artery occlusion was significantly increased in the conservative drug treatment group compared with the carotid endarterectomy group but the incidence of stroke was not significantly increased, suggesting that treatment choice for patients with ACS required further studies.11 In the current study the incidence of stroke at 30 days and long-term follow-up were both higher than in the abovementioned trials. Hence, if the current intensive drug treatment and control of risk factors had been implemented in this group of ACS patients, the incidence of stroke in these patients might have been lower than in patients receiving interventional therapy. Therefore, reference to the degree of carotid stenosis in ACS patients alone as the most important criterion is questionable. The ongoing AMTEC trial aims to compare the prophylactic effects of the most aggressive drug treatment and carotid endarterectomy in patients with ACS, and the results may provide a guiding basis for future treatment of ACS.12
Are procedural and complication risks of CAS lower in patients with ACS than in those with SCS? To date, no large-scale randomized clinical trial has been conducted. Based on theoretical analysis, the most prominent cause of ischemic manifestations or stroke in patients with SCS is rupture of the fibrous cap of the carotid plaque, leading to small artery embolization of plaque lipid components and crystals into the retinal artery or cerebral artery. Therefore, the vast majority of plaque in patients with SCS are unstable. In the process of balloon dilation or stent placement during CAS, the risk of cerebral infarction caused by plaque detachment is relatively high. As for SCS patients with cerebral infarction, reperfusion injury may occur in the infarct region after CAS. Patients with cerebral hypoperfusion on the lesion side mostly suffer from poor collateral circulation and compensation. In patients with severe persistent hypoperfusion, routine stenting is also likely to cause cerebral hyperperfusion syndrome. The risk of postoperative cerebral hyperperfusion syndrome is therefore theoretically higher in patients with SCS than in those with ACS. However, the current study found that the number of patients experiencing hyperperfusive cerebral hemorrhage, minor stroke, and major stroke within 30 days after surgery was numerically but not significantly smaller in the ACS group than in the SCS group. Long-term follow-up results also found no significant difference in the incidence of complications and mortality between the ACS and SCS groups, which suggests the association of complications with the risk of CAS itself has no difference with symptomatology. There has been no comparative study on such risks, and the risks of aggressive or conservative drug treatment and the degree of stenosis cannot serve as the only basis for interventional therapy for ACS. It appears that a decision on whether or not to perform interventional therapy should be based on the nature of the plaque, the patient’s condition, and the side effects of drug treatment.13
In our study, smoking and history of coronary artery disease were the predictors of the primary outcome in the ACS group but, in the SCS group, alcohol consumption was the predictor of the primary outcome. Radak et al14 reported that, in 319 patients who underwent carotid angioplasty, coronary artery disease and smoking history were associated with an adverse outcome after carotid angioplasty. Alcohol consumption may be a potentially modifiable risk factor for stroke.15
Limitations of study
There was no significant difference in the overall primary outcome between the ACS and SCS groups, which differs from the findings of previous studies. This may due to the small sample size in our study which may have caused a type II error.
Conclusion
Periprocedural and long-term follow-up outcomes of CAS appear to be similar for patients with ACS and SCS.
References
Supplementary materials
Supplementary Data
This web only file has been produced by the BMJ Publishing Group from an electronic file supplied by the author(s) and has not been edited for content.
- Data supplement 1 - Online supplement
Footnotes
DM and BW contributed equally.
Contributors DM and BW analyzed and interpreted the data, wrote the article and contributed equally to this article. ZM took responsibility for this work. DM, BW, NM, FG and ZM conceived the study and participated in its design and coordination. DM, BW, NM and FG collected and supplied the data. All authors agreed to publish this work and critically reviewed the article. The conception and design of this work were discussed with all of the authors.
Competing interests None.
Patient consent Obtained.
Ethics approval The study was approved by the institutional ethics committee at Beijing Tian Tan Hospital.
Provenance and peer review Not commissioned; externally peer reviewed.