Chinese Medical Journal 2013;126(3):532-535
A meta-analysis of carotid endarterectomy versus stenting in the treatment of symptomatic carotid stenosis

WANG Liang,  LIU Xiao-zhi,  LIU Zhen-lin,  LAN Feng-ming,  SHI Wan-chao,  LIU Jun ,  ZHANG Jian-ning

WANG Liang (Department of Neurosurgery, Tianjin 5th center Hospital, Tianjin 300450, China)

LIU Xiao-zhi (Department of Neurosurgery, Tianjin 5th center Hospital, Tianjin 300450, China)

LIU Zhen-lin (Department of Neurosurgery, Tianjin 5th center Hospital, Tianjin 300450, China)

LAN Feng-ming (Department of Neurosurgery, Tianjin 5th center Hospital, Tianjin 300450, China)

SHI Wan-chao (Department of Neurosurgery, Tianjin 5th center Hospital, Tianjin 300450, China)

LIU Jun (Department of Chemistry and Biochemistry, University of Delaware, Newark, DE 19716, USA)

ZHANG Jian-ning (Department of Neurosurgery, Tianjin Medical University General Hospital, Tianjin 300052, China)

Correspondence to:LIU Zhen-lin,Department of Neurosurgery, Tianjin 5th Center Hospital, Tianjin 300450, China (Tel: . Fax:. E-mail:wjzhenlin817@sina.com)
Keywords
carotid stenosis; angioplasty; endarterectomy; meta-analysis
Abstract
Background  Carotid stenosis is one of the common reasons for patients with ischemic stroke, and the two invasive options carotid endarterectomy (CEA) and carotid artery stenting (CAS) are the most popular treatments. But the relative efficacy and safety of the methods are not clear.
Methods  About 521 articles related to CAS and CEA for carotid stenosis published in 1995–2011 were retrieved from MEDLINE, Cochrane Library (CL), and China National Knowledge Infrastructure (CNKI) China Journal Full-Test database. Of them, eight articles were chosen. Meta-analysis was used to assess the relative risks.
Results  The eight studies included 3873 patients with symptomatic carotid artery stenosis, including 1941 cases in the carotid stent angioplasty group, and 1932 cases in the carotid endarterectomy group. Fixed effect model analysis showed that within 30 days of incidence of all types of strokes, surgery was significantly highly preferred in CAS patients (CAS group) than the CEA patients (CEA group), and the difference was statistically significant (relative ratio (RR)=1.80, 95% confidence interval (CI): 1.380–2.401, P <0.0001). But the incidence of death in the two groups is not showed and is not statistically significant after 30 days (RR=1.52, 95% CI: 0.82–2.82, P=0.18). The rate of cranial nerve injury in the CAS group is lower than the CEA group (RR=0.14, 95% CI: 0.05–0.43, P=0.0005). The incidence of CAS patients with myocardial infarction is lower than the CEA group after 30 days, but statistically meaningless (RR=0.22, 95% CI: 0.05–1.02, P=0.05). The stroke or death in CAS patients were higher than the CEA group after 1 year of treatment (RR=2.58, 95% CI: 1.03–6.48, P=0.04).
Conclusions  Compared to CAS, carotid endarterectomy is still the preferred treatment methodology of symptomatic carotid artery stenosis. Future meta-analyses should then be performed in long-term follow-up to support this treatment recommendation.
Substantial stenosis of the carotid artery leads to a major risk factor of ischemic stroke, and in the patients with recent transient ischemic attacks or strokes (symptomatic stenosis) acts as a warning sign often followed by severe permanent strokes, especially within the first two days. The goal of the treatment is to reduce the risk of stroke; carotid endarterectomy (CEA) and carotid artery stenting (CAS) are the most popular treatment choices. Randomized clinical trials (RCTs) have definitely shown CEA to reduce the incidence of stroke and death in patients with stenosis of the carotid artery.1-3 CAS has been increasingly performed as a possible alternative method to CEA. Compared to CEA, carotid artery stenting has emerged as a less invasive treatment: no need of incision in the neck, could be performed under general anesthesia, and some of the perioperative complications to endarterectomy could be avoided.4-6 Many major RCTs were done in order to determine the benefit of CEA and CAS in symptomatic and asymptomatic carotid stenosis, but it is still questionable. In general, higher complication rates are found when symptomatic patients are treated.7,8 So whether CAS is a reasonable alternative to CEA in cervical carotid artery stent placement depends on more definitive evidence. In this study we compared 1941 cases in the carotid stent angioplasty group, and 1932 cases in the CEA group to evaluate which was the better treatment in symptomatic carotid artery stenosis.
 
METHODS
 
Data sources
To identify all relevant reports and randomized trials we searched literatures in the following electronic databases: MEDLINE, Cochrane Library (CL), and China National Knowledge Infrastructure (CNKI) China Journal Full-Test database. The keywords included “carotid artery”, “carotid stenosis”, “endarterectomy”, “angioplasty”, “stent”, “endovascular”, “randomized controlled trial” in various combinations. Reports that enrolled patients with symptoms of carotid artery disease and were randomly allocated to either CEA or CAS treatment were eligible for research. Studies included both English and Chinese publications. Papers published between 1995 and 2011 were obtained as said above.
 
Standards of selection
Inclusion criteria
The patients with clear diagnosis of symptomatic carotid artery stenosis were included in the study. Carotid angioplasty surgery and CEA were performed to treat symptomatic carotid stenosis at random. We searched randomized trials of CAS or CEA treatment in patients of any age or sex. Included studies had to measure the outcomes of interest including at least one indicator, such as stroke, brain injury, myocardial infarction, or death.
 
Exclusion criteria
Animal trials, non-randomized controlled clinical trials, asymptomatic carotid stenosis randomized controlled trials, duplicate reporting, and poor quality or lack of data in literatures.
 
Statistical analysis
The quality evaluation criteria recommended by the Cochrane Library systematic reviews Handbook version 4.2.2 (Cochrane Center, Nothern Europe) were used to evaluate the quality of included studies. RevMan 4.2 software provided by the Cochrane Collaboration meta-analysis was used to assess the incidence of stroke relative risk (RR) and estimated the 95% confidence intervals (CI) for the outcomes of death, major and disabling stroke, and any stroke. We used the I2 statistic test which represents the proportion of heterogeneity of treatment effect across trials, that is, the percentage of total variation across studies that is due to heterogeneity rather than chance or random error. The value >50% represents significant heterogeneity that is caused by real differences in the study populations, protocols, interventions, and outcomes. Random effects model was used in the significant difference and no heterogeneity was calculated by the fixed effects model. P <0.05 was considered statistically significant.
 
RESULTS
 
Study identification
Between 1995 and 2010, 521 potentially eligible references were searched. We selected 13 randomized controlled clinical trials by reading the title, abstract, or full text. The eliminated reports were inconsistent with the purpose of this study, the non-randomized controlled studies, and the similar published literature. Two of 13 papers recently published in ICSS16 and CREST17 were included, and the last eight papers were enrolled excluding the non-symptomatic patients’ study (Table 1).
 

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Table 1. Characteristics of included randomized trials
 
Meta-analysis
Test for heterogeneity was performed in the selected eight papers, and the results demonstrated that all stroke incidences showed no heterogeneity (I2=43.2%, P=0.12) at 30 days post-surgery. Hence, the fixed effects model meta-analysis was used. Compared to the CEA group, CAS had a high incidence of stroke at 30 days post-treatment and the difference was statistically significant (RR=1.80, 95% CI: 1.380–2.401, P <0.0001) as shown in Figure 1A. Next we used random effects model to analyze the sensitivity. The results showed that the above mentioned analysis was stable and the difference was statistically significant (RR=1.93, 95% CI: 1.17–3.16, P=0.010).
 
The mortality was not heterogeneous (I2=32.6%, P=0.22) at 30 days post-operation. In the following fixed effects model meta-analysis was used to analyze safety data after 30 days of treatment which found no significant difference in the two groups’ mortality as shown in Figure 1B (RR=1.52, 95% CI: 0.82–2.82, P=0.18). Using random effects model to analyze the sensitivity of statistics, the difference was not statistically significant (RR=1.23, 95% CI: 0.50–3.02, P=0.65) which showed that the results are stable.
 
At the 30-day evaluation, we used fixed effects model meta-analysis because of the incidence in cranial nerve palsy with no heterogeneity (I2=0, P=0.84). Higher rate of nerve damage occurred in CEA group than the CAS group (RR=0.14, 95% CI: 0.05–0.43, P=0.0005) as shown in Figure 1C. Then the sensitivity was analyzed by random effects model having meaning difference (RR=0.14, 95% CI: 0.05–0.43, P=0.0005) which was consistent with the fixed effect model.
 
Myocardial infarction incidence was performed by fixed effect model analysis for two groups having no heterogeneity (I2=0%, P=0.65) after 30 days of treatment, shown in Figure 1D; myocardial infarction in CAS patients is lower than in the CEA group post-surgery at 30 days of evaluation, but statistically meaningless (RR=0.22, 95% CI: 0.05–1.02, P=0.05). Sensitivity analysis using random effects model (RR=0.27, 95% CI: 0.05–1.32, P=0.11) is consistent with the fixed effects model analysis which showed  stable results.
 

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Figure 1. Meta-analysis of carotid artery stenting (CAS) and endarterectomy (CEA). A: All stroke incidence at day 30 post-surgery. B: The mortality at day 30 post-surgery. C: Cranial nerve palsy incidence at 30 days post-surgery. D: Myocardial infarction incidence at 30 days post-surgery. E: Stroke or death incidence at 1 year post-surgery.
 
Stroke or death incidence was not heterogeneous (I2=0, P=0.38), hence fixed effects model was used at 1 year post-surgery. The CAS group had higher rates of major stroke or death compared to the CEA treatment group (RR=2.58, 95% CI: 1.03–6.48, P=0.04) as shown in figure 1E. Random effects model used for sensitivity test (RR=2.66, 95% CI: 1.00–7.06, P=0.05) indicated the credible analysis.
 
DISCUSSION
 
The morbidity of stroke in China ranked number one around the world and the occurrence rate is increasing with about 8.7% (Chinese Center Disease Control and Prvention) High-grade extracranial symptomatic internal carotid artery stenosis is an important factor of ischemia leading to stroke. Traditionally, there are two options to reduce the risk of stroke: first, medications alone (an antiplatelet drug and control of risk factors for atherosclerosis), and the other medical management plus CEA or carotid stenting. CEA is a surgical procedure performed to prevent stroke, by correcting the internal carotid artery stenosis in the common carotid artery. Compared to CEA, CAS is a minimally invasive treatment based on endovascular-catheter procedure which unblocks the stenosis of the carotid artery lumen to prevent a stroke.
 
More benefits of CEA were reported by some subgroups among the symptomatic patients. In the NASCET trial, CEA surgery was not only reducing stroke risk at 2 years but also still apparent at 8 years of follow-up than medical management alone.17 There are many studies to investigate whether CAS is comparable to CEA with respect to efficacy and safety. In some reports, CAS may become an alternative to CEA, especially in the patients treated with endarterectomy maybe at a higher risk.8 Many reports demonstrate that CAS can be performed with an acceptable complication rate in the short-term follow-up but has not been previously examined in the long-term durability. Wholey et al18 demonstrated a technical success rate of 98.40%, an overall minor stroke rate of 2.72%, a major stroke rate of 1.49%, and a mortality rate of 0.86% in the CAS group.
 
In the present study, we conducted a systematic review and meta-analyses to compare CAS and CEA for the treatment of symptomatic carotid stenosis. Eight random clinical trials for symptomatic carotid artery stenosis and a total of 3873 patients were randomly divided into the CAS and CEA groups. Seven studies mainly evaluated stroke incidence and mortality at 30 days post-treatment, which is a very important indicator to evaluate the efficacy and safety. Compared to the CEA group, CAS had a high incidence of stroke at 30 days after treatment and the difference was statistically significant (RR=1.80, 95% CI: 1.380–2.401, P <0.0001), whereas there was no significant difference in the two groups’ mortality (RR=1.52, 95% CI: 0.82–2.82, P=0.18). The test to analyze sensitivity confirmed that the results are stable. In the aspects of stroke, Murad et al19 Hreported the similar result: CAS significantly increased the risk of stroke than CEA, they also demonstrated a lower risk of myocardial infarction in the CAS group. While in our study, it was not statistically significant. The incidence of cranial nerve palsy in CAS was significantly lower than the CEA group that was consistent with the results reported by Wiesmann.4
 
Several limitations weaken the inferences of this meta analysis and there are still some factors to be further improved. First, most of the RCTs included in this study lack results in long-term follow-up and the time of follow-up varies tremendously. Only three researches attained 1 year follow-up, and the diversity of the follow-up time caused the difficulty to analyze data. Second, despite using extensive search, reporting bias may affect the results of this analysis because we cannot obtain unpublished literature, and therefore can not exclude a potential publication bias. In addition, applicability of our review may be limited because of the language bias: the retrieval languages are English and Chinese; other languages are not included. And finally, study bias was generated because some studies selected participant clinicians or medical centers on the basis of their surgical volume, outcomes, and operator experience and learning curve.
 
In conclusion, our random-effects meta-analyses clarified that carotid endarterectomy is still the preferred treatment methodology of symptomatic carotid artery stenosis compared to CAS which proved the credible short-term results published in the ICSS. But the selection of patients for either CAS or carotid endarterectomy may be decided by many complicated factors.20 With the development of new materials such as embolism protection devices, improvements in training and technique, and stent design, may reduce the risk of stroke after CAS. Future meta-analyses and long-term follow-up should be perform to support this treatment recommendation.
 
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