Endarterectomy versus Stenting in Patients with Symptomatic Severe Carotid Stenosis
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《新英格兰医药杂志》
ABSTRACT
Background Carotid stenting is less invasive than endarterectomy, but it is unclear whether it is as safe in patients with symptomatic carotid-artery stenosis.
Methods We conducted a multicenter, randomized, noninferiority trial to compare stenting with endarterectomy in patients with a symptomatic carotid stenosis of at least 60%. The primary end point was the incidence of any stroke or death within 30 days after treatment.
Results The trial was stopped prematurely after the inclusion of 527 patients for reasons of both safety and futility. The 30-day incidence of any stroke or death was 3.9% after endarterectomy (95% confidence interval , 2.0 to 7.2) and 9.6% after stenting (95% CI, 6.4 to 14.0); the relative risk of any stroke or death after stenting as compared with endarterectomy was 2.5 (95% CI, 1.2 to 5.1). The 30-day incidence of disabling stroke or death was 1.5% after endarterectomy (95% CI, 0.5 to 4.2) and 3.4% after stenting (95% CI, 1.7 to 6.7); the relative risk was 2.2 (95% CI, 0.7 to 7.2). At 6 months, the incidence of any stroke or death was 6.1% after endarterectomy and 11.7% after stenting (P=0.02). There were more major local complications after stenting and more systemic complications (mainly pulmonary) after endarterectomy, but the differences were not significant. Cranial-nerve injury was more common after endarterectomy than after stenting.
Conclusions In this study of patients with symptomatic carotid stenosis of 60% or more, the rates of death and stroke at 1 and 6 months were lower with endarterectomy than with stenting. (ClinicalTrials.gov number, NCT00190398 .)
Findings from two large randomized, clinical trials1,2,3 have established endarterectomy as the standard treatment for severe symptomatic carotid-artery stenosis. As compared with endarterectomy, stenting avoids the need for general anesthesia and an incision in the neck that could lead to nerve injury and wound complications. The costs may be less than those of surgery, mainly because the hospital stay is shorter. However, stenting also carries a risk of stroke and local complications, and the long-term efficacy of this technique is not well known. A systematic review4 of five randomized trials comparing stenting with endarterectomy5,6,7,8,9,10 concluded that the current evidence does not support a change from the recommendation of carotid endarterectomy as the standard treatment for carotid stenosis. Several more trials are in progress in Europe11,12,13 and the United States.14
We conducted this trial, which started in November 2000, to evaluate whether stenting is not inferior to endarterectomy with regard to the risks of the procedure and its long-term efficacy in patients with symptomatic carotid stenosis. In September 2005, the safety committee recommended that enrollment in the trial be stopped. We report on the risks of stroke or death within 30 days and 6 months after treatment.
Methods
The Endarterectomy versus Angioplasty in Patients with Symptomatic Severe Carotid Stenosis (EVA-3S) trial, a publicly funded, randomized, noninferiority trial, was conducted in 20 academic and 10 nonacademic centers in France. The study was approved by the ethics committee of H?pital Cochin in Paris. All patients provided written informed consent.
Centers and Investigators
To join the trial, each center was required to assemble a team of physicians comprising at least one neurologist, one vascular surgeon, and one interventional physician. The neurologist was responsible for the initial evaluation and follow-up of the patients. The vascular surgeon had to have performed at least 25 endarterectomies in the year before enrollment. The interventional physician had to have performed at least 12 carotid-stenting procedures or at least 35 stenting procedures in the supraaortic trunks, of which at least 5 were in the carotid artery. Centers fulfilling all requirements except those with regard to the interventional physician could join the EVA-3S study and randomly assign patients, but all stenting procedures had to be performed under the supervision of an experienced tutor (a clinician who qualified to perform stenting in this study) until the local interventional physician became self-sufficient (according to the tutor) and performed a sufficient number of procedures according to the predefined criteria.
Patients
Patients were eligible if they were 18 years of age or older, had had a hemispheric or retinal transient ischemic attack or a nondisabling stroke (or retinal infarct) within 120 days before enrollment, and had a stenosis of 60 to 99% in the symptomatic carotid artery, as determined by the North American Symptomatic Carotid Endarterectomy Trial (NASCET) method.15 The degree of stenosis warranting treatment, set at 70% or more at the start of the trial, was subsequently (in October 2003) set at 60% or more because endarterectomy was shown to benefit patients with symptomatic stenosis of 50 to 69%.3 The presence of an ipsilateral carotid stenosis of 60% or more had to be confirmed by means of catheter angiography or both duplex scanning and magnetic resonance angiography of the carotid artery.
Patients were excluded if one of the following was present: a modified Rankin score16 of 3 or more (disabling stroke) (on a scale of 0 to 5, with higher scores indicating more severe disability); nonatherosclerotic carotid disease; severe tandem lesions (stenosis of proximal common carotid artery or intracranial artery that was more severe than the cervical lesion); previous revascularization of the symptomatic stenosis; history of bleeding disorder; uncontrolled hypertension or diabetes; unstable angina; contraindication to heparin, ticlopidine, or clopidogrel; life expectancy of less than 2 years; or percutaneous or surgical intervention within 30 days before or after the study procedure. The appearance of the stenotic lesion on angiography was not a factor in the selection of patients.
Patients who were suitable candidates for both techniques were randomly assigned to undergo endarterectomy or stenting. Randomization was carried out centrally by means of a computer-generated sequence, involving randomized blocks of two, four, or six patients that were stratified according to study center and degree of stenosis (stenosis of 90% or <90%).
Endarterectomy and Stenting
The goal was for endarterectomy and stenting to be performed within 2 weeks after randomization. Surgeons performed endarterectomy according to customary practice. Carotid stenting had to be carried out through the femoral route with the use of stents and protection devices approved by the accreditation committee. Interventional physicians had to have performed at least two stenting procedures with any new device before its use in the trial. In January 2003, the safety committee recommended the systematic use of stents with cerebral protection devices because of a higher risk of stroke in patients treated without cerebral protection17; centers began using them on February 1, 2003. The daily use of aspirin (100 to 300 mg) and clopidogrel (75 mg) or ticlopidine (500 mg) for 3 days before and 30 days after stenting was also recommended.
Follow-up and End Points
The study neurologists performed follow-up evaluations at 48 hours, 30 days, 6 months after treatment, and every 6 months thereafter. The primary end point was a composite of any stroke or death occurring within 30 days after treatment. Secondary outcomes were myocardial infarction, transient ischemic attack, cranial-nerve injury, major local complications, and systemic complications within 30 days after treatment; and composites of any stroke or death within 30 days after treatment plus ipsilateral stroke, any stroke, or any stroke or death within 31 days through the end of follow-up. Neurologists assessed the degree of disability from stroke 30 days and 6 months after the event. Functional disability from cranial-nerve injury was categorized as absent, mild, moderate, or severe at the 30-day follow-up visit. Neurologists also recorded whether treatment-related outcomes were associated with a delay in discharge. The occurrence of stroke, death, and other outcomes was assessed by the events committee, which was unaware of the treatment assignments (except for patients who had local complications).
Statistical Analysis
We calculated18 that we would need to enroll 872 patients for the study to have a statistical power of 80% to assess whether stenting was not inferior to endarterectomy with regard to the 30-day incidence of stroke or death, given an expected 30-day incidence of stroke or death of 5.6% after endarterectomy19 and 4% after stenting,20,21 a true absolute difference between groups in the 30-day risk of stroke or death of no more than 2% (noninferiority margin), and a one-sided alpha of 0.05. A similar difference in the 30-day risk of stroke or death between endarterectomy and medical treatment was observed in NASCET.22 Our protocol required that an independent safety committee review safety issues each time 10 new validated primary outcome events occurred, with no predetermined rule for stopping the trial, and reassess the number of patients required to show an effect after 30 primary outcome events had occurred. In September 2005, the safety committee recommended stopping enrollment for reasons of both safety and futility. On the basis of the observed 30-day risk of stroke or death after endarterectomy, we would have needed to enroll more than 4000 patients to test the noninferiority of stenting (assuming that the relative noninferiority limit was unchanged). Given the observed 30-day risks of stenting, the committee considered it to be extremely unlikely that the trial, should it continue with more patients, would reach its objectives.
Analyses of the 30-day outcomes were based on all patients who were randomly assigned to treatment and who underwent carotid repair. The results are presented as relative risks with 95% confidence intervals (CIs), calculated with the use of superiority analysis. We also assessed noninferiority, as initially planned. We assessed homogeneity of the relative risks of stroke or death among centers using the Breslow–Day test. For this purpose, centers were categorized into three groups, according to the numbers of patients included in the study (<21, 21 to 40, and >40 patients). Analyses of the 6-month outcomes were based on all patients who were randomly assigned to treatment. Rates of stroke and death were estimated with the use of the Kaplan–Meier method. All data were analyzed according to the intention-to-treat principle. All P values are two-sided and were not adjusted for multiple testing. We used SAS software (version 8.2) for all analyses. The authors vouch for the completeness and veracity of the data and data analyses.
Results
Patients and Treatments
By September 2005, 527 patients had been randomly assigned to treatment, 7 of whom did not undergo carotid repair (Figure 1). The remaining 520 patients were included in the analysis of the 30-day risk of stroke or death. Three strokes that occurred between randomization and treatment were not included in the analysis of the 30-day risk of stroke or death but were included in the 6-month analysis of outcomes. The two groups were similar with respect to baseline characteristics, except for a greater proportion of patients 75 years of age or older and more patients with a history of stroke in the endarterectomy group and a higher proportion of contralateral carotid occlusion in the stenting group (Table 1).
Figure 1. Randomization and Treatment.
Carotid repair was successful in the five patients who had a transient ischemic attack (TIA), a nondisabling stroke, or myocardial infarction between randomization and carotid repair. The three strokes occurred within 2 days after randomization.
Table 1. Baseline Characteristics of the Patients.
Characteristics of the endarterectomy and stenting procedures are listed in Table 2. Two patients underwent a repeated procedure within 48 hours after the initial endarterectomy owing to residual stenosis or dissection. In 13 patients, stenting was converted intraoperatively to endarterectomy owing to problems with access. Two of these patients had a stroke before endarterectomy.
Table 2. Characteristics of Treatment for 257 Patients Who Completed Endarterectomy and 247 Patients Who Completed Stenting.
End Points
Although the trial was intended to assess noninferiority, we observed that stenting carried a greater risk than did endarterectomy. When we analyzed the data as planned, the 95% CI of the difference in the 30-day incidence of stroke or death between stenting and endarterectomy (2.1 to 9.3%) did not include the 2% limit used to define noninferiority. The 30-day incidence of any stroke or death was 3.9% (95% CI, 2.0 to 7.2) after endarterectomy and 9.6% (95% CI, 6.4 to 14.0) after stenting, with a relative risk of 2.5 (95% CI, 1.2 to 5.1). The absolute risk increase was 5.7%, suggesting that one additional stroke or death resulted when 17 patients underwent stenting rather than endarterectomy. The 30-day incidence of disabling stroke or death was 1.5% (95% CI, 0.5 to 4.2) after endarterectomy and 3.4% (95% CI, 1.7 to 6.7) after stenting, resulting in a relative risk of 2.2 (95% CI, 0.7 to 7.2) (Table 3). A greater proportion of strokes occurred on the day of the procedure in the stenting group than in the endarterectomy group (17 of 24 vs. 3 of 9, P=0.05).
Table 3. Risk of Stroke or Death and Other Treatment-Related Outcomes within 30 Days after Endarterectomy or Stenting.
The relative risk of stroke or death did not differ significantly among the centers that enrolled fewer than 21 patients (relative risk, 1.9; 95% CI, 0.6 to 6.2), those that enrolled 21 to 40 patients (relative risk, 3.3; 95% CI, 0.7 to 15.2), and those that enrolled more than 40 patients (relative risk, 2.7; 95% CI, 0.9 to 8.1) (P=0.83). The 30-day incidence of stroke or death was similar among patients treated by interventional physicians who were experienced (11 of 105, or 10.5%), tutored during training (7 of 98, or 7.1%), and tutored after training (7 of 57, or 12.3%) (P=0.54; chi-square statistic, 1.25).
The 30-day incidence of stroke or death was lower among patients who underwent stenting with cerebral protection (18 of 227, or 7.9%) than among those treated with stenting alone (5 of 20, or 25%; P=0.03). However, the relative risk of stroke or death for stenting over endarterectomy did not differ significantly before systematic use of a cerebral protection device was recommended (2.0; 95% CI, 0.8 to 5.0) or after (3.4; 95% CI, 1.1 to 10.0; P=0.50).
The relative risk of stroke or death adjusted for age was 2.4 (95% CI, 1.2 to 4.8) and adjusted for the presence or absence of a history of stroke was 2.6 (95% CI, 1.3 to 5.2). More patients in the stenting group had contralateral carotid occlusion; none of them had a stroke after stenting. The 30-day incidence of stroke or death after stenting did not differ significantly between patients who received dual antiplatelet therapy (19 of 211, or 9.0%) and those who received single antiplatelet therapy (4 of 36, or 11.1%; P=0.75).
There were more systemic complications (mainly pulmonary) after endarterectomy and more severe local complications after stenting than after endarterectomy, but these differences were not significant. Cranial-nerve injury was significantly more common after endarterectomy than after stenting (7.7% vs. 1.1%, P<0.001). The median duration of the hospital stay was shorter after stenting (3 days; interquartile range, 2 to 5) than after endarterectomy (4 days; interquartile range, 3 to 5; P=0.01).
Table 4 lists the incidence of primary outcome events at 6 months. The three composite outcomes were significantly more common after stenting than after endarterectomy.
Table 4. Incidence of Primary Outcome Events at 6 Months.
Discussion
This trial was stopped early for reasons of both safety and futility. The 30-day risk of any stroke or death was significantly higher after stenting (9.6%) than after endarterectomy (3.9%), resulting in a relative risk of 2.5 (95% CI, 1.2 to 5.1). Although early stopping of randomized clinical trials carries a risk of the overestimation of treatment effects (i.e., analyzing the data at a "random high"),23 the excess of primary outcome events after stenting was considered large enough (one additional stroke or death among each 17 patients treated by stenting) for the safety committee to recommend stopping the trial. In addition, the observed rates of the primary outcome made it very unlikely that the trial would show the noninferiority of stenting.
The 30-day incidence of stroke or death after endarterectomy was lower in our trial than in previous trials of endarterectomy in symptomatic patients.1,2 The lower surgical risk in our study is unlikely to be explained by the selection of surgeons with a very high level of expertise. Indeed, the surgeons worked in academic and nonacademic centers in various areas of France and had only to have performed 25 endarterectomies in the year before enrollment; there was no upper limit for perioperative stroke and death. The baseline characteristics of our patients were similar to those included in other trials of endarterectomy,2,5 which makes it unlikely that our findings are explained by the inclusion of patients at low risk for perioperative stroke or death. Moreover, to prevent the underreporting of minor strokes in patients who underwent surgery under general anesthesia and then were returned to surgical wards, all patients were examined 2 days after the procedure. Therefore, the most likely explanation for the low rate of complications from endarterectomy in our trial is that the risks of this procedure have decreased since the pivotal trials1,2 were conducted.
The combination of results of previous trials4 yielded a 30-day incidence of stroke or death after endovascular repair of the carotid artery of 8.1% (51 of 632 patients; range, 0.0 to 12.1%). There was significant heterogeneity among these trials, which may have resulted from the use of different endovascular techniques or different criteria for patient selection. The 30-day incidence of stroke after stenting in our study (9.2%) was higher than that in the Stenting and Angioplasty with Protection in Patients at High Risk for Endarterectomy (SAPPHIRE) trial10 (3.6%), despite the use of similar endovascular techniques. However, most patients (70%) included in the SAPPHIRE trial had asymptomatic stenosis, which carries a lower risk of stroke during carotid repair than does symptomatic stenosis.20,24 Patients in the Carotid and Vertebral Artery Transluminal Angioplasty Study (CAVATAS)5 were similar to those in our trial, but the majority (77%) underwent carotid angioplasty without stenting, and procedures were not performed with the use of cerebral protection devices.
A potential bias in the comparison of a relatively new procedure such as stenting with an established procedure such as endarterectomy is the effect of the learning curve. Our trial involved centers with staff members who had various degrees of experience in carotid stenting, including centers in which investigators treated enrolled patients under the supervision of a tutor. We tried to limit the effect of the learning curve through the careful training and supervision of interventional physicians. We did not find any significant differences in outcome related to the number of stenting procedures performed in individual centers or to the experience of the interventional physicians, although these analyses were able to detect only large differences. There may also be a learning curve related to changes in technique. Centers in our trial were not required to use a device from a particular manufacturer for stenting or cerebral protection, but experience with any new device was required before its use in the trial.
Cerebral-protection devices have been developed to reduce embolization of plaque fragments during stenting. Uncontrolled studies11,20,21 suggest that these devices may reduce the risk of procedural stroke. However, one could argue that protection devices may cause additional adverse events in some patients and increase costs.
In summary, our results indicate that in patients with symptomatic carotid stenosis of 60% or more, treatment with endarterectomy results in lower rates of stroke or death at 30 days and 6 months than does stenting. Long-term follow-up is ongoing to determine whether the advantage of endarterectomy is sustained. A larger number of patients are required to provide definite answers about the risk–benefit profile of stenting, as compared with endarterectomy, and to permit meaningful subgroup analyses.
Supported by a grant from the Programme Hospitalier de Recherche Clinique of the French Ministry of Health (AOM 97066), Assistance Publique–H?pitaux de Paris.
Dr. Beyssen reports having received lecture fees from ev3 and Guidant; and Dr. Becquemin, lecture fees from Cordis, Guidant, and Cook. No other potential conflict of interest relevant to this article was reported.
We are indebted to Véronique Favret, Ouafia Lakat, and Christine Mandet for their outstanding efforts in data management; to Ludovic Trinquart for statistical help; and to Jo?l Ménard and Nicolas Best for their constant support.
* Investigators and committees of the Endarterectomy versus Angioplasty in Patients with Symptomatic Severe Carotid Stenosis (EVA-3S) trial are listed in the Appendix.
Source Information
From H?pitaux Sainte-Anne (J.-L.M., B.B., E.T.) and Europeén Georges Pompidou (G.C.), Université René Descartes, Paris; H?pitaux La Timone (A.B.) and Sainte-Marguerite (P.P.), Université de la Méditerranée, Marseille; H?pital Jean Minjoz, Université de Franche-Comté, Besan?on (T.M., J.-F.B.); H?pital Henri Mondor, Université Paris-Val-de-Marne, Créteil (J.-P.B., H.H.); H?pitaux Rangueil (V.L., A.V.) and Purpan (J.-F.A.), Université Paul Sabatier, Toulouse; Université Claude Bernard, Lyon (M.L.); H?pital Roger Salengro, Université du Droit et de la Santé, Lille (D.L., J.-P.P.); H?pital Charles Nicolle, Université de Rouen, Rouen (J.W.); H?pital de Bellevue, Université Jean Monnet, Saint-Etienne (P.G.); H?pital C?te de Nacre, Université de Caen, Caen (F.V.); H?pital Général, Université de Bourgogne, Dijon (M.G.); Nouvelles Cliniques Nantaises, Nantes (J.-C.P.); H?pital Lariboisière, Université Denis Diderot, Paris (P.F.); H?pital La Milétrie, Université de Poitiers, Poitiers (J.-P.N.); and H?pital Saint-Julien Université Henri Poincaré, Nancy (X.D.) — all in France.
Address reprint requests to Dr. Mas at the Service de Neurologie, H?pital Sainte-Anne, 1 Rue Cabanis, 75674 Paris Cedex 14, France, or at jl.mas@ch-sainte-anne.fr.
References
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Background Carotid stenting is less invasive than endarterectomy, but it is unclear whether it is as safe in patients with symptomatic carotid-artery stenosis.
Methods We conducted a multicenter, randomized, noninferiority trial to compare stenting with endarterectomy in patients with a symptomatic carotid stenosis of at least 60%. The primary end point was the incidence of any stroke or death within 30 days after treatment.
Results The trial was stopped prematurely after the inclusion of 527 patients for reasons of both safety and futility. The 30-day incidence of any stroke or death was 3.9% after endarterectomy (95% confidence interval , 2.0 to 7.2) and 9.6% after stenting (95% CI, 6.4 to 14.0); the relative risk of any stroke or death after stenting as compared with endarterectomy was 2.5 (95% CI, 1.2 to 5.1). The 30-day incidence of disabling stroke or death was 1.5% after endarterectomy (95% CI, 0.5 to 4.2) and 3.4% after stenting (95% CI, 1.7 to 6.7); the relative risk was 2.2 (95% CI, 0.7 to 7.2). At 6 months, the incidence of any stroke or death was 6.1% after endarterectomy and 11.7% after stenting (P=0.02). There were more major local complications after stenting and more systemic complications (mainly pulmonary) after endarterectomy, but the differences were not significant. Cranial-nerve injury was more common after endarterectomy than after stenting.
Conclusions In this study of patients with symptomatic carotid stenosis of 60% or more, the rates of death and stroke at 1 and 6 months were lower with endarterectomy than with stenting. (ClinicalTrials.gov number, NCT00190398 .)
Findings from two large randomized, clinical trials1,2,3 have established endarterectomy as the standard treatment for severe symptomatic carotid-artery stenosis. As compared with endarterectomy, stenting avoids the need for general anesthesia and an incision in the neck that could lead to nerve injury and wound complications. The costs may be less than those of surgery, mainly because the hospital stay is shorter. However, stenting also carries a risk of stroke and local complications, and the long-term efficacy of this technique is not well known. A systematic review4 of five randomized trials comparing stenting with endarterectomy5,6,7,8,9,10 concluded that the current evidence does not support a change from the recommendation of carotid endarterectomy as the standard treatment for carotid stenosis. Several more trials are in progress in Europe11,12,13 and the United States.14
We conducted this trial, which started in November 2000, to evaluate whether stenting is not inferior to endarterectomy with regard to the risks of the procedure and its long-term efficacy in patients with symptomatic carotid stenosis. In September 2005, the safety committee recommended that enrollment in the trial be stopped. We report on the risks of stroke or death within 30 days and 6 months after treatment.
Methods
The Endarterectomy versus Angioplasty in Patients with Symptomatic Severe Carotid Stenosis (EVA-3S) trial, a publicly funded, randomized, noninferiority trial, was conducted in 20 academic and 10 nonacademic centers in France. The study was approved by the ethics committee of H?pital Cochin in Paris. All patients provided written informed consent.
Centers and Investigators
To join the trial, each center was required to assemble a team of physicians comprising at least one neurologist, one vascular surgeon, and one interventional physician. The neurologist was responsible for the initial evaluation and follow-up of the patients. The vascular surgeon had to have performed at least 25 endarterectomies in the year before enrollment. The interventional physician had to have performed at least 12 carotid-stenting procedures or at least 35 stenting procedures in the supraaortic trunks, of which at least 5 were in the carotid artery. Centers fulfilling all requirements except those with regard to the interventional physician could join the EVA-3S study and randomly assign patients, but all stenting procedures had to be performed under the supervision of an experienced tutor (a clinician who qualified to perform stenting in this study) until the local interventional physician became self-sufficient (according to the tutor) and performed a sufficient number of procedures according to the predefined criteria.
Patients
Patients were eligible if they were 18 years of age or older, had had a hemispheric or retinal transient ischemic attack or a nondisabling stroke (or retinal infarct) within 120 days before enrollment, and had a stenosis of 60 to 99% in the symptomatic carotid artery, as determined by the North American Symptomatic Carotid Endarterectomy Trial (NASCET) method.15 The degree of stenosis warranting treatment, set at 70% or more at the start of the trial, was subsequently (in October 2003) set at 60% or more because endarterectomy was shown to benefit patients with symptomatic stenosis of 50 to 69%.3 The presence of an ipsilateral carotid stenosis of 60% or more had to be confirmed by means of catheter angiography or both duplex scanning and magnetic resonance angiography of the carotid artery.
Patients were excluded if one of the following was present: a modified Rankin score16 of 3 or more (disabling stroke) (on a scale of 0 to 5, with higher scores indicating more severe disability); nonatherosclerotic carotid disease; severe tandem lesions (stenosis of proximal common carotid artery or intracranial artery that was more severe than the cervical lesion); previous revascularization of the symptomatic stenosis; history of bleeding disorder; uncontrolled hypertension or diabetes; unstable angina; contraindication to heparin, ticlopidine, or clopidogrel; life expectancy of less than 2 years; or percutaneous or surgical intervention within 30 days before or after the study procedure. The appearance of the stenotic lesion on angiography was not a factor in the selection of patients.
Patients who were suitable candidates for both techniques were randomly assigned to undergo endarterectomy or stenting. Randomization was carried out centrally by means of a computer-generated sequence, involving randomized blocks of two, four, or six patients that were stratified according to study center and degree of stenosis (stenosis of 90% or <90%).
Endarterectomy and Stenting
The goal was for endarterectomy and stenting to be performed within 2 weeks after randomization. Surgeons performed endarterectomy according to customary practice. Carotid stenting had to be carried out through the femoral route with the use of stents and protection devices approved by the accreditation committee. Interventional physicians had to have performed at least two stenting procedures with any new device before its use in the trial. In January 2003, the safety committee recommended the systematic use of stents with cerebral protection devices because of a higher risk of stroke in patients treated without cerebral protection17; centers began using them on February 1, 2003. The daily use of aspirin (100 to 300 mg) and clopidogrel (75 mg) or ticlopidine (500 mg) for 3 days before and 30 days after stenting was also recommended.
Follow-up and End Points
The study neurologists performed follow-up evaluations at 48 hours, 30 days, 6 months after treatment, and every 6 months thereafter. The primary end point was a composite of any stroke or death occurring within 30 days after treatment. Secondary outcomes were myocardial infarction, transient ischemic attack, cranial-nerve injury, major local complications, and systemic complications within 30 days after treatment; and composites of any stroke or death within 30 days after treatment plus ipsilateral stroke, any stroke, or any stroke or death within 31 days through the end of follow-up. Neurologists assessed the degree of disability from stroke 30 days and 6 months after the event. Functional disability from cranial-nerve injury was categorized as absent, mild, moderate, or severe at the 30-day follow-up visit. Neurologists also recorded whether treatment-related outcomes were associated with a delay in discharge. The occurrence of stroke, death, and other outcomes was assessed by the events committee, which was unaware of the treatment assignments (except for patients who had local complications).
Statistical Analysis
We calculated18 that we would need to enroll 872 patients for the study to have a statistical power of 80% to assess whether stenting was not inferior to endarterectomy with regard to the 30-day incidence of stroke or death, given an expected 30-day incidence of stroke or death of 5.6% after endarterectomy19 and 4% after stenting,20,21 a true absolute difference between groups in the 30-day risk of stroke or death of no more than 2% (noninferiority margin), and a one-sided alpha of 0.05. A similar difference in the 30-day risk of stroke or death between endarterectomy and medical treatment was observed in NASCET.22 Our protocol required that an independent safety committee review safety issues each time 10 new validated primary outcome events occurred, with no predetermined rule for stopping the trial, and reassess the number of patients required to show an effect after 30 primary outcome events had occurred. In September 2005, the safety committee recommended stopping enrollment for reasons of both safety and futility. On the basis of the observed 30-day risk of stroke or death after endarterectomy, we would have needed to enroll more than 4000 patients to test the noninferiority of stenting (assuming that the relative noninferiority limit was unchanged). Given the observed 30-day risks of stenting, the committee considered it to be extremely unlikely that the trial, should it continue with more patients, would reach its objectives.
Analyses of the 30-day outcomes were based on all patients who were randomly assigned to treatment and who underwent carotid repair. The results are presented as relative risks with 95% confidence intervals (CIs), calculated with the use of superiority analysis. We also assessed noninferiority, as initially planned. We assessed homogeneity of the relative risks of stroke or death among centers using the Breslow–Day test. For this purpose, centers were categorized into three groups, according to the numbers of patients included in the study (<21, 21 to 40, and >40 patients). Analyses of the 6-month outcomes were based on all patients who were randomly assigned to treatment. Rates of stroke and death were estimated with the use of the Kaplan–Meier method. All data were analyzed according to the intention-to-treat principle. All P values are two-sided and were not adjusted for multiple testing. We used SAS software (version 8.2) for all analyses. The authors vouch for the completeness and veracity of the data and data analyses.
Results
Patients and Treatments
By September 2005, 527 patients had been randomly assigned to treatment, 7 of whom did not undergo carotid repair (Figure 1). The remaining 520 patients were included in the analysis of the 30-day risk of stroke or death. Three strokes that occurred between randomization and treatment were not included in the analysis of the 30-day risk of stroke or death but were included in the 6-month analysis of outcomes. The two groups were similar with respect to baseline characteristics, except for a greater proportion of patients 75 years of age or older and more patients with a history of stroke in the endarterectomy group and a higher proportion of contralateral carotid occlusion in the stenting group (Table 1).
Figure 1. Randomization and Treatment.
Carotid repair was successful in the five patients who had a transient ischemic attack (TIA), a nondisabling stroke, or myocardial infarction between randomization and carotid repair. The three strokes occurred within 2 days after randomization.
Table 1. Baseline Characteristics of the Patients.
Characteristics of the endarterectomy and stenting procedures are listed in Table 2. Two patients underwent a repeated procedure within 48 hours after the initial endarterectomy owing to residual stenosis or dissection. In 13 patients, stenting was converted intraoperatively to endarterectomy owing to problems with access. Two of these patients had a stroke before endarterectomy.
Table 2. Characteristics of Treatment for 257 Patients Who Completed Endarterectomy and 247 Patients Who Completed Stenting.
End Points
Although the trial was intended to assess noninferiority, we observed that stenting carried a greater risk than did endarterectomy. When we analyzed the data as planned, the 95% CI of the difference in the 30-day incidence of stroke or death between stenting and endarterectomy (2.1 to 9.3%) did not include the 2% limit used to define noninferiority. The 30-day incidence of any stroke or death was 3.9% (95% CI, 2.0 to 7.2) after endarterectomy and 9.6% (95% CI, 6.4 to 14.0) after stenting, with a relative risk of 2.5 (95% CI, 1.2 to 5.1). The absolute risk increase was 5.7%, suggesting that one additional stroke or death resulted when 17 patients underwent stenting rather than endarterectomy. The 30-day incidence of disabling stroke or death was 1.5% (95% CI, 0.5 to 4.2) after endarterectomy and 3.4% (95% CI, 1.7 to 6.7) after stenting, resulting in a relative risk of 2.2 (95% CI, 0.7 to 7.2) (Table 3). A greater proportion of strokes occurred on the day of the procedure in the stenting group than in the endarterectomy group (17 of 24 vs. 3 of 9, P=0.05).
Table 3. Risk of Stroke or Death and Other Treatment-Related Outcomes within 30 Days after Endarterectomy or Stenting.
The relative risk of stroke or death did not differ significantly among the centers that enrolled fewer than 21 patients (relative risk, 1.9; 95% CI, 0.6 to 6.2), those that enrolled 21 to 40 patients (relative risk, 3.3; 95% CI, 0.7 to 15.2), and those that enrolled more than 40 patients (relative risk, 2.7; 95% CI, 0.9 to 8.1) (P=0.83). The 30-day incidence of stroke or death was similar among patients treated by interventional physicians who were experienced (11 of 105, or 10.5%), tutored during training (7 of 98, or 7.1%), and tutored after training (7 of 57, or 12.3%) (P=0.54; chi-square statistic, 1.25).
The 30-day incidence of stroke or death was lower among patients who underwent stenting with cerebral protection (18 of 227, or 7.9%) than among those treated with stenting alone (5 of 20, or 25%; P=0.03). However, the relative risk of stroke or death for stenting over endarterectomy did not differ significantly before systematic use of a cerebral protection device was recommended (2.0; 95% CI, 0.8 to 5.0) or after (3.4; 95% CI, 1.1 to 10.0; P=0.50).
The relative risk of stroke or death adjusted for age was 2.4 (95% CI, 1.2 to 4.8) and adjusted for the presence or absence of a history of stroke was 2.6 (95% CI, 1.3 to 5.2). More patients in the stenting group had contralateral carotid occlusion; none of them had a stroke after stenting. The 30-day incidence of stroke or death after stenting did not differ significantly between patients who received dual antiplatelet therapy (19 of 211, or 9.0%) and those who received single antiplatelet therapy (4 of 36, or 11.1%; P=0.75).
There were more systemic complications (mainly pulmonary) after endarterectomy and more severe local complications after stenting than after endarterectomy, but these differences were not significant. Cranial-nerve injury was significantly more common after endarterectomy than after stenting (7.7% vs. 1.1%, P<0.001). The median duration of the hospital stay was shorter after stenting (3 days; interquartile range, 2 to 5) than after endarterectomy (4 days; interquartile range, 3 to 5; P=0.01).
Table 4 lists the incidence of primary outcome events at 6 months. The three composite outcomes were significantly more common after stenting than after endarterectomy.
Table 4. Incidence of Primary Outcome Events at 6 Months.
Discussion
This trial was stopped early for reasons of both safety and futility. The 30-day risk of any stroke or death was significantly higher after stenting (9.6%) than after endarterectomy (3.9%), resulting in a relative risk of 2.5 (95% CI, 1.2 to 5.1). Although early stopping of randomized clinical trials carries a risk of the overestimation of treatment effects (i.e., analyzing the data at a "random high"),23 the excess of primary outcome events after stenting was considered large enough (one additional stroke or death among each 17 patients treated by stenting) for the safety committee to recommend stopping the trial. In addition, the observed rates of the primary outcome made it very unlikely that the trial would show the noninferiority of stenting.
The 30-day incidence of stroke or death after endarterectomy was lower in our trial than in previous trials of endarterectomy in symptomatic patients.1,2 The lower surgical risk in our study is unlikely to be explained by the selection of surgeons with a very high level of expertise. Indeed, the surgeons worked in academic and nonacademic centers in various areas of France and had only to have performed 25 endarterectomies in the year before enrollment; there was no upper limit for perioperative stroke and death. The baseline characteristics of our patients were similar to those included in other trials of endarterectomy,2,5 which makes it unlikely that our findings are explained by the inclusion of patients at low risk for perioperative stroke or death. Moreover, to prevent the underreporting of minor strokes in patients who underwent surgery under general anesthesia and then were returned to surgical wards, all patients were examined 2 days after the procedure. Therefore, the most likely explanation for the low rate of complications from endarterectomy in our trial is that the risks of this procedure have decreased since the pivotal trials1,2 were conducted.
The combination of results of previous trials4 yielded a 30-day incidence of stroke or death after endovascular repair of the carotid artery of 8.1% (51 of 632 patients; range, 0.0 to 12.1%). There was significant heterogeneity among these trials, which may have resulted from the use of different endovascular techniques or different criteria for patient selection. The 30-day incidence of stroke after stenting in our study (9.2%) was higher than that in the Stenting and Angioplasty with Protection in Patients at High Risk for Endarterectomy (SAPPHIRE) trial10 (3.6%), despite the use of similar endovascular techniques. However, most patients (70%) included in the SAPPHIRE trial had asymptomatic stenosis, which carries a lower risk of stroke during carotid repair than does symptomatic stenosis.20,24 Patients in the Carotid and Vertebral Artery Transluminal Angioplasty Study (CAVATAS)5 were similar to those in our trial, but the majority (77%) underwent carotid angioplasty without stenting, and procedures were not performed with the use of cerebral protection devices.
A potential bias in the comparison of a relatively new procedure such as stenting with an established procedure such as endarterectomy is the effect of the learning curve. Our trial involved centers with staff members who had various degrees of experience in carotid stenting, including centers in which investigators treated enrolled patients under the supervision of a tutor. We tried to limit the effect of the learning curve through the careful training and supervision of interventional physicians. We did not find any significant differences in outcome related to the number of stenting procedures performed in individual centers or to the experience of the interventional physicians, although these analyses were able to detect only large differences. There may also be a learning curve related to changes in technique. Centers in our trial were not required to use a device from a particular manufacturer for stenting or cerebral protection, but experience with any new device was required before its use in the trial.
Cerebral-protection devices have been developed to reduce embolization of plaque fragments during stenting. Uncontrolled studies11,20,21 suggest that these devices may reduce the risk of procedural stroke. However, one could argue that protection devices may cause additional adverse events in some patients and increase costs.
In summary, our results indicate that in patients with symptomatic carotid stenosis of 60% or more, treatment with endarterectomy results in lower rates of stroke or death at 30 days and 6 months than does stenting. Long-term follow-up is ongoing to determine whether the advantage of endarterectomy is sustained. A larger number of patients are required to provide definite answers about the risk–benefit profile of stenting, as compared with endarterectomy, and to permit meaningful subgroup analyses.
Supported by a grant from the Programme Hospitalier de Recherche Clinique of the French Ministry of Health (AOM 97066), Assistance Publique–H?pitaux de Paris.
Dr. Beyssen reports having received lecture fees from ev3 and Guidant; and Dr. Becquemin, lecture fees from Cordis, Guidant, and Cook. No other potential conflict of interest relevant to this article was reported.
We are indebted to Véronique Favret, Ouafia Lakat, and Christine Mandet for their outstanding efforts in data management; to Ludovic Trinquart for statistical help; and to Jo?l Ménard and Nicolas Best for their constant support.
* Investigators and committees of the Endarterectomy versus Angioplasty in Patients with Symptomatic Severe Carotid Stenosis (EVA-3S) trial are listed in the Appendix.
Source Information
From H?pitaux Sainte-Anne (J.-L.M., B.B., E.T.) and Europeén Georges Pompidou (G.C.), Université René Descartes, Paris; H?pitaux La Timone (A.B.) and Sainte-Marguerite (P.P.), Université de la Méditerranée, Marseille; H?pital Jean Minjoz, Université de Franche-Comté, Besan?on (T.M., J.-F.B.); H?pital Henri Mondor, Université Paris-Val-de-Marne, Créteil (J.-P.B., H.H.); H?pitaux Rangueil (V.L., A.V.) and Purpan (J.-F.A.), Université Paul Sabatier, Toulouse; Université Claude Bernard, Lyon (M.L.); H?pital Roger Salengro, Université du Droit et de la Santé, Lille (D.L., J.-P.P.); H?pital Charles Nicolle, Université de Rouen, Rouen (J.W.); H?pital de Bellevue, Université Jean Monnet, Saint-Etienne (P.G.); H?pital C?te de Nacre, Université de Caen, Caen (F.V.); H?pital Général, Université de Bourgogne, Dijon (M.G.); Nouvelles Cliniques Nantaises, Nantes (J.-C.P.); H?pital Lariboisière, Université Denis Diderot, Paris (P.F.); H?pital La Milétrie, Université de Poitiers, Poitiers (J.-P.N.); and H?pital Saint-Julien Université Henri Poincaré, Nancy (X.D.) — all in France.
Address reprint requests to Dr. Mas at the Service de Neurologie, H?pital Sainte-Anne, 1 Rue Cabanis, 75674 Paris Cedex 14, France, or at jl.mas@ch-sainte-anne.fr.
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