Protected carotid stenting in high-surgical-risk patients: The ARCHeR results

Article Outline

• Abstract
• Methods
  • Study devices
  • Trial design
  • Historical control
  • Intervention and study conduct
  • Study end points
  • Quantitative angiography
  • Doppler ultrasonography
  • Analysis of embolic material
  • Statistical analysis
• Results
  • Baseline characteristics
  • Technical and procedural results
  • Primary outcomes
  • Durability of revascularization and stroke prevention
• Discussion
• Author contributions
• Appendix I
• Appendix II
  • Medical comorbidities
  • High-surgical-risk features
  • Age 75 years or older
  • Surgical access or other anatomic conditions (hostile neck)
• References
• References
• Copyright

Background

Carotid endarterectomy is the standard of care for most patients with severe extracranial carotid bifurcation disease. However, its safety and efficacy in patients with significant surgical risk are unclear. The ARCHeR (ACCULINK for Revascularization of Carotids in High-Risk patients) trial was performed to determine whether carotid artery stenting with embolic protection is a safe and effective alternative to endarterectomy in high-surgical-risk patients.

Methods

The ARCHeR trial is a series of three sequential, multicenter, nonrandomized, prospective studies. Forty-eight sites enrolled 581 high-surgical-risk patients between May 2000 and September 2003. Patients with severe carotid artery stenosis (angiographically defined, symptomatic ≥50%, or asymptomatic ≥80%) had an ACCULINK nitinol stent implanted. The ACCUNET filter embolic protection system was added to the procedure in the final 2 studies (422 patients). The primary efficacy end point was a composite of periprocedural (≤30 days) death, stroke, and myocardial infarction, plus ipsilateral stroke between days 31 and 365.

Results

The 30-day rate of death/stroke/myocardial infarction was 8.3% (95% confidence interval [CI], 6.2%-10.8%), and that of stroke/death was 6.9% (95% CI, 5.0%-9.3%). Most (23/32) strokes were minor, of which more than half (12/23) returned to baseline National Institutes of Health Stroke Scale scores within 30 days. The 30-day major/fatal stroke rate was 1.5% (95% CI, 0.7%-2.9%). No hemorrhagic strokes were observed in the study. Ipsilateral cerebrovascular accident occurred in 1.3% between 30 days and 1 year, thus giving a primary composite end point of 30-day death/stroke/myocardial infarction plus ipsilateral stroke at 1 year of 9.6% (95% CI, 7.2%-12.0%), which is below the 14.4% historical control comparator. Target lesion revascularization at 12 months and 2 years was 2.2% and 2.9%, respectively.

Conclusions

The ARCHeR results demonstrate that extracranial carotid artery stenting with embolic filter protection is not inferior to historical results of endarterectomy and suggest that carotid artery stenting is a safe, durable, and effective alternative in high-surgical-risk patients.

Stroke is the third leading cause of death in the United States, with an estimated 164,000 deaths per year,¹ and approximately 30% of ischemic strokes result from extracranial carotid artery occlusive disease.² Although significant advances in pharmacologic therapy for vascular disease have occurred, including improved antiplatelet, antihypertensive, and lipid-lowering agents, which have reduced the risk of all vascular events, the stroke-prevention benefit of these therapies has not been demonstrated specifically for patients with established severe carotid artery disease. However, the superiority of carotid endarterectomy (CEA) over medical therapy in preventing stroke in patients with high-grade (>50% stenosis) symptomatic carotid artery disease is well established.³, ⁴ Similarly, in asymptomatic patients with severe carotid stenosis, the recently reported Asymptomatic Carotid Surgery Trial⁵ and other studies⁶, ⁷, ⁸ have established that CEA, when combined with medical management of modifiable risk factors, is superior to medical management alone in preventing stroke, with benefits seen as early as 2 years after surgery.

On the basis of these studies, CEA is generally considered the standard therapy for severe carotid artery disease, even among patients with anatomic factors or comorbid conditions associated with increased operative risk. In such patients, perioperative morbidity and mortality rates after CEA have been reported to range from 10% to 20%.⁹, ¹⁰, ¹¹, ¹², ¹³, ¹⁴, ¹⁵, ¹⁶, ¹⁷, ¹⁸, ¹⁹ In addition, patients with anatomic characteristics (postradiation therapy, tracheostomy, and so on) often termed hostile necks, although not systematically studied, pose obvious challenges to a surgical approach.

The ARCHeR (ACCULINK for Revascularization of Carotids in High-Risk patients) studies were designed to evaluate the safety and efficacy of the Guidant Corporation (Santa Clara, Calif) ACCULINK carotid stent with the ACCUNET embolic filter protection device as an alternative to surgical revascularization in these and other categories of high-surgical-risk patients. On the basis of these data from ARCHeR, the Food and Drug Administration approved the ACCULINK Carotid Stent System and ACCUNET Embolic Protection Device for use in high-surgical-risk patients in August 2004.

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Methods 

Study devices 

The ACCULINK carotid stent and ACCUNET embolic protection devices (Guidant Corporation) were designed specifically to treat carotid artery stenosis. The stent is self expanding and crush resistant and is constructed of nickel-titanium (nitinol). The stent is manufactured in both tapered and uniform diameters and in multiple lengths. The embolic protection system is a filtration-type device designed for use in combination with the stent. The filter is nitinol framed and joined with a porous (120-μm pores) polyurethane membrane. The filter basket is profile constrained within a sheath and expanded inside the artery once guided through and distal to the lesion. During the endovascular procedure, flow is maintained, and emboli are collected as blood moves through the filter basket. At the completion of the procedure, the filter basket is collapsed and removed by using a recovery sheath to retrieve any collected material.

Trial design 

The ARCHeR trial is a sequential series of three prospective, nonrandomized, multicenter studies that consecutively enrolled 581 patients from May 2000 to September 2003 at 43 sites in the United States and 5 sites outside of the United States. The three phases of ARCHeR paralleled the development of the devices and the introduction of embolic protection; all patients received the same carotid stent. ARCHeR 1 used the over-the-wire version of the stent delivery system without adjunctive filter embolic protection. The over-the-wire ACCUNET embolic protection device was introduced in ARCHeR 2. Finally, the rapid-exchange platform was introduced for both stent and filter embolic protection delivery systems in ARCHeR 3.

The aim of ARCHeR 1 was to test the hypothesis of noninferiority in the rate of composite 1-year end-point events (all deaths, strokes, and myocardial infarctions [MIs] within 30 days, plus ipsilateral strokes between days 31 and 365) for the study patients as compared with a historical control rate derived from published literature. ARCHeR 1 was originally powered at 80% with a 1-sided α of .05 to test this hypothesis in 339 patients, but enrollment in this phase was terminated at 158 patients to allow the introduction of embolic protection and then begin ARCHeR 2. By using updated assumptions, ARCHeR 2 was independently powered at 90% with a 1-sided α of .05 to test the same hypothesis and completed enrollment with 278 patients. ARCHeR 3 was powered at 85% with a one-sided α of .05 to demonstrate equivalence of the improved delivery system with the periprocedural 30-day safety results in ARCHeR 2. The requisite sample size of 145 was enrolled in this study.

For regulatory approval, each phase tested the primary hypothesis separately. However, for this analysis, the data from all three phases were pooled together for evaluation of the primary hypothesis of noninferiority to the historical control at 1 year. The poolability of data was based on the following: (1) all three ARCHeR phases used identical eligibility criteria (Table I), (2) the same stent implant was used in all patients, and (3) a multivariate regression of 30-day results indicated that the specific trial was not significant in predicting the outcome (ARCHeR 1 vs ARCHeR 2 vs ARCHeR 3; P > .7).

Table I. Key eligibility criteria

NYHA, New York Heart Association; CEA, carotid endarterectomy; FEV₁, forced expiratory volume in 1 second; ICA, internal carotid artery; MI, myocardial infarction.

The primary study hypothesis was constructed to statistically assess whether the 1-year composite primary end-point rate (anticipated at 10%) for stenting was within an acceptable margin of the historical control rate (14.4%) as follows:

and where delta (the noninferiority margin) was set at 4.0%. A pooled cohort with 581 patients yields more than 99% power to reject the null hypothesis in favor of the alternative with a 1-sided .05 level of significance.

Historical control 

Before the initiation of the trial, a historical control was derived from an extensive review of the literature on the results of the standard of care, principally CEA, in a similar high-surgical-risk patient population that was divided into two categories: medical/surgical comorbidities and unfavorable anatomy. For patients with medical/surgical comorbidities, periprocedural death, stroke, and MI rates from the North American Symptomatic Carotid Endarterectomy Trial (NASCET)³, ⁴ and Asymptomatic Carotid Atherosclerosis Study (ACAS)⁸ were used as starting points and were then adjusted to account for the risk associated with additional comorbidities, including unstable angina,¹⁹, ²⁰ congestive heart failure,¹³, ¹⁹ restenosis after CEA,¹¹, ¹⁶ contralateral occlusions,¹², ¹⁹ the concurrent need for coronary artery bypass graft or valve-replacement surgery,¹⁰, ¹³, ¹⁸, ²⁰ renal dysfunction,¹⁴, ¹⁷, ¹⁹ and advanced age¹³, ¹⁹, ²⁰; this resulted in a primary end-point estimate of stroke, death, and MI at 30 days plus ipsilateral stroke to 1 year of 15%. For patients with severe anatomic factors that would preclude surgical intervention (eg, prior radical neck surgery, tracheostomy stoma, contralateral laryngeal nerve palsy, or prior extensive radiation damage), their 1-year composite end-point rates were approximated from the medical arms of NASCET and ACAS and resulted in an estimate of 11%. At the completion of the study, the proportion of actual enrollment in these two broad categories was calculated, and the final 1-year primary composite endpoint comparator was estimated at 14.4%. The randomized CEA arm of the SAPPHIRE study validated this ARCHeR historical control method for a similar contemporary high-surgical-risk population with a 1-year end-point rate of 12.6%.²¹

Although direct comparisons with other reported CEA data are difficult because they are not neurologically audited, other registries have affirmed that 30-day adverse event rates in high-risk patients are in a similar range, generally between 8.4% and 17.7%.²², ²³, ²⁴, ²⁵ See Appendix II for details of weighted historical control (WHC) considerations. The Food and Drug Administration reviewed and approved this methodology for establishing the historical control before the initiation of the trial.

Of note, ARCHeR allowed patients to be enrolled even if they had open-heart surgery requirements within 30 days after the stenting procedure. Most other carotid stent studies have excluded these patients because adverse events resulting from open-heart surgery would be considered stent related if they occurred within this periprocedural period.

Intervention and study conduct 

Key eligibility criteria are shown in Table I. The sponsor of this study (Guidant Corporation) required that all investigators participating in the study have previous carotid stenting experience as well as records of performing at least 20 carotid stent procedures within 1 year of initiating the trial. In addition, all participating investigators received in vitro device training. The operators in this trial included interventional cardiologists, neurosurgeons, vascular surgeons, interventional neuroradiologists, and interventional radiologists. The study was approved by the local institutional review board or ethics committee at each participating center, and all patients provided a signed and dated patient informed consent before participation in the study.

Patients received aspirin (325 mg) twice a day and either clopidogrel (75 mg) twice a day or ticlopidine (250 mg) twice a day 48 hours before the carotid stent procedure. If antiplatelet therapy could not be started within 48 hours, a loading dose of 650 mg of aspirin and 450 mg of clopidogrel at least 4 hours before the carotid stent procedure was allowed. Under local anesthesia, a guiding catheter/sheath was then placed into the common carotid artery via femoral artery access. Little or no sedation was used to allow for intraprocedural neurologic assessment. The constrained embolic filter was passed through the lesion after scout angiography and deployed distally in the vessel (a standard 0.0014 inch guidewire was used in ARCHeR 1). In most cases, predilation was then performed with an undersized balloon to allow subsequent stent delivery system passage. An appropriate stent size was chosen according to lesion/artery-specific features and then deployed. A second, larger balloon dilation was performed in most cases after stent deployment to achieve the final result. The filter was then collapsed and withdrawn. In uncomplicated cases, patients were discharged the following day. After the procedure, patients were required to take aspirin (325 mg) daily for at least a year and either clopidogrel (75 mg) daily or ticlopidine (250 mg) twice a day for a minimum of 2 weeks.

The following assessments were performed throughout the trial: cardiac enzymes (creatine kinase and creatine kinase-MB fraction [CK-MB]) before and after the procedure and an electrocardiogram before the procedure and at 30 days; a neurologic examination by an independent (nonoperator) neurologist which included (National Institutes of Health Stroke Scale [NIHSS], Modified Rankin Scale, and Barthel Index) at 24 hours, 30 days, 6 months, 1 year, and every 6 months thereafter; transient ischemic attack/stroke questionnaire at 30 days, 3 months, 6 months, 9 months, 1 year, and every 6 months thereafter; and carotid duplex ultrasonography at 30 days, 6 months, and 12 months and annually thereafter. An independent clinical events committee adjudicated all primary end-point events, and a separate Data Safety and Monitoring Board oversaw the conduct of the trial.

Study end points 

The primary study end point was a composite of all deaths, strokes, and nonfatal MIs within 30 days of the procedure plus ipsilateral strokes between days 31 and 365. Stroke was defined as an acute neurologic ischemic event of at least 24 hours’ duration with focal signs and symptoms. Major stroke was defined as a stroke resulting in a change in the NIHSS score of 9 or more at 3 months; stroke events not reaching this threshold were considered minor. MI was defined as new evidence of myocardial damage as indicated by elevation of either creatine kinase or CK-MB to more than 2 times the upper limit of normal, usually in the setting of chest pain or electrocardiogram changes.

Key secondary end points were also adjudicated and included procedural success, embolic protection device success, clinical success, and target lesion revascularization (TLR). Procedural success was defined as successful delivery and deployment of the study stent with a residual stenosis less than 50% after stent placement by quantitative angiography. Embolic protection device success was defined as successful delivery, deployment, and retrieval of the embolic protection device. Clinical success was defined as device and procedural success in the absence of death, stroke, MI, emergency endarterectomy, repeat percutaneous transluminal angioplasty, or thrombolysis of the study vessel within 7 days of the index procedure. TLR was defined as any clinically indicated (as determined by the treating physician) repeat revascularization procedure of the original treatment site that was performed because of symptoms attributed to recurrent stenosis at the target lesion (by quantitative angiography) of 50% or more, or 80% or more in the absence of symptoms. An access-site complication necessitating treatment was defined as any complication at the arterial access site that necessitated ultrasound compression, surgical repair, embolectomy, or transfusion.

Quantitative angiography 

After stent placement, films were reviewed by a central core laboratory (J.P.), which performed quantitative angiographic assessments of prestent and poststent angiography and used the method described by NASCET²⁶ for determining the percentage stenosis in the target internal carotid artery.

Doppler ultrasonography 

A central core laboratory (University of Washington; Kirk Beach, MD) conducted analysis of Doppler ultrasound assessments performed at the prespecified intervals (noted previously) after stent implantation.

Analysis of embolic material 

At the completion of the procedure, the embolic protection filter was sent to a central laboratory (R.V.) for examination. Parameters evaluated included the proportion of filters containing debris, absolute particle counts, and histologic examination of the particles.

Statistical analysis 

Event rates beyond 30 days were computed with Kaplan-Meier methods. The primary noninferiority comparison was performed by comparing the upper 95% confidence bound for the primary end point (computed by the Peto method) with the prespecified historical comparator. As outlined in the analytic plan, if this difference did not exceed a margin of 4%, the experimental strategy (stenting) would be considered noninferior to the reference strategy (endarterectomy). Continuous measures are summarized as mean and standard deviation; frequencies are displayed as counts and percentages. All available data for all patients enrolled are included in the analysis.

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Results 

Baseline characteristics 

Demographics and baseline clinical/angiographic characteristics are shown in Table II. Symptomatic patients (ipsilateral transient ischemic attack, stroke, or amaurosis fugax within 6 months of trial entry) comprised 24% of the population studied. Forty-two percent of the patients had two or more medical/surgical inclusion criteria on enrollment. Approximately 27% of patients had two or more diseased coronary arteries, 33.6% had an ejection fraction less than 30% or New York Heart Association class III or IV congestive heart failure, and 15.7% were scheduled for coronary or valvular open heart surgery within 30 days. The mean stenosis severity at enrollment was 71.4% ± 10.8%, by quantitative angiography.

Table II. Baseline demographic and clinical characteristics

MI, Myocardial infarction; NYHA, New York Heart Association; CEA, carotid endarterectomy; ICA, internal carotid artery; FEV₁, forced expiratory volume in 1 second.

Data are % (n/N) [95% confidence interval]; Clopper-Pearson exact confidence interval.

⁎ Baseline hypertension data were not available for one patient.

† Baseline hypercholesterolemia status was not available for five patients.

‡ Angiographic core laboratory reading of the baseline lesion was not available for six patients.

§ A total of 6% of patients had both high-risk surgical/medical comorbidities and unfavorable anatomic risks; one patient had neither.

∥ A total of 2.7% of these patients were symptomatic.

Technical and procedural results 

Acute device results are displayed in Table III. Balloon predilation was required to facilitate filter passage through the lesion in 23.2% (97/419 [95% confidence interval, 19.2%, 27.5%]) of cases in ARCHeR 2 and 3. The embolic filter protection devices captured atherosclerotic debris in 57% of samples, and approximately 24% of the samples contained at least 20 particles. The debris consisted of foam cells, smooth muscle cells, cholesterol, collagen/elastin, and platelet/fibrin, as assessed by the pathology core laboratory.

Table III. Technical and procedural results

Unless otherwise noted, data are % (n/N) [95% confidence interval]; Clopper-Pearson exact confidence interval.

⁎ Eleven patients did not have adequate postprocedure angiographies to allow determination of device/procedural or clinical success.

† One of these 11 patients had a minor stroke on day 1 and was therefore added to the denominator of the clinical success end point.

A total of 15 (2.6%) access site events occurred in 581 patients. Twelve of these events necessitated blood transfusion, and four events necessitated surgical repair of the access site. In addition, there were five device placement complications involving failure to retrieve the filter device. Three were subsequently retrieved via endovascular means, one was sandwiched against the original stent with a second stent, and one was recovered with a surgical procedure. There were no acute neurologic sequelae in any of these cases, and there are no long-term consequences to date. Subsequent minor design modification has since eliminated filter detachment.

Primary outcomes 

The primary composite end point of 30-day death, stroke, and MI plus 1 year ipsilateral stroke was 9.6% (95% confidence interval [CI], 7.2%-12.0%). Freedom from primary composite end-point events with Kaplan-Meier analysis is shown in the Fig, along with the comparison historical control rate of 14.4% for the 1-year comparison. These results led to rejection of the null hypothesis (P < .001) according to the prespecified statistical analysis plan and, thus, established noninferiority between the ARCHeR data and the historical CEA control.

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• Figure. 

  Freedom from any stroke, death, or myocardial infarction up to 30 days or ipsilateral stroke beyond 30 days. The rate of event-free survival was 90.4% (95% confidence interval, 88.0%-92.8%) at 1 year and 88.4% at both 2 and 3 years.

The 30-day combined safety end-point rate of all-cause death, stroke, or MI was 8.3%; the 30 day rates for symptomatic and asymptomatic patients were 13.1% and 6.8%, respectively (Table IV). Minor strokes accounted for most (23/32) of the neurologic events (4.0%; 95% CI, 2.5%-5.9%), with MI and death accounting for 2.4% (95% CI, 1.3%-4.0%) and 2.1% (95% CI, 1.1%-3.6%), respectively. At 30 days, the rate of major or fatal stroke was 1.5% (95% CI, 0.7%-2.9%). No hemorrhagic stroke was observed during this study.

Table IV. Thirty-day primary end-point event rates

MI, Myocardial infarction.

Unless otherwise noted, data are % (n/N) [95% confidence interval]; Clopper-Pearson exact confidence interval.

⁎ By normal approximation.

† Nonhierarchical: includes only each patient’s first occurrence of each event.

‡ Hierarchical: includes only the most serious event for each patient and includes only each patient’s first occurrence of each event.

Durability of revascularization and stroke prevention 

Between 30 days and 1 year, the rate of ipsilateral stroke was 1.3%. Between 1 and 3 years of follow-up, only three major ipsilateral strokes occurred. Of note, two of these were hemorrhagic, thus suggesting a noncarotid origin in this high-risk cohort.

Duplex scans of carotid stent results to 3 years are listed in Table V. Five percent of patients had significant stenosis (>70%) at the primary 12-month end point, without significant attrition thereafter. Clinically-driven TLR for restenosis was 2.2% (95% CI, 0.9%-3.4%) at 12 months, typically based on angiography after Duplex evaluation. Sustained patency beyond 1 year was demonstrated with a TLR rate of 2.9% (95% CI, 1.3%-4.5%) at 24 months of follow-up.

Table V. Summary of ultrasound data (ARCHeR 1, 2 and 3)—registry patients

⁎ Disease categories obtained from the computed internal carotid artery/common carotid artery ratio (r), using the following guidelines: 0 < r < 2.0, <50%; 2.0 ≤ r < 4.0, 50%-69%; r = 4.0, ≥70%; and r = 0, ≥70%. If the angle between the ultrasound beam and the vessel centerline was <58° or >61°, then the ultrasound core laboratory did not attempt to compute an internal carotid artery/common carotid artery ratio. Instead, they interpreted the available data to assign the result into six categories: <50%, ∼50%+/−, 50%-69%, ∼70%+/−, ≥70%, and unclassifiable. The greatest certainty in these cases is associated with the <50% and ≥70% categories. For analysis, the category “∼50%” was combined with the “50%-69%” category, and “∼70%” was combined with “≥ 70%.”

As an indication of the minimal clinical effect of periprocedural minor strokes, 52% (12/23) of patients returned to baseline NIHSS levels within 30 days. Furthermore, 95% (20/21) of patients who sustained a periprocedural minor stroke did not have a significant deficit (eg, NIHSS >1) at 1 year. This indicates complete or nearly complete functional recovery and no long-term significant neurologic sequelae. The other two patients who experienced minor strokes at the time of the index procedure could not be assessed at 1 year.

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Discussion 

The results of the ARCHeR study demonstrate the procedural safety, clinical effectiveness, and long-term durability of carotid stenting compared with a historical control of surgery in a population of patients with severe carotid artery disease and medical or anatomic comorbidities that put them at increased risk for endarterectomy. These patients were generally excluded from the NASCET and ACAS studies that established endarterectomy as the standard of care in the United States for severe carotid disease.

Although this was not a randomized trial, a comparison of the ARCHeR 1-year composite end point of stroke, death, and MI with the expected event rate with endarterectomy (9.6% vs 14.4%) satisfied the prespecified criteria for noninferiority. The ARCHeR results, then, suggest the potential of carotid stenting to improve outcomes in these high-surgical-risk patients by using both historical and contemporary comparisons to endarterectomy.

Confirming the high-risk nature of the ARCHeR cohort, 15.7% of the patients qualified as high risk on the basis of a concurrent need for open heart surgery within 30 days after the stenting procedure. Eighteen underwent operation within that period, seven (39%) of whom died or had a stroke within 30 days. As a result, seven 30-day primary end-point events (two deaths, three MIs, and two minor strokes) occurred after open heart surgical procedures and were most likely unrelated to the stent procedure. The inclusion of this cohort increased the periprocedural rate observed in ARCHeR; had these patient events been excluded from the analysis, the 30-day composite end-point rate would have been reduced from 8.3% (48/581) to 7.3% (41/563), and the composite of death/stroke at 30 days would have been 6.2% (35/563).

The critical safety objective of extracranial carotid bifurcation prophylactic intervention is the avoidance of stroke—in particular, disabling stroke. The infrequent periprocedural minor strokes seen in this study were presumably related to small emboli released during catheter access into the carotid artery before embolic filter protection was in place, the inability to place a filter and provide protection (although this occurred infrequently), or incomplete protection despite filter placement. Regardless of the mechanism, there was a consistent lack of clinically important neurologic deficits at 1 year in these minor-stroke patients.

Results from this study show an overall rate of major/fatal ipsilateral stroke of 1.5% at 30 days. For symptomatic patients in ARCHeR, this rate was 4.3% and was comparable to the rate (2.1%) reported in the surgical arm of the normal-surgical-risk NASCET³ trial. Recent data from Asymptomatic Carotid Surgery Trial⁵ revealed a 30-day rate of disabling or fatal strokes of 1.4% (19/1348) in normal-risk asymptomatic carotid patients in the endarterectomy group, and this rate is similar to the 0.7% (3/443) rate observed in the high-surgical-risk asymptomatic subgroup in the ARCHeR trial. These outcomes demonstrate the procedural safety of carotid artery stenting as compared with other precedent endarterectomy trials and are consistent with the observation that high-risk surgical features generally do not connote the same risk for an endovascular approach.

Long-term stroke prevention in the at-risk patient is the hallmark of any successful carotid intervention. The 1-year rate of major ipsilateral stroke in this study (1.6%) is similar to the 1-year rate in the CEA arm of the SAPPHIRE trial (3.5%), and follow-up to 2 years demonstrates few additional events. Moreover, the low (2.2%) rate of TLR with stenting at 1 year is lower than rates in well-conducted surveys of restenosis after endarterectomy.²¹, ²⁷ The stability of the ARCHeR clinical results, along with the low rate of restenosis of carotid stenting, as seen in this study, further supports both the effectiveness and durability of stenting for prevention of stroke. These important efficacy and durability qualities are most likely inherent to all successful carotid stent procedures independently of the patient cohort treated, with or without significant comorbidities, and reflect more directly on stents’ ability to both revascularize and prevent clinical events.

This investigation is unique among similar pivotal Food and Drug Administration investigational device exemption trials in that the first phase did not involve a filter embolic protection device, whereas the last two phases used a filter. Although the study was not powered adequately to derive any conclusions regarding filter use, no significant differences in 30-day composite event rates with and without its use were noted (7.6%, 8.6%, and 8.3% for the three phases of the trial). The lack of a demonstrated outcome difference with and without filters is not surprising, however, given that a study adequately powered to detect a 1% difference in 30-day stroke rates would require several thousand patients. It is important to note, however, that embolic debris was returned in 57% of filters, and this suggests both a high degree of capture efficiency and an added level of cerebral protection. Data in prior studies using diffusion-weighted magnetic resonance imaging and transcranial Doppler monitoring demonstrate a reduction in subclinical embolic events and seem to confirm the efficacy of, and need for, embolic protection.²⁸, ²⁹, ³⁰ Notably, the concern at the outset of these studies that filter use in carotid stenting might actually increase complications as a result of added complexity and manipulation was not borne out in this trial.

A major limitation of this study is the nonrandomized design of the trial, which does not allow for a direct comparison with endarterectomy. Other limitations include an inability to compare the results of certain subgroups in the study (eg, stenting with vs without an embolic protection device or symptomatic vs asymptomatic patients) because the study was not designed or powered to detect differences among these subgroups.

In conclusion, the results of the ARCHeR study demonstrate that extracranial carotid artery stenting with embolic filter protection is not inferior to the historical results of CEA among high-surgical-risk patients and suggest that carotid stenting is a safe and effective stroke-prevention alternative to endarterectomy for such patients. The extended application of this technology in other patient cohorts awaits further study.²², ²³, ²⁴, ²⁵

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Author contributions 

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Appendix I 

The following is a list of participating centers and the principal investigator at each study center in descending order according to the number of patients enrolled at each center: L. Nelson Hopkins, M.D.-Millard Fillmore Hospital, Buffalo, NY; Sanjay Yadav, M.D.-The Cleveland Clinic Foundation, Cleveland, OH; Malcom Foster, M.D.-Baptist Hospital, Knoxville, TN; Thomas Davis, M.D.-St. John Hospital, Detroit, MI, Craig Walker, M.D.-Terrebonne General Medical Center, Houma, LA; Charles Zacharias, M.D.-St. Mary’s Hospital, Richmond, VA; Ray Matthews, M.D.- Hospital of Good Samaritan, Los Angeles, CA; Robert W. Hobson, II, M.D.-St. Michael’s Medical Center, Newark, NJ; Farrell Mendelsohn, M.D.-Baptist Medical Center, Birmingham, AL; Rick McClure, M.D.-Central Baptist Hospital, Lexington, KY; Tanvir Bajwa, M.D.-St. Francis Hospital, Milwaukee, WI; Rajesh Dave, M.D.-Central Pennsylvania Cardiovascular Research Institute, Harrisburg, PA; Hugo Londero, M.D.-Sanatorio Allende, Cordoba, Argentina; Robert Molnar, M.D.-McLaren Regional Medical Center, Flint, MI; Robert Leverton, M.D.-Abilene Regional Medical Center, Abilene, TX; William Gray, M.D.-Swedish Medical Center, Seattle, WA; J. King White, M.D.- Christus St. Patrick Hospital, Lake Charles, LA; Stephen Ramee, M.D.-Alton Ochsner Medical Foundation, New Orleans, LA; Timothy Fischell, M.D.-Borgess Medical Center, Kalamazoo, MI; Stanley Barnwell, M.D.-Oregon Health Science University (OHSU), Portand, OR; Dan Mccormick, D.O.-Drexel University College of Medicine, Philadelphia, PA; Anthony Bell, M.D.-Presbyterian Hospital, Charlotte, NC; Lowell Satler, M.D.-Washington Hospital Center, Washington, DC; Christopher Cates, M.D.-Emory University School of Medicine, Atlanta, GA; William Knopf, M.D.-St. Joseph Hospital of Atlanta, Atlanta, GA; Gary Ansel, M.D.-Grant Riverside Methodist Hospital, Columbus, OH; Tony Smith, M.D.- Duke University Medical Center, Durham, NC; Sriram Iyer, M.D. -Lenox Hill Hospital, New York, NY; Gregory Mishkel, M.D.-St. John’s Hospital (PERC), Springfield, IL ; Richard Fessler, M.D.-Harper Hospital, Detroit, MI; Richard Zelman, M.D.- Cape Cod Hospital, Hyannis, MA; Ronald Fairman, M.D.-Hospital at UPENN, Philadelphia; Lawrence Wechsler, M.D.-Shadyside Hospital, Pittsburgh, PA; Daniel Bouknight, M.D.-Columbia Providence Hospital, Columbia, SC; Peter Soukas, M.D.-St. Elizabeth’s Hospital, Boston, MA 02135-2997; James Lefler, M.D.-Tampa General Hospital, Tampa, FL; James Brorson, M.D.-University of Chicago Hospitals, Chicago, IL; Howard Roth, M.D.-Midwest Heart Research Foundation, Lombard, IL; Craig Narins, M.D.-Strong Memorial Hospital, University of Rochester Medical Center, Rochester, NY; Subbarao Myla, M.D.- Hoag Memorial Hospital Presbyterian, Newport Beach, CA; Ted Feldman. M.D.-Evanston Northwestern Healthcare, Evanston, IL; Romeo Mateo, M.D.-St. Agnes Hospital, Hawthorne, NY; Kerry Prewitt, M.D.- St. Joseph Medical Center, Towson, MD; I. Fourneau, M.D.-Universitaire Ziekenhuizen K.U. Leuven, Belgium; Bruce Gray, M.D.-Greenville Memorial Hospital, Greenville, SC; Elias Kassab, M.D.-Oakwood Medical Hospital, Dearborn, MI; Luc Stockx, M.D.- ZOL St Jan Ziekenhuis Oost-Limburg, Belgium; Prof. Dr. Med. Harald Mudra-Krankenhaus München, Neuperlach, München – Germany; Alberto Cremonesi, M.D.- Villa Maria Cecilia Hospital, Cervia (Ravenna) – Italy.

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Appendix II 

Carotid endarterectomy followed by aspirin has been proven to be superior to medical treatment with aspirin alone in the prevention of stroke in symptomatic (nondisabling stroke or transient ischemic attack within 180 days plus ≥50% stenosis by angiography) and asymptomatic (>60% stenosis by angiography) patients, with a relatively low risk of surgery identified by the North American Symptomatic Carotid Endarterectomy Trial (NASCET) and Asymptomatic Carotid Atherosclerosis Study (ACAS) criteria, respectively.¹, ² In 1995 and 1998, ad hoc committees of the American Heart Association published guidelines for CEA based partly on the results of these pivotal studies. The committees’ recommendations encompassed surgical risks ranging from a low of 3% to a high of 10%.³, ⁴ There is, however, consensus regarding certain patient characteristics that increase the risk of surgery (Appendix Table I).Considerable literature has documented complication rates in this group of patients that are well above the 10% maximum recommended by the American Heart Association.

There is an important subset of patients with symptomatic and asymptomatic carotid disease who are considered not only at risk for stroke, but also at increased risk for surgical repair. Such patients are reluctantly considered for surgery for which there is high perioperative risk or medical therapy for which there is poor long-term outcome and few data to guide management. This subset of patients is identified as high risk as a result of medical comorbidities, high-surgical-risk features (prior carotid endarterectomy [CEA] or contralateral occlusion of the carotid artery), age of 75 years or older, and anatomic conditions.

Medical comorbidities 

This group includes patients with (1) cardiovascular disease (coronary artery disease requiring coronary artery bypass graft surgery concurrent with CEA, angina [stable and unstable], congestive heart failure, and evolving or recent [within 30 days] myocardial infarction [MI]) and (2) renal insufficiency (creatinine >1.5 mg/dL). As shown in Appendix Table II, the reported complication rates for patients with cardiovascular risk factors range from 6% death alone to 40% stroke, death, and MI. Appendix Table III illustrates the complication rates observed (7%-43%) in patients with renal disease.

High-surgical-risk features 

This includes patients with previous CEA and those with contralateral occlusion of the carotid artery. Appendix Table III summarizes the literature that has reported the risks of CEA in these groups of patients. Complication rates range from a 7.6% to 14.3% rate of stroke and death.

Age 75 years or older 

Appendix Table IV illustrates that the observed complication rates for stroke, death, and MI in this group range from 7% to 9.9%.

Surgical access or other anatomic conditions (hostile neck) 

This includes high lesions (above the Blaisdell line), prior radical neck dissection for pharyngeal cancer with or without radiation therapy, any medical condition that necessitated placement of a tracheostomy, a variety of conditions that create spinal immobility, including anatomic factors and prior cervical spine surgery, and patients with short obese necks that have a more cephalad position of the bifurcation (Appendix Table I). Patients with the above-described anatomic conditions are usually excluded from CEA clinical trials and are often excluded from CEA in general. These patients are treated medically and, therefore, would be at a similar risk for stroke as those treated medically in randomized trials such as NASCET and ACAS. In the NASCET trial, medical patients with 70% stenosis or more had a 26% cumulative risk of any ipsilateral stroke at 2 years.⁵ In that same trial, medical patients with 50% to 69% stenosis had a 5-year rate of any ipsilateral stroke of 22.2%.¹ In the ACAS trial, asymptomatic patients with 60% stenosis or more who were treated medically had a 5-year aggregate risk for any perioperative stroke or death and ipsilateral stroke of 11%.²

A high-risk patient population may be initially evaluated as part of a multicenter nonrandomized trial that uses historical control data for comparison of results. The sample size for such a trial would be derived from (1) the anticipated risk of the study population for ipsilateral stroke and perioperative stroke and death and (2) the risk of the comparison population for the same end points. When all patients with medical comorbidities are considered (Appendix Table II, Appendix Table III, Appendix Table IV), it becomes apparent that their CEA complication rates are predominantly in the range of 10% to 20%. Because these rates were observed at 30 days or less after surgery, the 1-year complication rate is expected to be 1% to 2% higher, on the basis of data from the NASCET study. Thus, it seems reasonable to propose a historical control of 15% for the composite end point of stroke, death, and MI at 30 days and ipsilateral stroke at 1 year for this subset of patients. Similarly, the group of patients with anatomic conditions would be expected to have risks similar to those of patients treated medically. On the basis of data from the NASCET and ACAS trials, a proposed reasonable historical control for this set of patients is 11%.

Appendix Table I. High-surgical-risk patient characteristics

ECG, Electrocardiogram; FEV₁, forced expiratory volume in 1 second.

Appendix Table II. Cardiovascular and surgical risk factors for CEA

CEA, Carotid endarterectomy; CABG, coronary artery bypass graft; MI, myocardial infarction; CHF, congestive heart failure; ICA, internal carotid artery.

Appendix Table III. Renal risk factors for CEA

CEA, Carotid endarterectomy; MI, myocardial infarction.

Appendix Table IV. Age as an independent risk factor for CEA

CEA, Carotid endarterectomy; MI, myocardial infarction.

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References 

1. Barnett HJM , Taylor DW , Eliasziw M , et al.  North American Symptomatic Carotid Endarterectomy Trial Collaborators   Benefit of carotid endarterectomy in patients with symptomatic moderate or severe stenosis . N Engl J Med . 1998;339:1415–1425
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3. Moore WS , Barnett HJM , Beebe HG , et al.   Guidelines for carotid endarterectomy (a multidisciplinary consensus statement from the ad hoc committee, American Heart Association) . Stroke . 1995;26:188–201
4. Biller J , Feinberg WM , Castaldo JE , et al.   Guidelines for carotid endarterectomy (a statement for healthcare professionals from a special writing group of the stroke council, American Heart Association) . Circulation . 1998;97:501–509
5. North American Symptomatic Carotid Endarterectomy Trial Collaborators . Beneficial effect of carotid endarterectomy in symptomatic patients with high-grade carotid stenosis . N Engl J Med . 1991;325:445–453
6. McCrory DC , Goldstein LB , Samsa GP , et al.   Predicting complications of carotid endarterectomy . Stroke . 1993;24:1285–1291
7. Coyle KA , Gray BC , Smith RB , et al.   Morbidity and mortality associated with carotid endarterectomy (effect of adjunctive coronary revascularization) . Ann Vasc Surg . 1995;9:21–27
8. Vassilidze T , Cernaianu AC , Gaprindashvili T , et al.   Simultaneous coronary artery bypass and carotid endarterectomy (determinants of outcome) . Tex Heart Inst J . 1994;21:119–124
9. Vassilidze T , Cernaianu AC , Gaprindashvili T , et al.   Long-term results of simultaneous carotid endarterectomy and coronary artery revascularization in patients with unstable angina and cerebrovascular insufficiency . Vasc Surg . 1994;28:577–580
10. Goldstein LB , Samsa GP , Matchar DB , et al.   Multicenter review of preoperative risk factors for endarterectomy for asymptomatic carotid artery stenosis . Stroke . 1998;29:750–753
11. Wong JH , Findlay JM , Suarez-Almazor ME . Regional performance of carotid endarterectomy (appropriateness, outcomes, and risk factors for complications) . Stroke . 1997;28:891–898
12. Rothwell PM , Slattery J , Warlow CP . Clinical and angiographic predictors of stroke and death from carotid endarterectomy (systematic review) . Br Med J . 1997;315:1571–1577
13. Meyer FB , Piepgras DG , Sundt TM . Recurrent carotid stenosis (Sundt’s occlusive cerebrovascular disease) . In: 2nd ed.. Philadelphia: WB Saunders; 1994;p. 310–321
14. Das MB , Hertzer NR , Ratliff NB , et al.   Recurrent carotid stenosis (a five-year series of 65 reoperations) . Ann Surg . 1985;202:28–35
15. Gasecki AP , Eliasziw M , Ferguson GG , et al.  North American Symptomatic Carotid Endarterectomy Trial (NASCET) Group   Long-term prognosis and effect of endarterectomy in patients with symptomatic severe carotid stenosis and contralateral carotid stenosis or occlusion (results from NASCET) . J Neurosurg . 1995;83:778–782
16. Rigdon EE , Monajjem N , Rhodes RS . Is carotid endarterectomy justified in patients with severe chronic renal insufficiency? . Ann Vasc Surg . 1997;11:115–119
17. Hamdan AD , Pomposelli FB , Gibbons GW , et al.   Renal insufficiency and altered postoperative risk in carotid endarterectomy . J Vasc Surg . 1999;29:1006–1011