♦ Carotid Artery Stenting Trials (Tables 32.2 and 32.3)

The first randomized trial of endovascular and surgical treatments for carotid artery stenosis was the Carotid and Vertebral Artery Transluminal Angioplasty Study (CAVATAS).18 This trial was designed to compare balloon angioplasty alone and without embolic protection to CEA in symptomatic patients. Twenty-four centers in Europe, Australia, and Canada participated, and as in previous CEA trials, high-risk surgical patients were excluded from enrollment. For the 504 patients enrolled, no significant difference was found in the composite stroke or death rate at 30 days (10.0% endovascular group versus 9.9% CEA group) or at 3 years19 ^, 20 (14.3% endovascular group versus 14.2% CEA group). The lack of embolic protection and low rate of stent usage (26%), which are in contrast with current standard practice, are the main limitations of this study. The CAVATAS investigators recently reported the 5-year follow-up results.19 ^, 20 Severe carotid restenosis (≥70%) or occlusion occurred significantly more often in patients in the endovascular arm than in patients in the endarterectomy arm (adjusted hazard ratio [HR] 3.17; p <.0001). Patients in the endovascular arm who were treated with a stent (n = 50) had a significantly lower risk of developing restenosis of ≥70%, compared with those treated with balloon angioplasty alone (n = 145; HR 0.43; p = .04).

The Wallstent trial21 ^, 22 was the first multicenter randomized trial designed to assess CAS and CEA equivalence but was stopped early after an interim analysis revealed worse outcomes in the CAS arm, with a combined risk of stroke or death at 30 days of 12.1% in the CAS group versus 4.5% in the CEA group. Cerebral protection was not used, and this was thought to contribute in part to the high risk associated with CAS in this study.

Carotid Revascularization Using Endarterectomy or Stenting Systems (CaRESS),23 ^, 24 a multicenter, nonrandomized, prospective study comparing CAS with embolic protection (n = 143) and CEA (n = 254) in symptomatic (32%) and asymptomatic (68%) low- and high-surgical risk patients was the first CAS versus CEA trial to use an EPD. Although this study design likely introduced selection bias, CaRESS more closely represents the real-world setting. Baseline group demographics were similar, except that patients who had previous carotid intervention more often received CAS. No statistically significant differences existed in 30-day and 1-year death or stroke rates between the CAS and CEA groups (2.1% versus 3.6% and 10.0% versus 13.6%, respectively), nor did significant differences exist for restenosis, residual stenosis, repeat angiography, and need for carotid revascularization. Overall, the morbidity and mortality in CaRESS approached North American Symptomatic Carotid Endarterectomy Trial (NASCET)2 ^, 6 and Asymptomatic Carotid Atherosclerosis Study (ACAS)4 standards and represented the lowest rates among contemporary CAS trials. The low stroke and death rates may be attributable to the ability of treating physicians to consider patient-specific factors and successfully assign each patient to the safest therapy.

The SAPPHIRE trial12 was the first randomized trial to use mandatory distal EPDs. It was designed to demonstrate noninferiority of CAS in 334 patients with coexisting conditions that potentially increased the risk posed by endarterectomy and who had either a symptomatic carotid-artery stenosis of ≥50% or an asymptomatic stenosis of ≥80%. Most patients (>70%) enrolled in the trial were asymptomatic. The 30-day combined periprocedural adverse event rates were 4.8% for CAS patients and 9.8% for CEA patients (p = .09). At 1 year, the combined major adverse event rates were 12.2% for CAS patients and 20.1% for CEA patients (p = .004 for noninferiority analysis, p = .05 for intention-to-treat analysis). Myocardial infarction (MI) and major ipsilateral stroke rates were significantly better following CAS than following CEA (2.5% versus 8.1%, p = .03; 0% versus 3.5%, p = .02; respectively). These data strongly suggested noninferiority of CAS for high-risk, largely asymptomatic patients.

Two multicenter, randomized European trials, Stent-Protected Angioplasty versus Carotid Endarterectomy (SPACE) and Endarterectomy Versus Stenting in Patients with Symptomatic Severe Carotid Stenosis (EVA-3S) were done to establish noninferiority in standard risk, symptomatic patients. In SPACE,25 a variety of different stents were used, and embolic protection was not mandated. The 30-day analysis in the SPACE trial comprised 1183 patients, and the primary event rates (ipsilateral stroke or death) were 6.84% in the CAS group versus 6.34% in the CEA group (p = .09 for noninferiority analysis). Only 27% of SPACE CAS patients were treated with embolic protection, but there were no significant differences found between those who were treated with and without an EPD. After this interim analysis, the steering committee decided to terminate the study on the basis of both futility and financial constraints, because it was revealed that 2500 patients would be needed to adequately power the study to achieve trial end points. A subsequent subgroup analysis of the 30-day results from SPACE revealed that CAS was associated with a worse outcome in older patients: the risk of ipsilateral stroke or death increased significantly with age in the CAS group (p = .001) but not in the CEA group (p = .534).26

Similarly, the EVA-3S trial also failed to demonstrate non-inferiority of CAS in symptomatic patients.27 The primary end point was defined as a composite of any stroke or death occurring within 30 days after treatment. A variety of different stents were used at different centers. Cerebral protection was initially not required until the safety committee instituted a protocol change as a result of a 25% 30-day rate of stroke or death in patients treated without EPDs. The study randomized 527 patients and was subsequently ended prematurely for safety reasons after an interim analysis revealed a significantly higher 30-day event rate in the CAS group (9.6%) than in the CEA group (3.9%; p = .01). These results persisted at 6 months, with an event rate of 11.7% in the CAS arm versus 6.1% in the CEA group (p = .02). A significantly higher 30-day stroke rate was observed in the CAS arm of the EVA-3S study27 results from other studies published at that time, namely those from the SAPPHIRE trial (9.2% EVA-3S versus 3.6% in SAPPHIRE).12 The surgeons participating in EVA-3S and performing CEA had done at least 25 endarterectomies within 1 year before trial entry, but interventionists were certified after performing less than half that number and were allowed to enroll study participants while completing their training and certification,27 a factor that also could have, at least theoretically, increased the stroke risk in the CAS arm. Subgroup analysis based on CAS physician experience demonstrated a 12.3% stroke and death rate among endovascular physicians tutored in CAS during the trial,27 compared with 7.1% among those tutored in CAS during their endovascular training and 10.5% among physicians with CAS experience. EVA-3S emphasizes the importance of embolic protection as well as rigorous training and credentialing for CAS physicians.

♦ Carotid Artery Stenting Registries

Carotid registries are nonrandomized outcome records for symptomatic and asymptomatic high-risk CAS patients. These registries include Arbeitsgemeinschaft Leitende Kardiologische Krankenhausarzte (ALKK), Acculink for Revascularization of Carotids in High-Risk patients (ARCHeR), Boston Scientific EPI: A Carotid Stenting Trial for High-Risk Surgical Patients (BEACH), Carotid Artery Revascularization using the Boston Scientific FilterWire EX/EZ (CABERNET), Carotid Acculink/Accunet Post Approval Trial to Uncover Unanticipated or Rare Events (CAPTURE), Carotid Artery Stenting with Emboli protection Surveillance-Post Marketing Study (CASESPMS), and Carotid Revascularization with ev3 Arterial Technology Evolution (CREATE). Although registries do not provide direct comparison data, they do help establish true adverse event rates in high-risk CAS patients and are a crucial component in improving our understanding concerning the risks of CAS. The CABERNET collaborators found a 4.0% 30-day rate of death, stroke, and MI (n = 446 patients),28 whereas the investigators of ARCHeR (n = 581 patients) found a 30-day stroke or death rate of 6.9% as well as a 1-year composite outcome (30-day rate of MI, stroke, or death plus the 1-year rate of ipsilateral stroke) of 9.6%.29 CREATE (n = 419 patients) demonstrated a 6.2% 30-day rate of MI, stroke, and death.30 The CAPTURE registry (n = 3500) determined that the post-CAS incidence of stroke, MI, and death was 6.3% for patients treated with the Acculink/Accunet CAS system (Abbott Vascular, Santa Clara, CA), and the rate of major stroke or death was 2.9%.31 ^, 32 The BEACH investigators (n = 747 patients) found a 30-day MI, stroke, or death rate of 5.8%.33 These results were similar to those in the CASES-PMS registry (5.0%), which examined the use of distal protection by endovascular carotid surgeons who either had previous experience with the EPD (Angioguard XP, Cordis Endovascular, Warren, NJ) or who underwent formal training (n = 1493).34 Under these rigorous conditions, the 30-day major adverse event rate did not vary significantly between symptomatic and asymptomatic patients and among physicians with high and low volume or differing level of experience with the specific distal protection device. The German ALKK registry (n = 1888 patients), which included standard-risk patients, demonstrated an in-hospital death and stroke rate of 3.8%.35 Interestingly, when this risk was stratified by time period, the investigators saw improvement from 6.3% in 1996 to 1.9% in 2004 (p = .021). The recently reported SAPPHIRE worldwide registry36 is a multicenter, prospective, postapproval registry to evaluate CAS with distal protection in patients at high-risk for surgery. The registry reported results on the first 2001 patients with 30-day follow-up. The rate of adverse events was 4.4% (death 1.1%, stroke 3.2%, MI 0.7%) for the overall population. Patients with anatomic risk factors for CEA ( Table 32.4 ) had a significantly lower 30-day major adverse event (MAE) rates (composite of death, MI, and stroke) than patients with physiologic risk (2.8% versus 4.9%, p = .0306), respectively.

Continued efforts to maintain rigorous registries like the above are critical to our eventual understanding of appropriate patient selection and procedural risks. The CABERNET investigators recently reported their 3-year results: 7.2%, all stroke; 2.8%, major stroke; 4.8%, ipsilateral stroke; 17.7%, all death; 7.1%, MI; 4.4%, target vessel revascularization.37 Asymptomatic patients had significantly fewer major strokes than symptomatic patients (1.9% versus 5.7%, p = .03) and patients <80 years had significantly fewer ipsilateral strokes than those ≥80 years (3.2% versus 10.7%, p = .002). Stroke outcomes did not differ significantly between patients with anatomic risk factors compared with those with comorbid medical risk factors.

♦ Evidence for Embolic Protection Devices

A meta-analysis by Kastrup and colleagues38 compared 2357 patients from 26 trials who underwent carotid stenting without distal embolic protection (DEP) to 839 patients from 11 trials in which DEP was used. The primary end point of death or stroke was significantly lower in the patients treated with embolic protection (1.8 versus 5.2%, p = .001). There was also a significant reduction in the secondary end points of major stroke (0.3 versus 1.1%, p = .001) and minor stroke (0.5 versus 3.7%, p = .001). These results show that when distal protection is used, percutaneous carotid interventions have complication rates that are comparable to CEA. A recent meta-analysis by Garg et al39 compared 12,263 protected CAS patients and 11,198 unprotected CAS patients. The relative risk (RR) for stroke was 0.62 (95% confidence interval [CI] 0.54–0.72) in favor of protected CAS. Subgroup analysis revealed a significant benefit for protected CAS in both symptomatic (RR 0.67; 95% CI 0.52–0.56) and asymptomatic (RR 0.61; 95% CI 0.41–0.90) patients (p <.05).

♦ Current Studies

The two major current, randomized trials of CAS versus CEA are the Carotid Revascularization Endarterectomy versus Stent Trial (CREST) and the International Carotid Stenting Study (ICSS; also known as CAVATAS-2).

CREST is a National Institutes of Health (NIH)-funded, multicenter, randomized trial that enrolled 2502 patients with symptomatic carotid stenosis >50% or asymptomatic carotid stenosis >70% who were considered good surgical candidates for randomization to either CEA or CAS in a 1:1 ratio. Primary end points included 30-day stroke, death, and MI, and ipsilateral stroke within 60 days and at 1 year. The trial maintained a rigorous credentialing phase for CAS providers,40 requiring up to 20 supervised CAS procedures. During its lead-in phase, CREST demonstrated a 4.6% 30-day stroke and death rate, with stroke/death/MI rates of 3.5% for asymptomatic patients and 5.7% for symptomatic patients. There were no differences in stroke and death rates between men and women41 or, surprisingly, between those treated with and without cerebral protection.42 However, patients >80 years had a significantly increased stroke and death rate of 12.1%, compared with younger patients (60–69 years, 1.3%; 70–79 years, 5.3%; p = .0006).43 ^, 44 The investigators have completed enrollment, analyzed the data, and presented a summary of the findings at the International Stroke Conference 2010 (W. Clark for the CREST investigators, International Stroke Conference 2010, San Antonio, TX, February 26, 2010). The salient results are as follows: For 2502 subjects with a median follow-up of 2.46 years, there was no difference in the primary end point between CEA and CAS (6.8 versus 7.2; p = .51); perioperatively, the primary end point was similar for CEA and CAS (4.5 versus 5.2; p = .38). For CEA, the rate of stroke was lower (2.3 versus 4.1%; p = .012) and the rate of MI was higher (2.3 versus 1.1%; p = .03). There were no perioperative differences in rates of stroke, MI, or death for symptomatic patients (5.4 versus 6.7%; p = .30) or for asymptomatic patients (3.6 versus 3.5%; p = .96). There were procedural differences in rates of stroke and death in symptomatic patients (3.2 versus 6.0%, p = .019); the differences were not significant for asymptomatic patients (1.4 versus 2.5%, p = .15). Thereafter, the rates of ipsilateral stroke were low for CEA and CAS (2.4 versus 2.0%; p = .85). The CREST data demonstrated that CAS and CEA were similarly effective and thus support CAS as a reasonable alternative for CEA.

The International Carotid Stenting Study (ICSS) is a multinational, prospective trial randomizing symptomatic, lowrisk patients equally suited for CAS or CEA.45 All CAS operators are required to attend a training course prior to enrolling patients. Centers with limited CAS experience have been admitted to the trial on a probationary status. In addition, cerebral protection is required whenever the operator feels that an EPD can be safely deployed.

The Asymptomatic Carotid Stenosis, Stenting versus Endarterectomy Trial (ACT-I)46 is a randomized trial of low-risk patients with asymptomatic stenosis >80% using the Xact stent and Emboshield filter cerebral protection device (Abbott Vascular, Abbott Park, IL). This trial is comparing CAS with CEA in a 3:1 ratio at multiple centers across North America. The primary end points are 30-day stroke, death, and MI rates; ipsilateral stroke at 1 year; and 5-year stroke-free survival.

The TransAtlantic Asymptomatic Carotid Intervention Trial (TACIT)47 will randomize both standard and high-risk patients with asymptomatic carotid stenosis into one of three treatment arms: best medical therapy only (antiplatelet, antilipidemic, antihypertensive, strict diabetes control, and smoking cessation), best medical therapy plus CEA, or best medical therapy plus CAS with cerebral protection. Planned enrollment is 2400 patients with a primary end point of stroke and death at 3 years. Secondary end points include rates of transient ischemic attack (TIA) and MI, economic cost, quality-of-life analysis, neurocognitive function, and rate of carotid restenosis.

Recently, results have been made available for the Parodi flow-reversal system (Gore Flow Reversal System, W.L. Gore & Associates, Flagstaff, AZ) in the multicenter, prospective Embolic Protection with Reverse Flow (EMPiRE) trial, which demonstrated a 30-day rate of TIA, stroke, MI, and death of 4.5%.48 Additionally, the results of the Evaluating the Use of the FiberNet Embolic Protection System in Carotid Artery Stenting (EPIC) trial demonstrated a 30-day rate of 3% for TIA, stroke, MI, and death (n = 237 patients) using the FiberNet DEP system (Lumen Biomedical, Plymouth, MN).49 The ProximAl PRotection with the MO.ma device dUring caRotid stenting (ARMOUR) trial was a pivotal, prospective, multicenter, nonrandomized trial to evaluate the safety and effectiveness of cerebral protection with the MO.ma device (Invatec, Roncadelle, Italy) in high surgical risk subjects undergoing CAS. The results of this trial with 225 patients who were treated with an intention to treat in 25 United States and European centers were recently published.50 The 30-day rate of any MI, stroke, or death was 2.7%; the stroke rate was 2.3% (major stroke rate, <1%). Continuing efforts and eventual completion of these trials or publication of the final results of these trials will improve our understanding of the relative indications and contraindications for CAS and CEA.