Endovascular Therapy of Extracranial and Intracranial Occlusive Disease

Carotid Stenosis and Stroke Risk

The efficacy of carotid revascularization in reducing the risk of ischemic stroke was first demonstrated by comparison of CEA to medical therapy alone. In the North American Symptomatic Carotid Endarterectomy Trial (NASCET), the greatest benefit of surgical revascularization was seen in patients with severe (70%–99%) stenosis, with an absolute reduction of 17% in the risk of ipsilateral stroke at 2 years. An absolute reduction of 6% was demonstrated in patients with stenosis of 50%–69%. There was no benefit of surgery in patients with less than 50% symptomatic stenosis.

The benefit of CEA in asymptomatic carotid stenosis was assessed in another randomized trial, the Asymptomatic Carotid Atherosclerosis Study (ACAS). The trial included 1662 patients with asymptomatic carotid artery stenosis of 60% or more who were randomized to CEA or medical management with an antiplatelet agent and stroke risk factor modification. The 5-year risk for stroke or death was 5.1% for surgical patients and 11% for patients treated medically.

Several anatomic and physiologic features are associated with a higher risk of perioperative complication (including stroke and myocardial infarction [MI]) for patients undergoing CEA ( Table 66.1 ). Anatomic features include the presence of contralateral carotid occlusion, history of previous CEA or radiation to the neck, hostile neck, and extremely low or high anatomic location of the lesion, making CEA technically challenging. ^{, ,} Physiologic features include severe medical and surgical comorbidities ^, that make a minimally invasive CAS a safer alternative. CAS was first performed exclusively in patients who were considered “high risk” for CEA. Once the data from randomized trials demonstrated clinical equipoise between the two revascularization approaches, the popularity and utilization of CAS in clinical practice increased. Reviewed and discussed below are the results of pivotal randomized trials comparing safety and outcomes of carotid revascularization with CAS and CEA. Table 66.2 provides a summary of evidence that supports the role of CAS in the treatment of patients with extracranial carotid disease.

Randomized Trials of Carotid Angioplasty and Stenting Versus Carotid Endarterectomy

The Carotid Revascularization Endarterectomy versus Stenting Trial (CREST) is considered a landmark trial that compared outcomes associated with open surgical versus endovascular treatment of carotid atherosclerotic disease (symptomatic patients with >50% and asymptomatic patients with >60% stenosis). This randomized, controlled trial with blinded end-point adjudication conducted at 108 centers in the United States and 9 in Canada had a rigorous certification process; all participating operators had to undergo evaluation of their carotid stenting experience and participation in hands-on training. The study committee evaluated 427 applicants for participation in the trial, and only 224 interventionists were selected to participate in the randomized phase. Such a demanding process ensured that every selected operator was qualified to perform either CEA or CAS and emphasized the value of operator experience to avoid criticism seen with previously published trials. For example, in the EVA-3S trial, surgeons had to have performed at least 25 CEA procedures in the year before enrollment, whereas substantially less CAS procedure exposure was required—only 5 interventions were required for an interventionist to join the trial. The participation of operators with limited CAS training and experience in the EVA-3S trial was subsequently criticized as a potential factor explaining the unusually high perioperative complication risk in the CAS arm of this trial (the 30-day risk of stroke or death was 9.6% with CAS).

Among the 2522 patients enrolled in CREST, no significant difference was found in the estimated 4-year rates of the primary end point (stroke, MI, or death from any cause during the periprocedural period or any ipsilateral stroke within 4 years) between the stenting and endarterectomy groups (7.2% and 6.8%, respectively; P = .51). In the perioperative period, both procedures were associated with similar mortality rates (0.7% with CAS vs. 0.3% with CEA, P = .18). The risk of stroke was higher with CAS (4.1% vs. 2.3% with CEA, P = .01), and the risk of MI was higher with CEA (2.3% vs. 1.1% with CAS, P = .03).

A subsequent analysis of the CREST data showed that most strokes were minor (defined as National Institutes of Health stroke scale [NIHSS] score ≤8, which was the score in 81% of all strokes in CREST) with the median NIHSS score of 2. An important observation came from a breakdown of the distribution of strokes relative to the time of the interventions; most strokes associated with CAS occurred on the day of the procedure (29 events with CAS vs. 9 with CEA). Beyond day 0, there was no longer a significant difference in stroke rates between the two procedures. Major strokes were infrequent and occurred in 0.6% of all patients, mostly several days after the procedure (median, 3 days from the date of the procedure). These events included intracranial hemorrhages that were potentially related to hyperperfusion syndrome.

A strong relationship between patient age and stroke risk was shown in CREST. The hazard ratio for the primary end point indicated safety and efficacy of CAS at a younger age and CEA at an older age. At the age of approximately 70 years, both procedures were equally safe. A more detailed analysis of the CREST data on the impact of age in CAS-treated patients confirmed an increased risk for stroke with CAS at an older age. The risk of stroke with CEA remained relatively unchanged at both young and older ages. Such a relationship between age and stroke risk with CAS and CEA was true for both symptomatic and asymptomatic patients.

The influence of age on outcomes of carotid revascularization was addressed in a meta-analysis of three other major randomized trials—EVA-3S, SPACE, and the International Carotid Stenting Study (ICSS). Analysis of outcome data from 3433 patients with symptomatic carotid stenosis identified age as a strong predictor of primary outcome events (stroke and death) in patients treated with CAS. According to the intention-to-treat analysis, in patients younger than 70 years, the estimated 6-month risk of primary outcome events was similar with both types of treatment (5.8% with CAS and 5.7% with CEA); whereas in older patients, the risk doubled (12% with CAS and 5.9% with CEA).

Nevertheless, the theory that there is an association between age and risk of stroke from CAS is controversial. Other studies have suggested that perioperative stroke risk is increased secondary to unfavorable arch anatomy, such as types II, III, and bovine arch (left common carotid and brachiocephalic arteries with a common origin), which is more commonly seen in the elderly. ^, In a carefully selected group of elderly patients, including octogenarians, CAS can be performed with a low complication rate. ^, Age is often considered a high-risk feature for CEA. However, similar to CAS, in a highly selected group of elderly patients without major cardiovascular comorbidities, CEA can be performed with a safety profile comparable to that for younger patients.

The influence of gender on outcomes in patients undergoing CAS is another area of ongoing research and is not well understood. In the CREST design, a recruitment goal of 40% women was set to provide data on treatment differences between male and female gender and primary end points (stroke, MI, or death). When the trial was completed, 35% of randomized patients were women. No influence of gender on 4-year rates of primary outcomes from CAS and CEA were seen, based on a pre-specified analysis. Further subgroup analysis showed that women had higher rates of periprocedural events with CAS than with CEA (6.8% vs. 4.3%, P = .047) but men did not. The difference was mostly driven by a higher rate of stroke in women during the periprocedural period (5.5% with CAS compared to 3.7% with CEA, P = .013). Although a meta-analysis of other randomized trials of CEA versus CAS did not confirm the influence of gender on short-term outcomes, CREST data emphasize the need for further investigation.

The SPACE trial was a multicenter European randomized trial of CEA versus CAS that evaluated 1183 patients with ≥50% symptomatic stenosis (per NASCET criteria ) between 2001 and 2006. The 30-day rates of ipsilateral ischemic or hemorrhagic stroke or death were 6.8% with CAS and 6.3% with CEA ( P -value for noninferiority, .09). The 2-year follow-up results demonstrated similar rates of ipsilateral ischemic stroke and any stroke or death for both treatment groups.

Recurrent stenosis of ≥70% documented by carotid Doppler imaging was more frequent in the CAS group than the CEA group (intention-to-treat life-table estimate of 10.7% vs. 4.6%, P = .0009). Restenosis was most common in the first 6 months after treatment (52% of all restenosis cases after CAS or CEA). Of 54 total cases of restenosis following CAS during the 2-year period, only two led to neurologic symptoms.

A subanalysis of the SPACE data indicated a higher complication rate (ipsilateral stroke or death) with increased age in the CAS group but not in the CEA group ( P = .001 and P = .534, respectively). Similar to the CREST findings, a crossover at the age of 68 years showed the greatest separation between high- and low-risk populations of CAS-treated patients. Analogous to the CREST data, the CEA group in SPACE showed a homogeneous distribution of complication rates across different age groups.

Endarterectomy Versus Stenting in Patients With Symptomatic Severe Carotid Stenosis

The EVA-3S trial was conducted to compare CAS with CEA in patients with symptomatic carotid stenosis of 60% or more. After the enrollment of 527 patients, the trial was stopped for safety reasons because of the increased 30-day risk of stroke or death in the CAS group (9.6% vs. 3.9% with CEA, P = .01).

The trial was started in 2000 and initially did not mandate the use of embolic protection devices with carotid stenting. In 2003, the trial safety committee recommended stopping unprotected CAS because of the associated significant increase of stroke, which was 3.9 times higher than that of protected CAS. Upon completion of the EVA-3S study, a subsequent analysis confirmed the value of cerebral protection devices in reducing perioperative complications. Significant reduction in stroke or death rates was seen within 24 hours, as well as within 30 days in “protected” stenting cases. Proximal and distal protection devices demonstrated equal safety profiles.

Carotid Revascularization and Medical Management for Asymptomatic Carotid Stenosis Trial

The Carotid Revascularization and Medical Management for Asymptomatic Carotid Stenosis Trial (CREST-2) is a National Institute of Neurological Disorders and Stroke (NINDS)-sponsored study consisting of two independent multicenter, randomized, controlled trials of carotid revascularization and intensive medical management versus medical management alone in patients with asymptomatic high-grade carotid stenosis ( ClinicalTrials.gov Identifier: NCT02089217). In one trial, patients are randomized to CEA versus medical therapy alone. In the second trial, medical therapy is compared to CAS for asymptomatic stenosis. This landmark trial is expected to complete the enrollment of 2480 patients in 2020. It will provide the highest level of evidence on the role of revascularization versus medical therapy and will guide the treatment of asymptomatic extracranial carotid lesions in the future. The primary outcome of this study will be rates of stroke plus death within 44 days after randomization and ipsilateral stroke thereafter up to 4 years. It will also help answer other important clinical questions such as the effect of severe asymptomatic stenosis on cognitive function and the effects of age, sex, and risk factor level on outcomes with the treatments studied.