More than three-quarters of a million Americans will suffer a stroke this year. Stroke ranks as the third most common cause of death after heart disease and cancer. It is the number one cause of disability among adults and the main reason for rehabilitation. Many, but not all, strokes are related to atherosclerosisÔÇöthe same disease that causes heart attacks. Blockage of one of the two main arteries to the brain, the carotid arteries, is a preventable cause of stroke. These blockages can be detected by an ultrasound test and are confirmed by angiography. The conventional treatment for these blockages is a surgical operation, but a non-surgical treatment, carotid stenting, has recently been approved for use in patients at high surgical risk and is being tested as an alternative procedure to surgery for routine patients.
Introduction
Catheter-based therapies, such as stents, have been used in both peripheral and coronary arteries to great success, and in many circumstances have largely replaced surgical therapy as the standard treatment of blocked arteries. The use of carotid artery stents (CAS) to prevent strokes began in Europe.1,2 In a worldwide survey of carotid intervention published in 1998, the specialty of cardiology was dominant, responsible for more than 60% of all the reported cases of CAS.3 Cardiologists have continued to lead this field with the development of embolic protection devices (EPDs) used to trap debris released from the plaque.4
Pathophysiology
The majority of cerebral ischemic events are a focal manifestation of a systemic diseaseÔÇöatherosclerosis. There are two main types of stroke: ischemic and hemorrhagic. Ischemic stroke results from a reduction of blood flow due to emboli, thrombosis, or hypoperfusion. Hemorrhagic stroke includes primary cerebral hemorrhages or hemorrhage secondary to an ischemic event. Atherosclerotic carotid artery stenoses most often cause symptoms due to emboli events. Anatomically, the two internal carotid arteries and two vertebral arteries come together at the base of the skull to form an ideal anastomotic network, the Circle of Willis. In theory, a single vessel could supply the circulatory needs of the entire brain.
Stroke Prevention
Pharmacologic Therapy
Both primary and secondary stroke prevention require aggressive risk factor modifications, specifically blood pressure control and smoking cessation. Daily aspirin therapy (75-325mg) results in a 25% relative risk reduction compared with placebo.5,6 There is consensus that doses of aspirin greater than 325mg per day are not more effective for stroke prevention.7 The Clopidogrel versus Aspirin in Patients at Risk of Ischemic Events (CAPRIE) trial, comparing clopidogrel with aspirin, demonstrated a small but statistically significant benefit for clopidogrel for the combined end-point of ischemic stroke, myocardial infarction (MI), or vascular death, but it did not show a reduction in stroke risk with clopidogrel compared with aspirin alone.8 The Management of Atherothrombois with Recent Transient Ischaemic Attack or Ischaemic Stroke (MATCH) trial showed no stroke reduction benefit for aspirin and clopidogrel compared with clopidogrel alone, although the bleeding risk was increased with the combination therapy.6 Despite isolated data from a single trial regarding secondary prevention, the preponderance of evidence is that the addition of dipyridamole to aspirin alone for primary or secondary stroke prevention is of marginal benefit.5,6,9 With the exception of atrial fibrillation, there are no data to support the role of anticoagulation with warfarin to reduce the risk of stroke.10
Despite the absence of epidemiological data to link elevated cholesterol levels with stroke, large studies of several statins have demonstrated stroke reduction with this class of drugs.11 Both the Scandinavian Simvastatin Survival Study (4S) trial and the Cholesterol And Recurrent Events (CARE) trial with pravastatin demonstrated a 30% relative risk reduction for stroke compared with placebo.12,13 Interestingly, the stroke benefit did not appear in these trials until after three years of therapy.
Clinical Trials
Surgery Versus Medical Therapy
The initial surgery versus medical therapy trials compared best medical therapy, aspirin, versus carotid endarterectomy (CEA) for the prevention of stroke and death in symptomatic patients. Both the European Carotid Surgery Trial (ECST) and the North American Symptomatic Carotid Endarterectomy Trial (NASCET) demonstrated that for selected surgeons and selected patients with carotid stenoses (70% to 99%) causing hemispheric or ocular symptoms, there was an unequivocal benefit for surgery over medical therapy for the prevention of stroke (see Figure 1).14,15 This benefit was realized despite a 6% incidence of perioperative stroke and death. With more modest-severity carotid stenoses (50% to 69%), the number of patients needed to treat with CEA to prevent one stroke increased to 15.16 In these moderately severe carotid lesions, male patients demonstrated benefit, while female patients did not.
For asymptomatic carotid lesions, there is good evidence that with a low perioperative risk of stroke or death, patients with 60% to 99% lesions will benefit from CEA compared with medical therapy. In the Asymptomatic Carotid Surgery Trial (ACST), 3,120 patients were randomized to medical therapy or CEA with a perioperative stroke and death risk of 3.1%.17 The five-year risk of stroke was reduced from 11% in the medical group to 3.8% in the CEA group (p<0.001).This slightly exceeded the benefit seen with the Asymptomatic Carotid Atherosclerosis Study18 in which asymptomatic patients with 60% to 99% carotid stenoses were randomized to medical therapy or surgery with an estimated five-year risk of ipsilateral stroke of 11%, compared with only 5.1% in the CEA group.18 This was accomplished with a 30-day stroke and death risk of 2.3%.
The applicability of carefully controlled clinical trial results to everyday patient care has been debated. In a study comparing Medicare patients undergoing CEA, it was shown that the perioperative mortality rate for hospitals that had not qualified to participate in the major clinical trials was significantly higher than that for trial hospitals.19 Due to the fact that perioperative mortality for CEA in routine Medicare patients is substantially higher than that reported in the clinical trials, caution is advised in translating the efficacy of carefully controlled studies of CEA to effectiveness in everyday practice.
It is difficult to compare studies and outcomes of CEA among various groups because of the variability and inconsistency in the reporting of CEA. In a metaanalysis of CEA in symptomatic patients (n=51 studies), the strongest predictor of stroke or death was who performed the post-operative assessment.20 When a neurologist routinely evaluated post-operative patients, the risk of stroke and death was 7.7%; however, when a surgeon performed the evaluation, only 2.3% were reported to have this complication. The American Heart Association (AHA) expert consensus panel suggested that the perioperative risk of stroke and death should not exceed 3% for asymptomatic patients, 6% for symptomatic (transient ischaemic attack (TIA) or stroke) patients, or 10% for repeat CEA.21
Catheter-based Therapy
CAS placement has evolved over the past 20 years to become an accepted method for treating patients with selected carotid lesions.2,22-24 Due to the fact that the carotid artery is subject to external compression and rotation, self-expanding stents are used to avoid stent compression. Concern over the potential release of cerebral emboli has led to the development of emboli protection devices (EPDs) (see Figure 2).25 These protection systems fall into three categories:
- distal balloon occlusion with aspiration;26
- proximal occlusion with aspiration;27 and
- distal filter systems.28
Currently, the filter systems are the easiest to use and appear to be effective in preventing stroke. The initial trials of carotid artery angioplasty with stenting using an emboli protection device have focused on patients at increased risk for CEA as well as those at increased risk of complications from CAS (see Tables 1 and 2).
Multiple large non-randomized prospective registry studies (e.g. Boston Scientific EPI: A Carotid Stenting Trial for High-Risk Surgical Patients (BEACH), ACCULINK™ for Revascularization of Carotids in High Risk Patients (ARCHeR), and Registry Study to evaluate the Neuroshield Bare-Wire Cerebral Protection System and X-Act Stent in patients at high risk for Carotid Endarterectomy (SECuRITY)) have investigated the safety and efficacy of CAS with emboli protection in symptomatic and asymptomatic patients at increased risk for surgical treatment and have recently been completed.29-33 All of these trials have met their targets for safety and efficacy (see Figure 3). Germany has established a registry open to any investigator in Germany, Austria, or Switzerland who performs CAS.34
A total of 38 centers have enrolled 3,853 patients. To avoid selection bias, all patients had to be registered prior to the procedure and followed until hospital discharge or death. Carotid stent placement was actually attempted in 3,267 patients, of whom 70% were male, 10% were older than 80 years, and 56% were symptomatic. CAS was technically successful in 98%, with an embolic protection device (EPD) used in 64%. The combined end-point of mortality and/or a severe neurological deficit occurred in 2.8% of the patients; 2.4% in asymptomatic, and 3.1% in symptomatic patients. Interestingly, there did not appear to be any difference in adverse outcomes for those treated with or without EPDs (2.2% with EPD and 2.1% without EPD). This data indicates that excellent outcomes can be obtained from carotid stent placement when the procedure moves away from investigational centers and into community hospitals.
Surgery Versus Carotid Stent Placement
Carotid artery stent placement offers a less invasive alternative to CEA. Stent placement is performed without the risk of general anesthesia, offering a lower procedural morbidity and mortality, a shorter hospital stay, and lower costs. Non-surgical options become particularly attractive in patients with significant medical co-morbidities or other conditions that increase their risk of surgical complications (see Table 1). However, patient selection for carotid stent placement must also take into account complex anatomy that increases the risks for stent placement (see Table 2).
The Carotid and Vertebral Artery Transluminal Angioplasty Study (CAVATAS) was a European multicenter randomized trial of carotid angioplasty versus surgery.35 A total of 504 patients (more than 90% symptomatic) were randomized to CEA (n=253) or angioplasty (n=251). Only 26% of the angioplasty patients received a stent for a failed or suboptimal balloon angioplasty result. The 30-day end-point of disabling stroke or death showed no difference between the angioplasty arm (10%) or the surgical arm (9.9%). The 95% confidence intervals for the CAVATAS surgical event rate (6.2% to 13.6%) overlapped with the complication rates of both the European Carotid Surgery Trial (ECST) (7%, 95% confidence interval (CI) 5.8% to 8.1%) and the North American Symptomatic Carotid Endarterectomy Trial (NASCET) (6.5%, 95% CI 5.2% to 7.8%). Complications of cranial nerve injury and myocardial ischemia were seen only in the surgical arm. After three years of follow-up, there continues to be no difference in death or disabling stroke, or ipsilateral stroke, between the groups.
The Stenting and Angioplasty with Protection in Patients at High Risk for Endarterectomy (SAPPHIRE)36 trial compared CAS with distal emboli protection with CEA in patients at increased risk for complications at surgery.37 A total of 747 patients were entered into the trial, with 159 randomized to CAS with distal protection, and 151 randomized to CEA. An additional 406 patients were refused surgery and were treated in a stent registry, while only seven patients were refused CAS and were treated in a surgery registry.
In the randomized patients, the one-year combined end-point for the CAS group was 12.2% compared with 20.1% (p=0.053) in the CEA group. This randomized trial provides strong evidence that stent placement with distal protection is not inferior to CEA and is the procedure of choice for patients at increased risk for carotid surgery (see Figure 4).
Emboli Protection Devices
The Endarterectomy Versus Angioplasty in Patients with Symptomatic Severe Carotid Stenosis (EVA-3S) trial is an on-going trial that is a multicenter, randomized, open-label, assessor-blind, non-inferiority study to determine whether CAS (with or without an EPD) is as safe and effective as carotid surgery.38 After 80 patients had been enrolled in the carotid stent arm of the trial, the safety committee recommended stopping 'unprotectedÔÇÖ CAS due to an excess of strokes (both minor and major) in the relatively small number of patients treated without EPD.
This decision, to not allow CAS without EPD, is controversial, because:
- the differences between the groups did not reach statistical significance;
- patients were not randomly allocated treatment with an EPD;
- those without EPD were significantly older (66 versus 72.7 years; p=0.013), which is a known risk factor for stroke with CAS; and
- lesion predilation was performed three times more often in the group with EPD, which may have lowered the risk of procedural stroke.39
Remembering that EPDs can only reduce embolic strokes during the procedure, it is interesting to note that only two strokes occurred on the day of the procedure in the group treated without an EPD compared with three strokes in the group treated with an EPD, a difference that may have arisen by chance.
The use of EPDs is likely to decrease cerebral emboli during the procedure, at a 'potential costÔÇÖ of increasing the complexity of the procedure with an increase in complications directly related to the EPD. In the CAVATAS trial,40 the 30-day stroke rate without EPD was 10%, which is not very different to the 10.3% reported for EVA-3S.38 There remains no conclusive evidence that the use of EPDs reduces the risk of stroke, and the need for a randomized trial is becoming clear.
Current State of the Art
The indications for CAS are in patients at increased risk for surgical complications who are symptomatic with a carotid stenosis greater than 50% or asymptomatic with a carotid stenosis of 80%. The evidence from multiple clinical trials provides compelling evidence that CAS with emboli protection is preferred over CEA in high surgical risk patients with suitable anatomy. Patients who do not meet high surgical risk criteria should be offered conventional surgery or participation in a clinical trial.
Summary
Atherosclerotic carotid artery disease (CAD) is a major contributor to the incidence of stroke, particularly in the elderly. Atherosclerosis is a systemic illness and patients often present with multisystem involvement of several vascular beds including coronary, cerebral, and peripheral vascular territories. The majority of strokes related to CAD are embolic in nature, not occlusive. Medical therapy to reduce the risk of stroke includes antiplatelet agents, primarily aspirin in doses of 81-325mg per day. Control of blood pressure and the use of statin therapy is effective in reducing the incidence of stroke. Carotid endarterectomy is more effective for preventing stroke in symptomatic (TIA or stroke) patients with 50% diameter stenosis and in asymptomatic patients with 60% diameter stenosis than aspirin therapy. In patients at increased risk for surgical complications during stroke prevention surgery,15 carotid stents have been shown to be as good or better than surgery at improving outcomes.41