Stroke-related morbidity and mortality remain unacceptably high. Recent estimates suggest that it accounts for approximately one out of every 17 deaths in the US, and that a person dies from the direct consequences of stroke every three to four minutes.1 Of the almost 800,000 strokes that occur annually, 87% are ischaemic, the remainder occurring predominantly as a consequence of intracerebral haemorrhage.2 While 15% of patients who experience a stroke have suffered a preceding transient ischaemic attack (TIA), thereby potentially giving an opportunity for medical intervention, only about 50% are likely to report the episode to their physician.3 The 90-day risk of stroke after a TIA is as high as 17.3% and the 10-year cumulative risk of stroke, myocardial infarction (MI) or vascular death is over 42%.4 Confronted with these statistics, the personal and financial burden to the nation associated with stroke is overwhelming, often representing the single greatest medical fear among the public.
Although almost half of all strokes result from cerebral ischaemia within the vascular territory supplied by the internal carotid artery, brain parenchymal infarction results from carotid artery atheroembolic disease in only about 15% or less of all stroke patients.5,6 Ois et al. recently reported the factors associated with a high risk of stroke recurrence in almost 700 patients who had an initial minor stroke or TIA.7 The presence of weakness and a prior history of TIA together with severe extracranial arterial disease were strongly associated with the highest risk of recurrence. The accessibility of the extracranial carotid artery to revascularisation, together with the strong correlation between the severity of carotid artery stenosis and the further risk of stroke in patients who have already experienced a TIA or stroke (up to 35% at five years in one series),8 has driven the adoption of carotid artery endarterectomy (CEA) and stenting (CAS).
Given the fact that the vast majority of cerebrovascular accidents do not result from atheroembolic carotid artery disease, a comprehensive clinical evaluation, consisting of a thorough history (including a third-party account where possible) and physical examination of the patient, is warranted in all cases where either CEA or CAS is being considered. The true differentiation of the ‘symptomatic’ patient with a carotid artery lesion from the asymptomatic patient is of paramount importance when dictating further clinical management options. For the purposes of carotid artery revascularisation, patients are termed ‘symptomatic’ if they have experienced a TIA (defined as a focal neurological deficit as a consequence of ischaemia persistent for under 24 hours)9 or a non-disabling stroke within the carotid artery vascular territory. Patients who have suffered a major disabling or completed stroke were not enrolled in the pivotal North American Symptomatic Carotid Endarterectomy Trial (NASCET) and the European Carotid Surgery Trial (ECST).10,11 Norris and Hachinski, in a study of over 800 patients initially diagnosed with stroke, reported a misdiagnosis rate of 13%.12 Specific patient groups (i.e. women and African-Americans) need particular consideration as they may be more likely to present with atypical features of a TIA or stroke.13,14 Among the potential misdiagnoses for patients presenting with TIA or stroke are syncope, seizure activity, complex migraine headache, confusional states, toxin exposure, neoplasms and subdural haematomas.15 In a meta-analysis of thrombolysis for acute ischaemic stroke comprising 18 studies, Reeves et al. demonstrated that women undergo reperfusion therapy less frequently than men.16 Correct assignment of the vascular territory affected by the TIA or stroke, on the basis of clinical symptoms and signs, can be facilitated though the use of specified classification systems such as the Oxfordshire Classification of Subtypes of Cerebral Infarction (see Table 1).17 The clinical utility of this classification format has been found to be reasonably reliable18 and may be especially useful in highlighting neurological manifestations arising outside the carotid artery vascular network.
Carotid Endarterectomy
CEA was first performed more than 50 years ago, but robust data pertaining to its usefulness in stroke prevention only came to light in the late 1980s and early 1990s with the publication of NASCET19,20 and ECST.11,21 Indeed, prior to these pivotal trials, CEA had fallen from favour, as frequent complications pushed major adverse event rates (including death and stroke) to greater than 20%.22,23
In the NASCET trial, 595 symptomatic patients (those with a recent hemispheric TIA or mild stroke and ipsilateral carotid artery stenosis of between 70 and 99%) were randomised to ‘best medical care’ (n=295) or ‘best medical care and CEA’. In the CEA group the 30-day combined stroke and mortality rate was 5%, and the absolute risk reduction at 18 months was 7% compared with the medically treated group. Even more impressive was the absolute risk reduction of 17% in non-fatal and fatal strokes attributable to CEA. Barnett et al. reported the NASCET findings for symptomatic patients with moderate carotid stenosis (50–69%) with CEA.20 Overall, 1,100 patients in each arm were followed for five years. The ipsilateral stroke rate was reduced from 22.2% in the medically treated group to 15.7% of those who underwent CEA (p=0.045). The authors concluded that CEA for symptomatic moderate internal carotid artery stenosis has only a marginal benefit in stroke reduction and that 15 patients would have to undergo CEA to prevent one ipsilateral stroke at five years.
The ECST was a multicentre randomised trial involving more than 3,000 patients with at least one TIA or mild ischaemic stroke within the six months prior to enrolment.11 The peri-operative risk of major stoke or death did not vary significantly with the degree of stenosis, but patients with a stenosis in the range of 70–80% who were managed medically had the highest rate of major ipsilateral strokes. Despite the immediate risks of CEA, patients with severe stenosis (>80%) had the greatest benefit, with a reduction in major stroke or death by over 11% at three years. Due to differences in angiographic estimation of carotid lesions, an 80% stenosis in the ECST corresponded to a 60% lesion in the NASCET. 20,24
In 1991 Mayberg et al. published the results of the Veterans Affairs Cooperative Study Program, which compared CEA and best medical management (n=91) versus best medical management alone (n=98) in symptomatic men with >50% ipsilateral carotid artery stenosis.25 Results were similar to those seen in NASCET and ECST. The greatest risk reduction in the rate of stroke or worsening TIA was seen in men with stenosis >70% (absolute risk reduction of almost 18% during a mean follow-up of 11.9 months). The authors noted that the benefits of CEA in terms of risk reduction became apparent shortly after surgery. These trials firmly established CEA as the gold standard according to practice guidelines for patients with severe symptomatic CA stenosis.26 CEA performed for symptomatic ipsilateral severe (70–99%) and moderate (50–69%) stenosis has been given a class IA indication in the AHA/American Stroke Association guidelines provided the surgeon can document a peri-operative morbidity and mortality risk of <6%.26
However, despite these robust results, many limitations exist when attempting to translate these findings into the clinical setting. Wennberg et al. found a higher peri-operative mortality rate of 1.4% (versus 0.6% of patients enrolled in the trial) from an analysis of Medicare records from hospitals that had participated in NASCET.27 The Veterans Affairs Cooperative Study Program screened 5,000 patients before enrolling 189 in the trial. Likewise, the NASCET trial excluded patients deemed to have high surgical risk characteristics.28 Furthermore, best medical therapy largely consisted of high-dose aspirin during NASCET. The ASA and Carotid Endarterectomy Trial (ACE Trial), which included 2804 patients who were assigned to different doses of ASA as well as CEA, investigated lower doses of aspirin. The investigators reported a reduced risk of stroke, MI and death within 30 days and three months of surgery for patients taking 81 or 325mg of acetylsalicylic acid daily than for those taking 650 or 1,300mg.29 This trial also involved a majority of asymptomatic patients (54%) undergoing CEA. Although aspirin at lower doses remains the main antiplatelet agent of choice for secondary stroke prevention, some argue that clopidogrel may be more beneficial in reducing cardiovascular events, including stroke.30 The supplementation of aspirin with extended-release dipyridamole may reduce ischaemic vascular events further among symptomatic patients.31 Controversy as to which antiplatelet regimen is best at secondary stroke prevention continues in the aftermath of the Prevention Regimen for Effectively Avoiding Second Strokes (PRoFESS) study.32 Although therapy with ASA and dipyridamole produced similar outcomes in the risk reduction of recurrent stroke or the composite of stroke, MI or vascular death, there was an increased risk of non-fatal haemorrhagic stroke with ASA/dipyridamole. Other significant advances in optimal medical management now include statin therapy33 and aggressive blood pressure control, especially with the use of angiotensin-converting enzyme inhibition both alone or in combination with thiazide diueretics.34 Data have shown that even a reduction of as little as 6mmHg in diastolic BP may lower the risk of stroke by up to 30%.35 There have also been significant refinements and advances in the operative technique of CEA since the landmark trials have been reported.36 Although the optimal timing for intervention in a symptomatic patient is unclear, CEA performed within the first three to six weeks appears as safe as that deferred to a later date. However, urgent CEA for a patient with recurring ischaemic symptoms may carry a high risk of stroke or death (19.2%).37
Carotid Artery Stent
Endovascular therapy for internal carotid artery stenosis began with percutaneous balloon angioplasty in the late 1970s and early 1980s in patients deemed unsuitable for CEA (see Figure 1).38 Device and technical advances gained from experience in percutaneous coronary intervention have contributed to substantial refinements culminating in better stent design and allowing for the widespread use of distal embolic protection. The Carotid and Vertebral Artery Transluminal Angioplasty Study (CAVATAS) randomly assigned 251 patients to endovascular therapy and 253 to CEA.39 Exclusion criteria were comparable to previous CEA trials. Ninety-seven per cent of patients were described as symptomatic with a mean stenosis severity of 75.2% (using NASCET methodology). Twenty-six per cent of patients in the endovascular group received stent implantation, whereas the majority were treated with balloon angioplasty alone. Interest was generated by the results of this study, as the investigators did not find a significant difference in the rates of disabling stroke or death (6.4% for angioplasty with or without stenting versus 5.9% for CEA) between the two treatment modalities. Although endovascular treatment led to higher 12-month restenosis rates (14 versus 4%), there was no difference in the rate of ipsilateral stroke during three years of follow-up. In addition, the endovascular group had lower complication rates such as access or surgical site haematomas, cranial and peripheral nerve palsies and pulmonary emboli.
Results for the Wallstent trial were less favourable for CAS.40 This study involved 219 symptomatic patients with 60–99% stenosis who underwent CAS without embolic protection or CEA. The trial was stopped due to high adverse event rates in the CAS treatment arm. Thirty-day CVA rates were 12.1% in the CAS group versus 4.5% of those treated with CEA. The one-year results were even worse for CAS with 12.1% of stented patients having an ipsilateral stroke, procedure or vascular-related death compared with 3.6% of the surgical patients (p=0.022).
Although the Carotid Revascularisation Using Endarterectomy or Stenting Systems (CARESS) included only 32% symptomatic patients with stenosis, it was one of the preliminary studies to involve CAS with embolic protection.41 Treatment paths were directed by the physician and 254 patients were assigned to CEA and 143 to CAS. Death or stroke rates at 30 days (2.1 versus 3.6%) and one year (10.0 versus 13.6%) were non-significantly different between the two treatments.
One of the most important and widely discussed CAS trials to date is the Stenting and Angioplasty with Protection in Patients at High Risk for Endarterectomy (SAPPHIRE)42 trial, which played a key role in initial US Food and Drug Administration (FDA) approval of CAS. This was a non-inferiority trial designed to demonstrate that CAS was not worse than CEA as a treatment for high-risk symptomatic and asymptomatic patients. Of the 167 patients randomised to CAS, 29.9% were symptomatic, as were the 27.7% who underwent CEA. Importantly, all patients had to have at least one high-risk feature, such as significant cardiac or pulmonary disease, that would have excluded them from earlier CEA trials. Only those patients judged by a multidisciplinary team to be suitable for either CAS or CEA were randomised. Four hundred and six patients were entered in a prospective CAS registry and seven were enrolled in a similar CEA registry arm of the study. Embolic protection was used in over 95% of CAS procedures. The primary end-point, which was cumulative incidence of major cardiovascular events at one year (defined as death, stroke or MI within 30 days of the procedure), occurred in 12.2% of CAS patients and in 20.1% of those subjected to CEA (p=0.004 for non-inferiority). Importantly, the cumulative end-point for symptomatic patients was 16.8% for CAS versus 16.5% for those undergoing CEA (p=ns). The authors concluded that CAS with embolic protection was not inferior to CEA in high-risk patients for prevention of stroke, death or MI. Analysis of this trial has generated intense debate across the different specialities involved in the care of stroke patients. There was no statistical difference concerning the primary end-point at 30 days between the treatment modalities and much of the difference at one year may result from the substantially greater incidence of MI within the CEA group (8.1 versus 2.5% in the actual treatment CAS group; p=0.03). Concern has also been expressed regarding the declaration of non-inferiority as the trial was stopped short of enrolling the original planned cohort size at the outset.43 However, this trial firmly established the role of CAS in high-risk patients.
Gurm et al. described the three-year outcomes for almost 78% of the patients enrolled in SAPPHIRE.44 After three years of follow-up, no significant difference in major outcomes (composite of death, stroke or MI within 30 days after the procedure, or death or ipsilateral stroke between 31 and 1,080 days after the procedure) was found between CAS and CEA (cumulative incidence 24.6 versus 26.9%).
The European multicentre Stent-supported Percutaneous Angioplasty of the Carotid Artery versus Endarterectomy (SPACE) trial included 1,183 symptomatic patients with stenosis ≥70% on duplex ultrasonography (which corresponded to ≥50% as assessed in NASCET), who were randomised to CAS or CEA.45 Unlike SAPPHIRE, this trial involved patients at standard surgical risk. In the CAS group 44.4% had a prior stroke, 29.5% a TIA and 15.9% amaurosis fugax in the preceding 180 days. Despite the trial stipulating rigorous criteria for both the surgical and interventional experience levels, embolic protective devices were used in only 27% of the 599 patients who underwent CAS. There was no significant difference in the 30-day rates of ipsilateral stroke or death (6.84 versus 6.34% for CEA; p=NS). The trial was stopped and failed to enrol a substantial percentage of the target of 2,500 patients, primarily due to a lack of funding.
Unfortunately, the Endarterectomy versus Angioplasty in Patients with Symptomatic Severe Carotid Stenosis (EVA-3S) trial yielded poorer outcomes in those managed with CAS.46 This French-based multicentre trial involved 520 patients with symptomatic carotid disease who were randomised to either CEA or CAS. Patient details were similar between the two treatment strategies, apart from the CEA group having a greater number of elderly patients, as well as those patients who had a prior CVA. The CAS-assigned group contained more patients with contralateral carotid occlusion than the CEA group. The incidence of any stroke or death was 3.9% (95% confidence interval [CI] 2.0–7.2) after CEA and 9.6% (95% CI 6.4–14.0) in the CAS group, with a relative risk of 2.5 (95% CI 1.2–5.1; p=0.01). Strokes were more likely to happen on the day of the procedure with CAS compared with the CEA group (17 of 24 versus three of nine; p=0.05). In the CAS group the authors noted no difference in the stroke rates based on the operators’ experience, but it is worth pointing out, as the study was not powered for this particular analysis.47 Stroke or death rates at 30 days were 7.9% in CAS with embolic protection as opposed to 25% in the unprotected CAS group, although the overall use of embolic protective devices rose to 91.9% after interim analysis recommended their use. The CAS group had a six-month stroke or death rate that greatly exceeded that of patients treated with CEA (11.7 versus 6.1%; p=0.02). The trial was suspended early, and far short of the 872 planned enrolled patients, on the advice of the safety committee. Serious criticism has been expressed about the limited experience of the operators performing CAS and how this may have adversely affected outcomes leading to the highest rate of stoke and death among all randomised trials carried out to date.
In addition, over 17% of patients did not receive dual antiplatelet therapy prior to CAS. On a positive note, others have highlighted that this trial stresses the importance and necessity of comprehensive physician training and appropriate patient treatment selection.48 The importance of this is also reflected in registry data.49 For instance, the high CVA rate, despite the use of embolic protective devices, suggests technical failure may have resulted from use in unsuitable arteries, a critical factor in assessing patients for CAS. Gurm et al. performed a meta-analysis of five trials that evaluated CAS in symptomatic carotid disease.50 These were the aforementioned Wallstent, SAPPHIRE, SPACE and EVA-3 trials, in addition to the Kentucky trial,51 which randomised 53 patients to CAS (without EPD) and 51 patients to CEA. They concluded that there were no significant differences between CAS and CEA in the treatment of symptomatic carotid artery disease.
So, how should these data guide the physician’s management when faced with a patient with symptomatic carotid artery disease? A thorough assessment by a multidisciplinary team, composed of specialists from neurology, vascular medicine and surgery, and anaesthesiologists, in addition to the interventionalist, is ideal. A reasonable approach begins with an assessment of the individual’s perceived surgical risk. High-risk symptomatic patients (see Table 2), with a high-grade internal carotid artery stenosis, could be offered CAS with embolic protection performed by an experienced operator, provided there were no technical issues likely to adversely affect the outcome (i.e. aortic arch tortuosity or ‘unfolding’, intraluminal thrombus at the target lesion and dense circumferential calcification of the target lesion).
The definition of ‘high’ surgical risk for CEA has been challenged.52 Kang et al. analysed outcomes from almost 4,000 CEA procedures.53 Approximately 30% of these patients were classified high-risk, although the authors did not report increased stroke or death rates in this cohort. From the CAS perspective, procedural risk may be elevated by unstable plaques with significant atheroembolic potential and tortuous supra-aortic vascular anatomy. Those patients without significant co-morbidities and high-grade internal carotid artery stenosis, such as those included in NASCET, could be offered either CEA or CAS (the latter if involved in an FDA-approved trial in order to ensure reimbursement).26 It is hoped that the current large randomised trial (i.e. the Carotid Revascularisation Endarterectomy versus Stent Trial [CREST]) evaluating CAS and CEA in symptomatic patients will greatly clarify clinical decision making.
CREST, a National Institutes of Health (NIH)-sponsored trial, includes standard-risk symptomatic patients with >50% stenosis and those without symptoms with internal carotid artery stenosis (>70%). This is a multicentre trial that has completed the enrolment of ~2,500 patients. Strict monitoring of CAS operators was employed to ensure that adequately skilled and experienced interventionalists participated in the study.54 Initial reports have yielded a 5.7% rate of stroke or death after 30 days for symptomatic patients undergoing CAS. The corresponding value for patients above 80 years of age was 12.1%. The International Carotid Stenting Study (ICSS/CAVATAS 2) is enrolling symptomatic patients who are suitable for either CAS or surgery with a target recruitment of 1,500 by completion.55 The 30- day primary safety end-point data were presented recently.56 In the ‘intention-to-treat’ analysis, the cumulative incidence of stroke, MI or death was 8.5% (n=72) in patients undergoing CAS versus 5.1% (n=43) in those with CEA (p=0.004). Analysis of patient outcomes per protocol also showed superior results with CEA (4.0% rate of stroke, MI or death versus 7.4% for CAS patients; p=0.003). Sixty-five patients who underwent CAS experienced a stroke compared with 34 who had CEA. Long-term outcome results are expected to be presented in 2011.
Conclusion
Stroke prevention therapies continue to evolve as advances in medical therapy, CEA and CAS continue unabated. Key issues remain to be answered definitively, specifically with regard to the relative benefits of CAS compared with CEA in patients with symptomatic CA disease. It is hoped that ongoing trials will enhance clinical decision-making to ensure optimal patient outcomes.