When is carotid stenting acceptable as a means of stroke prevention?

Keywords::

• carotid atherosclerosis
• carotid endarterectomy
• carotid stenosis
• carotid stenting
• CREST trial
• stroke

Figure 1. Contrast-enhanced computed tomography scan of an acute internal carotid artery plaque rupture and intraluminal thrombus.

Stroke remains one of the leading causes of morbidity and death in the USA with an annual incidence of 780,000 cases and 270,000 deaths [1]. The majority of strokes are ischemic in etiology and approximately 30% of ischemic strokes are caused by emboli from the cervical carotid arteries [1]. Carotid endarterectomy (CEA) has been established as the standard of care for stroke prevention in patients with symptomatic carotid stenosis of 50% or more or asymptomatic stenosis of 60% or more [2,3]. Although CEA has proven to be safe and durable with a stroke risk–benefit superior to medical therapy for those who qualify, its inherent surgical risk may deter patients who present with significant comorbidities. As such, the initial premise for the development of carotid artery stenting (CAS), as with other percutaneous interventions for that matter, was to provide a viable alternative to surgery in patients who are considered high surgical risk owing to coexistent medical comorbidities and/or anatomical high-risk features.

With the evolution of technology and technique, prospective trials are beginning to justify the role of CAS, and their results progress toward achieving the durability and safety benchmarks established by CEA. The results of the recent Carotid Revascularization Endarterectomy Versus Stenting Trial (CREST) best reflect the continued maturation of CAS as an alternative therapy for stroke prevention [4]. Prior to CREST, randomized trials were largely conflicting in their assessment of CAS. In 2007, a Cochrane review of available level 1 data identified 12 randomized trials that compared the immediate procedural risks and long-term results of CAS to those of CEA [5]. At that time, the study concluded that the data were too heterogeneous to interpret and did not provide evidence to support a change in clinical practice away from recommending CEA as the treatment of choice for patients in whom both CEA and CAS are deemed technically feasible [5]. Among the 2502 patients studied, investigators of CREST found no significant difference in the estimated 4-year rates of the primary composite end points (defined as any stroke, myocardial infarction, or death from any cause during the periprocedural period or any ipsilateral stroke) between the CAS and CEA groups (7.2 and 6.8%, respectively; stenting hazard ratio [HR]: 1.11; 95% CI: 0.81–1.51; p = 0.51) [4].

Although the question of clinical success of CAS was answered by CREST, a difference in the periprocedural adverse events was noted from those found in other randomized trials. In CREST, stenting was associated with a higher risk of stroke than surgery (4.1 vs 2.3%; p = 0.01), but a lower risk of myocardial infarction (1.1 vs 2.3%; p = 0.03) [4]. The stroke rates in the CREST study, however, were much lower than rates reported in other contemporary randomized trials such as the Endarterectomy versus Angioplasty in Patients with Severe Symptomatic Carotid Stenosis (EVA-3S) [6]. In EVA-3S, the combined death and stroke rate was 9.6% in the CAS group and 3.9% in the CEA group, and the rate of severe stroke and death in the two arms was 3.4 and 1.5%, respectively, with a statistically significant difference [6]. Such improvements in safety are largely a reflection of the advancements in devices and technical experience. With regard to the patient’s perspective of the reported adverse events observed in CREST in which myocardial infarction was most likely after carotid endarterectomy, its effect on the quality of life was less than the effect of stroke [4]. Further analysis of periprocedural event data demonstrated that younger patients had slightly fewer events after carotid artery stenting than after carotid endarterectomy; older patients had fewer events after carotid endarterectomy [4]. Given these results, a conclusive indication for CAS based on patient characteristics cannot be fully endorsed. In short, despite the improved safety profile of CAS that recent trials such as CREST have reported in the last 5 years, a definitive consensus on patient selection for endovascular treatment of extracranial carotid stenosis does not exist.

So when should a vascular interventionalist decide on employing CAS for stroke prevention? As with any medical therapy, the clinician must first clearly define the goals of treatment and thoroughly balance the risks of surgery versus endovascular therapy for the potential CAS patient. Patient selection criteria must, therefore, be carefully examined before reviewing and referencing current prospective data on CAS to avoid generalizing the data to suit the indication. The experience standards, the devices and the protocols adhered to by the investigators in these controlled trials do not necessarily correlate with the disciplines of every institution. For instance, in the recent CREST study, certification requirements for the investigators in the trials were rigorous and required a minimum experience of 10–30 carotid stent procedures with 0.14-inch wire systems, experience with embolic protection devices (EPDs), and a documented 30-day stroke and death rate of 6–8% [4]. In addition, after admittance into the study, there was a required lead-in phase of up to 20 patients designed to ensure operators had adequate experience and acceptable complication rates prior to randomizing patients. In essence, the results and outcomes reported in the major trials may only be generalized to similarly qualified operators. Regardless of inherent institutional variability, the goals and indications for CAS should remain the same as for CEA. Asymptomatic patients with mild carotid stenosis or symptomatic patients with less than 50% stenosis are best served with optimal medical management.

Determining patients as ‘high risk’ for open carotid intervention in and of itself is viewed with controversy since CEA, in experienced hands, remains a relatively ‘low-risk’ operation. The general definition of ‘high risk’, however, includes those patients with systemic comorbidities including advanced age, severe cardiovascular disease, compromised pulmonary function, and compromised renal function. When weighing the various systemic and anatomic comorbidities into the risk–benefit equation, patients with severe respiratory disorders are probably the least disputable indication for CAS, since local groin or arm anesthesia would be a better option than general or cervical block anesthesia. Patients with renal insufficiency may also benefit from angioplasty, although care should be taken with the risk of contrast nephropathy. Evidence to support the role of CAS in high-risk individuals is shown in various other randomized trials and registries that have alluded to the decrease in cardiac complications following CAS versus CEA. Prior to CREST, the Stenting and Angioplasty with Protection in Patients at High Risk for Endarterectomy (SAPPHIRE) trial prospectively studied 334 ‘high-risk’ patients with either symptomatic stenosis of 50% or greater or asymptomatic stenosis of 80% or greater. The study demonstrated that patients undergoing CAS suffered fewer myocardial events compared with CEA and demonstrated the noninferiority of CAS therapy over CEA, with benefits persisting up to 2 years with respect to stroke prevention [7]. The increased risk of perioperative myocardial infarction in patients undergoing open surgery compared with endovascular treatment is further evidenced in the results of the International Carotid Stenting Study (ICSS) [8].

It is clearly evident that patients with symptomatic carotid stenosis are at the highest risk of suffering a debilitating stroke. For those symptomatic patients without high surgical risk, CAS may pose increased perioperative stroke risk compared with CEA. In the ICSS trial, investigators compared stenting with endarterectomy in 1713 patients with symptomatic carotid stenosis of greater than 50%. The primary end point was the rate of fatal or disabling stroke at 3 years. An interim safety analysis at 120 days of follow-up showed that the primary end point had occurred in 4.0% of stenting cases versus 3.2% of endarterectomy cases, a difference that was not statistically significant (HR: 1.28; 95% CI: 0.77–2.11) [8]. The risk of any stroke, however, was found to be higher with stenting, with a rate of 7.7 versus 4.1% in the surgical group (HR: 1.92; 95% CI: 1.27–2.89) [8]. In a substudy of ICSS, the investigators corroborated these findings using diffusion-weighted MRI to evaluate for new ischemic brain lesions periprocedurally. They found more new ischemic brain lesions in patients who underwent stenting than in patients who underwent surgery [9].

Anatomic features that may preclude CAS include hostile aortic arch anatomy, extreme vessel tortuosity, and plaques that are ulcerated or unstable with fresh thrombus material that clearly make endovascular procedures dangerous (Figure 1). The CREST trial had rigorous angiographic exclusion criteria such as severe tortuosity and calcification, intraluminal thrombi and large, bulky, plaques [4]. The frequency of unstable aortic plaques, vessel tortuosity and thrombus increases with age, and this may be why those patients with advanced age in CREST were found to benefit more from CEA [10,11]. The general consensus in our practice is to not treat elderly patients or patients who have challenging endovascular anatomy with CAS unless no other options exist. Anatomic ‘high-risk’ features for CEA pertain to those patients with local factors that potentiate surgical morbidity, such as previous endarterectomy, prior neck external-beam irradiation, prior cervical nerve injury, contralateral internal carotid artery (increased risk of intolerance to clamping) and the presence of a potential nidus for infection (i.e., tracheostomy). The rate of cervical nerve injury may be as high as 17% in patients who have had a previous neck operation or neck irradiation, thus, CAS is an accepted indication in such cases [12,13]. In retrospective studies, CAS for restenosis following a previous endarterectomy seems to provide excellent immediate and midterm clinical outcome [14,15]. In the multicenter, retrospective series reported by New et al., the 338 patients (358 arteries) who underwent CAS for restenosis following endarterectomy had an overall 30-day stroke and death rate of 3.7% [15]. The minor stroke rate was 1.7%, the major nonfatal stroke rate was 0.8%, the fatal stroke rate was 0.3%, and the nonstroke-related death rate was 0.9%. The overall 3-year rate of freedom from all fatal and nonfatal strokes was 96% [15]. Unfortunately, the long-term clinical durability of stenting for this indication is questioned, since severe in-stent restenosis and occlusion has been reported [16,17]. The routine use of EPDs is advocated with CAS. A meta-analysis comparing stenting without an embolic protection device (26 trials with 2357 patients) versus stenting with an embolic protection device (11 trials with 839 patients) demonstrated that embolic protection led to significantly better outcomes with fewer strokes [18]. Prospective trials that did not mandate the use of EPDs have shown a tendency toward worse periprocedural stroke outcomes [6]. There are a lack of data on which cerebral protection system provides the best stroke prevention. Filters may be the option selected when the patient has poorly developed collateral vessels or previous brain tissue damage. A reversed-flow system may be best suited to situations of severe stenosis or when vulnerable plaques need to be crossed.

Conclusion

Since its inception, CAS as a technique to manage extracranial carotid disease has been received with much controversy. The basis of the controversy has never been an issue of feasibility, but of how CAS measures up to the gold standard of CEA in terms of both safety and clinical durability for stroke prevention. The technique of CAS continues to evolve and, with substantial technological advancements in stent construction, routine employment of EPDs, and most notably, with significant increase in operator experience, data have shown that CAS can attain an equivalent safety profile and durability to CEA. Further improvements to devices, better protection devices and innovative methods to prevent in-stent hyperplasia may further solidify CAS as a comparable therapeutic option to endarterectomy in the prevention of stroke. At least for now, the task of defining the precise group of patients that will reap the most benefit from CAS over CEA still remains.

Financial & competing interests disclosure

The authors have no relevant affiliations or financial involvement with any organization or entity with a financial interest in or financial conflict with the subject matter or materials discussed in the manuscript. This includes employment, consultancies, honoraria, stock ownership or options, expert testimony, grants or patents received or pending, or royalties.

No writing assistance was utilized in the production of this manuscript.