Stenting for long-term stroke prevention

Atherosclerotic stenosis of the internal carotid artery causes 10–15% of all strokes.¹ Carotid stenosis is defined as severe when the atherosclerotic narrowing of the proximal internal carotid artery exceeds 70% and moderate if it exceeds 50%.² The prevalence of carotid artery stenosis increases with age and risk factors in Western countries, with males being more commonly affected.

Two landmark large trials, the North American Symptomatic Carotid Endarterectomy Trial (NASCET) and the European Carotid Surgery Trial (ECST) showed a benefit of carotid endarterectomy (CEA) over medical treatment in patients with more than 70% symptomatic internal carotid artery stenosis assessed on angiography with lesser degrees of benefit in those with 50–69% stenosis.^2,3 Pooled analysis of these trials has shown an absolute risk reduction in any stroke or death of 16% (p<0.001) and a number needed to treat of 6 in patients with a stenosis of 70–99%.⁴  Moreover, CEA within two weeks of a non-disabling stroke or TIA significantly improved outcomes compared with later surgery.

Despite the clear benefit of CEA on severe carotid stenosis, surgical intervention contains risks, such as development of cranial nerve palsy (CNP) and neck haematoma on site of surgery. This risk was 5.5% for CNP and 6.1% for haematoma in patients undergoing CEA in a recent series.⁵ Interestingly, both CNP and haemorrhage were more frequent in females. One explanation may be more challenging surgical anatomy and smaller average diameter of the carotid artery in women. Furthermore, CEA carries a significantly higher risk of perioperative death in women. The net benefit of surgery is therefore less in women than in men.

In the past few years, treatment by endovascular placement of a stent across the carotid stenosis has emerged as an alternative to carotid endarterectomy. Several randomised trials have analysed the effectiveness of carotid artery stenting (CAS) in comparison with surgical treatment. In 2010, the Carotid Stenting Trialist’s Collaboration published a meta analysis of pooled data from 3433 patients with symptomatic carotid stenosis who were randomly assigned CEA versus CAS.⁶

This meta-analysis included three different trials: the Symptomatic Severe Carotid Stenosis trial (EVA-3S), the Stent-Protected Angioplasty versus Carotid Endarterectomy trial (SPACE) and the International Carotid Stenting Study (ICSS). This meta-analysis showed that stenting was associated with a higher risk of procedure-related stroke in the first 120 days after randomisation. This increase in procedure-related risk was driven by non-disabling stroke and there was no significant difference in the rate of major or disabling stroke or death.

There was also strong evidence than this excess risk associated with endovascular treatment was dependent on age with twice the risk of death or stroke in patients older than 70 years.⁷ Another risk factor for stroke associated with CAS comes from a subgroup analysis of the ICSS trial, which evaluated the extent of white matter lesions (WML) in the stenting group versus surgical group.⁸ This analysis showed that a higher than average severity of WML increased the risk of procedural stroke only in the stenting group. This might be due to the correlation between WML and other cardiovascular risk factors or an increased proportion of atherosclerosis in the aortic arch raising the risk of plaque embolus during stenting. It might also represent increased sensitivity to damage from embolism during CAS in patients who already have some brain damage.

On the other hand, CAS had a significant lower rate of wound haemorrhage complications in comparison to CEA in ICSS and avoids cranial nerve palsy altogether.⁵ In ICSS, the rate of myocardial infarction was similar between both groups. This finding contrasted with the large North American trial, CREST study, where frequency of myocardial infarction within 30 days of the procedure was significantly lower in the stenting group.⁹

Fig. 1: Carotid imaging and carotid endarterectomy for people with TIA or non-disabling Stroke (NICE Pathway). In the International Carotid Stenting Study (data from reference 11).

The current UK recommendation concerning carotid endarterectomy (Figure 1) is that stable patients found to have symptomatic carotid stenosis of 50–99% after a non-disabling stroke or TIA should undergo endarterectomy within two weeks after symptom onset. Meanwhile, patients should receive best medical treatment including control of blood pressure, an antiplatelet agent, cholesterol-lowering drugs and lifestyle advice. In 2011, the NICE interventional procedure guidance considered that the evidence on safety and efficacy of carotid stent placement for symptomatic carotid stenosis was adequate to support its use provided that normal arrangements were in place for clinical governance and audit or research.¹⁰

In summary, the available data was interpreted as indicating that the short-term efficacy of carotid stenting was as good as endarterectomy, but the risk of non-disabling stroke associated with treatment was higher in older patients. On the other hand, this risk should be weighed against the risk of potential complications of endarterectomy in terms of cranial nerve injury and wound haemorrhage, particularly in female patients. However, without long-term results from the trials, there was, until now, a lack of good evidence concerning the long-term effectiveness of carotid stenting.

The lack of evidence concerning the long-term effectiveness of carotid stenting has been addressed by the recent publication of the long-term follow-up of patients included in the ICSS trial.¹¹ ICSS is an international, multicentre, randomised clinical trial of endarterectomy versus stenting for the treatment of symptomatic carotid stenosis.

Patients included were older than 40 years of age and had symptomatic atheromatous carotid artery stenosis measured as more than 50%. Patients were randomly assigned to stenting or endarterectomy and were followed for up to 10 years with a median follow-up of 4.2 years. The primary endpoint was a fatal or disabling stroke in any territory after randomisation. Secondary endpoints were all-cause of death, stroke and combined procedural stroke in any territory, procedural death and ipsilateral stroke during the follow-up. More than 1700 patients were recruited between May 2001 and October 2008, equally distributed to stenting and endarterectomy.

Fig. 2: Functional ability measured by the modified Rankin Scale during follow-up. In the International Carotid Stenting Study (data from reference 11).

In the intention-to-treat (ITT) population, after a median of 4.2 years follow-up, the rate of fatal or disabling stroke was the same in both groups. The situation was different considering the secondary endpoint of any stroke, with significantly more patients with non-disabling stroke in the stenting group than in the endarterectomy group (p=0.0003, Table 1, Figure 2). Most of this excess occurred at the time of treatment, as described above.

Interestingly despite of the higher rate of stroke in the stenting group, the functional outcome of the patients measured by the modified Rankin Scale (Table 3) and the EQ-5D questionnaire (mobility, self-care, usual activities and discomfort assessment) at the end of follow-up did not differ significantly between treatment groups. Interestingly, the increased long-term stroke risk with stenting included not only stroke in the ipsilateral territory of the carotid stenosis but also contralateral and vertebrobasilar territory stroke. The mechanism is not well understood and could represent a chance finding, because an excess of contralateral stroke has not been reported in the other trials.

In conclusion, this long-term trial provides reassurance that stenting can be offered as a durable alternative to carotid endarterectomy in patients with clinical and angiographic characteristics associated with low risks of procedure-related stroke, for example, younger age. Both stenting and endarterectomy are relatively safe and effective in preventing severe strokes that lead to disability or death.

Although carotid stenting is associated with a higher procedure-related risk of non-disabling stroke than endarterectomy, these strokes did not impact on long-term functional ability in ICSS as evaluated by the modified Rankin scale and the EQ-5D questionnaire. In the other hand, endarterectomy showed an increased risk of cranial nerve palsy and access-site haematoma, particularly in women.

Thus patients with recent minor stroke or TIA and ipsilateral carotid stenosis, should be offered a choice between endarterectomy and stenting depending on patient specific factors, such as age, sex and comorbidities, and the availability of suitable experts to provide either treatment.

1. Chaturvedi S et al. Carotid endarterectomy–an evidence-based review: report of the Therapeutics and Technology Assessment Subcommittee of the American Academy of Neurology. Neurology 2005;65:794–801.
2. Barnett HJ et al. Benefit of carotid endarterectomy in patients with symptomatic moderate or severe stenosis. North American Symptomatic Carotid Endarterectomy Trial Collaborators. N Engl J Med 1998;339:1415–25.
3. European Carotid Surgery Trialists’ Collaborative Group. Randomised trial of endarterectomy for recently symptomatic carotid stenosis: final results of the MRC European Carotid Surgery Trial (ECST). Lancet 1998;351:1379–87.
4. Rothwell PM et al. Analysis of pooled data from the randomised controlled trials of endarterectomy for symptomatic carotid stenosis. Lancet 2003;361:107–16.
5. Doig D et al. Incidence, impact, and predictors of cranial nerve palsy and haematoma following carotid endarterectomy in the international carotid stenting study. Eur J Vasc Endovasc Surg 2014;48:498–504.
6. Carotid Stenting Trialists C et al. Short-term outcome after stenting versus endarterectomy for symptomatic carotid stenosis: a preplanned meta-analysis of individual patient data. Lancet 2010;376:1062–73.
7. Bonati LH et al. Percutaneous transluminal balloon angioplasty and stenting for carotid artery stenosis. Cochrane Database Syst Rev 2012;9:CD000515.
8. Ederle J et al. Effect of white-matter lesions on the risk of periprocedural stroke after carotid artery stenting versus endarterectomy in the International Carotid Stenting Study (ICSS): a prespecified analysis of data from a randomised trial. Lancet Neurol 2013;12:866–72.
9. Brott TG et al. Stenting versus endarterectomy for treatment of carotid-artery stenosis. N Engl J Med 2010;363:11–23.
10. Neequaye SK, Halliday AW. Carotid artery stenting: the 2011 NICE guidelines. Heart 2012;98:274–5.
11. Bonati LH et al. Long-term outcomes after stenting versus endarterectomy for treatment of symptomatic carotid stenosis: the International Carotid Stenting Study (ICSS) randomised trial. Lancet 2015;385:529–38.