• 
• 

Three Part Question

Is [carotid-artery stenting] superior to [carotid endarterectomy] for the treatment of patients with [significant carotid artery stenosis?].

Clinical Scenario

You are a first year radiology registrar who performs a carotid-artery duplex ultrasound on a symptomatic patient that reveals an 80% unilateral stenosis. The patient has heard about endovascular carotid angioplasty with stenting (CAS) as an alternative to carotid endarterectomy (CEA) and is keen to have a minimally invasive procedure. However, you are unsure whether there is any evidence to suggest that CAS is equivalent to the traditional gold standard of CEA.

Search Strategy

A Medline search from 1966–July 2005 using the OVID interface
[exp carotid arteries/OR carotid.mp] AND [exp endarterectomy, carotid/OR endarterectomy.mp] AND [exp stents/OR stent.mp] LIMIT to Human. The reference lists of selected journals were also searched.

Search Outcome

Four hundred and ninety-four papers were found using Medline and hand searching, from which 14 were relevant. The relevant papers included one meta-analysis, five randomised controlled trials (RCTs) and four published protocols for RCTs in progress (CAVATAS-2, EVA-3S, SPACE and CREST Trials). The authors of each of these trials in progress were contacted via e-mail to get a progress report.

Relevant Paper(s)

Author, date and country	Patient group	Study type (level of evidence)	Outcomes	Key results	Study Weaknesses
CAVATAS, 2001, Europe, Australia and Canada.	504 patients were randomly assigned to either endovascular treatment (n=251) or to carotid endarterectomy (n=253) 8 year follow up	Multi-center trial from 1992-1997 (Level 1b)	All stroke and death at 1,6, and 12 months post-procedure and then yearly.	No difference between the two groups with regard to death and stroke at one year. The incidence of cranial neuropathy was greater in the CEA group (22/253) versus the CAS group (0/251), p < 0.0001.	74% of patients treated endovascularly had balloon angioplasty alone. From 1994 onwards stents were used at the discretion of the radiologist. Distal emboli protection device were not used.
Brooks et al, 2001, USA	Single center randomized trial of 104 patients with symptomatic carotid artery stenosis (>70%) randomized to either CAS or CEA	Single center PRCT (Level 2b)	Stroke and death within 30 days of the procedure 24 month follow up	No patients suffered a post-operative stroke. One patient in the CAS group (1/53) suffered a TIA and one patient in the CEA group (1/51) died from an MI.	Small study and a distal emboli protection device was not used in CAS group.
Naylor et al, 1998, UK	23 symptomatic patients with carotid-artery stenosis > 70% were randomised to either CEA or CAS	Single centre PRCT (Level 2b)	Any stroke or death within 30 days of the procedure.	0/10 patients in the CEA group suffered any complication compared to 5/7 patients in the CAS group, of whom 3 suffered a disabling stroke. 23 patients were entered into the study, but only 17 had received their allocated treatment before the trial was stopped.	Distal protection devices were not used in the CAS group. Too small a study to draw any meaningful conclusions. Lack of adequate pre-procedure imaging and pre-dilation technique.
Wallstent Trial, 2001, USA	219 patients with symptomatic internal carotid artery stenosis (TIA or completed stroke within 120 days of randomisation, with at least 60% stenosis) randomised to either carotid artery stenting or endarterectomy	Multi-center PRCT (Level 1b)	The primary endpoint was the cumulative incidence of ipsilateral stroke, procedure related or vascular death within one year. The primary endpoint after approximately 1 year was 12.1% for the stent group versus 3.6% for the endarterectomy group (P=0.022).	The 30 day peri-procedure complication rate (any stroke or death) was significantly higher in the stented group compared to the endarterectomy group (12.1% versus 4.5%, P=0.049)	This study was prematurely stopped by its sponsors and concerns were raised about the lack of experience of the individuals performing the carotid artery stenting.
Yadav et al (SAPPHIRE) 2004, USA	334 patients with either symptomatic (>50%) or asymptomatic carotid artery stenosis (> 80%) were randomised to either CAS (n=167) or CEA (n=167). All carotid artery stents were placed using a cerebral emboli protection device.	Multi-center PRCT (Level 1b)	The primary endpoints are the cumulative incidence of death, stroke or myocardial infarction within 30 days or death or ipsilateral stroke within 31 days to 1 year.	Occurrence of the primary endpoint was similar for carotid stenting (20/167) when compared to carotid endarterectomy 32/167. (p = 0.0004 for non-inferiority)	Well designed multicenter randomized trial. Of the 747 patients enrolled into the study, 406 (54%) patients were only suitable for stenting and were entered into a separate stent registry. The study was prematurely stopped because enrollment slowed due to increasing resistance from clinicians and patients to be randomised to CEA.
			The secondary endpoints are target vessel revascularization at one year, cranial nerve palsy and complications at the site of vascular access.	At one year, stented patients were less likely to have a cranial nerve palsy and to have target vessel revascularization (p= 0.004).
Featherstone et al (CAVATAS-2) 2004, UK	1500 symptomatic patients (>40yrs) who are suitable for both stenting and surgery to be randomised to either stenting or surgery. A distal protection device will be used in the stent group whenever it can be safely deployed. > 600 patients recruited so far.	Multi-center PRCT	The primary outcome is the difference in long term rate of fatal or disabling stroke in any territory.	Ongoing	Patients will be followed up annually for five years. Economic measures and quality of life will also be analysed.
			Secondary outcomes include any stroke, myocardial infarction or death within 30 days of treatment, treatment-related cranial nerve palsy or haematoma.	Ongoing
Hobson et al, 2004, USA	2500 symptomatic patients (¡Ý 50% ipsilateral carotid artery stenosis) or asymptomatic patients with ¡Ý 60% carotid artery stenosis to be randomised to either stenting (with a distal protection device) or surgery.	Multi-center PRCT	Patients will be followed up at 1, 6 and 12 months and then every 6 months for four years.	Ongoing	Recruitment began in December 2000 and currently 1175 lead-In participants and 454 randomised patients enrolled.
Ringleb et al, 2004, Germany	1200 patients (> 50 yrs) with symptomatic carotid –artery stenosis (TIA or stroke within the last 180 days) to be randomised to either carotid-artery stenting or surgery. The use of a distal protection device in the stent group is not mandatory and is left to the discretion of the interventionalist.	Multi-center PRCT	Primary endpoint any death or peri-procedure stroke at 30 days.	Ongoing	Started patient recruitment in 2002 and have included 970 patients to date (April 2005). Expected to present results at ESC meeting in Brussels (May 2006) - Personal communication.
			Secondary endpoint to include ipsilateral stroke and re-stenosis at 24 months follow up	Ongoing
Mas et al, 2004, France	1000 patients to be randomised to receive either CEA or CAS. So far, 452 patients recruited (April 2005-personal communication)	Multi-center PRCT	The primary aim is to evaluate whether CAS (with or without cerebral protection) is equivalent to CEA with regards to 30 day risk of stroke or death and the long term risk of ipsilateral stroke .		After preliminary analysis of first 80 patients, the safety committee recommended to stop unprotected CAS as 4/15 (26.7%) without distal protection suffered a stroke compared to 5/58 (8.6%) without.

Comment(s)

Brown et al. performed a comprehensive meta-analysis in 2003 comparing the peri-procedure death and stroke rates after either CAS or CEA. Using strict entry criteria, they selected five RCTs (1157 patients), of which two were completed (608 patients) [CAVATAS, Brooks] and three were stopped prematurely (549 patients) [Naylor, Wallstent, Yadav 2004]. They found no significant differences between the odds of death, any stroke or disabling stroke at either 30 days or one year post-procedure. However, due to significant heterogeneity within the data analysed, the authors were unable to suggest any changes to current clinical practice (Coward). The WALLSTENT trial [Wallstent, Alberts] was abandoned by the commercial sponsors and has only been published in abstract form. Preliminary analysis revealed a significantly higher 30-days peri-procedure complication rate (any death or stroke) for the CAS group compared to the CEA group. The weaknesses of the WALLSTENT study were that distal cerebral protection devices were not used in the CAS group, peri-procedure anti-platelet therapy was rudimentary (only aspirin was used) and the level of expertise of their interventionalist was not comparable to those performing the surgical endarterectomy. Furthermore, the stent used was not a dedicated carotid artery stent. It has subsequently been shown that the use of a dedicated carotid-stent system significantly reduces the adverse event rate when compared with stents adopted from the peripheral or coronary platforms (McKevitt). The Leicester trial (Naylor) was stopped by the data monitoring committee at the first interim analysis because 5/7 patients in the CAS arm of the study suffered a stroke compared to 0/10 for the CEA group. This study has several weaknesses: distal cerebral protection devices were not used, there was no prior imaging of the origin of the major head/neck vessels to exclude disease that would ordinarily constitute a contraindication to an endovascular approach, only a single anti-platelet agent was used (major endovascular units were already advocating a dual anti-platelet regime Yadav, 1996), the interventionalist had limited experience whilst the surgeons had considerable expertise, a non-dedicated wallstent was used and finally pre-dilation was not routine. Pre-dilation is essential because it is not possible to pass a 7 French device (2.3 mm) through a 70% carotid artery stenosis (best residual channel of 1.8 mm) without some uncontrolled plaque disruption. Pre-dilation is used to help with passage of the unexpanded stent and is not to be confused with angioplasty of the stenosed vessel. The numbers are small but this trial does highlight the problems associated with treating a relatively unselected population. The CAVATAS trial recruited patients from March 1992 to July 1997 and long-term follow up (more than five years) is ongoing. In 1994 carotid stents became available so the CAS group can be subdivided into two groups: a pre-1994 group which only had angioplasty (74%) and a post-1994 group that had angioplasty plus stenting at the discretion of the interventionalist. Because there was no mention of distal protection devices and the majority of the patients were not stented, the data available from this study are based on out-dated techniques and not relevant to best current clinical practice. The Kentucky trial (Brooks) recruited symptomatic patients with an ipsilateral stenosis of greater than 70% to either CAS (without distal cerebral protection) or CEA. At the 24-month follow up, there were no post-operative disabling strokes in this study. Follow-up was carried out within 24 h of the procedure and up until 24 months, using carotid duplex, but did not reveal any differences between the two groups with regards to carotid artery patency or recurrence of symptoms. The SAPPHIRE trial (Yadav, 1996) demonstrated that CAS (with a distal protection device) was not inferior to CEA with regards to the primary endpoint and in addition found that the CAS group had a significantly lower incidence of cranial nerve palsy and a reduced hospital stay compared to those in the CEA group. However, this trial has been criticised for being prematurely stopped as there was increasing reluctance amongst clinicians to recommend CEA and for the high adverse event rate in asymptomatic patients in both limbs of the trial relative to the AHA recommendations (Moore). There are four ongoing multi-centre trials comparing CEA with CAS: the International Carotid Stenting Study (ICSS) also known as CAVATAS-2, Carotid Revascularization Endarterectomy vs. Stenting Trial (CREST), Stent-protected Percutaneous Angioplasty of the Carotid vs. Endarterectomy (SPACE) and Endarterectomy vs. Angioplasty in patients with Severe Symptomatic Stenosis (EVA-3S). The results of the European trials (SPACE, ICSS and EVA-3S) will be pooled.

Clinical Bottom Line

The risk of peri-procedure stroke or death was similar for patients treated with carotid artery angioplasty±stenting and those treated with surgery. However, CAS did reduce the risk of minor complications at the site of vascular access, the incidence of cranial nerve injury and may reduce economic costs due to shorter hospital stays and earlier return to work. Long term follow-up of these patients is, however, lacking. There are currently four large multi-centre RCTs in progress and their results will determine whether CAS will surpass CEA as the gold standard.

References

1. Anonymous. Endovascular vs. surgical treatment in patients with carotid stenosis in the carotid and vertebral artery transluminal angioplasty study (CAVATAS): a randomised trial. Lancet 2001;357:1729–1737.
2. Brooks WH, McClure RR, Jones MR, Coleman TC, Breathitt L. Carotid angioplasty and stenting versus carotid endarterectomy: randomized trial in a community hospital. J Am Coll Cardiol 2001;38:1589–1595.
3. Naylor AR, Bolia A, Abbott RJ, Pye IF, Smith J, Lennard N, Lloyd AJ, London NJ, Bell PR. Randomized study of carotid angioplasty and stenting versus carotid endarterectomy: a stopped trial. J Vasc Surg 1998;28:326–334.
4. The Wallstent Study. Personal communication, 2001.
5. Yadav JS, Wholey MH, Kuntz RE et al. Protected carotid-artery stenting versus endarterectomy in high-risk patients. N Engl J Med 2004;351:1493–1501.
6. Coward LJ, Featherstone RL, Brown MM. Percutaneous transluminal angioplasty and stenting for carotid artery stenosis. The Cochrane Database of Systematic Reviews 2004, Issue 2. Art. No.: CD000515. DOI: 10.1002/14651858.CD000515.pub2.
7. Alberts MJ. Results of a multicentre prospective randomised trial of carotid artery stenting versus carotid endarterectomy. Stroke 2001;32:325.
8. McKevitt FM, Macdonald S, Venables GS, Cleveland TJ, Gaines PA Complications following carotid angioplasty and carotid stenting in patients with symptomatic carotid artery disease. Cerebrovasc Dis 2004;17:28–34.
9. Yadav JS, Roubin GS, King P, Iyer S, Vitek J. Angioplasty and stenting for restenosis after carotid endarterectomy. Initial experience. Stroke 1996;27:2075–2079.
10. Moore WS, Barnett HJ, Beebe HG et al. Guidelines for carotid endarterectomy. A multidisciplinary consensus statement from the Ad Hoc Committee, American Heart Association. Circulation 1995;91:566–579.
11. Featherstone RL, Brown MM, Coward LJ. International carotid stenting study: protocol for a randomised clinical trial comparing carotid stenting with endarterectomy in symptomatic carotid artery stenosis. Cerebrovasc Dis 2004;18:69–74.
12. Hobson 2nd RW, Howard VJ, Roubin GS et al. Carotid artery stenting is associated with increased complications in octogenarians: 30-day stroke and death rates in the CREST lead-in phase. J Vasc Surg 2004;40:1106¨C1111.
13. Ringleb PA, Kunze A, Allenberg JR et al. The Stent-Supported Percutaneous Angioplasty of the Carotid Artery vs. Endarterectomy Trial. Cerebrovasc Dis 2004;18:66–68.
14. Mas JL, Chatellier G, Beyssen B. EVA-3S Investigators. Carotid angioplasty and stenting with and without cerebral protection: clinical alert from the Endarterectomy vs. Angioplasty in Patients With Symptomatic Severe Carotid Stenosis (EVA-3S) trial. Stroke 2004;35:e18–20.