Critical remarks regarding carotid angioplasty and surgery for asymptomatic carotid artery stenosis

Jesper Swedenborg

Karolinska University Hospital, Stockholm Sweden

Abstract

Angioplasty of carotid stenosis has gained wide popularity in recent years. The goal of the treatment has been to minimize surgical trauma and postoperative stroke and death compared to carotid endarterectomy. Today the accepted method for carotid angioplasty includes stenting and use of protection devices. In order for carotid artery angioplasty to be ethically acceptable it should achieve equal or better short and long-term results compared to endarterectomy. Today the evidence base for this is lacking and in order to prove the efficacy of carotid angioplasty, randomised trials with long-term follow-up are needed. Such trials are under way. The benefit of surgery for asymptomatic carotid stenosis has been shown in large randomised trials. The overall benefit, however, is considerably smaller than for surgery of symptomatic carotid stenosis and the value of the procedure for women can be questioned. The publication of the 10-year results of one of the largest studies, the asymptomatic carotid surgery trial, will cast further light on the value of surgery for asymptomatic carotid stenosis.

1. Carotid angioplasty

Percutaneous transluminal angioplasty of carotid stenosis was introduced already during the eighties. Since then more than 5,000 procedures have been published (1) and it is likely that many more unpublished procedures have been performed. PTA alone was soon abandoned and the addition of stenting of the carotid artery was recommended during the nineties (2) . Later the use of protection devices was introduced in order to decrease the risk of cerebral embolisation during angioplasty. These devices have been shown to collect embolic debris but some difficulties are found during  introduction, deployment. and retrieving of the device (3) . The possibility of vessel injury caused by the device has also been discussed. In 2004 one trial abandoned the use of CAS without a protection device since the safety and monitoring committee found results without protection devices to be associated with an increased risk of cerebral embolisation (4) .

The 30-day stroke and death rates varies between 2 and 9% (mean 4.7%) in published series of carotid angioplasty (1) . For symptomatic patients this compares with 7.5% in the European Carotid Surgery Trial (ECST) (5) and 5.5% in the North American Surgical Carotid Endarterectomy Trial (NASCET) (6) . In trials studying asymptomatic carotid stenosis the event rates have been lower, 2,3% in the Asymptomatic Carotid Atherosclerosis Study (ACAS) (7) and 2.8% in the Asymptomatic Carotid Surgery trial (ACST) (8) . The comparison between published series of carotid angioplasty and the randomised trials of CEA for symptomatic and asymptomatic carotid stenosis is, however, impossible to make since almost all series reporting angioplasty include both asymptomatic and symptomatic cases usually with a  majority of asymptomatic patients. It is known that CEA in asymptomatic patients is associated with a lower risk for adverse events compared to those with symptomatic carotid stenosis (9) . In order to find out whether carotid angioplasty is superior or equal to CEA separate randomised trials for symptomatic and asymptomatic patients have to be performed. Such trials are underway  for symptomatic patients and their results have to be evaluated  before firm conclusions can be drawn (4,10-12).

Results from some trials have been published, but it should be noted that two trials have been stopped because of a high rate of periprocedural stroke in the group undergoing carotid angioplasty (13,14) . The Cavatas study was a multicenter trial including 90% symptomatic patients but stents were used in only 20% of the patients. No protection device was used. The stroke and death rate was high but not significantly different in the angioplasty group comparing to the CEA group (10%) (15) . A small trial performed in Kentucky including 104 symptomatic patients, using stents in all cases, could not record any difference in periprocedural stroke or death rate between CAS and CEA. This study did not use protection devices (16) . The Sapphire Trial is the only one so far using stent and protection device in all patients randomised to CAS but only 30% of the patients were symptomatic (17) . The trial included patients that were considered at high risk for open surgery, mostly due to severe concomitant coronary artery disease. The primary endpoint was stroke or death or myocardial infarction, the latter included both Q-wave and non-Q-wave infarctions. There was no difference in the traditional endpoint, stroke or death within 30 days, but the combined primary endpoint used in the study including death, stroke, and myocardial infarction at 30 days plus ipsilateral stroke or death from neurologic causes within 30 days to 1 year was significantly lower in the group receiving CAS. It is difficult to draw any firm conclusions from this study since it contains patients who are at high risk for myocardial infarction and the studied endpoints are not the conventional ones, which makes comparison with other studies almost impossible. The fact that the majority of the cases in this study had asymptomatic carotid stenosis further adds to the difficulty.

Another way to evaluate the effectiveness of carotid angioplasty compared to CEA is the study of registry reports. The global carotid stenting registry reported an overall stroke and death rate of 4.5% in more than 8,000 procedures (18) . Registries of this type can be criticised because the patient material is sometimes selected and tends to avoid patients with an unfavourable outcome. Many of these disadvantages can, however, be overcome by national registries. The Swedish Vascular Surgery Registry reported no procedure related stroke or death after surgery for asymptomatic carotid stenosis during the study period 1999-2003. During the same period the overall stroke and death rate decreased from 3% 1999 to 1.5% 2003 (19) . This registry has been validated against the National Hospital Registry, which records all surgical procedures in Sweden.

Carotid interventions are associated with low but recordable degree of restenosis which in most cases is asymptomatic. Available data, however, indicate that the risk of restenosis is higher after CAS than CEA. In the Cavatas study restenosis in the angioplasty group was 40% versus 4% in the CEA group (p<0.001) during a follow-up period of one year (15) . In a non-randomised prospective study the corresponding difference was 7.5% versus 1.4% (p<0.001) during a follow-up of 15 months, defining restenosis as >50% (20) . It could therefore be suspected that the durability of CAS may be negatively influenced by a higher risk of restenosis.

It is often stated that one advantage with carotid angioplasty is that it avoids the risk for cranial nerve injury. The most common injuries after CEA affect the hypoglossal nerve, the vagus nerve and the mandibular branch of the facial nerve. In patients with lesions that extend high occasional injuries of the glossopharyngeal nerve have been reported. Almost all injuries, however, are minor and transient. The Sapphire trail reported 4,9% after CEA but none after CAS. In the NASCET trial such injuries were documented in 8,6% but no patient suffered a major nerve injury and almost all had a full recovery after 30 days. In the ECST 0,5 % were reported as permanent injuries but the closer nature of the injuries in this trial are not reported (21) .

In conclusion the valid comparison is between CAS with protection devices and CEA. A recent Cochrane report concludes that “Available data in this respect are insufficient to support a change from routine clinical practice in patients, for which carotid endarterectomy is the current standard treatment” (1) . In order for a new treatment to be ethically acceptable a benefit has to be expected from the new treatment. This benefit is not clearly proven by available data from published trials. Furthermore available data regarding CAS with and without stenting is exclusively derived from highly specialised centres, mostly single centre reports. This is in contrast to the randomised trials on CEA which have broader recruitment base. A trial supported by independent organisations would have a greater impact than trials supported by industry.

2. Surgery for asymptomatic carotid stenosis

The results of surgery for asymptomatic carotid stenosis is largely based on two trials, the ACAS published in 1995 (7) and the recently published study ASCT (8) . Some previously published trials were also included in a Cochrane analysis, which was made before the publication of ACST (22) . This report leads the reviewers to conclude that “there is some evidence favouring CEA for asymptomatic carotid stenosis, but the effect is at best barely significant and extremely small in terms of absolute risk reduction”. The ACST is by far the largest trial and mainly confirms the results from the ACAS study, but due to its larger volume ACST reaches more statistically significant results. ACST, however, is reluctant to calculate numbers necessary to treat (NNT), but from the data it is obvious that the NNT for any stroke is approximately 16 and for disabling stroke 40, mimicking the results of ACAS. The absolute risk reduction for any type of stroke or perioperative death is 5.35% in favour of surgery. The curves for the two treatment groups cross at approximately 2 years and in order for the patients to benefit from the procedure their expected survival has to be at least four years.

The ACST trial failed to demonstrate an influence of the degree of stenosis for the benefit of surgery, which is in contrast to previous trials for symptomatic carotid stenosis. This may be a true conclusion, but could also be influenced by the fact that ACST used Duplex evaluation for the degree of stenosis. In previous trials evaluating symptomatic carotid stenosis angiographic measurement were used. Inclusion to ACST was started already 1993 and ended 2003. At least during the early time of this period it could be suspected that the accuracy of stenosis measurements were less than perfect and therefore the conclusion that the degree of stenosis is not related to the benefit of the procedure is uncertain and can not be completely accepted. A later study has highlighted the influence of the Doppler angle for accurate estimation of the true degree of stenosis using duplex (23) .  This may not have been common knowledge in the earlier part of the study.

A further critical question regarding ACST is that drug therapy changed over time regarding lipid lowering drugs. This possibly influenced both groups but could definitely alter the outcome of the control group causing the benefit in the later part of the series to be less. The most important issue, however, regarding ACST is whether women benefit from surgery. From symptomatic studies we know that women carry a higher risk in connection with surgery and also have a low risk of stroke without surgery, which means that women have a less overall benefit from CEA (9) . In the ACST study the difference between men and women is only presented based on non-perioperative strokes. It is not stated whether women actually benefit from the procedure when perioperative strokes are included and no mention of the specific perioperative stroke rate in women is reported. These figures may, however, be uncertain due to the low number of women included in the study. The overall stroke rate was 2.8%. Although the ACST as well as ACAS conclude that surgery for asymptomatic carotid stenosis reduces the risk of stroke the conclusion that it does so for women can not be drawn from either study.

The ACST will continue to record the outcome and will eventually publish 10-year results, which possibly will change the conclusion, but at the present moment it can be concluded that surgery for asymptomatic carotid stenosis has a small but significant benefit regarding stroke prevention. This benefit, however, is not proven for women. It is also possible that the results of best medical treatment decrease the benefit of the addition of surgery.

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