Two European carotid trials have failed to demonstrate the non-inferiority of carotid stenting vs. surgery and concluded that carotid stenting comes with a greater procedural risk than surgery. However, at a press conference at the Cardiovascular Research Foundation’s (CRF) eighteenth annual Transcatheter Cardiovascular Therapeutics (TCT) scientific symposium in Washington, DC, several physicians claimed their conclusions were questionable as both trials were stopped early, leaving them with smaller than anticipated number of patients, and therefore underpowered to provide definitive conclusions.
The results from the Endarterectomy versus Angioplasty in Patients with Symptomatic Severe Carotid Stenosis (EVA-3S) were recently published in the New England Journal of Medicine (2006;355:1660-1671), and the Stent-Supported Percutaneous Angioplasty of the Carotid Artery versus Endarterectomy (SPACE) trial results were recently published in The Lancet(2006;368:1239-1247).
As previously reported in Vascular News, the EVA-3S was a multi-centre, randomised, non-inferiority trial comparing carotid stenting with endarterectomy in patients with symptomatic carotid stenosis of at least 60%. An analysis of the results was presented by Professor Alain Branchereau, Paris, France, at the recent European Society for Vascular Surgery (ESVS) in Prague, Czech Republic. The study enrolled 527 patients (265 in the stenting arm; 262 in the surgical arm) at 31 centres. Thirty-day results showed that the risk of stroke or mortality was significantly increased in the stenting group compared with the endarterectomy group (3.9% vs. 9.6%, respectively; P=.01).
In addition, stenting showed a significantly lower risk for cranial nerve injury (10.4% vs. 1.5%), and non-significant trend for less systemic complications (3.1% vs. 1.9%;) but a much higher risk for both major local complications (1.2% vs. 3.1%) and TIA (0.8% vs. 2.3%).
At six months, the incidence of any stroke or death continued to be lower with surgery (6.1% vs. 11.7% after carotid stenting; P=.02). “The absolute risk increase was 5.7%, suggesting that one additional stroke or death resulted when 17 patients underwent stenting rather than endarterectomy,” commented Branchereau.
In September 2005, the Safety Committee recommended to stop inclusions into the trial because of safety concerns. In particular, the Committee said the benefit in favour of the surgical arm means that any further enrolment would be futile.
The SPACE trial was a multi-centre, prospective, randomised trial in Germany, Austria and Switzerland. The study was designed to test the hypothesis that carotid artery stenting and carotid endarterectomy are equivalent in treating patients with symptomatic carotid artery stenosis. The trial was carried out in 37 centres in Germany, Austria, and Switzerland, with neurologists, vascular surgeons, and interventionalists participating from each centre. A quality committee for each discipline enforced qualifications for each of these areas, with ten centres were ultimately not allowed to participate because they failed to reach these standards. Use of cerebral protection devices was at the discretion of the participating centre.
The primary endpoint was ipsilateral stroke or death of any cause from randomisation until 30 days after intervention. Secondary endpoints were ipsilateral stroke within 24 months after randomisation; ipsilateral stroke with permanent handicap (modified Rankin Score >=3) within 30 days after intervention; stroke of any localisation within 30 days and 24 months after intervention; residual stenosis and restenosis >= 70% in ultrasound and procedural failure. Up to January 2006, 1,200 (605 in the stent group; 595 in the surgical group) patients were randomised in 37 centres. The non-inferiority threshold was set at 2.5%.
In analysis of the 30-day results at the recent ESVS, Professor Hans-Henning Eckstein, Munich, Germany, revealed that ipsilateral stroke or death in the stenting arm was 6.8% (41/599) and 6.3% (37/584) in the surgical arm. The absolute difference was 0.51% (-2.4% vs. 3.4%, 95% CI). This exceeded the threshold of 2.5%, subsequently patient recruitment was stopped after recruitment of 1,200 patients as statisticians had calculated that with even 1,900 patients the chance to prove equivalence would have been only 50% rising to 80% if the study recruited 2,500 patients.
Eckstein noted that in most of the endpoints of the SPACE trial there is a trend towards better results in the surgical arm (although in most instances these were not statistically significant). He concluded that the SPACE trial failed to prove equivalence in terms of peri-procedural risk of stenting vs. surgery for the treatment of symptomatic carotid artery stenoses. Besides this Eckstein added that there is no evidence at all for stenting asymptomatic patients.
However, a panel of interventionalists at a press conference at the TCT meeting did not share the views of the EVA-3S and SPACE trial investigators when they assessed the results of both studies. In a critique of the EVA-3S trial,
Dr William Gray, Columbia University, NY, stated that the study’s conclusions were questionable because of the lack of experience of the investigators and the number of trained site/operators in carotid stenting. He added that slow enrolment added to the limited experience of the investigator/s.
In particular Gray was critical of the criteria that defined ‘experienced operator’: “According to the trial, if an operator had performed 12 carotid stenting procedures in a lifetime he was deemed an ‘experienced’ operator.” He also noted that there was no centralised training qualification process, with the ‘experienced’ operators allowed to tutor the non-experienced operators. Moreover, Gray added that the situation was compounded by the fact that approximately two thirds of the trial sites were under tutelage at the beginning of their randomised participation.
Klaus Mathias (Dortmund, Germany) commented that in Germany an experienced operator would normally have performed between 100-300 stenting procedures. Gray added that in the US guidelines published in 2005 stated that before even beginning training in carotid stenting, physicians must already be proficient in using catheters and stents in other parts of the body. To become competent in carotid stenting, the guidelines recommend that physicians perform a minimum of 30 diagnostic angiograms and 25 carotid stenting procedures.
Furthermore, the panel that also included Drs Jay Yadav, L Nelson Hopkins (University of Buffalo, NY), Subbarao Myla (Newport Beach, CA) and Michael R Jaff (Massachusetts General Hospital, Boston), were critical of the EVA-3S trial design claiming that the lack of standardised techniques resulted in unnecessary morbidity. In the study, different stents and cerebral-protection devices were used by the various participating centres. For example, they cited that the use of embolic protection devices (EPD) was not widespread or familiar and estimated that this could have been responsible for some four to five excess strokes (approximately 20% of all strokes in the stenting arm). In addition, Myla added that there was no pre-dilatation in >80% of the procedures, which is the standard in the US, and significant (beyond local) aesthesia was employed in approximately 30% of procedures, compared to an estimated <5% in the US.
Perhaps most interesting was Yadav’s claim that the 5% stent procedure failure requiring emergency surgery in the trial resulted in two strokes in the stenting arm: “In the two stenting trials, ARCHeR and SAPPHIRE, we have not reported any emergent surgical conversions.”
As regards the SPACE trial, the TCT panel said that it was important to note that the trial was stopped due to the lack of continued funding, not futility or safety, and therefore failed to achieve its statistical endpoint of non-inferiority. However, Eckstein told Vascular News that the trial was stopped because the chance to prove equivalence would have been only 50% (with 1,2000 patients enrolled). In contrast to Eckstein, the panel added that the results appear to be comparable between stenting and surgery. According to the panel, one limitation was the use of protection devices at ‘the discretion’ of the participating centre, which they panel said resulted in 73% of patients receiving a stent without an EPD. However, Eckstein again questioned the panels conclusions adding that this was not a limitation, but enabled each centre to perform their usual technique.
“The problem with the TCT panel is that at least no representative of the SPACE study was present, which might have biased the panel’s discussion and conclusion. It should be highlighted that EVA-3S and SPACE are investigator driven, neurologically controlled randomised trials. In my view, it sounds quite strange that the principal investigator of SAPPHIRE (in which the number of randomised patients where only about 50% of EVA-3S and 25% of SPACE) criticises methodological problems with the European studies,” Eckstein concluded.
CREST and ACT I
As for the current trials assessing the surgery vs. stenting debate, the panel hoped the Carotid Revascularization Endarterectomy versus Stent Trial (CREST) and the Carotid Angioplasty and Stenting vs. Endarterectomy in Asymptomatic Patients with Significant Extracranial Carotid Occlusive Disease Trial (ACT I) would provide some much needed answers. CREST is a NIH/NINDS sponsored trial contrasting the relative efficacy of carotid endarterectomy and carotid stenting in preventing primary outcomes of stroke, myocardial infarction, or death during a 30-day periprocedural period, or ipsilateral stroke over the follow-up period extending up to four years. Stroke events will be verified by an Adjudication Committee masked to the assigned treatment. The primary eligibility criterion is a significant (>50%) stenosis of the carotid artery in patients with transient ischemic attack or ipsilateral non-disabling stroke within the prior 180 days.
The trial is aiming to 2,500 patients (1,100 asymptomatic, 1,400 symptomatic) in 123 sites in North America. The investigators are aiming to recruit 12% of patients from minorities and 40% of women. Statistical analysis of the primary outcome will employ standard survival techniques and will result in 90% power to detect annual differences between groups of 1.2% or higher in event rates of the primary outcomes. There are currently 1,400 patients enrolled in this study.
ACT I is a multi-centre, randomised trial comparing carotid stenting to carotid surgery in asymptomatic patients, who normally would be referred for surgery. This randomised trial is designed to establish the non-inferiority of steting to surgery in this patient population. All patients enrolled in the trial will receive appropriate medications and lifestyle modification counselling during the study.
The trial will involve up to 50 hospitals in the US and approximately 1,500 patients, with primary endpoint data submitted after one year of patient follow-up. The trial’s primary endpoints are; 30-day major adverse event (MAE) rates combining stroke, death and myocardial infarction (heart attack); and, ipsilateral strokes (those occurring on the same side as the therapy) between 31 and 365 days. The trial’s secondary endpoints include target lesion revascularization rate, device/procedural success rates, cumulative composite morbidity (nerve damage, wound complications, general anaesthetic complications, etc.), and long-term ipsilateral stroke rates through five years of follow-up.
Discussing the two procedures, Hopkins said that he had been performing surgery for over 30 years and had now performed more carotid stenting procedures than carotid endarterectomies. “I am absolutely convinced that in this moment in time these are very complimentary procedures. If we want to optimise our results we need to look at the anatomy, which is the major contra-indication, the anatomy and the pathology that exists within the carotid artery. If we get someone who we know is not a good candidate for stenting, then that patient is usually ok for surgery.”
In Europe, there is also the Asymptomatic Carotid Surgery Trial-2 (ACST-2) that will randomise appropriate patients with asymptomatic disease to surgery vs. stenting. Patient eligibility will be based in unilateral or bilateral carotid artery stenosis appropriate for surgery or stenting (only one side allowed in trial). In addition, only patients fit for and willing to have surgery or stenting and accessible for follow-up to five-years (mostly by telephone) will be included, where both the doctor and patient are ‘substantially uncertain’ whether the patient should have carotid endarterectomy or carotid stenting.
The primary analysis will be clinical myocardial infarction, stroke and death within 30 days of surgery or stenting and long-term (five-year) survival free of stroke. Secondary analysis will include rates of symptomatic restenosis and cost-effectiveness. Each centre involved in the study should have a neurologist or stroke physician, vascular surgeon or neurosurgeon and interventionalist. The researchers will only use European approved devices, usually with cerebral protection.
Best medical therapy
When questioned whether best medical therapy still had a role to play in carotid stenoses, Gray replied that it is perhaps significant that the Transatlantic Asymptomatic Carotid Intervention Trial (TACIT), organised by the Society of Interventional Radiology (SIR) Foundation and Cardiovascular and Interventional Radiological Society of Europe (CIRSE), had failed in its first application to gain National Institutes of Health funding. He added that as far as he was concerned the case for medical therapy in the management of symptomatic and asymptomatic had already been established in the North American Symptomatic Carotid Endarterectomy Trial and the Asymptomatic Carotid Surgery Trial.
In conclusion, the panel said that further access for patients in the mainstream is predicated on the successful completion of the CREST and ACT I trials. The questions regarding carotid stenting to carotid surgery in asymptomatic and symptomatic normal surgical risk have not been answered by SPACE or EVA-3S.