May 28, 2009 (Stockholm, Sweden) — Safety data from the International Carotid Stenting Study (ICSS), comparing carotid endarterectomy with stenting in patients with recently symptomatic carotid stenosis eligible for either procedure, shows superior results with surgery, at least at 30 days' postprocedure.
"We have provided in this randomized trial strong evidence that carotid endarterectomy is safer than carotid artery stenting in the primary intention-to-treat (ITT) analysis and also in the per-protocol analysis, where there were twice as many strokes associated with stenting as with carotid endarterectomy," principal investigator Martin M. Brown, MD, from University College London, Institute of Neurology, in the United Kingdom, reported on behalf of ICSS investigators.
The difference in strokes was driven largely by nondisabling strokes associated with stenting, a finding that may have been balanced to some degree, Dr. Brown noted, by a much higher frequency of cranial nerve palsy seen with endarterectomy.
Still, he concluded, "Carotid endarterectomy is the treatment of choice for suitable patients with recently symptomatic carotid artery stenosis."
Their findings were presented here at the XVIII European Stroke Conference.
The new results bring to 3 the number of large trials that have assessed the use of carotid stenting as an alternative to endarterectomy to treat symptomatic carotid artery stenosis. In the first, called the Stent-Supported Percutaneous Angioplasty of the Carotid Artery vs Endarterectomy (SPACE) trial, carotid stenting failed to meet criteria for noninferiority vs endarterectomy and in fact showed slightly higher rates of ipsilateral ischemic stroke and death at 30 days (SPACE Collaborative Group. Lancet 2006;368:1239-1247).
Results of the Endarterectomy vs Angioplasty in Patients with Symptomatic Severe Carotid Stenosis (EVA-3S) were published within 2 weeks of the SPACE trial and again failed to show noninferiority with carotid stenting vs endarterectomy. Stroke and death rates were again lower with surgery (Mas JL et al. N Engl J Med 2006;355:1660-1671).
Longer-term follow-up of both of these trials, however, presented at last year's European Stroke Conference, showed rates of ipsilateral stroke were low and similar between carotid stenting and endarterectomy groups at 2 and 4 years of follow-up.
The ICSS trial is a randomized double-blind study comparing stenting with endarterectomy in patients with symptomatic carotid stenosis of greater than 50% within 6 months prior to randomization. At total of 1710 patients were included in the intention-to-treat analysis, 853 randomized to stenting and 857 to surgery.
The primary aim of the ICSS trial is to determine long-term survival free of disabling stroke. Sufficient follow-up for this end point is expected to be complete in 2011, Dr. Brown noted. At the meeting here, he presented primary safety data on the 30-day rate of stroke, myocardial infarction (MI), or death, measured up to 120 days after randomization.
Patients were enrolled from 50 centers in 15 countries in Europe, Canada, Australia, and New Zealand. Participating investigators were classified as experienced based on numbers of cases performed but could also enroll as supervised centers where procedures were done under the supervision of an experienced proctor.
Stenting was done using a range of stent and protection devices recommended by the trial steering committee. Use of protection devices was also recommended, but their use was at the discretion of the interventionalist, Dr. Brown noted. Surgeons used their preferred technique under local or general anesthetic.
"As you can see, those allocated to carotid artery stenting had more events than those allocated to carotid endarterectomy," he told delegates here. "This difference of 3.4% in the risk of the 2 procedures was highly statistically significant in favor of endarterectomy."
The per-protocol analysis was "almost identical," he added.
Table 1. ICSS: Primary Safety End Point
|End Point||CAS, n (%)||CEA, n (%)||Hazard Ratio (95% CI)||% Difference (SD)||P|
|Stroke, MI, or death (ITT)||72 (8.5)||43 (5.1)||1.73 (1.18 – 2.52)||3.4||.004|
|Stroke, MI, or death (per protocol)||61 (7.4)||33 (4.0)||1.83 (1.21 – 2.77)||3.4||.003|
CEA = carotid endarterectomy
ITT = intention to treat
The majority of these events were strokes, with nearly twice as many strokes in the stenting group than in the endarterectomy group, he noted. There was little effect of treatment modality on periprocedural MI.
Table 2. ICSS: End Points by Treatment Allocation
|Nonstroke, non-MI deaths||7||5|
CEA = carotid endarterectomy
However, the excess of strokes was driven largely by an increase in the risk for nondisabling strokes with stenting, he noted. Disabling strokes were nearly identical between the groups, but there was a small excess of fatal strokes with stenting.
Table 3. ICSS: Stroke Severity by Treatment Allocation
CEA = carotid endarterectomy
Almost all of these strokes were ipsilateral, on the side of treatment, and the majority were ischemic, with very small numbers of hemorrhagic strokes, he noted.
In terms of access complications, as expected, there was a large excess in cranial nerve palsy with endarterectomy, with 44 cases vs 1 in the stenting group, a patient who had also crossed over to endarterectomy. Only 1 case in each was disabling at 30 days. Severe hematoma or any hematoma was also more common in those randomized to surgery.
There were few differences in outcome by subgroup, although there was a trend to better outcome with stenting in younger patients and a trend to similar outcomes with stenting and surgery in female patients.
"Interestingly enough, there was no statistical differences in the results in supervised vs experienced centers, and in fact, supervised centers had a slightly lower difference between stenting and surgery than experienced centers," Dr. Brown noted.
New Ischemic Lesions
Finally, Dr. Brown also presented a magnetic-resonance-imaging (MRI) substudy that was carried out at 5 ICSS centers, performed and analyzed by Leo Bonati, MD, from University Hospital Basel, in Switzerland.
In a subgroup of patients, MRIs with vascular sequences were carried out before the procedure, and then an early scan (between 1 and 3 days' postprocedure) and a late scan (3 to 6 weeks' postprocedure) were done.
Scans were analyzed blind to treatment, he emphasized, "and I think this is the most important aspect of the study." Outcomes of interest were abnormalities on the early diffusion-weighted imaging, suggesting acute ischemia, or secondary outcomes on the late scan fluid-attenuated inversion-recovery (FLAIR) imaging, suggesting permanent damage to the brain, he noted.
New ischemias were found in about half of stenting patients, vs about 15% of endarterectomy patients, "again a highly significant difference in favor of endarterectomy," he said. The majority of these were asymptomatic events.
Table 4. CSS MRI Substudy: New Ischemic Lesions by Treatment
|End Point||CAS, n (%)||CEA, n (%)||Hazard Ratio (95% CI)||P|
|New ischemic lesions||50 (46.3)||13 (14.1)||5.24 (2.61 – 10.53)||< .001|
CEA = carotid endarterectomy
On follow-up imaging 4 to 6 weeks later, FLAIR was abnormal at the site of early ischemia in 30% of patients after stenting vs 8% of patients after carotid endarterectomy, he concluded, "again a highly significant odds ratio of 5 in favor of endarterectomy."
Does Distal Protection Protect?
After the presentation, Werner Hacke, MD, from the University of Heidelberg, in Germany, comoderator of the session and principal investigator for the SPACE trial, asked whether the ICSS investigators had analyzed outcomes for stenting on the basis of whether or not distal protection was used.
"If we look at the 3 trials, the trial with the lowest rate of protection devices (SPACE) had the best result for the stenters, so there may be an influence of that," Dr. Hacke said. "I think this is a very important question to be answered, whether protection really protects."
Dr. Brown noted that in the ICSS trial, about 80% of patients allocated to stenting had distal-protection devices used but said that analysis of outcomes with and without protection is not yet completed. "It's quite a complicated question; because it's not a randomized comparison between stent and surgery, we really need to correct the data for baseline data, we need to tidy it up a bit, and this is probably better answered by a repooled analysis of the 3 European trials," he said.
Still, he pointed out that in the MRI substudy, patients treated with stenting without protection had a significantly lower incidence of silent ischemic lesions on imaging than those treated using protection.
Higher Risk, Lower Benefit
Ralph Sacco, MD, from the Miller School of Medicine at the University of Miami, in Florida, and president-elect of the American Heart Association (AHA), comoderated the session with Dr. Hacke. Asked for his thoughts on the ICSS findings, Dr. Sacco called the results "interesting news."
"This is now the third big trial that has not shown convincing results of the superiority of angioplasty and stenting over endarterectomy," he told Medscape Neurology & Neurosurgery. "I think the issue is again, how safely can you do angioplasty and stenting?"
In ICSS, the 30-day risk for stroke, death, or periprocedural MI with angioplasty and stenting was 8.5%, he points out. "In our guidelines at AHA, we state that we have to do either of these procedures with a less than 6% risk to show benefit. They are above 6%, and it's worth noting that for endarterectomy in this trial, it's less than 6% — 5.1%."
When you can't do it as safely, it's pretty clear that you don't have similarity; you have a lack of efficacy of angioplasty and stenting vs the tried-and-true endarterectomy.
"When you can do things very safely, with less than a certain percent risk, we may have better evidence of similarity," he added. "But when you can't do it as safely, it's pretty clear that you don't have similarity; you have a lack of efficacy of angioplasty and stenting vs the tried-and-true endarterectomy."
Dr. Sacco also thought the question of the real effect of distal protection may be an open one. "We think that distal protection is supposed to reduce the risk of stroke, and it's interesting that the SPACE trial used a lot less distal protection," he pointed out. "I think probably a more rigorous meta-analysis could be done to evaluate distal protection vs no protection and whether it improves or worsens the risk."
More information on this question may also be provided by results of the ongoing CREST trial of about 2500 patients randomized to endarterectomy vs stenting. "I believe that distal protection is used more frequently than not in that trial, and those results should be out, I think, probably by early 2010 or late 2009, so that will be a big trial to see."
The trial was supported by the Stroke Association (UK), Sanofi-Synthelabo, and the European Union.
XVIII European Stroke Conference. Large Clinical-Trials Session Abstract 3. Presented May 27, 2009.
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Cite this: ESC 2009: ICSS: Carotid Endarterectomy Superior to Stenting, at Least in the Short Term - Medscape - May 28, 2009.