Longer follow-up from 2 randomized trials comparing carotid stenting
(CAS) with carotid endarterectomy (CEA) for stroke prevention have
shown rates of ipsilateral stroke are low, at about 1% or less, and
similar between these modalities at 2- and 4-year follow-up.

This, despite the fact that in the primary analyses from the Stent-
Protected Percutaneous Angioplasty of the Carotid Artery vs
Endarterectomy (SPACE) and Endarterectomy Versus Angioplasty in
Patients with Symptomatic Severe Carotid Stenosis (EVA-3S) trials,
CAS had failed to meet criteria for noninferiority in comparison with
CEA.

The results were published online September 5 in Lancet Neurology.
They were presented earlier this year at the European Stroke
Conference in Nice, France, and reported by Medscape Neurology &
Neurosurgery at that time.

"The conclusion from the SPACE trial is exactly the same as the EVA-
3S study; that is, if a patient has been treated successfully without
any complications, the [long-term] risk of a secondary stroke is very
small and very comparable between these 2 modalities," SPACE
investigator Peter A. Ringleb, MD, from Ruprecht-Karls-University, in
Heidelberg, Germany, said at the time these results were presented in
Nice.

SPACE Trial

The SPACE trial was a multinational, prospective randomized study
that aimed to test the hypothesis that CAS was not inferior to
endarterectomy for the treatment of patients with severe symptomatic
carotid stenosis of greater than 70%.

Thirty-day results from this trial did not prove noninferiority of
CAS compared with CEA. The current paper looks at results at 2 years.

A total of 1214 patients were randomized to carotid angioplasty with
stenting (n = 613) or CEA (n = 601). The authors report that in both
intention-to-treat (ITT) and per-protocol analyses, Kaplan-Meier
estimates of ipsilateral ischemic stroke up to 2 years after the
procedure and any periprocedural stroke or death were similar between
the groups.

Restenosis of 70% or greater was significantly more common in the
stenting group, again in both ITT and per-protocol analyses. However,
only 2 cases of restenosis were associated with neurological
symptoms, they note. Although the incidence of restenosis was higher,
they add, "it cannot be excluded that the degree of in-stent stenosis
is slightly overestimated by conventional ultrasound criteria."

"Patients who were successfully treated with stent-protected
angioplasty had a similar low risk of secondary cerebrovascular
events as patients who were treated with endarterectomy, indicative
of the similar preventive ability of endarterectomy and carotid
angioplasty with stenting," the authors conclude.

"To assess the long-term effects, and particularly the effect of
restenosis, most investigators agreed to collect follow-up data for
up to 5 years after the initial study protocol had ended," they add.

EVA-3S: Periprocedural Risk

The EVA-3S trial was also a randomized noninferiority trial comparing
CAS with endarterectomy in 527 patients with carotid stenosis of 60%
or more that had recently become symptomatic. The trial was actually
stopped early due to a higher risk of any stroke or death within 30
days of the procedure, and the main results published within a week
of those of the SPACE trial in 2006.

In this paper, the EVA-3S investigators, with lead author Jean-Louis
Mas, MD, from the Hôpital Sainte-Anne, in Paris, France, report on
follow-up of these patients out to 4 years. They report that the
cumulative probability of periprocedural stroke or death and
nonprocedural ipsilateral stroke was still higher among those in the
stenting group vs endarterectomy.

The risk for periprocedural disabling stroke or death and
nonprocedural fatal or disabling ipsilateral stroke was higher in the
stenting group at 4 years (HR, 2.00 [95% CI, 0.75 – 5.33]; P = .017).

However, a hazard function analysis showed that the differences in
cumulative outcomes between stenting and endarterectomy were largely
accounted for by events that occurred within 30 days of the original
procedure, the authors note. "After the periprocedural period, the
risk of ipsilateral stroke was low and similar in both treatment
groups."

"The safety of carotid stenting needs to be improved before it can
become a widespread alternative to carotid endarterectomy in patients
with symptomatic carotid stenosis," the authors conclude.

Acrimonious History

In a Reflection and Reaction commentary accompanying the papers, A.
Ross Naylor, MD, from the department of vascular surgery at the
Leicester Royal Infirmary, in the United Kingdom, prefaces his
remarks with a brief history of why the debate over CAS vs
endarterectomy continues to polarize opinion.

The 4 largest trials to date comparing these modalities are CAVATAS,
SAPPHIRE, SPACE, and EVA-3S, he notes, the only ones thought large
enough to influence contemporary practice. CAVATAS results
received "widespread censure" for a 10% periprocedural rate that
essentially negated any benefit from stenting, although 3-year
results were similar between modalities. The trial was "criticized by
virtually everyone who had a vested interest," he writes.

Results of the SAPPHIRE trial showed significant benefit for stenting
over endarterectomy, although only if non-Q-wave myocardial
infarction was included in the composite 30-day end point. Although
most of the SAPPHIRE patients had asymptomatic carotid stenosis, the
Food and Drug Administration granted approval for the sponsor's stent
for symptomatic patients deemed at high surgical risk. "Thereafter,
it was only a matter of time before the number of high-surgical-risk
CAS registries proliferated as other stent companies sought approval
for their devices, whereas recruitment into randomized trials
declined," Dr. Naylor writes.

This swing toward stenting faltered, he notes, with the primary
results from the SPACE and EVA-3S studies. "In light of the preceding
acrimonious history and high stakes, it was inevitable that attitudes
to the EVA-3S and SPACE trial data would be polarized by professional
or corporate allegiances, selective interpretation of the data, and
at times, uncritical vilification," he writes. In 2007, authors of
the Cochrane Review concluded that "the evidence did not support a
change in clinical practice away from recommending endarterectomy as
the treatment of choice for suitable carotid stenosis," he notes.

So what is new with these results from SPACE and EVA-3S? "To this
observer," he writes, "the most important finding . . . is
recognition that the average annual risk of ipsilateral stroke is 1%
or less, irrespective of whether the patients was treated by CEA or
CAS," he writes. The results corroborate those of both CAVATAS and
SAPPHIRE. "Therefore the next Cochrane Review is likely to conclude
that after successful angioplasty, CAS is as durable as CEA."

Still, better criteria for the selection of patients for either
stenting or endarterectomy are needed. Dr. Naylor feels the results
of these trials warrant a "clarion call for greater intertrial
collaboration," specifically a pooling of results from 4 large trials
to carry out a meta-analysis of the data from individual patients,
including SPACE, EVA-3S, and the ongoing International Carotid
Stenting Study (ICSS) and Carotid Revascularization Endarterectomy
Versus Stenting Trial (CREST), similar to what was done with the data
from the large CEA trials. The resulting large database would provide
more information on periprocedural risks associated with both of
these procedures, he suggests.

"EVA-3S was absolutely hammered by the critics for a much higher
angioplasty complication rate, and they blamed it on the
inexperienced interventionalists," Dr. Naylor told Medscape Neurology
& Neurosurgery. "But what nobody has highlighted is that 45% of the
angioplasty patients in EVA-3S were treated within 4 weeks of their
index event. Now, no other randomized trial has ever come close to
that, and so an alternative interpretation of EVA-3S is perhaps
because they treated people so quickly they were getting more
complications with angioplasty."

Treatment early after the onset of index symptoms is important in
preventing a second event, he noted. Combining these trials would
provide individual patient data on almost 6000 patients randomized to
either stenting or endarterectomy. "Then we could look and see
whether early treatment is more unsafe with angioplasty, and
therefore surgery would be better, say in the first 2 weeks, and
perhaps angioplasty increasingly thereafter."

Both CREST and ICSS were due to finish recruitment this summer and
are expected to be reported sometime in the spring of 2009, he said.

The EVA-3S study was funded by the French Ministry of Health. The
SPACE trial was supported by the Federal Ministry of Education and
Research, the German Research Foundation, the German Society of
Neurology, German Society of Neuroradiology, the German Radiological
Society, Boston Scientific, Guidant, and Sanofi-Aventis. Drs. Mas,
Eckstein, and Naylor report no conflicts of interest. Dr. Ringleb
reports he has received speaker's fees from Sanofi-Aventis.
Disclosures for other coauthors appear in the papers.

Lancet Neurol. 2008; Published online September 5, 2008. Abstract
Abstract Abstract