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Asymptomatic carotid stenosis Surgery's the answer but that's not the question.

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Asymptomatic Carotid Stenosis: Surgery’s the
Answer, but That‘s not the Question
James L. Frey, MD
Two important studies have addressed the value of surgery for stroke prevention in patients with asymptomatic carotid stenosis. The first of these, the Veterans
Affairs trial [I], studied 444 men with stenoses greater
than 50%. The results suggested possible benefit from
surgery, but perioperative stroke and death combined
with the small number of patients in the study precluded statistical support for carotid endarterectomy
for stroke alone as an end point.
The second major trial, the Asymptomatic Carotid
Atherosclerosis Study (ACAS) [2], evaluated 1,662 patients, both men and women, with stenoses of more
than 60%. The recently published results of this trial
indicate that carotid endarterectomy confers a statistically significant, 53% 5-year relative risk reduction for
ipsilateral stroke and any perioperative stroke or death.
Strictly interpreted, these results justify surgery with
important qualifications: (1) Patients must have reasonable 5-year survival to achieve benefit from surgery,
and (2) angiography and surgery must be performed
with less than a 2.3% risk of stroke or death. Although
the answer to the ACAS primary end point question
is statistically clear, the data harbor other important
facts of relevance to clinical decision making.
First, although surgery confers a 53% relative risk
reduction after 5 years, the annual event rate for patients treated medically is only 2.2% (surgery reduces
this risk to 1%). Viewed in this light, a 2.3% risk of
stroke or death from the combination of angiography
and surgery may be less readily acceptable. Furthermore, the level of expertise in the ACAS centers was
high, and angiography and surgery cannot be recommended in any center where the combined risk exceeds
2.3% or where patient survivability is much less than
5 years.
Second, although the primary question of ACAS was
answered in favor of surgery, five of the six remaining
questions were not. Surgery did not reduce the risk of
(1) major ipsilateral stroke or any perioperative major
stroke or death, (2) any stroke or any perioperative
death, (3) any major stroke or perioperative death, (4)
any stroke or death, or (5) any major stroke or death.
Third, although the relative risk reduction with sur-
gery was 66% for men, which was statistically significant, it was 17% for women, which was not statistically
significant. The data suggest that perioperative complications may be at least one reason for the failure of
surgery to benefit women (3.6% for women and 1.7%
for men), but the smaller numbers of women in the
ACAS preclude conclusions about other factors, such
as age, degree of stenosis, and other risk factors.
Fourth, anticlotting therapy for medical management in the ACAS was limited to aspirin, 325 mg
daily. Although this seemed reasonable at the time the
ACAS began, it may not be the best medical management today. Recent data suggest that higher doses of
aspirin may work better [3, 41. Ticlopidine reduces
stroke better than even high-dose aspirin [5]. The combination of warfarin and aspirin is also thought to be
a potentially more effective anticlotting regimen for
stroke prevention [6-91. Although rhese data are not
from studies of primary prevention for asymptomatic
carotid stenosis, they suggest the possibility that other
anticlotting regimens may be more effective than aspirin, 325 mg daily. This diminishes the significance of
the surgical benefit found in the ACAS.
Fifth, the cost-effectiveness of endarterectomy for
asymptomatic carotid stenosis remains to be established.
In the ACAS, approximately 800 endarterectomies prevented 50 strokes. The 90-day cost of stroke has been
estimated at $15,000 [lo]. Excluding the value of economic loss from stroke, which is hard to know, the medical savings from the prevention of 50 strokes would be
$750,000. O n asimple equivalency basis, if800 endarterectomies (and angiograms) were performed for $750,000,
then each pair of procedures would cost less than $1,000.
Because the actual cost of these procedures is many times
higher than this in most centers, the cost-effectiveness of
surgery for asymptomatic carotid stenosis is open to legitimate question.
Even though the ACAS has provided an answer to
the question about surgery for asymptomatic carotid
stenosis, the above-mentioned facts compel us to address one other question: “Who with asymptomatic carotid stenosis is really at risk of stroke?” If an answer
to this question can be found, a more clearly favorable
From the Division of Neurology, Barrow Neurological Institute,
Phoenix, AZ.
Address correspondence to Dr Frey, Division of Neurology, Barrow
Neurological Institute, Suite 415, 222 West Thomas Road, Phoenix, AZ 85013.
Received Aug 1, 1995, and in revised form Oct 5. Accepted for
publication Oct 5, 1995.
Copyright 0 1996 by the American Neurological Association
benefit from surgery may be obtainable relative to risk
and cost.
Although the North American Symptomatic Carotid
Endarterectomy Trial [I 11 and the European Carotid
Surgery Trial [ 121 demonstrated thait ipsilateral stroke
risk correlates with degree of stenosis, ulceration, and
contralateral occlusion in symptomatic patients, the
ACAS data cannot answer these questions, because the
event rates are relatively small in the asymptomatic
group. The European Trial on Asymptomatic Carotid
Stenosis [I31 intends to study this question with attention to plaque morphology, stenosis progression, blood
flow characteristics, and systemic risk factors. Results
of this trial will not likely be available for 5 to 10 years,
and there is no guarantee that it will produce the answer to the question.
Existing data suggest that disease progression and
stroke may be predictable in patients with asymptomatic carotid stenosis. Grotta and colleagues [14] followed 38 patients with asymptomatic carotid stenosis
with serial ultrasound examinations and found that the
8 patients in whom stenosis progressed had higher levels of low-density lipoprotein and fibrinogen and a
higher incidence of coronary artery disease than did
patients whose disease did not progress. Roederer and
associates [ 151 studied 167 patients with asymptomatic
carotid stenosis with serial ultrasound and found that
symptoms developed in 10 patients, 8 of whom had
demonstrable disease progression. Stenosis of more
than 80% or progression to stenosis of more than 80%
correlated with either occlusion or symptoms.
Especially intriguing is the prospect of predicting
stroke based on blood flow data. Powers [16], Yonas
and colleagues [ 171, and Kleiser and ’Widder [ 181 studied a total of 209 patients with carorid stenosis or occlusion using positron emission tomography, xenon
scanning, and transcranial Doppler flow technology.
Analysis of their pooled data discloses a 28% two-year
stroke incidence ipsilateral to the carotid lesion in patients with significant blood flow impairment in the
hemisphere distal to the lesion. By comparison, the
stroke incidence was 4% in patients with adequate
blood flow.
As yet, a reliable approach to predicting stroke risk
in patients with asymptomatic carotid stenosis does not
exist. Available information suggests. that certain parameters may be relevant, but none of these has been
studied prospectively in large enough numbers to be
relied on. Flow data may be the parameter whose predictive value could be investigated, ac least preliminarily, by a study of angiograms from patients in the
ACAS and the Veterans Affairs trial. Collateral flow
in patients who had strokes could b e compared with
collateral flow in patients who did not.
In conclusion, although surgery effectively prevents
ipsilateral stroke in patients with asyrnptomatic carotid
stenosis, the stroke risk in this popul.ation is small; the
Annals of Neurology
Vol 39
No 3
March 1996
absolute risk reduction with surgery is small; surgery
does not prevent stroke and death overall; aspirin, 325
mg daily, may not now be the best option for medical
management; and the cost of surgery relative to the
cost of stroke for the population at risk is large. For
these reasons it is appropriate for us to address the
question: “Who, exactly, is at risk?” This question may
prove to be more challenging than the original one.
The author wishes to thank Georgia Frederic, Barrow Neurological
Institute, for her editorial assistance and manuscript preparation.
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carotid, stenosis, surgery, questions, asymptomatic, answers
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