CAROTID ENDARTERECTOMY IN SYMPTOMATIC PATIENTS WITH SEVERE INTERNAL CAROTID ARTERY STENOSIS

CAROTID ENDARTERECTOMY IN SYMPTOMATIC

PATIENTS WITH SEVERE INTERNAL CAROTIDARTERY STENOSIS

Maurizio Paciaroni and Virgilio Gallai*

Department of Neuroscience, University of Perugia, 06126 Perugia, Italy

ABSTRACT

Several clinical trials have demonstrated that carotid endarterectomy (CE) in

symptomatic patients with 70–99% internal carotid artery (ICA) stenosis, when

used appropriately in experienced surgical hands (postoperative complications

of stroke and death must not exceed 7%) is safe and effective in preventing

recurrence of ipsilateral carotid ischemia and, in particular, in preventing

disabling ipsilateral stroke. Only five patients need to be treated to prevent one

stroke in three years. The time of greatest risk of stroke after the development of

symptoms was in the first six months, and the incremental risk decreased out to

two years. Instead the risk of stroke with asymptomatic carotid stenosis is low.

Forty-five percent of strokes in patients with asymptomatic 60% to 99%

stenosis are attributable to lacunes or cardioembolism. Because CE cannot

prevent stroke of cardioembolic origin and is less likely to prevent stroke of

lacunar origin, it is doubtful that CE can be justified for most patients with

asymptomatic arteries.

Key Words: Carotid stenosis; Endarterectomy; Cerebral ischemia

INTRODUCTION

The internal carotid artery (ICA) in the neck has proved to be among the

favored sites for development of atherosclerosis and the subsequent stenosis is an

*Corresponding author. E-mail: [email protected]

623

DOI: 10.1081=CEH-120015338 1064-1963 (Print); 1525-6006 (Online)

Copyright # 2002 by Marcel Dekker, Inc. www.dekker.com

CLINICAL AND EXPERIMENTAL HYPERTENSION

Vol. 24, Nos. 7 & 8, pp. 623–629, 2002

©2002 Marcel Dekker, Inc. All rights reserved. This material may not be used or reproduced in any form without the express written permission of Marcel Dekker, Inc.

MARCEL DEKKER, INC. • 270 MADISON AVENUE • NEW YORK, NY 10016

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important risk factor for stroke. The introduction of carotid endarterectomy (CE) in

1954, was a logical procedure for the prevention of ischemic stroke due to carotid

artery stenosis,[1] but two trials conducted in the 1960s for symptomatic patients

were unable to detect benefit for CE because of unacceptably high postoperative

rates of complications.[2,3] From these initial experiences, CE evolved. Subse-

quently, several clinical trials [North American Symptomatic Carotid Endar-

terectomy Trial (NASCET),[4] European Carotid Surgery Trial,[5] and Veterans

Affairs trial[6]] have demonstrated that CE in symptomatic patients with 70–99%

ICA stenosis, when used appropriately and performed with acceptable postsurgical

morbidity and mortality, is effective in preventing cerebral infarction. Sympto-

matic patients with moderate-grade stenosis (50% to 69%) showed benefits of CE

only in a carefully selected group of patients. Patients with <50% stenosis did not

benefit.[7,8]

This report relates particularly to the evidence accumulated from the

NASCET in patients with severe ICA stenosis. The fate of patients with severe

stenosis who were assigned to medical care and who eventually were recommended

to have delayed surgery was studied and is reported.

NORTH AMERICAN SYMPTOMATIC CAROTID

ENDARTERECTOMY TRIAL (NASCET) DESIGN[9]

North American Symptomatic Carotid Endarterectomy Trial was a

randomized clinical trial designed to compare the benefit of best medical therapy

alone with best medical therapy plus CE in patients with transient or nondisabling

neurological deficit (Rankin <3) caused by cerebral or retinal ischemia in the

territory of the ICA within 180 days of randomization. Among the exclusions were

patients with recent history of myocardial infarction, unstable angina pectoris,

atrial fibrillation, recent congestive heart failure, valvular heart disease, serious

disease likely to cause death within five years or intracranial disease that was more

significant than the surgically accessible carotid bifurcation lesion. For inclusion,

the ICA had to have a 30% to 99% stenosis as assessed by selective carotid

angiography and to be technically suitable for CE. Surgeons were invited to join

NASCET if the center had a documented CE stroke and death rate �6% in a

minimum of 50 consecutive cases over a 2-year period.

The severe stenosis phase of NASCET was conducted at 50 medical center

across North America. Randomization began in December 1987 and follow-up

ended in December 1997. Before February 1991, follow-up for these patients

consisted of clinic visits every four months. After February 1991, patients were

followed up with annual clinic visits and telephone assessments twice a year, and

an annual carotid ultrasound study was requested.

The primary outcome event for the trial was any fatal or nonfatal stroke

ipsilateral to the randomized carotid artery. Secondary outcomes included strokes

624 PACIARONI AND GALLAI



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in any territory and any death. Ischemic strokes were assigned to a single

underlying origin (large artery, lacunar or cardioembolic) and to level of disability.

BENEFICIAL EFFECT OF CAROTID ENDARTERECTOMY IN

SYMPTOMATIC PATIENTS

On 21 February, 1991, the NASCET reported in a clinical alert that CE was

beneficial for symptomatic patients with 70 to 99% ICA stenosis, and

randomization for these patients was stopped.[10] Life-table estimates of the

cumulative risk of any ipsilateral stroke at two years were 26% in the 331 medical

patients and 9% in the 328 surgical patients (an absolute risk reduction of 17%).

For a major or fatal ipsilateral stroke, the corresponding estimates were 13.1% and

2.5% (an absolute risk reduction of 10.6%). Carotid endarterectomy was still

found to be beneficial when all strokes and deaths were included in the analysis.[4]

The number needed to treat (NNT) with CE to prevent 1 stroke in two years was 6.

The risk for medical therapy increases with the degree of stenosis and reaches its

maximum at 90% to 94%.

In the perioperative period (from randomization to 30 days after surgery),

5.8% of the patients had stroke and death. Restricting the analysis to the most

serious events resulted in a rate of 2.1% for major stroke and death and a fatality

rate of 0.6%. Similar results have been reported from the European Carotid

Surgery Trial.[5] Several risk factors were associated with a statistically significant

increased risk of perioperative stroke and death: a hemispheric transient ischemic

attacks (TIA) compared with a retinal TIA as the qualifying event, a left-sided

procedure, the presence of contralateral carotid occlusion, an ipsilateral ischemic

lesion on the entry CT scan, and irregular or ulcerated plaque detection by

angiography on the side of surgery.[11] The incidence of other perioperative

surgical and medical complications was low.[11,12] There was a doubling of the

perioperative stroke and death rate for patients in whom the opposite carotid artery

was occluded. Despite higher perioperative morbidity, the long term outlook for

patients who had CE performed on the recently symptomatic, severily stenosed

ipsilateral carotid artery was considerably better than for medically treated

patients.[13]

By on-treatment analysis, the risk of any ipsilateral stroke at three years was

28.3% for medically randomized and 8.9% for surgically randomized patients,

19.4% absolute risk reduction, indicating a need for only five patients to undergo

CE to prevent one ipsilateral stroke during this time period. For combined

disabling or fatal ipsilateral stroke, the risks were 14% and 3.4% respectively,

10.6% absolute risk reduction, corresponding to an NNT of nine. Comparison

between treatment groups was restricted to a 3-year time period, because

approximately one-half of the medically assigned patients underwent surgery after

February 1991, leaving a smaller number of patients in the medical arm for long

term follow-up. The benefit from the procedure was durable and the risk of

CAROTID ENDARTERECTOMY 625



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ipsilateral stroke for surgical patients after eight years of follow-up, remained low

(15.1% any ipsilateral stroke, 6.6% disabling or fatal ipsilateral stroke).[14] Over

80% of the first ipsilateral strokes were of large artery origin.[15,16]

The incremental increase in cumulative stroke risk was not constant over

time. Among patients treated surgically, the risk of ipsilateral stroke dropped

within 10 days after endarterectomy to about 2% per year.[7] In the medically

treated patients, the risk of stroke facing patients in the first year, after recent

ischemic events, was 16.9%. Patients who remained stroke free during the first

year had an 8.2% risk of stroke in the second year. Those who continued to remain

stroke free had a stroke risk of only 3.2% in the third year.[7,15]

Further analysis were conducted to ascertain the importance of commonly

recognized risk factors associated with stroke and there was only one subgroup who

did not benefit: patients in whom an intraluminal thrombus was visualized on the

angiogram at enrollment.[17] Subgroups in which patients received a more favorable

benefit included men but not women, those with hemispheric but not retinal events,

those with an infarction at enrollment rather than a transient ischemic attack as the

qualifying event, and, unexpectedly, those with evidence of concomitant intracranial

carotid artery stenosis rather than normal intracranial arteries.[18]

The presence of collaterals supplying the symptomatic artery increased with

the severity of the stenosis. Two-year risk of hemispheric stroke in medically

treated patients with severe ICA stenosis was reduced in the presence of

collaterals: 27.8% to 11.3%. For patients submitted to endarterectomy the

perioperative risk of stroke and death was 1.1% in the presence of collaterals and

4.9% when collaterals were absent.[19]

Immediately after the clinical alert, CE was recommended for the patients

randomized to the medical arm, provided that they were still suitable candidates

for the procedure. Of the 331 patients randomized to the medical arm, 100 were no

longer available or suitable for CE at the time of the clinical alert. Of the 231

patients remaining eligible for CE, 116 had CE within six months of the clinical

alert. Forty percent of these had symptoms in the year before the date of their CE,

whereas only 15% of the 115 patients continuing on medical therapy had ischemic

symptoms in the year before the clinical alert. The risk of ipsilateral stroke at three

years for the delayed CE group was 7.9% compared with 15.0% for the continuing

medical group ( P¼ 0.11). The NNT was 14 patients.[14] The time of greatest risk

of stroke after the development of symptoms was in the first six months, and the

incremental risk decreased out to two years. Beyond two years of being symptom

free, CE may be unnecessary in most patients because between years 2 and 3, the

additional risk added was only 3.2%.

ASYMPTOMATIC INTERNAL CAROTID ARTERY STENOSIS

North American Symptomatic Carotid Endarterectomy Trial also studied

patients with unilateral symptomatic carotid artery stenosis and contralateral




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asymptomatic stenosis.[20] The risk of stroke with asymptomatic carotid stenosis is

low. Forty-five percent of strokes in patients with asymptomatic 60% to 99%

stenosis are attributable to lacunes or cardioembolism. Because CE cannot prevent

stroke of cardioembolic origin and is less likely to prevent stroke of lacunar origin,

it is doubtful that CE can be justified for most patients with asymptomatic arteries.

CONCLUSIONS

The results from NASCET demonstrate that in experienced surgical hands

(postoperative complications of stroke and death must not exceed 7%),[21] CE for

patients with 70% to 99% ICA stenosis is safe and effective in the near term and

remarkably effective in the longer term in preventing recurrence of ipsilateral

carotid ischemia and, in particular, in preventing disabling ipsilateral stroke. Only

five patients need to be treated to prevent one stroke in three years.[14] The time of

greatest risk of stroke after the development of symptoms was in the first six

months, and the incremental risk decreased out to two years. The longer the

patients were free of symptoms, the less likely they were to have a stroke and the

less likely they were to benefit from endarterectomy.

Patients with asymptomatic carotid artery stenosis should be considered for

CE with caution because the risk of large-artery stroke at five years was only 9.9%

while the risk of non-large-artery stroke was nearly equal at 8.1%.[20,22]

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CAROTID ENDARTERECTOMY IN SYMPTOMATIC PATIENTS WITH SEVERE INTERNAL CAROTID ARTERY STENOSIS