The New England Journal of Medicine

Clinical Practice
Volume 345:1113-1118

October 11, 2001

Number 15
Extracranial Carotid Stenosis
Ralph L. Sacco, M.D.

This Journal feature begins with a case vignette highlighting a common
clinical problem. Evidence supporting various strategies is then presented,
followed by a review of formal guidelines, when they exist. The article ends
with the author's clinical recommendations.
A 64-year-old man with a history of smoking and hypercholesterolemia has a
sudden, transient loss of vision in his left eye. He reports a prior episode
during which he had difficulty speaking and mild weakness of the right hand.
The results of an examination are normal except for a bruit in the left side
of the neck. He is found to have stenosis of the left carotid artery of 60
to 79 percent on high-resolution carotid ultrasonography, confirmed by
magnetic resonance angiography. How should he be treated?
The Clinical Problem
Carotid stenosis is an important cause of transient ischemic attacks and
stroke. With the introduction of cerebral angiography in the 1920s,
carotid-artery disease was found among persons with stroke. Beginning in the
1950s, C.M. Fisher called attention to atherosclerosis involving the
bifurcation of the extracranial carotid artery as an important cause of
stroke and suggested surgery as a possible therapy. 1
<http://content.nejm.org/cgi/content/short/345/15/#R1>  The cause of carotid
stenosis is most often atherosclerosis; endothelial injury, inflammation,
lipid deposition, plaque formation, fibrin, platelets, and thrombin all
contribute to the pathogenesis of the lesion. Carotid atherosclerosis
accounts for 10 to 20 percent of cases of brain infarction, depending on the
population studied. 2 <http://content.nejm.org/cgi/content/short/345/15/#R2>
In a patient with sudden, transient loss of vision in one eye — known as
transient monocular blindness, or amaurosis fugax — who has a history of
diabetes, hypercholesterolemia, or cigarette smoking, carotid stenosis
should rank first on the differential-diagnosis list. In patients with
clonic, limb-shaking transient ischemic attacks that resemble focal
seizures, a fractional hemiparesis in which the hand is weaker than the
shoulder, or a mild sensorimotor syndrome in the absence of localizing
cortical signs such as aphasia or neglect, the diagnosis may be more
difficult. 3 <http://content.nejm.org/cgi/content/short/345/15/#R3>  Methods
of diagnostic evaluation include high-resolution Doppler ultrasonography,
magnetic resonance angiography, and spiral computed tomography, all of which
have reasonable sensitivity and specificity for the diagnosis of carotid
stenosis. These noninvasive techniques have reduced the need for
conventional cerebral angiography. 4
<http://content.nejm.org/cgi/content/short/345/15/#R4>  Other imaging
techniques — such as positron-emission tomography, xenon computed
tomography, single-photon-emission computed tomography, and transcranial
Doppler ultrasonography with evaluation of vasoreactivity and detection of
embolism — have been developed to identify patients who have hemodynamic
insufficiency due to carotid disease and are thus at increased risk for
stroke. 5 <http://content.nejm.org/cgi/content/short/345/15/#R5>
Strategies and Evidence
There are two main strategies for the treatment of carotid stenosis. The
first approach is to stabilize or halt the progression of the carotid plaque
through risk-factor modification and medication ( Table 1
<http://content.nejm.org/cgi/content/short/345/15/#T1> ). Hypertension,
diabetes, smoking, obesity, and high cholesterol levels are closely
associated with carotid stenosis and stroke; control of these factors may
decrease the risk of plaque formation and progression. A small study of
obese patients demonstrated that weight loss over a period of four years may
reduce the progression of carotid plaques. 6
<http://content.nejm.org/cgi/content/short/345/15/#R6>  Studies of statin
therapy among high-risk patients with signs of subclinical carotid
atherosclerosis have shown that plaque regression can be achieved, although
it may be restricted to patients with nonstenosing carotid plaque. 7
<http://content.nejm.org/cgi/content/short/345/15/#R7> , 8
<http://content.nejm.org/cgi/content/short/345/15/#R8>  Treatment with
angiotensin-converting–enzyme inhibitors has also reduced the intima–media
thickness of the carotid artery and decreased the risk of stroke in
high-risk patients. 9 <http://content.nejm.org/cgi/content/short/345/15/#R9>
, 10 <http://content.nejm.org/cgi/content/short/345/15/#R10>  Finally,
antithrombotic therapies have been proved to reduce the risk of stroke among
those with a history of transient ischemic attacks or stroke, whereas a
benefit of oral anticoagulants has not been shown. 11
<http://content.nejm.org/cgi/content/short/345/15/#R11> , 12
<http://content.nejm.org/cgi/content/short/345/15/#R12>


View this table:
[in this window] <http://content.nejm.org/cgi/content/full/345/15/1113/T1>
[in a new window]
<http://content.nejm.org/cgi/content-nw/full/345/15/1113/T1>

Table 1. Management of Risk Factors for Stroke in Patients with
Atherosclerotic Carotid Stenosis.

The second approach is to eliminate or reduce carotid stenosis through
carotid endarterectomy or carotid angioplasty and stenting. Carotid
endarterectomy is the mainstay of therapy and is discussed later.
Extracranial–intracranial bypass surgery was not found to provide a
significant benefit in patients with carotid-artery occlusion or narrowing
of the carotid artery distal to the carotid bifurcation. 13
<http://content.nejm.org/cgi/content/short/345/15/#R13>  The use of more
sensitive imaging techniques to refine the selection criteria in randomized
clinical trials of extracranial–intracranial bypass surgery will be
necessary if this procedure is to be reconsidered. 14
<http://content.nejm.org/cgi/content/short/345/15/#R14>
Angioplasty and stenting of the carotid artery have only recently become
available, and therefore, there is no evidence that this approach is more
effective than conventional carotid endarterectomy. Thus far, early trials
and case series have shown that the outcomes of stenting are worse than or
no different from those of carotid endarterectomy. 15
<http://content.nejm.org/cgi/content/short/345/15/#R15> , 16
<http://content.nejm.org/cgi/content/short/345/15/#R16> , 17
<http://content.nejm.org/cgi/content/short/345/15/#R17>  Most of these
studies were small, involved highly selected patients (many of whom would
not have met the criteria for surgery), and were limited by the inexperience
of the physicians with this new procedure. The recently initiated Carotid
Revascularization with Endarterectomy or Stent Trial should provide more
definitive evidence. As physicians performing carotid angioplasty and
stenting become more skilled, the risks and benefits may approach those of
carotid endarterectomy. More evidence is needed before we can advocate the
widespread use of angioplasty plus stenting as routine care for patients
with extracranial carotid stenosis.
Carotid Endarterectomy for Symptomatic Carotid Stenosis
For patients with symptomatic carotid stenosis of more than 70 percent, the
value of carotid endarterectomy has been firmly established on the basis of
the results of three major randomized trials, the North American Symptomatic
Carotid Endarterectomy Trial (NASCET), the European Carotid Surgery Trial
(ECST), and the trial by the Veterans Affairs Cooperative Studies Program.
18 <http://content.nejm.org/cgi/content/short/345/15/#R18> , 19
<http://content.nejm.org/cgi/content/short/345/15/#R19> , 20
<http://content.nejm.org/cgi/content/short/345/15/#R20>  Among patients with
high-grade, symptomatic carotid stenosis, each trial showed impressive
relative and absolute reductions in risk for those randomly assigned to
surgery. 21 <http://content.nejm.org/cgi/content/short/345/15/#R21>  In
NASCET, the two-year rate of ipsilateral stroke was 26 percent in the
medical group and 9 percent in the surgical group, providing a relative
reduction in risk of 65 percent and an absolute reduction in risk of 17
percent. 18 <http://content.nejm.org/cgi/content/short/345/15/#R18>  Both
NASCET and ECST showed that only seven or eight patients would need to
undergo endarterectomy to prevent one stroke in a five-year period. A
consensus was reached that carotid endarterectomy was the best option for
the prevention of a recurrent event in the case of patients with
symptomatic, ipsilateral carotid stenosis of more than 70 percent.
For patients with symptomatic carotid stenosis of less than 50 percent,
these trials showed that there was no significant benefit of surgery. In
ECST, no benefit of surgery was demonstrated among those with ipsilateral
carotid stenosis of less than 30 percent. 19
<http://content.nejm.org/cgi/content/short/345/15/#R19>  Among patients with
stenosis of less than 50 percent in NASCET, there was no significant
difference in the risk of ipsilateral stroke between those who were treated
with endarterectomy and those who were treated medically. 22
<http://content.nejm.org/cgi/content/short/345/15/#R22>
The benefits of endarterectomy in patients with moderate symptomatic carotid
stenosis (i.e., of 50 to 69 percent) in NASCET and ECST were clearly less
than those seen in patients with more severe stenosis. 22
<http://content.nejm.org/cgi/content/short/345/15/#R22> , 23
<http://content.nejm.org/cgi/content/short/345/15/#R23>  In ECST, there was
no significant benefit of surgery for those with moderate stenosis. In
NASCET, the five-year risk of fatal or nonfatal ipsilateral stroke among
patients with stenosis of 50 to 69 percent was 22.2 percent in the medical
group and 15.7 percent in the surgical group (P=0.045). 22
<http://content.nejm.org/cgi/content/short/345/15/#R22>  The absolute
reduction in risk was 6.5 percent — in other words, for every 15 patients
treated one stroke was prevented within five years after surgery.
The benefits of carotid endarterectomy for moderate carotid stenosis were
greatest in those with more severe stenosis, those 75 years of age and
older, men, patients with a recent (within three months) history of stroke
(rather than transient ischemic attacks) as the qualifying event, and
patients with hemispheric transient ischemic attacks rather than transient
monocular blindness. 22
<http://content.nejm.org/cgi/content/short/345/15/#R22> , 24
<http://content.nejm.org/cgi/content/short/345/15/#R24>  Patients with
transient monocular blindness have a better prognosis than those with
hemispheric transient ischemic attack; however, when other risk factors are
present, the benefits of endarterectomy are more apparent. 25
<http://content.nejm.org/cgi/content/short/345/15/#R25>  Radiographic
factors that predicted more favorable outcomes after carotid endarterectomy
included the presence of intracranial stenosis, the absence of microvascular
ischemia (i.e., leukoariosis, or periventricular white-matter lucencies seen
on computed tomography of the head), and the presence of collateral vessels.
26 <http://content.nejm.org/cgi/content/short/345/15/#R26> , 27
<http://content.nejm.org/cgi/content/short/345/15/#R27>  Sex, age, the
presence or absence of coexisting conditions, and the experience of the
surgeon must be considered during evaluation of treatment options for
patients with stenosis of 50 to 69 percent, because the absolute benefit of
surgery is less than that for patients with severe stenosis.
Carotid Endarterectomy for Asymptomatic Carotid Stenosis
Asymptomatic carotid stenosis is a clear risk factor for stroke; however,
the risk is lower than that associated with symptomatic disease. In
observational studies, the rate of ipsilateral stroke was 1 to 3 percent per
year among patients with asymptomatic stenosis of greater than 50 percent,
28 <http://content.nejm.org/cgi/content/short/345/15/#R28> , 29
<http://content.nejm.org/cgi/content/short/345/15/#R29>  and the risk in
NASCET was 3.2 percent per year for asymptomatic stenosis of 60 to 99
percent. 30 <http://content.nejm.org/cgi/content/short/345/15/#R30>  The
risk of stroke increased only slightly with increasing stenosis. The
occurrence of symptoms may depend on the severity and progression of the
stenosis, the adequacy of collateral vessels, the character of the
atherosclerotic plaque, and the presence or absence of other risk factors
for stroke.
The surgical treatment of asymptomatic carotid stenosis is a source of
continuing debate. Four randomized, controlled trials have addressed this
question. 31 <http://content.nejm.org/cgi/content/short/345/15/#R31> , 32
<http://content.nejm.org/cgi/content/short/345/15/#R32> , 33
<http://content.nejm.org/cgi/content/short/345/15/#R33> , 34
<http://content.nejm.org/cgi/content/short/345/15/#R34>  Some have been
impaired by small sample sizes, a lack of uniform treatment of the medical
and surgical groups with aspirin, high perioperative mortality rates, or the
exclusion of certain high-risk groups. 31
<http://content.nejm.org/cgi/content/short/345/15/#R31> , 32
<http://content.nejm.org/cgi/content/short/345/15/#R32>  The Veterans
Affairs Cooperative Study of carotid endarterectomy randomly assigned 444
men with asymptomatic carotid stenosis of at least 50 percent (determined by
cerebral angiography) to undergo carotid endarterectomy or receive 650 mg of
aspirin twice daily. 33
<http://content.nejm.org/cgi/content/short/345/15/#R33>  The incidence of
fatal or nonfatal stroke after angiography and surgery was 4.7 percent. The
incidence of the primary outcome of ipsilateral transient ischemic attacks,
transient monocular blindness, or stroke within two years of follow-up was
significantly lower in the surgical group (8.0 percent vs. 20.6 percent;
relative risk reduction, 61 percent; P<0.001). The incidence of fatal or
nonfatal ipsilateral stroke was not significantly lower in the surgical
group (4.7 percent vs. 9.4 percent, P=0.08), but a much larger sample would
have been needed to detect a difference in the risk of stroke alone.
The largest randomized trial to evaluate the efficacy of endarterectomy for
patients with asymptomatic disease was the Asymptomatic Carotid
Atherosclerosis Study (ACAS). 34
<http://content.nejm.org/cgi/content/short/345/15/#R34>  Patients were
younger than 80 years and had asymptomatic carotid stenosis of 60 percent or
more, as determined by Doppler ultrasonography, and stable cardiac disease.
Complications of angiography occurred in 1.2 percent, and the perioperative
risk of stroke was 2.3 percent. After a median follow-up of 2.7 years, the
study was stopped early because a significant benefit from surgery was
found. The risk of ipsilateral stroke or any perioperative stroke or death
was 5 percent during five years of follow-up in surgically treated patients
and 11 percent in medically treated patients. The absolute annual rates of
adverse events — 1 percent in the surgically treated group and 2 percent in
the medically treated group — were consistent with the results of the
Veterans Affairs Cooperative Studies. As compared with the trials in
patients with symptomatic disease, ACAS found smaller absolute reductions in
risk (approximately 6 percent at five years), indicating that 17 patients
would need to undergo surgery to prevent one event within five years.
In ACAS, the benefit of surgery was greater for men than women (reduction in
risk, 66 percent vs. 17 percent), and the rate of perioperative
complications was higher among women than men (3.6 percent vs. 1.7 percent).
The benefit of surgery was not related to the degree of carotid-artery
stenosis. On the basis of the absolute risks of stroke, it was clear that a
rate of perioperative complications (stroke or death) of more than 3 percent
would eliminate the potential benefit of the operation. Such low
complication rates are unusual in community-hospital settings. 35
<http://content.nejm.org/cgi/content/short/345/15/#R35>  There are numerous
risks associated with the surgical procedure that need to be considered. 36
<http://content.nejm.org/cgi/content/short/345/15/#R36>  At present, any
decision regarding the use of endarterectomy depends on minimizing the
complication rates by having an experienced surgeon (one whose patients have
a complication rate of less than 3 percent) perform the surgery. 37
<http://content.nejm.org/cgi/content/short/345/15/#R37>
Areas of Uncertainty
Effective strategies are needed to identify which patients with asymptomatic
carotid stenosis or symptomatic moderate stenosis are likely to benefit from
surgery. Two ongoing trials may provide more information to direct the care
of patients with asymptomatic disease. 38
<http://content.nejm.org/cgi/content/short/345/15/#R38> , 39
<http://content.nejm.org/cgi/content/short/345/15/#R39>  More data on the
role of hemodynamic testing, schemes for risk stratification, and
preoperative cardiac testing are needed to help select the best candidates
for surgery. The optimal time to perform carotid surgery in a patient with
symptomatic disease remains uncertain, as does the optimal short-term
therapy for patients awaiting endarterectomy. More data are needed to
clarify the role of carotid angioplasty with stenting; this is currently
being studied. Finally, it is not known whether patients with carotid
stenosis should be routinely treated with statins and
angiotensin-converting–enzyme inhibitors.
Guidelines
The American Heart Association and the National Stroke Association have
published the most comprehensive guidelines for the prevention of stroke
among persons with carotid stenosis 28
<http://content.nejm.org/cgi/content/short/345/15/#R28> , 40
<http://content.nejm.org/cgi/content/short/345/15/#R40> , 41
<http://content.nejm.org/cgi/content/short/345/15/#R41> , 42
<http://content.nejm.org/cgi/content/short/345/15/#R42> , 43
<http://content.nejm.org/cgi/content/short/345/15/#R43>  ( Table 1
<http://content.nejm.org/cgi/content/short/345/15/#T1>  and Table 2
<http://content.nejm.org/cgi/content/short/345/15/#T2> ). Management
algorithms are dependent on whether the patient has symptomatic or
asymptomatic disease, the degree of carotid stenosis, and the underlying
risk of stroke on the basis of coexisting conditions. The American Heart
Association guidelines for the care of patients with transient ischemic
attacks and minor stroke due to carotid stenosis include recommendations
regarding risk factors, the use of antithrombotic medications, and the use
of angioplasty and endarterectomy. 42
<http://content.nejm.org/cgi/content/short/345/15/#R42>  The guidelines for
asymptomatic carotid stenosis have not been accepted as widely as those for
symptomatic carotid stenosis ( Table 2
<http://content.nejm.org/cgi/content/short/345/15/#T2> ).


View this table:
[in this window] <http://content.nejm.org/cgi/content/full/345/15/1113/T2>
[in a new window]
<http://content.nejm.org/cgi/content-nw/full/345/15/1113/T2>

Table 2. Guidelines for the Care of Patients with Carotid Disease.

Conclusions and Recommendations
Among patients with severe symptomatic carotid stenosis, the evidence in
favor of endarterectomy is clear ( Figure 1
<http://content.nejm.org/cgi/content/short/345/15/#F1> ). Unless there is a
major contraindication, I discuss the benefits of surgery with my patients
and their families, and most undergo carotid endarterectomy. This would be
my approach for the patient described in the case vignette. For those for
whom surgery carries a particularly high risk (e.g., those with coexisting
conditions, atherosclerotic disease beyond the bifurcation, or recurrent
carotid stenosis), I would consider referral for angioplasty and stenting,
especially if medical therapies are failing. Surgery is not indicated for
patients with mild symptomatic carotid stenosis (of less than 50 percent).
Some patients with symptomatic stenosis of 50 to 69 percent will benefit
from surgery, but the decision should be individualized on the basis of
several factors, including the presence or absence of risk factors for
stroke and local surgical expertise ( Figure 1
<http://content.nejm.org/cgi/content/short/345/15/#F1> ).


  <http://content.nejm.org/cgi/content/full/345/15/1113/F1>
View larger version (22K):
[in this window] <http://content.nejm.org/cgi/content/full/345/15/1113/F1>
[in a new window]
<http://content.nejm.org/cgi/content-nw/full/345/15/1113/F1>

Figure 1. Algorithm for the Management of Extracranial Carotid Stenosis.
The algorithm is partially based on the Guidelines of the American Heart
Association and the National Stroke Association. 28
<http://content.nejm.org/cgi/content/short/345/15/#R28> , 41
<http://content.nejm.org/cgi/content/short/345/15/#R41> , 42
<http://content.nejm.org/cgi/content/short/345/15/#R42> , 43
<http://content.nejm.org/cgi/content/short/345/15/#R43>  Other factors not
included in the figure may also be relevant in risk stratification (e.g.,
the results of cardiac evaluation or hemodynamic testing).

For patients with asymptomatic carotid stenosis of 60 percent or more, the
decisions are difficult. From a public health perspective, it is clear that
carotid endarterectomy would not be cost effective for all patients with
asymptomatic disease. 44
<http://content.nejm.org/cgi/content/short/345/15/#R44>  Clinicians should
consider surgery for patients without apparent contraindications at a center
where they know the surgeons can perform the operation at a rate of
perioperative stroke or death of less than 3 percent. Preoperative cardiac
or hemodynamic evaluation may help in risk stratification. After the risks
and benefits are explained to the patient, the ultimate decision depends on
whether the patient is willing to accept the early risk and nuisance of the
surgery in the hope of long-term benefit.
In all cases, risk-factor control should be emphasized. I more frequently
recommend angiotensin-converting–enzyme inhibitors to patients with
hypertension and prescribe statins even for patients with
normal-to-borderline cholesterol levels. Antiplatelet therapy is appropriate
for all patients who do not have a contraindication, and changes in
lifestyle (smoking cessation, weight control, exercise, and avoidance of
excessive alcohol consumption) should be routinely encouraged.
Supported by grants (R01 NS 27517, R01 NS 29993, and T32 NS 07153) from the
National Institute of Neurological Disorders and Stroke.
I am indebted to my colleagues at the New York–Presbyterian Hospital,
including Drs. J.P. Mohr, R.A. Solomon, M. Elkind, R. Marshall, T. Rundek,
J. Pile-Spellman, D.O. Quest, S.A. Connolly, and J. Krakauer.

Source Information
From the Department of Neurology, Division of Epidemiology, of the Mailman
School of Public Health and the Sergievsky Center, Columbia University
College of Physicians and Surgeons and New York Presbyterian Hospital, New
York.
Address reprint requests to Dr. Sacco at the Neurological Institute, 710 W.
168th St., New York, NY 10032, or at [log in to unmask]
<mailto:[log in to unmask]> .
References
1.      Fisher CM, Gore I, Okabe N, White PD. Atherosclerosis of the carotid and
vertebral arteries -- extracranial and intracranial. J Neuropathol Exp
Neurol 1965;24:455-476.
2.      Sacco RL, Ellenberg JA, Mohr JP, et al. Infarcts of undetermined cause:
the NINCDS Stroke Data Bank. Ann Neurol 1989;25:382-390. [Medline]
<http://content.nejm.org/cgi/external_ref?access_num=2712533&link_type=MED>
3.      Timsit SG, Sacco RL, Mohr JP, et al. Early clinical differentiation of
cerebral infarction from severe atherosclerotic stenosis and cardioembolism.
Stroke 1992;23:486-491. [Abstract]
<http://content.nejm.org/cgi/ijlink?linkType=ABST&journalCode=strokeaha&resi
d=23/4/486>
4.      Johnston DCC, Goldstein LB. Clinical carotid endarterectomy decision
making: noninvasive vascular imaging versus angiography. Neurology
2001;56:1009-1015. [Abstract/Full Text]
<http://content.nejm.org/cgi/ijlink?linkType=ABST&journalCode=neurology&resi
d=56/8/1009>
5.      Silvestrini M, Vernieri F, Pasqualetti P, et al. Impaired cerebral
vasoreactivity and risk of stroke in patients with asymptomatic carotid
stenosis. JAMA 2000;283:2122-2127. [Medline]
<http://content.nejm.org/cgi/external_ref?access_num=10791504&link_type=MED>
6.      Karason K, Wikstrand J, Sjostrom L, Wendelhag I. Weight loss and
progression of early atherosclerosis in the carotid artery: a four-year
controlled study of obese subjects. Int J Obes Relat Metab Disord
1999;23:948-956. [Medline]
<http://content.nejm.org/cgi/external_ref?access_num=10490801&link_type=MED>
7.      Furberg CD, Adams HP Jr, Applegate WB, et al. Effects of lovastatin on
early carotid atherosclerosis and cardiovascular events. Circulation
1994;90:1679-1687. [Abstract]
<http://content.nejm.org/cgi/ijlink?linkType=ABST&journalCode=circulationaha
&resid=90/4/1679>
8.      Crouse JR III, Byington RP, Bond MA, et al. Pravastatin, Lipids, and
Atherosclerosis in the Carotid Arteries (PLAC-II). Am J Cardiol
1995;75:455-459. [Erratum, Am J Cardiol 1995;75:862.] [Medline]
<http://content.nejm.org/cgi/external_ref?access_num=7863988&link_type=MED>
9.      The Heart Outcomes Prevention Evaluation Study Investigators. Effects of
an angiotensin-converting-enzyme inhibitor, ramipril, on cardiovascular
events in high-risk patients. N Engl J Med 2000;342:145-153. [Erratum, N
Engl J Med 2000;342:748.] [Abstract/Full Text]
<http://content.nejm.org/cgi/ijlink?linkType=ABST&journalCode=nejm&resid=342
/3/145>
10.     Lonn E, Yusuf S, Dzavik V, et al. Effects of ramipril and vitamin E on
atherosclerosis: the Study to Evaluate Carotid Ultrasound changes in
patients treated with Ramipril and vitamin E (SECURE). Circulation
2001;103:919-925. [Abstract/Full Text]
<http://content.nejm.org/cgi/ijlink?linkType=ABST&journalCode=circulationaha
&resid=103/7/919>
11.     Albers GW, Amarenco P, Easton JD, Sacco RL, Teal P. Antithrombotic and
thrombolytic therapy for ischemic stroke. Chest 2001;119:Suppl:300S-320S.
[Full Text]
<http://content.nejm.org/cgi/ijlink?linkType=FULL&journalCode=chest&resid=11
9/1_suppl/300S>
12.     The WARSS, APASS, PICSS, and HAS Study Groups. The feasibility of a
collaborative double-blind study using an anticoagulant: the
Warfarin-Aspirin Recurrent Stroke Study (WARSS), the Antiphospholipid
Antibodies and Stroke Study (APASS), the Patent Foramen Ovale in Cryptogenic
Stroke Study (PICSS), and the Hemostatic System Activation Study (HAS).
Cerebrovasc Dis 1997;7:100-112.
13.     EC/IC Bypass Study Group. Failure of extracranial-intracranial arterial
bypass to reduce the risk of ischemic stroke: results of an international
randomized trial. N Engl J Med 1985;313:1191-1200. [Abstract]
<http://content.nejm.org/cgi/ijlink?linkType=ABST&journalCode=nejm&resid=313
/19/1191>
14.     Grubb RL Jr, Derdeyn CP, Fritsch SM, et al. Importance of hemodynamic
factors in the prognosis of symptomatic carotid occlusion. JAMA
1998;280:1055-1060. [Medline]
<http://content.nejm.org/cgi/external_ref?access_num=9757852&link_type=MED>
15.     Endovascular versus surgical treatment in patients with carotid stenosis
in the Carotid and Vertebral Artery Transluminal Angioplasty Study
(CAVATAS): a randomised trial. Lancet 2001;357:1729-1737. [Medline]
<http://content.nejm.org/cgi/external_ref?access_num=11403808&link_type=MED>
16.     Naylor AR, Bolia A, Abbott RJ, et al. Randomized study of carotid
angioplasty and stenting versus carotid endarterectomy: a stopped trial. J
Vasc Surg 1998;28:326-334. [Medline]
<http://content.nejm.org/cgi/external_ref?access_num=9719328&link_type=MED>
17.     Alberts MJ. Results of a multicenter prospective randomized trial of
carotid artery stenting vs. carotid endarterectomy. Stroke 2001;32:325-325.
18.     North American Symptomatic Carotid Endarterectomy Trial Collaborators.
Beneficial effect of carotid endarterectomy in symptomatic patients with
high-grade carotid stenosis. N Engl J Med 1991;325:445-453. [Abstract]
<http://content.nejm.org/cgi/ijlink?linkType=ABST&journalCode=nejm&resid=325
/7/445>
19.     European Carotid Surgery Trialists' Collaborative Group. MRC European
Carotid Surgery Trial: interim results for symptomatic patients with severe
(70-99%) or with mild (0-29%) carotid stenosis. Lancet 1991;337:1235-1243.
[Medline]
<http://content.nejm.org/cgi/external_ref?access_num=1674060&link_type=MED>
20.     Mayberg MR, Wilson SE, Yatsu F, et al. Carotid endarterectomy and
prevention of cerebral ischemia in symptomatic carotid stenosis. JAMA
1991;266:3289-3294. [Medline]
<http://content.nejm.org/cgi/external_ref?access_num=1960828&link_type=MED>
21.     Rothwell PM, Gutnikov SA, Eliasziw M, et al. Overall results of a pooled
analysis of individual patient data from trials of endarterectomy for
symptomatic carotid stenosis. Stroke 2001;32:327-327.
22.     Barnett HJM, Taylor DW, Eliasziw M, et al. Benefit of carotid
endarterectomy in patients with symptomatic moderate or severe stenosis. N
Engl J Med 1998;339:1415-1425. [Abstract/Full Text]
<http://content.nejm.org/cgi/ijlink?linkType=ABST&journalCode=nejm&resid=339
/20/1415>
23.     Randomised trial of endarterectomy for recently symptomatic carotid
stenosis: final results of the MRC European Carotid Surgery Trial (ECST).
Lancet 1998;351:1379-1387. [Medline]
<http://content.nejm.org/cgi/external_ref?access_num=9593407&link_type=MED>
24.     Streifler JY, Eliasziw M, Benavente OR, et al. The risk of stroke in
patients with first-ever retinal vs hemispheric transient ischemic attacks
and high-grade carotid stenosis: North American Symptomatic Carotid
Endarterectomy Trial. Arch Neurol 1995;52:246-249. [Medline]
<http://content.nejm.org/cgi/external_ref?access_num=7872876&link_type=MED>
25.     Benavente O, Eliasziw M, Streifler JY, Fox AJ, Barnett HJM, Meldrum H.
Prognosis after transient monocular blindness associated with carotid-artery
stenosis. N Engl J Med 2001;345:1084-1090. [Abstract/Full Text]
<http://content.nejm.org/cgi/ijlink?linkType=ABST&journalCode=nejm&resid=345
/15/1084>
26.     Kappelle LJ, Eliasziw M, Fox AJ, Sharpe BL, Barnett HJM. Importance of
intracranial atherosclerotic disease in patients with symptomatic stenosis
of the internal carotid artery: the North American Symptomatic Carotid
Endarterectomy Trial. Stroke 1999;30:282-286. [Abstract/Full Text]
<http://content.nejm.org/cgi/ijlink?linkType=ABST&journalCode=strokeaha&resi
d=30/2/282>
27.     Henderson RD, Eliasziw M, Fox AJ, Rothwell PM, Barnett HJM.
Angiographically defined collateral circulation and risk of stroke in
patients with severe carotid artery stenosis. Stroke 2000;31:128-132.
[Abstract/Full Text]
<http://content.nejm.org/cgi/ijlink?linkType=ABST&journalCode=strokeaha&resi
d=31/1/128>
28.     Goldstein LB, Adams R, Becker K, et al. Primary prevention of ischemic
stroke: a statement for healthcare professionals from the Stroke Council of
the American Heart Association. Stroke 2001;32:280-299. [Full Text]
<http://content.nejm.org/cgi/ijlink?linkType=FULL&journalCode=strokeaha&resi
d=32/1/280>
29.     Norris JW, Zhu CZ, Bornstein NM, Chambers BR. Vascular risks of
asymptomatic carotid stenosis. Stroke 1991;22:1485-1490. [Abstract]
<http://content.nejm.org/cgi/ijlink?linkType=ABST&journalCode=strokeaha&resi
d=22/12/1485>
30.     Inzitari D, Eliasziw M, Gates P, et al. The causes and risk of stroke in
patients with asymptomatic internal-carotid-artery stenosis. N Engl J Med
2000;342:1693-1700. [Abstract/Full Text]
<http://content.nejm.org/cgi/ijlink?linkType=ABST&journalCode=nejm&resid=342
/23/1693>
31.     The CASANOVA Study Group. Carotid surgery versus medical therapy in
asymptomatic carotid stenosis. Stroke 1991;22:1229-1235. [Abstract]
<http://content.nejm.org/cgi/ijlink?linkType=ABST&journalCode=strokeaha&resi
d=22/10/1229>
32.     Mayo Asymptomatic Carotid Endarterectomy Study Group. Results of a
randomized controlled trial of carotid endarterectomy for asymptomatic
carotid stenosis. Mayo Clin Proc 1992;67:513-518. [Medline]
<http://content.nejm.org/cgi/external_ref?access_num=1434877&link_type=MED>
33.     Hobson RW II, Weiss DG, Fields WS, et al. Efficacy of carotid
endarterectomy for asymptomatic carotid stenosis. N Engl J Med
1993;328:221-227. [Abstract/Full Text]
<http://content.nejm.org/cgi/ijlink?linkType=ABST&journalCode=nejm&resid=328
/4/221>
34.     Executive Committee for the Asymptomatic Carotid Atherosclerosis Study.
Endarterectomy for asymptomatic carotid artery stenosis. JAMA
1995;273:1421-1428. [Medline]
<http://content.nejm.org/cgi/external_ref?access_num=7723155&link_type=MED>
35.     Goldstein LB, Samsa GP, Matchar DB, Oddone EZ. Multicenter review of
preoperative risk factors for endarterectomy for asymptomatic carotid artery
stenosis. Stroke 1998;29:750-753. [Abstract/Full Text]
<http://content.nejm.org/cgi/ijlink?linkType=ABST&journalCode=strokeaha&resi
d=29/4/750>
36.     Caplan LR. A 79-year-old musician with asymptomatic carotid artery
disease. JAMA 1995;274:1383-1389. [Medline]
<http://content.nejm.org/cgi/external_ref?access_num=7563565&link_type=MED>
37.     Goldstein LB, Moore WS, Robertson JT, Chaturvedi S. Complication rates
for carotid endarterectomy: a call to action. Stroke 1997;28:889-890. [Full
Text]
<http://content.nejm.org/cgi/ijlink?linkType=FULL&journalCode=strokeaha&resi
d=28/5/889>
38.     Halliday AW, Thomas D, Mansfield A. The Asymptomatic Carotid Surgery
Trial (ACST): rationale and design. Eur J Vasc Surg 1994;8:703-710.
[Medline]
<http://content.nejm.org/cgi/external_ref?access_num=7828747&link_type=MED>
39.     Nicolaides AN. Asymptomatic carotid stenosis and risk of stroke:
identification of a high risk group (ACSRS): a natural history study. Int
Angiol 1995;14:21-23. [Medline]
<http://content.nejm.org/cgi/external_ref?access_num=7658100&link_type=MED>
40.     Moore WS, Barnett HJM, Beebe HG, et al. Guidelines for carotid
endarterectomy: a multidisciplinary consensus statement from the Ad Hoc
Committee, American Heart Association. Circulation 1995;91:566-579.
[Abstract/Full Text]
<http://content.nejm.org/cgi/ijlink?linkType=ABST&journalCode=circulationaha
&resid=91/2/566>
41.     Wolf PA, Clagett GP, Easton JD, et al. Preventing ischemic stroke in
patients with prior stroke and transient ischemic attack: a statement for
healthcare professionals from the Stroke Council of the American Heart
Association. Stroke 1999;30:1991-1994. [Full Text]
<http://content.nejm.org/cgi/ijlink?linkType=FULL&journalCode=strokeaha&resi
d=30/9/1991>
42.     Albers GW, Hart RG, Lutsep HL, Newell DW, Sacco RL. Supplement to the
guidelines for the management of transient ischemic attacks: a statement
from the Ad Hoc Committee on Guidelines for the Management of Transient
Ischemic Attacks, Stroke Council, American Heart Association. Stroke
1999;30:2502-2511. [Full Text]
<http://content.nejm.org/cgi/ijlink?linkType=FULL&journalCode=strokeaha&resi
d=30/11/2502>
43.     Gorelick PB, Sacco RL, Smith DB, et al. Prevention of a first stroke: a
review of guidelines and a multidisciplinary consensus statement from the
National Stroke Association. JAMA 1999;281:1112-1120. [Medline]
<http://content.nejm.org/cgi/external_ref?access_num=10188663&link_type=MED>
44.     Kuntz KM, Kent KC. Is carotid endarterectomy cost-effective? An analysis
of symptomatic and asymptomatic patients. Circulation 1996;94:Suppl
II:II-194.

Edward E. Rylander, M.D.
Diplomat American Board of Family Practice.
Diplomat American Board of Palliative Medicine.