711
Original Contributions
North American Symptomatic Carotid
Endarterectomy Trial
Methods, Patient Characteristics, and Progress
North American Symptomatic Carotid Endarterectomy Trial (NASCET)
Steering Committee
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Fifty North American centers have combined to evaluate the benefit of carotid endarterectomy in
randomized patients who have experienced symptoms related to arteriosclerotic stenosis of the
carotid artery and who have received either best medical therapy alone or best medical therapy plus
carotid endarterectomy. The outcome events are nonfatal and fatal stroke or death. A three-tier
system identifies and adjudicates the type, severity, and location of each stroke and the cause of any
death. Data about patients submitted to carotid endarterectomy outside the trial are compiled at
the Nonrandomized Data Center at the Mayo Clinic Between December 27,1987, and October 1,
1990, 1,212 patients were randomized, 596 to medical therapy, 616 to carotid endarterectomy.
Cross-over from the medical to the surgical arm has been low (4.2%). Patients eligible for the trial,
but not randomized totaled 1,044; their characteristics were similar to those randomized so that, for
the type of symptomatic patient in this study, our conclusions about the benefit of carotid
endarterectomy can be generalized. Patients excluded by medical criteria totaled 679. Another 1,591
had carotid endarterectomy, but either lacked the disease under study, were asymptomatic, or
received inadequate investigation to meet entry criteria. We set sample size at 1,900 patients, with
continuing enroUment. The Monitoring Committee reviews at intervals the confidential analyses
performed on the groups with moderate (30-69%) and severe (70-99%) stenosis. Stopping rules
will be invoked for one or both groups if unequivocal benefit or harm is identified. (Stroke
1991^2:711-720)
T
he era of the surgical prevention of stroke
began when the first carotid endarterectomy
was performed in 1954.] The popularity of
carotid endarterectomy in the United States increased
from 15,000 performed in 1971 to 107,000 in 1985.
Because differing opinions developed about the efficacy of this procedure, great geographic differences in
its utilization have been documented. In the United
States and Canada, utilization rates were 27 and 7
times, respectively, those in England and Wales.2-3
The first randomized trial evaluating this procedure was published in 1970.4 Although sometimes
interpreted as showing benefit for the surgically
treated groups, the initial report omitted the 11% of
surgical patients who suffered perioperative stroke
morbidity and mortality. After the data for these
patients was replaced, total strokes and deaths were
not different at 42 months in the medical and surgical
groups.5 Moreover, this trial involved only 316 patients with carotid stenosis, and only 42% of these
had carotid artery symptomatology. A second attempt at a randomized trial was abandoned because
of a 35% perioperative stroke and death rate among
the first 43 patients admitted to the study.6
Rationale for the Reevaluation of
Carotid Endarterectomy
Further randomized trials of carotid endarterectomy have been initiated for compelling reasons.
Many studies have confirmed the benefit of antihypertensive drugs and platelet inhibitors in reducing
cerebral ischemia7"9; all varieties of stroke, both
ischemic and hemorrhagic, are declining in countries
See p 816
Supported by National Institute of Neurological Disorders and
Stroke grant R01NS24456 and Canadian Medical Research Council grant Ul-0013.
Address for reprints: Dr. H J.M. Barnett, The John P. Robarts
Research Institute, 100 Perth Drive, London, Ontario N6A 5K8,
Canada.
Received March 2, 1991; accepted March 4, 1991.
where many (United States), fewer (United Kingdom), and almost no (Japan) carotid endarterectomies are being performed.10 On the other hand, the
possibility exists that these improvements in medical
therapy have been exceeded by improvements in surgical management. Many centers report low rates of
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serious perioperative stroke and death, some as low as
2% and 3%. 1 1 1 2 The most carefully documented study
involving only symptomatic patients, coupled with
neurologic input and sufficient numbers to avoid bias,
reports a combined morbidity and mortality of 4.0%.13
However, Hospital Discharge Registry data and data
from other pooled sources document perioperative
complication rates in the United States averaging
close to 10%.2-14 A net benefit from surgery is implausible at these higher rates, but if the lower rates can be
achieved, the operation might be beneficial to selected
patients, if only we knew who they are.
Given these opposing trends, it is understandable
that many experts in the medical and surgical community are uncertain about the efficacy of carotid endarterectomy, but many now have the equipoise that
permits randomized clinical trials of this procedure.15
Three such trials have been launched to evaluate the
benefit of carotid endarterectomy in symptomatic patients, and three others are being carried out in
asymptomatic patients.16 This report describes the
design of the North American Symptomatic Carotid
Endarterectomy Trial (NASCET), its methods and
quality control, and the entry characteristics of its first
1,212 patients. It compares their characteristics with
those of the 1,044 patients who during this period of
time were eligible but were not randomized at these
same participating centers.
Patient Eligibility
Objectives and Organization
The study will determine if carotid endarterectomy is beneficial to patients with carotid stenosis
and transient cerebral ischemia or partial stroke by
comparing patients randomly assigned to receive
carotid endarterectomy in addition to best medical
care with those assigned to receive best medical
care alone. The study is addressing the following
specific questions: 1) Does carotid endarterectomy
reduce the risk of subsequent stroke and strokerelated death? 2) Does the degree of carotid stenosis identify patients who will benefit most from
carotid endarterectomy? and 3) Will carotid endarterectomy maintain or improve the functional status
of patients over time?
The trial was funded in 1987 by the National
Institutes of Neurological Disease and Stroke
(NINDS). The Central Office and Data Management
Center are located at The John P. Robarts Research
Institute, London, Ontario; the Statistical and Quality Control Center is located in the Department of
Clinical Epidemiology and Biostatistics at McMaster
University, Hamilton, Ontario; and a further quality
control center, the Nonrandomized Data Center, is
located at the Mayo Clinic, Rochester, Minn. A steering committee supervises the daily conduct of the trial
and reviews the entry characteristics of ah" randomized
patients and all outcome events; an executive committee supervises the conduct of the trial and adherence
to protocol; a surgical committee reviews the credentials of all surgeons before they are considered eligible
to perform carotid endarterectomy on patients ran-
Clinical requirements. Patients must have experienced, within the past 120 days in the appropriate
carotid artery distribution, either 1) one or more
transient ischemic attacks, characterized by distinct
focal neurologic dysfunction or monocular blindness
with clearing of signs and symptoms within 24 hours,
or 2) one or more minor (nondisabling) completed
strokes with persistence of symptoms or signs for
more than 24 hours. The most recent event is used as
the basis for randomization in patients with symptoms and signs referable to both sides or with more
than one transient ischemic attack or minor stroke.
Radiological requirements. Selective carotid angiography must have been performed within 120 days of
entry with a minimum of two projections showing both
the cervical and intracranial portions of the carotid
arteries and their major intracranial branches. Ipsilateral atheromatous carotid stenosis must be technically
suitable for carotid endarterectomy, with luminal narrowing of 30% or more and without more significant
tandem lesions or complete carotid occlusion. In
addition, computerized tomography of the head, duplex ultrasound of the carotid arteries, and chest
radiograph are required before randomization.
Exclusion criteria. Patients are not eligible for the
study if they 1) are not competent to give informed
consent because of receptive language difficulty, intellectual decline, or psychiatric illness; 2) are without clear and adequate selective angiographic visualization of the carotid arteries or their intracranial
branches; 3) have carotid occlusive disease distal to
the body of the second cervical vertebral body that is
more significant than the surgically accessible lesion
domized to surgery and monitors the ongoing penoperative record from each center; an adjudication
committee of nonparticipating physicians and surgeons reviews all the details of each outcome event;
and a monitoring committee appointed by and reporting to NINDS ensures adherence to protocol and the
responsible conduct of the trial. The study personnel
are presented in the "Appendix."
Methods
Center Eligibility
To be admitted to the study, a potential participating center has to demonstrate effective collaboration
among surgeons, neurologists with special interest in
cerebrovascular disease, and neuroradiologists; perform a review of the last 50 carotid endarterectomies
performed within the prior 24 months by potential
participating surgeons in a center that demonstrates
a 30-day perioperative stroke and death rate of
<6%; agree to offer randomization to all eligible
patients; agree to document all eligible, but not
randomized, patients; confirm that continuing neurologic follow-up and documentation of all randomized
patients and all events will be feasible; and obtain
approval by the local human ethics committee.
NASCET Steering Committee NASCET Trial
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in the more proximal portion of the artery; 4) have
total internal carotid artery occlusion or carotid
stenosis of less than 30%; 5) have no symptoms
appropriate to the stenotic lesion; 6) are more than
79 years of age; 7) have organ failure of kidney, liver,
heart, or lung or have cancer likely to cause death
within 5 years; 8) have had a cerebral infarction on
either side of sufficient size to deprive the patient of
all useful function in the affected territory; 9) have
symptoms due to nonarteriosclerotic disease; 10)
have a cardiac valvular lesion or rhythm disorder of a
type likely to be associated with cardioembolic cerebral vascular symptoms; 11) have not had an ischemic
event in the appropriate territory within the previous
120 days; and 12) have had a previous ipsilateral
carotid endarterectomy. Patients who fulfill the other
criteria but will not accept randomization or are
persuaded by their medical advisors to decline it
cannot be enrolled. Every ineligible patient and every
eligible but not randomized patient, including every
patient undergoing carotid endarterectomy outside
the trial for whatever reason at each participating
center, are entered in the nonrandomized data base.
Temporary ineligibility. Temporary ineligibility is
imposed if the patient 1) has uncontrolled diabetes
or hypertension, 2) has unstable angina or has had a
myocardial infarction within the past 6 months, 3)
has progressing neurologic signs, 4) has had a contralateral carotid endarterectomy within 4 months, or
5) has had a major surgical procedure within the last
30 days. This ineligibility is only temporary if these
conditions are corrected within the 120-day limit.
Patients who have had a recent cerebral infarction
with no residual useful function of limbs appropriate
to the carotid stenosis or speech also are accepted for
randomization if some useful function develops before the 120-day time limit is reached.
Baseline Investigations
Standardized forms are used to record pertinent
history and detailed neurologic and general medical
examinations, including blood pressure, cardiac rate,
rhythm, and murmurs; a 12-point functional status
assessment relating to the patient's ability to perform
the activities of daily living17; history of other vascular
disease, diabetes mellitus, hypertension, angina pectoris, myocardial infarction, intermittent claudication, and cigarette smoking; employment status; current medications and recent changes in medications;
blood tests (CBC, PT, BUN, creatinine, fasting or
random glucose, fasting cholesterol, HDL, LDL, and
triglycerides); and 12-lead electrocardiogram.
Randomization
If the patient satisfies eligibility on clinical and
radiological grounds, informed consent is requested
and the patient is given a tentative date for surgery.
The center coordinator immediately communicates
via a computerized telecommunications network with
the Data Management Center where the patient's
eligibility is confirmed, and based on a computer-
713
generated randomization scheme stratified by center,
the patient is assigned to receive either best medical
care alone or best medical care plus surgery.
Treatment
Participating physicians apply the best available
medical therapy to all treatable risk factors. Blood
pressure and blood cholesterol levels are monitored,
and physicians are advised any time their patients
exceed preset limits so that individualized treatment
can be applied. Aspirin is recommended for all
patients at a dose of 1,300 mg/day; lesser amounts
are administered when required by side effects. Intolerance to aspirin is not an exclusion criterion.
Surgery, if assigned, is completed at the earliest
opportunity after randomization by a surgeon accredited by the surgical committee. Surgical technique,
including anesthetic method and the use of intraoperative monitoring, shunting and patch-grafting, are
left to the discretion of the surgeon but are recorded.
The appearance of the plaque is described. Patients
randomized to surgery who have bilateral lesions may
have carotid endarterectomy on one or both carotid
arteries as decided by their attending clinicians, but
the initial surgery is to be on the symptomatic side.
Patients with bilateral lesions when randomized to
medical care should not have surgery on either side.
Simultaneous coronary bypass grafting or simultaneous bilateral carotid endarterectomy are proscribed. The performance of other major elective
surgical procedures within the 30-day period after
carotid endarterectomy is strongly discouraged.
Follow-up
All surgical patients are scheduled to be seen 30
days after surgery, with medical patients seen at 32
days after randomization. Within 30 days of surgery
or at discharge, whichever comes first, the participating surgeon completes the surgical report of the
carotid endarterectomy. Any perioperative complications or outcome events (stroke or death) are reported. Patients are seen every 3 months for the first
year and every 4 months thereafter. Medical, neurologic, and functional status are reported at each visit,
documenting the occurrence of transient ischemic
attack, the presence and severity of all nonfatal
strokes, and all deaths. Medical therapy, changes in
medication, and any interval operative procedures
are noted. Progress in the management of risk factors, smoking, blood pressure, and cardiac status are
recorded, as is the interval employment history.
At each anniversary, patients undergo repeat
complete blood count, biochemistry, and examination of blood lipids. The electrocardiogram is repeated when clinically indicated and at the end of
the trial. A computed tomographic scan of the head
is obtained after any interim cerebral vascular event
and at the end of the trial. The duplex carotid
ultrasound is repeated at 1 month, after any interim
ischemic event in the carotid distribution, and at
the end of the trial. Carotid angiography is repeated
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after any interim cerebral vascular event when
considered clinically appropriate.
Stroke and death constitute the outcome events and
are reported to the Data Management Center. As
soon as all information about outcome events becomes
available to the Central Office, it is evaluated—first, in
the case of death, as to cause, and second, as fatal
versus nonfatal stroke, to determine location, type
(ischemic infarction with or without a hemorrhagic
component, cardioembolic infarction, intracerebral
hematoma, subarachnoid hemorrhage), laterality, severity, and duration. Stroke types are defined in the
protocol, the operating manual, and in the instructions
to NASCET adjudicators and follow the standard
definitions published by the NINDS Committee on
Classification of Cerebrovascular Disease.18
A lesion with the appearance of an ischemic infarction identified on a computed tomographic scan
is not recorded as a stroke unless appropriate signs or
symptoms have persisted beyond 24 hours.
Multilevel adjudication occurs, both for the eligibility of patients at the time of randomization and for
outcome events of stroke or death. The first level is
where the participating neurologist and surgeon
agree that each patient is eligible and where they
agree on the nature of each outcome event, and in
the case of stroke, on its type, location, and severity.
After documentation at the participating center, such
data are sent to the Data Management Center. Here,
a staff neurologist examines all entry forms and all
information on outcome events.
Entries for which there are no deviations from the
protocol are designated as "ideal cases"; the data are
entered directly into the computer, and the patients
are notified for regular follow-up visits. Entries for
which questions of conformity to the protocol arise
are reviewed weekly by the steering committee, constituting the second level of adjudication. If entry has
occurred with the appropriate baseline criteria but
designated exclusion criteria have been overlooked,
the patient is kept in the trial, followed regularly, but
categorized as an "imperfect case." If the patient
does not have arteriosclerotic disease or appropriate
symptoms, the patient is an "exclusion" and is followed only at annual intervals.
NASCET staff neurologists present all outcome
events to the steering committee without disclosing
the treatment arm to which the patients were randomized. Finally, at the third level of adjudication, all
pertinent data about outcome events are submitted
to one member of a panel of senior neurologists and
surgeons not involved in the trial nor aware of the
treatment category. They also are denied all information that would betray treatment except in the
case of immediate postoperative events for which
blinding of documents cannot be accomplished. Disagreement in conclusions between the steering committee and the external adjudicators leads to further
independent adjudication until resolution.
Hard copies of all angiograms, computerized tomographic studies, and duplex ultrasound studies are
analyzed at the Central Office by the principal neuroradiologist and principal ultrasonographer. Special
attention is given to the stenotic plaque both on
angiography and ultrasound. Residual plaque 30
days after surgery is compared to the prerandomization images. From the films made during angiography, measurements are recorded of 1) the luminal
diameter, from two projections when possible, identifying the narrowest lumen; 2) the diameter of the
normal artery just beyond the stenosis; and 3) the
diameter of the normal artery beyond the carotid
bulb. For eligibility purposes only, the percent
luminal narrowing derived from the first two diameters is accepted, whereas for analysis purposes, the
percent luminal narrowing is derived from the first
and third diameters (Figure 1).
Sample Size and Statistical Analyses
The trial was designed to evaluate carotid endarterectomy in each of four angiographic subgroups defined by the degree of stenosis (30-69% and 70-99%)
and the presence or absence of ulceration. Sample size
requirements were derived from estimates of the
annual risk of fatal and nonfatal stroke from 4%
among patients with moderate stenosis and no ulceration to 7% among patients with severe stenosis plus
ulceration; the desire to detect a 50% reduction in the
risk of stroke if surgery is efficacious; a perioperative
risk of stroke or death not exceeding 6%; an average
patient follow-up of 5 years; and Type I and Type II
error rates of 5% (one-tailed) and 10%, respectively.
The original sample size calculations, which allowed
for independent analyses of each of these four angiographic subgroups, summed to a target of 3,000 patients. It became clear, as the Central Office angiographic review was compared with the appearance of
the plaque described in the surgical reports, that
ulceration could not be assessed reliably.19 This factor
was removed from the planned primary analysis, leaving just the two subgroups of high-grade (70-99%)
and moderate stenosis (30-69%).
Revised sample size calculations were made for
these two subgroups, taking into account current
estimates of overall stroke from our own data base.
The revised sample size requires 600 patients with
high-grade stenosis and 1,300 with moderate stenosis
and in each subgroup still provides 90% power to
detect a 50% reduction in stroke with an average
patient follow-up of 5 years, with a one-tailed significance level (a) of 0.05.
The primary method of analysis will compare
medical and surgical patients on "time to treatment
failure" using the Mantel-Haenszel \2 test and Kaplan-Meier survival curves. Treatment failure is defined as 1) any stroke ipsilateral to the carotid lesion,
2) any stroke ipsilateral or contralateral to the qualifying carotid artery lesion, or in vertebral-basilar
territory, and 3) any stroke or any death.
In all three of these analyses, we will count also any
stroke (regardless of side) and any death (regardless
of cause) that occurs during the 30-day postoperative
NASCET Steering Committee NASCET Trial
715
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FIGURE 1. For each projection, three
measurements record the luminal diameter of the site of greatest narrowing (measure 1), the artery beyond the visible plaque
(measure 2), and the artery beyond the
plaque and bulb (measure 3). Using the
worst projection, with measure 1 as numerator and measures 2 or 3 as denominator, the percent stenosis is calculated.
For randomization calculations, the formula is (1—[measure 1 /measure 2])*.
100%; for data analysis, (1—[measure
1/measure 3])xl00%. Panels A-F depict
the more common combinations of plaque
location, bulb changes, and altered distal
artery diameter. Calculated percent stenosis for panels A-E, using measure 1 as
numerator and measures 2 and 3 as denominator, respectively, are panel A: 0%,
0%; panel B: 40%, 40%; panel C: 79%,
70%; panel D: 40%, -10%; panel E:
69%, 50%. In panel F, the distal narrowing from reduced flow, flaws calculations,
and 95% is assigned to both calculations.
period among surgical patients and during a comparable period after randomization among medical
patients. These three analyses will be repeated after
minor strokes are removed and only those major
strokes that lead to significant disability or death are
counted. Thus, a total of six separate survival analyses will be presented for each of the two angiographic
subgroups. Efficacy analysis and intention-to-treat
analysis will be conducted in each instance. In addition to the survival analyses, treatment groups also
will be compared on the basis of the patients' functional status over time. Tables will be prepared that
describe the type and number of strokes and deaths
observed in each treatment group.
Interim analyses, initiated in January 1990 (2 years
after the randomization of the first patient), are
performed monthly for each of the above definitions
of treatment failure in each of the two angiographic
subgroups. The results of these analyses, known only
to a senior study biostatistician and a senior study
epidemiologist, will trigger notification of the chairman of the National Institutes of Health monitoring
committee if any monthly analysis crosses the 0.001
level of statistical significance, with all cases complete
and all events adjudicated. These results, however,
will only trigger the stopping rule if this difference
persists at the 0.001 level over a 6-month period and
if the supporting analyses that will be undertaken to
explore the results in detail indicate that the interpretation of these results is unambiguous and clinically important. The stopping rule for lack of surgical
benefit will be invoked if the results make it possible
to rule out confidently the possibility of even a 10%
relative risk reduction with carotid endarterectomy.
Results in Terms of Patient Acquisition
Entry Characteristics
The comparison between the baseline characteristics of the patients randomized to medical care
(n=596) or medical care plus carotid endarterectomy
(n=616) between December 27,1987, and October 1,
1990, is presented in Table 1. There are no statistically significant differences in those assigned to the
medical and surgical arms. A good balance in past
medical history resulted from randomization (Table
2). The protocol called for the exclusion of patients
with cardiac conditions likely to lead to cerebral
embolization, so that threatening heart disease is
infrequent. For example, only 11 patients with a
history of atrial fibrillation were randomized to the
TABLE 1.
Baseline Characteristics of Randomized Patients
Sex(%)
Male
Female
Age (yrs)
Median
Range
Race (%)
White
Black
Other
Employment status (%)
Employed
Unemployed
Retired
Medical
(«=596)
Surgical
(n=616)
Total
(n = l,212)
71
29
69
31
70
30
66
31-79
65
31-79
66
31-79
92
92
93
3
4
4
3
4
36
26
38
26
38
39
36
36
5
25
716
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Vol 22, No 6 June 1991
TABLE 2. Medical History at Baseline
TABLE 3. Cerebral Vascular Status at Baseline
Medical Surgical
(n=596) (n=616)
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Smoking
Nonsmoker
Current smoker
Past smoker
Alcohol abuse
None
Current
Past
Past medical history
Congestive heart failure
Atrial fibrillation
Other cardiac arrhythmia
Valvular heart disease
Previous myocardial infarction
Angina pectoris
Intermittent claudication
Status at entry
Hypertension
No
Yes, on treatment
Yes, not on treatment
Diabetes
No
Yes, on insulin
Yes, not on insulin
Hyperlipidemia
No
Yes, on treatment
Yes, not on treatment
Antithrorabotic medication
ASA, -325 rag
ASA, -650 rag
ASA, - 1 3 0 0 mg
Other drug
None
Total
18
36
46
18
38
44
18
37
45
84
6
10
83
4
13
83
5
12
2
2
4
2
18
24
15
2
1
4
2
19
23
13
2
1
4
2
19
24
14
39
54
7
37
56
8
38
55
8
79
7
15
80
7
14
79
7
14
75
17
8
79
14
7
77
15
8
36
21
29
10
4
37
22
27
8
6
37
21
28
9
5
ASA, aspirin.
medical group and seven to the surgical arm. In all
but one instance, the fibrillation had been transient
and related to a previous cardiac event, sepsis, or
anesthesia. The cerebral vascular features (Table 3)
indicate that 61% of the patients were entered
because of transient events and 39% because of a
recent nondisabling ischemic event of more than 24
hours' duration. Twenty-eight percent of the entrants
had experienced retinal as opposed to hemispheric
ischemia. The recency of the event or events that led
to randomization was at a median of 27 days.
Table 3 records the percentage of patients with
degrees of stenosis measured both at the participating centers and in the Central Office. The use of the
Central Office measurement to catalogue the degrees
Medical
Surgical
(n=616)
Qualifying event (%)
TIA
62
60
Stroke
38
40
Vascular distribution (%)
Hemispheric TIA
39
36
Hemispheric stroke
33
36
Retinal TIA
23
24
Retinal stroke
5
4
Recency (days)
26
Median
28
0-122
0-122
Range
Angiography reported by participating centers
Stenosis (%)
33
34
Moderate (30-69%)
67
Severe (70-99%)
66
Central angiographic review
Stenosis (%)
12
Mild (<30%)
14
40
Moderate (30-69%)
39
Severe (70-99%)
48
47
Total
(/! = 1,212)
61
39
38
34
24
4
27
0-122
33
67
13
39
48
Degrees of stenosis vary between the participating centers and
the Central Office review because of the use of different denominators (see Figure 1).
TIA, transient ischemic attack
of stenosis (described in "Methods") places 13% of
the patients below the 30% level ("imperfect cases").
Nonrandomized
Patients
The clinical coordinator in each participating center is authorized by the participating institution to
identify from the operating room lists and the angiography suite all patients eligible for randomization
into the trial and all patients submitted to carotid
endarterectomy. For each institution, four groups of
patients emerge, and the numbers in each group
identified by October 1, 1990, are 1,212 for those
eligible and randomized (ER), 1,044 for those eligible but not randomized (ENR), 679 for those eligible
but with medical exclusions for which our protocol
proscribes entry into the trial, and 1,591 for those
who do not fulfill our baseline criteria but are submitted to carotid endarterectomy.
Table 4 summarizes the characteristics of the
ENR patients. The similarity between ER and ENR
patients has persisted at each quarterly comparison
made since the first year of the trial. A larger
proportion of those who were assigned without
randomization to surgery had severe stenosis
(78%). Conversely, a lower proportion of those
assigned empirically to be treated only medically
had severe stenosis (43%). The available measurements of degree of stenosis recorded in the ENR
patients are those made in the participating centers,
not amended to meet our strict analysis needs.
When comparable measurement methods are used,
NASCET Steering Committee NASCET Trial
TABLE 4. Baseline Characteristics of Eligible
Nonrandomized Patients
TABLE 5. Reasons for Eligible Patients Not Being
Randomized (n = 1,044)
Medical Surgical
Total
(n=2O4) [n =840) („=. 1,044)
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Sex(%)
Male
Female
Age (mean yrs)
Race (%)
White
Black
Other
Employment status (%)
Employed
Retired
Unemployed
Smoking (%)
Nonsmoker
Current smoker
Past smoker
Past medical history (%)
Diabetes
Angina pectoris
Previous myocardial infarction
Hypertension
Intermittent claudication
Qualifying event (%)
TIA
Stroke
Vascular distribution (%)
Hemispheric TIA
Hemispheric stroke
Retinal TIA
Retinal stroke
Both, TIA
Both, stroke
Angiography reported by centers
Stenosis (%)
Moderate (30-69%)
Severe (70-99%)
717
70
30
66
66
34
64
67
33
65
94
1
5
96
2
2
95
2
3
32
39
29
28
39
33
33
39
28
27
43
30
27
35
38
27
37
36
21
18
22
65
9
17
25
21
57
18
17
23
21
58
17
62
38
78
22
75
25
45
34
16
4
1.4
0
43
19
32
3.9
2.6
0.5
43
22
29
3
2.3
0.4
57
43
22
78
29
71
Features of these patients are not different compared to the
randomized group.
TIA, transient ischemic attack.
there is little difference between the numbers of
ENR and ER patients with severe stenosis (71%
and 67%, respectively).
Table 5 summarizes reasons given for not submitting patients to randomization even though they meet
all eligibility criteria. Table 6 indicates reasons for
exclusion due to medical ineligibility. The majority
(rc=486) of the ineligible patients received surgery
outside the study; 193 were treated medically.
A fourth category of patients (n=l,591) received
carotid endarterectomy in our centers. They were not
eligible for the trial because they did not meet our
baseline criteria either because they lacked an angio-
Reason
Percent
Patient insisted on surgical therapy
Patient insisted on medical therapy
Patient did not wish to participate in a trial
Attending surgeon did not wish patient to
participate in a trial
Referring physician did not wish patient to
participate in a trial
Attending neurologist did not wish patient to
participate in a trial
Inadequate communication to patient about study
58
18
26
25
9
8
9
Many patients are included in more than one category.
graphically defined and surgically accessible carotid
stenosis between 30% and 99% or lacked ipsilateral
appropriate carotid artery ischemic symptoms less
than 120 days before randomization. The reasons for
patients not qualifying are set out in Table 7. The
majority lacked recent symptoms (74%) or were
asymptomatic (66%). Although 27% did not fulfill our
baseline criteria because of inadequate angiography,
only 10.9% were inadmissible for this reason alone.
Conduct of the Trial
Accrual
Commitment to engage in the trial has involved 49
centers. Five have become inactive because of an
unanticipated paucity of suitable patients. A mean of
24.7 patients have been randomized in each of the
centers continuing to be active, and a median number
of 20 patients have been randomized in each center.
The average length of follow-up of the 1,212 patients
at October 1,1990, was 16.5 months. All centers have
encountered declining referral of appropriate patients compared with carefully constructed pretrial
estimates based on the centers' activity in carotid
endarterectomy in recent years (Figure 2).
Medical Management
The supervision of the medical therapy of each
patient throughout the trial, whether in the medical
or surgical arm, is assigned to the center neurologist.
An internist at the Quality Control Center keeps this
medical therapy under surveillance, with particular
reference to the regulation of blood pressure and use
of platelet inhibitors. Antihypertensive therapy was
being given at baseline in 60% of the patients and in
56% at the last available follow-up. Antithrombotic
therapy was administered at baseline and follow-up
in 95% and 98%, respectively. Medical and surgical
arms were similar in respect to these therapies.
Crossovers
Of 596 patients assigned to medical therapy, 25
(4.2%) have received surgery. Eight of the 25 had
reached an outcome event of stroke before crossover.
Of 616 assigned to surgery, nine (1.5%) declined
carotid endarterectomy after randomization. Strokes
718
Stroke Vol 22, No 6 June 1991
# Patients
Jan Feb Mar Apr May Jun Jul Aug Ssp Oct Nov Doc Jan Fab Mar Apr May Jun Jul
I
89
I
SO
I
FIGURE 2. NASCET trial monthly log; number of
randomized vs. nonrandomized patients. Upper line
indicates a declining number ofpatients submitted to
carotid endarterectomy in all centers and includes
patients both eligible and noneligible. Lower lines
indicate a continuing ratio of approximately 1:1 for
patients eligible who have been randomized and
those eligible who have not been randomized
(ENR).
Month
' Total Rwtorrind
T O M Non-Rtndamtud
*
TOM ENR
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occurring after crossover are counted and reported
but will not be included in the statistical analyses.
Two common reasons account for the decision of the
patient or his attending medical advisors to seek treatment other than in the randomized assignment First,
some patients do not understand the randomization
process and soon after assignation demand the other
treatment. Second, some patients assigned to medical
care become apprehensive about continuing transient
ischemic attacks and seek the alternative of surgery.
Surgical Performance in the Study
The performance of each surgeon in each center is
evaluated continuously by the principal surgical investigators. Notification of a perioperative death or
stroke leads to a personal call to the surgeon involved
to discuss the details of the perioperative event.
Based on the first 616 surgical cases, the 30-day
perioperative rate of death and stroke remains below
the 6% limit set for entry into the trial.
Conduct of the Surgery
The majority of procedures have been conducted
under general anesthesia; a few surgeons have favored local anesthesia. The median anesthetic time
has been 3 hours, indicating a surgical time between
2 and 2.5 hours. Shunts have been used in 40% of
patients. The unshunted clamp times (median, 32
TABLE 6. Reasons for Exclusion of Ineligible Patients (n=679)
Reason
Prior ipsilateral carotid endarterectomy
Cardiac source of emboli
Coronary artery disease
Major cardiac arrhythmia
Age greater than 79 yrs
Cancer other than skin
Pulmonary/liver/renal failure
Stroke too severe
Cardiomegaly
Incompetent to give informed consent
Percent
14
14
13
12
11
11
10
9
9
9
Ten most common categories of exclusion are shown; a number
of patients had more than one excluding reason.
minutes) are characteristic of most reports.20 Arteriotomy closure techniques have varied; simple closure
was used in the majority (83%) and fabric and vein
patches in 8% and 9%, respectively.
The amount of residual plaque in postoperative
ultrasound examinations is viewed as a measure of
surgical competence. The ultrasound examinations
performed 1 month after carotid endarterectomy
have been reviewed: in the first 523 patients, there
was either severe residual stenosis, moderate residual plaque, or mild residual plaque in 1.5%, 2.4%,
and 7.5% of patients, respectively. Occlusion was
detected in 1.7%. These figures compare favorably
with published reports.21"23 A mild stenosis is defined
as a visible wall irregularity impinging on the vascular
lumen, without Doppler abnormality; a moderate
stenosis is defined as a visible wall abnormality with
luminal narrowing up to 50% diameter, with a peak
systolic frequency change less than 4 kHz or a peak
systolic velocity of less than 120 cm/sec; a severe
stenosis is defined as a visible abnormality with a
systolic frequency change of greater than 4 kHz or a
peak systolic velocity of greater than 120 cm/sec.
Nonoutcome Surgical Complications
The majority of the nonoutcome surgical complications, such as wound hematomas, infection, or
cranial nerve injury, have been trivial and of no
clinical consequence. Wound complications severe
enough to cause patients to require extension of
hospitalization or to return to the operating room
TABLE 7. Characteristics of Nonrandomized, Noneligible Carotid
Endarterectomy Group (n=1,591)
Characteristic
No qualifying event in last 120 days
Technically inadequate angiogram
Atherosclerotic stenosis above C2
Stenosis less than 30% or occlusion
Side of carotid stenosis did not match symptoms
(includes asymptomatic patients)
Percent
74
27
2
11
66
Many patients had more than one reason for being outside basic
protocol demands.
NASCET Steering Committee NASCET Trial
(for hematoma or infection) occurred in 4.3% of the
patients. General or systemic complications that have
lengthened the patient's hospital stay or have resulted in permanent disability have occurred in 1.3%.
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Discussion
Forty-nine participating centers randomized 1,212
patients within 26 months of receiving approval to
join NASCET. The patients have had recent hemispheric or retinal events appropriate to ipsilateral
arteriosclerotic stenosis equally divided between
those with severe and those with moderate degrees
of stenosis. All patients exhibit the clinical and
radiological features that experts recommend as the
best currently accepted indications for carotid endarterectomy.24-26 There are two other trials in progress evaluating carotid endarterectomy in symptomatic patients: a European one, which at the end of
1990 had randomized 2,498 patients (C. Warlow,
personal communication), and a trial that involves
patients in the Veterans Administration Hospitals
in the United States.16
The rate of accrual is below early estimates. The
major reasons for this are perceived as twofold: the
tendency of participating centers to underestimate the
effect of the restrictions by a protocol on the numbers
of predicted entrants into a trial, and a decline in
enthusiasm for carotid endarterectomy, which began
coincident with the planning of NASCET.
The question arises of whether the "really appropriate patients" are being operated on outside the
trial. A similar criticism was directed against the
extracranial-intracranial arterial bypass trial.27"30 To
obviate this criticism in NASCET, all patients appropriate for randomization are identified in all participating institutions. As the data reveal, there are no
essential difiFerences between the first 1,212 patients
who were randomized and the first 1,044 who were
eligible but not randomized. There is no evidence
that a group of patients is being deviated from the
trial who would more appropriately respond to the
procedure. The trial is studying results in a representative sample of patients.
Addendum
On February 21, 1991, the NINDS monitoring
committee was presented in confidence with the
latest analyses of the results of this trial. Because a
clinically and statistically significant benefit was evident for the patients who had symptoms related to a
stenosis of 70-99%, the monitoring committee advised the investigators that the trial should be
stopped for these patients. In addition, they advised
that there was need of further accrual of patients
with moderate (30-69%) stenosis and that this arm
of the trial continue.
NINDS has circulated a clinical alert advising the
profession and the public of these results. A copy of
this alert is published in this issue of Stroke.
719
Appendix
Participants and Participating Centers*
Executive and Steering Committee. H.J.M. Barnett,
MD, Principal Investigator, The John P. Robarts
Research Institute; S.J. Peerless, MD, Co-Principal
Investigator (Surgical), and AJ. Fox, MD, Co-Principal Investigator (Radiological), University of Western Ontario; R.B. Haynes, MD, Co-Principal Investigator (Epidemiological), D.W. Taylor, MA, CoPrincipal Investigator (Statistical), and D.L. Sackett,
MD, Co-Investigator (Epidemiological), McMaster
University; R.N. Rankin, MD, Co-Principal Investigator (Ultrasonographic), V.C. Hachinski, MD, CoPrincipal Investigator (Neurology), and G.G. Ferguson, MD, Co-Principal Investigator (Surgery),
University of Western Ontario; D.O. Wiebers, MD,
Co-Principal Investigator (Neurology), Mayo Clinic;
D.A. Sim, PhD, Data Management Director (19871990), and M. Eliasziw, PhD, Data Management
Director (1991), The John P. Robarts Research
Institute.
Additional Members of Executive Committee. G.P.
Clagett, MD, University of Texas at Dallas; J.D.
Easton, MD, Brown University; J.W. Harbison, MD,
Virginia Commonwealth University; R.C. Heros,
MD, University of Minnesota; A.R. Hudson, MD,
University of Toronto; J.R. Marler, MD, National
Institutes of Health; R.A. Ratcheson, MD, Case
Western Reserve; D. Simard, MD, Laval University,
Quebec; M.D. Walker, MD, National Institutes of
Health; P.M. Walker, MD, University of Toronto;
P.A. Wolf, Boston University.
Participating Centers and Principal Contact. V.P.
Sweeney, MD, University of British Columbia; K.M.
Hoyte, MD, University of Calgary; B. Anderson, MD,
University of Manitoba; M.G. Elleker, MD, University of Alberta; A. Shuaib, MD, University of
Saskatchewan; J.D. Spence, MD, University of Western Ontario; V. Hachinski, MD, University of Western Ontario; J.W. Noms, MD, Sunnybrook HospitalToronto; G. Sawa, MD, Mississauga HospitalToronto; F. Silver, MD, University of Toronto; R.
Duke, McMaster University; B.G. Benoit, MD, University of Ottawa; R. Cote, MD, McGill University;
L.H. Lebrun, MD, University of Montreal; D.
Simard, MD, Laval University; C.W. McCormick,
MD, Dalhousie University; E. Daigle, MD, Laval
University; B.M. Coull, MD, University of Oregon;
M. Fisher, MD, University of Southern California; R.
Spetzler, MD, Barrow Neurological Institute; L.
Kesterson, MD, University of New Mexico; R.E.
Kelley, Jr., MD, University of Miami; J. Grotta, MD,
University of Texas at Houston; G.P. Clagett, MD,
University of Texas at Dallas; D.G. Sherman, MD,
University of Texas at San Antonio; R.R. Smith, MD,
University of Mississippi; J.T. Robertson, MD, University of Tennessee; J. Byer, MD, University of
Missouri; C. Gomez, MD, St. Louis University; C.
'Complete listing to appear in forthcoming Results article.
720
Stroke
Vol 22, No 6 June 1991
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Helgason, MD, University of Illinois; H. Adams,
MD, University of Iowa; S. Haines, MD, University
of Minnesota; P. Karanjia, MD, Marshfield Clinic;
R.E. Welling, MD, Good Samaritan Hospital, Cincinnati; R.H. Rosenwasser, MD, Temple University;
O. Reinmuth, MD, University of Pittsburgh; J.W.
Harbison, MD, Virginia Commonwealth University;
A.P. Slivka, MD, Ohio State University; A.G. Reeves,
MD, Hitchcock Clinic; C. Mayman, MD, Beth Israel
Hospital; A. Culebras, MD, State University of New
York; D. Rosenbaum, MD, Albert Einstein College;
J.D. Easton, MD, Brown University; PA. Wolf, MD,
Boston University; W.K. Hass, MD, New York University; J.P. Mohr, MD, Neurological Institute, Columbia University, G. Mohr, MD, Jewish General
Hospital; A.E. Goodridge, MD, Memorial University;
J. Rothrock, MD, University of California; S. Cohen,
MD, Wadsworth Veterans Affairs Hospital.
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KEY WORDS • carotid artery diseases • endarterectomy
North American Symptomatic Carotid Endarterectomy Trial. Methods, patient
characteristics, and progress.
Stroke. 1991;22:711-720
doi: 10.1161/01.STR.22.6.711
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