(Stroke. 1998;29:2371-2376.)
© 1998 American Heart Association, Inc.
Original Contributions |
From the Departments of Neurology (W.T.L.), Epidemiology (W.T.L.), and
Biostatistics (L.S.), University of Washington, Seattle, Wash; Department of
Neurology (D.L.), Wake Forest University, Winston-Salem, NC; Department of
Radiology (D.H.O.), TuftsNew England Medical Center, Boston, Mass;
Department of Radiology (J.F.P.), Brigham and Women's Hospital, Boston,
Mass; and Departments of Surgery and Neurosurgery (S.K.W.), University of
Pittsburgh School of Medicine, Pittsburgh, Pa. Participating institutions and
principal staff are listed in the Appendix
.
Correspondence to W.T. Longstreth, Jr, MD, Department of Neurology, Box 359775, Harborview Medical Center, 325 Ninth Ave, Seattle WA 98104-2499. E-mail wl{at}u.washington.edu
| Abstract |
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MethodsThe Cardiovascular Health Study (CHS) is a longitudinal study of people 65 years and older. Analyses of internal carotid artery stenosis defined by multiple different cutoffs of peak systolic velocity, rather than one particular cutoff, were performed in the 5441 participants who underwent carotid ultrasound and lacked a history of transient ischemic attack or stroke. The 5-year risks of 7 cerebrovascular disease outcomes used in ACAS were estimated for each cutoff.
ResultsAssociations with the 5-year risk of outcomes were substantially elevated only at cutoffs with high peak systolic velocities. In this population, the number of people with such high velocities was small. For example, with a cutoff of approximately 2.5 m/s, suggesting a stenosis of >70%, the 5-year risk of an ipsilateral fatal or nonfatal stroke was 5%, and only 0.5% of the group had velocities at least this high.
ConclusionsIn a group of older adults likely to participate in a screening program, as evidenced by willingness to participate in CHS, high peak systolic velocities consistent with high-grade carotid stenosis were uncommon and risk of subsequent cerebrovascular disease outcomes was relatively low. These findings do not suggest that similar populations of older adults would benefit from a program using ultrasound to screen for asymptomatic carotid stenosis.
Key Words: aged carotid artery diseases ultrasonography, Doppler
| Introduction |
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60% reduction in diameter. The
aggregate 5-year risk for ipsilateral stroke was 5.1% for patients
randomized to the surgical arm and 11.0% for those randomized to the
medical arm. To help clinicians and policy makers decide how best to
generalize the results of such clinical trials, information is needed
from other populations on outcomes such as those reported in ACAS. The
prognosis for patients enrolled in clinical trials may differ from the
prognosis for people from the general population. If so, the results of
such clinical trials should be generalized to other populations with
caution, if at all. The Cardiovascular Health Study (CHS)2 3 is a prospective, multicenter, epidemiological study of risk factors for coronary and cerebrovascular disease in older adults. As part of the study, >5000 participants underwent carotid ultrasound. CHS offers a unique opportunity to evaluate the frequency of high-grade ICA stenosis defined by ultrasound and the risk of subsequent cerebrovascular disease outcomes in an aged population likely to participate in screening programs, as evidenced by their willingness to participate in CHS. Thus, use of data from CHS can help us judge whether the findings of ACAS can be generalized to similar populations of elderly people. Use of data from CHS for this purpose is complicated because different studies have used different ultrasound definitions of high-grade carotid artery stenosis. In this article, rather than examining a single ultrasound velocity cutoff to define stenosis, we examine multiple cutoffs to document both their prevalence and their association with cerebrovascular disease outcomes. These outcomes are contrasted with those reported in ACAS.
| Subjects and Methods |
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65 years, able to
give informed consent, and able to respond to questions without the aid
of a surrogate respondent. They could not be institutionalized,
wheelchair-bound in the home, or under treatment for cancer. Details
about the study design and characteristics of the 5888 participants are
published elsewhere.2 3
Eligible and consenting participants underwent an extensive baseline
evaluation that included standard questionnaires, physical examination,
and laboratory testing, as detailed elsewhere.2 3
Testing included carotid ultrasound, which was performed in a standard
fashion with all 4 centers using identically equipped imaging units
capable of color Doppler imaging and pulsed Doppler
analysis.4 5 All sonographers and readers
underwent the same training. Ultrasound studies were recorded and
sent weekly to the Ultrasound Reading Center for standardized readings.
Pulsed-wave Doppler frequency spectra were obtained from the area
of highest flow velocity in the internal carotid
arteries,4 and peak systolic velocities
were recorded. The peak systolic velocity of the ICA has
been suggested as the single best Doppler measurement for
identifying severe stenosis.6 In previous
reports from CHS,4 5 peak systolic
velocities of
1.5 m/s were assumed to indicate an ICA lumen
stenosis of
50% diameter reduction and those of
2.5 m/s
70% or greater. Of the 5888 members of the CHS cohort, 5859 (99.5%)
underwent carotid ultrasound. Thirty-six participants lacked results on
the peak systolic velocity for technical reasons, and 2
participants had bilateral ICA occlusions. Thus, 5821 (98.8%) had
results on the peak systolic velocity for at least 1 ICA.
For the analyses that follow, we tried to duplicate as closely as possible the methods used in ACAS. The study artery was defined as the ICA with the highest peak systolic velocity. If the velocities were identical on the right and left, the left was chosen, as in ACAS. If one ICA was occluded (n=23), the artery on the opposite side was the study artery. Participants with a confirmed history, prior to their carotid ultrasound examination, of carotid endarterectomy for asymptomatic carotid artery disease (n=49) or of transient ischemic attack (TIA) or stroke (n=331) were excluded because the side of the event was not always reliably known. After excluding these 380 participants, 5441 remained for the analyses.
Incident TIAs or stroke was identified during annual follow-up examinations and at 6-month telephone contact.7 8 All potential TIA and stroke events were adjudicated by a committee of neurologists, neuroradiologists, and internists, who used information from interviews, medical records, and available brain imaging studies. Strokes were classified as ischemic or hemorrhagic, and both were included in these analyses because the two were not seemingly distinguished in ACAS. Strokes were further subdivided by vascular distribution.
Based on these adjudicated events, 7 sets of outcomes listed in
the Table
were defined as follows, using the same classification
as in ACAS: (1) any ipsilateral stroke, fatal or nonfatal; (2) major
ipsilateral stroke, where major stroke is defined as below; (3) any
ipsilateral stroke or TIA; (4) any stroke, whether ipsilateral,
contralateral, or in the posterior circulation; (5) any major stroke;
(6) any stroke or death from any cause; and (7) any major stroke or
death from any cause.
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In ACAS, a major stroke was defined with use of the Glasgow Outcome Scale9 as resulting in moderate or severe disability, persistent vegetative state, or death. Because we did not have the Glasgow Outcome Scale available in CHS, we defined a major stroke as a fatal stroke or as a nonfatal stroke in which the score on the activities of daily living (ADL) measure10 deteriorated by 2 or more points between the most recent prestroke score and one performed at least 3 months but not more than 3 years after the incident stroke. After their stroke, some patients were no longer able to return for follow-up examinations, and no information was available on their ADL score after the stroke. If a CHS participant missed a visit, information was collected to establish the reason. If follow-up visits after a stroke were missed for health-related reasons, we assumed that such patients had experienced a major stroke.
In ACAS, the investigators included all strokes or deaths occurring within 42 days after randomization to the medical group as an outcome to make determinations comparable to the surgical group's postoperative morbidity and mortality.1 No randomization occurred in CHS. To maintain comparability with ACAS as much as possible, we considered instead the 42 days following the day that the carotid ultrasound was performed. During this interval, 5 participants experienced strokes and 7 died. These events were included as outcomes in all the analyses described below.
For each of the 7 outcomes described above and listed in the Table
, we
constructed a separate graph to summarize the results. The horizontal
axis included cutoffs for the peak systolic velocity, ranging
from 0 to 4 m/s. Two vertical axes were used: one indicated the
percentage of participants with a peak systolic velocity of
that value or more, and the other indicated the 5-year risk of the
particular outcome in percentage for participants with a peak
systolic velocity of that value or more. The 5-year risk was
estimated in two ways, one with use of the Kaplan-Meier estimate and
the other with more idealized estimates from Cox proportional hazards
models.11 For the Cox models, we followed the
approach taken by others.12 First, Cox models
were used to compute the 5-year survival estimate when the degree of
stenosis equals 0. The log of this baseline survival estimate
was multiplied by -1 to derive an estimate of the baseline hazard
function. Using this estimate of the baseline hazard function and the
parameter estimated from the Cox model, with the peak
systolic velocity as predictor, we computed the average hazard
rate over 5 years for different cutoffs of peak systolic
velocity.
For these survival analyses, participants were considered to
have achieved 1 of the outcomes specified above at the time of the
incident event that qualified for that particular outcome. A
participant could have experienced >1 event and thus qualified for >1
of the 7 outcomes described above and in the Table
, depending on which
event occurred first. Death unrelated to stroke was a censoring event
except for those outcomes that included death from any cause.
Participants were also censored at the time of either their last
follow-up or a carotid endarterectomy, regardless
of side. Only 62 otherwise eligible participants underwent carotid
endarterectomy during follow-up. The occurrence of
a TIA or stroke prompted the endarterectomy in 24
participants. In the remaining 38, carotid
endarterectomy was performed for
asymptomatic disease. Two (5.3%) of the 38 experienced
postoperative strokes on the day of surgery (95% confidence interval
from the binomial distribution, 0.6 to 17.8).
All of these analyses were based on the updated CHS database, which incorporates minor corrections through March 1997. The analyses include all events adjudicated through June 30, 1995.
| Results |
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The table indicates the number of participants qualifying for each of
the 7 outcomes. The 7 graphs comprising the Figure
display the percent
with a specified velocity or more and the two estimates of 5-year risk
for each of the 7 outcomes considering multiple cutoffs for the peak
systolic velocity. The percent with the specified velocity or
more decreases as the cutoff of the peak systolic velocity
increases. This curve is the same in all of the graphs. Only a small
percentage of the participants are at or above cutoffs for high peak
systolic velocities that would indicate high-grade ICA
stenoses. For example, the percentage with peak
systolic velocity of
1.5 m/s is 3.4%; 2.0, 1.1%; 2.5,
0.5%; and 3.0, 0.3%. The estimates of 5-year risk from the
Kaplan-Meier analyses fall to 0 at the higher velocities for 5
of the 7 outcomes. The fall to 0 indicates that none of the
participants with cutoffs for peak systolic velocity above
these values experienced these outcomes. The estimates from the Cox
models are more idealized and smoothly increase. In all of the figure
panels, the 5-year risks of the outcomes tend to rise as the peak
systolic velocity used for the cutoff increases, regardless of
which method is used to estimate the risk.
|
The risk when the prevalence is at one half of 1% can be found on
these graphs and is listed for each of the outcomes in the Table
. This
prevalence conveniently corresponds to a cutoff for peak
systolic velocity of approximately 2.5 m/s. For comparison, the
Kaplan-Meier estimate of 5-year risk of these outcomes based on
subjects in ACAS who were randomized to the medical and surgical arms
of the study are also listed.1
Of the 5441 participants included in these analyses, 4743 (87.2%) had been examined in a standard fashion by study personnel for cervical bruits and 170 (3.6%) had a bruit on one or both sides. Of the 4743 participants who were examined for bruits, 28 (0.6%) had peak systolic velocity of 2.5 m/s or greater, and 12 of the 28 (42.9%) had a cervical bruit. Thus, considering all 170 participants with a cervical bruit, only 12 (7.1%) were found to have peak systolic velocities of 2.5 m/s or greater.
| Discussion |
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The only 5-year risks that approached those seen in the medically treated group in ACAS were for those outcomes that included death. This finding is not unexpected, given that the mean age of the ACAS subjects was 67 years compared with 73 years for the CHS participants. Also, the participants in CHS were not given optimal preventive care, as was attempted in ACAS. Although they were older, participants in CHS were less likely than those in ACAS to have coronary artery disease, hypertension, and diabetes, and they were less likely to be men and current cigarette smokers.1
Cost-effectiveness analyses incorporating prevalence values for
critical carotid stenosis from ACAS and other studies may
provide exaggerated estimates of the benefits of screening for
asymptomatic carotid artery disease in the
elderly.17 18 In such studies, authors need to
estimate the prevalence of key factors used in the decision
analysis models. In one study,17 the
authors estimated the prevalence of a critical stenosis in a
"high-prevalence model" at 20% (range of values, 10% to 30%) and
in a "low-prevalence model" at 4% (range, 1% to 8%). In the
other study,18 the authors estimated the
prevalence of the critical stenosis at 5% (range, 2% to
13%). These authors showed that the cost of screening for
asymptomatic carotid artery disease does not drop below
$50 000 for a quality-adjusted life-year until the prevalence of a
critical stenosis reaches 40%. In the current study, when we
picked a definition of critical stenosis based on a peak
systolic velocity cutoff of
2.5 m/s, prevalence was 0.5%,
lower than the lowest estimates used in either study of
cost-effectiveness.17 18 In addition, the risk
associated with such stenoses in CHS is similar to the risk
found in the patients treated surgically in ACAS (Table 1
). Picking a
lower cutoff would result in a higher prevalence but also in even lower
risk. Using estimates from CHS on the prevalence of certain
stenoses and the risk associated with such stenoses,
benefit is unlikely to be derived from screening of aged people such as
those in CHS, regardless of the cost.
Some investigators have suggested that the presence of a cervical bruit
would identify a group of people in whom the yield from screening for
high-grade carotid stenosis on ultrasound would be much
higher.19 In CHS, such a strategy would increase
the percent with peak systolic velocities of 2.5 m/s or greater
on ultrasound from about 0.5% (see the Table
and Figure
) to 7%. Such
a strategy would fail to identify over half of those with high-grade
carotid stenosis on ultrasound. The major advantage to such a
strategy would be that only 3.6% of the entire group being screened
would need to undergo ultrasound.
CHS has many strengths, including having characterized a large group of elderly people with respect to cardiovascular and cerebrovascular risk factors and outcomes. Although carotid ultrasound has been performed in over 5000 participants, carotid angiography has not. Correlation of stenosis defined by ultrasound with stenosis defined by angiography is not practical in this study. To address questions about screening with ultrasound in a population like the CHS participants, such a correlation may not be necessary because the cutoffs associated with high risk are encountered in so few participants. Of more concern, the participants studied may not be representative of all such elderly people. For example, 49 participants were excluded because of prior carotid endarterectomy. Such patients may have been eligible for inclusion in ACAS. In addition, 47 of 5441 participants in CHS (0.9%) underwent carotid endarterectomy for asymptomatic carotid artery disease during follow-up. According to the findings in ACAS, 11% (or 5) of them may have experienced an ipsilateral stroke if only treated medically. The influence of such considerations on the results presented is difficult to judge but unlikely to change the conclusions.
The findings of this study fail to support mass screening of aged populations with ultrasound to identify asymptomatic high-grade carotid stenosis for endarterectomy. CHS participants may be healthier than the general population over age 65, but they may be similar in health to the population of elderly people who would likely participate in a mass screening program, as reflected by their willingness to participate in CHS. To be effective, a screening program will need to identify a higher-risk population than the CHS participants and use more than just age and a single carotid ultrasound as a marker for increased risk of future stroke.
| Appendix 1 |
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| Acknowledgments |
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Received May 21, 1998; revision received July 9, 1998; accepted August 13, 1998.
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