Stroke

stroke.ahajournals.org
Stroke. 1996; 27: 1479-1486
doi: 10.1161/01.STR.27.9.1479

Articles
ShorttermPredictorsofIncidentStrokeinOlderAdults
TheCardiovascularHealthStudy
Teri A. Manolio, MD, MHS; Richard A. Kronmal, PhD; Gregory L. Burke, MD, MS;
Daniel H. O'Leary, MD; Thomas R. Price, MD; for the CHS Collaborative Research
Group
+

Author Affiliations

Correspondence to Teri Manolio, MD, MHS, National Heart, Lung, and Blood
Institute, 6701 Rockledge Dr, Rm 8160, Bethesda, MD 20892-7934.

Abstract
Background and Purpose Risk factors for incident stroke have been examined in
middle-aged persons, but less is known about stroke precursors in the elderly, who
suffer the highest rates of stroke. Short-term risk factors for incident stroke were
examined in a longitudinal, population-based study including extensive measures
of subclinical disease.
Methods Prospective study of 5201 women and men aged 65 years and older was
undertaken in the multicenter Cardiovascular Health Study.
Results During an average 3.31-year follow-up, 188 incident strokes occurred.
Stroke incidence increased significantly with age and was similar in women and
men. Factors associated with increased stroke risk in multivariate analysis included
age, aspirin use, diabetes, impaired glucose tolerance, higher systolic blood
pressure, increased time needed to walk 15 ft, frequent falls, elevated creatinine
level, abnormal left ventricular (LV) wall motion and increased LV mass on
echocardiography, ultrasound-defined carotid stenosis, and atrial fibrillation.
Increased LV mass and carotid stenosis were associated with twofold and threefold
increases in incidences of stroke, respectively (P<.001). Aspirin users had a 52%
higher risk of stroke (relative risk, 1.52; 95% confidence interval, 1.1 to 2.0;
P<.007) after adjustment for other factors. This association was present only
among aspirin users without prior coronary disease, atrial fibrillation, claudication,
or transient ischemic attack, who had an 84% higher risk (relative risk, 1.84; 95%
confidence interval, 1.2 to 2.8).
Conclusions Short-term risk of stroke has a complex relationship with aspirin use
and is strongly related to subclinical disease in this sample of older adults. These
relationships should be considered in assessing stroke risk in the elderly, in whom
recognized and subclinical cardiovascular disease is highly prevalent.
Key Words:
aged
stroke, cerebrovascular disorders
epidemiology
risk factors

Stroke is the third leading cause of death in the United States and a leading cause
of serious disability, particularly among the elderly. Stroke incidence rises sharply
with advancing age, but most studies have examined stroke risk factors
2 3 4
predominantly in middle age.
Other than a report from the Framingham
5
study, which focused on AF, studies assessing stroke risk in the elderly have been
678
relatively small or limited to men.
Risk factors for stroke in middle-aged population samples have included age; male

sex; hypertension; obesity; smoking; low vital capacity; ECG LV hypertrophy; prior
heart disease; AF; increased alcohol intake; decreased physical activity; maternal
history of stroke; and elevated levels of fibrinogen, uric acid, hematocrit,
triglycerides, and fasting and postchallenge glucose. Some differences in risk
factors for thromboembolic versus hemorrhagic stroke have been noted,
particularly in the relationship of the latter with increased alcohol intake and low
3
cholesterol levels. Relationships of cerebrovascular disease with established risk
factors may also differ with increasing age, as has been suggested for such
9 10
coronary disease risk factors as systolic blood pressure and total cholesterol.
The CHS cohort represents a large multicenter sample of older men and women
followed up for the development of stroke and other cardiovascular diseases.
Incident stroke data from an average follow-up of 3.31 years were analyzed to (1)
determine the age- and sex-specific incidence of stroke and stroke subtypes
among women and men aged 65 years and older, (2) compare baseline
characteristics in women and men with and without incident stroke to identify
bivariate associations with stroke incidence, and (3) determine the strength and
independence of these risk factors in multivariate analysis.

SubjectsandMethods
CHS participants were recruited from a random sample of the Health Care Financing
Administration Medicare eligibility lists in four US communities: Forsyth County,
NC; Sacramento County, Calif; Washington County, Md; and Pittsburgh (Allegheny
1 11
County), Penn. Details of design and methods have been published.
AscertainmentofIncidentStroke
Potential stroke events were identified during annual follow-up examinations and
at interim 6-month phone contacts. The participant or his or her next of kin were
interviewed shortly after the event about the surrounding circumstances. Hospital
records for all reported strokes, as well as nonstroke hospitalizations with
12
International Classification of Diseases, 9th Revision,
codes 430 through 438
identifying cerebrovascular disease, were abstracted for pertinent information and
reviewed by a neurologist at each field center. Information on reported
nonhospitalized stroke patients was obtained by physician questionnaire. This
information was reviewed by a CHS neurologist at each field center, and any
inconsistencies were reviewed with the participant's physician. When available,
copies of CT and/or MRI scans were obtained and reviewed centrally; films were
available in 70% of adjudicated strokes and hard-copy reports in an additional 17%.
Potential stroke cases were adjudicated by a committee of neurologists,
neuroradiologists, and internists using information from interviews, medical
records, and available cerebral imaging studies. Adjudication decisions were usually
unanimous in terms of presence of stroke, stroke subtype, and stroke as a cause of
death.
Criteria for stroke were similar to those used in the Systolic Hypertension in the
13
Elderly Program.
Stroke was defined as a subarachnoid hemorrhage or a
neurological deficit of rapid onset lasting more than 24 hours unless death
supervenes or, if less than 24 hours, an appropriate lesion to explain the deficit
was seen on brain imaging.
Strokes were classified as due to hemorrhage if there was evidence of blood in the
subarachnoid space, ventricles, or parenchyma seen on cerebral imaging that did
not appear consistent with hemorrhage into an infarction. Strokes were classified as
hemorrhagic if there was bloody spinal fluid on lumbar puncture or evidence of
hemorrhage at surgery or autopsy. Patients dying less than 24 hours after onset
were assumed to have hemorrhage as a cause if they did not have lumbar puncture,
cerebral imaging, or autopsy.
Strokes were classified as ischemic infarction if there was evidence of focal brain
deficit without lumbar puncture or imaging, surgical, or autopsy evidence for
primary hemorrhage. The stroke type was defined as unknown if information was
insufficient to classify it as due to hemorrhage or ischemia. Methods of stroke
14
classification and subtyping have been published.
StatisticalAnalysis
Significance of differences between participants with and without stroke was
2

assessed with tests for proportions and t tests for continuous variables. The logrank test was used to test equality of event-rate curves.
All factors examined for associations with stroke incidence in bivariate analysis
were entered into a forward stepwise proportional-hazards analysis to identify
independent predictors of stroke. Variables that could be considered subsets of
other variables, such as individual neurological symptoms or different
antihypertensive medications, were presented to models only if the overall variable
was significantly associated (P<.05) in stepwise analyses. Multivariate analyses were
initially stratified by sex and then repeated for women and men combined because
sex-specific results showed similar associations (model 1). All analyses were
performed using the SPSS/Windows System.
Linearity of associations for ordinal variables significant in bivariate analysis was
assessed by comparing stroke incidence at varying levels; if risk appeared to show
a threshold at some distinct value, data were recorded as discrete variables above
and below that threshold. This was particularly true for timed walking and number
of days of aspirin use.
Potential nonlinear relationships of continuous variables were assessed using
quintiles of these variables defined only in persons suffering stroke so as to yield
an equal number of strokes in each event-defined quintile. Compared with
quintiles defined in the entire population at risk, this method increases the ability
to detect nonlinear relationships and provides a larger number of events in the
lowest-risk quintile, which is usually used as a comparison group for estimating
relative risk. Increased numbers of events in the event-defined lowest quintile
enhances the stability of the incidence estimate in this group, thus decreasing the
variability of risk estimates generated from it.
When a variable was a significant predictor of stroke both as a continuous variable
and for the event-defined quintiles, and excess risk was clearly confined to the last
category, it was dichotomized above and below the fifth-quintile cut point. When
there was no evidence of nonlinear associations or nonlinear interactions with key
variables, the variable was used in its continuous form.
15

Missing data were frequent for LV mass, so an imputation formula was calculated
from the linear regression equation based on the best predictors of LV mass for the
observed data. These predictors included sex, coronary disease, left atrial
dimension, weight, ECG LV mass, diastolic and systolic blood pressures, maximum
carotid diameter, presence of definite CHF, and resting heart rate. When any of
these variables was missing, LV mass was imputed from sex, weight, and presence
of major ECG abnormalities. Where missing data seemed likely to be associated
with high-risk categories (timed walking, for instance, cannot be performed by
disabled persons, and intimal-medial thickness cannot be measured in calcified
plaque) and bivariate analyses of risk supported this supposition, missing data
were replaced with the highest-risk category. Aspirin use, AF, and LV wall motion
abnormalities were assumed to be absent if data were missing. Multivariate
modeling was repeated with imputation for missing data (model 2). To permit
comparison with published studies that did not conduct noninvasive testing,
modeling was also repeated excluding echocardiographic and ultrasound variables
(model 3).

Results
Prior stroke was reported in 70 women and 114 men (total, 184) of whom 41 (22%)
had a recurrent stroke. These 184 prevalent cases were excluded from analysis for
incident stroke, leaving 5017 participants at risk during an average follow-up of
3.31 years (maximum, 4 years).
Ninety-four women and 94 men suffered an incident stroke during follow-up.
Stroke incidence increased significantly with age in women and men (P<.0001) but
did not differ significantly by sex after adjustment for age (Fig 1). Nonfatal
strokes were further classified by stroke subtype. Of incident nonfatal strokes, 5%
(n=18) were classified as due to hemorrhage (not including hemorrhagic
infarctions) and 87% as ischemic, and 8% were unclassified. Hemorrhage was
slightly more common in men and unclassified subtype in women, but these
differences were not significant.

Figure 1.
Incident stroke by age and sex.

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Participants suffering a stroke during follow-up were older, more likely to have
hypertension and higher systolic and diastolic blood pressures, and more often
taking antihypertensive agents and aspirin at baseline than those not suffering a
stroke (Table 1). They were also more likely to have diabetes; higher levels of
fasting and 2-hour glucose, 2-hour insulin, creatinine, and factor VIII; lower levels
of HDL cholesterol and factor VII; and greater chair-stand and 15-ft walk times.
Because relationships with 15-ft walk and creatinine appeared distinctly nonlinear,
these variables were also analyzed categorically. Participants with stroke were less
likely to have creatinine levels 0.9 mg/dL and more likely to have creatinine levels
1.5 mg/dL than those without stroke. They were also more likely to have walk
times of 8 seconds and to report neurological symptoms (especially dizziness,
loss of balance, difficulty walking, and frequent falls). No relationships were noted
with black race, hemoglobin, hematocrit, fibrinogen, LDL cholesterol, fasting
insulin, fibrinogen, orthostatic hypotension, obesity or anthropometric measures,
smoking, pack-years, alcohol intake, physical activity, total cholesterol,
triglycerides, fasting insulin, uric acid, sibling history of stroke, loss of or changed
speech, loss of or blurred vision, double vision, numbness/tingling, spinning
sensation, paralysis/weakness, blackouts/fainting, or dizziness on standing.
Table 1.
Bivariate Associations of
Coronary Heart Disease Risk
Factors and Neurological
Symptoms With Incident Stroke

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Subclinical disease (abnormalities detected on noninvasive testing that have not yet
produced signs or symptoms) and clinical cardiovascular disease were also more
common at baseline in participants subsequently suffering stroke (Table 2).
Participants with incident stroke were nearly twice as likely as those without stroke
to have qualitatively abnormal LV systolic function or abnormal LV wall motion on
echocardiography. They were also more than three times as likely to have ECG LVH.
They also had greater carotid wall thicknesses, more frequent and severe carotid
stenosis, and lower ankle-arm indices and spirometric lung volumes. They were
more likely to have reported a prior myocardial infarction at entry and more than
three times as likely to have AF on baseline ECG. No associations were detected
with LV diastolic dimension, prior CHF, prior TIA, echocardiographic LVH, or mitral
stenosis.
Table 2.
Bivariate Associations of
Subclinical and Clinical Disease
With Incident Stroke

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Factors associated with stroke on stepwise proportional hazards analysis in women

and men (sex-specific models did not differ, and no sex-interaction terms were
significant) included aspirin use, diabetes, event-defined quintile of systolic blood
pressure, increase in timed walk, frequent falls, serum creatinine, abnormal LV wall
motion, carotid stenosis, LV mass >fifth event-specified quintile, and AF (Table 3,

model 1).
Table 3.
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Hazard Ratios From Cox

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Proportional Hazards Regresson
for Incident Stroke, Unadjusted
and Adjusted, With and Without Imputation for Missing Data and
Noninvasive Data

Inclusion of imputed data did not appreciably alter most of these relationships
except for an attenuation of the risk associated with systolic blood pressure (model
2). Use of imputed data did lead to narrowing of many of the CIs around risk
estimates and made age, impaired glucose tolerance, creatinine, and moderate
carotid stenosis significant predictors. After excluding echocardiographic and
carotid ultrasound variables, age was much stronger and male sex was significant,
and ECG-LVH and definite CHF were added as independent predictors (model 3).
Stratification of the associations with systolic-pressure quintile by use of
antihypertensive medications suggested an increased risk of low systolic pressure
(127 mmHg) compared with the next higher quintile (128 to 140 mmHg) in users
only (Table 4). Medication users in the second quintile had a 23% lower incidence
of stroke compared with those in the lowest quintile. Incidence of stroke at blood
pressures 127 mmHg was 12.8 per 1000 person-years in medication users and
2.5 per 1000 person-years in nonusers, yielding a hazard ratio (after adjustment
for factors in model 2) of 2.93 associated with medication use in this blood
pressure category (95% CI, 1.41 to 6.10; P<.004). In the other four blood pressure
quintiles, medication use was not associated with increased risk of stroke after
adjustment for the same factors (data not shown).
Table 4.
Stroke Risk by Quintile of
Systolic Blood Pressure in
Nonusers and Users of
Antihypertensive Medications

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Stratification of the association of aspirin use with stroke by history of coronary

disease, TIA, or AF showed an 84% greater risk of stroke associated with aspirin use
in subjects with none of these conditions (Table 5). Aspirin use was not
associated with increased stroke risk in subjects with these conditions (Fig 2).
Increased risk associated with aspirin use in nondiseased subjects was noted for
nonhemorrhagic strokes (P<.003), as well as for the small number of hemorrhagic
strokes (P<.003). Aspirin use was not associated with either category of stroke in
diseased subjects (data not shown).
Figure 2.
Incident stroke by aspirin use
and presence of clinical disease.

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Table 5.
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Stroke Risk by Use of Aspirin in
at Least 7 of Past 14 Days or by
Prescription in Those Without
(Nondiseased) and With (Diseased) Coronary Heart Disease, TIA,
Claudication, or AF

Discussion
Incidence,Mortality,andSubtypes
Annual stroke incidence in the first 3.3 years of CHS follow-up was 9.82 cases per
1000 women and 13.4 cases per 1000 men, comparable with rates in similar age
16 17
groups in other studies published since 1980.
These lower rates are likely due
to the relatively selective nature of the CHS cohort, since persons with serious
18
disease and disability were excluded at entry or elected not to participate, and
since persons with prior stroke at entry were excluded from this analysis.
Approximately 87% of strokes in CHS participants were classified as cerebral
infarction, which was the highest proportion among several published population16 17 19
based studies.
CHS also had one of the lowest proportions of hemorrhagic
stroke, particularly subarachnoid hemorrhage. These differences are likely due to
the advanced age of CHS participants, since hemorrhagic stroke does not increase
with age as rapidly as ischemic stroke, thus hemorrhages make up a smaller
20
proportion of strokes with increasing age.
This supposition is supported by
unpublished data from the Systolic Hypertension in the Elderly Program, in which
83% of strokes were classified as ischemic and 10.7% as hemorrhagic, proportions
very similar to those seen in CHS (T.R. Price, personal communication).
RelationshipofIncidentStroketoAgeandSex
Stroke incidence was more than three times higher in women aged 80 years and
older than in women aged 65 to 74 in CHS, and nearly twice as high in men aged
80 years and older compared with those aged 65 to 74. Stroke incidence is known
3 21
to be strongly related to age,
and given the relatively small numbers of men at
advanced ages and the possible impact of selective survival, the modest sex
difference in strength of the age association is not surprising. Age was associated
with slightly increased risk in multivariate analysis, which was significant in the
model with imputed data. The age relationship was attenuated by adjustment for
subclinical disease, as demonstrated in model 3 (excluding noninvasive
measurements). The fact that the age relationship remained after adjustment for
other risk factors that increase with age (such as blood pressure, diabetes, and
subclinical disease) suggests either that age itself is somehow a risk factor for
22
stroke, which seems unlikely, or that age is acting as a surrogate for other risk
factors as yet unidentified or inadequately adjusted for. The advanced age range of
the CHS cohort provides an excellent opportunity for identifying such factors, which
will be an important focus of continued follow-up in this cohort.
Stroke incidence did not differ by sex in the full age range of CHS, although there
was a borderline significant trend toward greater incidence in men aged 65 to 74
years than women of the same age (P<.03). Gender relationships with stroke
21
incidence show little consistency with published data showing men at higher,
16
23
similar,
or lower
risk than women. Sex was not significantly associated with
stroke in multivariate analysis, nor were significant interactions with gender
detected in these models. The significant association of gender with stroke after
excluding subclinical disease measures suggests that any sex differences in stroke
incidence in these data are related to differences in subclinical disease between
women and men.
IncidentStrokeandBaselineRiskFactors
Because models with imputed data differed little (except in increased precision of
point estimates) from models for subjects with complete data only, discussion will
be limited to models with imputed data. Systolic blood pressure, aspirin use,
diabetes, creatinine level, timed walking, and frequent falls retained their predictive
relationships with stroke in multivariate analysis. Hypertension has long been
24
known to be a major risk factor for stroke, with systolic pressure appearing to be
25
a stronger risk factor than diastolic. The relation of low systolic blood pressure to
stroke in medication users was somewhat surprising and was detected in a search
for potential interaction between medication use and systolic pressure level. As has
26

26

been pointed out,

ignoring the effect of antihypertensive medication use is
similar to assuming that blood pressures attained after treatment in hypertensive
patients confer risk equivalent to those that occur naturally (or without
antihypertensive medication). Although antihypertensive treatment markedly
27
reduces the increased risk of stroke associated with hypertension, it may not be
reasonable to assume that it eliminates this risk entirely, especially when treatment
may have begun shortly before an event. Treated hypertensive patients with low
blood pressure have been noted to be at increased risk of coronary heart disease
28
and mortality,
presumably due to advanced end-organ damage impeding their
ability to sustain higher pressure levels. To our knowledge, this is the first
suggestion that treated hypertensive patients with low blood pressure may be at
increased risk of stroke. CIs were overlapping, however, for stroke incidence
estimates by systolic pressure category, so chance cannot be excluded as an
explanation of these findings. Further follow-up of this cohort and extension of
this analysis to other cohorts may help clarify these relationships, but a definitive
answer on the appropriate level of target blood pressure in treated hypertensive
patients probably awaits the results of clinical trials, one of which is currently under
29
way.
30 31

Diabetes has shown strong and consistent relationships with stroke incidence,
as was demonstrated in the present study. Less consistent associations have been
32 33
demonstrated for impaired glucose tolerance,
and few studies have included
standard glucose tolerance testing as performed in the present study. Impaired
glucose tolerance is common in elderly subjects and has been demonstrated to be
associated with increased prevalence of cardiovascular disease and its risk
34
factors.
The current data confirm prior evidence that asymptomatic
hyperglycemia is not a benign condition in the elderly and that its previously
35
demonstrated association with coronary disease also extends to cerebrovascular
disease.
Associations detected with timed walking and frequent falls have not been
previously reported, perhaps because they were not included in prior
investigations. Timed walking is a strong correlate of coronary disease,
36 37
cardiovascular impairment, and disability
and presumably reflects the known
21
associations of these conditions with stroke.
Frequent falls were assessed as a
11
part of a questionnaire on TIA and may simply be a marker for that condition,
38
which is known to increase risk of completed stroke. Falls have been associated
39
40
with white matter abnormalities on CT and with prior stroke but not in and of
themselves (and after adjustment for other factors) specifically with subsequent
stroke.
Serum creatinine level was weakly related to incident stroke as detected in models
with creatinine as a linear term. Categorizing creatinine into event-defined
quintiles, however, showed almost all of the excess risk to be limited to the highest
creatinine category. Although this might reflect some potential role of renal
damage in the pathogenesis of stroke, it seems more likely to be a marker for
severity or duration of hypertension and for individual susceptibility to end-organ
damage not explained by systolic pressure and subclinical disease measures.
Participants reporting aspirin use in at least 7 of the 14 days preceding their
baseline clinic visit (or having a prescription) were nearly twice as likely to have an
incident stroke during follow-up than nonusers of aspirin. Although this may be
consistent with aspirin being prescribed or taken preferentially by subjects with
known cardiovascular disease, in whom it has been shown to reduce risk of
myocardial infarction and stroke, stratification on presence of coronary disease,
TIA, claudication, or AF suggested that the increased risk associated with aspirin
was limited to subjects without these conditions. This association may be due to
other indications (for which aspirin was prescribed or taken) also being associated
with increased risk of stroke, but only 66 of the 1412 aspirin users had a
prescription for it. History of arthritis was reported by 58% of all aspirin users
(compared with 49% of nonusers), and arthritis was not associated with increased
risk of stroke in this study (P=.6). Aspirin has been associated with modestly
41
42
increased risk of stroke in healthy male physicians,
elderly persons with AF,
43
and unselected elderly persons,
but the mechanism for this association is not
clear. Given the antiplatelet properties of aspirin, an increased risk of hemorrhagic
stroke might be understandable in aspirin users, but both nonhemorrhagic and
hemorrhagic stroke risk were increased in these studies, as well as the present one.
Until larger numbers of events accrue, this relationship will remain difficult to

understand, particularly in an observational nonrandomized study. A clinical trial is

currently under way to assess the benefit of aspirin in primary prevention of stroke
44
among women.
IncidentStrokeandBaselineSubclinicalDisease
Subclinical disease was also strongly related to incident stroke. Participants with
echocardiographic abnormalities of LV wall motion at baseline were 50% more likely
to suffer stroke during follow-up after adjustment for other factors, consistent with
21 45
the known increased risk of stroke in persons with LV dysfunction.
Abnormal
15
wall motion (which was predominantly hypokinesis
) may be associated with a
tendency to form clots that eventually cause embolic stroke. The greater strength
of the relationship with subclinical LV dysfunction than with reported CHF may be
due to improved and/or unbiased detection, since all CHS participants underwent
echocardiography according to a standard protocol, and assessment of LV wall
motion was possible in 99%.
Carotid stenosis of 50% to 74% was associated with a threefold increased risk of
stroke in multivariate analysis, and all measures of carotid atherosclerosis were
more common in bivariate analyses in incident stroke cases. This is not surprising
because carotid disease has been shown to be associated with stroke in cross46 47
sectional and longitudinal analyses.
A lesser but still significant association
was observed with milder degrees of carotid stenosis. Carotid atherosclerosis may
be a marker for vascular disease at other sites closer to the brain but may also be a
site for occlusion, embolization, or clot formation as a direct cause of stroke.
Inclusion of subclinical disease measures such as these in multivariate models may
explain the loss of association of such established stroke risk factors as CHF and
prevalent coronary disease. When these factors were excluded from analysis (model
3), ECG-LVH and CHF became significant, consistent with prior studies of these
48
factors and stroke risk.
Conclusions
Short-term incidence of stroke was associated with age, aspirin use, diabetes,
abnormal LV wall motion, systolic blood pressure, serum creatinine level, AF, 50%
carotid stenosis, and prolonged timed walk in this large cohort of older adults.
Inclusion of measures of subclinical disease such as echocardiography and carotid
ultrasonography appears to have led to loss of relationships with many previously
reported risk factors but did not account for lack of relationships with risk factors
such as cholesterol and smoking. Increased risk associated with aspirin use was
intriguing and deserves further follow-up, but it will be difficult to define in
nonrandomized comparisons. Short-term stroke risk appears to be strongly related
to noninvasive measures of subclinical cardiovascular disease, and such measures
should be considered for use in identifying persons at increased risk of stroke.

SelectedAbbreviationsandAcronyms

AF

=atrial fibrillation

CHF

=congestive heart failure

CHS

=Cardiovascular Health Study

CI

=confidence interval

ECG

=electrocardiographic,

ECG-

=ECG-defined left ventricular

electrocardiogram
LVH

hypertrophy

LV

=left ventricular

TIA

=transient ischemic attack

Acknowledgments
This study was supported by contracts N01-HC-85079 through N01-HC-85086
from the National Heart, Lung, and Blood Institute.

Footnotes
1

Participating institutions and principal staff have been previously published.

Received March 11, 1996.

Revision received May 31, 1996.
Accepted May 31, 1996.
Copyright 1996 by American Heart Association

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