From the Department of Biostatistics, University of Washington, Seattle
(R.A.K.); Division of Neurology, Department of Medicine (R.G.H.), and
Department of Clinical Pharmacology (R.L.T.), University of Texas, San
Antonio; Division of Epidemiology and Clinical Applications, National Heart,
Lung, and Blood Institute, Bethesda, Md (T.A.M.); Neuroradiology Division,
Johns Hopkins University, Baltimore, Md (N.J.B.); and Department of Geriatric
Medicine, University of Pittsburgh (Pa) (A.N.).
Correspondence to Richard A. Kronmal, PhD, Cardiovascular Health Study, 1501 Fourth Ave, Suite 2105, Seattle, WA 98101. E-mail kronmal{at}biostat.washington.edu
Methods—We conducted a multivariate
analysis of incident stroke rates in a prospectively assessed,
observational cohort of 5011 elderly people followed for a mean of 4.2
years.
Results—Participants had a mean age of 72 years, and 58% were
women. Twenty-three percent used aspirin frequently, and 17% used
aspirin infrequently at study entry. Frequent aspirin use was
associated with an increased rate of ischemic stroke compared
with nonusers (relative risk=1.6; 95% confidence interval
[CI], 1.2 to 2.2; P=0.001). After adjustment for other
stroke risk factors, women who used aspirin frequently or infrequently
at study entry had a 1.8-fold (95% CI, 1.2 to 2.8) and 1.6-fold (95%
CI, 0.9 to 3.0) increased risk of ischemic stroke, respectively
(P<0.01, test for trend), compared with
nonusers. In men, aspirin use was not statistically
significantly associated with stroke risk. Findings were similar when
aspirin use in the years before the incident stroke was used in the
modeling. Aspirin use at entry was also associated with a 4-fold (95%
CI, 1.6 to 10.0) increase in risk of hemorrhagic stroke for both
infrequent and frequent users of aspirin (P=0.003).
Conclusions—Aspirin use was associated with increased risks of
ischemic stroke in women and hemorrhagic stroke overall in this
elderly cohort, after adjustment for other stroke predictors. The
possibility exists of confounding by reasons for aspirin use rather
than cause and effect. Whether regular aspirin use increases stroke
risk for elderly people without cardiovascular disease
can only be determined by randomized clinical trials.
Aspirin use was determined at entry interview by participant recall,
recorded as the number of days on which aspirin was taken during
the prior 14 days. Patients were categorized as frequent users if they
reported taking any dose of aspirin on at least 10 of the 14 days
before entry (only by self-report; n=1075; 92% of frequent users) or
if they had a prescription for the daily use of any dose of aspirin at
enrollment (only by prescription; n=25; 2% of frequent users).
Seventy-two frequent users (6%) were identified by both self-report
and a prescription. Aspirin dose was recorded only for those with
prescriptions (n=97); only four (4%) were using less than 325 mg/d.
Participants who took aspirin 2 to 9 days, on average, during the 14
days before entry (n=583) were categorized as less frequent users and
the remainder as nonusers. The reasons for aspirin use and its
duration before CHS entry were not specifically ascertained. This
categorization of aspirin usage was made arbitrarily without reference
to any results for stroke risk. At annual follow-up visits, aspirin use
by the criteria above was reassessed.
For the time-dependent analyses, persistent frequent aspirin
users were those who were frequent aspirin users at baseline and each
follow-up visit preceding the occurrence of a stroke. Never users were
nonusers at baseline and each follow-up preceding the
occurrence of a stroke. The remainder of the participants were
classified as "sporadic/infrequent" users. A persistent frequent
user could change to a sporadic/infrequent user later in the follow-up
if the person reported no or infrequent aspirin use. A never user could
later become a sporadic/infrequent user by reporting usage later in the
follow-up. Finally, once a person was classified as a
sporadic/infrequent user, he or she remained in that category
throughout the remainder of the follow-up. This scheme was used to try
to minimize two potential problems. First, many people take aspirin in
response to acute illnesses and may not be regular frequent users. This
causes misclassification in the frequent user group. In the
time-dependent analysis, this misclassification can cause
serious bias toward an RR of 1 for the persistent frequent category. By
insisting that a persistent frequent user must be a frequent user at
all follow-ups before an event, this bias is minimized. Second, a
person may either stop aspirin usage because of an illness (eg, in
preparation for surgery or due to gastrointestinal disease) or start
aspirin because of new illness (eg, angina, TIA, atrial fibrillation).
To analytically adjust for this in the time-dependent analysis,
it would be necessary to know the exact date that the person started or
stopped taking aspirin and the date of all events that could influence
aspirin usage. Because we only determined aspirin usage at the annual
follow-up, it is not possible to know whether change in aspirin usage
was before or after other potentially biasing events. Thus, adjustment
with the use of multiple time-dependent covariates was not possible. We
are certain that persistent frequent aspirin use preceded any new
reason to begin aspirin use, since a persistent frequent user was
required to be a frequent aspirin user at baseline. However, any
stopping of frequent aspirin use due to illness might bias our
analysis toward the null. Thus, these definitions are
conservative, and any bias would be toward the null hypothesis of no
aspirin effect.
Participants were categorized as having clinical
cardiovascular disease at entry or not, based on the
presence of histories of TIA, myocardial infarction, angina pectoris,
coronary or carotid revascularization
procedures, atrial fibrillation, aortic aneurysm repair, venous
thromboembolism, or peripheral vascular disease. Among
those without clinical cardiovascular disease,
subclinical cardiovascular disease status was defined
by a combined index, published previously,8 based
on ECG and echocardiogram abnormalities, carotid artery wall thickness
and stenosis based on carotid ultrasound, decreased
ankle-brachial blood pressure, and positive response to a Rose
Questionnaire for angina or intermittent claudication.
To assess the association of aspirin with stroke risk, statistical
adjustment was made for previously determined predictors of stroke in
the CHS and other variables associated with aspirin use (Table 1
Strokes were identified during annual follow-up examinations and at
6-month telephone contacts, as previously
reported.5 7 Stroke cases were adjudicated by a
committee of neurologists, neuroradiologists, and internists, with
information from patient interviews, medical records, and
brain-imaging studies; imaging studies were available in 87% of
adjudicated strokes. Criteria for stroke classification and subtyping
have been reported.9 In brief, ischemic
strokes were diagnosed when rapid onset of focal neurological deficit
occurred without evidence of hemorrhage by neuroimaging, lumbar
puncture, or autopsy. Strokes were classified as hemorrhagic if there
was evidence of blood in the subarachnoid space, ventricles, or
parenchyma by neuroimaging that was not due to secondary
hemorrhage into an infarct. Strokes were also classified as
hemorrhagic if autopsy found bloody spinal fluid or evidence of
hemorrhage. Participants who died less than 24 hours after
stroke onset were assumed to have hemorrhage as a cause if they
did not undergo lumbar puncture, neuroimaging, or autopsy. The stroke
type was classified as unknown if information was insufficient to
categorize as hemorrhagic or ischemic. Analyses of
hemorrhagic strokes excluded 61 participants taking warfarin at entry
and four participants for whom this was unknown.
To test for differences between variables by aspirin use in
descriptive tables, either the
During follow-up, 249 verified strokes occurred (an overall rate of 12
per 1000 person-years) (Table 2
Figure 1
Figures 2
The rate of ischemic stroke increased with increasing frequency
of aspirin use at rates of 9.3, 10.4, and 15.2 per 1000 person-years
for the nonusers, infrequent users, and frequent users of
aspirin, respectively. The proportional hazards regression, adjusted
for other stroke risk factors, revealed a significant
(P<0.05) interaction of sex with the relationship of
aspirin and ischemic stroke, and thus all subsequent
analyses considered men and women separately. As shown in Table 3
Table 3
For women without cardiovascular disease, an increase
in RR of 2.11 (95% CI, 1.13 to 3.92; P=0.02) in
ischemic stroke risk was associated with frequent aspirin use
compared with nonusers after adjustment for other stroke risk
factors (Table 3
For women with clinical vascular disease, the adjusted RR of
ischemic stroke for frequent users was 1.62 (95% CI, 0.86 to
3.07) compared with nonusers (Table 3
When the subgroup with no cardiovascular disease was
further subdivided into those with (n=1684) and without (n=1626)
subclinical cardiovascular disease, the results of the
regression modeling were also similar, except possibly for women
without subclinical disease. For women without subclinical disease
(n=1083, 25 ischemic strokes), the RRs of ischemic
stroke were 1.16 (95% CI, 0.32 to 4.24) for infrequent users and 3.57
(95% CI, 1.45 to 8.76) for frequent users (P<0.05, test
for trend). For women with subclinical disease (n=926, 33
ischemic strokes), the RRs were 2.29 (95% CI, 0.96 to 5.43)
and 1.08 (95% CI, 0.42 to 2.79) for infrequent and frequent users,
respectively (P>0.80, test for trend). For men, the RRs
were not significantly different from 1, but the number of
ischemic strokes was small (38 strokes in 758 participants with
no subclinical disease and 54 strokes in 1301 participants with
subclinical disease), and therefore power is limited (results not
shown).
The results from the time-dependent proportional hazards
regression (Table 4
For hemorrhagic stroke, the small number of events precluded
sex-stratified analyses of cardiovascular
disease or use of a time-dependent aspirin variable. Aspirin use at
entry was associated with an increased risk of hemorrhagic stroke, with
RRs of 4.07 (95% CI, 1.60 to 10.31) for frequent users and 2.77 (95%
CI, 0.83 to 9.24) for infrequent users compared with nonusers
(P<0.005, test for trend) after adjustment for other risk
factors (Table 3
Other studies support that regular aspirin use may be associated with
increased rates of ischemic stroke in low-risk populations (ie,
those without cardiovascular
disease).2 3 4 10 In the large US Physicians
Health Study,2 although the 12% increased risk
of ischemic stroke among middle-aged, relatively healthy
participants assigned aspirin was not statistically significant, it
differed from the effect of aspirin defined by meta-analysis of
clinical trials involving patients with cardiovascular
disease (a 26% reduction in ischemic stroke [95% CI, 19% to
37%]).1
The large RR associated with regular, frequent aspirin use for women in
the CHS cohort (adjusted RR=1.82 based on entry usage and 1.93 in the
time-dependent analysis) compared with other studies could
reflect the older patient population, daily aspirin dose (likely higher
in the CHS), the duration of aspirin use, and/or a component of
confounding by indication. Randomized clinical trials to date for
primary prevention have been largely restricted to middle-aged
men.2 3 Among women at high risk for vascular
events, antiplatelet therapy appears to reduce the occurrence of
the constellation of stroke, myocardial infarction, or vascular
death.1 However, the effect of aspirin alone on
ischemic stroke among elderly women at lower risk of vascular
events has not been fully elucidated in previous studies. Our results
suggest that this issue may merit special attention. Whether women are
at particular risk, as suggested by our results, might be answered when
the results of the Women's Health Study11 are
available.
If the relationship between aspirin use and the increased rate of
ischemic stroke in women is actually due to confounding by
indication, then major nontraditional risk factors for ischemic
stroke must exist that are undefined or poorly characterized in the
CHS. Such potential unidentified risk factors would have to be powerful
stroke predictors because the reasons for taking nonprescription
aspirin are so varied, and hence only a fraction of aspirin users would
harbor them. Furthermore, arthritis, probably the most frequent
indication for aspirin use in the elderly, was not associated with
stroke risk in the CHS (data not shown) and thus cannot be a confounder
of the aspirin association.
Both the analysis of aspirin use based on self-report of
participants at enrollment and the time-dependent analysis that
used both the enrollment and follow-up reports are prone to bias due to
misclassification of aspirin usage and crossover during follow-up. A
person reporting frequent aspirin use in the 2 weeks before entry or
the follow-up examination may have been using aspirin for an acute
condition (eg, the flu) and may rarely have used it during the 5 years
of follow-up. On the other hand, some participants who were
nonusers or infrequent users at baseline (or at a particular
follow-up visit) may actually be frequent users who happened to not
take aspirin during those 2 weeks or may later have become frequent
users. However, any error in measuring the aspirin exposure in this
study will tend to cause an underestimation of the RR because the bias
induced tends to dampen the RR estimates toward 1.
Among those with no clinical cardiovascular disease, an
association between aspirin and the presence of subclinical
cardiovascular disease did not explain the findings. In
fact, the RRs associated with aspirin use in women were larger in those
with no subclinical cardiovascular disease than in
those with indications of the presence of unsuspected
cardiovascular disease.
The potential mechanisms by which frequent aspirin use could increase
ischemic stroke are not well defined. Aspirin has been variably
reported to increase systolic blood pressure and to antagonize
the effect of certain antihypertensive drugs (I.B. Puddey, C.D.
Furberg, R.A. Kronmal, R.H. McDonald, B. Psaty, J.D. Williamson,
unpublished data, 1997); hypertension is a strong, prevalent risk
factor for stroke.5 Thrombogenic effects of
aspirin have been demonstrated experimentally, particularly at high
doses, and possibly relate to inhibition of
endothelially derived prostacyclin synthesis or, in
some patients, increase in platelet
adhesiveness.13 14 15 16 Hypothetically, a separate
and competing effect of aspirin to enhance thrombosis would be
detectable in low-risk patients, in contrast to those with manifest
vascular disease, in which the antiplatelet effect dominates.
Aspirin in doses that reduce systemic prostacyclin appear to inhibit
intrinsic thrombolytic
mechanisms,17 18 possibly by interference with
nitric oxide synthase.19 20 21 If
aspirin-accentuated stroke is mediated by hypertension, then the
adjustments for blood pressure in our model would tend to underestimate
the risk associated with aspirin use.
The duration of aspirin use before CHS entry was not recorded. In a
large meta-analysis of the effect of antiplatelet agents on
vascular events, the protective effect diminished over time and
disappeared after 4 years (although this was tentatively attributed to
methodological reasons).1 Depending on the
mechanism of aspirin-potentiated ischemic stroke, the duration
of use could be an important factor (ie, chronic elevation of blood
pressure versus acute effects on prostacyclin).
The association of aspirin with hemorrhagic stroke in this
analysis parallels a literature consistently relating
aspirin use to intracranial hemorrhage (RR
In summary, these analyses of the CHS cohort in which aspirin
use was largely self-determined suggest that the regular use of aspirin
may be associated with increased risk of stroke, both ischemic
and hemorrhagic, in older women. Among men, those with recognized
cardiovascular disease who used aspirin had lower rates
of stroke than nonusers of aspirin, while those who were
aspirin users without cardiovascular disease had
slightly higher rates, but none of these findings were statistically
significant.
Millions of elderly people without cardiovascular
disease regularly consume aspirin.25 26 Thus, the
question of whether regular aspirin use increases the risk of stroke in
elderly people without clinical vascular disease is important to
answer. This question can only truly be settled by randomized trials
with adequate sample size to assess stroke in low-risk, older adults
taking aspirin.
Received October 2, 1997;
revision received February 25, 1998;
accepted February 25, 1998.
© 1998 American Heart Association, Inc.
Original Contributions
Aspirin Use and Incident Stroke in the Cardiovascular Health Study
Abstract
Top
Abstract
Introduction
Subjects and Methods
Results
Discussion
References
Background and Purpose—Randomized
clinical trials testing aspirin in relatively low-risk, middle-aged
people have consistently shown small increases in stroke
associated with aspirin use. We analyzed the relationship
between the regular use of aspirin and incident ischemic and
hemorrhagic stroke among people aged 65 years or older participating in
the Cardiovascular Health Study.
Key Words: aspirin • cerebral infarction • cerebral hemorrhage • elderly • risk factors • stroke
Introduction
Top
Abstract
Introduction
Subjects and Methods
Results
Discussion
References
The regular use of
aspirin reduces the risk of ischemic stroke for many patients
with clinically manifest atherosclerotic vascular
disease.1 In contrast, randomized clinical trials
involving people at relatively low risk for stroke have shown an
opposite trend. Although aggregate data are inconclusive, these trials
associated aspirin use with an increased risk of
stroke.2 3 4 In a previously reported
analysis of the population-based Cardiovascular
Health Study (CHS), regular aspirin use emerged as an independent risk
factor for stroke (P<0.007) even after adjustment for other
stroke risk factors.5 Here we explore this
association further, considering additional follow-up of the CHS cohort
with more stroke events, analyzing ischemic and hemorrhagic
strokes separately, stratifying by the frequency of aspirin use, and
accounting for changes in aspirin use at the start of each year of
follow-up.
Subjects and Methods
Top
Abstract
Introduction
Subjects and Methods
Results
Discussion
References
CHS participants were recruited in 1989 and 1990 from a random
sample of the Health Care Financing Administration Medicare eligibility
lists in four communities: Forsyth County, North Carolina; Sacramento
County, California; Washington County, Maryland; and Allegheny County,
Pennsylvania. Details of design and methods have been
reported.6 7 Participants were all aged 65 years
or older at study entry; those verified as having stroke before
enrollment (n=190) were excluded from this analysis. (In a
previous report5 we described 184 participants
with a history of stroke at entry. During the extra year of follow-up
reported here, CHS investigators, in the course of adjudicating
incident cardiovascular and stroke events, identified
an additional six participants who had a stroke before entry in the
CHS.) 
). Predictors of stroke in this cohort
included age, diabetes, atrial fibrillation, systolic blood
pressure, left ventricular hypertrophy by ECG,
left ventricular mass and wall motion by
echocardiography, carotid stenosis, time to
walk 15 feet, serum creatinine, heart failure, and a
history of frequent falls.5
View this table:
[in a new window]
Table 1. Participant Characteristics and Aspirin Use at Entry 
2 test for
proportions or the two-sample t test for means was used as
appropriate. Kaplan-Meier survival curves were computed and tested for
equality with the use of the log-rank test. Proportional hazards models
were used to adjust for statistically significant stroke risk factors.
In these models, the nonuser comparison group consisted of
participants who reported using aspirin less than 2 days or not at all
in the prior 2 weeks. Variables shown in Table 1
were allowed to
enter the regression model in a stepwise fashion if they were
statistically significant (P<0.05). All interactions of
aspirin use with variables that entered the model were also tested.
Hazard ratios are referred to throughout as RRs. For the aspirin
variable, a test for trend was computed. Separate analyses
were done for those with and without cardiovascular
disease by sex. The group without cardiovascular
disease was further stratified into those with and without subclinical
cardiovascular disease. Time-dependent Cox proportional
hazards regression analyses were also performed in a similar
fashion using the definitions for the time-dependent aspirin usage
given previously. Only aspirin usage was treated in a time-dependent
manner. Analyses were performed with the use of the
SPSS/Windows computer package. All P values and CIs should
be interpreted with caution because this is an observational study and
because of the exploratory nature of the analyses.
Results
Top
Abstract
Introduction
Subjects and Methods
Results
Discussion
References
The 5011 CHS participants (mean age, 72 years; 58% women) were
followed for a mean of 4.2 years (range, 4 to 5 years). Follow-up was
more than 98% complete. Aspirin was frequently used at entry by 22%
of participants and was used less frequently by 12%. Participants
using aspirin frequently were more often men, were slightly older, were
more likely to have histories of hypertension, diabetes, TIA, heart
failure, atrial fibrillation, and arthritis, and had more signs and
symptoms of cardiovascular disease than
nonusers (all P<0.001 compared with
nonusers) (Table 1). ). Of
these strokes, 85% were ischemic, 10% hemorrhagic, and 4% of
unknown cause; in subsequent analyses, strokes of unknown cause
(n=10) were combined with ischemic strokes. The rate of
ischemic stroke was higher in those with
cardiovascular disease (P<0.0001) than in
those without cardiovascular disease.
View this table:
[in a new window]
Table 2. Incident Stroke in the CHS shows the distribution of
aspirin use in the three categories of frequent, infrequent, and nonuse
at entry and at each follow-up examination. These rates are further
divided for follow-up years 1 to 4 by aspirin use in the previous year.
At entry, 66% were nonusers. The rate of nonuse declined to
59% at the year 4 follow-up. The infrequent use category was fairly
constant, at approximately 10%. The frequent user category showed an
increase from 22% at entry level to 28% at year 4. Most participants
who were nonusers or frequent users in the previous year stayed
in the same category in the next year. However, for the infrequent
category there was considerable switching from year to year.
View larger version (37K):
[in a new window]
Figure 1. Frequency of aspirin use at each year's
examination categorized by use at the previous year's
examination. and 3 show the cumulative ischemic
stroke-free event curves by aspirin usage at baseline for women and
men, respectively. The difference in the survival curves was
statistically significant for women (P<0.00001) but not for
men.
View larger version (17K):
[in a new window]
Figure 2. Cumulative ischemic stroke–free event
curves for women by entry aspirin use.
View larger version (16K):
[in a new window]
Figure 3. Cumulative ischemic stroke–free event
curves for men by entry aspirin use. , there is a clear pattern of increasing
rates for women without cardiovascular disease (5.2,
9.2, and 12.0 per 1000 person-years for 0 to 2, 3 to 9, and 
10,
respectively) and a suggestion of increased rates for those with
cardiovascular disease. For men, no clear trend is
shown in the rates for those either with or without vascular disease.
View this table:
[in a new window]
Table 3. Aspirin Use at Entry and Ischemic Stroke
Risk by Sex and Cardiovascular Disease Status shows the results for the Cox proportional hazards regression
for all ischemic and hemorrhagic strokes for all participants
by sex and further subdivided by cardiovascular
disease, with adjustment for other significant predictors of stroke
risk. Women who used aspirin frequently or infrequently showed an
increased risk for ischemic stroke (RRs of 1.82 [95% CI, 1.18
to 2.81] and 1.57 [CI, 0.87 to 2.84], respectively; test for trend,
P<0.01, adjusted for stroke risk factors), compared with
nonusers, while men did not. ). For men without cardiovascular
disease, while the estimates of RR for aspirin users were greater than
1, none reached statistical significance, nor was the test for trend
significant (Table 3). ). In contrast, for men
with clinical vascular disease the observed RRs were less than 1 for
both frequent and infrequent users (Table 3). None of the RRS (or
trends) for women or men with clinical vascular disease reached
statistical significance. ) also showed a
statistically significant relationship between aspirin use and
ischemic stroke risk for women but not for men. In the
time-dependent proportional hazards regression, women who were
persistent frequent users had an adjusted RR of 1.93 (95% CI, 1.15 to
3.23) compared with never users. In contrast, the RRs for men were not
significantly different from 1. When the analysis was
restricted to those without cardiovascular disease, the
adjusted RR for women who were persistent users compared with never
users was 1.67 (95% CI, 0.75 to 3.68), while for men in this group
there was no relationship between aspirin use and ischemic
stroke risk. For women with cardiovascular disease the
RR for persistent frequent users compared with never users was 2.22
(95% CI, 1.06 to 4.66). For men with cardiovascular
disease the RRs were below 1 and not statistically significant. In all
analyses, the RRs for the sporadic and/or infrequent users were
not significantly different from 1.
View this table:
[in a new window]
Table 4. Aspirin Use and Ischemic Stroke Risk by Sex
and Cardiovascular Disease Status From a Time-Dependent
Cox Proportional Hazards Regression ).
Discussion
Top
Abstract
Introduction
Subjects and Methods
Results
Discussion
References
Frequent aspirin use was associated with a paradoxically increased
rate of ischemic stroke among participants in the CHS. This
excess risk was primarily due to increased risk in women. Aspirin use
was not randomly assigned in this observational study, and while we
adjusted for coexisting factors predictive of stroke risk in this data
set, the definite possibility remains of confounding by indication (ie,
reasons for aspirin use were also related to a higher stroke risk). 
1.75 with no
apparent relationship to aspirin dose).1 22 23
For most people, the absolute risk of hemorrhagic stroke is low, and
the incremental increase by aspirin may be of marginal clinical
importance.1 2 However, among those at
substantial risk for intracerebral hemorrhage,
such as elderly patients receiving oral anticoagulants, the addition of
aspirin may importantly increase the risk of hemorrhagic
stroke.24
Selected Abbreviations and Acronyms
CHS
=
Cardiovascular Health Study
CI
=
confidence interval
RR
=
relative risk
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.
References
Top
Abstract
Introduction
Subjects and Methods
Results
Discussion
References
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