You are on page 1of 8

Effect of Low-Dose Aspirin on Functional Outcome From Cerebral Vascular Events in

Women
Pamela M. Rist, Julie E. Buring, Carlos S. Kase and Tobias Kurth

Stroke. 2013;44:432-436; originally published online January 10, 2013;


doi: 10.1161/STROKEAHA.112.672451
Stroke is published by the American Heart Association, 7272 Greenville Avenue, Dallas, TX 75231
Copyright © 2013 American Heart Association, Inc. All rights reserved.
Print ISSN: 0039-2499. Online ISSN: 1524-4628

The online version of this article, along with updated information and services, is located on the
World Wide Web at:
http://stroke.ahajournals.org/content/44/2/432

Data Supplement (unedited) at:


http://stroke.ahajournals.org/content/suppl/2013/01/10/STROKEAHA.112.672451.DC1.html

Permissions: Requests for permissions to reproduce figures, tables, or portions of articles originally published
in Stroke can be obtained via RightsLink, a service of the Copyright Clearance Center, not the Editorial Office.
Once the online version of the published article for which permission is being requested is located, click
Request Permissions in the middle column of the Web page under Services. Further information about this
process is available in the Permissions and Rights Question and Answer document.

Reprints: Information about reprints can be found online at:


http://www.lww.com/reprints

Subscriptions: Information about subscribing to Stroke is online at:


http://stroke.ahajournals.org//subscriptions/

Downloaded from http://stroke.ahajournals.org/ by guest on April 22, 2014


Effect of Low-Dose Aspirin on Functional Outcome From
Cerebral Vascular Events in Women
Pamela M. Rist, ScD; Julie E. Buring, ScD; Carlos S. Kase, MD; Tobias Kurth, MD, ScD

Background and Purpose—Although aspirin is effective in prevention of stroke, fewer studies have examined the impact
of aspirin on stroke morbidity.
Methods—The Women’s Health Study is a completed randomized, placebo-controlled trial designed to test the effect of
low-dose aspirin and vitamin E in the primary prevention of cardiovascular disease and cancer, which enrolled 39 876
women. We used multinomial logistic regression to evaluate the relationship between randomized aspirin assignment and
functional outcomes from stroke. Possible functional outcomes were neither stroke nor transient ischemic attack (TIA),
modified Rankin scale (mRS) score 0 to 1, 2 to 3, and 4 to 6.
Results—After a mean of 9.9 years of follow-up, 460 confirmed strokes (366 ischemic, 90 hemorrhagic, and 4 unknown
type) and 405 confirmed TIAs occurred. With regard to total and ischemic stroke, women who were randomized to aspirin
had a nonsignificant decrease in risk of any outcome compared to women not randomized to aspirin. This decrease in
risk only reached statistical significance for those experiencing TIA compared to participants without stroke or TIA
(odds ratio=0.77; 95% confidence interval, 0.63–0.94). For hemorrhagic stroke, a nonsignificant increase in the risk of
achieving an mRS score 2 to 3 or 4 to 6 compared with no stroke or TIA was observed for the women randomized to
aspirin compared to those randomized to placebo.
Conclusions—Results from this large randomized clinical trial provide evidence that 100 mg of aspirin every other day may
reduce the risk of ischemic cerebral vascular events but does not have differential effects on functional outcomes from
stroke.  (Stroke. 2013;44:432-436.)
Key Words: aspirin ■ cerebrovascular disease ■ epidemiology

A s the morbidity burden from stroke grows, it has become


increasingly important to determine the impact of expo-
sures not only on the risk of stroke but also on stroke mor-
increased risk of fatal hemorrhagic stroke.2 A previous analy-
sis in the Women’s Health Study did not observe a significant
increase in the risk of fatal stroke events.8 Additionally, those
bidity. Finding ways to reduce stroke morbidity is especially randomized to receive aspirin had a significantly decreased
critical among women who are at increased risk of worse risk of experiencing a transient ischemic attack (TIA).8 Given
functional outcomes after stroke compared with men.1 One the decreased risk of TIA observed, it is plausible that aspirin
factor that has been investigated for its ability to reduce the treatment may also reduce the risk of strokes with a mild func-
risk of stroke is aspirin. Results from a meta-analysis of pri- tional impairment.
mary prevention trials showed that randomized assignment to Using data from the Women's Health Study (WHS), we
aspirin resulted in a significantly decreased risk of ischemic examined the effect of randomized assignment to 100 mg
stroke among women.2 aspirin every other day and functional outcomes after incident
Although aspirin is effective in the prevention of stroke, cerebral vascular events.
fewer studies have examined the impact of aspirin on stroke
morbidity. Observational studies among cohorts of stroke Methods
patients are inconclusive, with some suggesting a beneficial The WHS was a randomized, placebo-controlled trial designed to
effect of prestroke aspirin use on functional outcomes after test the effect of low-dose aspirin (100 mg every other day; Bayer
stroke or stroke severity,3,4 whereas other studies showed no HealthCare) and vitamin E (600 IU every other day; Natural Source
Vitamin E Association) in the primary prevention of cardiovascu-
benefit.5–7 In a large meta-analysis, randomized assignment to lar disease and cancer. The design, methods, and results have been
aspirin was associated with nonsignificant increase in the risk described previously.8–10 In brief, 39 876 US female healthcare pro-
of fatal stroke among men and women, which was driven by an fessionals aged 45 years or older at study entry without a previous

Received July 27, 2012; final revision received November 19, 2012; accepted November 26, 2012.
From the Division of Preventive Medicine, Department of Medicine, Brigham and Women’s Hospital, Harvard Medical School, Boston, MA (P.M.R.,
J.E.B., T.K.); Department of Neurology, Boston University School of Medicine, Boston, MA (C.S.K); the Departments of Epidemiology (J.E.B., T.K.) and
Society, Human Development, and Health (P.M.R.), Harvard School of Public Health, Boston, MA; INSERM Unit 708–Neuroepidemiology, Bordeaux,
France (T.K.); and University of Bordeaux, Bordeaux, France (T.K).
The online-only Data Supplement is available with this article at http://stroke.ahajournals.org/lookup/suppl/doi:10.1161/STROKEAHA.
112.672451/-/DC1.
Correspondence to Pamela M. Rist, ScD, 900 Commonwealth Ave, 3rd floor, Boston, MA 02215. E-mail prist@partners.org
© 2013 American Heart Association, Inc.
Stroke is available at http://stroke.ahajournals.org DOI: 10.1161/STROKEAHA.112.672451

432
Downloaded from http://stroke.ahajournals.org/ by guest on April 22, 2014
Rist et al   Aspirin and Stroke Outcomes   433

history of cardiovascular, cancer or other major illnesses, were ran- Table 1.  Baseline Characteristics of Participants by
domized to receive aspirin, vitamin E, both active agents, or both Randomized Treatment Assignment (n=39 876)
placebos according to a 2 by 2 factorial design (see the online-only
Data Supplement). Written informed consent was obtained from all Aspirin Placebo Total
trial participants, and the Institutional Review Board of Brigham and Characteristics (n=19 934) (n=19 942) (n=39 876)
Women’s Hospital, Boston, MA, approved the trial. Age
At baseline, women completed a questionnaire about lifestyle and
demographic characteristics. Follow-up questionnaires asking about   Mean±SD, y 54.6±7.0 54.6±7.0 54.6±7.0
study outcomes and other information were sent every 6 months   45–54 y (%) 60.2 60.2 60.2
during the first year and annually thereafter. This analysis includes
  55–64 y (%) 29.5 29.5 29.5
information from randomization to March 31, 2004, the end of the
randomized trial. Morbidity and mortality follow-up were 97.2% and   ≥65 y (%) 10.3 10.3 10.3
99.4% complete as of the end of the trial, respectively. Smoking status (%)
 Current 13.0 13.3 13.1
Outcome Ascertainment   Past or never 87.0 86.7 86.9
When a woman reported a newly diagnosed medical condition, in-
Body mass index*
cluding a TIA or stroke, in her yearly questionnaire, her medical re-
cord was obtained. An end-points committee of physicians, including   Mean±SD, y 26.1±5.1 26.0±5.0 26.0±5.1
a board-certified vascular neurologist blinded to treatment assign-   <25.0 (%) 50.8 50.8 50.8
ment, reviewed the medical record and confirmed the event. A con-
firmed TIA was defined as a new focal-neurological deficit of sudden   25.0–29.9 (%) 30.9 31.0 30.9
or rapid onset that lasted for <24 hours. A confirmed stroke was de-   ≥30.0 (%) 18.3 18.2 18.2
fined as a new focal-neurological deficit of sudden or rapid onset that Menopausal status and use of HRT (%)
persisted for at least 24 hours. In the event of a fatal stroke, autopsy
reports, death certificates, medical records, and information obtained  Premenopausal 27.5 27.6 27.6
from next of kin or other family members were used to find evidence  Uncertain 17.7 18.2 18.0
of a cerebrovascular mechanism. Clinical information, computed  Postmenopausal 30.4 29.7 30.0
tomographic scans, and magnetic resonance images were used to and current HRT
distinguish hemorrhagic from ischemic stroke events. Interobserver
agreement for stroke subtype classification was excellent.11  Postmenopausal 24.4 24.4 24.4
In the event of a confirmed stroke, medical record information was and no HRT
also used to determine the functional outcome from the stroke ac- Hypertension (%)†
cording to the 6-point modified Rankin scale (mRS; 0=no symptoms
 Yes 26.0 25.7 25.9
at all, 1=no significant disability, 2=slight disability, 3=moderate
disability, 4=moderately severe disability, 5=severe disability, and  No 74.0 74.3 74.1
6=death).12,13 To avoid problems with model convergence attributable Diabetes mellitus (%)
to sparse data, we a priori categorized the mRS into 3 levels (0–1, 2–3,
and 4–6) similar to previous studies.14,15 Possible functional outcomes  Yes 2.7 2.5 2.6
were no stroke, TIA, and the 3 categories of the mRS. All statistical  No 97.3 97.5 97.4
analyses were performed using SAS 9.1 (Cary, NC). All P values are Physical activity at baseline
2-tailed, and we considered P<0.05 as statistically significant.
 Rarely/never 38.4 38.3 38.3
 <1/wk 19.5 20.2 19.9
Statistical Analysis
  1–3 times/wk 31.3 31.0 31.1
We used Cox proportional hazards models to determine the relative
risk (RR) of total, ischemic, and hemorrhagic stroke and TIA for   ≥4 times/wk 10.7 10.5 10.6
those randomized to aspirin compared to those randomized to pla- HRT indicates hormone replacement therapy.
cebo using an intention-to-treat approach. Our model adjusted for age *Body mass index is the weight in kilograms divided by the square of the
at randomization and for randomized assignment to vitamin E and height in meters.
beta carotene. Because we considered TIA to be part of our functional †Hypertension was defined as a systolic blood pressure of at least 140
outcomes from cerebral vascular events, only the first stroke or TIA
mm Hg, diastolic blood pressure of at least 90 mm Hg, or self-reported
was counted in our analysis. This is in contrast to a previous analysis
physician-diagnosed hypertension.
in WHS, which counted first stroke and first TIA separately.8
We used multinomial logistic regression to evaluate the relation-
ship between randomized aspirin assignment and functional out- event that a woman experienced multiple strokes or TIAs, only the
comes from stoke. Multinomial logistic regression is an extension of first event was included in our analysis. We used an intention-to-treat
binary logistic regression that allows the dependent variable to have analysis approach.
>2 categories. Each category is then simultaneously compared with In secondary analyses, we examined whether age at randomization
the reference category of no stroke or TIA. Unlike ordinal logistic (45–54 years of age, 55–64 years of age, ≥65 years of age), smoking
regression, multinomial logistic regression does not assume that the status (current, past, or never), body mass index (<25.0, 25.0–29.9, or
response categories are ordered. We a priori chose multinomial logis-
≥30.0 kg/m2), postmenopausal status and hormone replacement ther-
tic regression because it allows for more flexibility and makes fewer
apy (premenopausal, uncertain, postmenopausal and current hormone
assumptions than ordinal logistic regression. The resulting odds ra-
tios and 95% confidence intervals (CIs) are used as a measure of the replacement therapy, and postmenopausal and no hormone replace-
RR of each functional outcome among those randomized to aspirin ment therapy), history of hypertension (yes/no), history of diabetes
compared to those randomized to placebo. For the analysis testing mellitus (yes/no), or vigorous physical activity (rarely/never, <1 time/
the effect of randomized assignment to aspirin and functional out- wk, 1–3 times/wk, or ≥4 times/wk) modified the relationship between
comes from hemorrhagic stroke, TIA was not included as a potential randomized aspirin assignment and functional outcomes from total
outcome. Our multinomial models adjusted for age at randomization stroke by including an interaction between aspirin assignment and
and randomized assignment to vitamin E and beta carotene. In the each variable in separate models.

Downloaded from http://stroke.ahajournals.org/ by guest on April 22, 2014


434  Stroke  February 2013

Total Stroke

Aspirin (N=391)

TIA
Figure 1.  Distribution of transient ischemic attack
mRS 0-1
(TIA) and scores on the modified Rankin scale
mRS 2-3
(mRS) for total stroke (n=39 876).
mRS 4-6

Placebo (N=474)

0% 20% 40% 60% 80% 100%

Results postmenopausal status and hormone replacement therapy sta-


The baseline characteristics of the aspirin and placebos groups tus, history of hypertension, history of diabetes mellitus, or
were similar (Table 1). After a mean of 9.9 years of follow-up, vigorous physical activity (P>0.14). We did observe evidence
460 confirmed strokes (366 ischemic, 90 hemorrhagic, and 4 of effect modification by smoking status (P=0.03). Among
unknown type) and 405 confirmed TIAs occurred. Those ran- never or past smokers, there was a significant decrease in the
domly assigned to 100 mg of aspirin every other day had lower risk of TIA or mild functional outcomes from stroke for those
risk of TIA (RR=0.77; 95% CI, 0.63–0.94) and a tendency randomized to aspirin compared to those randomized to pla-
toward a lower risk of total stroke (RR=0.86; 95% CI, 0.72– cebo (odds ratio=0.71; 95% CI, 0.58–0.89 for TIA and odds
1.04), which was driven by a significant decrease in the risk ratio=0.67; 95% CI, 0.48–0.93 for mRS 0–1). Among current
of ischemic stroke (RR=0.80; 95% CI, 0.65–0.98) but not in smokers, however, we did not observe a beneficial effect of
the risk of hemorrhagic stroke (RR=1.30; 95% CI, 0.86–1.97). aspirin use on the risk of functional outcomes from cerebral
The distribution of TIA and scores on the mRS for total, vascular events (Table 3).
ischemic, and hemorrhagic stroke can be seen in Figures 1
through 3. The effect between randomized assignment to aspi- Discussion
rin and functional outcomes from total, ischemic, and hemor- Results from this large randomized clinical trial provide
rhagic stroke are shown in Table 2. With regard to total and evidence that 100 mg of aspirin every other day prevent first
ischemic stroke, women who were randomized to aspirin had TIA and stroke, particularly ischemic stroke. However, our
a significantly lower risk of TIA compared to participants results do not show differential effects of aspirin on functional
without any stroke or TIA (odds ratio=0.77; 95% CI, 0.63– outcome from stroke. We observed interaction with smoking
0.94) and a tendency towards lower risk of other outcomes status, showing that the beneficial effect of aspirin on ischemic
compared to women not randomized to aspirin, but this reduc- cerebral vascular events is not apparent for current smokers
tion in risk did not reach statistical significance. With regard for any functional outcome.
to hemorrhagic stroke, a nonsignificant increase in the risk of Two other primary prevention trials of the effect of aspirin
experiencing mRS 2 to 3 or mRS 4 to 6 compared to no stroke on incident stroke have enrolled women besides the WHS. One
was observed for the women randomized to aspirin compared trial did not present information on stroke severity.16 In the
with those randomized to placebo. other trial, 3 of the 16 stroke events were considered disabling
Secondary analyses showed no evidence of effect in the group randomized to aspirin, whereas in the placebo
modification by age at randomization, body mass index, group, 4 of the 24 stroke cases were considered disabling.17

Ischemic Stroke

Aspirin (N=340)

TIA
Figure 2.  Distribution of transient ischemic attack
mRS 0-1
(TIA) and scores on the modified Rankin scale
mRS 2-3
(mRS) for ischemic stroke (n=39 782).
mRS 4-6

Placebo (N=431)

0% 20% 40% 60% 80% 100%

Downloaded from http://stroke.ahajournals.org/ by guest on April 22, 2014


Rist et al   Aspirin and Stroke Outcomes   435

Hemorrhagic Stroke

Aspirin (N=51)

mRS 0-1 Figure 3.  Distribution of scores on the modi-


mRS 2-3 fied Rankin scale (mRS) for hemorrhagic stroke
mRS 4-6 (n=39 101).

Placebo (N=39)

0% 20% 40% 60% 80% 100%

Other studies on the impact of aspirin on stroke severity study enrolling stroke patients found no difference in stroke
have been observational and only enrolled stroke patients. One severity as measured by impairment of activities of daily
study using data from the Trial of Org 10172 in Acute Stroke living within 24 hours of admission between those in whom
Treatment (TOAST) assessed aspirin use in the 7 days before aspirin treatment of any dose had been initiated because of
stroke and found lower mean National Institutes of Health previous ischemic heart disease, peripheral vascular disease,
Stroke Scale scores and Supplemental Motor Examination or migraine and who took aspirin regularly for at least 1 month
scores within 24 hours of stroke onset among aspirin users com- before their stroke compared to those who did not meet these
pared with nonusers.4 Another study also found lower median criteria. A nonsignificant reduction in stroke mortality was
National Institutes of Health Stroke Scale scores at admission observed among aspirin users.6
and greater odds of a good outcome according to the mRS Unlike the previous observational studies, the present study
(mRS=0 or 1) among those taking antiplatelet agents (includ- enrolled a cohort of apparently healthy individuals and ran-
ing aspirin) compared with those not taking antiplatelet agents.3 domized them to receive aspirin or placebo. This allowed us
In contrast, another study using data from the International to assess the impact of randomized assignment to aspirin on
Stroke Trial found no benefit of aspirin use in the 3 days before the risk of experiencing a TIA or a mild, moderate, or severe
stroke on stroke severity as measured by the Oxford Community stroke outcome compared to not experiencing any cerebral
Stroke Project stroke syndrome, baseline-predicted poor vascular event.
outcome, and observed poor outcome. However, this study did Although we did not have information on prestroke dis-
not have information on previous vascular events, including a ability, the women had to be free of many major diseases to
history of previous stroke.7 A small study among those with be enrolled in the study and, therefore, are likely to be able-
first ischemic stroke in the territory of the middle cerebral bodied at baseline. Additionally, the mRS accounts for pre-
artery found that low-dose aspirin use was not associated with stroke disability.13 Although there are limitations to using the
decreased stroke severity, as assessed by the Mathew scale, mRS,18,19 it has strong test–retest reliability, interrater reliabil-
or better stroke outcome, as assessed by the Barthel Index, ity, and validity18 and is widely accepted for use in clinical
and mortality 21 days after the stroke event.5 Another larger trials.20,21 Because a previous meta-analysis did not show a

Table 2.  Effect of Low-Dose Aspirin on Functional Outcomes After Stroke and Stroke Subtypes (n=39 876)
No TIA or
Stroke TIA mRS 0–1 mRS 2–3 mRS 4–6
n % n % OR* (95% CI) n % OR* (95% CI) n % OR* (95% CI) n % OR* (95% CI)
Total stroke (n = 405) (n = 185) (n = 158) (n = 117)
Placebo 19 468 49.9 228 56.3 1.00 105 56.8 1.00 81 51.3 1.00 60 51.3 1.00
Aspirin 19 543 50.1 177 43.7 0.77 (0.63–0.94) 80 43.2 0.76 (0.57–1.01) 77 48.7 0.94 (0.69–1.29) 57 48.7 0.94 (0.65–1.35)
Ischemic stroke (n = 405) (n = 166) (n = 141) (n = 59)
Placebo 19 468 49.9 228 56.3 1.00 93 56.0 1.00 74 52.5 1.00 36 61.0 1.00
Aspirin 19 543 50.1 177 43.7 0.77 (0.63–0.94) 73 44.0 0.78 (0.57–1.06) 67 47.5 0.90 (0.64–1.25) 23 39.0 0.63 (0.37–1.07)
Hemorrhagic stroke (n = 17) (n = 16) (n = 57)
Placebo 19 468 49.9 NA NA NA 10 58.8 1.00 6 37.5 1.00 23 40.4 1.00
Aspirin 19 543 50.1 NA NA NA 7 41.2 0.70 (0.27–1.83) 10 62.5 1.66 (0.60–4.56) 34 59.7 1.47 (0.86–2.49)
CI indicates confidence interval; mRS, modified Rankin scale; NA, not applicable; OR, odds ratio; and TIA, transient ischemic attack.
*Adjusted for age and randomized assignment to beta carotene and vitamin E.

Downloaded from http://stroke.ahajournals.org/ by guest on April 22, 2014


436  Stroke  February 2013

Table 3.  Effect of Low-Dose Aspirin on Functional Outcomes After Total Stroke by Smoking Status (n=39 843)
No TIA or
Stroke TIA mRS 0–1 mRS 2–3 mRS 4–6
n % n % OR* (95% CI) n % OR* (95% CI) n % OR* (95% CI) n % OR* (95% CI)
Current smokers (n = 61) (n = 38) (n = 40) (n = 40)
Placebo 2570 50.8 29 47.5 1.00 18 47.4 1.00 15 37.5 1.00 23 57.5 1.00
Aspirin 2489 49.2 32 52.5 1.21 (0.73–2.01) 20 52.6 1.18 (0.62–2.24) 25 62.5 1.78 (0.94–3.40) 17 42.5 0.79 (0.42–1.48)
Past or never smokers (n = 344) (n = 146) (n = 117) (n = 77)
Placebo 16 879 49.8 199 57.9 1.00 87 59.6 1.00 65 55.6 1.00 37 48.1 1.00
Aspirin 17 042 50.2 145 42.1 0.71 (0.58–0.89) 59 40.4 0.67 (0.48–0.93) 52 44.4 0.78 (0.54–1.13) 40 51.9 1.06 (0.68–1.66)
CI indicates confidence interval; mRS, modified Rankin scale; OR, odds ratio; and TIA, transient ischemic attack.
*Adjusted for age and randomized assignment to beta carotene and vitamin E.

beneficial effect of aspirin on the risk of stroke among men, 4. Wilterdink JL, Bendixen B, Adams HP Jr, Woolson RF, Clarke WR,
Hansen MD. Effect of prior aspirin use on stroke severity in the trial of Org
our results may not be generalizable to men. Additionally,
10172 in acute stroke treatment (TOAST). Stroke. 2001;32:2836–2840.
although the women were randomized to receive aspirin or 5. De Keyser J, Herroelen L, De Klippel N. Early outcome in acute isch-
placebo, they may not have complied with their randomized emic stroke is not influenced by the prophylactic use of low-dose aspirin.
treatment assignment. A sensitivity analysis only including J Neurol Sci. 1997;145:93–96.
6. Karepov V, Bornstein NM, Hass Y, Korczyn AD. Does daily aspirin
women who reported taking two thirds of their pills found diminish severity of first-ever stroke? Arch Neurol. 1997;54:1369–1371.
similar results as our primary analysis (results not shown). 7. Ricci S, Lewis S, Sandercock P; IST Collaborative Group. Previous use
In conclusion, whereas randomized assignment to 100 mg of aspirin and baseline stroke severity: an analysis of 17,850 patients in
of aspirin every other day may reduce the risk of ischemic the International Stroke Trial. Stroke. 2006;37:1737–1740.
8. Ridker PM, Cook NR, Lee IM, Gordon D, Gaziano JM, Manson JE, et
cerebral vascular events, especially TIA, we did not observe al. A randomized trial of low-dose aspirin in the primary prevention of
differential effects on functional outcomes from stroke. This cardiovascular disease in women. N Engl J Med. 2005;352:1293–1304.
underscores the importance of using primary prevention meth- 9. Lee IM, Cook NR, Gaziano JM, Gordon D, Ridker PM, Manson JE,
et al. Vitamin E in the primary prevention of cardiovascular disease and
ods, for example, aspirin or blood pressure-lowering treat-
cancer: the Women’s Health Study: a randomized controlled trial. J Am
ment to reduce stroke incidence and its associated morbidity. Med Assoc. 2005;294:56–65.
10. Rexrode KM, Lee IM, Cook NR, Hennekens CH, Buring JE. Baseline
Sources of Funding characteristics of participants in the Women’s Health Study. J Womens
Health Gend Based Med. 2000;9:19–27.
The WHS is supported by grants from the National Institutes of
11. Atiya M, Kurth T, Berger K, Buring JE, Kase CS; Women’s Health
Health (HL-043851 and CA-047988). Dr Rist was funded by a train-
Study. Interobserver agreement in the classification of stroke in the
ing grant from the National Institute of Aging (AG-00158). Women’s Health Study. Stroke. 2003;34:565–567.
12. Uyttenboogaart M, Stewart RE, Vroomen PC, De Keyser J, Luijckx GJ.
Disclosures Optimizing cutoff scores for the Barthel index and the modified Rankin scale
Dr Rist was funded by a training grant from the US National Institute for defining outcome in acute stroke trials. Stroke. 2005;36:1984–1987.
of Aging and has received funding from the Rose Traveling Fellowship 13. van Swieten JC, Koudstaal PJ, Visser MC, Schouten HJ, van Gijn
Program in Chronic Disease Epidemiology and Biostatistics from the J. Interobserver agreement for the assessment of handicap in stroke
patients. Stroke. 1988;19:604–607.
Harvard School of Public Health and a travel grant from the Department
14. Rist PM, Berger K, Buring JE, Kase CS, Gaziano JM, Kurth T. Alcohol
of Epidemiology at the Harvard School of Public Health. Dr Buring
consumption and functional outcome after stroke in men. Stroke.
has received investigator-initiated research funding and support as 2010;41:141–146.
Principal Investigator from the US National Institutes of Health and 15. Rist PM, Buring JE, Kase CS, Schürks M, Kurth T. Migraine and func-
research support for pills and packaging from Bayer Heath Care and tional outcome from ischemic cerebral events in women. Circulation.
the Natural Source Vitamin E Association. Dr Kase has received hono- 2010;122:2551–2557.
raria as a consultant for Sanofi-Aventis. Dr Kurth has received inves- 16. Kjeldsen SE, Kolloch RE, Leonetti G, Mallion JM, Zanchetti A, Elmfeldt
tigator-initiated research funding from the French National Research D, et al. Influence of gender and age on preventing cardiovascular dis-
Agency, the US National Institutes of Health, Merck, the Migraine ease by antihypertensive treatment and acetylsalicylic acid. The HOT
Research Foundation, and the Parkinson Disease Foundation, and hon- study. Hypertension Optimal Treatment. J Hypertens. 2000;18:629–642.
orariums from the BMJ for editorial services, Allergan, the American 17. de Gaetano G; Collaborative Group of the Primary Prevention Project.
Academy of Neurology, Merck for educational lectures, and MAP Low-dose aspirin and vitamin E in people at cardiovascular risk: a ran-
Pharmaceutical for contributing to a scientific advisory panel. domised trial in general practice. Collaborative Group of the Primary
Prevention Project. Lancet. 2001;357:89–95.
18. Banks JL, Marotta CA. Outcomes validity and reliability of the modified
References Rankin scale: implications for stroke clinical trials: a literature review
1. Reeves MJ, Bushnell CD, Howard G, Gargano JW, Duncan PW, Lynch and synthesis. Stroke. 2007;38:1091–1096.
G, et al. Sex differences in stroke: epidemiology, clinical presentation, 19. New PW, Buchbinder R. Critical appraisal and review of the Rankin
medical care, and outcomes. Lancet Neurol. 2008;7:915–926. scale and its derivatives. Neuroepidemiology. 2006;26:4–15.
2. Baigent C, Blackwell L, Collins R, Emberson J, Godwin J, Peto R, et al. 20. Farrell B, Godwin J, Richards S, Warlow C. The United Kingdom tran-
Aspirin in the primary and secondary prevention of vascular disease: col- sient ischaemic attack (UK-TIA) aspirin trial: final results. J Neurol
laborative meta-analysis of individual participant data from randomised Neurosurg Psychiatr. 1991;54:1044–1054.
trials. Lancet. 2009;373:1849–1860 21. Hacke W, Kaste M, Fieschi C, Toni D, Lesaffre E, von Kummer R, et al.
3. Sanossian N, Saver JL, Rajajee V, Selco SL, Kim D, Razinia T, et al. Intravenous thrombolysis with recombinant tissue plasminogen activator
Premorbid antiplatelet use and ischemic stroke outcomes. Neurology. for acute hemispheric stroke. The European Cooperative Acute Stroke
2006;66:319–323. Study (ECASS). J Am Med Assoc. 1995;274:1017–1025.

Downloaded from http://stroke.ahajournals.org/ by guest on April 22, 2014


Supplemental Material
1.7 million women invited to participate

453787 completed baseline questionnaire

65169 entered run-in phase

25293 excluded after run-in


(noncompliance,
unwillingness or ineligibility
39876 randomized

19934 assigned to receive aspirin 19942 assigned to receive placebo

Status on March 31, 2044 Status on March 31, 2044


19147 Alive 19133 Alive
699 Dead 693 Dead
118 Unknown vital status 116 Unknown vital status

Figure 1. Enrollment and randomization scheme for the Women’s Health Study.