Gender Differences in the Primary

Prevention of Stroke With Aspirin

Faculty: Eric E. Adelman, MD; Lynda Lisabeth, PhD; Devin L. Brown, MD

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1. Describe gender-specific findings from trials of aspirin focusing on the effectiveness of

primary prevention of stroke and other cardiovascular events
2. Describe professional society guidelines regarding use of aspirin for primary prevention
of stroke and other cardiovascular events in women
3. Describe risks of aspirin used for primary prevention of stroke and other cardiovascular
events in women

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Author(s)

Eric E. Adelman, MD

Stroke Program, Department of Neurology, University of Michigan, Cardiovascular Center, Ann

Arbor, Michigan. Disclosure: Eric E. Adelman, MD, has disclosed no relevant financial
relationships.

Lynda Lisabeth, PhD

Stroke Program, Department of Neurology, University of Michigan, Cardiovascular Center;

Department of Epidemiology, School of Public Health, University of Michigan, Ann Arbor,
Michigan Disclosure: Lynda Lisabeth, PhD, has disclosed no relevant financial relationships.

Devin L. Brown, MD

Stroke Program, Department of Neurology, University of Michigan, Cardiovascular Center, Ann

Arbor, Michigan. Disclosure: Devin L. Brown, MD, has disclosed no relevant financial
relationships.

Editor(s)

Elisa Manzotti

Editorial Director, Future Science Group, London, United Kingdom. Disclosure: Elisa Manzotti
has disclosed no relevant financial relationships.
CME Author(s)

Laurie Barclay, MD

Freelance writer and reviewer, Medscape, LLC. Disclosure: Laurie Barclay, MD, has disclosed
no relevant financial relationships.

CME Reviewer(s)

Nafeez Zawahir, MD

CME Clinical Director, Medscape, LLC. Disclosure: Nafeez Zawahir, MD, has disclosed no
relevant financial relationships.

Sarah Fleischman

CME Program Manager, Medscape, LLC. Disclosure: Sarah Fleischman has disclosed no
relevant financial relationships.

From Women's Health

Gender Differences in the Primary Prevention of

Stroke With Aspirin CME
Eric E. Adelman, MD; Lynda Lisabeth, PhD; Devin L. Brown, MD

Posted: 01/01/1970; Women's Health. 2011;7(3):341-353. © 2011 Future Medicine Ltd.

CME Released: 05/25/2011; Valid for credit through 05/25/2012

Abstract and Introduction

Abstract

Aspirin is used to prevent ischemic stroke and other types of cardiovascular disease. Seven trials
of aspirin focusing on the effectiveness of primary prevention of stroke and other cardiovascular
events have been performed, but three of these did not include women. Data from these trials,
and one meta-analysis, suggest that aspirin prevents myocardial infarction in men and stroke in
women, although the findings in women were driven by the results of a single large study, and a
subsequent meta-analysis did not find a gender difference. The reasons for the possible gender
differences in aspirin’s effectiveness are not entirely clear.

Introduction
In the USA, stroke is the third leading cause of death and the leading cause of disability.[1] While
treatments for acute stroke and options for secondary stroke prevention have proliferated in
recent years, the greatest potential to reduce the impact of stroke lies in primary prevention.

Every year in the USA there are close to 800,000 strokes.[1] While approximately 185,000 are
recurrent strokes, approximately three-quarters are new events and greater than half occur in
women.[1] Risk factors for stroke such as hypertension, smoking, diabetes, physical inactivity and
obesity are becoming more prevalent in an aging US population. Lost earnings and caregiving
costs due to stroke put a tremendous burden on society and underscore the need for effective
preventive strategies.[2] Given disparities in stroke burden by gender, these strategies should be
assessed in both men and women.

The ancient Greeks knew that willow bark had analgesic properties but it was centuries before
chemists working in Bayer’s laboratories synthesized aspirin.[3] Although it was recognized that
aspirin contributed to bleeding, it was not until the 1960s that the anti-thrombotic effects of
aspirin were described.[4] At present, aspirin has a well-defined role in the treatment of acute
ischemic stroke.[5] In secondary prevention, where patients are at high risk of future
cardiovascular events, aspirin is effective in preventing stroke in men and women.[6] Aspirin’s
effectiveness in primary stroke prevention is less clear, and may differ by gender.

Aspirin’s Mechanism of Action & Hypothesized Role in Stroke Prevention

In platelets, COX-1 is an enzyme that metabolizes arachadonic acid into prostaglandins,

including thromboxane A2, which induces platelet aggregation.[7] Aspirin inhibits platelet
aggregation by irreversibly inhibiting COX-1, preventing the production of thromboxane A2.
The inhibition lasts for the life of the platelet, which is approximately 8 days.[8] In addition to
platelet inhibition, aspirin may also improve reactivity in atherosclerotic blood vessels.[9]

The majority of strokes are due to cerebral ischemia, but a substantial minority are hemorrhagic.
[1]
While antiplatelet therapy is thought to reduce the risk of ischemic stroke, it may increase the
risk of hemorrhagic strokes, including intraparenchymal and subarachnoid hemorrhages. The
purported benefit of aspirin in the primary prevention of stroke lies in its ability to prevent
ischemic stroke without increasing the risk of hemorrhagic stroke.

Gender & Stroke

Men have a higher age-adjusted incidence of stroke than women.[10,11] However, older women,
aged over 75 years, appear to have a higher risk of stroke than men.[12,13] Compared with men, on
average women are older when they experience their first ischemic stroke.[14] Since women live
longer than men, and have a higher incidence than men at older ages, the cumulative lifetime risk
of stroke in women exceeds that of men.[15]

After a stroke, women are more likely than men to have worse functional outcomes and poorer
quality of life.[16] The source of these disparities is not fully understood; although it has been
suggested that women are less likely than men to be treated with thrombolytic medication, which
can reduce the risk of disability.[17] However, so few stroke patients are treated with
thrombolytics that this probably does not account for poorer stroke outcomes among women.
The increased burden of stroke in women highlights the need to examine gender differences in
stroke prevention.

Objective
Over the past 25 years there have been seven large randomized trials that have attempted to
determine whether aspirin is effective for the primary prevention of stroke and other
cardiovascular events. Three of these trials did not enroll women; a small number of the events
occurred in women in the nongender-specific trials, and one trial enrolled exclusively women.
This article aims to examine gender difference observed in the primary prevention of stroke with
aspirin.

Method

We performed a MEDLINE search of primary prevention trials that studied aspirin with stroke as
an outcome. Guidelines from US, British and European organizations were reviewed. We also
reviewed the citations from the articles to find additional references.

The seven primary prevention trials of aspirin in cardiovascular disease (CVD) are summarized
in Table 1 and described later. In the trials, the primary end point was generally a combination of
myocardial infarction (MI), stroke or vascular death. Stroke was typically specified as a
secondary end point.

Table 1. Primary Prevention Trials of Aspirin in Preventing Cardiovascular Disease.

This article first summarizes each of the seven primary prevention trials. Trials that included
only men are briefly summarized while the trials that included both genders and only women
will be discussed in more detail. Next, the two meta-analyses of the first six primary prevention
trials are discussed and we explore reasons for the gender differences. Finally, because
recommendations based on trial interpretation are conflicting, we conclude with a summary of
the various guidelines dictating the use of aspirin for primary prevention.

Primary Prevention Trials

Trials That Included Only Men

Three early trials of aspirin in primary prevention enrolled only men: the British Doctors Trial
(BDT), Physicians’ Health Study (PHS) and Thrombosis Prevention Trial (TPT) and all assessed
stroke as a secondary outcome.[18–20] In the BDT there was no significant difference in the stroke
rate between the aspirin and control groups (32.4/10,000 patient-years in the aspirin group versus
28.5/10,000 patient-years in the control group); in addition, the 95% CI was wide and included
the null. In the PHS, there were more strokes in the aspirin group when compared with the
placebo group (119 vs 98), but the increase in relative risk (RR) was not statistically significant
(RR: 1.22; 95% CI: 0.93–1.60; p = 0.15). The TPT found no difference in the risk of ischemic
and hemorrhagic stroke between the aspirin and placebo groups (2.9 per 1000 person-years vs
3.0 per 1000 person-years, respectively).

Hypertension Optimal Treatment Trial

The Hypertension Optimal Treatment (HOT) trial examined aspirin and blood pressure control
for prevention of cardiovascular events.[21] This was the first randomized controlled trial of
aspirin in primary prevention of CVD to include women – 47% of the 18,790 subjects. Men and
women aged 50–80 years with hypertension (i.e., diastolic blood pressure ≥100 and ≤115
mmHg) were recruited for the study.[22] The participants were randomly assigned to aspirin 75
mg daily or placebo. They were also randomized into three diastolic goal blood pressure groups:
≤90, ≤85 or ≤80 mmHg. The primary antihypertensive agent used was felodipine, although
angiotensin-converting enzyme inhibitors, β-blockers and diuretics were also used at various
stages. The randomization was stratified by various cardiovascular risk factors, including gender.
The average follow-up was 3.8 years and 491 patients (2.6%) were lost to follow-up. No primary
outcome measure was defined in the published report, but the investigators examined stroke, MI
and cardiovascular death. Gender differences in effectiveness were not explicitly reported.

There was no difference in the risk of hemorrhagic and ischemic strokes between the aspirin and
placebo groups (RR: 0.98; 95% CI: 0.78–1.24; p = 0.88). While there were five fatal
hemorrhagic strokes in the aspirin group compared with three in the placebo group, there was no
difference in the frequency of nonfatal hemorrhagic strokes between the two groups. Aspirin
significantly reduced the risk of clinical MI (RR: 0.64; 95% CI: 0.49–0.85; p = 0.002), but not
the combination of clinical and silent MI (RR: 0.85; 95% CI: 0.69–1.05; p = 0.13) or
cardiovascular mortality (RR: 0.95; 95% CI: 0.75–1.20; p = 0.65). There was no difference in
fatal hemorrhages, but major and minor bleeding was more common in the aspirin group.

Primary Prevention Project

The Primary Prevention Project (PPP) examined the effect of aspirin and vitamin E in the
primary prevention of cardiovascular events in patients aged ≥65 years with at least one
cardiovascular risk factor.[23] Subjects were randomized, open-label, to aspirin 100 mg daily or no
aspirin, along with vitamin E 300 mg daily or no vitamin E in a 2 × 2 factorial design. The study
was stopped prematurely after the results of the TPT and HOT studies became available. A total
of 4495 subjects participated and 58% were women. The median follow-up was 4 years and
92.3% of subjects had complete follow-up.

The primary outcome was a combined end point that included nonfatal stroke, nonfatal MI and
cardiovascular death. Aspirin provided a nonsignificant 29% reduction in the primary outcome
(RR: 0.71; 95% CI: 0.48–1.04), but no effect on the risk of all stroke types (RR: 0.67; 95% CI:
0.36–1.27). There were two intracranial hemorrhages in the aspirin group and none in the
placebo group. Aspirin was associated with a significant decrease in cardiovascular death (RR:
0.56; 95% CI: 0.31–0.99; p = 0.049). While overall bleeding episodes were more common in the
aspirin group, fatal bleeding was more common in the placebo group (one vs three deaths). The
primary end point, cardiovascular deaths, total deaths and combined cardiovascular events were
similar between men and women.

Women’s Health Study

The Women’s Health Study (WHS) evaluated aspirin 100 mg every other day and vitamin E 600
IU every other day in a double-blind, placebo controlled, 2 × 2 factorial design for the primary
prevention of CVD and cancer in women.[24] Female health professionals aged 45 years and older
were recruited to participate. No men were enrolled in the trial. The study enrolled 39,876
women and the primary end point was a combination of cardiovascular death, stroke and MI.
Secondary end points included stroke and MI. The average follow-up time was 10.1 years and
2.8% of patients were lost to follow-up.

Aspirin provided a nonsignificant reduction in the risk of the primary combined end point (RR:
0.91; 95% CI: 0.80–1.03; p = 0.13). There was a 17% reduction in the risk of stroke (RR: 0.83;
95% CI: 0.69–0.99; p = 0.04). When stroke was subdivided into ischemic and hemorrhagic
types, aspirin conferred a 24% risk reduction in ischemic stroke (RR: 0.76; 95% CI: 0.63–0.93; p
= 0.0009) and a nonsignificant increase in the risk of hemorrhagic stroke (RR: 1.24; 95% CI:
0.82–1.87; p = 0.31). There was no difference in the risk of MI between the aspirin and placebo
groups (RR: 1.02; 95% CI: 0.84–1.25; p = 0.83) and aspirin did not reduce the risk of
cardiovascular death (RR: 0.95; 95% CI: 0.74–1.22; p = 0.68). Subgroup analysis showed that
older women (>65 years) tended to have more benefit from aspirin than younger women,
although a formal test for effect measure modification was not reported. Vitamin E did not
significantly impact the effect of aspirin. Bleeding requiring a transfusion was more common in
the aspirin group (RR: 1.40; 95% CI: 1.07–1.83; p = 0.02), but there was no excess of fatal
bleeding.

Aspirin for Asymptomatic Atherosclerosis

The Aspirin for Asymptomatic Atherosclerosis (AAA) study was a double-blind, placebo
controlled, randomized trial that enrolled 3350 subjects aged 50–75 years with asymptomatic
peripheral vascular disease to enteric coated aspirin 100 mg daily or placebo.[25] In total, 72% of
the study population were women and the subjects were followed for an average of 8.2 years and
0.3% of patients were lost to follow-up. The trial was stopped early owing to futility.

The primary end point was a composite of fatal and nonfatal stroke, coronary event or
revascularization. There was no difference in the primary outcome between the aspirin and
placebo groups (hazard ratio [HR]: 1.03; 95% CI: 0.84–1.27). In a subgroup analysis, there was a
suggestion that aspirin was harmful for men (HR: 1.15; 95% CI: 0.86–1.54) and beneficial for
women (HR: 0.92; 95% CI: 0.68–1.23) with respect to the primary outcome, but neither result
was statistically significant. A test for effect measure modification by gender was not reported.
There was no difference in the risk of stroke between the aspirin (fatal: 0.4%; 95% CI: 0.2–0.9;
nonfatal: 2.2%; 95% CI: 1.6–3.0) and placebo groups (fatal: 0.7%; 95% CI: 0.4–1.2; nonfatal:
2.3; 95% CI: 1.7–3.1). The risk of death was not reduced by aspirin (HR: 0.95; 95% CI: 0.77–
1.16). There were more major hemorrhages in the aspirin group (HR: 1.71; 95% CI: 0.99–2.97),
including 11 intracranial bleeds, compared with seven intracranial bleeds in the placebo group.

Summary of Primary Prevention Trial Results

In the seven trials described previously, aspirin reduced the risk of stroke, a secondary end point,
only in the WHS, a study that exclusively enrolled women and had the largest sample size of all
of the studies. Gender differences were not reported in the HOT trial. In the PPP, aspirin did not
reduce the risk of stroke overall, or in women in subgroup analysis. The lack of efficacy for
aspirin may be due to a low number of strokes in these trials and low power.[26] Combining trial
data in a meta-analysis has the potential to reduce the probability of type II error, thus it is an
attractive tool when examining the trials of aspirin in the primary prevention of stroke.

Meta-analyses

The primary prevention trials used differing doses and formulations of aspirin, which challenges
the appropriateness of combining data across trials. However, the variation in doses in the trials
was small and is unlikely to be clinically significant. Nevertheless, in healthy women, aspirin
100 mg every other day, the dose used in the WHS, produced less platelet inhibition than 81 mg
daily,[27] although it is unclear if differences in a platelet function assay are clinically meaningful.
It is also noteworthy that a single trial, the WHS, which enrolled exclusively women, contributed
approximately 40% of the total subjects, and approximately 78% of the female subjects to the
meta-analyses.

A gender-specific meta-analysis of the first six aspirin primary prevention trials (all except the
AAA) by Berger et al., was published in 2006.[28] When the trials were pooled, there were a total
of 1285 cardiovascular events in the 51,342 female participants and 2047 cardiovascular events
in the 44,114 male participants. There was no significant heterogeneity across trials for the end
points analyzed.

Strokes were experienced in 625 women and 597 men. In women, there was a 17% reduction in
the odds of stroke (95% CI: 0.70–0.97; p = 0.02); however, aspirin did not have an effect on
stroke in men (odds ratio [OR]: 1.13; 95% CI: 0.96–1.33; p = 0.14). In women, aspirin decreased
the odds of an ischemic stroke (OR: 0.76; 95% CI: 0.63–0.93; p = 0.008) without increasing the
risk of hemorrhagic stroke (OR: 1.07; 95% CI: 0.42–2.69; p = 0.89). In men, there was no effect
on ischemic stroke (OR: 1.00; 95% CI: 0.72–1.41; p = 0.98), but aspirin increased the odds of a
hemorrhagic stroke by 69% (95% CI: 1.04–2.73; p = 0.03). These results are summarized in
Figure 1.
Figure 1. Effect of Aspirin on the Primary Prevention of Stroke.
Reproduced with permission from [28] © American Medical Association (2006).
BDT: British Doctors Trial; HOT: Hypertension Optimal Treatment; PHS: Physicians Health
Study; PPP: Primary Prevention Project; TPT: Thrombosis Prevention Trial; WHS: Women’s
Health Study.

Aspirin reduced the odds of MI in men by 32% (95% CI: 0.54–0.86; p = 0.001), but it had no
statistically significant effect in women (OR: 1.01; 95% CI: 0.84–1.21; p = 0.95). When all-cause
and cardiovascular mortality was examined, aspirin did not have a significant effect in men or
women.

The Antithrombotic Trialists’ Collaboration (ATTC) reported results from a combined analysis,
from the same six primary prevention trials (BDT, PHS, TPT, HOT, PPP and WHS).[29] They
found a small, but significant reduction in the risk of vascular events for patients taking aspirin
compared with the control group (absolute difference 0.06% per year; RR: 0.88; 95% CI: 0.82–
0.94; p = 0.0001). There was no significant heterogeneity across the subgroups including gender.
There was also no difference in stroke outcome between the aspirin and control groups (RR:
0.95; 95% CI: 0.85–1.06). When stroke types were examined, aspirin reduced the risk of
ischemic stroke by 14% (RR: 0.86; 95% CI: 0.74–1.00; p = 0.05), but increased the risk of
hemorrhagic stroke by 32% (RR: 1.32; 95% CI: 1.00–1.75; p = 0.05). When the effect of aspirin
on ischemic stroke was examined by gender, there was a benefit for women (RR: 0.77; 95% CI:
0.59–0.99) but not men (RR: 1.01; 95% CI: 0.74–1.39). This conclusion was supported by a
borderline significant test for heterogeneity across genders (χ2 1 = 3.1; p = 0.08). However, the
authors note that when this was adjusted for multiple comparisons (an adjustment not undertaken
in the Berger et al. meta-analysis[28]), it was no longer significant (p = 0.88).

There was no difference in vascular death between the aspirin and control groups (rate ratio:
0.97; 95% CI: 0.87–1.09). Aspirin was associated with an 18% reduction in major coronary
events (95% CI: 0.75–0.90; p < 0.0001), but the absolute difference between the groups was
small (0.06% per year) and this was driven by nonfatal events. Aspirin seemed to reduce the risk
of major coronary events in men but was not significant in women, but this difference was no
longer significant after correcting for multiple comparisons.

Summary of Meta-analyses Results

The Berger meta-analysis supported gender differences in aspirin’s effectiveness in primary

stroke prevention. Aspirin reduced the risk of ischemic stroke for women without an increase in
hemorrhagic stroke. While in men, aspirin had no effect on the risk of ischemic stroke, but
increased the risk of hemorrhagic stroke. The ATTC study found similar gender differences for
ischemic stroke, but with adjustment for multiple comparisons, the test for effect measure
modification by gender was no longer significant.

Aspirin & the Risk of Hemorrhage: Results of Meta-analyses

The most feared bleeding complication of aspirin is hemorrhagic stroke. In the Berger et al.
meta-analysis, aspirin was associated with a 69% (OR: 1.69; 95% CI: 1.04–2.73) increase in the
risk of hemorrhagic stroke in men, but no increased risk in women (OR: 1.07; 95% CI: 0.42–
2.69).[28] In the ATTC analysis, aspirin increased the risk of hemorrhagic stroke by 32% (95% CI:
1.00–1.75).[29] The risk of hemorrhagic stroke due to aspirin was studied specifically in a meta-
analysis that examined studies that randomized subjects to aspirin for both primary and
secondary prevention of cardiovascular events, and used hemorrhagic stroke as an outcome.[30]
This analysis found that aspirin was associated with an 84% increase in the risk of hemorrhagic
stroke (RR: 1.84; 95% CI: 1.24–2.74; p < 0.001).[30] They found no association between subject
age group (<64 vs ≥64 years) or aspirin dose (<413 vs ≥413 mg per day) and risk of hemorrhagic
stroke, but women were not specifically analyzed and the study was published before the WHS
was completed. A review article on aspirin and hemorrhagic stroke estimated the risk of
intracranial hemorrhage while taking aspirin as 0.2 events per 1000 patient-years.[31]

Aspirin also increases the risk of gastrointestinal (GI) bleeding (RR: 1.54; 95% CI: 1.30–1.82 in
the ATTC meta-analysis).[29] In the Berger et al. meta-analysis, ‘major bleeding’, which was
predominantly GI bleeding, was more common in the aspirin group for both women (OR: 1.68;
95% CI: 1.13–2.52; p = 0.01) and men (OR: 1.72; 95% CI: 1.35–2.20; p < 0.001).[28]
Additional considerations may inform the risk–benefit ratio of aspirin use, such as is the relative
consequences of GI bleeding compared with stroke. Patients may be willing to take the risk of GI
bleeding to prevent an ischemic stroke because stroke is likely to have more pronounced
negative impact on their quality of life.[32] The risk benefit calculation may be different in women
compared with men because they have poorer quality of life after stroke.[33]

Reason for the Gender Difference

The etiology of aspirin’s gender-specific effects is not entirely clear. Many drugs are metabolized
differently and have different pharmacodynamic properties in women compared with men.[34]
However, this does not account for differing aspirin effects by gender in primary but not in
secondary stroke prevention studies.[6,29]

Becker et al. compared the effects of low dose (81 mg per day) aspirin on platelets in close to
1300 healthy generally middle-aged men and women with a family history of premature
coronary artery disease.[35] Prior to aspirin treatment, women had more reactive platelets than
men. While aspirin decreased platelet reactivity by a relatively similar amount in men and
women, platelet reactivity was still higher in women because they had more reactive platelets at
baseline. Higher dose aspirin (325 mg) did not seem to overcome this effect, but even higher
doses were not tested.[36] In addition, resistance to aspirin therapy appears to be more common in
women than men.[37] It is unclear how gender differences in platelet inhibition and aspirin
resistance contribute to aspirin’s beneficial effect for stroke in women, but not men. This is
particularly puzzling in light of the lack of gender-specific effects in secondary prevention of
stroke and CVD.[6,29]

Summary of Guidelines

The recommendations from relevant guidelines are summarized in Table 2 . Many guidelines do
not separate recommendations regarding aspirin use in primary prevention of stroke from
primary prevention of all types of CVD.

Table 2. Guideline Statements Regarding Aspirin for the Primary Prevention of Stroke†.
The American Heart Association (AHA) recommends aspirin for primary prevention of
cardiovascular events, including stroke, for men and women who are at high risk (6–10% 10-
year risk) when the benefits outweigh the risks of treatment.[38] Aspirin is recommended for
stroke prevention for women when the risk of stroke is high enough that the benefits of aspirin
outweigh the risks.[38] The AHA notes that aspirin is not useful in preventing stroke in patients at
low risk.[38]

The US Preventative Services Task Force (USPSTF) recommends aspirin for men aged 45–79
years and women aged 55–79 years, when the potential protective benefits in CVD (stroke in
women, MI in men) outweigh the risk of GI bleeding.[39] They note that there is not enough
evidence to make a recommendation for patients aged 80 years and over and recommend against
the use of aspirin in women younger than 55 years and in men younger than 45 years for
prevention of stroke and MI, respectively.[39]

The European Stroke Organization (ESO) recommends aspirin for ischemic stroke prevention in
women aged over 45 years who have ‘good GI tolerance’ and are at low risk of intracerebral
hemorrhage, but comment that the magnitude of benefit is small. For men, aspirin can be
considered to prevent MI, but the authors of the ESO guidelines note it does not reduce the risk
of stroke.[101] The European Society of Cardiology (ESC) guidelines recommend aspirin for
primary prevention of CVD only if patients are at high cardiovascular risk and their blood
pressure is controlled, and notes that aspirin reduces the risk of stroke, but not MI in women.[40]
The Joint British Societies’ (JBS) 2 Guidelines recommend aspirin for women aged 65 years or
older, who have a 10-year risk of CVD ≥20% who have a blood pressure of less than 150/90.[41]
There were no specific recommendations for men, but the guidelines provide a general
recommendation to use aspirin in patients aged 50 years or older, who have a 10-year risk of
CVD ≥20% and a blood pressure of less than 150/90.[41]

Owing to the lack of clear evidence of benefit for aspirin in patients with diabetes, the various
guideline statements are more heterogeneous.[42] For patients with diabetes, the AHA states that
aspirin is not useful in stroke prevention.[38] The American Diabetes Association (ADA) indicates
that aspirin (75–162 mg daily) can be considered for the primary prevention of CVD, including
stroke, for patients at high risk (10-year risk >10%).[43] For lower risk patients (men aged <50
years or women aged <60 years without major risk factors) the ADA notes that there is not
sufficient evidence to recommend aspirin for the primary prevention of CVD.[43] European
guidelines that address patients with diabetes recommend using aspirin (75–250 mg daily) to
prevent stroke.[44] British guidelines recommend aspirin for people with diabetes who have had
the disease for more than 10 years or are aged 50 years or older whose hypertension is being
treated.[41] Aspirin is recommended by US, British and European agencies to prevent stroke in
patients with atrial fibrillation who are at low risk of embolism or unable to take anticoagulation
medication.[38,41,101]

Future Perspective

There is some concern that despite the many primary prevention trials that have enrolled tens of
thousands of patients, aspirin still has uncertain benefits in the primary prevention of stroke. The
negative trials may have been underpowered to detect an effect of aspirin because of the low
number of strokes.[26] In total, the data suggest that aspirin prevents MI in men and stroke in
women. The mortality benefit for aspirin is small, if present. Aspirin also puts patients at
increased risk for bleeding complications, including hemorrhagic stroke. It could be argued that a
GI bleed is not as debilitating as an ischemic stroke or MI; therefore, patients may be willing to
accept the bleeding risks of aspirin to prevent ischemic disease. The lack of a clear signal of
efficacy from the trials suggests that if aspirin has a clinically meaningful benefit, it is modest.

The Aspirin to Reduce Risk of Initial Vascular Events (ARRIVE) study, scheduled for
completion in 2014, is examining aspirin use in patients at higher risk of CVD and includes men
and women.[102] The expected higher rate of events in this trial will increase the power needed to
show a benefit for aspirin, if it is truly present. Until more data are available, it seems reasonable
to offer, but not strongly recommend, aspirin for the primary prevention of stroke in women who
are at low risk of bleeding complications. The data suggest that aspirin does not reduce the risk
of stroke in men, but that its benefit in reducing the risk of MI may justify its use in this
population.

Executive Summary

The Burden of Stroke & Aspirin’s Utility

 Stroke is a common cause of death and a leading cause of disability.

 Stroke has a tremendous economic impact on society.
 Aspirin has a well-defined role in treatment of acute ischemic stroke and secondary
ischemic stroke prevention. No gender differences are observed in these settings.

Aspirin’s Mechanism of Action

 Aspirin inhibits platelet aggregation by blocking thromboxane A2.

 Aspirin’s mechanism in decreasing the risk of ischemic stroke is unclear.
 Aspirin may increase the risk of hemorrhagic stroke.

Gender & Stroke

  Men have a higher age-adjusted incidence of stroke than women; however, amongst the
elderly (those aged over 75 years), women have a higher incidence of stroke than men.
 Since women live longer than men, their cumulative lifetime risk of stroke exceeds that
of men.
 There are gender disparities in the acute treatment of stroke and in stroke outcomes.

Primary Prevention Trials

 No primary prevention trial has had stroke as a primary end point.

 The British Doctors Trial (BDT), Physicians’ Health Study (PHS) and Thrombosis
Prevention Trial (TPT) enrolled only men and found no difference in the risk of stroke
between the aspirin and no aspirin groups or placebo groups.
 The Hypertension Optimal Treatment trial enrolled men and women and found no
difference in the risk of stroke between aspirin and placebo.
 The Primary Prevention Project (PPP) enrolled men and women and found no difference
in the risk of stroke between aspirin and placebo; however, aspirin was found to decrease
the risk of cardiac death.
 The Women’s Health Study (WHS), which enrolled only women and was the largest of
the trials, found a 17% reduction in the risk of stroke (relative risk: 0.83; 95% CI: 0.69–
0.99).
 The Aspirin for Asymptomatic Atherosclerosis (AAA) study enrolled men and women
and found no difference in the risk of stroke between aspirin and placebo.

Meta-analyses

 When combining the trials, the WHS contributed close to 80% of the female subjects to
the analyses.
 An early meta-analysis of the first six primary prevention trials found that aspirin reduced
the odds of stroke in women by 17% but did not reduce the odds of stroke in men.
 A subsequent meta-analysis found the same gender differences in aspirin’s effectiveness
but with additional statistical adjustments the differences were not significant.
 Neither meta-analysis found that aspirin reduced the risk of mortality.

Aspirin & the Risk of Hemorrhage

 Aspirin probably increases the risk of hemorrhagic stroke. Men may be at higher risk of
hemorrhagic stroke while taking aspirin compared with women.
 Aspirin increases the risk of gastrointestinal (GI) bleeding.
 Owing to the poorer quality of life associated with a stroke compared with a GI bleed,
patients may be willing to tolerate the risk of GI bleeding to reduce the risk of stroke.

Reasons for the Gender Differences

 Many drugs are metabolized differently and have different pharmacodynamic properties
in men and women.
 Women may have more reactive platelets than men, leading to less inhibition by aspirin.
Aspirin resistance may also be more common in women.
 How these differences in platelet reactivity and aspirin resistance contribute, if at all, to
gender differences in aspirin’s effectiveness in preventing stroke is unclear.

Summary of Guidelines
  The American Heart Association (AHA) recommends aspirin for patients at high risk of
cardiovascular disease (CVD) when the benefits outweigh the risks. Aspirin is
recommended specifically for stroke prevention in women when the risk of stroke is high
enough that the benefits outweigh the risks.
 The US Preventative Services Task Force (USPSTF) recommends aspirin for men aged
45–79 years and women aged 55–79 years when the potential benefits (stroke in women,
myocardial infarction in men) outweigh the risks of GI bleeding.
 The European Stroke Organization (ESO) recommends aspirin to reduce the risk of
ischemic stroke in women over the age of 45 years who have ‘good GI tolerance’ and are
at low risk of intracerebral hemorrhage.
 The European Society of Cardiology (ESC) recommends aspirin for primary prevention
of CVD only if patients are at high cardiovascular risk and their blood pressure is
controlled, and notes that aspirin reduces the risk of stroke, but not myocardial infarction
in women.
 The Joint British Societies’ (JBS) 2 Guidelines recommend aspirin for women aged 65
years or older, who have a 10-year risk of CVD ≥20% and a blood pressure of less than
150/90. There were no specific recommendations for men, but the guidelines provide a
general recommendation to use aspirin in patients aged 50 years or older, who have a 10-
year risk of CVD ≥20% and a blood pressure of less than 150/90.
 The American Diabetes Association (ADA) indicates that aspirin can be considered for
the primary prevention of stroke and CVD for patients at high risk.

Future Perspective

 The lack of benefit observed in most trials of aspirin in the primary prevention of stroke
may be related to underpowered trials.
 The trials do suggest that aspirin reduces the risk of stroke in women but not men.
 More research is necessary in order to determine if aspirin reduces the risk of stroke in
men and has a mortality benefit when used in primary prevention.
 It is reasonable to offer, but not strongly recommend, aspirin for the primary prevention
of stroke in women who are at low risk of bleeding. The data suggest that aspirin does not
reduce the risk of stroke in men, but its benefit in reducing the risk of myocardial
infarction may justify its use in this population.

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Papers of special note have been highlighted as:

• of interest
•• of considerable interest

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Reprint Address
Stroke Program, Department of Neurology, University of Michigan, Cardiovascular Center, 1500
East Medical Center Drive, Ann Arbor, MI 48109, USA. Tel.: +1 734 936 9075 Fax: +1 734 232
4447 Devin L. Brown, MD devinb@med.umich.edu

Women's Health. 2011;7(3):341-353. © 2011 Future Medicine Ltd.

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