Aspirin for the Primary Prevention of Cardiovascular Events in Women and Men: A Sex-Specific Meta-analysis of Randomized Controlled Trials

Abstract

Aspirin therapy reduces the risk of cardiovascular disease in adults who are at increased risk. However, it is unclear if women derive the same benefit as men.
To determine if the benefits and risks of aspirin treatment in the primary prevention of cardiovascular disease vary by sex.
MEDLINE and the Cochrane Central Register of Controlled Trials databases (1966 to March 2005), bibliographies of retrieved trials, and reports presented at major scientific meetings. Eligible studies were prospective, randomized controlled trials of aspirin therapy in participants without cardiovascular disease that reported data on myocardial infarction (MI), stroke, and cardiovascular mortality. Six trials with a total of 95 456 individuals were identified; 3 trials included only men, 1 included only women, and 2 included both sexes.
Studies were reviewed to determine the number of patients randomized, mean duration of follow-up, and end points (a composite of cardiovascular events [nonfatal MI, nonfatal stroke, and cardiovascular mortality], each of these individual components separately, and major bleeding).
Among 51,342 women, there were 1285 major cardiovascular events: 625 strokes, 469 MIs, and 364 cardiovascular deaths. Aspirin therapy was associated with a significant 12% reduction in cardiovascular events (odds ratio [OR], 0.88; 95% confidence interval [CI], 0.79-0.99; P = .03) and a 17% reduction in stroke (OR, 0.83; 95% CI, 0.70-0.97; P = .02), which was a reflection of reduced rates of ischemic stroke (OR, 0.76; 95% CI, 0.63-0.93; P = .008). There was no significant effect on MI or cardiovascular mortality. Among 44,114 men, there were 2047 major cardiovascular events: 597 strokes, 1023 MIs, and 776 cardiovascular deaths. Aspirin therapy was associated with a significant 14% reduction in cardiovascular events (OR, 0.86; 95% CI, 0.78-0.94; P = .01) and a 32% reduction in MI (OR, 0.68; 95% CI, 0.54-0.86; P = .001). There was no significant effect on stroke or cardiovascular mortality. Aspirin treatment increased the risk of bleeding in women (OR, 1.68; 95% CI, 1.13-2.52; P = .01) and in men (OR, 1.72; 95% CI, 1.35-2.20; P<.001).
For women and men, aspirin therapy reduced the risk of a composite of cardiovascular events due to its effect on reducing the risk of ischemic stroke in women and MI in men. Aspirin significantly increased the risk of bleeding to a similar degree among women and men.

Full text

REVIEW
Aspirin for the Primary Prevention of
Cardiovascular Events in Women and Men
A Sex-Specific Meta-analysis
of Randomized Controlled Trials
Jeffrey S. Berger, MD, MS
Maria C. Roncaglioni, MD
Fausto Avanzini, MD
Ierta Pangrazzi, MD
Gianni Tognoni, MD
David L. Brown, MD
ALTHOUGH THE BENEFITS OF AS-
pirin therapy for reducing the
risk of myocardial infarc-
tion (MI), stroke, and vascu-
lar death among men and women with
preexisting cardiovascular disease are
well established,1-3 the role of aspirin
in primary prevention is less clear. An
overview of 5 randomized trials inves-
tigating aspirin therapy for the pri-
mary prevention of vascular disease
found a significant beneficial effect of
aspirin therapy on the prevention of a
first MI, but no significant effects on the
risk of stroke or vascular death.4
Although women were included in
only 2 of these studies and accounted
for only 20% of the population stud-
ied, the US Preventive Services Task
Force5and the American Heart Asso-
ciation6deemed aspirin therapy effec-
tive in decreasing the incidence of
coronary heart disease in adults of
both sexes who are at increased risk.
Subsequently, guidelines from the
American Heart Association on the
primary prevention of cardiovascular
disease in women recommended use
of low-dose aspirin therapy in women
whose 10-year risk of a first coronary
event exceeds 20% and consideration
Author Affiliations: Department of Cardiovascular
Medicine, Duke University, Durham, NC (Dr Berger);
Department of Cardiovascular Medicine, Instituto di
Ricerche Farmacologiche “Mario Negri,” Milan, Italy
(Drs Roncaglioni, Avanzini, Pangrazzi, and Tognoni);
and Division of Cardiovascular Medicine, School of
Medicine, State University of New York, Stony Brook
(Dr Brown).
Corresponding Author: David L. Brown, MD, Divi-
sion of Cardiovascular Medicine, SUNY-Stony Brook,
Health Sciences Center T16-080, Stony Brook, NY
11794 (david.brown@stonybrook.edu).
Context Aspirin therapy reduces the risk of cardiovascular disease in adults who are
at increased risk. However, it is unclear if women derive the same benefit as men.
Objective To determine if the benefits and risks of aspirin treatment in the primary
prevention of cardiovascular disease vary by sex.
Data Sources and Study Selection MEDLINE and the Cochrane Central Regis-
ter of Controlled Trials databases (1966 to March 2005), bibliographies of retrieved
trials, and reports presented at major scientific meetings. Eligible studies were pro-
spective, randomized controlled trials of aspirin therapy in participants without car-
diovascular disease that reported data on myocardial infarction (MI), stroke, and car-
diovascular mortality. Six trials with a total of 95 456 individuals were identified; 3 trials
included only men, 1 included only women, and 2 included both sexes.
Data Extraction Studies were reviewed to determine the number of patients ran-
domized, mean duration of follow-up, and end points (a composite of cardiovascular
events [nonfatal MI, nonfatal stroke, and cardiovascular mortality], each of these in-
dividual components separately, and major bleeding).
Data Synthesis Among 51 342 women, there were 1285 major cardiovascular
events: 625 strokes, 469 MIs, and 364 cardiovascular deaths. Aspirin therapy was
associated with a significant 12% reduction in cardiovascular events (odds ratio
[OR], 0.88; 95% confidence interval [CI], 0.79-0.99; P=.03) and a 17% reduction
in stroke (OR, 0.83; 95% CI, 0.70-0.97; P=.02), which was a reflection of reduced
rates of ischemic stroke (OR, 0.76; 95% CI, 0.63-0.93; P=.008). There was no sig-
nificant effect on MI or cardiovascular mortality. Among 44 114 men, there were
2047 major cardiovascular events: 597 strokes, 1023 MIs, and 776 cardiovascular
deaths. Aspirin therapy was associated with a significant 14% reduction in cardio-
vascular events (OR, 0.86; 95% CI, 0.78-0.94; P=.01) and a 32% reduction in MI
(OR, 0.68; 95% CI, 0.54-0.86; P=.001). There was no significant effect on stroke
or cardiovascular mortality. Aspirin treatment increased the risk of bleeding in
women (OR, 1.68; 95% CI, 1.13-2.52; P=.01) and in men (OR, 1.72; 95% CI,
1.35-2.20; P⬍.001).
Conclusions For women and men, aspirin therapy reduced the risk of a composite
of cardiovascular events due to its effect on reducing the risk of ischemic stroke in
women and MI in men. Aspirin significantly increased the risk of bleeding to a similar
degree among women and men.
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of use in women whose 10-year risk is
10% to 20%.7
In actuality, because of the paucity
of data, the effect of aspirin in the pri-
mary prevention of cardiovascular dis-
ease in women remains uncertain. As
a result, the European Society of Car-
diology has recommended low-dose as-
pirin for men at particularly high risk
for coronary heart disease, but not for
all persons at high risk.8The recent
Women’s Health Study, the first pri-
mary prevention trial of aspirin therapy
specific to women,9demonstrated that
aspirin decreased the risk of stroke
without affecting the risk of MI or vas-
cular death—an effect different from
that found in studies that enrolled ex-
clusively or predominantly men. Thus,
a differential beneficial effect of aspi-
rin therapy may exist between men and
women.
To better understand the impact of
sex on the response to aspirin, we per-
formed a sex-specific meta-analysis of
aspirin therapy for the primary preven-
tion of cardiovascular events.
METHODS
The primary aim of this meta-analysis
was to determine the effect of aspirin
in the primary prevention of cardio-
vascular disease in women and men
independently. A comprehensive
MEDLINE database search using Ovid
software (Ovid Technologies Inc, New
York, NY) was performed to find hu-
man studies published in the English
language between 1966 and March
2005 using the search terms aspirin, pri-
mary prevention, myocardial infarc-
tion, stroke, and randomized controlled
trials, as well as combinations of these
terms. The bibliographies of retrieved
articles were searched for other rel-
evant studies and major scientific meet-
ings were monitored for the results of
trials still under way at the time of the
MEDLINE search. Data concerning
study design, baseline patient charac-
teristics, treatment, follow-up, and re-
sults were extracted from these re-
ports. Additional data, when necessary,
were derived from personal communi-
cation with trial investigators.
Study Selection
Trials that met the following criteria were
included: (1) prospective, random-
ized, controlled, open, or blinded trials;
(2) assignment of participants to aspi-
rin treatment or a control group for the
primary prevention of cardiovascular
disease; and (3) data on cardiovascular
death, MI, and stroke. Quality was as-
sessed using criteria that were previ-
ously published10,11 (adequate blinding
of randomization, completeness of fol-
low-up, and objectivity of outcome as-
sessments). A total of 102 potentially eli-
gible studies were identified and 89 were
excluded because they were not ran-
domized controlled trials (eg, review ar-
ticles, editorials, letters to the editor, case
reports, case-control studies, and meta-
analyses). Of the randomized trials, 7
trials did not report end points of inter-
est (eg, improvement in angina pecto-
ris), used aspirin as an adjunct to clo-
pidogrel, were not primary prevention,
or included duplicate results and were
excluded (FIGURE 1).
Clinical End Points
The clinical end point definitions were
similar among the trials. Outcomes ex-
amined in the current overview were
a composite end point of any major car-
diovascular event (cardiovascular mor-
tality, nonfatal MI, or nonfatal stroke),
each of the individual components of
the composite end point separately, all-
cause mortality, and major bleeding.
We also examined stroke subtypes (is-
chemic vs hemorrhagic) from data
available in 5 studies. The Hyperten-
sion Optimal Treatment trial12 did not
record the type of stroke.
Statistical Analysis
All statistical analyses were performed us-
ing the Comprehensive MetaAnalysis
program (Biostat, Englewood, NJ). Data
were analyzed according to the intention-
to-treat principle. The Cochrane Q sta-
tistic was calculated to assess heteroge-
neity among the trials. The Q statistic
failed to indicate statistical heterogene-
ity for any end point. However, because
the lack of heterogeneity does not nec-
essarily imply homogeneity, a sum-
mary odds ratio (OR) was calculated us-
ing a random-effects model from the ORs
and the 95% confidence intervals (CIs)
for each end point in each study using
Mantel-Haenszel methods. The statisti-
cal rationale for combining the data have
been previously described.13 The basic
principle is that patients allocated to an
intervention in a specific trial are only
compared with those allocated to the
control treatment in the same trial, avoid-
ing direct comparisons of patients across
different trials with different designs and
lengths of follow-up. These methods pro-
vide for combination of information from
multiple 2 ⫻2 tables, generating a sum-
mary OR and its 95% CI. The data were
also analyzed using a random-effects
model to generate relative risks and 95%
CIs. These results did not qualitatively
differ from the primary analysis. A P
value of less than .05 was judged as sta-
tistically significant. To assess publica-
tion bias, we generated a funnel plot of
the logarithm of effect size and com-
pared it with the SE for each trial.
Figure 1. Flow Diagram of the Trial
Selection Process
13 Randomized Controlled Trials
of Aspirin Therapy Identified
102 Potentially Relevant Articles
Identified
7 Excluded
1 Assessed Effect on Angina
Pectoris
1 Initial Results (Physicians’
Health Study)
2 Assessed Aspirin as
Adjunct to Clopidogrel
1 Pilot Study (Terminated Early)
2 Not Primary Prevention
89 Articles Excluded
72 Reviews, Commentaries, or
Letters to the Editor
4 Nonrandomized,
Observational Trials
3 Case-Control Studies
5 Case Reports or Case Series
5 Meta-analyses
6 Included in Analysis
3 Assessed Effects in Men
1 Assessed Effects in Women
2 Assessed Effects in Men
and Women
SEX DIFFERENCE IN ASPIRIN FOR CARDIOVASCULAR EVENT PREVENTION
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RESULTS
Search Results
We identified 6 randomized con-
trolled trials9,12,14-17 for inclusion. Three
trials included only men,14-16 1 trial in-
cluded only women,9and 2 trials in-
cluded both sexes.12,17 In total, 95 456
individuals were enrolled in the 6 trials,
of which 51 342 were women.
Details of the included studies ap-
pear in TABLE 1. The weighted mean du-
ration of follow-up was 6.4 years. Base-
line characteristics of the individuals are
presented in TABLE 2. All 6 studies in-
cluded individuals without docu-
mented cardiovascular disease. Specifi-
cally, 3 trials9,14,15 included apparently
healthy health care professionals and 3
trials12,16,17 included individuals with risk
factors for cardiovascular disease.
Study Quality
Randomized treatment allocation se-
quences were generated in all 6 stud-
ies. Treatment in 4 of the studies9,14,16,17
was randomly assigned according to a
2⫻2 factorial design. The Physicians’
Health Study,14 the Women’s Health
Study,9and the Primary Prevention
Project17 each had a vitamin E compo-
nent, whereas the Thrombosis Preven-
tion Trial16 had a warfarin component.
The Hypertension Optimal Treatment
trial12 assigned participants to a target
blood pressure level and to an aspirin or
placebo group in a 3 ⫻2 factorial de-
sign. Four studies9,12,14,16 were placebo-
controlled and double-blinded. The Brit-
ish Doctor’s Trial15 and the Primary
Prevention Project17 compared an aspi-
rin group with an open-label control
group. All studies randomized equal
numbers of individuals to aspirin
therapy and to placebo, except the Brit-
ish Doctor’s Trial,15 which used a 2:1 al-
location ratio. Three of the trials12,15,16
were partially or completely funded by
pharmaceutical companies. An end
points committee in 4 studies,9,12,14,17 a
physician in 1 study,15 and a research
nurse in 1 study16 adjudicated out-
comes in a blinded fashion. Dosage of
aspirin ranged from 100 mg every other
day to 500 mg daily. Follow-up ranged
from 3.6 years to 10.1 years and was
more than 95% complete in all trials.
There was no evidence of publication
bias.
Major Cardiovascular Events
A total of 1285 major cardiovascular
events occurred among 51 342 women
(FIGURE 2). Each trial reported a
decreased risk of cardiovascular
events among participants assigned
to aspirin. Pooled results confirmed a
statistically significant 12% reduction
in the odds of cardiovascular events
with aspirin therapy among women
(OR, 0.88; 95% CI, 0.79-0.99;
P=.03).
A total of 2047 major cardiovascu-
lar events occurred among 44 114 men.
Aspirin therapy was associated with a
statistically significant 14% reduction
in the odds of cardiovascular events
among men (OR, 0.86; 95% CI, 0.78-
0.94; P=.01).
Table 1. Design of Trials Included in the Meta-analysis
Source
No. of
Individuals Description of Trial Participants Female, %
Aspirin
Dosage
Mean
Follow-up, y
Physicians Health Study,14 1989 22 071 Apparently healthy male physicians 0 325 mg every
other day
5
British Doctor’s Trial,15 1988 5139 Apparently healthy male physicians 0 500 mg/d 6
Thrombosis Prevention Trial,16 1998 5085 Men at high risk for ischemic heart disease 0 75 mg/d 6.4
Hypertension Optimal Treatment trial,12 1998 18 790 Men and women with hypertension 47 75 mg/d 4
Primary Prevention Project,17 2001 4495 Men and women with ⱖ1 major
cardiovascular risk factor
58 100 mg/d 3.6
Women’s Health Study,92005 39 876 Apparently healthy female health care
professionals
100 100 mg every
other day
10.1
Table 2. Characteristics of Men and Women Included in Trials of Aspirin for the Primary Prevention of Cardiovascular Disease*
Men Only Hypertension
Optimal Treatment
Primary Prevention
Project
Women’s
Health Study
(N = 39 876)
Physicians’
Health Study
(N = 22 071)
British
Doctor’s Trial
(N = 5139)
Thrombosis
Prevention Trial
(N = 5085)
Men
(n = 9907)
Women
(n = 8883)
Men
(n = 1912)
Women
(n = 2583)
Age, mean (SD), y NA NA 57.3 (6.6) 60.8 (7.1) 62.3 (7.8) 64.0 (7.7) 64.7 (7.4) 54.6 (7.0)
BMI, mean (SD) NA NA 27.5 (3.8) 28.5 (NA) 28.4 (NA) 27.5 (3.8) 27.7 (5.2) 26.0 (5.1)
Smoker 2428 (11) 668 (13) 2100 (41) 2100 (21) 888 (10) 391 (21) 276 (11) 5224 (13)
Hypertension 1986 (9) 514 (10) 1322 (26) 9907 (100) 8883 (100) 1285 (67) 1780 (69) 10 328 (26)
SBP, mean (SD),
mm Hg
NA 135.1 (0.41)† 139 (18) NA NA 144.3 (16.1) 145.7 (16.2) NA
Cholesterol NA NA 325 (6) 585 (6) 551 (6) 599 (31) 1143 (44) 11 763 (29)
Diabetes 441 (2) 103 (2) NA 773 (8) 728 (8) 355 (19) 387 (15) 1037 (3)
Abbreviations: BMI, body mass index (calculated as weight in kilograms divided by the square of height in meters); NA, data not available; SBP, systolic blood pressure.
*Values are expressed as number (percentage) unless otherwise indicated.
†The value in parentheses is a SE.
SEX DIFFERENCE IN ASPIRIN FOR CARDIOVASCULAR EVENT PREVENTION
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Myocardial Infarction
Among 51 342 women, there were
469 MIs (Figure 2). The rate of MI
was similar both among women
receiving aspirin and women receiv-
ing control treatment/placebo (OR,
1.01; 95% CI, 0.84-1.21; P=.95).
Among 44 144 men, there were
1023 MIs. Aspirin therapy was asso-
ciated with a statistically significant
32% reduction in the odds of MI
among men (OR, 0.68; 95% CI, 0.54-
0.86; P=.001).
Stroke
A total of 625 strokes occurred among
the women (FIGURE 3). Aspirin therapy
was associated with a significant 17%
reduction in the odds of stroke (OR,
0.83; 95% CI, 0.70-0.97; P=.02). With
respect to stroke subtypes in women,
aspirin was associated with a signifi-
cant 24% reduction in ischemic stroke
(OR, 0.76; 95% CI, 0.63-0.93; P=.008)
with no apparent effect on hemor-
rhagic stroke (OR, 1.07; 95% CI, 0.42-
2.69; P=.89).
A total of 597 strokes occurred
among the men. There was a nonsig-
nificant increase in odds of stroke
associated with aspirin (OR, 1.13;
95% CI, 0.96-1.33; P=.14). With
respect to stroke subtypes (Figure 3)
in men, aspirin had no significant
effect on ischemic stroke (OR, 1.00;
95% CI, 0.72-1.41; P=.98) but was
associated with a significant 69%
increase in the odds of hemorrhagic
stroke (OR, 1.69; 95% CI, 1.04-2.73;
P=.03).
Cardiovascular and
All-Cause Mortality
A total of 364 deaths from cardiovascu-
lar causes occurred among women while
there were 776 cardiovascular deaths
among men (FIGURE 4). No aspirin
effect was noted among women (OR,
0.90; 95% CI, 0.64-1.28; P=.56) or men
(OR, 0.99; 95% CI, 0.86-1.14; P=.87).
Death from any cause occurred in
1515 women and 1752 men. Again, no
aspirin effect was noted among women
(OR, 0.94; 95% CI, 0.74-1.19; P=.62)
or men (OR, 0.93; 95% CI, 0.85-1.03;
P=.15).
Major Bleeding
A total of 301 major bleeding events oc-
curred among the women (FIGURE 5).
Each trial reported an increased risk of
Figure 2. Effect of Aspirin Treatment on the Primary Prevention of Major Cardiovascular Events and Myocardial Infarction
Cardiovascular Events
Events, No./Total
Favors
Aspirin
Favors
Control/Placebo
10
1.00.1
Odds Ratio (95% CI)
Aspirin
Control/
Placebo
Odds Ratio
(95% CI)Study, y
0.81 (0.63-1.05)HOT,12 1998 109/4437 134/4446
0.66 (0.36-1.23)PPP,17 2001 17/1277 26/1306
0.91 (0.80-1.03)WHS,9 2005 477/19
934 522/19
942
603/25
648 682/25
694 0.88 (0.79-0.99)To t al
Women
0.98 (0.80-1.20)BDT,15 1988 289/3429 147/1710
0.83 (0.67-1.02)HOT,12 1998 173/4962 207/4945
0.86 (0.71-0.96)PHS,14 1989 307/11
037 370/11
034
0.74 (0.45-1.22)PPP,17 2001 28/949 38/963
0.86 (0.72-1.04)TPT,16 1998 228/2545 260/2540
1025/22
922 1022/21
192 0.86 (0.78-0.94)To t a l
Men
Myocardial Infarction
Events, No./Total
Aspirin
Control/
Placebo
Odds Ratio
(95% CI)Study, y
0.83 (0.51-1.36)HOT,12 1998 29/4437 35/4446
1.37 (0.47-3.95)PPP,17 2001 8/1277 6/1306
1.03 (0.84-1.25)WHS,9 2005 198/19
934 193/19
942
235/25
648 234/25
694 1.01 (0.84-1.21)To t al
Women
0.97 (0.66-1.42)BDT,15 1988 80/3429 41/1710
0.57 (0.41-0.81)HOT,12 1998 54/4962 93/4945
0.58 (0.47-0.71)PHS,14 1989 139/11
037 239/11
034
0.50 (0.24-1.04)PPP,17 2001 11/949 22/963
0.80 (0.64-0.99)TPT,16 1998 154/2545 190/2540
438/22
922 585/21
192 0.68 (0.54-0.86)To t al
Men
Sizes of data markers are proportional to the amount of data contributed by each trial. Test for heterogeneity for cardiovascular events: women, P=.47; men, P= .25;
and myocardial infarction: women, P=.62; men, P= .05. BDT indicates British Doctor’s Trial; CI, confidence interval; HOT, Hypertension Optimal Treatment trial; PHS,
Physicians’ Health Study; PPP, Primary Prevention Project; TPT, Thrombosis Prevention Trial; WHS, Women’s Health Study.
SEX DIFFERENCE IN ASPIRIN FOR CARDIOVASCULAR EVENT PREVENTION
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major bleeding associated with aspi-
rin treatment. Pooled results confirm
a statistically significant increase in the
odds of major bleeding events with as-
pirin (OR, 1.68; 95% CI, 1.13-2.52;
P=.01).
A total of 288 major bleeding events
occurred among the men. Aspirin
therapy was associated with a statisti-
cally significant increased odds of ma-
jor bleeding events among men (OR,
1.72; 95% CI, 1.35-2.20; P⬍.001). The
predominant site of bleeding was the
gastrointestinal tract.
COMMENT
This sex-specific meta-analysis
demonstrates that aspirin therapy is
Figure 3. Effect of Aspirin Treatment on the Primary Prevention of Stroke, Ischemic Stroke, and Hemorrhagic Stroke
101.00.1
Odds Ratio (95% CI)
Ischemic Stroke
Events, No./Total
Aspirin
Control/
Placebo
Odds Ratio
(95% CI)
Study, y
0.68 (0.24-1.92)PPP,17 2001 6/1277 9/1306
0.77 (0.63-0.94)WHS,9 2005 179/19
934 221/19
942
Women
179/21
211 230/21
248 0.76 (0.63-0.93)To t al
1.50 (0.64-3.53)BDT,15 1988 61/3429 27/1710
1.11 (0.82-1.50)PHS,14 1989 119/11
037 95/11
034
1.16 (0.42-3.22)PPP,17 2001 10/949 13/963
0.64 (0.37-1.11)TPT,16 1998 47/2545 48/2540
1.00 (0.72-1.41)Tot a l 331/17
960 266/16
247
Men
Hemorrhagic Stroke
Events, No./Total
Aspirin
Control/
Placebo
Odds Ratio
(95% CI)
Study, y
0.20 (0.01-4.23)PPP,17 2001 8/1277 2/1306
1.25 (0.83-1.88)WHS,9 2005 51/19
934 41/19
942
Women
51/21
211 43/21
248 1.07 (0.42-2.69)To t al
1.08 (0.41-2.85)BDT,15 1988 13/3429 5/1710
1.92 (0.95-3.86)PHS,14 1989 23/11
037 12/11
034
2.03 (0.18-22.44)PPP,17 2001 2/949 1/963
2.00 (0.75-5.34)TPT,16 1998 12/2545 6/2540
1.69 (1.04-2.73)Tot a l 50/17
960 25/16
247
Men
Favors
Aspirin
Favors
Contol/Placebo
Stroke
Events, No./Total
Aspirin
Control/
Placebo
Odds Ratio
(95% CI)Study, y
0.81 (0.56-1.16)HOT,12 1998 54/4437 67/4446
0.56 (0.21-1.51)PPP,17 2001 6/1277 11/1306
0.84 (0.70-1.01)WHS,9 2005 221/19
934 266/19
942
281/25
648 344/25
694 0.83 (0.70-0.97)To t al
Women
1.13 (0.72-1.78)BDT,15 1988 61/3429 27/1710
1.17 (0.87-1.57)HOT,12 1998 94/4962 80/4945
1.22 (0.93-1.59)PHS,14 1989 119/11
037 95/11
034
0.78 (0.34-1.78)PPP,17 2001 10/949 13/963
0.98 (0.65-1.47)TPT,16 1998 47/2545 48/2540
331/22
922 266/21
192 1.13 (0.96-1.33)To t al
Men
Sizes of data markers are proportional to the amount of data contributed by each trial. Test for heterogeneity for stroke: women, P=.72; men, P= .80; ischemic stroke:
women, P=.82; men, P= .81; and hemorrhagic stroke: women, P=.25; men, P=.78. See legend of Figure 2 for expansions of study names. CI indicates confidence
interval.
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Figure 5. Effect of Aspirin Treatment on Major Bleeding
Favors
Aspirin
Favors
Control/Placebo
10
1.00.1
Odds Ratio (95% CI)
Major Bleeding
Events, No./Total
Aspirin
Control/
Placebo
Odds Ratio
(95% CI)
Study, y
1.89 (1.16-3.08)HOT,12 1998 47/4437 25/4446
4.63 (1.00-21.46)PPP,17 2001 9/1277 2/1306
1.40 (1.07-1.83)WHS,9 2005 127/19
934 91/19
942
183/25
648 118/25
694 1.68 (1.13-2.52)To t al
Women
1.43 (0.60-3.38)BDT,15 1988 29/3429 7/1710
1.70 (1.19-2.41)HOT,12 1998 83/4962 50/5035
1.71 (1.07-2.73)PHS,14 1989 48/11
037 28/10
979
3.85 (1.27-11.64)PPP,17 2001 15/949 4/963
1.54 (0.76-3.10)TPT,16 1998 20/2545 13/2540
186/22
922 102/21
227 1.72 (1.35-2.20)To t al
Men
Sizes of data markers are proportional to the amount of data contributed by each trial. Test for heterogeneity: women, P=.21; men, P= .68. See legend of Figure 2 for
expansions of study names. CI indicates confidence interval.
Figure 4. Effect of Aspirin Treatment on the Primary Prevention of Cardiovascular Mortality and Total Mortality
Cardiovascular Mortality
Events, No./Total
Favors
Aspirin
Favors
Control/Placebo
10
1.00.1
Odds Ratio (95% CI)
Aspirin
Control/
Placebo
Odds Ratio
(95% CI)Study, y
1.07 (0.72-1.59)HOT,12 1998 50/4437 47/4446
0.41 (0.16-1.05)PPP,17 2001 6/1277 15/1306
0.95 (0.74-1.22)WHS,9 2005 120/19
934 126/19
942
176/25
648 188/25
694 0.90 (0.64-1.28)To t al
Women
0.93 (0.70-1.23)BDT,15 1988 148/3429 79/1710
0.89 (0.66-1.20)HOT,12 1998 83/4962 93/4945
0.98 (0.72-1.33)PHS,14 1989 81/11
037 83/11
034
0.69 (0.32-1.50)PPP,17 2001 11/949 16/963
1.26 (0.93-1.69)TPT,16 1998 101/2545 81/2540
424/22
922 352/21
192 0.99 (0.86-1.14)To t al
Men
Total Mortality
Events, No./Total
Aspirin
Control/
Placebo
Odds Ratio
(95% CI)Study, y
1.13 (0.86-1.48)HOT,12 1998 111/4437 99/4446
0.60 (0.34-1.04)PPP,17 2001 20/1277 34/1306
0.95 (0.85-1.06)WHS,9 2005 609/19
934 642/19
942
740/25
648 775/25
694 0.94 (0.74-1.19)To t al
Women
0.88 (0.72-1.09)BDT,15 1988 270/3429 151/1710
0.83 (0.67-1.02)HOT,12 1998 173/4962 207/4945
0.96 (0.79-1.15)PHS,14 1989 217/11
037 227/11
034
0.97 (0.63-1.49)PPP,17 2001 42/949 44/963
1.06 (0.87-1.29)TPT,16 1998 216/2545 205/2540
918/22
922 834/21
192 0.93 (0.85-1.03)To t al
Men
Sizes of data markers are proportional to the amount of data contributed by each trial. Test for heterogeneity for cardiovascular mortality: women, P=.18; men, P= .41;
and total mortality: women, P=.12; men, P= .53. See legend of Figure 2 for expansions of study names. CI indicates confidence interval.
SEX DIFFERENCE IN ASPIRIN FOR CARDIOVASCULAR EVENT PREVENTION
©2006 American Medical Association. All rights reserved. (Reprinted) JAMA, January 18, 2006—Vol 295, No. 3 311
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associated with a significant reduc-
tion in the risk of cardiovascular events
in both sexes. However, the specific
types of benefit differ in important ways
between women and men. For pri-
mary prevention of cardiovascular dis-
ease in women, aspirin therapy signifi-
cantly reduced the risk of the composite
of cardiovascular events primarily by its
effect on reducing the risk of ischemic
stroke. Among women, aspirin had no
significant effect on the risk of MI. In
contrast, for the primary prevention of
cardiovascular disease in men, aspirin
therapy significantly reduced the risk
of the composite of cardiovascular
events predominantly by reducing the
risk of MI. Among men, aspirin dem-
onstrated a nonsignificant increase in
the risk of stroke that was related to the
significant increase in the risk of hem-
orrhagic stroke.
Benefit of Aspirin Therapy
Based on the absolute risk reduction of
0.30% and 0.37% in women and men,
respectively, the number needed to treat
to prevent 1 cardiovascular event over
the mean follow-up of 6.4 years was 333
women and 270 men. In other words,
aspirin therapy for an average of 6.4
years results in an average absolute
benefit of approximately 3 cardiovas-
cular events prevented per 1000
women and 4 cardiovascular events
prevented per 1000 men. Of note, the
population studied had a low risk of
fatal or nonfatal vascular events. It has
been shown that the cardioprotective
benefit of aspirin is related to the car-
diovascular risk in the population
studied.3As a result, the absolute risk
reduction for these events was small.
In addition, the risk of stroke was sig-
nificantly reduced in women receiving
aspirin therapy, corresponding to
an average absolute benefit of approx-
imately 2 stroke events per 1000
women treated. By contrast, the risk of
MI was significantly reduced in men
(and not in women) receiving aspirin
therapy, corresponding to an average
absolute benefit of approximately 8
MI events prevented per 1000 men
treated for 6.4 years.
Harm of Aspirin Therapy
Aspirin treatment resulted in an ap-
proximately 70% increase in the risk of
major bleeding events among women
and men. Based on the absolute risk in-
crease of 0.25% and 0.33% in women
and men, respectively, the number
needed to harm over 6.4 years of aspi-
rin treatment by causing 1 major bleed-
ing event was 400 women and 303 men.
In other words, aspirin therapy for an
average of 6.4 years results in an aver-
age absolute increase of approxi-
mately 2.5 major bleeding events caused
per 1000 women and 3 major bleed-
ing events caused per 1000 men.
Mechanism of Aspirin
The mechanisms underlying the effec-
tiveness of aspirin have been studied ex-
tensively.3,18 Experimentally, a single
oral 100-mg dose of aspirin is suffi-
cient to completely block the synthe-
sis of thromboxane A2,19,20 the predomi-
nant pathway by which aspirin inhibits
platelet aggregation.18 When taken
daily, the effect of repeated doses is cu-
mulative.21 At higher doses, the syn-
thesis of prostacyclin is also inhib-
ited,3which could paradoxically lead
to thrombosis and vasoconstriction.
Currently, there is an increasing focus
on the role of inflammation in cardio-
vascular risk. Aspirin has been dem-
onstrated to reduce C-reactive pro-
tein.22 In the Physicians’ Health Study,
aspirin was most effective in reducing
cardiovascular risk in men with the
most elevated levels of C-reactive pro-
tein.23 However, the dose of aspirin re-
quired to achieve the maximal anti-
inflammatory effect remains unknown.
Sex Effect
Several possibilities may explain the dif-
ferences in cardioprotection observed
between the sexes. First, evidence ex-
ists that there is a difference in aspirin
metabolism.24 Several studies have sug-
gested a reduced pharmacological effect
of aspirin among women compared
with men.25,26 Second, event rates of
stroke and MI differ. Women have a
greater proportion of strokes com-
pared with MIs, whereas men have a
greater proportion of MIs compared
with strokes. Based on the number of
events recorded in our analysis, it would
be easiest to find a statistically mean-
ingful difference in the risk of stroke
among women and in the risk of MI
among men. Third, aspirin resistance
tends to be more common among
women than men.27
Based on laboratory and clinical
data,3,18 current guidelines recom-
mend 75 mg/d to 162 mg/d of aspirin
for primary prevention.5-8 Only the Brit-
ish Doctor’s Trial used a dose (500
mg/d) that exceeded this current rec-
ommendation. This higher dose is just
as effective at inhibiting thromboxane
and is more potent at inhibiting pros-
tacyclin, a mechanism with the poten-
tial to increase thrombotic events.18
When the British Doctor’s Trial was
censored from our analysis of men, the
proportional reduction of cardiovascu-
lar events increased from 14% to 17%
and the proportional reduction in the
risk of MI increased from 32% to 36%.
The recent Women’s Health Study9used
a lower dose (100 mg every other day)
than currently recommended. How-
ever, 100 mg every other day has been
found to be as effective as 81 mg/d at
inhibiting thromboxane and prostacy-
clin levels.28
Limitations
The present study has several poten-
tial limitations. First, as in most meta-
analyses, these results should be inter-
preted with caution because aspirin
dose, duration of treatment, and
lengths of follow-up were not uni-
form. However, these differences did
not result in any statistical difference
in the effect size between the trials.
Second, despite examination of the
totality of the evidence by pooling
results from all available randomized
trials, the numbers of individual out-
come events were infrequent because
of the low-risk nature of the popula-
tions studied. Consequently, this
analysis has limited statistical power
to reliably detect differences in the
individual end points with aspirin
therapy. Third, we were unable to
SEX DIFFERENCE IN ASPIRIN FOR CARDIOVASCULAR EVENT PREVENTION
312 JAMA, January 18, 2006—Vol 295, No. 3 (Reprinted) ©2006 American Medical Association. All rights reserved.
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determine what effect aspirin has on
particular subgroups. Only analysis of
data from the participants of all avail-
able trials would allow the examina-
tion of aspirin benefit in particular
subgroups. Finally, meta-analysis
remains retrospective research that is
subject to the methodological defi-
ciencies of the included studies. We
minimized the likelihood of bias by
developing a detailed protocol before
initiating the study, by performing a
meticulous search for published and
unpublished studies, and by using
explicit methods for study selection,
data extraction, and data analysis.
CONCLUSION
This meta-analysis of more than
50 000 women and 40 000 men
enrolled in 6 randomized trials indi-
cates that low-dose aspirin therapy is
associated with a significant reduction
in cardiovascular events in both
women and men. Our results are par-
ticularly noteworthy for the beneficial
effect of aspirin on the risk of stroke
for women and on the risk of MI for
men. Although the present meta-
analysis indicates that aspirin may
have different effects between the
sexes, the relatively small number of
MIs among women and strokes
among men suggest that further stud-
ies are needed before we can conclude
that men and women differ in their
cardiovascular response to aspirin.
Nevertheless, the favorable effect of
aspirin on the combined risk of car-
diovascular events for women and
men is apparent from these random-
ized studies. Aspirin use is also associ-
ated with a significant risk of major
bleeding irrespective of sex. Both the
beneficial and harmful effects of aspi-
rin should be considered by the physi-
cian and patient before initiating aspi-
rin for the primary prevention of
cardiovascular disease in both sexes.
Author Contributions: Dr Brown had full access to all
of the data in the study and takes responsibility for
the integrity of the data and the accuracy of the data
analysis.
Study concept and design: Berger, Brown.
Acquisition of data: Berger, Roncaglioni, Avanzini, Pan-
grazzi, Tognoni, Brown.
Analysis and interpretation of data: Berger, Brown.
Drafting of the manuscript: Berger, Brown.
Critical revision of the manuscript for important in-
tellectual content: Roncaglioni, Avanzini, Pangrazzi,
Tognoni, Brown.
Statistical expertise: Berger, Brown.
Financial Disclosures: None reported.
REFERENCES
1. Antiplatelet Trialists’ Collaboration. Collaborative
overview of randomised trials of antiplatelet therapy:
prevention of death, myocardial infarction, and stroke
by prolonged antiplatelet therapy in various catego-
ries of patients. BMJ. 1994;308:81-106.
2. Antiplatelet Trialists’ Collaboration. Collaborative
meta-analysis of randomised trials of antiplatelet
therapy for prevention of death, myocardial infarc-
tion, and stroke in high risk patients. BMJ. 2002;324:
71-86.
3. Patrono C, Coller B, FitzGerald GA, Hirsh J, Roth
G. Platelet-active drugs: the relationships among dose,
effectiveness, and side effects: the Seventh ACCP Con-
ference on Antithrombotic and Thrombolytic Therapy.
Chest. 2004;126:234S-264S.
4. Eidelman RS, Herbert PR, Weisman SM, Hennek-
ens CH. An update on the primary prevention of car-
diovascular disease. Arch Intern Med. 2003;163:2006-
2010.
5. US Preventive Services Task Force. Aspirin for the
primary prevention of cardiovascular events: recom-
mendation and rationale. Ann Intern Med. 2002;136:
157-160.
6. Pearson TA, Blair SN, Daniels SR, et al; American
Heart Association Science Advisory and Coordinat-
ing Committee. AHA guidelines for primary preven-
tion of cardiovascular disease and stroke: 2002 up-
date: consensus panel guide to comprehensive risk
reduction for adult patients without coronary or other
atherosclerotic vascular diseases. Circulation. 2002;106:
388-391.
7. Mosca L, Appel LJ, Benjamin EJ, et al. Evidence-
based guidelines for cardiovascular prevention in
women. Circulation. 2004;109:672-693.
8. Prevention of coronary heart disease in clinical prac-
tice: recommendations of the Second Joint Task Force
of European and other Societies on coronary
prevention. Eur Heart J. 1998;19:1434-1503.
9. Ridker PM, Cook NR, Lee IM, et al. A randomized
trial of low-dose aspirin in the primary prevention of
cardiovascular disease in women. N Engl J Med. 2005;
352:1293-1304.
10. Meade MO, Richardson WS. Selecting and ap-
praising studies for a systematic review. Ann Intern
Med. 1997;127:531-537.
11. Schulz KF, Chalmers I, Hayes RJ, et al. Empirical
evidence of bias: dimensions of methodologic qual-
ity associated with estimates of treatment effects in
controlled trials. JAMA. 1995;273:408-412.
12. Hansson L, Zanchetti A, Carruthers SG, et al; HOT
Study Group. Effects of intensive blood-pressure low-
ering and low-dose aspirin in patients with hyperten-
sion: principal results of the Hypertension Optimal
Treatment (HOT) randomized trial. Lancet. 1998;351:
1755-1762.
13. Mehta SR, Cannon CP, Fox KAA, et al. Routine
vs selective invasive strategies in patients with acute
coronary syndromes: a collaborative meta-analysis of
randomized trials. JAMA. 2005;293:2908-2917.
14. Steering Committee for the Physicians’ Health
Study Research Group. Final report on the aspirin com-
ponent of the ongoing Physicians’ Health Study. N Engl
J Med. 1989;321:129-135.
15. Peto R, Gray R, Collins R, et al. Randomized trial
of prophylactic daily aspirin in British male doctors. BMJ.
1988;296:313-316.
16. Medical Research Council. Thrombosis Preven-
tion Trial: randomized trial of low-intensity oral anti-
coagulation with warfarin and low-dose aspirin in the
primary prevention of ischaemic heart disease in men
at increased risk. Lancet. 1998;351:233-241.
17. Collaborative Group of the Primary Prevention
Project. Low-dose aspirin and vitamin E in people at
cardiovascular risk: a randomized trial in general
practice. Lancet. 2001;357:89-95.
18. Awtry EH, Loscalzo J. Aspirin. Circulation. 2000;
101:1206-1218.
19. Patrignani P, Filabozzi P, Patrono C. Selective
cumulative inhibition of platelet thromboxane pro-
duction by low-dose aspirin in healthy subjects. J Clin
Invest. 1982;69:1366-1372.
20. Weksler BB, Pett SB, Alonso D, et al. Differential
inhibition by aspirin of vascular and platelet prosta-
glandin synthesis in atherosclerotic patients. N Engl J
Med. 1983;308:800-805.
21. Patrono C, Ciabattoni G, Patrignani P, et al. Clini-
cal pharmacology of platelet cyclooxygenase inhibition.
Circulation. 1985;72:1177-1184.
22. Ikonomidis I, Andreotti F, Economou E, et al. In-
creased proinflammatory cytokines in patients with
chronic stable angina and their reduction by aspirin.
Circulation. 1999;100:793-798.
23. Ridker PM, Cushman M, Stampfer MJ, Tracey RP,
Hennekens CH. Inflammation, aspirin, and the risk of
cardiovascular disease in apparently healthy men.
N Engl J Med. 1997;336:973-979.
24. Spranger M, Aspey BS, Harrison MJG. Sex dif-
ferences in antithrombotic effect of aspirin. Stroke.
1989;20:34-37.
25. Escolar G, Bastida E, Garrido M, et al. Sex-
related differences in the effects of aspirin on the in-
teraction of platelets with subendothelium. Thromb
Res. 1986;44:837-847.
26. Harrison MJ, Weisblatt E. A sex difference in the
effect of aspirin on “spontaneous” platelet aggrega-
tion in whole blood. Thromb Haemost. 1983;50:773-
774.
27. Gum PA, Kottke-Marchant K, Poggio ED, et al.
Profile and prevalence of aspirin resistance in pa-
tients with cardiovascular disease. Am J Cardiol. 2001;
88:230-235.
28. Ridker PM, Hennekens CH, Tofler GH, et al.
Anti-platelet effects of 100 mg alternate day oral
aspirin: a randomized, double-blind, placebo-
controlled trial of regular and enteric coated formu-
lations in men and women. J Cardiovasc Risk. 1996;
3:209-212.
SEX DIFFERENCE IN ASPIRIN FOR CARDIOVASCULAR EVENT PREVENTION
©2006 American Medical Association. All rights reserved. (Reprinted) JAMA, January 18, 2006—Vol 295, No. 3 313
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CORRECTION
Incorrect Numbers of Events: In the Review entitled “Aspirin for the Primary Prevention of Cardiovascular Events in Women and Men: A Sex-Specific Meta-analysis of
Randomized Controlled Trials” published in the January 18, 2006, issue of JAMA (2006;295:306-313), the wrong numbers of events appeared in FIGURE 3; the cor-
rected Figure 3 appears below. On page 309, in the first column, in the second full paragraph, the first sentence should have been “Among 44 114 men, there were
1023 MIs.” On page 311, in Figure 5, under “Men, BDT,15 1988,” it should be 20/3429 for the aspirin group.
101.00.1
Odds Ratio
(
95% CI
)
Ischemic Stroke
Events, No./Total
Aspirin
Control/
Placebo
Odds Ratio
(95% CI)
Study, y
0.68 (0.24-1.92)PPP,17 2001 6/1277 9/1306
0.77 (0.63-0.94)WHS,9 2005 170/19
934 221/19
942
Women
176/21
211 230/21
248 0.76 (0.63-0.93)To t al
1.50 (0.64-3.53)BDT,15 1988 21/3429 7/1710
1.11 (0.82-1.50)PHS,14 1989 91/11
037 82/11
034
1.16 (0.42-3.22)PPP,17 2001 8/949 7/963
0.64 (0.37-1.11)TPT,16 1998 21/2545 33/2567
1.00 (0.72-1.41)Tot a l 141/17
960 129/16
274
Men
Hemorrhagic Stroke
Events, No./Total
Aspirin
Control/
Placebo
Odds Ratio
(95% CI)
Study, y
0.20 (0.01-4.23)PPP,17 2001 0/1277 2/1306
1.25 (0.83-1.88)WHS,9 2005 51/19
934 41/19
942
Women
51/21
211 43/21
248 1.07 (0.42-2.69)To t al
1.08 (0.41-2.85)BDT,15 1988 13/3429 6/1710
1.92 (0.95-3.86)PHS,14 1989 23/11
037 12/11
034
2.03 (0.18-22.44)PPP,17 2001 2/949 1/963
2.00 (0.75-5.34)TPT,16 1998 12/2545 6/2540
1.69 (1.04-2.73)Tot a l 50/17
960 25/16
247
Men
Favors
Aspirin
Favors
Contol/Placebo
Stroke
Events, No./Total
Aspirin
Control/
Placebo
Odds Ratio
(95% CI)Study, y
0.81 (0.56-1.16)HOT,12 1998 54/4437 67/4446
0.56 (0.21-1.51)PPP,17 2001 6/1277 11/1306
0.84 (0.70-1.01)WHS,9 2005 221/19
678 266/19
942
281/25
392 344/25
694 0.83 (0.70-0.97)To t al
Women
1.13 (0.72-1.78)BDT,15 1988 61/3429 27/1710
1.17 (0.87-1.57)HOT,12 1998 94/4962 80/4945
1.22 (0.93-1.59)PHS,14 1989 119/11
037 98/11
034
0.78 (0.34-1.78)PPP,17 2001 10/949 13/963
0.98 (0.65-1.47)TPT,16 1998 47/2545 48/2540
331/22
922 266/21
192 1.13 (0.96-1.33)To t al
Men
2002 JAMA, May 3, 2006—Vol 295, No. 17 (Reprinted) ©2006 American Medical Association. All rights reserved.
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