Review

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Reducing stroke in women with risk

factor management: blood pressure and
cholesterol

Stroke is a major cause of death and disability in adults worldwide. Prevention focused
on modifiable risk factors, such as hypertension and hyperlipidemia, has shown them
to be of significant importance in decreasing the risk of stroke. Multiple studies have
brought to light the differences between men and women with regards to stroke
and these risk factors. Women have a higher prevalence of stroke, mortality and
disability and it has been shown that preventive and treatment options are not as
comprehensive for women. Hence, it is of great necessity to evaluate and summarize
the differences in gender and stroke risk factors in order to target disparities and
optimize prevention, especially because women have a higher lifetime risk of stroke.
The purpose of this review is to summarize sex differences in the prevalence of
hypertension and hyperlipidemia. In addition, we will review the sex differences in
stroke prevention effectiveness and adherence to blood pressure and cholesterol
medications, and suggest future directions for research to reduce the burden of
stroke in women.

Sanam Baghshomali1
&Cheryl Bushnell*,1
1
Department of Neurology, Wake Forest
School of Medicine, Winston Salem,
NC27157, USA
*Author for correspondence:
cbushnel@ wakehealth.edu

Keywords: female gender hyperlipidemia hypertension risk factor stroke differences

Stroke is the fourth leading cause of death

in the USA, after heart disease, cancer and
chronic lower respiratory disease, and the
most common cause of permanent disability
in adults worldwide [1] . Statistics from the
American Heart Association (AHA) Heart
Disease and Stroke 2014 updates shows that
the relative rate of stroke death fell by 35.8%
and the actual number of stroke deaths
declined by 22.8% from 2000 to 2010. Yet
each year, 795,000 new or recurrent strokes
occur in the USA with approximately
610,000 first attacks and 185,000 recurrent attacks. One of every 19 deaths in the
USA is due to stroke. On average, every 40s,
someone in USA has a stroke and dies of one
approximately every 4min [1] .
Hypercholesterolemia and hypertension
are well-established risk factors for stroke,
they are modifiable, and thus are a major
focus of stroke prevention [2] . The identification of patients who may be targeted for
prevention with lifestyle changes is also

10.2217/WHE.14.47 2014 Future Medicine Ltd

well established[3] . In addition, the AHA

has identified total cholesterol less than
200mg/dl (untreated) and untreated blood
pressure (BP) less than 120/<80 mm Hg
for adults as two of the seven components
of ideal cardiovascular health [4] . According to 2014 AHA statistics, 77% of patients
with first-time stroke have BPs greater than
140/90 [1] .
Elevated total cholesterol levels are also a
major focus of prevention programs because
nearly 32 million adults over 20years of
age have total cholesterol levels greater than
240, for a prevalence of 13.8% [1] . In addition, 33.0% of US adults, or approximately
78 million people over 20years of age, have
hypertension. Unfortunately, this is a major
public health problem because although
nearly 82% of people with hypertension are
aware of their condition, a smaller fraction
(75%) are using antihypertensive medication; but more important, only 53% of those
with hypertension are controlled to target

Womens Health (2014) 10(5), 535544

part of

ISSN 1745-5057

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Review Baghshomali & Bushnell

levels[1] . Statistics for these risk factors are even worse
in developing countries compared with developed
countries. Although patients are prescribed medications for these conditions, they are not effectively
treated, so the numbers of patients who reach treatment goals in developing countries are lower compared
with the USAA and Europe [5] .
Considering there are 795,000 strokes per year in
the USA and that hypertension has a 49% population
attributable risk for stroke, approximately 390,000
strokes could be prevented with adequate BP control.
For cholesterol, an estimated 168,000 strokes could be
prevented if adequately treated [2,6] . Hypertension and
hyperlipidemia account for a very large proportion of
preventable strokes in men and women.
In this review, we performed a literature search using
Medline for articles focused on sex differences in hypertension and hyperlipidemia in relationship to primary
and secondary stroke prevention. We also included
carotid atherosclerosis as an intermediate outcome
for stroke because hypertension and hyperlipidemia
are major contributors to carotid disease. We selected
cohort studies of both sexes and those with women only
if BP and cholesterol were the focus. Also, clinical trials
were included if they included the topics of interest, but
we excluded case reports. Only studies with stroke or
carotid atherosclerosis as outcomes were included.
Sex differences in stroke: outcomes
There are increasingly recognizable differences in various aspects of stroke outcomes between women and
men. Nearly 55,000 more women than men suffer from
stroke each year [1] . This is in part because women have
a higher lifetime risk of stroke. Shown by the Framingham Heart Study, for people between the ages of 55
and 75years, the lifetime risk of stroke was one out of
five for women and one out of six for men [7] . Women,
have a lower incidence of stroke than men between the
ages of 45 to 84years, but after the age of 85years, the
incidence in women is similar to, or exceeds that of
men [8] . Women not only have a higher lifetime risk of
stroke, but of those who die from stroke, women comprise nearly 60% [1] . Younger women are also at risk for
worse outcomes than men [9] .
Sex differences in hyperlipidemia
&hypertension
In the USA, the National Health and Nutrition Evaluation Survey (NHANES) data shows that prevalence
of hypertension increases in women, particularly in
midlife. Specifically, men are more likely to have
hypertension below the age of 45years, between the
ages of 45 to 64years this prevalence is similar and
after the 65years of age hypertension is more common

536

Womens Health (2014) 10(5)

in women [1] . For hyperlipidemia in adults over the age

of 20years, women have a higher prevalence of total
cholesterol greater than 200mg/dl (44.9% vs 41.3% in
men), but men have a higher prevalence of low-density
lipoprotein (LDL) greater than 130mg/dl (31.9% vs
30.0% in women) and high-density lipoprotein (HDL)
less than 40mg/dl (31.8% vs 12.3% in women) [1] ,
suggesting a worse overall pattern of cholesterol in men
than women.
Sex differences in primary prevention
ofstroke
Baseline sex differences in BP and cholesterol levels
were noted in the Management of Elevated Cholesterol
in the primary prevention Group of Adult Japanese
(MEGA), which evaluated the usefulness of pravastatin in primary prevention of cardiovascular events
[10] . This prospective, randomized, open, blinded end
point study was conducted between 1994 and 2004,
evaluating 7,832 patients (women: 5356, 68.4%)
between the ages of 40 and 70years with hypercholesterolemia and no history of coronary heart disease (CHD) or stroke. The aim was to compare the
effects of pravastatin plus diet on the incidence of
cardiovascular events compared with diet alone, with
a special emphasis on the outcomes in women. The
comparison of baseline characteristics between men
and women enrolled in this study showed that more
women (42.6%) than men (40.2%) had hypertension
(Table 1) . Baseline triglycerides were higher in men, but
HDL-cholesterol (HDL-C) was higher in women and
total cholesterol and LDL-C were similar [10] .
There was no significant difference between diet
plus pravastatin versus diet alone in prevention of
stroke events in men or women and, thus, no sex difference in the treatment impact. However, men had a
trend towards benefit in diet plus pravastatin for CHD
protection, whereas women had no significant benefit
(Table 2) [10] .
The Asia Pacific Cohort Studies Collaboration,
which includes 29 cohorts from Asia and 7 cohorts
from Australia and New Zealand, assessed the joint
effects of blood pressure and cholesterol on the risk of
stroke, both ischemic and hemorrhagic subtypes. The
investigators found that the slope of stroke risk jointly
impacted by the various strata of cholesterol and systolic BP was similar in men and women [11] . Another
analysis of 214,032 women in the same cohort assessed
the impact of various risk factors on stroke risk. They
reported that for every extra 10 mmHg increase in
systolic BP, the risk of ischemic stroke increased by
36%, even after adjustment for other risk factors [12] .
For total cholesterol, there was a 12% increased risk for
each 1 mmol/l increase. These results emphasize the

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Review Baghshomali & Bushnell

levels[1] . Statistics for these risk factors are even worse
in developing countries compared with developed
countries. Although patients are prescribed medications for these conditions, they are not effectively
treated, so the numbers of patients who reach treatment goals in developing countries are lower compared
with the USAA and Europe [5] .
Considering there are 795,000 strokes per year in
the USA and that hypertension has a 49% population
attributable risk for stroke, approximately 390,000
strokes could be prevented with adequate BP control.
For cholesterol, an estimated 168,000 strokes could be
prevented if adequately treated [2,6] . Hypertension and
hyperlipidemia account for a very large proportion of
preventable strokes in men and women.
In this review, we performed a literature search using
Medline for articles focused on sex differences in hypertension and hyperlipidemia in relationship to primary
and secondary stroke prevention. We also included
carotid atherosclerosis as an intermediate outcome
for stroke because hypertension and hyperlipidemia
are major contributors to carotid disease. We selected
cohort studies of both sexes and those with women only
if BP and cholesterol were the focus. Also, clinical trials
were included if they included the topics of interest, but
we excluded case reports. Only studies with stroke or
carotid atherosclerosis as outcomes were included.
Sex differences in stroke: outcomes
There are increasingly recognizable differences in various aspects of stroke outcomes between women and
men. Nearly 55,000 more women than men suffer from
stroke each year [1] . This is in part because women have
a higher lifetime risk of stroke. Shown by the Framingham Heart Study, for people between the ages of 55
and 75years, the lifetime risk of stroke was one out of
five for women and one out of six for men [7] . Women,
have a lower incidence of stroke than men between the
ages of 45 to 84years, but after the age of 85years, the
incidence in women is similar to, or exceeds that of
men [8] . Women not only have a higher lifetime risk of
stroke, but of those who die from stroke, women comprise nearly 60% [1] . Younger women are also at risk for
worse outcomes than men [9] .
Sex differences in hyperlipidemia
&hypertension
In the USA, the National Health and Nutrition Evaluation Survey (NHANES) data shows that prevalence
of hypertension increases in women, particularly in
midlife. Specifically, men are more likely to have
hypertension below the age of 45years, between the
ages of 45 to 64years this prevalence is similar and
after the 65years of age hypertension is more common

536

Womens Health (2014) 10(5)

in women [1] . For hyperlipidemia in adults over the age

of 20years, women have a higher prevalence of total
cholesterol greater than 200mg/dl (44.9% vs 41.3% in
men), but men have a higher prevalence of low-density
lipoprotein (LDL) greater than 130mg/dl (31.9% vs
30.0% in women) and high-density lipoprotein (HDL)
less than 40mg/dl (31.8% vs 12.3% in women) [1] ,
suggesting a worse overall pattern of cholesterol in men
than women.
Sex differences in primary prevention
ofstroke
Baseline sex differences in BP and cholesterol levels
were noted in the Management of Elevated Cholesterol
in the primary prevention Group of Adult Japanese
(MEGA), which evaluated the usefulness of pravastatin in primary prevention of cardiovascular events
[10] . This prospective, randomized, open, blinded end
point study was conducted between 1994 and 2004,
evaluating 7,832 patients (women: 5356, 68.4%)
between the ages of 40 and 70years with hypercholesterolemia and no history of coronary heart disease (CHD) or stroke. The aim was to compare the
effects of pravastatin plus diet on the incidence of
cardiovascular events compared with diet alone, with
a special emphasis on the outcomes in women. The
comparison of baseline characteristics between men
and women enrolled in this study showed that more
women (42.6%) than men (40.2%) had hypertension
(Table 1) . Baseline triglycerides were higher in men, but
HDL-cholesterol (HDL-C) was higher in women and
total cholesterol and LDL-C were similar [10] .
There was no significant difference between diet
plus pravastatin versus diet alone in prevention of
stroke events in men or women and, thus, no sex difference in the treatment impact. However, men had a
trend towards benefit in diet plus pravastatin for CHD
protection, whereas women had no significant benefit
(Table 2) [10] .
The Asia Pacific Cohort Studies Collaboration,
which includes 29 cohorts from Asia and 7 cohorts
from Australia and New Zealand, assessed the joint
effects of blood pressure and cholesterol on the risk of
stroke, both ischemic and hemorrhagic subtypes. The
investigators found that the slope of stroke risk jointly
impacted by the various strata of cholesterol and systolic BP was similar in men and women [11] . Another
analysis of 214,032 women in the same cohort assessed
the impact of various risk factors on stroke risk. They
reported that for every extra 10 mmHg increase in
systolic BP, the risk of ischemic stroke increased by
36%, even after adjustment for other risk factors [12] .
For total cholesterol, there was a 12% increased risk for
each 1 mmol/l increase. These results emphasize the

future science group

Reducing stroke in women with risk factor management: blood pressure & cholesterol

Review

Table 1. Baseline characteristic of participants of Management of Elevated Cholesterol in the

primary prevention Group of Adult Japanese (MEGA) study.

Women (n=5356)

Men (n=2476)

Hypertension, n (%)

2281 (42.6)

996 (40.2)

SBP, mean (SD), mmHg

132.3 (17.0)

132.0 (16.2)

DBP, mean (SD), mmHg

77.9 (10.2)

80.2 (10.3)

Total cholesterol, mean (SD), mmol/l

6.3 (0.3)

6.2 (0.3)

LDL-C, mean (SD), mmol/l

4.1 (0.4)

4.0 (0.5)

HDL-C, mean (SD), mmol/l

1.5 (0.4)

1.4 (0.4)

DBP: Diastolic blood pressure; HDL-C: High-density lipoprotein-cholesterol; LDL-C: Low-density lipoprotein-cholesterol; SBP: Systolic blood
pressure.
Adapted with permission from [10].

impact that improved risk factor management could

have on stroke risk in Asia and Australia/New Zealand.
Sex differences in risk factor profiles of
stroke patients
Cohort studies have pointed out the difference between
risk factor profiles in men and women who have suffered a stroke [1315] , although the results from these
studies are very inconsistent and differ greatly between
countries [16] . In a meta-analysis done specifically to
focus on sex differences in stroke and risk factors, 45
articles with data from 673,935 patients were reviewed
[17] . The cumulative analysis showed that women, on
average, were 5.2years older than men at the onset of
stroke (p<0.001). Hypertension was more prevalent
in women (69% vs 65% in men) and hyperlipidemia
was more common in men (37% vs 34% in women;
Table 3). Subgroup analysis showed there was some
geographic variation. For example, hyperlipidemia was
more common in men than women in North America
(odds ratio [OR]: 0.87, 95% CI: 0.7870.98; p=0.02)
but this difference was not observed in Europe (OR:
0.95, 95% CI: 0.7871.14; p=0.56) [17] . A cohort
study from Australia with data obtained from the late
1990s noted that women were less often taking lipid-

lowering therapy on presentation with a stroke, but

this difference was attenuated when adjusted for age,
history of cardiovascular disease and other medical
and sociodemographic factors[18] .
Sex differences in younger stroke patients have also
been documented. An Israeli study of men and women
with stroke between the ages of 45 and 65years showed
that women were more likely to have diabetes, hypertension and hypercholesterolemia (29%) than men
(14%), whereas men were more likely to have ischemic
heart disease, smoking and alcohol consumption [19] .
A study from Korea also evaluated gender differences in risk factors in 9,417 patients with ischemic
stroke (42% women) admitted to 11 participating
hospitals [20] . The aim of the analysis in this large
cohort was to use statistical techniques to better understand the impact that age strata have on the sex differences among stroke risk factors. As expected, the
mean age at stroke onset in women was approximately
6years older than men. A number of risk factors were
more prevalent in women versus men, specifically
hypertension (64.1% in men and 71.0% in women)
and hyperlipidemia (26.0% in men and 32.3% in
women). When the prevalence ratios (men to women)
were assessed by age strata, hypertension was more

Table 2. Incidence of end points in the MEGA study stratified by sex

End point

Men (n=2476)

Women (n=5356)

HR for diet + pravastatin p-value

vs diet alone (95%CI)

HR diet + pravastatin p-value

vs diet alone (95% CI)

p-value for
heterogeneity
bysex

CHD

0.65
(0.4141.02)

0.06

0.75
(0.4541.25)

0.27

0.67

Stroke

0.66
(0.3731.20)

0.17

0.63
(0.3631.10)

0.10

0.90

CHD+stroke

0.59
(0.4040.87)

0.007

0.74
(0.5051.12)

0.15

0.42

CHD: Coronary heart disease; HR: Hazard ratio.

Adapted with permission from [10].

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Review Baghshomali & Bushnell

Table 3. Meta-analysis evaluating risk factor differences between men and women with
ischemicstroke.

Number of
studies

Women, n
(% of total)

Men, n
(% of total)

OR
(95% CI)

p-value

Hypertension

33

214,728 (69)

187,858 (65)

1.15 (1.0701.24)

<0.001

Hyperlipidemia

19

76,623 (34)

75,462 (37)

0.90 (0.8280.99)

0.033

OR: Odds ratio (represents women as the comparator).

Data taken from [17].

prevalent in men with stroke until 55years of age, after

which hypertension was more prevalent in women
(p<0.001; Table 4). Although the prevalence of hyperlipidemia decreased in both sexes with increasing age,
this was still higher in women than men older than
age 45years and throughout the continuum of the age
strata. When adjusted for age strata and other risk factors, only hyperlipidemia remained significantly more
prevalent in women versus men. As for hypertension,
the sex difference was no longer significant after BMI
was added as a covariate [20] . These data are different
from the meta-analysis, which suggested that cumulatively, hyperlipidemia appeared to be more common in
men [17] . One could speculate that the Korean study
illustrates unique geographic differences or differences
in the criteria for hyperlipidemia from other studies.
Menopause & stroke risk factors in women
Hypertension and hyperlipidemia as classified in
guidelines were assessed in a multiethnic cohort of
women undergoing the menopausal transition (Study
of Womens Health Across the Nation [SWAN])
[21] . Evaluation of lipid profiles of 1,349 women followed in this cohort showed that Chinese and Japanese women had the highest mean HDL levels and
Hispanic women had the lowest mean HDL level
(Table 5) . Among all participants, 15% had LDL levels
above the National Cholesterol Education Programs
Adult Treatment Panel (ATP) III goals [22] , with 9.5%
requiring lifestyle modification, whereas 5.8% met

criteria for additional drug therapy. In total, 9% of

AfricanAmerican and 6.6% of Hispanic women met
criteria for drug therapy secondary to highest levels of
LDL-cholesterol (LDL-C) and additional risk factors
or history of CHD/Framingham 10-year risk greater
than 20%, followed by 4.7% of Caucasian, 2% of
Japanese and 0% of Chinese women [21] . The most
recently published American College of Cardiology/
AHA cholesterol treatment guidelines [23] focused on
prevention of atherosclerotic cardiovascular disease
(ASCVD) and do not specify a target, and they use a
different ASCVD risk calculator, so it is unclear how
the SWAN cohort results would be applied in terms
of treatment.
Since the prevalence of hypertension in women
increases in midlife and begins to exceed that of men,
it is important to also evaluate BP in the menopausal
transition. The SWAN investigators applied the criteria for the Joint National Committee (JNC-7) [24] for
blood pressure to 1,460 participants in SWAN. They
found that BP was highest among AfricanAmerican
(systolic BP [SBP] 125.2 mmHg) and Hispanic women
(SBP 121.7 mmHg; Table 5) . The rate of untreated
hypertension among all participants was 9.1%.
Unfortunately, the highest rate of untreated hypertension and lowest rate of control with medication was
also among AfricanAmerican and Hispanic women,
whereas the lowest rate of untreated hypertension and
highest rate of control with antihypertensive treatment
was among Chinese and Japanese women [21] .

Table 4. Prevalence of hypertension and hyperlipidemia between male and females in Korean ischemic stroke
patients, stratified by age.
Prevalence ratio, men to women (95% CI)
Age, years

<44

4554

Hypertension

1.95
(1.0201.18)

Hyperlipidemia

1.76
(1.0902.83)

5564

6574

7584

>85

1.15
0.93
0.93
(1.0001.33) (0.8681.00) (0.8880.97)

0.93
(0.8880.98)

0.90
<0.001/0.11
(0.8081.01)

0.89
(0.7271.10)

0.87
(0.7671.00)

0.82
(0.5851.16)

0.81
0.74
(0.7070.93) (0.6760.83)

p-value for
heterogeneity
unadj/adj

0.01/0.049

adj: Adjusted for diabetes, atrial fibrillation, prior stroke, prior CHD, BMI, smoking, residence and education; unadj: Unadjusted p-value for prevalence ratio of men
to women by age strata.
Data taken from [20].

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Womens Health (2014) 10(5)

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Reducing stroke in women with risk factor management: blood pressure & cholesterol

Review

Table 5. Baseline characteristics of women participating in SWAN study by ethnic group.

AfricanAmerican Caucasian
n=462
n=719

Chinese
n=94

Hispanic
n=110

Japanese
n=105

Total
n=1490

Age (years)

46.6

46.8

46.8

46.4

47.1

46.7

Total cholesterol 196.3 (39.8)

(mg/dl)

197.8 (34.1)

195.0 (33.3)

199.4 (40.3) 197.9 (31.0)

197.3 (36.2)

LDL-C
(mg/dl)

119.1 (35.0)

118.5. (30.2) 112.7 (28.5)

120.1 (29.3)

113.8 (26.9)

18.1 (31.4)

HDL-C
(mg/dl)

56.3 (16.6)

55.2 (14.2)

48.3 (11.0)

60.7 (14.0)

55.7 14.9)

60.0 (11.7)

SBP

125.2 (21.0)

114.3 (14.5)

110.3 (15.9)

121.7 (9.8)

109.6 (10.8)

117.6 (17.4)

DBP

76.8. (11.8)

73.9. (9.5)

71.2 (11.0)

81.2 (6.5)

74.2 (8.8)

75.2 (10.4)

DBP: Diastolic blood pressure; HDL-C: High density lipoprotein cholesterol; LDL-C: Low-density lipoprotein cholesterol; SBP: Systolic blood
pressure.
Adapted with permission from [21].

Differentiating the impact of age versus the menopause (i.e., the physiologic hormonal changes) on
hypertension and hyperlipidemia is important as
women experience this midlife transition. As part of the
SWAN, the investigators evaluated changes in CHD
risk factors in 1,054 women during their transition to
their final menstrual period (FMP) [25] . They divided
the longitudinal transition into three segments: more
than 12 months before the FMP; within 12 months
before and after the FMP (corresponding to the decrease
in follicle stimulating hormone or FSH); and, more
than 12 months after the FMP. Using the slope of the
changes in each risk factor during each of these timeframes allowed the investigators to determine whether
the risk factor change slope was steepest during one of
the phases or was linear across all three timeframes.
Analyzing the slopes of change in risk factors during
the year immediately before and after the FMP would
suggest this occurred because of menopause rather than
age alone. Results of this study showed that there was
a significant increase in LDL-C and total cholesterol
within a year of the FMP [25] . HDL-C showed a steady
increase with peak at FMP and then declined after and
plateaued during the transition to menopause. Interestingly, there was no difference between changes in lipid
profile and ethnicity among participants in this study.
Another important finding was that changes in systolic and diastolic BP and other risk factors (glucose,
insulin, lipoprotein(a), C reactive protein, Factor VII-c)
were linear across all three timeframes, and therefore
likely to be a function of age rather than the menopausal
transition.
The recognition of modifiable risk factors in women,
such as hypertension and hyperlipidemia, is increasingly
important, especially in midlife. As described in this
review, the prevalence of hyperlipidemia increases in
women after menopause and hypertension increases

future science group

after midlife due to aging. Recognition of these risk factors early, and the initiation of healthy lifestyle practices
before or during the perimenopausal timeframe, could
improve cardiovascular risk profiles [26] , potentially
reduce the need for cholesterol- and BP-lowering drugs,
and provide the long-term benefit of reducing the risk of
stroke and cardiovascular disease [3] .
Sex differences in intermediate outcomes of
stroke: carotid artery atherosclerosis
Subclinical detection of stroke risk can be performed
with ultrasound through measurement of carotid
intimal media thickness (CIMT) or with clinical
ultrasound to detect stenosis or plaque size. Since BP
and cholesterol are major factors in the progression of
carotid disease, this review includes the sex differences
in this intermediate outcome because of its importance
in stroke risk identification [27,28] .
Carotid atherosclerosis manifested in stenosis
greater than 6070% stenosis is associated with a risk
of ischemic stroke [27] . Based on multiple clinical trials
of carotid endarterectomy (CEA) for symptomatic or
asymptomatic stenosis, the procedure is recommended
if the surgical risk is appropriately low [28] .
However, there are significant differences in benefit from CEA in men and women, especially in
asymptomatic carotid stenosis. A Cochrane Systematic Review from 2005 reported the stroke relative
risk (RR) reduction after CEA for asymptomatic
carotid stenosis was 51% for men (RR: 0.49, 95% CI:
0.3630.66) versus 4% for women (RR: 0.96, 95%
CI: 0.6461.44; p=0.008), suggesting it was more
beneficial for men[29] . There are many theories as to
why women do not benefit as much or do worse after
CEA for asymptomatic stenosis. Women have smaller
arteries, have higher surgical risk, and may have more
embolic phenomenon during the surgery [30] .

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Review Baghshomali & Bushnell

Another potential explanation for the sex differences
in benefit from CEA for asymptomatic carotid stenosis
is based on the differing morphology of carotid plaques.
For example, Ota et al. evaluated sex differences in
carotid plaque with 3.0 Tesla MRI in 131 patients (64
women) with asymptomatic moderate or severe carotid
stenosis (5099%) [31] . There were no sex differences
in the prevalence of hypertension or hyperlipidemia at
baseline. The imaging results showed a higher odds of
thin/ruptured caps (OR: 4.41, 95% CI: 1.9799.87;
p<0.01), lipid-rich/necrotic core (OR: 3.66, 95%
CI: 1.6768.00; p=0.01) and a trend toward hemorrhage (OR: 2.15, 95% CI:0.9394.98; p=0.07) in
men compared with women, after adjustment for stain
use or MR angiographic degree of stenosis [31] . Similarly, Hellings et al. evaluated 450 patients undergoing
CEA, and demonstrated that men had higher rates of
unstable plaque with more inflammatory features, for
example, higher concentration of fat, higher number
of macrophages and higher levels of IL-8 and matrix
metalloproteinase (MMP)-8 activity [32] . This was
regardless of the types of symptoms attributed to the
carotid (amaurosis fugax, hemispheric transient ischemic attack or ischemic stroke) or the cardiovascular
risk profile [32] .
In another study looking at sex-related differences in
carotid plaque features and inflammation, 457 carotid
plaques from 132 women and 325 men obtained with
CEA from symptomatic and asymptomatic patients
confirmed gender-related differences in pathology of
the plaques [33] . Although in this study women had
higher prevalence of hypertension (67.0% vs 53.1%
in men; p=0.023) and hypercholesterolemia (67.4%
vs 56.3%;p=0.028), they had a lower prevalence of
thrombotic plaque and smaller area of necrotic core
and hemorrhage. Men had more complex plaques with
higher rates of ulceration and erosion compared with
women with more stable fibrocalcific plaques. However, gender was no longer significantly associated with
plaque features in the multivariable model when cardiovascular risk factors, baseline stenosis severity and
symptom status were included [33] .
Sex differences in the development of atherosclerosis have also been described. For example, CIMT
obtained using standard ultrasound protocols was
evaluated in 17 men and 35 women between the ages
of 45 and 64years who had at least one stroke risk factor (tobacco smoking, hypertension, hyperlipidemia or
noninsulin-dependent diabetes) [34] . In whole blood,
gene expression analysis was performed on hybridized
RNA, and correlations between increasing CIMT as
measured with standardized ultrasound methods and
up- or downregulation of genes were compared. The
main findings were that the expression of hundreds of

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Womens Health (2014) 10(5)

genes correlated with CIMT that were unique to each

sex, that there were genes that showed similar correlation patterns in men and women, but that there were
also genes that correlated with CIMT in opposite
directions [34] . Several of the genes with opposite correlation were associated with or regulated by estrogen.
Other pathways include inflammation, such as IL-8,
thrombin and endothelin-1 signaling, all of which are
important in vascular diseases [34] . Although this study
is small, lacked statistical correction for multiple comparisons and does not demonstrate cause and effect
based on stroke events, it is a descriptive study showing
that there are pathophysiologic sex differences in the
development of atherosclerosis in a middle-aged cohort
with risk factors for stroke. Therefore, further research
and validation of these findings in a larger, adequately
powered cohort are needed.
Sex differences in stroke prevention
&adherence to prevention therapies
Guidelines recommend medications for treatment of
hypertension and hyperlipidemia to reduce the risk of
recurrent stroke, that is, secondary prevention [35] . For
example, the Stroke Prevention by Aggressive Reduction in Cholesterol Levels (SPARCL) study evaluated
the effect of atorvastatin 80mg/day on reduction
of fatal and nonfatal stroke. It showed that participants randomized to the treatment group had a 16%
reduction in stroke events compared with the placebo
group[36] . A post hoc study used the same participants
to evaluate any possible sex differences in the end
points of this trial. The baseline characteristics and
incidence of stroke (fatal and nonfatal) were compared
between men and women [37] . Results showed that men
were younger (62.0+0.21 vs 63.9+0.27), had lower
SBP (138.1+0.35 vs 139.5+0.47), higher diastolic
BP (82.2+0.20 vs 81.0+0.25), lower mean LDL-C
(132.4+0.44 vs 134.4+0.57, p=0.986), lower mean
HDL-C (46.1+0.21 vs 55.8+0.34, p=0.126) and
lower total cholesterol (207.0+0.54 vs 218.9+0.67,
p=0.452) compared with women in their baseline
characteristics. When end point results were compared, there was no significant difference between men
and women in regards to stroke events and treatmentassociated benefit was similar, emphasizing the importance of treatment in both men and women regardless
of their baseline characteristics [37] .
A meta-analysis of BP-lowering clinical trials showed
that women received a similar benefit in reduction of
stroke from antihypertensives as men, across all classes
of these drugs [38] . A separate Cochrane review of over
26,000 women showed that black women may receive
more benefit than white women. For example there
was a 53% reduction in the risk of fatal and nonfatal

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Reducing stroke in women with risk factor management: blood pressure & cholesterol

cerebrovascular events in black women, whereas women

overall had a 38% reduction of these events with BP
lowering [39] . Although there have been some studies
showing differences in the prescribed antihypertensive
medications between men and women, there are no
studies that definitively show a difference in response to
BP medications. Therefore, control of BP, rather than
the pharmacological approach, remains the goal for
prevention of stroke in both men and women equally[8] .
Nonadherence to cardiovascular medications in people with heart disease is associated with an increased
risk for stroke [40] . Therefore, adherence to medications
for hyperlipidemia and hypertension is very important
in the management of these risk factors and ultimately
stroke prevention. Gender has also been assessed as a
factor that can influence medication adherence. Results
of a study evaluating self-reported intentional and
unintentional nonadherence and difference between
male and female users, showed a total of 66.4% nonadherence among all participants with 67% in the female
group and 65.4% in the male group [41] . Women had
higher rates of intentional and combined (intentional
and unintentional) nonadherence (n=1151 women
67% vs n=709 men 65.4%), and lower rates of unintentional nonadherence (women 49% vs men 51.8%)
compared with men, but these results were only significant (p<0.01) in the 5564years age group. Overall,
unintentional nonadherence was the most frequent
nonadherence behavior for both sexes. Among the reasons for nonadherence, forgetting to take medication
(unintentional) is the most commonly reported in both
genders and also more common in men than women.
Women had higher rates of filling their prescriptions
but not taking them, whereas men had higher rates of
changing their medication doses [41] . In regards to selfdiscontinuation of medication, men had higher rates
in the age group of 3544years, whereas women had
higher rates in the age group of 4554years. There
was no significant difference between men and women
in relation to discontinuation of medication. Development of adverse reactions, another reason for medication nonadherence, was also reported by women more
than men [41] .
Adherence is also extremely important in patients
who have suffered a stroke, since evidence-based recommendations include medications for secondary
prevention. A study from Sweden tracked the use of
stroke prevention medications in over 24,000 patients
for 1 year after discharge from acute stroke [42] . In the
multivariable model, men were less likely to be persistent with antihypertensive and antiplatelet drugs, there
was no gender difference with warfarin and there was
a trend toward lower persistence with statins in men.
Other important factors associated with lower persis-

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Review

tence included not receiving stroke unit care, having a

recurrent stroke, low mood and poor perceived health
status [42] . The Adherence Evaluation After Ischemic
Stroke-Longitudinal (AVAIL) study assessed medication regimen persistence at 3 months and 12 months
after stroke discharge. The persistent use of medications at 3 months was 76% [43] and 65.9% at 1 year
[44] . There were no significant differences in men and
women with medication persistence, although marital
status was an important factor in maintaining medications when the analysis focused on self-discontinuation
by 1 year [44] .
Overall, prevention treatments with BP-lowering
and cholesterol-lowering medications are key strategies for decreasing stroke risk in both men and women.
However, nonadherence is common and should always
be considered when evaluating patients with poor outcome, such as a first-ever or recurrent stroke. Since
patients with stroke may not be recognized as having
hypertension and hyperlipidemia until after the first
stroke, new medications for prevention will be initiated
at that time. The AVAIL study showed that patients
who did not know why they were taking medication,
how to take them and how to refill them were at high
risk for nonadherence [43] . Therefore, counseling and
education about medications, reminder systems and
pill boxes could potentially improve adherence to treatment regimens and subsequently optimize prevention
effectiveness in both men and women.
Conclusion
Despite substantial progress in the treatment of acute
ischemic stroke, ultimately, prevention will be more
effective than acute interventions to reduce the burden of stroke. The higher lifetime risk of stroke and
the prevalence of major vascular risk factors in elderly
women in those who have experienced a stroke indicate
that we need to redouble our efforts to prevent or treat
these factors in women. There are major variations in
the gender differences in these risk factors, which also
varies by geographic region. In addition, when assessing
these risk factors in stroke patients, age likely plays a significant role, especially in hyperlipidemia. In addition,
hyperlipidemia appears to be the risk factor most influenced by menopause as opposed to age alone. The
major impact of hypertension and hyperlipidemia is in
the development of carotid atherosclerosis, in which significant gender differences are being more widely recognized. Lastly, the impact of stroke prevention with
cholesterol lowering and BP lowering appears to be the
same in men and women, but the attitudes about taking
these medications may differ by gender.
It is now widely recognized that the prevalence of
hypertension and hyperlipidemia is high in women,

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Review Baghshomali & Bushnell

especially after menopause. Despite findings that major
risk factors are more prevalent in women after middle
age, cardiovascular and stroke risk is often underrecognized in women and, therefore, prevention and
treatment strategies are less comprehensive than for
men [45,46] . More work needs to be done to ensure that
women receive adequate treatment of stroke risk factors in order to decrease the burden of stroke, especially
in the elderly population.
Future perspective
Knowledge about stroke modifiable risk factors and
their prevalence can help guide health policy-makers
in developing more effective and tailored strategies for
stroke prevention. Special attention is required to subpopulations having higher prevalence of certain risk

factors. Not only do these subpopulations need to be

recognized and the reasons for higher prevalence in
their subgroup be identified, but further efforts have to
be made to provide them with appropriate education
regarding stroke, risk factors and medications to make
prevention more effective.
Financial & competing interest disclosures
The authors have no relevant affiliations or financial involvement with any organization or entity with a financial interest in or financial conflict with the subject matter or materials discussed in the manuscript. This includes employment,
consultancies, honoraria, stock ownership or options, expert
testimony, grants or patents received or pending, or royalties.
No writing assistance was utilized in the production of this
manuscript.

Executive summary
Sex differences in stroke outcomes
Demographic studies have shown, that when matched by age, women have a lower risk of stroke but their
rates of stroke are higher after the age of 85years, since they are more likely to reach and exceed that age.
Women compose 60% of stroke mortality, have higher rates of disability and it has been shown that
preventive and treatment options are not as comprehensive for women as for men.

Sex differences in stroke risk factors: hypertension & hyperlipidemia

Multiple studies evaluating baseline characteristics of patients with ischemic stroke and their comparison
between men and women have shown that women have higher rates of hypertension and hyperlipidemia,
which varies by geographic region.
Age plays a major role in the sex differences between risk factor prevalences in stroke patients, particularly
hypertension, whereas hyperlipidemia is more prevalent in women regardless of age, as shown in a Korean
study.

Hypertension & hyperlipidemia in women at menopause

In women going through the menopausal transition, hyperlipidemia appears to be the risk factor most
influenced by menopause, whereas hypertension appears to be more a factor of age due to its linear increase
before, during, and after menopause.

Prevention & adherence to treatment of major risk factors

Gender differences in relationship to adherence to stroke prevention medications are unclear because
the results vary by the study. Regardless, nonadherence is of critical importance to the management of
hypertension and hyperlipidemia and effective prevention of stroke in both men and women.
Knowledge of differences in modifiable risk factors between men and women with special attention to
subgroups (raceethnicities and geographic disparities) can help us in developing more effective strategies for
stroke prevention and decrease its global burden.

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