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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 Sanam Baghshomali1
focused on modifiable risk factors, such as hypertension and hyperlipidemia, has & Cheryl Bushnell*,1
shown them to be of significant importance in decreasing the risk of stroke. 1
DepartmentofNeurology,WakeForest
Multiple studies have brought to light the differences between men and women SchoolofMedicine,WinstonSalem,
NC27157,USA
with regards to stroke and these risk factors. Women have a higher prevalence of
*Authorforcorrespondence:
stroke, mortality and disability and it has been shown that preventive and cbushnel @ wakehealth.edu
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.

Keywords: femalegenderhyperlipidemiahypertensionriskfactorstrokedifferences

Stroke is the fourth leading cause of death well established [3] . In addition, the a smaller
in the USA, after heart disease, cancer and AHA fraction (75%)
chronic lower respiratory disease, and the has identified total cholesterol less than are using
most common cause of permanent disability 200 mg/dl (untreated) and untreated blood antihypertensive
in adults worldwide [1] . Statistics from pressure (BP) less than 120/<80 mm Hg medica- tion;
the American Heart Association (AHA) for adults as two of the seven components but more
Heart Disease and Stroke 2014 updates of ideal cardiovascular health [4] . important, only
shows that the relative rate of stroke death Accord- ing to 2014 AHA statistics, 77% 53% of those
fell by 35.8% and the actual number of of patients with first-time stroke have BPs with
stroke deaths declined by 22.8% from greater than hypertension
2000 to 2010. Yet each year, 795,000 new 140/90 [1] are controlled
or recurrent strokes occur in the USA . to target
with approximately Elevated total cholesterol levels are also a
610,000 first attacks and 185,000 major focus of prevention programs because
recur- rent attacks. One of every 19 deaths nearly 32 million adults over 20 years of
in the USA is due to stroke. On average, age have total cholesterol levels greater
every 40 s, someone in USA has a stroke and than
dies of one approximately every 4 min [1] . 240, for a prevalence of 13.8% [1] . In
Hypercholesterolemia and hypertension addi- tion, 33.0% of US adults, or
are well-established risk factors for stroke, approximately
they are modifiable, and thus are a major 78 million people over 20 years of age,
focus of stroke prevention [2] . The have hypertension. Unfortunately, this is a
identifi- cation of patients who may be major public health problem because
targeted for prevention with lifestyle although nearly 82% of people with
changes is also hypertension are aware of their condition,
10.2217/WHE.14.47 2014 Future Medicine Womens Health (2014) 10(5), 535 ISSN 1745- 1
Ltd 544 5057 11
part of

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

levels [1] . Statistics for these risk factors are even hypertension is more common
worse in developing countries compared with
developed countries. Although patients are
prescribed medica- tions for these conditions, they
are not effectively treated, so the numbers of
patients who reach treat- ment goals in developing
countries are lower compared with the USA A 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
hyper- tension 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
vari- ous 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 Framing- ham Heart Study, for
people between the ages of 55 and 75 years, 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 84 years, but after the age of 85 years, 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
com- prise 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
Evalu- ation 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 45
years, between the ages of 45 to 64 years this
prevalence is similar and after the 65 years of age
Review Baghshomali & Bushnell
in women [1] . For hyperlipidemia in adults over the age of 20 years, There was no significant difference between diet
women have a higher prevalence of total cholesterol greater than 200 plus pravastatin versus diet alone in prevention of
mg/dl (44.9% vs 41.3% in men), but men have a higher prevalence of stroke events in men or women and, thus, no sex
low-density lipoprotein (LDL) greater than 130 mg/dl (31.9% vs dif- ference in the treatment impact. However, men
30.0% in women) and high-density lipoprotein (HDL) less than 40 had a trend towards benefit in diet plus pravastatin for
mg/dl (31.8% vs 12.3% in women) [1] , suggesting a worse overall CHD protection, whereas women had no significant
pattern of cholesterol in men than women. benefit (Table 2) [10] .
The Asia Pacific Cohort Studies Collaboration,
Sex differences in primary prevention of stroke which includes 29 cohorts from Asia and 7 cohorts
Baseline sex differences in BP and cholesterol levels were noted in the from Australia and New Zealand, assessed the joint
Management of Elevated Cholesterol in the primary prevention Group effects of blood pressure and cholesterol on the risk of
of Adult Japanese (MEGA), which evaluated the usefulness of pravas- stroke, both ischemic and hemorrhagic subtypes. The
tatin in primary prevention of cardiovascular events [10] . This investigators found that the slope of stroke risk
prospective, randomized, open, blinded end point study was conducted jointly impacted by the various strata of cholesterol
between 1994 and 2004, evaluating 7,832 patients (women: 5356, and sys- tolic BP was similar in men and women
68.4%) between the ages of 40 and 70 years with hypercho- [11] . Another analysis of 214,032 women in the same
lesterolemia and no history of coronary heart dis- ease (CHD) or cohort assessed the impact of various risk factors on
stroke. The aim was to compare the effects of pravastatin plus diet stroke risk. They reported that for every extra 10
on the incidence of cardiovascular events compared with diet alone, mmHg increase in systolic BP, the risk of ischemic
with a special emphasis on the outcomes in women. The comparison stroke increased by
of baseline characteristics between men and women enrolled in this 36%, even after adjustment for other risk factors
study showed that more women (42.6%) than men (40.2%) had [12] . For total cholesterol, there was a 12% increased
hypertension (Table 1) . Baseline triglycerides were higher in men, but risk for each 1 mmol/l increase. These results
HDL-cholesterol (HDL-C) was higher in women and total cholesterol emphasize the
and LDL-C were similar [10] .
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:Diastolicbloodpressure;HDL-C:High-densitylipoprotein-cholesterol;LDL-C:Low-densitylipoprotein-cholesterol;SBP:Systolicblood
pressure.
Adaptedwithpermissionfrom[10].

impact that improved risk factor management could lowering therapy on presentation with a stroke, but
have on stroke risk in Asia and Australia/New this difference was attenuated when adjusted for age,
Zealand. history of cardiovascular disease and other medical
and sociodemographic factors [18] .
Sex differences in risk factor profiles of Sex differences in younger stroke patients have also
stroke patients been documented. An Israeli study of men and
Cohort studies have pointed out the difference women with stroke between the ages of 45 and 65
between risk factor profiles in men and women who years showed that women were more likely to have
have suf- fered a stroke [1315] , although the results diabetes, hyper- tension and hypercholesterolemia
from these studies are very inconsistent and differ (29%) than men (14%), whereas men were more
greatly between countries [16] . In a meta-analysis likely to have ischemic heart disease, smoking and
done specifically to focus on sex differences in stroke alcohol consumption [19] .
and risk factors, 45 articles with data from 673,935 A study from Korea also evaluated gender
patients were reviewed [17] . The cumulative analysis differ- ences in risk factors in 9,417 patients with
showed that women, on average, were 5.2 years older ischemic stroke (42% women) admitted to 11
than men at the onset of stroke (p < 0.001). participating hospitals [20] . The aim of the
Hypertension was more prevalent in women (69% analysis in this large cohort was to use statistical
vs 65% in men) and hyperlipidemia was more techniques to better under- stand the impact that age
common in men (37% vs 34% in women; Table 3). strata have on the sex dif- ferences among stroke
Subgroup analysis showed there was some risk factors. As expected, the mean age at stroke
geographic variation. For example, hyperlipidemia was onset in women was approximately
more common in men than women in North 6 years older than men. A number of risk factors
America (odds ratio [OR]: 0.87, 95% CI: 0.78 were more prevalent in women versus men,
70.98; p = 0.02) but this difference was not observed specifically hypertension (64.1% in men and 71.0%
in Europe (OR: in women) and hyperlipidemia (26.0% in men
0.95, 95% CI: 0.7871.14; p = 0.56) [17] . A and 32.3% in women). When the prevalence ratios
cohort study from Australia with data obtained from (men to women) were assessed by age strata,
the late hypertension was more
1990s noted that women were less often taking
lipid-

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


End point Men (n = 2476) Women (n = 5356) p-value for
HR for diet + pravastatin p-value HR diet + pravastatin p-value heterogeneity
vs diet alone (95% CI) vs diet alone (95% CI) by sex

CHD 0.65 (0 87)


(0.41 41.02) .4 CHD:Coronaryheartdisease;HR:Hazardratio. Adapted
0 withpermissionfrom[10].
Stroke 0.66 (0.37
31.20) 4
CHD + stroke 0.59 0.

future science group ww w.futuremedicine.com 1


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0.06 0.75 0.27 0.67 0.15 0.42
(0.45 41.25)
0.17 0.63 (0.36 31.10) 0.10 0.90
0.007 0.74
(0.50 51.12)

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

Number of Women, n Men, n OR p-value studies (%


of total) (% of total) (95% CI)
Hypertension 33 214,728 (69) 187,858 (65) 1.15 (1.07 01.24) < 0.001
Hyperlipidemia 19 76,623 (34) 75,462 (37) 0.90 (0.8280.99) 0.033
OR:Oddsratio(representswomenasthecomparator). Datatakenfrom[17].

prevalent in men with stroke until 55 years of age, criteria for additional drug therapy. In total, 9% of
after which hypertension was more prevalent in AfricanAmerican and 6.6% of Hispanic women met
women (p < 0.001; Table 4). Although the prevalence criteria for drug therapy secondary to highest levels
of hyper- lipidemia decreased in both sexes with of LDL-cholesterol (LDL-C) and additional risk
increasing age, this was still higher in women than factors or history of CHD/Framingham 10-year risk
men older than age 45 years and throughout the greater than 20% , followed by 4.7% of
continuum of the age strata. When adjusted for age Caucasian, 2% of Japanese and 0% of Chinese
strata and other risk fac- tors, only hyperlipidemia women [21] . The most recently published
remained significantly more prevalent in women American College of Cardiology/ AHA cholesterol
versus men. As for hypertension, the sex difference treatment guidelines [23] focused on prevention of
was no longer significant after BMI was added as a atherosclerotic cardiovascular disease (ASCVD) and
covariate [20] . These data are different from the do not specify a target, and they use a different
meta-analysis, which suggested that cumula- tively, ASCVD risk calculator, so it is unclear how the
hyperlipidemia appeared to be more common in men SWAN cohort results would be applied in terms of
[17] . One could speculate that the Korean study treatment.
illustrates unique geographic differences or differences Since the prevalence of hypertension in women
in the criteria for hyperlipidemia from other studies. increases in midlife and begins to exceed that of men,
it is important to also evaluate BP in the menopausal
Menopause & stroke risk factors in women transition. The SWAN investigators applied the
Hypertension and hyperlipidemia as classified in crite- ria for the Joint National Committee (JNC-7)
guidelines were assessed in a multiethnic cohort of [24] for blood pressure to 1,460 participants in
women undergoing the menopausal transition SWAN. They found that BP was highest among
(Study of Womens Health Across the Nation AfricanAmerican (systolic BP [SBP] 125.2 mmHg)
[SWAN]) [21] . Evaluation of lipid profiles of and Hispanic women (SBP 121.7 mmHg; Table 5) .
1,349 women fol- lowed in this cohort showed that The rate of untreated hypertension among all
Chinese and Japa- nese women had the highest participants was 9.1%. Unfortunately, the highest
mean HDL levels and Hispanic women had the rate of untreated hyperten- sion and lowest rate of
lowest mean HDL level (Table 5) . Among all control with medication was also among African
participants, 15% had LDL levels above the National American and Hispanic women, whereas the lowest
Cholesterol Education Programs Adult Treatment rate of untreated hypertension and highest rate of
Panel (ATP) III goals [22] , with 9.5% requiring control with antihypertensive treatment was among
lifestyle modification, whereas 5.8% met 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 55 64 6574 7584 >85 p-value for
heterogeneity
unadj/adj
Hypertension 1.95 1.15 0.93 0.93 0.93 0.90 < 0.001/ 0.11
(1.02 01.18) (1.00 01.33) (0.86 81.00) (0.8880.97) (0.8880.98) (0.80 81.01)
Hyperlipidemia 1.76 0.89 0.81 0.74 0.87 0.82 0.01/ 0.049
(1.09 02.83) (0.7271.10) (0.70 70.93) (0.67 60.83) (0.76 71.00) (0.5851.16)
adj:Adjustedfordiabetes,atrialfibrillation,priorstroke,priorCHD,BMI,smoking,residenceandeducation;unadj:Unadjustedp-valueforprevalenceratioofmen
towomenbyagestrata.
Datatakenfrom[20].
Table 5. Baseline characteristics of women participating in SWAN study by ethnic group.
AfricanAmerican Caucasian Chinese Hispanic Japanese Total
n = 462 n = 719 n = 94 n = 110 n = 105 n = 1490
Age (years) 46.6 46.8 46.8 46.4 47.1 46.7
Total cholesterol 196.3 (39.8) 197.8 (34.1) 195.0 (33.3) 199.4 (40.3) 197.9 (31.0) 197.3 (36.2)
(mg /dl)
LDL-C 119.1 (35.0) 118.5. (30.2) 112.7 (28.5) 120.1 (29.3) 113.8 (26.9) 18.1 (31.4)
(mg /dl)
HDL-C 56.3 (16.6) 55.2 (14.2) 60.0 (11.7) 48.3 (11.0) 60.7 (14.0) 55.7 14.9)
(mg /dl)
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:Diastolicbloodpressure;HDL-C:Highdensitylipoproteincholesterol;LDL-C:Low-densitylipoproteincholesterol;SBP:Systolicblood
pressure.
Adaptedwithpermissionfrom[21].

Differentiating the impact of age versus the after midlife due to aging. Recognition of these risk
meno- pause (i.e., the physiologic hormonal changes) fac- tors early, and the initiation of healthy lifestyle
on hypertension and hyperlipidemia is important practices before or during the perimenopausal
as women experience this midlife transition. As part of timeframe, could improve cardiovascular risk
the SWAN, the investigators evaluated changes in profiles [26] , potentially reduce the need for
CHD risk factors in 1,054 women during their cholesterol- and BP-lowering drugs, and provide the
transition to their final menstrual period (FMP) [25] . long-term benefit of reducing the risk of stroke and
They divided the longitudinal transition into three cardiovascular disease [3] .
segments: more than 12 months before the FMP;
within 12 months before and after the FMP Sex differences in intermediate outcomes
(corresponding to the decrease in follicle stimulating of stroke: carotid artery atherosclerosis
hormone or FSH); and, more than 12 months after Subclinical detection of stroke risk can be performed
the FMP. Using the slope of the changes in each risk with ultrasound through measurement of carotid
factor during each of these time- frames allowed the intimal media thickness (CIMT) or with clinical
investigators to determine whether the risk factor ultrasound to detect stenosis or plaque size. Since BP
change slope was steepest during one of the phases or and cholesterol are major factors in the progression
was linear across all three timeframes. Analyzing the of carotid disease, this review includes the sex
slopes of change in risk factors during the year differences in this intermediate outcome because of its
immediately before and after the FMP would suggest importance in stroke risk identification [27,28] .
this occurred because of menopause rather than age Carotid atherosclerosis manifested in stenosis
alone. Results of this study showed that there was a greater than 6070% stenosis is associated with a risk
significant increase in LDL-C and total cholesterol of ischemic stroke [27] . Based on multiple clinical
within a year of the FMP [25] . HDL-C showed a trials of carotid endarterectomy (CEA) for
steady increase with peak at FMP and then declined symptomatic or asymptomatic stenosis, the procedure
after and plateaued during the transition to is recommended if the surgical risk is appropriately
menopause. Interest- ingly, there was no difference low [28] .
between changes in lipid profile and ethnicity among However, there are significant differences in ben-
participants in this study. efit from CEA in men and women, especially in
Another important finding was that changes in asymptomatic carotid stenosis. A Cochrane System-
sys- tolic and diastolic BP and other risk factors atic Review from 2005 reported the stroke
(glucose, insulin, lipoprotein(a), C reactive protein, relative risk (RR) reduction after CEA for
Factor VII-c) were linear across all three timeframes, asymptomatic carotid stenosis was 51% for men (RR:
and therefore likely to be a function of age rather than 0.49, 95% CI:
the menopausal transition. 0.3630.66) versus 4% for women (RR: 0.96, 95%
The recognition of modifiable risk factors in CI: 0.6461.44; p = 0.008), suggesting it was more
women, such as hypertension and hyperlipidemia, is beneficial for men [29] . There are many theories as
increasingly important, especially in midlife. As to why women do not benefit as much or do worse
described in this review, the prevalence of after CEA for asymptomatic stenosis. Women have
hyperlipidemia increases in women after menopause smaller arteries, have higher surgical risk, and may
and hypertension increases have more embolic phenomenon during the surgery
[30] .
Another potential explanation for the sex between increasing CIMT as
differences in benefit from CEA for asymptomatic measured with standardized
carotid stenosis is based on the differing morphology ultrasound methods and up- or
of carotid plaques. For example, Ota et al. downregulation of genes were
evaluated sex differences in carotid plaque with 3.0 compared. The main findings were
Tesla MRI in 131 patients (64 women) with that the expression of hundreds of
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: 1.97
99.87; p < 0.01), lipid-rich/necrotic core (OR:
3.66, 95% CI: 1.6768.00; p = 0.01) and a trend
toward hem- orrhage (OR: 2.15, 95% CI:0.93
94.98; p = 0.07) in men compared with women, after
adjustment for stain use or MR angiographic degree
of stenosis [31] . Simi- larly, 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
isch- emic 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. How- ever, gender was no longer significantly
associated with plaque features in the multivariable
model when car- diovascular risk factors, baseline
stenosis severity and symptom status were included
[33] .
Sex differences in the development of atheroscle-
rosis 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 64 years who had at least one stroke
risk fac- tor (tobacco smoking, hypertension,
hyperlipidemia or noninsulin-dependent diabetes)
[34] . In whole blood, gene expression analysis was
performed on hybridized RNA, and correlations

future science group ww w.futuremedicine.com 11


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

22 Womens Health (2014) 10(5) future science group


cerebrovascular events in black women, whereas factors associated with lower persis-
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 peo-
ple 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% nonad- herence
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
unin- tentional nonadherence (women 49% vs men
51.8%) compared with men, but these results were
only signifi- cant (p < 0.01) in the 5564 years age
group. Overall, unintentional nonadherence was
the most frequent nonadherence behavior for both
sexes. Among the rea- sons 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
self- discontinuation of medication, men had higher
rates in the age group of 3544 years, whereas
women had higher rates in the age group of 4554
years. There was no significant difference between
men and women in relation to discontinuation of
medication. Develop- ment of adverse reactions,
another reason for medica- tion 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
rec- ommendations 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 persis- tent 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
tence included not receiving stroke study showed that patients who did not know why
unit care, having a recurrent they were taking medication, how to take them and
stroke, low mood and poor how to refill them were at high risk for nonadherence
perceived health status [42] . The [43] . Therefore, counseling and education about
Adherence Evaluation After medications, reminder systems and pill boxes could
Ischemic Stroke-Longitudinal potentially improve adherence to treat- ment regimens
(AVAIL) study assessed medica- and subsequently optimize prevention effectiveness
tion regimen persistence at 3 in both men and women.
months and 12 months after
stroke discharge. The persistent Conclusion
use of medica- tions at 3 months Despite substantial progress in the treatment of acute
was 76% [43] and 65.9% at 1 ischemic stroke, ultimately, prevention will be more
year [44] . There were no effective than acute interventions to reduce the bur-
significant differences in men and den of stroke. The higher lifetime risk of stroke and
women with medication the prevalence of major vascular risk factors in
persistence, although marital status elderly women in those who have experienced a stroke
was an important factor in indicate that we need to redouble our efforts to
maintaining medica- tions when prevent or treat these factors in women. There are
the analysis focused on self- major variations in the gender differences in these
discontinuation by 1 year [44] . risk factors, which also varies by geographic region. In
Overall, prevention treatments addition, when assessing these risk factors in stroke
with BP-lowering and cholesterol- patients, age likely plays a sig- nificant role, especially
lowering medications are key in hyperlipidemia. In addition, hyperlipidemia appears
strate- gies for decreasing stroke to be the risk factor most influ- enced by menopause
risk in both men and women. as opposed to age alone. The major impact of
However, nonadherence is hypertension and hyperlipidemia is in the development
common and should always be of carotid atherosclerosis, in which sig- nificant gender
considered when evaluating differences are being more widely rec- ognized.
patients with poor out- come, such Lastly, the impact of stroke prevention with
as a first-ever or recurrent stroke. cholesterol lowering and BP lowering appears to be
Since patients with stroke may not the same in men and women, but the attitudes about
be recognized as having taking these medications may differ by gender.
hypertension and hyperlipidemia It is now widely recognized that the prevalence of
until after the first stroke, new hypertension and hyperlipidemia is high in
medications for prevention will be women,
initiated at that time. The AVAIL
especially after menopause. Despite findings that factors. Not only do these subpopulations need to be
major risk factors are more prevalent in women after recognized and the reasons for higher prevalence in
middle age, cardiovascular and stroke risk is often their subgroup be identified, but further efforts have
under- recognized in women and, therefore, to be made to provide them with appropriate
prevention and treatment strategies are less education regarding stroke, risk factors and
comprehensive than for men [45,46] . More work medications to make prevention more effective.
needs to be done to ensure that women receive
adequate treatment of stroke risk fac- tors in order to Financial & competing interest disclosures
decrease the burden of stroke, especially in the elderly The authors have no relevant affiliations or financial
population. involve- ment with any organization or entity with a
financial inter- est in or financial conflict with the subject
Future perspective matter or mate- rials discussed in the manuscript. This
Knowledge about stroke modifiable risk factors includes employment,consultancies, honoraria, stock
and their prevalence can help guide health policy- ownership or options, experttestimony,grantsorpatents
makers in developing more effective and tailored receivedorpending,orroyalties.
strategies for stroke prevention. Special attention is Nowritingassistancewasutilizedintheproductionofthis
required to sub- populations having higher manuscript.
prevalence of certain risk

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 85 years, 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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