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We describe the current and future objectives of the Women cerebrovascular (CVD) and cardiovascular disease (CAD) in
Stroke Association, a nonprofit multidisciplinary organization women. Here, we will address only CVD, whereas CAD will be
promoting research awareness on medical, psychological,
addressed in a future paper. We have founded WSA for the fol-
and social issues concerning women affected by cerebro-
cardiovascular disease. In this paper, we deal with only cere- lowing reason: women are often underrepresented or excluded
brovascular disease, whereas cardiovascular disorders will be from clinical studies on CVD, thereby study results tend to be
addressed in a future paper. Gender differences in the clinical biased. Possible reasons might be that women are generally older
presentation of cerebrovascular diseases have been repeatedly than men at stroke onset, live alone, and have less access to care-
suggested, and some treatment options may not be as effec-
givers. In addition, women are more frequently afflicted by
tive and safe in men and women. For many years, women have
either been underrepresented or excluded from randomized depression before and after stroke contributing to their poor
clinical trials, and the majority of therapeutic research has been outcome compared with men (1). The WSA was founded in 2010
carried on predominantly male populations. Furthermore, and, to date, has published papers in several international peer-
gender differences have been shown to contribute to different reviewed journals (25).
responses to cerebrovascular drugs in women when compared
with men, regarding pharmacokinetics, pharmacodynamics,
and physiology. In this statement, we discuss main research Epidemiology of stroke in women
fields relevant to Women Stroke Associations mission and
commitment, highlighting opportunities and critical from the Population-based studies have shown that postmenopausal
womens health perspective. Future directions and goals of the
Women Stroke Association arise from these considerations and
women, especially after >65 years of age, have a higher risk of
represent the associations commitment to combating stroke. stroke than men (6). A recent review has reported a 33% higher
Key words: epidemiology, gender medicine, methodology, risk factors, stroke incidence in men, compared with 41% higher stroke preva-
stroke, therapy lence in women (6). Moreover, women have been reported to have
a higher lifetime risk of stroke compared with men (7), along with
Introduction higher rates of poststroke mortality, disability, depression, and
dementia (8). Specific pathophysiological aspects of stroke in
The Women Stroke Association (WSA) is a nonprofit member- women include pregnancy, puerperium, and older age.
ship organization of multidisciplinary scientists and physicians Regarding elderly women, their poorer outcome is influenced
who study and promote awareness of cardio-cerebrovascular by the fact that they are more likely to be living alone or in an
disease in women. The key objectives of WSA include monitoring assisted living arrangement before stroke onset (1). Also from a
and influencing public policies in order to reduce the number of clinical point of view, their presentations at stroke onset tend to
stroke-associated deaths and increase public awareness on be poorly communicated. Stroke in women is more frequently
Correspondence: Francesca Romana Pezzella*, Stroke Unit associated with anterior circulation ischemia, whereas men are
Department of Emergency Medicine, AO S Camillo Forlanini, Piazza more likely to have cerebellar and brainstem symptoms and
Carlo Forlanini 1, 00151 Rome, Italy. higher incidences of posterior circulation syndromes than women
E-mail: frpezzella@gmail.com (9). Concerning stroke awareness, women have been reported to
1
Stroke Unit Department of Emergency Medicine, AO S Camillo Forla-
nini, Rome, Italy
possess a better knowledge of major stroke symptoms and stroke
2
Direzione Scientifica and U.O. Medicina dUrgenza, Fondazione IRCCS risk factors (10,11) and to learn from health behavior and stroke
C Granda, Ospedale Maggiore Policlinico, Milan, Italy campaigns independently from educational level than men,
3
NeuroRadiology, IRCCS Fondazione S Lucia, Rome, Italy instead it was found that the level of education influences the
4
Fondazione Biomedica Europea Onlus, Rome, Italy process of experiential learning in men (12).
5
Neurology Department, Arcispedale Santa Maria Nuova, Reggio
nellEmilia, Italy
6
Stroke Unit Department of Neurology and Neurophysiology, San Raf- Premenopause vascular risk factors in women
faele Scientific Institute, Milan, Italy
7
Stroke Unit, University of Perugia, Santa Maria della Misericordia Hos- Oral contraception
pital, Perugia, Italy Several studies have investigated the risk of stroke in women
Received: 5 October 2012; Accepted: 7 February 2013; Published online 19
treated with hormonal contraception. Results are controversial,
December 2013 according to most studies progesterone-only formulations, as well
as greater estrogen dosage seems to increase stroke risk in young
Conflict of interest: None declared.
women (13). The third generation of low-dose oral contraceptive
DOI: 10.1111/ijs.12110 (OCs) is associated with a twofold increased risk of stroke (14). In
migraine (137, 089211) (34). The relationship between MA and time in women, in parallel with the increases in prevalence of
ischemic stroke appears to be independent of traditional cardio- overweight and obesity (44,50). In one large academic medical
vascular risk factors, except for smoking and oral contraceptive center, outpatients with type 2 DM showed that CVD risk factors
use (35). Women with migraine have been found to have an in- among women with DM were managed less aggressively than
creased frequency of deep white matter lesions on imaging, which among men with DM. Women were less likely to have HbA1c
may indicate the occurrence of silent sub-clinical infarcts (35). <7% than men [without CHD: adjusted odds ratio (OR) for
An association between patent foramen ovale (PFO) and women vs. men 084, P = 0005; with CHD: 063, P = 00001] (51).
migraine has been reported. Case control studies have indicated Nevertheless, no reduction in stroke risk was identified in RCT
that as many as 50% of MA cases occur in the context of a PFO trials that tested whether close control of serum glucose levels in
(36), and migraine patients have larger right-to-left shunts com- diabetic patients would reduce the risk for stroke (5254).
pared with controls (37). Observational studies had reported that
Hormone replacement therapy
PFO closure resulted in migraine cessation or improvement in
The Heart and Estrogen/Progestin Replacement Study reported
80% of such patients (38). The Migraine Intervention with
that postmenopausal women with coronary heart disease on exog-
STARFlex Technology trial investigated the effects of PFO closure
enous estrogen and progesterone had no reduction in coronary
for migraine in a randomized, double-blind, sham-controlled
events (55) and a higher risk of thromboembolic events (hazard
trial (39). The primary efficacy end-point was cessation of
risk (HR) 289) compared with controls. In the Womens Estrogen
migraine headache 91180 days after the procedure. No signifi-
for Stroke Trial (56), exogenous estrogen did not reduce the risk of
cant difference was observed in the primary end-point of
stroke or mortality among postmenopausal women with a recent
migraine headache cessation between implant and sham groups
stroke or transient ischemic attack (TIA) (within 90 days of ran-
(P = 051). Additionally, the implant arm experienced more pro-
domization). Among healthy postmenopausal women in the
cedural serious adverse events.
Womens Health Initiative study, a large multicenter, double-
Menopause vascular risk factor blinded, randomized, placebo-controlled trial that investigated
the effect of estrogen on primary prevention of stroke, estrogen
Conventional risk factor
was seen to increase the risk of stroke (57). One explanation for
The Anticoagulation and Risk factors in Atrial Fibrillation study
this could be that most of the enrolled women were well past
found that atrial fibrillation (AR) was more common in men than
menopause, thereby, adding the confounding risks of comorbidi-
in women (11% vs. 08%, P < 001), and a gender analysis indi-
ties related to elderly age. Two other possible explanations include:
cated that nonanticoagulated women had a significantly greater
(1) the effect of delayed estrogen exposure on a possibly diseased
annual rate of thrombo-embolic events than men (35% vs. 18%;
vasculature (58); and (2) applying animal model results on
95% CI 1319), even after correction for other stroke risk factors
humans that have reported benefit from short-term estrogen
including age and diabetes (40).
treatment during reperfusion. According to the so-called timing
In CHA2DS2-VASc, female gender was added as a risk factor
hypothesis, estrogen is supposed to be protective for ischemic
for systemic embolism in patients with AF (41,42). A recent meta-
stroke before the age of 50 years and may become a risk factor for
analysis on gender differences in stroke incidence has reported
ischemic stroke after the age of 50 years or, more likely, after the
that cardioembolic stroke accounted for a larger proportion of
age of 60 years, particularly if given orally at high doses (59).
strokes among women, and case fatality at one-month was higher
Ongoing trials such as the Kronos Early Estrogen Prevention
among women compared with men (6). This may be due to the
Trial may shed some light on the effects of estrogen exposure
fact that women are older when they get their first stroke, and
shortly after menopause, as well as the differences by route of
other possibly present comorbidities may worsen outcome. A
estrogen delivery (oral vs. transdermal) (60). Preliminary and not
management concern has been raised by a Swedish study that
yet conclusive results of this trial showed that low-dose oral or
showed that women with atrial fibrillation receive oral anticoagu-
transdermal estrogen and cyclic monthly progesterone improve
lant therapy less often than men (43).
menopause-related symptoms without statistically significant dif-
Another major stroke risk factor for women is hypertension. In
ferences in rates of breast cancer, endometrial cancer, myocardial
fact, the National Health and Nutrition Examination Survey data
infarction (MI), TIA, stroke, or venous thromboembolic disease
have reported that more men have hypertension up until 45 years
between the trial arms.
of age than women. However, from 45 to 64 years of age, there are
no gender differences, whereas from 65 years onward, women Unusual cause of stroke in women
have more hypertension than men (44). However, women are less Takayasu arteritis is a chronic granulomatous inflammatory
likely to receive antiplatelet, lipid-lowering, and -blocker therapy disease of the aorta and large-diameter arteries. The etiology is
in the presence of either peripheral or CAD (45,46). Another issue unknown. It is more common in young women with an average
is that women have been underrepresented in randomized con- 4:1 ratio over men; it is rarely observed in Europe and North
trolled trials (RCTs) (>30%) for cardiovascular drugs despite the America, and it is more frequent in Asia and Mexico (61). Disease
National Institute of Health (NIH) revitalization act (PL-103 manifestations are heterogeneous and depend on race-ethnicity
143) that urged the inclusion of women in RCTs (47). and geographical location; patients may present with history of
Diabetes mellitus (DM) is another major risk factor for stroke limb ischemia, absent pulses and asymmetric blood pressure, in
(48,49). The prevalence of DM is increasing dramatically over advanced phases of the disease hypertension, renal artery stenosis,
women in the medical arm (P < 0001) compared with men (P < Carotid surgery (CEA) for asymptomatic carotid
003). These data are consistent with the known gender-related stenosis in women
difference in the patho-physiologylogy of atherothrombotic pla- RCTs investigating the role of CEA for asymptomatic carotid
que inflammation as women more frequently have transient en- stenosis have suggested that there may be benefit from CEA in
dothelial erosion than plaque rupture compared with men (79). asymptomatic men, whereas there is considerable uncertainty in
Female gender is classified as a surgical risk in CEA: combined asymptomatic women. The Asymptomatic Carotid Atherosclero-
data from NASCET, and Acetylsalycilic Acid (ASA) and carotid sis Study (ACAS) Endarterectomy Versus Angioplasty in Patients
endarterectomy trials showed that the 30-day perioperative risk of With Severe Symptomatic Carotid Stenosis found that women
death after CEA was higher in women than in men (23% vs. had a death rate and perioperative stroke rate of 36% compared
08%, P = 0002) (71), mainly due to higher risk of fatal stroke. with 17% in men. Specifically, compared with medical therapy
Possible differences in the internal carotid artery size or alone, men had a 66% relative risk reduction (RRR) in overall
anatomy of women may render surgery more difficult to perform five-year risk of fatal and nonfatal ipsilateral carotid stroke with
or lead to a higher incidence of carotid thrombosis (67,75). CEA, whereas in women, the event rate was reduced by only 17%
Regarding surgery for symptomatic moderate (5069%) stenosis, (84). However, differences between gender were not statistically
a significant benefit is evident only in patients randomized less significant (P = 010), and the ACAS had not established women
than two-weeks after their last event and men appear to benefit as a prespecified sub-group for trial analysis as it was indeed
more from CEA than women (78). Indeed, women with 5069% preplanned later in the Asymptomatic Carotid Surgery Trial
internal carotid artery (ICA) stenosis had no benefit from CEA (ACST1) trial. In both ACAS and ACST1 trials, the benefit from
because they generally have a lower risk of stroke than men when CEA was superior in men over women. At five-years, the benefit
they are medically treated. The five-year absolute risk reduction of gain from surgery in women was half (adjusted relative risk
ipsilateral stroke after CEA was 30% in women compared with (ARR) 408%) of that achieved in men (ARR 821%) (82). The
10% in men (five-year number needed to treat (NNT) of 33 and 10-year ACST follow-up has reported a benefit from CEA also in
10, respectively (80). women (85). In women over 75 years, considering stroke other
than the perioperative events, the net benefit still remains (gain at
Carotid stenting (CAS) 10 years with CEA, 8.2%; 95%CI 2.913.6), while, combining
Published RCTs on CAS in symptomatic patients showed an perioperative events and strokes, the benefit gain in women was of
increased risk from CAS vs. CEA in symptomatic populations, borderline significance at 10 years (gain 5.8%, 95% CI 0.111.4,
regardless of gender, whereas large randomized CAS trials on P = 0.05 at 10 years) (86).
asymptomatic patients are ongoing.
In the Stent-Protected Angioplasty versus Carotid Endarterec-
Outcomes
tomy (SPACE) trial, women had a slightly nonsignificant increase
of ipsilateral stroke or death within 30 days compared with men
Women have worse functional outcome at five-years after their
(82% vs. 64%) (78). The rate of ipsilateral stroke within two-
first stroke compared with men (84). Some studies showed that
years plus periprocedural stroke and death was lower in women
30-day mortality and poor outcome rates are significantly higher
(83% vs. 99%, P = n.s.) (81).
in women than men (87). Specifically, a Polish study conducted
The prospective meta-analysis of patient data at 120 days after
on 1379 women and 1155 men found that female gender was
treatment from Endarterectomy versus Angioplasty in Patients
independently associated with a higher risk of an early poor
with Symptomatic Severe Carotid Stenosis (EVA-3S), SPACE, and
outcome (172% vs. 131% and 599% vs. 462%) (88). In addi-
ICSS, performed by Carotid Stenting Trialists Collaboration,
tion, Gargano et al. analyzed 2566 records from 15 hospitals of the
confirmed higher surgical risk in women, whereas risk of stenting
Michigan Acute Stroke Care Overview and Treatment Surveil-
was virtually unaffected by gender. The risk ratio of any stroke or
lance System to see whether acute stroke care and discharge status
death within 120 days between CAS and CEA was higher in men
differed by gender (89). The authors concluded that during hos-
(168) than in women (122); in the CAS group, women did not
pitalization, women had substantially higher probabilities of
have significant hazards (95% CI 079189), whereas the risk of
experiencing a urinary tract infection and poorer functional
CAS in men was significantly worse (95% CI 125224) (82).
status at hospital discharge compared with their male survivors
Nevertheless, there was no significant difference in treatment
as measured by the modified Rankin Scale (mRS). As far as
effects between men and women (P = 024) (82). The Carotid
in-hospital mortality was concerned, it was equivalent between
Revascularization Endarterectomy vs. Stenting Trial (CREST)
the genders.
showed that carotid-artery stenting and carotid endarterectomy
were associated with similar rates of periprocedural cumulative
stroke, MI, death, or ipsilateral stroke [72% and 68% respec- Poststroke depression and sexual issues
tively; HR for stenting was 111 (95% CI 081151, P = 051)] after stroke
among men and women with either symptomatic or asymptom-
atic carotid stenosis. Prespecified analyses did not show any modi- Women are more likely to report depression after stroke, which
fications in the treatment effects by gender, even if women can impair functional recovery, cognitive function, survival, and
represented only 35% of all randomized patients (83). quality of life (90).
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