Stroke statement
Women Stroke Association statement on stroke
Francesca Romana Pezzella1*, Paola Santalucia2, Rita Vadal3, Elisabetta Giugni4,
Maria Luisa Zedde5, Maria Sessa6, Sabrina Anticoli1, and Valeria Caso7 on behalf of the
Women Stroke Association
We describe the current and future objectives of the Women
Stroke Association, a nonprofit multidisciplinary organization
promoting research awareness on medical, psychological,
and social issues concerning women affected by cerebro-
cardiovascular disease. In this paper, we deal with only cere-
brovascular disease, whereas cardiovascular disorders will be
addressed in a future paper. Gender differences in the clinical
presentation of cerebrovascular diseases have been repeatedly
suggested, and some treatment options may not be as effec-
tive and safe in men and women. For many years, women have
either been underrepresented or excluded from randomized
clinical trials, and the majority of therapeutic research has been
carried on predominantly male populations. Furthermore,
gender differences have been shown to contribute to different
responses to cerebrovascular drugs in women when compared
with men, regarding pharmacokinetics, pharmacodynamics,
and physiology. In this statement, we discuss main research
fields relevant to Women Stroke Associations mission and
commitment, highlighting opportunities and critical from the
womens health perspective. Future directions and goals of the
Women Stroke Association arise from these considerations and
represent the associations commitment to combating stroke.
Key words: epidemiology, gender medicine, methodology, risk factors,
stroke, therapy
Introduction
The Women Stroke Association (WSA) is a nonprofit member-
ship organization of multidisciplinary scientists and physicians
who study and promote awareness of cardio-cerebrovascular
disease in women. The key objectives of WSA include monitoring
and influencing public policies in order to reduce the number of
stroke-associated deaths and increase public awareness on
Correspondence: Francesca Romana Pezzella*, Stroke Unit
Department of Emergency Medicine, AO S Camillo Forlanini, Piazza
Carlo Forlanini 1, 00151 Rome, Italy.
E-mail: frpezzella@gmail.com
1
Stroke Unit Department of Emergency Medicine, AO S Camillo Forla-
nini, Rome, Italy
2
Direzione Scientifica and U.O. Medicina dUrgenza, Fondazione IRCCS
C Granda, Ospedale Maggiore Policlinico, Milan, Italy
3
NeuroRadiology, IRCCS Fondazione S Lucia, Rome, Italy
4
Fondazione Biomedica Europea Onlus, Rome, Italy
5
Neurology Department, Arcispedale Santa Maria Nuova, Reggio
nellEmilia, Italy
6
Stroke Unit Department of Neurology and Neurophysiology, San Raf-
faele Scientific Institute, Milan, Italy
7
Stroke Unit, University of Perugia, Santa Maria della Misericordia Hos-
pital, Perugia, Italy
Received: 5 October 2012; Accepted: 7 February 2013; Published online 19
December 2013
Conflict of interest: None declared.
DOI: 10.1111/ijs.12110
20 Vol 9, October 2014, 2027
cerebrovascular (CVD) and cardiovascular disease (CAD) in
women. Here, we will address only CVD, whereas CAD will be
addressed in a future paper. We have founded WSA for the fol-
lowing reason: women are often underrepresented or excluded
from clinical studies on CVD, thereby study results tend to be
biased. Possible reasons might be that women are generally older
than men at stroke onset, live alone, and have less access to care-
givers. In addition, women are more frequently afflicted by
depression before and after stroke contributing to their poor
outcome compared with men (1). The WSA was founded in 2010
and, to date, has published papers in several international peer-
reviewed journals (25).
Epidemiology of stroke in women
Population-based studies have shown that postmenopausal
women, especially after >65 years of age, have a higher risk of
stroke than men (6). A recent review has reported a 33% higher
stroke incidence in men, compared with 41% higher stroke preva-
lence in women (6). Moreover, women have been reported to have
a higher lifetime risk of stroke compared with men (7), along with
higher rates of poststroke mortality, disability, depression, and
dementia (8). Specific pathophysiological aspects of stroke in
women include pregnancy, puerperium, and older age.
Regarding elderly women, their poorer outcome is influenced
by the fact that they are more likely to be living alone or in an
assisted living arrangement before stroke onset (1). Also from a
clinical point of view, their presentations at stroke onset tend to
be poorly communicated. Stroke in women is more frequently
associated with anterior circulation ischemia, whereas men are
more likely to have cerebellar and brainstem symptoms and
higher incidences of posterior circulation syndromes than women
(9). Concerning stroke awareness, women have been reported to
possess a better knowledge of major stroke symptoms and stroke
risk factors (10,11) and to learn from health behavior and stroke
campaigns independently from educational level than men,
instead it was found that the level of education influences the
process of experiential learning in men (12).
Premenopause vascular risk factors in women
Oral contraception
Several studies have investigated the risk of stroke in women
treated with hormonal contraception. Results are controversial,
according to most studies progesterone-only formulations, as well
as greater estrogen dosage seems to increase stroke risk in young
women (13). The third generation of low-dose oral contraceptive
(OCs) is associated with a twofold increased risk of stroke (14). In
2013 Women Stroke Association.
International Journal of Stroke 2013 World Stroke Organization
 F. R. Pezzella et al. Stroke statement
addition to oral contraceptive pills, other options currently
Table 1 Risk factors and comorbidities for stroke during pregnancy
include vaginal ring, transdermal patches, subcutaneous implants,
and the levonorgestrel-releasing intrauterine device (IUD). A Nonmodifiable Age (age >35 years)
recent Danish study on a population of 17 million women (age risk factors Race-ethnicity
1549) followed up for 15 years since 1995 has shown that women Asian race for hemorragic stroke
Black race for thromboembolism
taking contraceptive pills with a combination of estrogen and
Modifiable risk Obesity
progestin seemed to have a higher risk of stroke, although factors Substance use: tobacco, alcohol, recreational
minimal; neither the subcutaneous implants nor the IUD contain- drugs, particularly cocaine
ing progestin was associated to an increased risk of stroke, whereas Complications/ Pregnancy-specific disorders:
chance of stroke almost doubled for women using a vaginal ring comorbidities Preeclampsia
Peripartum cardiomyopathy
compared with those not using hormonal contraception (15). For
Amniotic fluid embolism
contraceptive patches, there was a trend toward more strokes that Choriocarcinoma
was not statistically significant (15). Previous studies have sug- Hypertension
gested that characteristics of OC agents, such as higher hormonal Gestational diabetes
dosages and higher percentages of estrogens, increase stroke risks; Peripartum migraine
Hematologic disorders:
other factors that increase stroke risks in combination with OC
Thrombophilia
include hypertension, hyperlipidemia, obesity, age (>35), and Lupus
smoking. All of which have a dose-responsive risk effect (16). Heart disease
Genetic testing for thrombophilia before OC has been recom- Sickle cell disease
mended even if it has a poor cost-effectiveness profile (17). The Rheumatic fever and valvular heart disease
Patent foramen ovale/pulmonary arteriovenous
use of OC in migraine with aura (MA) patients is controversial
malformation
and generally contraindicated (18), especially in those with one or Particulars of pregnancy:
more vascular risk factors including smoking (19). Cesarian delivery
Multiparity
Pregnancy and puerperium Multiple gestation
Complications
Pregnancy increases the risk for several types of stroke (20), even
Traumatic cervical artery dissection
if the real incidence and prevalence are still a matter of debate. Postpartum infection
According to published data, the estimated incidence of all stroke Disseminated intravascular coagulation
is 946/100 000 deliveries, whereas the incidence of ischemic Fluid and electrolyte imbalance, and
stroke is 3818/100 000 deliveries (2123), intracerebral hemor- acidbase disorder
Transfusion
rhage is 9/100 000 of deliveries, cerebral venous thrombosis, a rare
type of stroke, is 12/100 000 deliveries (23), and uncommon
stroke accounts for 512% of all maternal deaths during preg-
nancy and found that comorbidity of stroke and active migraine
nancy (24,25).
was the most frequent among the association observed in those
The peri/postpartum period, more than pregnancy itself, rep-
women. However, further studies are needed to clarify whether
resents a period of elevated vascular disease due to hormonal
migraine is a vascular risk factor or a marker of vascular disease in
alterations, hemodynamic changes, hypercoagulability, and blood
women (27). Recently, it has been observed that gestational dia-
pressure fluctuation that may interact at a systemic level in sus-
betes and even mild glucose intolerance during pregnancy may
ceptible subjects and cause stoke. There may be other local effect
play a role as a predictor of increased vascular risk (28) particu-
such as vascular stasis (especially third trimester) and trauma
larly in women with familiar history of type 2 diabetes.
during delivery that may result in paradoxical thromboembolism
Stroke management in pregnancy requires special attention,
or cerebral artery dissection (mainly vertebral artery) in vulner-
concerning the acute phase and the possibility to treat patients
able subjects.
with thrombolysis. This procedure is contraindicated during ges-
Other pregnancy-specific disorder may result in stroke, such as
tational period and the four-weeks following child birth; never-
peripartum cardiomyopathy, disseminated intravascular coagula-
theless, there have been a small number of case reports of
tion, and amniotic fluid embolism (26).
intravenous and intra-arterial thrombolysis during pregnancy
Chorioncarcinoma, a malignant tumor of gestational tropho-
with positive results (23).
blasts, may rarely metastasize to the brain, causing intracerebral
or sub-arachnoid bleeding (25). Migraine and stroke
There are few modifiable and nonmodifiable risk factors that Epidemiological studies have reported associations between
may play a role in increasing the risk of stroke during pregnancy, migraine, mostly with aura, and both hemorrhagic and ischemic
and they are discussed in the current literature, as well as concur- strokes (19,2932), coronary events (33,34), and all-cause mortal-
rent disorders that may enhance stroke risks. These are summa- ity. A recent meta-analysis has reported an increased risk of isch-
rized in Table 1. emic stroke in women with any migraine vs. women with no
A recent epidemiological study on clinical records analyzed migraine [pooled relative risk (RR) 208, 95% confidence interval
peripartum migraine and vascular complications during preg- (CI) 113384], but not in men with migraine vs. men with no

2013 Women Stroke Association. Vol 9, October 2014, 2027 21

International Journal of Stroke 2013 World Stroke Organization
 Stroke statement
migraine (137, 089211) (34). The relationship between MA and
ischemic stroke appears to be independent of traditional cardio-
vascular risk factors, except for smoking and oral contraceptive
use (35). Women with migraine have been found to have an in-
creased frequency of deep white matter lesions on imaging, which
may indicate the occurrence of silent sub-clinical infarcts (35).
An association between patent foramen ovale (PFO) and
migraine has been reported. Case control studies have indicated
that as many as 50% of MA cases occur in the context of a PFO
(36), and migraine patients have larger right-to-left shunts com-
pared with controls (37). Observational studies had reported that
PFO closure resulted in migraine cessation or improvement in
80% of such patients (38). The Migraine Intervention with
STARFlex Technology trial investigated the effects of PFO closure
for migraine in a randomized, double-blind, sham-controlled
trial (39). The primary efficacy end-point was cessation of
migraine headache 91180 days after the procedure. No signifi-
cant difference was observed in the primary end-point of
migraine headache cessation between implant and sham groups
(P = 051). Additionally, the implant arm experienced more pro-
cedural serious adverse events.
Menopause vascular risk factor
Conventional risk factor
The Anticoagulation and Risk factors in Atrial Fibrillation study
found that atrial fibrillation (AR) was more common in men than
in women (11% vs. 08%, P < 001), and a gender analysis indi-
cated that nonanticoagulated women had a significantly greater
annual rate of thrombo-embolic events than men (35% vs. 18%;
95% CI 1319), even after correction for other stroke risk factors
including age and diabetes (40).
In CHA2DS2-VASc, female gender was added as a risk factor
for systemic embolism in patients with AF (41,42). A recent meta-
analysis on gender differences in stroke incidence has reported
that cardioembolic stroke accounted for a larger proportion of
strokes among women, and case fatality at one-month was higher
among women compared with men (6). This may be due to the
fact that women are older when they get their first stroke, and
other possibly present comorbidities may worsen outcome. A
management concern has been raised by a Swedish study that
showed that women with atrial fibrillation receive oral anticoagu-
lant therapy less often than men (43).
Another major stroke risk factor for women is hypertension. In
fact, the National Health and Nutrition Examination Survey data
have reported that more men have hypertension up until 45 years
of age than women. However, from 45 to 64 years of age, there are
no gender differences, whereas from 65 years onward, women
have more hypertension than men (44). However, women are less
likely to receive antiplatelet, lipid-lowering, and -blocker therapy
in the presence of either peripheral or CAD (45,46). Another issue
is that women have been underrepresented in randomized con-
trolled trials (RCTs) (>30%) for cardiovascular drugs despite the
National Institute of Health (NIH) revitalization act (PL-103
143) that urged the inclusion of women in RCTs (47).
Diabetes mellitus (DM) is another major risk factor for stroke
(48,49). The prevalence of DM is increasing dramatically over
22 Vol 9, October 2014, 2027
F. R. Pezzella et al.
time in women, in parallel with the increases in prevalence of
overweight and obesity (44,50). In one large academic medical
center, outpatients with type 2 DM showed that CVD risk factors
among women with DM were managed less aggressively than
among men with DM. Women were less likely to have HbA1c
<7% than men [without CHD: adjusted odds ratio (OR) for
women vs. men 084, P = 0005; with CHD: 063, P = 00001] (51).
Nevertheless, no reduction in stroke risk was identified in RCT
trials that tested whether close control of serum glucose levels in
diabetic patients would reduce the risk for stroke (5254).
Hormone replacement therapy
The Heart and Estrogen/Progestin Replacement Study reported
that postmenopausal women with coronary heart disease on exog-
enous estrogen and progesterone had no reduction in coronary
events (55) and a higher risk of thromboembolic events (hazard
risk (HR) 289) compared with controls. In the Womens Estrogen
for Stroke Trial (56), exogenous estrogen did not reduce the risk of
stroke or mortality among postmenopausal women with a recent
stroke or transient ischemic attack (TIA) (within 90 days of ran-
domization). Among healthy postmenopausal women in the
Womens Health Initiative study, a large multicenter, double-
blinded, randomized, placebo-controlled trial that investigated
the effect of estrogen on primary prevention of stroke, estrogen
was seen to increase the risk of stroke (57). One explanation for
this could be that most of the enrolled women were well past
menopause, thereby, adding the confounding risks of comorbidi-
ties related to elderly age. Two other possible explanations include:
(1) the effect of delayed estrogen exposure on a possibly diseased
vasculature (58); and (2) applying animal model results on
humans that have reported benefit from short-term estrogen
treatment during reperfusion. According to the so-called timing
hypothesis, estrogen is supposed to be protective for ischemic
stroke before the age of 50 years and may become a risk factor for
ischemic stroke after the age of 50 years or, more likely, after the
age of 60 years, particularly if given orally at high doses (59).
Ongoing trials such as the Kronos Early Estrogen Prevention
Trial may shed some light on the effects of estrogen exposure
shortly after menopause, as well as the differences by route of
estrogen delivery (oral vs. transdermal) (60). Preliminary and not
yet conclusive results of this trial showed that low-dose oral or
transdermal estrogen and cyclic monthly progesterone improve
menopause-related symptoms without statistically significant dif-
ferences in rates of breast cancer, endometrial cancer, myocardial
infarction (MI), TIA, stroke, or venous thromboembolic disease
between the trial arms.
Unusual cause of stroke in women
Takayasu arteritis is a chronic granulomatous inflammatory
disease of the aorta and large-diameter arteries. The etiology is
unknown. It is more common in young women with an average
4:1 ratio over men; it is rarely observed in Europe and North
America, and it is more frequent in Asia and Mexico (61). Disease
manifestations are heterogeneous and depend on race-ethnicity
and geographical location; patients may present with history of
limb ischemia, absent pulses and asymmetric blood pressure, in
advanced phases of the disease hypertension, renal artery stenosis,
2013 Women Stroke Association.
International Journal of Stroke 2013 World Stroke Organization
 F. R. Pezzella et al.
ischemic heart disease, severe intermittent claudication, and brain
ischemia that may be fatal to patients.
Susac syndrome is a rare autoimmune endotheliopathy of
small-diameter artery causing retinocochleocerebral vasculopa-
thy. It affects women aged between 20 and 40, with 5:1 ratio of
women over men. It usually presents with the triad of brain eye
and hear involvement: multiple retinal arterial occlusions, hearing
loss, seizures, cognitive impairment, psychiatric disorders, and
focal neurological signs due to brain microangiopathy may be
present (62).
Sneddon syndrome is a rare progressive noninflammatory
artheriopathy of small, medium size vessels, affecting women in
their thirties; it is characterized by lacunar sub-cortical infarcts
and livedo reticularis of the skin. Neurological symptoms range
from headache, vertigo, TIA, stroke, and seizures to mental dete-
rioration and dementia. It is a sporadic uncommon disorder, even
if recently, some familiar cases have been described (63). Diagno-
sis is mainly based on skin biopsy and consistent findings in
neurological examination and neuroimaging.
Reversible cerebral vasoconstriction syndrome (RCVS) is a
disease characterized by acute onset and severe headaches, usually
qualified as a thunderclap headache that recurs over a period
from a few days to two-weeks with or without focal neurological
deficits or seizures due to a prolonged but reversible vasoconstric-
tion of cerebral arteries. It may occur spontaneously or as a
response to various factors such as sympathomimetic and sero-
tonergic substances, uncontrolled hypertension, or during preg-
nancy and the puerperium. This syndrome is sometimes followed
by stroke, ischemic or hemorrhagic, or by nonaneurismal cortical
sub-arachnoid hemorrhage, leading to permanent neurologic
deficits or death (64). In a prospective French study, female
gender and a migraine history were identified as independent risk
factors for hemorrhagic sequelae in RCVS (65).
Specific treatment aspects in women
Acute treatment
Current literature suggests possible gender differences in stroke
care in the inpatient setting and in rates of thrombolytic admin-
istration. Women have longer waiting times at emergency rooms
and receive less intensive treatment and therapeutic workup once
they are admitted (6668). In a recent report from Get With The
Guidelines-Stroke program, data from 2003 to 2009 were ana-
lyzed to determine overall imaging rates, temporal trends, and
predictive variables associated with door-to-imaging times in
patients who presented to an emergency department within two-
hours of stroke symptom onset (69). The following variables were
associated with less likelihood of imaging being completed within
25 min: age >70 years; female gender; non-Caucasian race ethnic-
ity; history of diabetes, peripheral vascular disease, or prosthetic
heart valve; transportation other than ambulance; and arrival
>60 min after symptom onset (69).
Reeves et al. conducted a meta-analysis on gender differences in
the use of intravenous rt-PA thrombolysis treatment for acute
ischemic stroke (66). Eighteen studies were included. The sum-
mary OR was 070 (95% CI = 055088), indicating that women gender related (P < 0001). The main determinant of this gender
had a 30% lower odds of receiving rt-PA treatment than men.
2013 Women Stroke Association.
International Journal of Stroke 2013 World Stroke Organization
Stroke statement
However, substantial between-study variability existed. Among 13
hospital-based studies, the summary OR was 078 (95% CI = 071
086) with no significant heterogeneity. Among the three admin-
istrative studies, the OR was 055 (95% CI = 034090) but with
significant heterogeneity. Among four studies that included data
on the eligible sub-group, women had a nonsignificant lower odds
of treatment (OR = 081, 95% CI = 058113) (66).
Another recent review has suggested that significant gender
differences in both the efficacy and utilization of IV tPA exist,
with women gaining more benefit from treatment than men (66).
This is probably due to the fact that the early recanalization rates
are higher in women than men after IV tPA treatment (70),
although these findings have not been replicated in the studies of
IA tPA use (71,72). Possible explanations in the greater efficacy of
IV tPA in women could be that occlusions from cardioembolic
sources are richer in fibrin and are more easily dissolved, com-
pared with the platelet-rich occlusions that characterize thombo-
embolic strokes (73). In addition, another possibility could be
that women have greater endogenous fibrinolytic activity com-
pared with men (74).
Aspirin treatment
The Womens Health Study was the first randomized study evalu-
ating only women (39 876) to determine efficacy of aspirin for
primary prevention of vascular events (75). Results reported that
aspirin lowers the risk of ischemic stroke by 24% but does not
alter the risk of MI or death.
Berger et al. conducted a meta-analysis to assess whether ben-
efits and risks of aspirin treatment in the primary prevention of
CAD can vary by gender (76). Among 51 342 women, aspirin
therapy was associated with a significant 12% reduction in car-
diovascular events (OR, 088; 95% CI, 079099; P = 003) and a
17% reduction in stroke (OR, 083; 95% CI, 070097; P = 002),
which was due to reduced rates of ischemic stroke (OR, 076; 95%
CI, 063093; P = 0008). There was no reported significant effect
on MI or cardiovascular mortality.
For secondary prevention trials, the meta-analysis of the Anti-
thrombotic Trialists Collaboration reported no difference in pro-
portional reductions of all serious vascular events between the
genders (77). Yet, some studies have found that the use of aspirin
was lower at admission and at discharge for women, especially in
women aged more than 85 years (43).
Carotid stenosis management
Carotid endarterectomy (CEA)
The benefit of CEA in symptomatic patients decreases if surgery is
not performed immediately after the event. This time-dependent
benefit ratio is especially true for women, as a sub-group analysis of
pooled individual patient data from European Carotid Surgery
Trial (ECST) and North American Symptomatic Carotid Endart-
erectomy Trial (NASCET) (78) has shown. The benefit from CEA
significantly diminished with increasing time from last event to
randomization in women (P < 0001) but not in men (P = 074),
and the trend toward reducing benefit from CEA over time was
difference was a more rapid decline over time of the stroke risk in
Vol 9, October 2014, 2027 23
 Stroke statement
women in the medical arm (P < 0001) compared with men (P <
003). These data are consistent with the known gender-related
difference in the patho-physiologylogy of atherothrombotic pla-
que inflammation as women more frequently have transient en-
dothelial erosion than plaque rupture compared with men (79).
Female gender is classified as a surgical risk in CEA: combined
data from NASCET, and Acetylsalycilic Acid (ASA) and carotid
endarterectomy trials showed that the 30-day perioperative risk of
death after CEA was higher in women than in men (23% vs.
08%, P = 0002) (71), mainly due to higher risk of fatal stroke.
Possible differences in the internal carotid artery size or
anatomy of women may render surgery more difficult to perform
or lead to a higher incidence of carotid thrombosis (67,75).
Regarding surgery for symptomatic moderate (5069%) stenosis,
a significant benefit is evident only in patients randomized less
than two-weeks after their last event and men appear to benefit
more from CEA than women (78). Indeed, women with 5069%
internal carotid artery (ICA) stenosis had no benefit from CEA
because they generally have a lower risk of stroke than men when
they are medically treated. The five-year absolute risk reduction of
ipsilateral stroke after CEA was 30% in women compared with
10% in men (five-year number needed to treat (NNT) of 33 and
10, respectively (80).
Carotid stenting (CAS)
Published RCTs on CAS in symptomatic patients showed an
increased risk from CAS vs. CEA in symptomatic populations,
regardless of gender, whereas large randomized CAS trials on
asymptomatic patients are ongoing.
In the Stent-Protected Angioplasty versus Carotid Endarterec-
tomy (SPACE) trial, women had a slightly nonsignificant increase
of ipsilateral stroke or death within 30 days compared with men
(82% vs. 64%) (78). The rate of ipsilateral stroke within two-
years plus periprocedural stroke and death was lower in women
(83% vs. 99%, P = n.s.) (81).
The prospective meta-analysis of patient data at 120 days after
treatment from Endarterectomy versus Angioplasty in Patients
with Symptomatic Severe Carotid Stenosis (EVA-3S), SPACE, and
ICSS, performed by Carotid Stenting Trialists Collaboration,
confirmed higher surgical risk in women, whereas risk of stenting
was virtually unaffected by gender. The risk ratio of any stroke or
death within 120 days between CAS and CEA was higher in men
(168) than in women (122); in the CAS group, women did not
have significant hazards (95% CI 079189), whereas the risk of
CAS in men was significantly worse (95% CI 125224) (82).
Nevertheless, there was no significant difference in treatment
effects between men and women (P = 024) (82). The Carotid
Revascularization Endarterectomy vs. Stenting Trial (CREST)
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-
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-
fications in the treatment effects by gender, even if women
represented only 35% of all randomized patients (83).
24 Vol 9, October 2014, 2027
F. R. Pezzella et al.
Carotid surgery (CEA) for asymptomatic carotid
stenosis in women
RCTs investigating the role of CEA for asymptomatic carotid
stenosis have suggested that there may be benefit from CEA in
asymptomatic men, whereas there is considerable uncertainty in
asymptomatic women. The Asymptomatic Carotid Atherosclero-
sis Study (ACAS) Endarterectomy Versus Angioplasty in Patients
With Severe Symptomatic Carotid Stenosis found that women
had a death rate and perioperative stroke rate of 36% compared
with 17% in men. Specifically, compared with medical therapy
alone, men had a 66% relative risk reduction (RRR) in overall
five-year risk of fatal and nonfatal ipsilateral carotid stroke with
CEA, whereas in women, the event rate was reduced by only 17%
(84). However, differences between gender were not statistically
significant (P = 010), and the ACAS had not established women
as a prespecified sub-group for trial analysis as it was indeed
preplanned later in the Asymptomatic Carotid Surgery Trial
(ACST1) trial. In both ACAS and ACST1 trials, the benefit from
CEA was superior in men over women. At five-years, the benefit
gain from surgery in women was half (adjusted relative risk
(ARR) 408%) of that achieved in men (ARR 821%) (82). The
10-year ACST follow-up has reported a benefit from CEA also in
women (85). In women over 75 years, considering stroke other
than the perioperative events, the net benefit still remains (gain at
10 years with CEA, 8.2%; 95%CI 2.913.6), while, combining
perioperative events and strokes, the benefit gain in women was of
borderline significance at 10 years (gain 5.8%, 95% CI 0.111.4,
P = 0.05 at 10 years) (86).
Outcomes
Women have worse functional outcome at five-years after their
first stroke compared with men (84). Some studies showed that
30-day mortality and poor outcome rates are significantly higher
in women than men (87). Specifically, a Polish study conducted
on 1379 women and 1155 men found that female gender was
independently associated with a higher risk of an early poor
outcome (172% vs. 131% and 599% vs. 462%) (88). In addi-
tion, Gargano et al. analyzed 2566 records from 15 hospitals of the
Michigan Acute Stroke Care Overview and Treatment Surveil-
lance System to see whether acute stroke care and discharge status
differed by gender (89). The authors concluded that during hos-
pitalization, women had substantially higher probabilities of
experiencing a urinary tract infection and poorer functional
status at hospital discharge compared with their male survivors
as measured by the modified Rankin Scale (mRS). As far as
in-hospital mortality was concerned, it was equivalent between
the genders.
Poststroke depression and sexual issues
Women are more likely to report depression after stroke, which
can impair functional recovery, cognitive function, survival, and
quality of life (90).
2013 Women Stroke Association.
International Journal of Stroke 2013 World Stroke Organization
 F. R. Pezzella et al.
Stroke survivors report decreased sexual activity due to a lower
sense of well-being and increased sexual dysfunction; however,
sexual concerns are generally overlooked in current stroke reha-
bilitation despite their impact on quality of life (91). Researchers
should begin investigating possible gender differences in post-
stroke depression treatment aimed at improving patients well-
being and sexual and affective satisfaction.
Conclusions
The studies that have examined gender differences in stroke epi-
demiology, clinical presentation, therapies, and outcome have
demonstrated that gender differences do, in fact, exist. Currently,
WSA aims to influence public health policies in order to reduce
the number of stroke-associated deaths as well as raise public
awareness on CVD in women. Additionally, WSA future agenda
will aim to foster the creation of clinical trials that accurately
reflect the percentages of elderly women having ischemic event in
order to reduce mortality and morbidity.
References
1 Reeves MJ, Bushnell CD, Howard G et al. Sex differences in stroke:
epidemiology, clinical presentation, medical care, and outcomes.
Lancet Neurol 2008; 7:91526.
2 Acciarresi M, Caso V, Venti M et al. First-ever stroke and outcome in
patients admitted to Perugia Stroke Unit: predictors for death, depen-
dency, and recurrence of stroke within the first three months. Clin Exp
Hypertens 2006; 28:28794.
3 Caso V, Santalucia P, Acciarresi M, Pezzella FR, Paciaroni M. Anti-
platelet treatment in primary and secondary stroke prevention in
women. Eur J Intern Med 2012; 23:5805.
4 Santalucia P, Pezzella FR, Sessa M et al. Sex differences in clinical
presentation, severity and outcome of stroke: results from a hospital-
based registry. Eur J Intern Med 2013; 24:16771.
5 Caso V, Santalucia P, Pezzella FR. Depression and stroke risk. Womens
Health (Lond Engl) 2012; 8:357.
6 Appelros P, Stegmayr B, Terent A. Sex differences in stroke epidemi-
ology: a systematic review. Stroke 2009; 40:108290.
7 Seshadri S, Beiser A, Kelly-Hayes M et al. The lifetime risk of stroke:
estimates from the Framingham Study. Stroke 2006; 37:34550.
8 Kapral MK, Fang J, Hill MD et al. Sex differences in stroke care and
outcomes: results from the Registry of the Canadian Stroke Network.
Stroke 2005; 36:80914.
9 Reid JM, Dai D, Gubitz GJ, Kapral MK, Christian C, Phillips SJ.
Gender differences in stroke examined in a 10-year cohort of
patients admitted to a Canadian teaching hospital. Stroke 2008;
39:10905.
10 Stroebele N, Muller-Riemenschneider F, Nolte CH, Muller-Nordhorn
J, Bockelbrink A, Willich SN. Knowledge of risk factors, and warning
signs of stroke: a systematic review from a gender perspective. Int J
Stroke 2011; 6:606.
11 Truelsen T, Krarup LH. Stroke awareness in Denmark. Neuroepidemi-
ology 2010; 35:16570.
12 Kautzky-Willer A, Dorner T, Jensby A, Rieder A. Women show a closer
association between educational level and hypertension or diabetes
mellitus than males: a secondary analysis from the Austrian HIS. BMC
Public Health 2012; 12:392.
13 Allais G, Gabellari IC, Mana O, Schiapparelli P, Terzi MG, Benedetto
C. Migraine and stroke: the role of oral contraceptives. Neurol Sci
2008; 29(Suppl. 1):S124.
14 Baillargeon JP, McClish DK, Essah PA, Nestler JE. Association between
the current use of low-dose oral contraceptives and cardiovascular
2013 Women Stroke Association.
International Journal of Stroke 2013 World Stroke Organization
Stroke statement
arterial disease: a meta-analysis. J Clin Endocrinol Metab 2005;
90:386370.
15 Lidegaard O, Lokkegaard E, Jensen A, Skovlund CW, Keiding N.
Thrombotic stroke and myocardial infarction with hormonal contra-
ception. N Engl J Med 2012; 366:225766.
16 Bhat VM, Cole JW, Sorkin JD et al. Dose-response relationship
between cigarette smoking and risk of ischemic stroke in young
women. Stroke 2008; 39:243943.
17 Blickstein D, Blickstein I. Oral contraception and thrombophilia. Curr
Opin Obstet Gynecol 2007; 19:3706.
18 Curtis KM, Mohllajee AP, Peterson HB. Use of combined oral contra-
ceptives among women with migraine and nonmigrainous headaches:
a systematic review. Contraception 2006; 73:18994.
19 Chang CL, Donaghy M, Poulter N. Migraine and stroke in young
women: case-control study. The World Health Organisation Collab-
orative Study of Cardiovascular Disease and Steroid Hormone Con-
traception. BMJ 1999; 318:138.
20 Kittner SJ, Stern BJ, Feeser BR et al. Pregnancy and the risk of stroke.
N Engl J Med 1996; 335:76874.
21 Salonen Ros H, Lichtenstein P, Bellocco R, Petersson G, Cnattingius S.
Increased risks of circulatory diseases in late pregnancy and puerpe-
rium. Epidemiology 2001; 12:45660.
22 James AH, Bushnell CD, Jamison MG, Myers ER. Incidence and risk
factors for stroke in pregnancy and the puerperium. Obstet Gynecol
2005; 106:50916.
23 Lanska DJ, Kryscio RJ. Risk factors for peripartum and postpartum
stroke and intracranial venous thrombosis. Stroke 2000; 31:127482.
24 Meyers PM, Halbach VV, Malek AM et al. Endovascular treatment of
cerebral artery aneurysms during pregnancy: report of three cases.
AJNR Am J Neuroradiol 2000; 21:130611.
25 Davie CA, OBrien P. Stroke and pregnancy. J Neurol Neurosurg Psy-
chiatry 2008; 79:2405.
26 Sharshar T, Lamy C, Mas JL. Incidence and causes of strokes associated
with pregnancy and puerperium. A study in public hospitals of Ile de
France. Stroke in Pregnancy Study Group. Stroke 1995; 26:9306.
27 Bushnell CD, Jamison M, James AH. Migraines during pregnancy
linked to stroke and vascular diseases: US population based case-
control study. BMJ 2009; 338:b664.
28 Retnakaran R, Shah BR. Mild glucose intolerance in pregnancy and
risk of cardiovascular disease: a population-based cohort study. CMAJ
2009; 181:3716.
29 Tzourio C, Iglesias S, Hubert JB et al. Migraine and risk of ischaemic
stroke: a case-control study. BMJ 1993; 307:28992.
30 Kurth T, Slomke MA, Kase CS et al. Migraine, headache, and the
risk of stroke in women: a prospective study. Neurology 2005;
64:10206.
31 Stang PE, Carson AP, Rose KM et al. Headache, cerebrovascular symp-
toms, and stroke: the Atherosclerosis Risk in Communities Study.
Neurology 2005; 64:15737.
32 Kurth T, Kase CS, Schurks M, Tzourio C, Buring JE. Migraine and risk
of haemorrhagic stroke in women: prospective cohort study. BMJ
2010; 341:c3659.
33 Bigal ME, Kurth T, Santanello N et al. Migraine and cardiovascular
disease: a population-based study. Neurology 2010; 74:62835.
34 Schurks M, Rist PM, Bigal ME, Buring JE, Lipton RB, Kurth T.
Migraine and cardiovascular disease: systematic review and meta-
analysis. BMJ 2009; 339:b3914.
35 Kruit MC, van Buchem MA, Hofman PA et al. Migraine as a risk factor
for subclinical brain lesions. JAMA 2004; 291:42734.
36 Sacco S, Cerone D, Carolei A. Comorbid neuropathologies in
migraine: an update on cerebrovascular and cardiovascular aspects.
J Headache Pain 2008; 9:23748.
37 Jesurum JT, Fuller CJ, Velez CA et al. Migraineurs with patent foramen
ovale have larger right-to-left shunt despite similar atrial septal char-
acteristics. J Headache Pain 2007; 8:20916.
38 Wilmshurst PT, Nightingale S, Walsh KP, Morrison WL. Effect on
migraine of closure of cardiac right-to-left shunts to prevent
Vol 9, October 2014, 2027 25
 Stroke statement
recurrence of decompression illness or stroke or for haemodynamic
reasons. Lancet 2000; 356:164851.
39 Dowson A, Mullen MJ, Peatfield R et al. Migraine Intervention With
STARFlex Technology (MIST) trial: a prospective, multicenter,
double-blind, sham-controlled trial to evaluate the effectiveness of
patent foramen ovale closure with STARFlex septal repair implant
to resolve refractory migraine headache. Circulation 2008; 117:1397
404.
40 Fang MC, Singer DE, Chang Y et al. Gender differences in the risk of
ischemic stroke and peripheral embolism in atrial fibrillation: the
AnTicoagulation and Risk factors In Atrial fibrillation (ATRIA) study.
Circulation 2005; 112:168791.
41 Gage BF, Waterman AD, Shannon W, Boechler M, Rich MW, Radford
MJ. Validation of clinical classification schemes for predicting stroke:
results from the National Registry of Atrial Fibrillation. JAMA 2001;
285:286470.
42 Lip GY, Nieuwlaat R, Pisters R, Lane DA, Crijns HJ. Refining clinical
risk stratification for predicting stroke and thromboembolism in atrial
fibrillation using a novel risk factor-based approach: the euro heart
survey on atrial fibrillation. Chest 2010; 137:26372.
43 Glader EL, Stegmayr B, Norrving B et al. Sex differences in manage-
ment and outcome after stroke: a Swedish national perspective. Stroke
2003; 34:19705.
44 Roger VL, Go AS, Lloyd-Jones DM et al. Heart disease and stroke
statistics 2012 update: a report from the American Heart Associa-
tion. Circulation 2012; 125:e2e220.
45 Poisson SN, Johnston SC, Sidney S, Klingman JG, Nguyen-Huynh
MN. Gender differences in treatment of severe carotid stenosis after
transient ischemic attack. Stroke 2010; 41:18915.
46 Murphy NF, Simpson CR, MacIntyre K, McAlister FA, Chalmers J,
McMurray JJ. Prevalence, incidence, primary care burden and medical
treatment of angina in Scotland: age, sex and socioeconomic dispari-
ties: a population-based study. Heart 2006; 92:104754.
47 Melloni C, Berger JS, Wang TY et al. Representation of women in
randomized clinical trials of cardiovascular disease prevention. Circ
Cardiovasc Qual Outcomes 2010; 3:13542.
48 Goldstein LB, Bushnell CD, Adams RJ et al. Guidelines for the primary
prevention of stroke: a guideline for healthcare professionals from the
American Heart Association/American Stroke Association. Stroke
2011; 42:51784.
49 Gurm HS, Rajagopal V, Sachar R et al. Impact of diabetes mellitus on
outcome of patients undergoing carotid artery stenting: insights from
a single center registry. Catheter Cardiovasc Interv 2007; 69:5415.
50 Mosca L, Benjamin EJ, Berra K et al. Effectiveness-based guidelines for
the prevention of cardiovascular disease in women 2011 update: a
guideline from the American Heart Association. J Am Coll Cardiol
2011; 57:140423.
51 Wexler DJ, Grant RW, Meigs JB, Nathan DM, Cagliero E. Sex dispari-
ties in treatment of cardiac risk factors in patients with type 2 diabetes.
Diabetes Care 2005; 28:51420.
52 Turner RC, Millns H, Neil HA et al. Risk factors for coronary artery
disease in non-insulin dependent diabetes mellitus: United Kingdom
Prospective Diabetes Study (UKPDS: 23). BMJ 1998; 316:8238.
53 Gerstein HC, Miller ME, Byington RP et al. Effects of intensive glucose
lowering in type 2 diabetes. N Engl J Med 2008; 358:254559.
54 Kengne AP, Patel A, Colagiuri S et al. The Framingham and UK Pro-
spective Diabetes Study (UKPDS) risk equations do not reliably esti-
mate the probability of cardiovascular events in a large ethnically
diverse sample of patients with diabetes: the Action in Diabetes and
Vascular Disease: Preterax and Diamicron-MR Controlled Evaluation
(ADVANCE) Study. Diabetologia 2010; 53:82131.
55 Hulley S, Grady D, Bush T et al. Randomized trial of estrogen plus
progestin for secondary prevention of coronary heart disease in post-
menopausal women. Heart and Estrogen/progestin Replacement
Study (HERS) Research Group. JAMA 1998; 280:60513.
56 Viscoli CM, Brass LM, Kernan WN, Sarrel PM, Suissa S, Horwitz RI.
Estrogen therapy and risk of cognitive decline: results from the
26 Vol 9, October 2014, 2027
F. R. Pezzella et al.
Womens Estrogen for Stroke Trial (WEST). Am J Obstet Gynecol 2005;
192:38793.
57 Wassertheil-Smoller S, Hendrix SL, Limacher M et al. Effect of
estrogen plus progestin on stroke in postmenopausal women: the
Womens Health Initiative: a randomized trial. JAMA 2003; 289:2673
84.
58 Turtzo LC, McCullough LD. Sex differences in stroke. Cerebrovasc Dis
2008; 26:46274.
59 Rocca WA, Shuster LT, Brown RD. Could estrogen protect younger
menopausal women from stroke? Expert Rev Neurother 2012;
12:3635.
60 Harman SM, Brinton EA, Cedars M et al. KEEPS: the Kronos early
estrogen prevention study. Climacteric 2005; 8:312.
61 Hall S, Barr W, Lie JT, Stanson AW, Kazmier FJ, Hunder GG. Takayasu
arteritis. A study of 32 North American patients. Medicine (Baltimore)
1985; 64:8999.
62 Mateen FJ, Zubkov AY, Muralidharan R et al. Susac syndrome: clinical
characteristics and treatment in 29 new cases. Eur J Neurol 2012;
19:80011.
63 Mascarenhas R, Santo G, Goncalo M, Ferro MA, Tellechea O,
Figueiredo A. Familial Sneddons syndrome. Eur J Dermatol 2003;
13:2837.
64 Calabrese LH, Dodick DW, Schwedt TJ, Singhal AB. Narrative review:
reversible cerebral vasoconstriction syndromes. Ann Intern Med 2007;
146:3444.
65 Ducros A, Fiedler U, Porcher R, Boukobza M, Stapf C, Bousser MG.
Hemorrhagic manifestations of reversible cerebral vasoconstriction
syndrome: frequency, features, and risk factors. Stroke 2010; 41:2505
11.
66 Reeves MJ, Wilkins T, Lisabeth LD, Schwamm LH. Thrombolysis
treatment for acute stroke: issues of efficacy and utilization in women.
Womens Health (Lond Engl) 2011; 7:38390.
67 Di Carlo A, Lamassa M, Baldereschi M et al. Sex differences in the
clinical presentation, resource use, and 3-month outcome of acute
stroke in Europe: data from a multicenter multinational hospital-
based registry. Stroke 2003; 34:11149.
68 Smith MA, Lisabeth LD, Brown DL, Morgenstern LB. Gender com-
parisons of diagnostic evaluation for ischemic stroke patients. Neurol-
ogy 2005; 65:8558.
69 Kelly AG, Hellkamp AS, Olson D, Smith EE, Schwamm LH. Predictors
of rapid brain imaging in acute stroke: analysis of the get with the
guidelines-stroke program. Stroke 2012; 43:127984.
70 Savitz SI, Schlaug G, Caplan L, Selim M. Arterial occlusive lesions
recanalize more frequently in women than in men after intravenous
tissue plasminogen activator administration for acute stroke. Stroke
2005; 36:144751.
71 Arnold M, Fischer U, Compter A et al. Acute basilar artery occlusion
in the Basilar Artery International Cooperation Study: does gender
matter? Stroke 2010; 41:26936.
72 Shah SH, Liebeskind DS, Saver JL et al. Influence of gender on out-
comes after intra-arterial thrombolysis for acute ischemic stroke. Neu-
rology 2006; 66:17456.
73 Forster A, Gass A, Kern R et al. Gender differences in acute ischemic
stroke: etiology, stroke patterns and response to thrombolysis. Stroke
2009; 40:242832.
74 Hill MD, Kent DM, Hinchey J et al. Sex-based differences in the effect
of intra-arterial treatment of stroke: analysis of the PROACT-2 study.
Stroke 2006; 37:23225.
75 Ridker PM, Cook NR, Lee IM et al. A randomized trial of low-dose
aspirin in the primary prevention of cardiovascular disease in women.
N Engl J Med 2005; 352:1293304.
76 Berger JS, Roncaglioni MC, Avanzini F, Pangrazzi I, Tognoni G, Brown
DL. Aspirin for the primary prevention of cardiovascular events in
women and men: a sex-specific meta-analysis of randomized con-
trolled trials. JAMA 2006; 295:30613.
77 Baigent C, Blackwell L, Collins R et al. Aspirin in the primary and
secondary prevention of vascular disease: collaborative meta-analysis
2013 Women Stroke Association.
International Journal of Stroke 2013 World Stroke Organization
 F. R. Pezzella et al.
of individual participant data from randomised trials. Lancet 2009;
373:184960.
78 Rothwell PM, Eliasziw M, Gutnikov SA, Warlow CP, Barnett HJ. Sex
difference in the effect of time from symptoms to surgery on benefit
from carotid endarterectomy for transient ischemic attack and non-
disabling stroke. Stroke 2004; 35:285561.
79 Hellings WE, Pasterkamp G, Verhoeven BA et al. Gender-associated
differences in plaque phenotype of patients undergoing carotid endar-
terectomy. J Vasc Surg 2007; 45:28996; discussion 967.
80 Alamowitch S, Eliasziw M, Barnett HJ. The risk and benefit of endar-
terectomy in women with symptomatic internal carotid artery disease.
Stroke 2005; 36:2731.
81 Stingele R, Berger J, Alfke K et al. Clinical and angiographic risk
factors for stroke and death within 30 days after carotid endarterec-
tomy and stent-protected angioplasty: a subanalysis of the SPACE
study. Lancet Neurol 2008; 7:21622.
82 Bonati LH, Dobson J, Algra A et al. Short-term outcome after stenting
versus endarterectomy for symptomatic carotid stenosis: a preplanned
meta-analysis of individual patient data. Lancet 2010; 376:106273.
83 Howard VJ, Lutsep HL, Mackey A et al. Influence of sex on outcomes
of stenting versus endarterectomy: a subgroup analysis of the Carotid
Revascularization Endarterectomy versus Stenting Trial (CREST).
Lancet Neurol 2011; 10:5307.
2013 Women Stroke Association.
International Journal of Stroke 2013 World Stroke Organization
Stroke statement
84 Endarterectomy for asymptomatic carotid artery stenosis. Executive
Committee for the Asymptomatic Carotid Atherosclerosis Study.
JAMA 1995; 273:14218.
85 Halliday A, Mansfield A, Marro J et al. Prevention of disabling and
fatal strokes by successful carotid endarterectomy in patients without
recent neurological symptoms: randomised controlled trial. Lancet
2004; 363:1491502.
86 Halliday A, Harrison M, Hayter E et al. 10-year stroke prevention after
successful carotid endarterectomy for asymptomatic stenosis (ACST-
1): a multicentre randomised trial. Lancet 2010; 376:107484.
87 Gall SL, Donnan G, Dewey HM et al. Sex differences in presentation,
severity, and management of stroke in a population-based study. Neu-
rology 2010; 74:97581.
88 Wiszniewska M, Niewada M, Czlonkowska A. Sex differences in risk
factor distribution, severity, and outcome of ischemic stroke. Acta Clin
Croat 2011; 50:218.
89 Gargano JW, Wehner S, Reeves M. Sex differences in acute stroke care
in a statewide stroke registry. Stroke 2008; 39:249.
90 Gray LJ, Sprigg N, Bath PM et al. Sex differences in quality of life in
stroke survivors: data from the Tinzaparin in Acute Ischaemic Stroke
Trial (TAIST). Stroke 2007; 38:29604.
91 Cheung RT. Sexual functioning in Chinese stroke patients with mild
or no disability. Cerebrovasc Dis 2002; 14:1228.
Vol 9, October 2014, 2027 27