Review
Expert Review of Cardiovascular Therapy Downloaded from informahealthcare.com by Oregon Health Sciences University on 03/27/15 For personal use only.
Prevention and management of stroke in women Expert Rev. Cardiovasc. Ther. 13(4), 403–415 (2015)
Matthew D Howe1 and Louise D McCullough*1,2 1 Department of Neuroscience, The University of Connecticut Health Center, Farmington, CT 06030, USA 2 Hartford Hospital Stroke Center, Hartford, CT, USA *Author for correspondence: Tel.: +1 860 679 2271 Fax: +1 860 679 1181 [email protected]
Stroke is the leading cause of acquired disability and the third leading cause of death in women worldwide. Sex differences in risk factors, treatment response and quality of life after stroke complicate stroke management in women. Women have an increased lifetime incidence of stroke compared to men, largely due to a sharp increase in stroke risk in older postmenopausal women. Women also have an increased lifetime prevalence of stroke risk factors, including hypertension and atrial fibrillation in postmenopausal women, as well as abdominal obesity and metabolic syndrome in middle-aged women. Controversy continues over the risks of oral contraceptives, hormone therapy and surgical intervention for carotid stenosis in women. Pregnancy and the postpartum period represent a time of increased risk, presenting challenges to stroke management. Recognition of these issues is critical to improving acute care and functional recovery after stroke in women. KEYWORDS: atrial fibrillation . carotid stenosis . hormones . hypertension . obesity . pregnancy . sex . stroke . women
Stroke is a leading cause of death and disability worldwide, with stroke being the third leading cause of death in women and the fifth leading cause of death in men [1]. It is a sexually dimorphic disease, with women over the age of 75 sharing a disproportionate amount of the burden compared to men of the same age [2]. Part of this is secondary to increased lifespan; more women live to old age than men and therefore they experience more strokes [3]. Social factors likely play a role as more women live alone in old age, which could result in poor preventative care or increased social stress [4,5]. In addition, female physiology is unique in a variety of ways that are relevant to stroke; differences in coagulation [6], immunity [7] and hormone exposure [8] all contribute sex-specific effects on stroke incidence and outcome. While there is a desperate need for sexspecific studies and/or sex specific analysis of outcomes in ongoing trials, it is also clear that stroke is a different disease in men and women. Men and women differ in their likelihood of having a stroke, the relative importance of various risk factors and in the efficacy of different treatments during and after stroke. These differences present both obstacles and opportunities for women’s health. After a brief discussion of sex-specific epidemiologic data on stroke, this review will address the unique informahealthcare.com
10.1586/14779072.2015.1020300
challenges physicians face in preventing and managing stroke in women, first highlighting the importance of targeted risk reduction in women, then addressing the causes and signs of stroke in pregnant women and finally reviewing sex-specific data related to interventional approaches to treat ischemic stroke (IS) in the acute phase as well as during the recovery phase. Epidemiology
Stroke is the third leading cause of death in women, with an incidence of approximately 425,000 cases in women annually [1,2]. Stroke may be broadly classified as ischemic or hemorrhagic. IS accounts for 87% of cases annually, while the remaining cases are hemorrhagic (10% intracerebral [ICH], 3% subarachnoid) [1]. Women have a higher lifetime risk of stroke compared to men [9] and also experience higher rates of mortality at age 65 [10]. Women also experience markedly increased risk of stroke in the peripartum and postpartum periods as discussed later [11]. Furthermore, there is evidence to suggest that women may experience higher rates of subarachnoid hemorrhage, the most lethal form of stroke, than men [12]. Nearly half of stroke survivors experience residual neurological deficits, including motor weakness and cognitive dysfunction for at least
2015 Informa UK Ltd
ISSN 1477-9072
403
Review
Howe & McCullough
Table 1. Risk factors for stroke.
Expert Review of Cardiovascular Therapy Downloaded from informahealthcare.com by Oregon Health Sciences University on 03/27/15 For personal use only.
Risk factor
Female-specific risk factors
Female-biased risk factors
Atrial fibrillation
X
Hypertension
X
Diabetes
X
Migraine headache
X
Depression
X
Abdominal obesity
X
Pregnancy
X
Oral contraceptives
X
Age Cardiovascular disease Smoking Metabolic syndrome Adapted from Bushnell and McCullough [16].
6 months after the insult [4]. Stroke survivors also experience impaired cognitive function and higher rates of subsequent dementia independent of related vascular risk factors [13]. Female stroke survivors are more likely to be disabled and single after stroke and are institutionalized at 3.5-times the rate of male stroke survivors [14]. With more than 3.8 million female and 3 million male stroke survivors living in the US today [1], caring for these disabled individuals places a significant burden on the American health care system beyond the period of initial management. Worse still, these numbers are only expected to increase in both men and women as our society continues to age [15]. Stroke risk reduction in women
Women have a different risk factor profile for stroke compared to men, with a higher prevalence of hypertension, depression, obesity, metabolic syndrome and atrial fibrillation (AF), all of which are important risk factors for stroke (TABLE 1) [16]. Blood pressure and weight control remain difficult to attain in women, especially in those over the age of 65, who are also most vulnerable to stroke [1]. Furthermore, AF is an especially common cause of stroke in women over the age of 80 [17], and who to treat with anticoagulants remains a controversial question. Carotid stenosis is equally common in men and women, but recent work suggests that medical management may be superior to surgical management of asymptomatic carotid stenosis in women [18]. This section will discuss the management of hypertension, obesity, AF and carotid stenosis from the perspective of sex-specific stroke risk reduction. Hypertension
Hypertension (systolic BP ‡140 mm Hg or diastolic BP ‡90 mm Hg) is the most common and significant risk factor 404
for stroke in both men and women [2]. Female stroke patients have higher rates Sex-independent of hypertension than male stroke risk factors patients [19]. Even prehypertension (systolic BP = 120–139 mm Hg or diastolic BP = 80–89 mm Hg) adds significant stroke risk in men and women; the Women’s Health Initiative (WHI) found that prehypertensive older women (mean age ± standard deviation (SD) = 62.8 ± 7 years) had a 93% increased risk of stroke over their normotensive counterparts [20]. As such, aggressive management of hypertension becomes even more critical to the prevention of acute and recurX rent stroke in women. While it is true that females have lower X blood pressure than men for most of X their lives, the prevalence of hypertension X dramatically increases following menopause, and surpasses that of men after age 55 [1]. For example, the prevalence of hypertension (defined as blood pressure >140/90 mm Hg or taking antihypertensive medications) from 2007 to 2010 in the US was 69.3% in women between the ages of 65 and 74 and increased to 83.1% in women over the age of 75, compared to just 64.1 and 65%, respectively, in men [2]. One potential explanation for this difference is that hormonal changes that occur with menopause compound age-associated changes seen in both sexes. Studies have reported hormone-dependent sex differences in sympathetic tone, vascular reactivity and water regulation [21,22]. Hormone-independent changes exist in the vasculature as well, which may become more important after menopause [23]. Another, more worrisome explanation for this sex difference is that women could be receiving suboptimal treatments to manage their blood pressure. Interestingly, women are prescribed diuretics for high blood pressure 65% more frequently than men and angiotensin receptor blockers (ARBs) 30% more frequently than men [24]. However, there is no scientific basis for choosing this regimen, as men and women experience similar stroke risk reduction when treated with b-blockers, angiotensin-converting enzyme (ACE) inhibitors, ARBs or diuretics [25]. Women also experience higher rates of side effects from diuretics, ACE inhibitors and calcium channel blockers (CCBs) [26], potentially affecting compliance. Yet more women than men are taking these antihypertensive drugs, with poor results from the perspective of blood pressure control – while 51.1% of men achieve blood pressure targets with their prescribed antihypertensive regimen, only 44.8% of treated women achieve similarly positive results [24]. In conclusion, while underlying sex differences exist in baseline BP and response to treatment, there is no evidence to suggest that any one antihypertensive therapy is more effective in women than in men [27]. More studies are needed to examine Expert Rev. Cardiovasc. Ther. 13(4), (2015)
Expert Review of Cardiovascular Therapy Downloaded from informahealthcare.com by Oregon Health Sciences University on 03/27/15 For personal use only.
Prevention & management of stroke in women
Review
the efficacy of specific drugs and combinations of drugs in normalizing hypertension in both pre- and post-menopausal women. Until more studies are available, physicians should aggressively monitor and treat hypertension in women with all available agents, adjusting therapies when necessary to meet blood pressure targets.
Table 2. CHA2DS2-VASc risk stratification system.
Obesity & metabolic syndrome
Obesity represents an important and growing risk factor for stroke in the US which disproportionately affects women. Obesity is an independent risk factor for stroke, even when factors such as age, smoking, alcohol intake, exercise, hypertension and diabetes mellitus are taken into account [28]. While the overall prevalence of obesity (BMI ‡30) appears to be similar in both sexes (35.2% in women vs 32% in men), that is not the case with abdominal obesity, where a striking 61.8% of women over the age of 20 meet the criteria (waist circumference ‡88 cm) compared to 43.7% of men (waist circumference ‡102 cm) [29]. Importantly, the degree of abdominal obesity is more strongly correlated with insulin resistance, diabetes mellitus, atherogenic dyslipidemia and stroke than BMI [30]. Metabolic syndrome is an increasingly common combination of abdominal obesity, insulin resistance, dyslipidemia and hypertension [31]. While women and men experience similar rates of metabolic syndrome, studies have shown that metabolic syndrome contributes to 30% of strokes in women, compared to just 4% in men [31,32]. Obesity and metabolic syndrome cause increased stroke risk due to increased atherosclerosis [33], chronic inflammation [34], hypercoagulability [35] and endothelial dysfunction [36]. It remains unclear if these differences in risk are related to specific hormonal, genetic or age-related features of females, or if it is an interaction between all three [37]. In light of the strong relationship between abdominal obesity, metabolic syndrome and elevated risk of stroke, lifestyle changes become even more important in the prevention of stroke in women [27]. Maintaining a healthy diet [38], physical activity [39] and a normal BMI [40] all have been shown to significantly reduce the risk of and improve outcomes following stroke in both men and women. However, this is problematic as studies have shown that women have more difficulty than men in maintaining weight loss, even while following medically supervised weight loss programs [41]. Furthermore, the PREDIMED trial (Prevencion con Dieta Mediterra´nea) found that the Mediterranean diet clearly reduced the risk of cardiovascular disease, stroke and death from cardiovascular causes in men, but despite a trend in benefit failed to reach significance in women (HR: 0.73, 95% CI: 0.5–1.07) [42]. Further studies, specifically designed and sufficiently powered to evaluate sex-specific outcomes, are needed to evaluate the efficacy of various regimens of diet and exercise in stroke prevention. Furthermore, sex-specific pathways of obesity and metabolic dysregulation could perhaps be targeted by more targeted therapies tailored to women. Regardless, current guidelines recommend that women be encouraged to maintain a healthy lifestyle consisting of regular physical activity, moderate alcohol consumption, not smoking informahealthcare.com
Condition
Points
C
Congestive heart failure
1
H
Hypertension
1
A2
Age ‡75 years
2
D
Diabetes mellitus
1
S2
Prior stroke, TIA or thromboembolism
2
V
Vascular disease
1
A
Age 65–74 years
1
Sc
Sex category (female)
1
and consuming a diet of primarily vegetables, fruits, nuts, grains, olive oil and low in saturated fats [27]. Atrial fibrillation
AF is the most prevalent arrhythmia worldwide, and patients with AF experience – four to five times the risk of IS compared to individuals without AF [43]. The risk of stroke attributable to AF rises with age, increasing from just 1.5% for AF patients aged 50–59 years to approximately 25% for patients older than 80 [44,45]. While men and women experience similar rates of AF overall, 60% of AF patients over the age of 75 are women, making AF a more common cause of stroke in women than men [44]. AF will likely cause even more strokes, particularly in women, as our society continues to age [15]. Oral anticoagulation is indicated in high-risk AF patients to reduce the risk of IS [27]. CHADS2 and CHA2DS2-VASc are risk stratification tools which have been developed to aid physicians in deciding which patients should receive oral anticoagulation to prevent IS [46]. CHA2DS2-VASc is a refinement of CHADS2 which takes female sex and peripheral vascular disease into account, both of which are independent risk factors for stroke in AF patients (TABLE 2) [47]. Using the CHA2DS2VASc score could lead to changes in the assessment of stroke risk. For example, one study found that 32% of women with a CHADS2 score of 0 had a CHA2DS2-VASc score ‡2, increasing their predicted risk from 1.9 to 2.2% annually [48]. Therefore, the CHA2DS2-VASc is a more sensitive predictor of thromboembolic risk in women, and more widespread adoption will likely lead to an increase in oral anticoagulation, especially in postmenopausal women [48]. The cutoff point where anticoagulation should be initiated also remains controversial. The European Society of Cardiology (ESC) recommends that patients with AF and a CHA2DS2VASc score ‡1 (annual stroke risk ‡1.3% [48]) receive aspirin or oral anticoagulation to prevent stroke [49]. Technically, under the ESC guidelines, any female AF patient should be anticoagulated, even in the absence of other risk factors. However, a study in Denmark found that female AF patients under the age of 65 without other risk factors did not have an increased risk of thromboembolic events, but risk rose in women over the age 405
Expert Review of Cardiovascular Therapy Downloaded from informahealthcare.com by Oregon Health Sciences University on 03/27/15 For personal use only.
Review
Howe & McCullough
of 65 and the benefit of oral anticoagulant therapy became clear [50]. Accordingly, the American Heart Association does not recommend anticoagulation for women under the age of 65 with AF alone [27]. Since AF is the etiology for more strokes in women than men, it follows that women, especially those over the age of 80, should have higher rates of anticoagulant use. However, women are slightly less likely to receive anticoagulants than men [51]. This is problematic because female AF patients could potentially benefit more than men from anticoagulant therapy [48,50]. Clinical trials of newer anticoagulants, including apixaban and dabigatran demonstrated equal efficacy, as measured by reduction in the occurrence of stroke or systemic embolism, in women and men, but were associated with a greater number of major bleeding events in women [52,53]. More sex-specific studies are needed to confirm that these drugs are as effective and safe in women as they are in men. Carotid stenosis
Carotid stenosis is a narrowing of the internal carotid artery caused by an atherosclerotic plaque. When symptomatic, carotid stenosis typically presents as a transient ischemic attack characterized by focal neurologic deficits in a carotid artery distribution, which may also include the eye. Painless, transient monocular blindness can occur based on hemodynamic underperfusion or embolic events to the ophthalmic artery (amaurosis fugax). When the carotid is completely occluded, there is no role for revascularization, so identifying symptomatic carotid stenosis prior to occlusion is important for both men and women. When asymptomatic, carotid stenosis may be identified by a carotid bruit (which is not particularly sensitive or specific) or by vascular imaging [54]. While the overall prevalence of carotid stenosis is similar in men and women, men experience higher rates of symptomatic events than women (RR: 3.19; 95% CI: 1.95–5.23; p = 0.0003) [55]. Symptomatic carotid stenosis may be managed surgically or medically, depending on the degree of stenosis and the patient’s life expectancy. Intervention is preferred for symptomatic stenosis which can be performed surgically with CEA or CAS. While the evidence is somewhat mixed [56], most studies indicate that women experience higher rates of periprocedural morbidity and mortality after both CEA [57–59] and CAS [18,60] compared to men. A recent study found that CAS carries a higher risk of periprocedural myocardial infarction, stroke or death than CEA for women (6.8% in women undergoing CAS vs 3.8% in women undergoing CEA; HR: 1.84; 95% CI: 1.01–3.37; p = 0.064) [18]. However, more studies are needed to confirm that CAS carries more risk than CEA in women. Current guidelines recommend intervention for women with symptomatic stenosis and cautiously recommend it in select cases of high-grade (>70%) asymptomatic stenosis [27]. Medical management of carotid stenosis is preferred in cases of asymptomatic stenosis, or in patients with symptomatic stenosis who cannot tolerate surgery. Medical management may consist of a combination of drugs and includes aggressive 406
treatment with statins, antihypertensive drugs as well as aspirin or other antiplatelet agents [54]. The Women’s Health Study found that 100 mg aspirin, taken every other day, reduced the risk of IS in women by 24% (RR: 0.76; 95% CI: 0.63–0.93; p = 0.009) with a nonsignificant increase in hemorrhagic stroke risk [61]. Similarly, other antiplatelet agents, such as ticlopidine, clopidigrel and trifusal, have all been shown equally effective in the secondary prevention of stroke in both men and women [62], and may be considered if there is a high risk of hemorrhage or gastrointestinal bleeding. Current recommendations include aspirin (75–325 mg/day) or clopidigrel prophylaxis for prevention of stroke in all women with a 10% or more predicted 10-year cardiovascular disease risk, women with diabetes mellitus and women over the age of 65 with low risk of gastrointestinal bleeding [27]. In conclusion, carotid stenosis can be effectively managed with surgical or medical interventions. The appropriate therapy depends on the degree of stenosis, the presence of symptoms, the patient’s age and their tolerance of medical or surgical therapy. The question of when to intervene, and the revascularization technique (carotid artery stenting vs open carotid endarectomy), remains a subject of debate. In addition, it remains unclear if revascularization of asymptomatic carotid stenosis is beneficial, especially in elderly women. While women do experience higher rates of adverse events with interventions compared to men, these procedures are warranted for symptomatic or progressive high-grade asymptomatic carotid stenosis in patients with >5-year life expectancy. Aspirin has been shown to be an effective method of primary stroke prevention in women and is recommended for women of all ages who are at risk of stroke in the absence of specific contraindications. Rethinking oral contraceptives & hormone therapy
Estrogen exposure and cardiovascular disease risk have a complex and apparent U-shaped relationship, as women who experience menarche either earlier or later than average have an increased risk of coronary artery disease, stroke and hypertension [63]. Observational cohort studies have shown that premenopausal women experience fewer and smaller strokes than postmenopausal women, and that early menopause is associated with increased lifetime risk of stroke [64]. As such, hormone therapy initiated after menopause has been investigated as a potential strategy to reduce the incidence and severity of stroke in postmenopausal women. Estrogen, in a variety of formulations, is neuroprotective in the vast majority of pre-clinical models of stroke [65]. In rodents, estrogen levels are inversely correlated with infarct volume [66] and positively correlated with functional recovery in models of IS [67]. However, it is becoming increasingly clear that both oral contraceptives and postmenopausal hormone therapy can increase stroke risk, especially in select groups of high-risk patients. Oral contraceptives
The use of hormonal contraceptives may increase stroke risk, although the overall risk is generally very low in patients under Expert Rev. Cardiovasc. Ther. 13(4), (2015)
Expert Review of Cardiovascular Therapy Downloaded from informahealthcare.com by Oregon Health Sciences University on 03/27/15 For personal use only.
Prevention & management of stroke in women
the age of 40. Approximately 61.8 million women in the US between the ages of 15 and 44 use oral contraceptives (OCs) on a regular basis [2] and they are generally considered to be quite safe, especially with the newer, lower-dose ethinyl estradiol formulations [68]. The relative risk of stroke associated with low-dose OCs is small (1.4–2.0) [68], but certain patient factors increase risk. Advancing age, and a history of tobacco use, hypertension, diabetes mellitus, obesity, hypercholesterolemia, complicated migraines and prothrombotic mutations, all increase stroke risk with OC use [69]. Current guidelines recommend more aggressive management of stroke risk factors for patients taking birth control, and measurement of blood pressure before and after initiating hormonal contraception [27]. Other non-oral formulations have also been evaluated, including the vaginal ring and transdermal patch, which seem to have similar (the ring) or lower (patch) risk for thrombotic events; however the number of events was low, and at this point it is unknown if these non-oral formulations are safer than standard, low-dose OCs [68]. One important and often underdiagnosed vascular complication of OC is cerebral venous thrombosis (CVT), a venous thrombosis in a draining vein such as the sagittal or transverse sinus. This can lead to increased intracranial pressure, venous congestion and ICH hemorrhage. Patients often presents with sub-acute onset of headache and visual changes and a high index of suspicion is needed; patients should be asked about hormone use, as well as recent pregnancy (please see Saposnik et al. [70] for current guidelines on the diagnosis and management of CVT). Hormone therapy
Controlled clinical trials of estrogen replacement in postmenopausal women failed to show a protective effect against stroke [71,72] in stark contrast to the protective effects seen in the majority of pre-clinical studies. This increase in risk may be in part due to pro-coagulant effects of estrogen on the cerebral vasculature, coagulation cascade and platelets [6], which are not accounted for in many commonly used animal models of stroke. Clearly, many differences exist in pre-clinical studies, in which a stroke is induced by a thrombus or filament occlusion often in a rodent [73], and clinical studies, where stroke is a spontaneous event and incidence is tracked. The WHI was the largest randomized, double-blind, placebocontrolled clinical trial of hormone therapy (HT), which tested the efficacy of estrogen with or without progesterone in preventing stroke, dementia and cognitive decline in 27,341 postmenopausal women [71]. Estrogen with or without progesterone was found to increase stroke risk by 50% and dementia by 76% [71]. However, one criticism of the study is that HT was not initiated at menopause; in fact, the study included women up to the age of 79 that had been without pre-menopausal levels of estrogen for decades [71]. While some meta-analyses suggest there may be a negative effect in the younger group as well [74,75], the power of these analyses are relatively low, and more studies are needed to determine whether there is a positive or negative effect on informahealthcare.com
Review
stroke incidence in women who begin HT during or immediately following menopause. The discrepancy between animal models and the findings of the WHI prompted further basic and clinical studies to determine if the timing of estrogen supplementation was responsible for the detrimental effects of HT. Studies in animal models confirmed that the timing of estrogen replacement plays an important role in determining its therapeutic effect. Early initiation of estrogen therapy after either surgical ovariectomy or at natural ‘menopause’ in aging mice reduced infarct size. Importantly, initiation of therapy after a prolonged period without estrogen (months) led to an increase in stroke size and inflammation, similar to that seen in clinical populations [76,77]. These results confirmed that estrogen can have differential effects in healthy versus diseased/aged endothelium and emphasize the importance of using appropriate animal models (aged/females etc). The detrimental effects of estrogen are mediated in part by immune cell activation, leukocyte adhesion to the vascular surface, inflammation and cytokine release (FIGURE 1). However, preliminary findings from two recent clinical trials, the Kronos Early Estrogen Prevention Study (KEEPS) [78] and the Early versus Late Intervention Trial with Estradiol [79], appear to be consistent with the idea that initiating HT in the peri-menopausal period may be safe. These trials were specifically designed to examine the effect of HT on younger recently postmenopausal women. KEEPS, a multicenter clinical trial of 727 women aged 42–58 years, examined whether HT for 4 years (transdermal (50 mcg/d) versus oral (0.45 mg/d) estrogen with progesterone vs placebo) initiated between 6 and 36 months from last menses in healthy menopausal women could reduce the progression of subclinical atherosclerosis as measured by carotid intimal medial thickness (CIMT) and coronary artery calcification [78,80,81]. The study found no differences in CIMT or coronary artery calcification progression in estrogen-treated women compared to women treated with placebo. Importantly, estrogen treatment did not increase blood pressure. Oral estrogen lowered HDL and LDL levels, but increased CRP. Transdermal therapy improved insulin resistance [78]. Continued follow-up of the KEEPS cohort will be needed as enrolled women were young and not yet at high risk for stroke and were only followed for 4 years. Interestingly, preliminary data from the Early versus Late Intervention Trial with Estradiol study, which included 643 women who were followed for six to seven years after treatment initiation, showed a reduction in CIMT in estrogen treated women when treatment was initiated within six years of menopause (average age of 55.4 years), but no effect when treatment was initiated 10 years after menopause (average age of 65.4 years) [79,82]. There continues to be considerable debate about the safety of postmenopausal HT, particularly in specific, higher-risk patient populations. The approach should be individualized to account for this risk [83]. In conclusion, while guidelines do not recommend HT for the prevention of stroke at this time [27], newly emerging lines of evidence may change this view. As noted in an excellent 407
Review
Howe & McCullough
in pregnant women occur after or around the time of delivery, the remaining 10% occurring during the antenatal period at Estrogen replacement a rate comparable to that of nonin Younger postmenopausal women pregnant women [86]. In contrast to the Vessel lumen general population, pregnant and recently pregnant women experience IS and ICH Beneficial effects hemorrhage at similar rates [11]. Changes ↑ Vasodilation ↓ Inflammation in cerebrovascular tone, coagulation fac↓ Lesion progression tors, hematocrit, cardiovascular hemodynamics, endothelial function and Years since inflammatory state all put pregnant menopause women at increased risk of both ischemic Estrogen replacement and hemorrhagic stroke [87,88]. in Older postmenopausal women Atherosclerotic plaque Not all pregnant women are at equal risk of stroke. Women who have preHarmful effects existing risk factors for stroke, such as ↓ ER expression and function history of hypertension, smoking, hyperVessel lumen ↓ Vasodilation lipidemia, arterial disease, heart disease, ↑ Inflammation thrombophilia, migraine, an age over ↑ Plaque instability 35 and black race are at a higher risk of Fibrous plaque stroke in general, especially during Endothelial cell Macrophage pregnancy [27,86]. Additionally, pregnancySmooth muscle cell Foam cell induced hypertension (such as preeclampsia), cesarean delivery [89], sickle cell disease and postpartum infection [86] Figure 1. Differential effects of estrogen replacement with age. In recently postmenopausal women with healthy vasculature, estrogen replacement inhibits all represent independent risk factors for inflammation, delays the progression of atherosclerotic lesions and promotes stroke in pregnant women. Identification vasodilation. Conversely, in later postmenopausal women with more advanced of at-risk patients and the institution of atherosclerosis, estrogen replacement can act on the existing lesions to increase appropriate preventative therapies and inflammation, plaque instability and decrease vasodilation, while also downregulating lifestyle changes are critical to the prevenendogenous estrogen signaling pathways. ER: Estrogen receptor. tion of stroke and best done before a patient becomes pregnant [27]. While the prevalence of hypertension review by Manson [84], HT is most appropriate in recently is much lower in women of childbearing age, when it does menopausal women with no history of cerebrovascular or arise, management is critical, as pre-pregnancy hypertension cardiovascular disease and a Framingham Stroke Score of increases the risk of both preeclampsia/eclampsia and stroke
Expert Review of Cardiovascular Therapy Downloaded from informahealthcare.com by Oregon Health Sciences University on 03/27/15 For personal use only.
Prevention and management of stroke in women Expert Rev. Cardiovasc. Ther. 13(4), 403–415 (2015)
Matthew D Howe1 and Louise D McCullough*1,2 1 Department of Neuroscience, The University of Connecticut Health Center, Farmington, CT 06030, USA 2 Hartford Hospital Stroke Center, Hartford, CT, USA *Author for correspondence: Tel.: +1 860 679 2271 Fax: +1 860 679 1181 [email protected]
Stroke is the leading cause of acquired disability and the third leading cause of death in women worldwide. Sex differences in risk factors, treatment response and quality of life after stroke complicate stroke management in women. Women have an increased lifetime incidence of stroke compared to men, largely due to a sharp increase in stroke risk in older postmenopausal women. Women also have an increased lifetime prevalence of stroke risk factors, including hypertension and atrial fibrillation in postmenopausal women, as well as abdominal obesity and metabolic syndrome in middle-aged women. Controversy continues over the risks of oral contraceptives, hormone therapy and surgical intervention for carotid stenosis in women. Pregnancy and the postpartum period represent a time of increased risk, presenting challenges to stroke management. Recognition of these issues is critical to improving acute care and functional recovery after stroke in women. KEYWORDS: atrial fibrillation . carotid stenosis . hormones . hypertension . obesity . pregnancy . sex . stroke . women
Stroke is a leading cause of death and disability worldwide, with stroke being the third leading cause of death in women and the fifth leading cause of death in men [1]. It is a sexually dimorphic disease, with women over the age of 75 sharing a disproportionate amount of the burden compared to men of the same age [2]. Part of this is secondary to increased lifespan; more women live to old age than men and therefore they experience more strokes [3]. Social factors likely play a role as more women live alone in old age, which could result in poor preventative care or increased social stress [4,5]. In addition, female physiology is unique in a variety of ways that are relevant to stroke; differences in coagulation [6], immunity [7] and hormone exposure [8] all contribute sex-specific effects on stroke incidence and outcome. While there is a desperate need for sexspecific studies and/or sex specific analysis of outcomes in ongoing trials, it is also clear that stroke is a different disease in men and women. Men and women differ in their likelihood of having a stroke, the relative importance of various risk factors and in the efficacy of different treatments during and after stroke. These differences present both obstacles and opportunities for women’s health. After a brief discussion of sex-specific epidemiologic data on stroke, this review will address the unique informahealthcare.com
10.1586/14779072.2015.1020300
challenges physicians face in preventing and managing stroke in women, first highlighting the importance of targeted risk reduction in women, then addressing the causes and signs of stroke in pregnant women and finally reviewing sex-specific data related to interventional approaches to treat ischemic stroke (IS) in the acute phase as well as during the recovery phase. Epidemiology
Stroke is the third leading cause of death in women, with an incidence of approximately 425,000 cases in women annually [1,2]. Stroke may be broadly classified as ischemic or hemorrhagic. IS accounts for 87% of cases annually, while the remaining cases are hemorrhagic (10% intracerebral [ICH], 3% subarachnoid) [1]. Women have a higher lifetime risk of stroke compared to men [9] and also experience higher rates of mortality at age 65 [10]. Women also experience markedly increased risk of stroke in the peripartum and postpartum periods as discussed later [11]. Furthermore, there is evidence to suggest that women may experience higher rates of subarachnoid hemorrhage, the most lethal form of stroke, than men [12]. Nearly half of stroke survivors experience residual neurological deficits, including motor weakness and cognitive dysfunction for at least
2015 Informa UK Ltd
ISSN 1477-9072
403
Review
Howe & McCullough
Table 1. Risk factors for stroke.
Expert Review of Cardiovascular Therapy Downloaded from informahealthcare.com by Oregon Health Sciences University on 03/27/15 For personal use only.
Risk factor
Female-specific risk factors
Female-biased risk factors
Atrial fibrillation
X
Hypertension
X
Diabetes
X
Migraine headache
X
Depression
X
Abdominal obesity
X
Pregnancy
X
Oral contraceptives
X
Age Cardiovascular disease Smoking Metabolic syndrome Adapted from Bushnell and McCullough [16].
6 months after the insult [4]. Stroke survivors also experience impaired cognitive function and higher rates of subsequent dementia independent of related vascular risk factors [13]. Female stroke survivors are more likely to be disabled and single after stroke and are institutionalized at 3.5-times the rate of male stroke survivors [14]. With more than 3.8 million female and 3 million male stroke survivors living in the US today [1], caring for these disabled individuals places a significant burden on the American health care system beyond the period of initial management. Worse still, these numbers are only expected to increase in both men and women as our society continues to age [15]. Stroke risk reduction in women
Women have a different risk factor profile for stroke compared to men, with a higher prevalence of hypertension, depression, obesity, metabolic syndrome and atrial fibrillation (AF), all of which are important risk factors for stroke (TABLE 1) [16]. Blood pressure and weight control remain difficult to attain in women, especially in those over the age of 65, who are also most vulnerable to stroke [1]. Furthermore, AF is an especially common cause of stroke in women over the age of 80 [17], and who to treat with anticoagulants remains a controversial question. Carotid stenosis is equally common in men and women, but recent work suggests that medical management may be superior to surgical management of asymptomatic carotid stenosis in women [18]. This section will discuss the management of hypertension, obesity, AF and carotid stenosis from the perspective of sex-specific stroke risk reduction. Hypertension
Hypertension (systolic BP ‡140 mm Hg or diastolic BP ‡90 mm Hg) is the most common and significant risk factor 404
for stroke in both men and women [2]. Female stroke patients have higher rates Sex-independent of hypertension than male stroke risk factors patients [19]. Even prehypertension (systolic BP = 120–139 mm Hg or diastolic BP = 80–89 mm Hg) adds significant stroke risk in men and women; the Women’s Health Initiative (WHI) found that prehypertensive older women (mean age ± standard deviation (SD) = 62.8 ± 7 years) had a 93% increased risk of stroke over their normotensive counterparts [20]. As such, aggressive management of hypertension becomes even more critical to the prevention of acute and recurX rent stroke in women. While it is true that females have lower X blood pressure than men for most of X their lives, the prevalence of hypertension X dramatically increases following menopause, and surpasses that of men after age 55 [1]. For example, the prevalence of hypertension (defined as blood pressure >140/90 mm Hg or taking antihypertensive medications) from 2007 to 2010 in the US was 69.3% in women between the ages of 65 and 74 and increased to 83.1% in women over the age of 75, compared to just 64.1 and 65%, respectively, in men [2]. One potential explanation for this difference is that hormonal changes that occur with menopause compound age-associated changes seen in both sexes. Studies have reported hormone-dependent sex differences in sympathetic tone, vascular reactivity and water regulation [21,22]. Hormone-independent changes exist in the vasculature as well, which may become more important after menopause [23]. Another, more worrisome explanation for this sex difference is that women could be receiving suboptimal treatments to manage their blood pressure. Interestingly, women are prescribed diuretics for high blood pressure 65% more frequently than men and angiotensin receptor blockers (ARBs) 30% more frequently than men [24]. However, there is no scientific basis for choosing this regimen, as men and women experience similar stroke risk reduction when treated with b-blockers, angiotensin-converting enzyme (ACE) inhibitors, ARBs or diuretics [25]. Women also experience higher rates of side effects from diuretics, ACE inhibitors and calcium channel blockers (CCBs) [26], potentially affecting compliance. Yet more women than men are taking these antihypertensive drugs, with poor results from the perspective of blood pressure control – while 51.1% of men achieve blood pressure targets with their prescribed antihypertensive regimen, only 44.8% of treated women achieve similarly positive results [24]. In conclusion, while underlying sex differences exist in baseline BP and response to treatment, there is no evidence to suggest that any one antihypertensive therapy is more effective in women than in men [27]. More studies are needed to examine Expert Rev. Cardiovasc. Ther. 13(4), (2015)
Expert Review of Cardiovascular Therapy Downloaded from informahealthcare.com by Oregon Health Sciences University on 03/27/15 For personal use only.
Prevention & management of stroke in women
Review
the efficacy of specific drugs and combinations of drugs in normalizing hypertension in both pre- and post-menopausal women. Until more studies are available, physicians should aggressively monitor and treat hypertension in women with all available agents, adjusting therapies when necessary to meet blood pressure targets.
Table 2. CHA2DS2-VASc risk stratification system.
Obesity & metabolic syndrome
Obesity represents an important and growing risk factor for stroke in the US which disproportionately affects women. Obesity is an independent risk factor for stroke, even when factors such as age, smoking, alcohol intake, exercise, hypertension and diabetes mellitus are taken into account [28]. While the overall prevalence of obesity (BMI ‡30) appears to be similar in both sexes (35.2% in women vs 32% in men), that is not the case with abdominal obesity, where a striking 61.8% of women over the age of 20 meet the criteria (waist circumference ‡88 cm) compared to 43.7% of men (waist circumference ‡102 cm) [29]. Importantly, the degree of abdominal obesity is more strongly correlated with insulin resistance, diabetes mellitus, atherogenic dyslipidemia and stroke than BMI [30]. Metabolic syndrome is an increasingly common combination of abdominal obesity, insulin resistance, dyslipidemia and hypertension [31]. While women and men experience similar rates of metabolic syndrome, studies have shown that metabolic syndrome contributes to 30% of strokes in women, compared to just 4% in men [31,32]. Obesity and metabolic syndrome cause increased stroke risk due to increased atherosclerosis [33], chronic inflammation [34], hypercoagulability [35] and endothelial dysfunction [36]. It remains unclear if these differences in risk are related to specific hormonal, genetic or age-related features of females, or if it is an interaction between all three [37]. In light of the strong relationship between abdominal obesity, metabolic syndrome and elevated risk of stroke, lifestyle changes become even more important in the prevention of stroke in women [27]. Maintaining a healthy diet [38], physical activity [39] and a normal BMI [40] all have been shown to significantly reduce the risk of and improve outcomes following stroke in both men and women. However, this is problematic as studies have shown that women have more difficulty than men in maintaining weight loss, even while following medically supervised weight loss programs [41]. Furthermore, the PREDIMED trial (Prevencion con Dieta Mediterra´nea) found that the Mediterranean diet clearly reduced the risk of cardiovascular disease, stroke and death from cardiovascular causes in men, but despite a trend in benefit failed to reach significance in women (HR: 0.73, 95% CI: 0.5–1.07) [42]. Further studies, specifically designed and sufficiently powered to evaluate sex-specific outcomes, are needed to evaluate the efficacy of various regimens of diet and exercise in stroke prevention. Furthermore, sex-specific pathways of obesity and metabolic dysregulation could perhaps be targeted by more targeted therapies tailored to women. Regardless, current guidelines recommend that women be encouraged to maintain a healthy lifestyle consisting of regular physical activity, moderate alcohol consumption, not smoking informahealthcare.com
Condition
Points
C
Congestive heart failure
1
H
Hypertension
1
A2
Age ‡75 years
2
D
Diabetes mellitus
1
S2
Prior stroke, TIA or thromboembolism
2
V
Vascular disease
1
A
Age 65–74 years
1
Sc
Sex category (female)
1
and consuming a diet of primarily vegetables, fruits, nuts, grains, olive oil and low in saturated fats [27]. Atrial fibrillation
AF is the most prevalent arrhythmia worldwide, and patients with AF experience – four to five times the risk of IS compared to individuals without AF [43]. The risk of stroke attributable to AF rises with age, increasing from just 1.5% for AF patients aged 50–59 years to approximately 25% for patients older than 80 [44,45]. While men and women experience similar rates of AF overall, 60% of AF patients over the age of 75 are women, making AF a more common cause of stroke in women than men [44]. AF will likely cause even more strokes, particularly in women, as our society continues to age [15]. Oral anticoagulation is indicated in high-risk AF patients to reduce the risk of IS [27]. CHADS2 and CHA2DS2-VASc are risk stratification tools which have been developed to aid physicians in deciding which patients should receive oral anticoagulation to prevent IS [46]. CHA2DS2-VASc is a refinement of CHADS2 which takes female sex and peripheral vascular disease into account, both of which are independent risk factors for stroke in AF patients (TABLE 2) [47]. Using the CHA2DS2VASc score could lead to changes in the assessment of stroke risk. For example, one study found that 32% of women with a CHADS2 score of 0 had a CHA2DS2-VASc score ‡2, increasing their predicted risk from 1.9 to 2.2% annually [48]. Therefore, the CHA2DS2-VASc is a more sensitive predictor of thromboembolic risk in women, and more widespread adoption will likely lead to an increase in oral anticoagulation, especially in postmenopausal women [48]. The cutoff point where anticoagulation should be initiated also remains controversial. The European Society of Cardiology (ESC) recommends that patients with AF and a CHA2DS2VASc score ‡1 (annual stroke risk ‡1.3% [48]) receive aspirin or oral anticoagulation to prevent stroke [49]. Technically, under the ESC guidelines, any female AF patient should be anticoagulated, even in the absence of other risk factors. However, a study in Denmark found that female AF patients under the age of 65 without other risk factors did not have an increased risk of thromboembolic events, but risk rose in women over the age 405
Expert Review of Cardiovascular Therapy Downloaded from informahealthcare.com by Oregon Health Sciences University on 03/27/15 For personal use only.
Review
Howe & McCullough
of 65 and the benefit of oral anticoagulant therapy became clear [50]. Accordingly, the American Heart Association does not recommend anticoagulation for women under the age of 65 with AF alone [27]. Since AF is the etiology for more strokes in women than men, it follows that women, especially those over the age of 80, should have higher rates of anticoagulant use. However, women are slightly less likely to receive anticoagulants than men [51]. This is problematic because female AF patients could potentially benefit more than men from anticoagulant therapy [48,50]. Clinical trials of newer anticoagulants, including apixaban and dabigatran demonstrated equal efficacy, as measured by reduction in the occurrence of stroke or systemic embolism, in women and men, but were associated with a greater number of major bleeding events in women [52,53]. More sex-specific studies are needed to confirm that these drugs are as effective and safe in women as they are in men. Carotid stenosis
Carotid stenosis is a narrowing of the internal carotid artery caused by an atherosclerotic plaque. When symptomatic, carotid stenosis typically presents as a transient ischemic attack characterized by focal neurologic deficits in a carotid artery distribution, which may also include the eye. Painless, transient monocular blindness can occur based on hemodynamic underperfusion or embolic events to the ophthalmic artery (amaurosis fugax). When the carotid is completely occluded, there is no role for revascularization, so identifying symptomatic carotid stenosis prior to occlusion is important for both men and women. When asymptomatic, carotid stenosis may be identified by a carotid bruit (which is not particularly sensitive or specific) or by vascular imaging [54]. While the overall prevalence of carotid stenosis is similar in men and women, men experience higher rates of symptomatic events than women (RR: 3.19; 95% CI: 1.95–5.23; p = 0.0003) [55]. Symptomatic carotid stenosis may be managed surgically or medically, depending on the degree of stenosis and the patient’s life expectancy. Intervention is preferred for symptomatic stenosis which can be performed surgically with CEA or CAS. While the evidence is somewhat mixed [56], most studies indicate that women experience higher rates of periprocedural morbidity and mortality after both CEA [57–59] and CAS [18,60] compared to men. A recent study found that CAS carries a higher risk of periprocedural myocardial infarction, stroke or death than CEA for women (6.8% in women undergoing CAS vs 3.8% in women undergoing CEA; HR: 1.84; 95% CI: 1.01–3.37; p = 0.064) [18]. However, more studies are needed to confirm that CAS carries more risk than CEA in women. Current guidelines recommend intervention for women with symptomatic stenosis and cautiously recommend it in select cases of high-grade (>70%) asymptomatic stenosis [27]. Medical management of carotid stenosis is preferred in cases of asymptomatic stenosis, or in patients with symptomatic stenosis who cannot tolerate surgery. Medical management may consist of a combination of drugs and includes aggressive 406
treatment with statins, antihypertensive drugs as well as aspirin or other antiplatelet agents [54]. The Women’s Health Study found that 100 mg aspirin, taken every other day, reduced the risk of IS in women by 24% (RR: 0.76; 95% CI: 0.63–0.93; p = 0.009) with a nonsignificant increase in hemorrhagic stroke risk [61]. Similarly, other antiplatelet agents, such as ticlopidine, clopidigrel and trifusal, have all been shown equally effective in the secondary prevention of stroke in both men and women [62], and may be considered if there is a high risk of hemorrhage or gastrointestinal bleeding. Current recommendations include aspirin (75–325 mg/day) or clopidigrel prophylaxis for prevention of stroke in all women with a 10% or more predicted 10-year cardiovascular disease risk, women with diabetes mellitus and women over the age of 65 with low risk of gastrointestinal bleeding [27]. In conclusion, carotid stenosis can be effectively managed with surgical or medical interventions. The appropriate therapy depends on the degree of stenosis, the presence of symptoms, the patient’s age and their tolerance of medical or surgical therapy. The question of when to intervene, and the revascularization technique (carotid artery stenting vs open carotid endarectomy), remains a subject of debate. In addition, it remains unclear if revascularization of asymptomatic carotid stenosis is beneficial, especially in elderly women. While women do experience higher rates of adverse events with interventions compared to men, these procedures are warranted for symptomatic or progressive high-grade asymptomatic carotid stenosis in patients with >5-year life expectancy. Aspirin has been shown to be an effective method of primary stroke prevention in women and is recommended for women of all ages who are at risk of stroke in the absence of specific contraindications. Rethinking oral contraceptives & hormone therapy
Estrogen exposure and cardiovascular disease risk have a complex and apparent U-shaped relationship, as women who experience menarche either earlier or later than average have an increased risk of coronary artery disease, stroke and hypertension [63]. Observational cohort studies have shown that premenopausal women experience fewer and smaller strokes than postmenopausal women, and that early menopause is associated with increased lifetime risk of stroke [64]. As such, hormone therapy initiated after menopause has been investigated as a potential strategy to reduce the incidence and severity of stroke in postmenopausal women. Estrogen, in a variety of formulations, is neuroprotective in the vast majority of pre-clinical models of stroke [65]. In rodents, estrogen levels are inversely correlated with infarct volume [66] and positively correlated with functional recovery in models of IS [67]. However, it is becoming increasingly clear that both oral contraceptives and postmenopausal hormone therapy can increase stroke risk, especially in select groups of high-risk patients. Oral contraceptives
The use of hormonal contraceptives may increase stroke risk, although the overall risk is generally very low in patients under Expert Rev. Cardiovasc. Ther. 13(4), (2015)
Expert Review of Cardiovascular Therapy Downloaded from informahealthcare.com by Oregon Health Sciences University on 03/27/15 For personal use only.
Prevention & management of stroke in women
the age of 40. Approximately 61.8 million women in the US between the ages of 15 and 44 use oral contraceptives (OCs) on a regular basis [2] and they are generally considered to be quite safe, especially with the newer, lower-dose ethinyl estradiol formulations [68]. The relative risk of stroke associated with low-dose OCs is small (1.4–2.0) [68], but certain patient factors increase risk. Advancing age, and a history of tobacco use, hypertension, diabetes mellitus, obesity, hypercholesterolemia, complicated migraines and prothrombotic mutations, all increase stroke risk with OC use [69]. Current guidelines recommend more aggressive management of stroke risk factors for patients taking birth control, and measurement of blood pressure before and after initiating hormonal contraception [27]. Other non-oral formulations have also been evaluated, including the vaginal ring and transdermal patch, which seem to have similar (the ring) or lower (patch) risk for thrombotic events; however the number of events was low, and at this point it is unknown if these non-oral formulations are safer than standard, low-dose OCs [68]. One important and often underdiagnosed vascular complication of OC is cerebral venous thrombosis (CVT), a venous thrombosis in a draining vein such as the sagittal or transverse sinus. This can lead to increased intracranial pressure, venous congestion and ICH hemorrhage. Patients often presents with sub-acute onset of headache and visual changes and a high index of suspicion is needed; patients should be asked about hormone use, as well as recent pregnancy (please see Saposnik et al. [70] for current guidelines on the diagnosis and management of CVT). Hormone therapy
Controlled clinical trials of estrogen replacement in postmenopausal women failed to show a protective effect against stroke [71,72] in stark contrast to the protective effects seen in the majority of pre-clinical studies. This increase in risk may be in part due to pro-coagulant effects of estrogen on the cerebral vasculature, coagulation cascade and platelets [6], which are not accounted for in many commonly used animal models of stroke. Clearly, many differences exist in pre-clinical studies, in which a stroke is induced by a thrombus or filament occlusion often in a rodent [73], and clinical studies, where stroke is a spontaneous event and incidence is tracked. The WHI was the largest randomized, double-blind, placebocontrolled clinical trial of hormone therapy (HT), which tested the efficacy of estrogen with or without progesterone in preventing stroke, dementia and cognitive decline in 27,341 postmenopausal women [71]. Estrogen with or without progesterone was found to increase stroke risk by 50% and dementia by 76% [71]. However, one criticism of the study is that HT was not initiated at menopause; in fact, the study included women up to the age of 79 that had been without pre-menopausal levels of estrogen for decades [71]. While some meta-analyses suggest there may be a negative effect in the younger group as well [74,75], the power of these analyses are relatively low, and more studies are needed to determine whether there is a positive or negative effect on informahealthcare.com
Review
stroke incidence in women who begin HT during or immediately following menopause. The discrepancy between animal models and the findings of the WHI prompted further basic and clinical studies to determine if the timing of estrogen supplementation was responsible for the detrimental effects of HT. Studies in animal models confirmed that the timing of estrogen replacement plays an important role in determining its therapeutic effect. Early initiation of estrogen therapy after either surgical ovariectomy or at natural ‘menopause’ in aging mice reduced infarct size. Importantly, initiation of therapy after a prolonged period without estrogen (months) led to an increase in stroke size and inflammation, similar to that seen in clinical populations [76,77]. These results confirmed that estrogen can have differential effects in healthy versus diseased/aged endothelium and emphasize the importance of using appropriate animal models (aged/females etc). The detrimental effects of estrogen are mediated in part by immune cell activation, leukocyte adhesion to the vascular surface, inflammation and cytokine release (FIGURE 1). However, preliminary findings from two recent clinical trials, the Kronos Early Estrogen Prevention Study (KEEPS) [78] and the Early versus Late Intervention Trial with Estradiol [79], appear to be consistent with the idea that initiating HT in the peri-menopausal period may be safe. These trials were specifically designed to examine the effect of HT on younger recently postmenopausal women. KEEPS, a multicenter clinical trial of 727 women aged 42–58 years, examined whether HT for 4 years (transdermal (50 mcg/d) versus oral (0.45 mg/d) estrogen with progesterone vs placebo) initiated between 6 and 36 months from last menses in healthy menopausal women could reduce the progression of subclinical atherosclerosis as measured by carotid intimal medial thickness (CIMT) and coronary artery calcification [78,80,81]. The study found no differences in CIMT or coronary artery calcification progression in estrogen-treated women compared to women treated with placebo. Importantly, estrogen treatment did not increase blood pressure. Oral estrogen lowered HDL and LDL levels, but increased CRP. Transdermal therapy improved insulin resistance [78]. Continued follow-up of the KEEPS cohort will be needed as enrolled women were young and not yet at high risk for stroke and were only followed for 4 years. Interestingly, preliminary data from the Early versus Late Intervention Trial with Estradiol study, which included 643 women who were followed for six to seven years after treatment initiation, showed a reduction in CIMT in estrogen treated women when treatment was initiated within six years of menopause (average age of 55.4 years), but no effect when treatment was initiated 10 years after menopause (average age of 65.4 years) [79,82]. There continues to be considerable debate about the safety of postmenopausal HT, particularly in specific, higher-risk patient populations. The approach should be individualized to account for this risk [83]. In conclusion, while guidelines do not recommend HT for the prevention of stroke at this time [27], newly emerging lines of evidence may change this view. As noted in an excellent 407
Review
Howe & McCullough
in pregnant women occur after or around the time of delivery, the remaining 10% occurring during the antenatal period at Estrogen replacement a rate comparable to that of nonin Younger postmenopausal women pregnant women [86]. In contrast to the Vessel lumen general population, pregnant and recently pregnant women experience IS and ICH Beneficial effects hemorrhage at similar rates [11]. Changes ↑ Vasodilation ↓ Inflammation in cerebrovascular tone, coagulation fac↓ Lesion progression tors, hematocrit, cardiovascular hemodynamics, endothelial function and Years since inflammatory state all put pregnant menopause women at increased risk of both ischemic Estrogen replacement and hemorrhagic stroke [87,88]. in Older postmenopausal women Atherosclerotic plaque Not all pregnant women are at equal risk of stroke. Women who have preHarmful effects existing risk factors for stroke, such as ↓ ER expression and function history of hypertension, smoking, hyperVessel lumen ↓ Vasodilation lipidemia, arterial disease, heart disease, ↑ Inflammation thrombophilia, migraine, an age over ↑ Plaque instability 35 and black race are at a higher risk of Fibrous plaque stroke in general, especially during Endothelial cell Macrophage pregnancy [27,86]. Additionally, pregnancySmooth muscle cell Foam cell induced hypertension (such as preeclampsia), cesarean delivery [89], sickle cell disease and postpartum infection [86] Figure 1. Differential effects of estrogen replacement with age. In recently postmenopausal women with healthy vasculature, estrogen replacement inhibits all represent independent risk factors for inflammation, delays the progression of atherosclerotic lesions and promotes stroke in pregnant women. Identification vasodilation. Conversely, in later postmenopausal women with more advanced of at-risk patients and the institution of atherosclerosis, estrogen replacement can act on the existing lesions to increase appropriate preventative therapies and inflammation, plaque instability and decrease vasodilation, while also downregulating lifestyle changes are critical to the prevenendogenous estrogen signaling pathways. ER: Estrogen receptor. tion of stroke and best done before a patient becomes pregnant [27]. While the prevalence of hypertension review by Manson [84], HT is most appropriate in recently is much lower in women of childbearing age, when it does menopausal women with no history of cerebrovascular or arise, management is critical, as pre-pregnancy hypertension cardiovascular disease and a Framingham Stroke Score of increases the risk of both preeclampsia/eclampsia and stroke
