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Abstract

Stroke is among the most important causes of death and disability for both women and men worldwide. Although stroke and cardiovascular disease are often considered primarily conditions of men, more women than men die from stroke each year, and women who survive have worse outcomes than men. Fortunately, clinical trials have shown that there are a variety of interventions that can improve stroke outcomes and reduce the risk of recurrent stroke, and the majority of these are effective in both women and men. Certain causes of stroke are unique to women (strokes in pregnancy) or more common in women (strokes associated with migraine headaches); however, a detailed discussion of these specific causes of stroke is beyond the scope of this review. The focus of this article is an overview of some of the key issues related to the management of stroke in women.

Keywords

cerebrovascular diseases gender difference stroke women's health

Worldwide, approximately 15 million people suffer a stroke each year. Of these, 5 million die and 5 million are left disabled [1]. Although men have higher stroke incidence rates, women are more likely than men to die from a stroke, primarily because women are over-represented in the older age groups and because stroke mortality is higher with increasing age [1]. In 2002, for example, stroke accounted for 11% of deaths in women versus 8.4% in men [6]. In addition, women who survive a stroke have worse outcomes than men: they are less likely than men to make a complete recovery; are more likely to be dependent on others for self-care activities; have a longer hospital length of stay; and are more likely to be transferred to long-term care facilities after stroke admission [7 –12].

Over the past decade, there have been enormous advances in stroke therapy, with clinical trials demonstrating the effectiveness of a variety of interventions for acute stroke management and secondary stroke prevention. In the setting of acute stroke, there is evidence that aspirin and thrombolysis treatment and care on an acute stroke unit can improve outcomes [13 –16]. In addition, studies have established the effectiveness of a number of therapies for secondary stroke prevention, including antiplatelet therapy, anticoagulation for atrial fibrillation (AF), and carotid endarterectomy for carotid stenosis [17 –19]. Despite this clinical trials research into stroke therapy, there has been limited study of gender differences in stroke management or outcomes. This article summarizes the available literature related to stroke management in women.

Stroke presentation in women

At the time of first stroke, women tend to be older than men, are more likely to have a history of comorbid illness such as hypertension and/or A F, and are more likely to have a poor functional status prior to stroke [8 –10,20]. Compared with men, women with stroke are also more likely to live alone and less likely to have social supports [7,11]. Given the knowledge that women with acute coronary syndromes tend to present with atypical symptoms, there has been interest in exploring potential gender differences in the presenting signs and symptoms of acute stroke. Although some studies have found a higher frequency of presenting symptoms such as aphasia and dysphagia in women, this has not been a consistent finding, with other studies documenting no significant gender differences in stroke symptoms or presentation [8 –11,20]. Similarly, while some studies have found that women have a greater stroke severity on presentation, this has not been confirmed in other studies [8,10,11]. Thus, at the present time, it is not known whether there are consistent gender differences in stroke presentation or severity, and it is recommended that campaigns to educate women on stroke warning signs continue to focus on the typical presenting symptoms, including weakness, difficulty speaking, problems with vision, unexplained dizziness and sudden severe headache. A recent survey by the American Heart Association found that knowledge of stroke warning signs is suboptimal in American women, with only 39% of white women citing weakness as a stroke warning sign, with lower rates of recognition in other ethnic groups and for other warning signs [21].

Acute stroke therapy

Aspirin therapy for acute ischemic stroke

Two large, randomized, controlled trials have demonstrated that aspirin 160–300 mg/day, initiated within 48 h of ischemic stroke onset improves outcomes, with an increased proportion of patients achieving a complete recovery (relative risk of recovery 1.04; 95% confidence interval [CI]: 1.01–1.07), reduced death or dependency at 6 months, and a reduced rate of recurrent stroke or death [13,14]. The effectiveness of acute aspirin therapy appears similar in women and men. Thus, in the absence of contraindications, it is recommended that both women and men with acute ischemic stroke receive aspirin within 48 h of stroke onset.

Thrombolysis

Thrombolytic therapy for acute ischemic stroke has been evaluated in several randomized trials. Based on meta-analyses, thrombolytic therapy administered up to 6 h after ischemic stroke reduces the risk of death or dependency (modified Rankin scale score of 3–6) at the end of follow-up at 3–6 months (odds ratio [OR]: 0.84; CI: 0.75–0.95). This is in spite of a significant increase in the odds of death within the first 10 days, mainly due to fatal intracranial hemorrhage [22]. However, if given within 6 h of stroke onset, thrombolytic therapy also increases the risk of death at the end of follow-up at 3–6 months (OR: 1.33; CI: 1.15–1.53). For patients treated within 3 h of stroke, thrombolytic therapy appears more effective in reducing death or dependency at study follow-up (OR: 0.66; 95% CI: 0.53–0.83) with no statistically significant adverse effect on death (OR: 1.13; 95% CI: 0.86–1.48). Limiting the analysis to trials of intravenous tissue plasminogen activator (tPA) suggests that it may be associated with slightly less hazard and more benefit than other drugs. Based on these data, practice guidelines advocate consideration of thrombolysis with tPA for eligible patients who present within 3 h of onset of acute ischemic stroke [23,24].

Women may benefit more from thrombolysis than men: a case series of patients who received tPA for acute ischemic stroke found that vascular occlusive lesions were more likely to recanalize in women [25]. Similarly, a pooled analysis of five randomized trials of tPA therapy for acute ischemic stroke found an effect modification by sex: women who were not treated with tPA had worse outcomes than men, whereas those who received tPA had similar outcomes to men, suggesting that tPA may nullify the gender gradient in stroke outcomes [26]. The authors conclude that for patients presenting at later time intervals, when the risks and benefits of thrombolysis are more finely balanced, sex may be an important variable to consider for patient selection. Although there have been few studies in this area, there do not appear to be any significant gender differences in rates of thrombolysis use for acute stroke [11].

Stroke units

A meta-analysis of over 3500 patients from 23 controlled trials found that, compared with alternative services, stroke unit care demonstrated reductions in the odds of death (OR: 0.86; CI: 0.71–0.94; p = 0.005), the risk of death or institutionalized care (OR: 0.80; CI: 0.71–0.90; p = 0.0002), and death or dependency (OR: 0.78; CI: 0.68–0.89; p = 0.0003) [16]. Outcomes were independent of patient age, sex and stroke severity. Thus, it is recommended that both women and men who have experienced a stroke receive care in an organized stroke unit, where available. Studies to date suggest that there are no significant gender differences in rates of admission to stroke units [9,11].

Primary & secondary stroke prevention

Hormonal therapy

A large, well-designed trial of healthy postmenopausal women found that hormone replacement therapy (HRT) with conjugated equine estrogen (with medroxyprogesterone for those with an intact uterus) increased the risk of cardiovascular events, including stroke [27,28]. The increase in stroke risk was seen in all subgroups of women [29]. In addition, two well-designed trials of HRT for the secondary prevention of cardiovascular disease found no net reduction in the risk of stroke in women with a history of stroke or cardiovascular disease, and an increase in the risk of events within the first 6 months of estrogen therapy [30,31]. These trials also suggested an increase in the risk of stroke-related death and an increase in stroke severity in women treated with estrogen [30 –32]. Thus, HRT is not recommended for either primary or secondary stroke prevention in women.

Raloxifene is a selective estrogen receptor modulator that acts as an estrogen antagonist on the breast and uterus, and as an estrogen agonist on bone and lipids [33]. A subgroup analysis of a randomized, controlled trial of raloxifene for osteoporosis found that the drug decreased the risk of stroke in women with established cardiovascular disease [34]. An ongoing clinical trial of raloxifene for the prevention of cardiovascular events in high-risk women is expected to provide a more definitive assessment of the effectiveness of raloxifene for stroke prevention [35]. At this time, until further data are available, raloxifene is not recommended for primary or secondary stroke prevention in women.

Antithrombotic therapy

A large, randomized trial of aspirin for primary prevention of cardiovascular disease in women aged over 45 years found that aspirin 100 mg every other day decreased the risk of stroke, with a relative risk of 0.83 (95% CI: 0.69–0.99), but had no effect on the primary end point of major vascular events (nonfatal myocardial infarction [MI], nonfatal stroke or cardiovascular death), except in the subgroup of women aged over 65 years [36]. Based on this trial, aspirin can be considered for the primary prevention of stroke, but is not recommended for primary prevention of overall cardiovascular disease in postmenopausal women, except in high-risk patients aged over 65 years.

Substantial evidence from randomized trials and meta-analyses supports the use of antithrombotic agents for secondary prevention of stroke in patients who have experienced an ischemic stroke. Among patients with previous stroke or transient ischemic attack (TIA), aspirin and other forms of antiplatelet drugs have been found to reduce the incidence of nonfatal stroke by a quarter, with an absolute reduction in the risk of having a serious vascular event of 36/1000 2 years after treatment [17]. Although some controversy regarding dosage still exists, most guidelines recommend medium-dose aspirin (75–325 mg/day) as the first choice in secondary prevention of stroke [23,101]. Other antiplatelet agents, including clopidogrel and the combination of aspirin and dipyridamole, are acceptable alternatives. Antiplatelet therapy appears to be effective for both women and men, and the bleeding risks associated with aspirin therapy are similar in women and men [37,38]. Despite this, some studies have found that antithrombotic therapy is prescribed to women less often than men [9,39].

Warfarin for atrial fibrillation

Warfarin has been shown to be effective for both primary and secondary stroke prevention in patients with AF. For primary prevention, a systematic review of five trials with 2313 participants without prior cerebral ischemia found that warfarin therapy was associated with significant reductions in ischemic stroke (OR: 0.34; CI: 0.23–0.52), all stroke (OR: 0.39; CI: 0.26–0.59), all disabling or fatal stroke (OR: 0.47; CI: 0.28–0.80), and the combined end point of all stroke, MI or vascular death (OR: 0.56; CI: 0.42–0.76) [40]. A review that focused on secondary prevention based its recommendations on one randomized trial that compared warfarin (target international normalized ratio [INR]: 2.5–4.0) with aspirin 300 mg/day in patients with AF who had experienced recent TIA or minor stroke [18]. In this trial, the risk of recurrent stroke was markedly reduced by anticoagulant therapy (OR: 0.35; CI: 0.22–0.59) compared with aspirin. Based on these findings, anticoagulation with warfarin is recommended for patients with AF and recent cerebral ischemia.

An analysis of administrative data collected on over 13,000 adults found that, compared with men, women with AF had higher rates of ischemic stroke and peripheral embolism while not receiving warfarin, even after adjustment for other stroke risk factors [41]. However, data from this study, as well as from a pooled analysis of five studies of warfarin for primary stroke prevention in the setting of A F, demonstrated that warfarin appeared to be at least as effective at preventing thromboembolism in women as in men, with no increase in bleeding risk [41,42]. Thus, in the absence of contraindications, both women and men with AF should be prescribed warfarin for stroke prevention. Of note, some data suggest that women with AF are less likely than men to be prescribed warfarin for both primary and secondary stroke prevention [9,43 –45].

Carotid endarterectomy

Data from large, well-designed, randomized, controlled trials have shown that carotid endarterectomy is highly effective for stroke prevention in individuals with symptomatic carotid artery stenosis [46,47]. Analyses of pooled data from these trials demonstrated that for patients with severe internal carotid artery stenosis (>70% stenosis based on criteria from the North American Symptomatic Carotid Endarterectomy Trial [NASCET]), surgery significantly reduced the risk of disabling stroke or death (relative risk reduction [RRR] 48%; CI: 27–63%) [19]. For patients with moderate stenosis (50–69% stenosis based on NASCET criteria), surgery also reduced the risk of disabling stroke or death, with a RRR of 27% (CI: 5–44%). Surgery was not beneficial for patients with lesser degrees of stenosis. These results were found in the context of patients operated on by surgeons with low complication rates (<6%).

Subgroup analyses of these trials have found that women and men with severe stenosis appear to benefit equally from carotid surgery, but that women with moderate stenosis derive less benefit than men, primarily due to a lower risk of stroke with medical therapy [48 –52]. Therefore, although carotid endarterectomy is recommended for both women and men with severe stenosis, the potential risks and benefits must be considered more carefully for women with moderate stenosis, many of whom may not benefit from the procedure.

It has also been hypothesized that carotid surgery might be riskier for women than men, possibly related to smaller blood vessels making surgery more technically difficult, or to older age and greater comorbidity in women undergoing surgery. A systematic review of all publications reporting data on the association between sex and carotid surgery complications found that women were at a higher risk of perioperative stroke or death compared with men (OR: 1.31; CI: 1.17–1.47), but were not at a higher risk of perioperative death alone [53]. Of note, this meta-analysis included studies of varying methodological quality, which may have affected the accuracy of the conclusions. Despite the potential for higher perioperative risks, the benefits of carotid surgery are substantial for appropriately selected women, who should not be discouraged from carotid endarterectomy solely on the basis of potential surgical risks.

Analyses of both clinical trials and administrative data demonstrate that carotid surgery tends to be performed half as often in women as in men. This may be partly explained by sex differences in the prevalence of large-vessel atherosclerosis; however, some studies have also found that women may be referred less often than men for screening investigations such as carotid imaging [8,10].

Risk-factor modification

The major risk factors for stroke, including hypertension, diabetes, smoking and hyperlipidemia, are similar for women and men, and no major gender differences in the effectiveness of interventions have been documented. Therefore, it is recommended that similar approaches, including blood-pressure-lowering medications, smoking cessation, diabetes control and prescription of lipid-lowering agents, be undertaken in both women and men [24,54,101].

Conclusion

Stroke is a major health problem for women worldwide. Recommendations for acute stroke management and for the primary and secondary prevention of stroke are similar in women and men. In acute stroke, care on a stroke unit, early use of aspirin and consideration of thrombolysis for those who present within 3 h of onset of ischemic stroke are recommended for both women and men. For primary stroke prevention, aspirin, warfarin for A F, and control of risk factors such as hypertension and hyperlipidemia are effective in women, while HRT is not effective. For secondary stroke prevention, antithrombotic therapy, warfarin for A F, carotid endarterectomy for severe carotid stenosis and control of cardiovascular risk factors are all effective in women. HRT is not effective, and carotid endarterectomy may not be beneficial for women with moderate carotid stenosis. Some therapeutic interventions appear to be underutilized in women, and healthcare practitioners and policy makers should endeavour to address these discrepancies. A summary is shown in Table 1.

Table 1.

Stroke therapy in women.

Intervention	Effective in women	Comments
Primary stroke prevention
Aspirin	Yes	Not effective for primary prevention of coronary artery disease
Hormone replacement therapy	No	Increases risk of stroke and cardiovascular disease
Acute stroke therapy
Thrombolysis	Yes	Women may derive more benefit than men
Aspirin	Yes
Stroke unit care	Yes
Secondary stroke prevention
Antithrombotic therapy*	Yes
Warfarin for atrial fibrillation*	Yes
Carotid endarterectomy for severe (>70%) carotid stenosis*	Yes
Carotid endarterectomy for moderate (50–69%) stenosis	Probably not	Can be considered in selected cases
Hormone replacement therapy	No	Increases stroke risk and may increase stroke severity
Raloxifene	Undecided	Awaiting results from ongoing clinical trial

May be used less often in women than in men.

Future perspective

The past decade has seen dramatic advances in therapies to decrease death and disability from stroke. Although women stand to benefit from most of these interventions, the current literature suggests that some of these treatments are underutilized in women. Future research should focus on confirming these findings and understanding the reasons for gender-based variations in stroke-care delivery. In addition, compared with men, women continue to have worse functional outcomes after stroke, and future research should focus on determining the reasons for variations in outcomes, targeting therapy to improve stroke outcomes in women as well as men, and evaluating the effectiveness of stroke rehabilitation interventions in women and men.

Executive summary

Stroke outcomes

Women with stroke are more likely than men to be disabled and require institutionalization after stroke admission.

Stroke presentation

Some studies suggest subtle differences in presenting symptoms in women compared with men, but there are no consistent findings in the literature. Until further data are available, the classic stroke warning signs should be considered applicable to both women and men.

Acute stroke therapy

Early administration of aspirin, care on a dedicated stroke unit and consideration of thrombolysis for patients who present within 3 h of stroke onset are recommended for both women and men with stroke. Women may derive more benefit from thrombolysis than men.

Stroke prevention

Hormone replacement therapy is not effective for either primary or secondary stroke prevention in postmenopausal women. Ongoing trials will determine the effectiveness of raloxifene for stroke prevention in high-risk women.

Antithrombotic therapy, warfarin for atrial fibrillation and carotid endarterectomy for severe (>70%) carotid stenosis have all been shown to be effective for stroke prevention in women and men. However, these interventions may be underutilized in women. Women with moderate carotid stenosis may not benefit from surgical therapy.

Both women and men benefit from risk-factor modification to decrease stroke risk, including blood-pressure control, cholesterol lowering and smoking cessation.

Footnotes

Acknowledgements

The author is supported by a career award from the Canadian Institutes for Health Research (Ottowa, Canada), and by the University Health Network Women's Health Program (Toronto, Canada) and the Canadian Stroke Network (Ottowa, Canada).

The conclusions and recommendations are those of the author, and should not be attributed to any supporting or sponsoring agencies.

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Stroke Management in Women

Abstract

Keywords

Stroke presentation in women

Acute stroke therapy

Aspirin therapy for acute ischemic stroke

Thrombolysis

Stroke units

Primary & secondary stroke prevention

Hormonal therapy

Antithrombotic therapy

Warfarin for atrial fibrillation

Carotid endarterectomy

Risk-factor modification

Conclusion

Future perspective

Footnotes

Acknowledgements

References