Stroke Prevention in Women: From Young Adulthood to Older Age

Stroke is the fourth leading cause of death in women. Given that women live longer than men, women who survive a stroke and have residual physical and cognitive deficits will outnumber men. Increasingly strokes occur in younger women as well, which is devastating for young stroke survivors and their families. The Guidelines for the Prevention of Stroke in Women is the first guideline to provide emphasis on risk factors unique to women (such as hormonal factors, pregnancy, and childbirth) and risk factors that more commonly occur in women, including migraine with aura, obesity and metabolic syndrome, and atrial fibrillation.¹ The writing group provides evidence-based recommendations that are unique to women and, of equal importance, identifies gaps in knowledge where additional research is needed to better assess risk and improve strategies for stroke prevention in women. The authors wish not only to improve the understanding of clinicians and researchers about stroke risk and prevention in women, but also to empower women to learn about their risk and how to reduce their chances of having a stroke.

• Although women benefit from drug therapies for hypertension similarly as men, fewer treated women achieve blood pressure control compared to men. Further research should uncover reasons for why this is the case, e.g., less intense treatment in women, inappropriate drug choices, lack of compliance, treatment resistance, biological factors that account for hormonal status, and perhaps others,
• Pregnancy-related hypertension is the leading cause of both hemorrhagic and ischemic stroke in pregnant and postpartum women. Women with pregnancy-related complications (pre-eclampsia, gestational diabetes, pregnancy-induced hypertension) have a substantially higher risk for future cardiovascular disease and stroke. Prospective studies in diverse populations are needed to discern whether pre-pregnancy risk factors or pregnancy-associated risk factors predispose women to subsequent risk of stroke. Additionally, there is need for studies in women who have had pregnancy complications to understand the trajectory of the development of cerebrovascular disease, and then to develop screening, risk stratification, and preventive strategies. The guidelines provide specific recommendations for the prevention and treatment of pre-eclampsia and pregnancy-related hypertension. Although only a Class IIa, Level of Evidence C recommendation, guidelines suggest that all women are evaluated for a history of pre-eclampsia/eclampsia and to document this history as a risk factor, then to evaluate and treat cardiovascular and stroke risk factors (hypertension, obesity, smoking, dyslipidemia). This is particularly important for those providers from whom women seek healthcare, such as primary care providers and obstetrician/gynecologists.
• Stroke from central venous and sinus thrombosis (CVT) is remarkably more common in women, and has been related to hormonal factors (contraceptive use, pregnancy) and thrombophilia. The guidelines provide recommendations for screening, testing for prothrombotic conditions, and anticoagulation for women with CVT and a history of CVT.
• The overall stroke risk is low from hormonal contraception; however, certain subgroups of women may be at higher risk for stroke, including women who are older, smoke cigarettes, have hypertension, diabetes, obesity, hypercholesterolemia, and prothrombotic mutations. Additional research is needed to learn about subgroups of women at risk for hemorrhagic stroke with oral contraceptive use, with respect to age, race/ethnicity, genetics, and parity. Research should also assess the value of biomarkers of endothelial dysfunction during the course of oral contraceptive use and arterial thrombotic event. The guidelines advocate for blood pressure evaluation prior to hormonal contraceptive initiation as well as the treatment of stroke risk factors among oral contraceptive users. Oral contraceptives should not be given to women who smoke cigarettes or those with prior thromboembolic events.
• Studies of the association between age at menopause or premature menopause and stroke risk suggest an increased risk of stroke with earlier onset of menopause, but results are inconsistent. Additional research is necessary to fully discern the impact of onset of menopause on stroke risk.
• An increase in stroke risk is associated with the use of hormone therapy in standard formulations of CEE/MPA as well as the use of SERMs. Additional studies are needed to draw conclusions about long-term hormone therapy use when initiated in perimenopausal women or postmenopausal women younger than 50 years of age. Prospective randomized trials of alternate forms of hormone therapy are ongoing. As stated in previous guidelines, neither hormone therapy nor SERMs should be used for the primary or secondary prevention of stroke.
• Migraine with aura is associated with an increased risk for ischemic and hemorrhagic stroke in women, especially in women under the age of 55 years. Data are insufficient to recommend specific strategies to treat migraine while lowering stroke risk. However, since an association exists between migraine frequency and stroke risk, guidelines support treatments to reduce migraine frequency. Smoking cessation is strongly recommended for women with migraine headaches with aura.
• Obesity, abdominal obesity, and metabolic syndrome are independent risk factors for stroke; however, there is no clear evidence that obesity has a stronger impact on stroke risk and stroke outcomes in women compared to men. On the other hand, studies show that metabolic syndrome imparts a higher stroke risk in women and accounts for more stroke events in women than in men. Adherence to healthy lifestyle behaviors (maintaining a normal body mass index, eating a diet rich in fruits and vegetables, drinking a moderate amount of alcohol, abstaining from smoking, exercising regularly) has been shown to reduce stroke incidence in women and improve stroke outcomes in both men and women. Guidelines recommend healthy lifestyle practices for primary stroke prevention in women with cardiovascular and stroke risk factors. Further research is needed to develop lifestyle interventions tailored for women that are effective for primary and secondary stroke prevention.
• Atrial fibrillation is a major risk factor for stroke, and the risk of stroke from atrial fibrillation increases with age. More women over the age of 75 years have atrial fibrillation compared to men. Anticoagulation is effective in reducing stroke risk. Risk stratification tools, such as CHADS₂ and CHADS-VASc, are useful for guiding clinicians in the decision to initiate anticoagulation therapy. New oral anticoagulants are efficacious alternatives to warfarin for stroke prevention, but research is needed to determine the appropriate dose in older women with a lower weight or women with comorbidities such as renal disease. Guidelines recommend the use of risk stratification tools for patients with atrial fibrillation that account for age and sex differences in the incidence of stroke. Primary care clinicians should actively screen women over the age of 75 years for atrial fibrillation using pulse taking followed by ECG as appropriate. New oral anticoagulants are recommended alternatives to warfarin in women with atrial fibrillation at increased stroke risk according to CHADS-VASc. Oral anticoagulation is not recommended for women age 65 years and younger who have atrial fibrillation without other stroke risk factors; antiplatelet therapy is a reasonable option for selected low-risk women.
• Depression is associated with an increased risk of stroke, but research is needed to understand the mechanisms underlying this association and which women with depression are at greatest risk for stroke.
• In clinical trials of primary and secondary stroke prevention, women need to be included in adequate numbers for preplanned subgroup analysis to examine sex differences.
• Additional research is needed to determine the benefits and risks of carotid procedures in women with asymptomatic high-grade stenosis and symptomatic moderate (50% to 69%) stenosis. Women with asymptomatic carotid stenosis should be assessed and treated for other stroke risk factors with lifestyle changes and medical therapies. The guidelines include several recommendations regarding the appropriate use of carotid endarterectomy.
• Guideline recommendations for aspirin use in women (unless contraindicated) include diabetes, high risk for cardiovascular disease events, and women 65 years of age or older if blood pressure is controlled and benefit outweighs risk.
• Risk factors that are unique to women, more prevalent in women, or differentially increase risk in women compared to men may improve the accuracy of stroke risk prediction compared to current risk prediction models, especially for younger women of reproductive age. Development of risk prediction models can be achieved by using data from large, diverse longitudinal studies such as the Women’s Health Initiative, Women’s Health Study, Nurses’ Health Study, ARIC, and REGARDS.

The writing group suggests that current risk assessment methods are inadequate to predict stroke risk in women and suggest that a female-specific stroke risk score is warranted. Although risk factors unique to women were not incorporated in the new pooled cohort ASCVD risk equations,² this risk assessment modality used data from community-based cohorts of adults to estimate the sex- and race-specific 10-year risk for developing a first ASCVD event, defined as coronary heart disease death, nonfatal myocardial infarction, and fatal or nonfatal stroke. The Pooled Cohort Equations were validated for African American and White men and women 40 to 79 years of age. The final pooled cohorts included participants from several large, racially and geographically diverse NHLBI-sponsored cohort studies, including ARIC, the Cardiovascular Health Study, and the CARDIA study, combined with data from the Framingham original and offspring cohorts. Therefore, the new Pooled Cohort ASCVD Risk Equations should be evaluated prospectively for prediction of stroke risk.

The AHA/ASA Guidelines for Prevention of Stroke in Women represent a comprehensive analysis of stroke risk factors unique to women, as well as those risk factors more common in women compared to men. Gaps in current research are clearly identified along with recommendations for future research. Evidence-based recommendations tailored to women provide clear direction for clinicians. The comprehensive nature of this document makes it quite lengthy and may not be read by those who need to read it the most and apply it to their practice, such as primary care providers and obstetrician/gynecological practitioners. Key information from the guidelines should be incorporated in publications read by the primary care and OB/GYN communities. All providers should document a woman’s history of pregnancy-related complications, carefully evaluate her cardiovascular and stroke risk factors, and partner with her to aggressively reduce her risk through lifestyle interventions and drug therapies as appropriate. The stroke prevention guidelines for women should be used to develop educational resources for our female patients so that they understand their risk, know what measures they can take to reduce their risk, and know what stroke prevention measures they should expect to be implemented by their healthcare providers.