Risk Factors More Common in Women Than Men Migraine With Aura The prevalence of migraine in the population is 18.5%, and for migraine with aura, it is 4.4%.277 Women are 4 times more likely to have migraines than men.277 Very rarely are migraines associated with stroke, however. Migraine with aura is defined as a typical migraine headache plus the presence of homony- mous visual disturbance, unilateral paresthesias or numbness, unilateral weakness, or aphasia or unclassifiable speech dif- ficulty that might typically precede the migraine headache.278 This type of migraine is associated with double the risk for IS based on meta-analyses of diverse cohorts of patients. The most recently published meta-analysis reported a increase in IS in patients with migraine with aura (OR, 2.51; similar to a previous analysis that showed an OR of 2.16 (95% CI, 1.53 3.03).280 The associa- tion between migraine aura and IS is higher in women than men. In women with migraine with aura, the risk increases even more in those using oral contraceptives (OR, 7.02; 95% CI, 1.51 32.68) and in cigarette smokers (OR, 9.03; 95% CI, The absolute risk of migraine-associated stroke is relatively low. On the basis of data from the Women s Health Study (WHS), migraine with aura accounted for 4 additional IS cases per 10000 women per year when migraine with aura was the assumed underlying cause of stroke.281 The risk is higher with increasing frequency of migraine282 and if the aura does not include nausea and vomiting.283 Data from the WHS suggest that migraine with aura is associated with increased risk of TIA (RR, 1.56; 95% CI, 1.03 2.36) and nondisabling stroke (RR, 2.33; 95% CI, 1.37 3.97) compared with women with no history of migraine284 and that the presence of migraine with aura does not modify the beneficial effects of aspirin.285 Therefore, migraine aura appears to be associated with a bet- ter prognosis because of the link to milder strokes and TIAs than with non migraine-associated strokes in the WHS. Migraines with aura have also been associated with a risk of hemorrhagic stroke in the WHS, but this association was stronger in the subset of women with fatal hemorrhagic stroke and in women <55 years of age.286 In pregnant women with an International Classification of Diseases, 9th Revision, hospi- tal code for migraine, there was a large association with hem- orrhagic stroke (OR, 9.1; 95% CI, 3.0 27.8); however, in the pregnant population, the risk of vascular diseases was closely associated with a concomitant diagnosis of preeclampsia/ Interestingly, there is an emerging literature on the asso- ciation between migraines and preeclampsia.288 290 The most recent analysis of the United Kingdom Obstetric Surveillance System found 30 cases of antenatal stroke, for an estimated incidence of 1.5 cases per 100000 women who delivered babies (95% CI, 1.0 2.1). Factors associated with increased risk of antenatal stroke were history of migraine (adjusted OR, 8.5; 95% CI, 1.5 62.1), gestational diabetes (adjusted OR, 26.8; 95% CI, 3.2 ), and preeclampsia or eclampsia Migraine With Aura: Summary and Gaps Migraine with aura (but not without aura) is associated with risk for IS and hemorrhagic stroke in women, especially those <55 years of age, although the absolute risk is low, and these women appear to have a good poststroke prognosis. Not only do the majority of studies with both men and women support this as a predominantly female issue, but the largest cohorts that have been studied are limited to women. There are not sufficient data to recommend specific approaches to treat migraine with the intention of lowering risk of stroke. Migraine treatment with triptans is contraindicated in patients with a history of cerebrovascular disease or coronary heart as explicitly stated in guidelines from the American Academy of Neurology. As for the risk of treatment with trip- tans in women with migraine with aura, there are no data to guide this decision other than the observational data related to higher risk of stroke among those who smoke cigarettes or use OCs (see Oral Contraceptives ). Given the number of stud- ies that consistently show a higher risk of stroke in younger women with migraine with aura, it may be reasonable to include this in a woman-specific risk profile. The general rec- ommendations for men and women with migraine with aura and stroke are as stated in the primary prevention guideline.19 Migraine With Aura: Recommendations 1. Because there is an association between higher migraine frequency and stroke risk, treatments to reduce migraine frequency might be reasonable, although evidence is lacking that this treatment reduces the risk of first stroke (Class IIb; Level of Evidence C). 2. Because of the increased stroke risk seen in women with migraine headaches with aura and smoking, it is reasonable to strongly recommend smoking cessation in women with migraine headaches with aura (Class IIa; Level of Evidence B). Obesity, Metabolic Syndrome, and Lifestyle Factors By the year 2030, an estimated 86% of Americans will be overweight or obese.292 Obesity affects a disproportionate number of women in the United States; in 2007 to 2008, the age-adjusted prevalence of obesity in the United States was 35.2% in women compared with 32.0% in men.293 Non- Hispanic black women have the highest prevalence of obesity The distribution of obesity has important cardiovascular coined the term android obe- sity to describe the high-risk form of obesity, at that time more frequently found in men, in which the body fat is concentrated in the abdominal area; he introduced the term gynoid obesity to describe the low-risk lower-body adiposity, more frequently found in premenopausal women. Abdominal obesity (defined as waist circumference >88 cm in women and >102 cm in men), however, is now far more prevalent in women than men, and android obesity is a misnomer. In fact, data from NHANES in 2007 to 2008 revealed that among adults 20 years old, age-adjusted prevalence of abdominal obesity was 61.8% in women compared with 43.7% in men.293 In addi- tion, premenopausal women are increasingly likely to have abdominal obesity; a recent study of women aged 35 to 54 years in the United States revealed that from 1988 1994 until 1999 2004, the prevalence of abdominal obesity increased The escalating obesity epidemic may counter the tremendous advances that have been made Bushnell et al Guidelines for Prevention of Stroke in Women 1565 in smoking cessation and hypertension and dyslipidemia awareness and control in the United States. Understanding the effects of obesity and abdominal adiposity on stroke risk, and the potentially differential impact of these conditions on women compared with men, may elucidate avenues for reduc- ing the incidence and morbidity of stroke. Association Between Obesity and Abdominal Adiposity and Stroke Risk and Outcomes Obesity is an independent risk factor for stroke. Studies have revealed a graded association between BMI and stroke risk; the risk of total stroke or IS rises linearly with increasing BMI and in a stepwise fashion for higher BMI categories.297 299 Obesity affects stroke risk in both men and women, even after adjustment for factors such as age, physical activity, smok- ing, alcohol consumption, and comorbid conditions such as hypertension and diabetes mellitus297 307 (Table 10). There is no clear evidence that obesity has a stronger impact on stroke risk in women than in men (Table 10). Numerous epidemiological and metabolic studies have shown that abdominal obesity has a stronger correlation with insulin resistance, atherogenic dyslipidemia, diabetes mellitus, and CVD than other distributions of body fat.309 Abdominal obesity can be measured by use of waist circum- ference, waist-to-hip ratio, and waist-to-stature ratio. As with BMI, there is a graded association between abdominal obesity and stroke risk. A study of 67000 women found a 2% relative increase in total stroke risk with each 1-unit increase in waist Other studies have shown similar associa- tions between abdominal obesity and stroke risk.304,307,310,311 Although many studies have shown that abdominal obesity is associated with stroke in women, even after adjustment for age, lifestyle habits, and medical comorbidities,301,303,307,310 312 some studies have shown that the association is no longer sig- nificant in multivariable models300,313,314 (Table 11). Studies of sex differences in the effect of abdominal obesity on stroke risk have had conflicting results (Table 11). The impact of obesity on poststroke outcomes remains unclear. One retrospective analysis of cross-sectional and pro- spective data from a nationally representative survey of the US adult population followed up from survey participation in 1988 to 1994 through mortality assessment in 2000 revealed that the overall risk for all-cause mortality among stroke sur- vivors increased per 1 kg/m2 of higher BMI (P=0.030), but an interaction between age and BMI (P=0.009) revealed that the association of higher BMI with mortality risk was strongest in younger individuals and declined linearly with On the other hand, a post hoc analysis of the Telemedical Project for Integrative Stroke Care (TEMPiS) revealed that mortality risk was lower in overweight patients (HR, 0.69; 95% CI, 0.56 0.86) and lowest in obese (HR, 0.50; 0.66) patients compared with those with normal BMI.316 It is unclear whether obesity has a differential impact on stroke outcomes in women compared with men.317 Metabolic Syndrome Metabolic syndrome, a combination of cardiometabolic risk factors that tend to cluster together (insulin resistance, abdominal adiposity, dyslipidemia, and hypertension) affects approximately one third of the US adult population.318 Analysis of data from NHANES 2003 to 2006 revealed that 36.1% of men and 32.4% of women in the United States had metabolic Numerous studies have shown an association between metabolic syndrome and stroke in both men and women303,310,311,314,319 326 (Table 12). The exact mecha- nism whereby metabolic syndrome affects cardiovascular risk is unknown; it is thought that components of the syndrome synergistically increase vascular risk through mechanisms that include insulin resistance, hypercoagulability, endothelial dysfunction, and inflammation. Studies suggest that meta- bolic syndrome confers a higher stroke risk on women than and metabolic syndrome accounts for a larger percentage of stroke events in women than in men (30% ver- The mechanisms for this difference are not completely understood. Pathophysiologic Mechanisms of Obesity, Abdominal Adiposity, and Metabolic Syndrome That Affect Stroke Risk The pathophysiological mechanisms by which general obesity increases stroke risk remain unclear. One proposed mecha- nism is that obesity is associated with a prothrombotic and BMI is directly associated with fibrinogen, factor VII, plasminogen activator inhibitor, and tis- sue-type plasminogen activator antigen levels in both men and Similar associations are present between abdomi- nal obesity and hemostatic factors. These associations persist after controlling for age, smoking, total and high- density lipo- protein cholesterol, triglycerides, glucose level, BP, and use of In addition, higher levels of acute phase reactants such as C-reactive protein may decrease endothelial cell production of nitric oxide, which may in turn instigate a cascade of events leading to vasoconstriction, leu- kocyte adherence, platelet activation, oxidation, and thrombo- Attenuation of the protective effect of high-density attributable to general obesity may also play a role. The biological pathways by which abdomi- nal adiposity increases stroke risk are also not yet understood, but platelet activation, inflammation, endothelial dysfunction, or an overactive endocannabinoid system335 may all serve key roles in the process. In addition, increased very low-density lipoprotein production caused by the high lipolytic activity of abdominal adipose tissue304,312 may increase stroke risk. Lifestyle Lifestyle factors such as a healthy diet,336 338 physical activ- abstinence from smoking,344 346 moderate alcohol and maintenance of a healthy BMI299,308 reduce the risk of CVD and mortality. Adherence to a combination of healthy lifestyle practices has been shown to decrease stroke incidence in women327 and improve outcomes after stroke in both men and women.349 All-cause mortality after stroke decreases with higher numbers of healthy behaviors (1 3 factors versus none: HR, 0.12 [95% CI, 0.03 0.47]; 4 5 factors versus none: are observed for cardiovascular mortality after stroke (4 5 fac- tors versus none: HR, 0.08 [95% CI, 0.01 0.66]; 1 3 factors ver- A multitude of randomized controlled trials of lifestyle inter- ventions targeting individuals at high risk for diabetes mel- litus and CVD have been conducted.350 362 Although many of the studies have proved effective in improving lifestyle habits and vascular risk factors in the short term, it has proved more challenging to maintain such changes and reduce cardiovascu- lar events. For example, in the WHI Randomized Controlled Dietary Modification Trial, over a mean of 8.1 years, the dietary intervention reduced total fat intake and increased intakes of vegetables, fruits, and grains but did not significantly reduce the risk of coronary heart disease, stroke, or cardiovascular death in postmenopausal women and achieved only modest effects on cardiovascular risk factors.358 In addition, a 2-year behavior- ally based physical activity and diet program implemented to reduce obesity in a primary care setting showed a significant reduction in waist circumference at 6 and 12 months, but the reduction in waist circumference was sustained in men but not On the other hand, a recent primary Table 10. Relationship Between Elevated BMI and Stroke HR (95% CI) First Author Study Site n Follow-up, y Study Type End Point BMI, kg/m2 Women Men China 154736 Mean: 8.3 Prospective cohort Clinically defined total stroke* Finland 49996 Mean: 19.5 Prospective cohort Clinically defined total stroke Germany 1137 1 Case-control Clinically defined total stroke, TIA Japan 71722 Median: 7.9 Prospective cohort Clinically defined total stroke USA 39053 Mean: 10 Prospective cohort Clinically defined total stroke NA cohort Clinically defined total stroke USA 13549 Median: 16.9 Prospective cohort Clinically defined ischemic stroke# China 67083 Mean: 7.3 Prospective cohort Clinically defined total stroke** NA Sweden 33578 Mean: 11 Prospective cohort Clinically defined total stroke NA cohort Clinically defined total stroke NA cohort Clinically defined total stroke BMI indicates body mass index; CI, confidence interval; HR, hazard ratio; NA, not available; and TIA, transient ischemic attack. *Adjusted for age, smoking, alcohol consumption, physical inactivity, education, residence in northern China, and residence in urban area. Adjusted for age, study year, smoking, physical activity, educational level, family history of stroke, alcohol consumption, systolic blood pressure, total cholesterol level, and history of diabetes mellitus. Matched for age and sex and adjusted for physical inactivity, smoking, history of hypertension, and history of diabetes mellitus. Adjusted for age, smoking, alcohol consumption, sports and physical exercise, medications or past history of hypertension or diabetes mellitus, and Japan Public Health Center community. Adjusted for age, smoking status, exercise, alcohol consumption, and postmenopausal hormone use. Adjusted for age, smoking, alcohol consumption, exercise, history of angina, parental history of myocardial infarction at age <60 y, and randomized treatment assignment. #Adjusted for age, education, smoking status, cigarette-years, alcohol consumption, and physical activity. **Adjusted for age; education; occupation; family income; menopausal status; use of oral contraceptives, hormone therapy (HT), and aspirin; amount of exercise; cigarette smoking; alcohol consumption; and intakes of saturated fat, vegetables, fruits, and sodium comparing the highest versus lowest quintiles of BMI. Adjusted for age, smoking, alcohol intake, age at first childbirth, years of education, and oral contraceptive use. Adjusted for age, smoking, oral contraceptive use, menopausal status, HT, and time period. Adjusted for age, educational level, smoking status, and alcohol consumption. Bushnell et al Guidelines for Prevention of Stroke in Women 1567 prevention trial of an energy-unrestricted Mediterranean diet supplemented with either extra-virgin olive oil or nuts in high- risk people without CVD revealed that the groups randomly assigned to a Mediterranean diet with extra-virgin olive oil and to a Mediterranean diet with nuts had lower odds of MI, stroke, or cardiovascular death (HR, 0.70 [95% CI, 0.54 0.92] and HR 0.72 [95% CI, 0.54 0.96], respectively) compared with usual care.362 Regarding components of the primary end point, only the comparisons of stroke risk reached statistical Prespecified Table 11. Abdominal Obesity and Stroke in Women and Men HR or OR (95% CI) First Author Study Site No. of Subjects Follow-up, y Study Type End Point Stroke Subtypes Measure of Abdominal Obesity Women Men Finland 49996 Mean: Prospective cohort Clinically defined stroke* Ischemic, hemorrhagic WC 4th vs WHR 4th vs Germany 1137 Undefined Case-control Clinically defined stroke, TIA Ischemic, hemorrhagic F: WC 88 cm vs <80 cm M: WC >102 cm vs <94 cm F: WHR 0.85 M: WHR 1.0 USA 1718 4 Case-control Clinically defined stroke Ischemic F: WHR 0.86 M: WHR 0.93 USA 13549 Median: Prospective cohort Clinically defined stroke Ischemic WC 5th vs Black HR: White HR: Black HR: White HR: WHR 5th vs Black HR: White HR: Black HR: White HR: China 67083 Mean: Prospective cohort Clinically defined stroke Ischemic, hemorrhagic WC 5th vs WHR 5th vs WSR 5th vs NA NA Sweden 33578 Mean: Prospective cohort Clinically defined stroke Ischemic, hemorrhagic WC 4th vs quintile NA NA NA Japan 5474 Mean: Prospective cohort Clinically defined stroke# Not stated WC 4th vs 1st quartile CI indicates confidence interval; HR, hazard ratio; F, female; M, male; NA, not applicable; OR, odds ratio; TIA, transient ischemic attack; WC, waist circumference; WHR, waist-hip ratio; and WSR, waist-to-stature ratio. *Adjusted for age; study year; smoking; physical activity; education level; family history of stroke; alcohol, vegetable, fruit, sausage, and bread consumption; systolic blood pressure; total cholesterol level; and history of diabetes mellitus. Matched for age and sex and adjusted for physical inactivity, smoking, history of hypertension, and history of diabetes mellitus. Matched by age, sex, and race/ethnicity, and adjusted for hypertension, diabetes mellitus, any cardiac disease, current smoking status, no physical activity, moderate alcohol drinking, level of LDL cholesterol, level of HDL cholesterol, and education. Adjusted for age, education, smoking status, cigarette-years, usual alcohol consumption, and physical activity. Adjusted for age; education; occupation; family income; menopausal status; use of oral contraceptives; hormone therapy; aspirin; amount of exercise; cigarette smoking; alcohol consumption; and intakes of saturated fat, vegetables, fruits, and sodium comparing the highest versus lowest quintiles. Adjusted for age, smoking, alcohol intake, age at first birth, years of education, and ever use of oral contraceptives by the time of cohort enrollment. #Adjusted for age, smoking, and drinking status. subgroup analyses revealed that men derived a significant benefit, whereas women did not. Further studies are needed to determine whether these results can be replicated, particularly because they are based on subgroup analyses. In addition, the pathophysiology underlying these potential sex differences is poorly understood and deserves additional exploration. Although lifestyle habits have an important impact on post- stroke outcomes, there are no published trials of lifestyle inter- ventions for secondary stroke prevention. The Healthy Eating and Lifestyle After Stroke (HEALS) trial, a randomized con- trolled trial of an occupational therapist led series of 6 group clinics aimed at changing lifestyle habits among stroke survi- vors, is attempting to address this knowledge gap.363 Finally, little is known regarding how and whether lifestyle interven- tions should be tailored in women. Obesity, Abdominal Adiposity, and Metabolic Syndrome: Summary and Gaps In the United States, 1 in 3 individuals is obese. The preva- lence of obesity is higher in women than men and is expected to increase over time in both sexes. Prospective studies have shown that obesity, abdominal adiposity, and metabolic syn- drome are independent risk factors for stroke in both men and women. Further research is needed to determine whether sex modifies the impact of these conditions on stroke risk and out- comes. Healthy lifestyle practices, including maintaining a normal BMI, eating a diet rich in fruits and vegetables, moder- ate alcohol use, abstaining from smoking, and regular exercise, are associated with lower stroke incidence and better outcomes after stroke; however, little is known about sex differences in the effect of healthy lifestyle on stroke incidence and outcomes. Further research is needed to determine effective lifestyle interventions for preventing stroke occurrence and recurrence in women. Research is needed to develop lifestyle interven- tions that are effective for both primary and secondary stroke prevention and for tailoring such interventions in women. Obesity, Metabolic Syndrome, and Lifestyle Factors: Recommendations 1. A healthy lifestyle consisting of regular physical activity, moderate alcohol consumption (<1 drink/d for nonpregnant women), abstention from cigarette smoking, and a diet rich in fruits, vegetables, grains, nuts, olive oil, and low in saturated fat (such as the DASH [Dietary Approaches to Stop Hypertension] diet) is recommended for primary stroke prevention in women with cardiovascular risk factors (Class I; Level of Evidence B). 2. Lifestyle interventions focusing on diet and exercise are recommended for primary stroke prevention among individuals at high risk for stroke (Class I; Level of Evidence B). Atrial Fibrillation AF is the most common arrhythmia and a major modifiable risk factor for stroke. AF increases 4- to 5-fold the risk of IS and is associated with higher death and disability.19 The attrib- utable risk of stroke from AF increases with age, from 1.5% for those aged 50 to 59 years to nearly 25% for those aged 80 Whites carry the highest prevalence ofAF compared with blacks, Hispanics, Asians, and other ethnic groups.365 367 The overall number of men and women with AF is similar, but 60% of AF patients aged >75 years are women.368,369 Given that AF increases with age and that women have greater life expectancy, there will be an increasing number of Table 12. Metabolic Syndrome and Stroke HR, OR, or RR (95% CI) First Author Study Site n Follow-up, y Type of Study End Point Stroke Subtypes MetSD Definition Women Men Boden- USA 3298 Median: Prospective cohort Clinically defined stroke* Taiwan 3453 Mean: Prospective cohort Clinically defined stroke USA 10357 NA Cross-sectional Self-reported stroke cohort Clinically defined stroke Ischemic, hemorrhagic Japan 1493 Mean: Prospective cohort Clinically defined stroke Ischemic Other RR: 23.1 (2.7 196) NA USA, Europe, Asia 92732 Variable Review of prospective cohort Clinically defined stroke Ischemic, hemorrhagic NCEP-ATP III, WHO ATP III indicates Adult Treatment Panel III; CI, confidence interval; EGIR, European Group for the Study of Insulin Resistance; HR, hazard ratio; IDF, International Diabetes Federation; MetSD, metabolic syndrome; NA, not available; NCEP, National Cholesterol Education Program; OR, odds ratio; RR, relative risk; and WHO, World Health Organization. *Adjusted for MetSD, age, education, insurance status, any physical activity, smoking, moderate alcohol use, and cardiac disease. Adjusted for age, age squared, residential township, smoking, alcohol intake, physical activity level, parental history of stroke, and education level. Adjusted for age, sex, race, and cigarette smoking. Adjusted for age; systolic blood pressure; treatment for hypertension; history of cardiovascular disease, atrial fibrillation, and/or left ventricular hypertrophy; and smoking status. Adjusted for age and smoking. Bushnell et al Guidelines for Prevention of Stroke in Women 1569 elderly women with AF as the population ages.19 For exam- ple, in Get With The Guidelines Stroke, one third of hospital admissions for stroke were for stroke patients 80 years of age, and AF was identified in 15.6% of men and 20.4% of Moreover, women with AF are slightly less likely to receive anticoagulation therapy than men (88% Similar findings were observed in other studies.71,372 376 Risk Stratification for Women With AF The occurrence of stroke is one of the most feared compli- cations in patients with AF. Risk stratification tools, such as -VASc scores, are useful in guid- ing the decision making for anticoagulation therapy.377,378 The score uses a point system that includes congestive heart failure (1 point), hypertension (1 point), age 75 years (1 point), diabetes mellitus (1 point), and 2 points for prior stroke/ This scheme has been tested in several independent cohorts of patients with AF, with a score of 0 points indicating per year); and 2 points, high risk (1.9% to 7.6% per year).364 Female sex is an independent predictor of stroke in patients This has been incorporated into other risk strati- fication tools used in the decision making for anticoagulation -VASc score can be considered an exten- sion of the CHADS2 with extra points added for female sex (1 point), previous MI, peripheral arterial disease or aortic plaque (1 point), and age 65 to 74 years (1 point) or 75 years (2 points). The American College of Cardiology/AHA/European Society of Cardiology guidelines included similar risk strati- fication strategies as CHADS2 , with the inclusion of left ven- tricular ejection fraction <35% in the high-risk category. The -VASc score has been recommended recently by the European Society of Cardiology for risk classification.368,384 387 Two large cohort studies have both confirmed an age-sex interaction in patients with AF, which suggests a higher risk of stroke in women 75 years with AF compared with men.372,382 For example, in a large study that included 100802 patients with nonvalvular AF in Sweden, the incident risk of IS was greater in women than in men (6.2% versus 4.2% per year, Another large population-based study comprising 39398 men (47.2%) and 44115 women (52.8%) aged 65 years with AF from Canada showed a higher crude stroke incidence in men (1.61 per 100 person-years; 95% CI, 1.54 1.69; P<0.001). The observed difference was mainly driven by women aged 75 years. The stroke incidence per 100 person- years among participants aged 75 years was 2.38 (95% CI, 2.28 2.49) in women and 1.95 (95% CI, 1.84 2.07) in men (P<0.001). The stroke risk was significantly higher for women both for those taking or not taking warfarin. The multivariable analysis also revealed a similar increased risk of stroke in women (adjusted baseline comorbid conditions, individual components of the score, and warfarin treatment.372 There was a signifi- cant (P=0.02) interaction of age with sex, with the increased stroke risk confined to women aged 75 years. The age-sex interaction on stroke risk in patients with AF was again con- firmed recently in a large Swedish nationwide drug registry Interestingly, warfarin use was associated with greater stroke reduction in women (60%; RR, 0.4; 95% CI, Appropriateness of Anticoagulation by Sex The appropriateness of anticoagulation in women with AF <65 years of age with no other major or clinically relevant risk factors is controversial. The European Society of Cardiology recommends anticoagulation for patients with AF and a -VASc score 1.387 The Canadian Cardiovascular Society recommends anticoagulation for AF patients with a According to these guidelines, anticoag- ulation would be recommended for all women with AF alone (and no other risk factors). Two large observational studies provide some guidance. The Swedish study (n=100802) found that the risk of stroke among patients with AF aged 65 years without risk fac- tors was comparably low in both women (0.7%) and men Another nationwide study from Denmark that included 73538 patients with AF looked at the short- and long-term risk of thromboembolic events by combining the risk factors included in CHA2 The authors found that female sex alone was the weaker risk factor, showing a nonsignificant increase in the risk of thromboembolic events 0.70 1.06) and 10-year (0.82; 95% CI, 0.68 1.00) follow-up. The increased risk of thromboembolic events rose in women The AHA provides recommendations based on CHADS2 . The great majority of patients being assessed at stroke pre- vention clinics have a CHADS2 score 2, the clinical situation with strong evidence in favor of anticoagulation for high-risk patients (Class I; Level of Evidence A).377 These data suggest that women, especially those aged 75 years, have a higher stroke risk, and most benefit from anticoagulation therapy. Younger women (<65 years old) with AF alone (no other risk factors) have a lower risk of stroke. No specific sex benefits were observed when rate versus rhythm control strategies Evidence From Randomized Clinical Trials of New Oral Anticoagulants Most recent randomized clinical trials of new oral antico- agulants showed better stroke risk reduction and lower risk of intracranial bleeding. The benefit in women was compa- rable to that in men391 393 (Table 13). The RELY (Randomized Evaluation of Long-term Anticoagulant Therapy) study ran- domly assigned 18113 patients (36.4% women) withAF and a risk of stroke (mean CHADS2 score 2.2) to receive fixed doses of dabigatran (110 or 150 mg twice daily) or adjusted-dose warfarin. The median follow-up period was 2.0 years. The pri- mary outcome was stroke or systemic embolism. ARISTOTLE (Apixaban for the Prevention of Stroke in Subjects With Atrial Fibrillation) was a randomized, double- blind trial comparing apixaban (5 mg twice daily) versus warfarin (target international normalized ratio, 2.0 3.0) in 18201 patients with AF and at least 1 additional risk factor for stroke (mean CHADS2 score 2.1). Women constituted one third (35.3%) of participants. The primary outcome was isch- emic or hemorrhagic stroke or systemic embolism.391,391a ROCKET AF (Rivaroxaban Once Daily, Oral, Direct Factor Xa Inhibition Compared With Vitamin K Antagonism for Prevention of Stroke and Embolism Trial in Atrial Fibrillation) was a double-blind trial that randomly assigned 14264 patients with nonvalvular AF who were at increased risk for stroke to receive either rivaroxaban (20 mg daily) or dose-adjusted warfarin. Women represented 39.7% of the participants. The primary end point was stroke or systemic Of note, the risk of stroke was greater among participants in ROCKET AF than in RELY or ARISTOTLE, because the mean CHADS2 score was 3.47, with no patients in the lowest categories. Although all 3 trials using new oral anti- coagulants consistently showed a greater number of events per year among women, none demonstrated a differential benefit by sex for the primary or secondary outcomes (P value for the interaction was not significant).391 393 These results should be interpreted with caution, because none of these studies were powered to determine a sex difference in the efficacy of new oral anticoagulants over warfarin. In addition, women with AF had on average 30% higher concentrations of dabigatran than their male counterparts for the same given dose. The effect is most likely attributable to the average 30% lower creatinine clearance in women. No dose adjustment is required according to the product mono- graph or approval by regulatory agencies.394 396 Limited infor- mation is available among patients who participated in RELY with a body weight <50 kg.392 There were no differences in serum concentrations by sex for apixaban and rivaroxa- Finally, some questions remain regarding the incom- plete or scarce information on sex differences in the dosing of new oral anticoagulants. AF: Summary and Gaps AF is a major modifiable stroke risk factor, independently associated with a 4- to 5-fold increased risk of IS. AF is responsible for 1.5% to 25% of all IS depending on the age group. Anticoagulation is the most effective therapeutic strategy to decrease the risk of stroke. Risk stratification tools, such as CHA2 -VASc, are useful to stratify the risk of stroke and assist clinicians in the decision to initiate antico- agulation therapy. New oral anticoagulants are a useful alter- native to warfarin for the prevention of stroke and systemic thromboembolism; however, caution about overdosing must be used considering the additive effect of age, sex, renal func- tion, and concomitant medications (acetylsalicylic acid, clopi- dogrel, nonsteroidal anti-inflammatory drugs, P-glycoprotein inhibitors) in increasing the concentrations of new oral anticoagulants. Future research is needed to determine the appropriate dose of new oral anticoagulants in older women with a lower weight (eg, <50 kg) who are also exposed to other comor- bidities (eg, renal impairment) that influence the pharmaco- kinetics of these agents. In addition, none of the trials of new anticoagulants were powered to determine a sex difference in efficacy versus warfarin. AF: Recommendations 1. Risk stratification tools in AF that account for age- and sex-specific differences in the incidence of stroke are recommended (Class I; Level of Evidence A). 2. Considering the increased prevalence of AF with age and the higher risk of stroke in elderly women with AF, active screening (in particular of women >75 years of age) in primary care settings using pulse taking followed by an ECG as appropriate is recom- mended (Class I; Level of Evidence B). 3. Oral anticoagulation in women aged 65 years with AF alone (no other risk factors; women with -VASc=1) is not recom- mended (Class III; Level of Evidence B). Antiplatelet therapy is a reasonable therapeutic option for selected low-risk women (Class IIa; Level of Evidence B). 4. New oral anticoagulants are a useful alternative to warfarin for the prevention of stroke and systemic thromboembolism in women with paroxysmal or permanent AF and prespecified risk factors (accord- ing to CHA2 -VASc) who do not have a prosthetic heart valve or hemodynamically significant valve dis- ease, severe renal failure (creatinine clearance <15 Table 13. Primary and Secondary Outcomes Among Participants in the ARISTOTLE, RELY, and ROCKET AF Trials Stratified by Sex ARISTOTLE RELY ROCKET AF No. of Events (%/y) No. of Events (%/y) No. of Events (%/y) n Apixaban Warfarin n Dabigatran Dabigatran 150 mg Warfarin n Rivaroxaban Warfarin Primary outcome Major bleeding ARISTOTLE indicates Apixaban for the Prevention of Stroke in Subjects With Atrial Fibrillation; RELY, Randomized Evaluation of Long-term Anticoagulant Therapy; and ROCKET AF, Rivaroxaban Once Daily, Oral, Direct Factor Xa Inhibition Compared With Vitamin K Antagonism for Prevention of Stroke and Embolism Trial in Atrial Fibrillation. Bushnell et al Guidelines for Prevention of Stroke in Women 1571 mL/min), lower weight (<50 kg), or advanced liver disease (impaired baseline clotting function) (Class I; Level of Evidence A). Depression and Psychosocial Stress In addition to being a well-recognized sequela of stroke,397 depression is associated with increased risk of stroke inci- dence among both women and men. In the INTERSTROKE case-control study of stroke participants from 22 countries,92 investigators found that self-reported depression (defined as feeling sad, blue, or depressed for 2 consecutive weeks dur- ing the past 12 months) was associated with a 35% increased odds of stroke (95% CI, 1.10 1.66) after adjustment for age, sex, and region. In addition, psychosocial stress (defined with a combined measure of general stress at home and in the workplace and categorized by permanent or several periods of stress versus no or some periods of stress in the past year) was associated with a 30% increased odds of stroke (95% CI, 1.06 1.60) in the adjusted model. Although the multivariable models were adjusted for sex, there were no sex-specific anal- yses performed in this cohort. In the Nurses Health Study, women with a history of depression had a 29% increased risk of incident total stroke (multivariate RR, 1.29; 95% CI, 1.13 In a meta-analysis of prospective studies of depres- sion and stroke, the pooled adjusted HRs were 1.45 (95% CI, 1.29 1.63) for total stroke and 1.25 (95% CI, 1.11 1.40) for IS. The cumulative ORs for studies that included only men or only women revealed no difference in the strength of associa- tion between depression and stroke compared with the cumu- lative OR for studies that included both sexes.399 Depression and Psychosocial Stress: Summary and Gaps Depression is associated with increased risk of stroke. More research is needed to understand the mechanisms underlying the association between depression and stroke, as well as to determine which women with depression may be at risk, such as those who are treated versus untreated, and whether self- reported measures such as those used in the INTERSTROKE study are the most accurate to determine stroke risk. There is also a lack of sex-specific analyses in many of the cohorts that have assessed multiple risk factors. Because depression and psychosocial stressors are more common in women, it may be reasonable to test these risk factors in a woman-specific stroke risk score. Strategies for Prevention of Stroke: Are They Different in Women? Representation of Women in Stroke Clinical Trials Women account for less than half of all subjects enrolled in National Institutes of Health funded stroke prevention clini- cal drug trials of the past decade. It has also been recognized that women have been underrepresented in clinical trials in surgery, overall CVD, and cancer.400 403 Sex disparities in cerebrovascular disease clinical trial participation have been less well examined.404 The low proportion of women in clini- cal stroke prevention trials limits the generalization of results across the sexes. Conventional subgroup analyses in women are commonly flawed by type II error. As a result, it remains unclear whether current evidence-based practices apply to women, who represent half of all stroke victims. In response to recognition that overall, women were under- represented in National Institutes of Health sponsored trials, the National Institutes of Health Revitalization Act (public law 103-43), which required inclusion of women in clinical trials of diseases affecting women, was enacted in 1993.402,405 Unfortunately, to date, the legislation appears to have had little impact. A review of articles published in The New England Journal of Medicine after enactment of the legislation reported that there was no change in the overall rate of enrollment of females, which remained at roughly 25%.406 Neurological clinical trials were among the most successful in enrolling women, with a participation rate of 45%. A subsequent review of National Institutes of Health funded studies found that only 24% of enrolled drug study populations were women.400 This lack of recruitment continues in recent trials. For example, only 20% of women were recruited in the WARCEF trial (Warfarin Versus Aspirin Use in Patients With Impaired LV Function) as recently as 2012.407 Factors that may play a role in the appar- ent underrepresentation of women in clinical trials may be sex differences in disease prevalence and age at onset in women. A systematic review of enrollment of women in trials of coronary artery disease, heart failure, arrhythmia, and primary preven- tion reported that after accounting for age- and sex-specific dif- ferences in disease prevalence, the enrollment gaps for women narrowed, ranging from 3% for primary prevention to 13% for heart failure. Stroke was not included in this analysis, how- The percentage of women enrolled in recent stroke pre- vention trials of carotid disease and antiplatelet agents ranges from 25% to 53%, with an average of 34%, which is generally below the stroke prevalence rates by sex (Tables 14 and15). CEA Versus Medical Management for Symptomatic or Asymptomatic Carotid Stenosis Differences in the anatomy of the internal carotid arter- ies and differences in the composition of plaque between women and men have fueled speculation that there may be differential risk or benefit to intervention. Compared with men, women have smaller-caliber internal carotid arteries and shorter stenotic segments.425,426 CEA is also performed less often in women, likely because of the lower incidence of high-grade symptomatic stenosis.427,428 In a retrospective cohort study at Kaiser Permanente Medical Care Plan, for the period 2003 to 2004, 299 patients were identified on the basis of a diagnosis of TIA and carotid stenosis (>70%), that is, symptomatic stenosis.427 Approximately half (47%) were women. Women were less likely to undergo CEA (36.4% versus 53.8% in men; P=0.004). Being female remained an independent predictor for not receiving CEA after adjust- ment for age, number of TIAs, specificity of TIA symptoms, and degree of stenosis. In patients who underwent CEA, the time to surgery was longer in women (mean of 35 days) than men (mean of 18 days; P=0.03),427 whereas the current recommendations are to perform CEA within 2 weeks of symptoms of TIA or mild stroke.20 In the surgical subgroup, women were older and less likely to have coronary artery disease. Outcomes were similar in men and women in both the CEA and medical management groups.427 In subgroup analyses of some trials comparing medi- cal management to CEA in patients with symptomatic or asymptomatic carotid stenosis, women appeared to derive less benefit from surgery than men, potentially because of an increased risk of perioperative events411 413 ; however, the data were inconclusive because of small sample sizes within sex strata and the post hoc nature of some of the analyses. Only 1 trial, the Asymptomatic Carotid Surgery Trial, conducted a prespecified secondary analysis by sex Although for all the subgroup analyses, the results were similar to that first found in the Asymptomatic Carotid they were statistically significant only for the European Carotid Surgery Trial, but this was a post hoc analysis.411 CEA Versus Carotid Artery Stenting Carotid artery stenting (CAS) has emerged as an alternative strategy for the management of carotid stenosis.414 416,429,430 In a meta-analysis of 3 European trials comparing CEA to CAS in symptomatic patients, there was no interaction between sex and 120-day outcome.431 The North American Carotid Revascularization Endarterectomy Versus Stenting Trial (CREST) assigned 2502 patients with symptomatic and asymptomatic carotid stenosis to either CEA or CAS. Roughly 35% (n=872) of the subjects were women. Rates of stroke, MI, or death of any cause during the periprocedural period or any ipsilateral stroke within 4 years after random- ization for CAS compared with CEA were 6.2% versus 6.8% Periprocedural events (from randomization to 30 days after the procedure) occurred in 4.3% of 807 men versus 6.8% of 455 women assigned to CAS and 4.9% of 823 men versus 3.8% of 417 women assigned to CEA, with significant interaction The CAS-to-CEA treatment difference was also affected by age (P=0.02), with older patients faring bet- ter with CEA and younger patients faring better with CAS.433 There was no evidence (P=0.45) that this effect by age was different for women than men. Although data from CREST suggest that women with CAS (relative to CEA) may be at higher risk for the composite outcome of stroke, death, or MI during the periprocedural period, this finding should be inter- preted with caution pending confirmation from other trials. At present, there may not be sufficient data to conclude that high-grade symptomatic or asymptomatic carotid stenosis should be managed differently in men and women with regard to the type of procedure, or whether it should be managed medically. Without definitive data, the recommendations in the guidelines for prevention of first or recurrent stroke should be applied to women.19,20,434 Aspirin for Prevention of Stroke in Women One of the seminal trials of primary prevention of CVD, including stroke, in women is the WHS, a randomized trial of 100 mg of aspirin on alternate days versus placebo in 39876 initially asymptomatic women 45 years of age, followed up for 10 years for a first major vascular event (nonfatal MI, non- fatal stroke, or cardiovascular death).435 Although there was a P=0.13) in the combined primary end point among women, the study found a 17% reduction in the risk of stroke (RR, reduction in the risk of IS (RR, 0.76; 95% CI, 0.63 0.93; P=0.009) and a nonsignificant increase in the risk of hemor- overall average stroke rates were 0.11% per year in aspirin- treated women and 0.13% per year in placebo- treated women (RR, 0.02% per year; number needed to treat, 5000). An important adverse outcome, gastrointestinal hemorrhage requiring transfusion, was more frequent in the aspirin group increase, 0.01% per year; number needed to harm, 10000). The most consistent benefit for aspirin was in women 65 years of age at study entry, among whom the risk of major cardiovascular events was reduced by 26% (RR, 0.74; 95% CI, 0.59 0.92; P=0.008), including a 30% reduction in the Table 14. Representation of Women in Carotid Intervention Trials Trial Total Patients (% Women) ACAS indicates Asymptomatic Carotid Atherosclerosis Study; ACST, Asymptomatic Carotid Surgery Trial; CREST, Carotid Revascularization Endarterectomy Versus Stenting Trial; ECST, European Carotid Surgery Trial; EVA-3S, Endarterectomy Versus Angioplasty in Patients With Symptomatic Severe Carotid Stenosis; NASCET, North American Symptomatic Carotid Endarterectomy Trial; NASCET moderate, North American Symptomatic Carotid Endarterectomy Trial (patients with moderate stenosis only); and SPACE, Stent- Protected Angioplasty Versus Carotid Endarterectomy. Table 15. Representation of Women in Antiplatelet Trials Trial Total Patients Enrolled (% Women) AAASPS indicates African American Antiplatelet Stroke Prevention Study; ACE, ASA [acetylsalicylic acid] and Carotid Endarterectomy Trial; CAPRIE, Clopidogrel Versus Aspirin in Patients at Risk of Ischaemic Events; ESPS-2, European Stroke Prevention Study 2; ESPRIT, European/Australasian Stroke Prevention in Reversible Ischaemia Trial; MATCH, Management of Atherosclerosis With Clopidogrel in High-Risk Patients; PRoFESS, Prevention Regimen for Effectively Avoiding Second Strokes; and SPS3, Secondary Prevention of Small Subcortical Strokes. Bushnell et al Guidelines for Prevention of Stroke in Women 1573 risk of IS (RR, 0.70; 95% CI, 0.49 1.00; P=0.05); how- ever, the benefit was reduced when the combination of IS and hemorrhagic stroke was considered (RR, 0.78; 95% CI, 0.57 1.08; P=0.13). On the basis of the WHS results, aspirin is recommended for primary prevention for women after con- sideration of the 10-year risk of CVD and whether this and age outweigh the risk of hemorrhage.21 A large, sex-specific meta-analysis of aspirin for primary prevention of IS (separate from other cardiovascular events) showed that women appeared to benefit from aspirin (OR, 0.76; 95% CI, 0.63 0.93), whereas men showed no benefit For heart disease, however, men benefited from aspirin for prevention against coronary heart disease, whereas women did not. As in men, aspirin allocation in primary prevention trials increased the risk of hemorrhagic stroke and major gastrointestinal and extracra- nial bleeds among women and resulted in uncertain net value. There is no evidence of a differential effect of antiplate- let agents for secondary stroke in women compared with The Antithrombotic Trialists meta-analysis of aspirin for the primary and secondary prevention of vascu- lar events (MI, stroke, vascular death) also included individual patient data from each of the trials.437 They found similar pro- portional reductions in risk for men and women for the com- bined outcome; however, there was a trend toward benefit for primary prevention in women versus men, although this was no longer the case when the P value was adjusted for multiple In secondary prevention (among patients who already have occlusive vascular disease), aspirin appears to result in a greater absolute benefit for stroke prevention, with similar magnitude of effect for women and men, and a 19% reduction in stroke risk.437 Strategies for Prevention of Stroke in Women: Summary and Gaps In all clinical trials of primary and secondary stroke pre- vention, women need to be included in sufficient numbers for preplanned subgroup analysis, with reasonable statisti- cal power to provide for valid analysis to test for sex inter- Questions about the benefits and risks of carotid procedures in women with asymptomatic high-grade carotid stenosis and symptomatic treatment for moderate (50% 69%) carotid stenosis remain unanswered. Until further studies are performed, the recommendations for prevention of stroke in women with carotid disease (symptomatic or asymptom- atic) remain the same as for men, as published in the primary and secondary prevention guidelines.19,20 For aspirin, the recommendations below for women are as published in the AHA s Effectiveness-Based Guidelines for the Prevention of Cardiovascular Disease in Women. 21 Strategies for Prevention of Stroke in Women: Recommendations 1. Women with asymptomatic carotid stenosis should be screened for other treatable risk factors for stroke, and appropriate lifestyle changes and medi- cal therapies should be instituted (Class I; Level of 2. In women who are to undergo CEA, aspirin is recom- mended unless contraindicated, because aspirin was used in every major trial that demonstrated efficacy of CEA (Class I; Level of Evidence C). 3. Prophylactic CEA performed with <3% morbidity/ mortality can be useful in highly selected patients with an asymptomatic carotid stenosis (minimum 60% by angiography, 70% by validated Doppler ultrasound) (Class IIa; Level of Evidence A). 4. For women with recent TIA or IS within the past 6 months and ipsilateral severe (70% 99%) carotid artery stenosis, CEA is recommended if the periop- erative morbidity and mortality risk is estimated to be <6% (Class I; Level of Evidence A).20 5. For women with recent TIA or IS and ipsilateral moderate (50% 69%) carotid stenosis, CEA is rec- ommended depending on patient-specific factors, such as age and comorbidities, if the perioperative morbidity and mortality risk is estimated to be <6% (Class I; Level of Evidence B).20 6. When CEA is indicated for women with TIA or stroke, surgery within 2 weeks is reasonable rather than delaying surgery, if there are no contraindica- tions to early revascularization (Class IIa; Level of 7. Aspirin therapy (75 325 mg/d) is reasonable in women with diabetes mellitus unless contraindicated (Class IIa; Level of Evidence B).21 8. If a high-risk (ie, 10-year predicted CVD risk 10%) woman has an indication for aspirin but is intolerant of aspirin therapy, clopidogrel should be substituted (Class I; Level of Evidence B).21 9. Aspirin therapy can be useful in women 65 years of age (81 mg/d or 100 mg every other day) if BP is controlled and the benefit for IS and MI prevention is likely to outweigh the risk of gastrointestinal bleeding and hemorrhagic stroke (Class IIa; Level of Evidence B) and may be reasonable for women <65 years of age for IS prevention (Class IIb; Level of Evidence B).21 Data Shaping Development and Validation of Risk Scores Use of Sex-Specific Stroke Risk Prediction Scores Risk scores have been advocated to clinically classify indi- viduals according to their overall risk to guide prevention and treatment recommendations. The goal of such scores is to accurately classify individuals as high or low risk so that high-risk individuals receive appropriate interventions to reduce risk. Although there are several general cardiovascular risk there are fewer stroke-specific scores. Risk prediction models that are specific to women have not been developed. Furthermore, whether risk factors differ by age and racial/ethnic group has not been established. The Framingham stroke risk calculator does take sex into The number of points assigned to particular con- ditions differs by sex, with diabetes mellitus, systolic BP, and AF garnering a higher number of points in women than men, whereas women with existing CVD receive fewer points than do men (Table 16). Moreover, the 10-year probability of stroke from the Framingham Stroke Risk Score (FSRS) is lower for women than for men with the same score (Table 17); however, few other widely validated stroke prediction scores for the general population are available. Data in minorities and women are limited. The FSRS was derived in a predominantly white, middle- to older-aged population in a single community. The FSRS was applied to the Cardiovascular Health Study (CHS) population of men and women >65 years of age, and it was found that the FSRS model predicted stroke less effectively in elderly women than men. A CHS stroke risk model and applet were created that improved discrimination in women (area under the receiver operating characteristic curve of 0.73 for FSRS in women compared with 0.77 for the CHS model in women; Additional variables included in the CHS score included time to walk 15 feet (functional status) and creati- nine. When the FSRS was used to evaluate risk in a group of elderly French men and women (aged 65 84 years at base- line), it overestimated the risk substantially (by a factor of 4.4 in women and 3.7 in men), which led to a recalibrated stroke score for that population.442 Therefore, comparative data are needed on how well risk scores perform in women versus men and in different racial and ethnic populations. Several stroke risk scores were developed exclusively for use in men,443,444 but woman-specific models are needed to more accurately reflect risk across the lifespan. Specific risk factors are unique to or more common in women that have not been included in traditional risk assessment (Table 3). Prospective research is needed for these woman-specific risk factors, including pregnancy-related risk factors and hormonal exposure (OCs and postmenopausal HT), as well as changes in hormone status across the lifespan (menarche, menopause, and oophorectomy). For example, preeclampsia clearly increases risk of stroke in the peripartum period and has been listed as a risk factor for CVD in women in the 2011 AHA Effectiveness-Based Guidelines for the Prevention of Cardiovascular Disease in Women 21 ; however, relatively lim- ited data on long-term risk of stroke among women with a history of preeclampsia are available.180 In addition, several less traditional risk factors, including psychosocial stress and depression, were important in the INTERSTROKE study92 and other observational studies398,399 but are not included in tradi- tional risk scores.440,445 Women have higher rates of depression, and thus, these factors may be of greater impact for women.446 Additionally, there are potential differences in the risk of stroke among older individuals with AF, with higher rates in women despite warfarin therapy, as discussed above.372 Whether bio- markers, in addition to lipid measures, additionally contribute to risk stratification in women is unclear. C-reactive protein, an inflammatory marker that is also included in the Reynolds Cardiovascular Risk Score,439,447 was found to improve predic- tion of risk of IS, particularly cardioembolic stroke, in older women in the WHI.448 Lipoprotein-associated phospholipase was associated with improvement in the prediction of large- Additional evaluation of other biomarkers for risk prediction will be of continued interest. Woman-Specific Risk Score: Summary and Gaps Consideration of the risk factors that are unique to women and are more prevalent or differentially increase risk, compared with men, may improve the accuracy of stroke risk assessment compared with current risk scores. This is especially true for younger women of reproductive age. Prospective data on the long-term stroke risk of women with a history of preeclampsia Table 16. Risk Factors and Points Included in the Framingham Stroke Risk Score for 10-Year Stroke Risk Prediction in Women* Diabetes mellitus No Yes Cigarette smoking No Yes Prior CVD No Yes AF No Yes LVH on ECG No Yes Yes AF indicates atrial fibrillation; CVD, cardiovascular disease; ECG, electrocardiogram; LVH, left ventricular hypertrophy; and SBP, systolic blood pressure. *Available at http://www.framinghamheartstudy.org/risk-functions/stroke/stroke.php. CVD is defined as any of the following: history of myocardial infarction, angina pectoris, coronary insufficiency, intermittent claudication, or congestive heart failure. Table 17. Ten-Year Stroke Probability in Women According to Framingham Stroke Risk Score Points Probability, % Points Probability, % Points Probability, % Bushnell et al Guidelines for Prevention of Stroke in Women 1575 and other pregnancy-related complications are also needed.449 Further development of stroke risk prediction models in women could be achieved by use of data from large, diverse longitudinal studies including the WHI, WHS, Nurses Health Study, ARIC study, Multi-Ethnic Study of Atherosclerosis (MESA), and Reasons for Geographic and Racial Differences in Stroke (REGARDS) study. Sex-specific and race- and eth- nic-specific analyses need to be conducted explicitly to deter- mine whether current and future risk scores perform equally well in white, black, and Latina women. Conclusions and Summary In this guideline, we have summarized the current evidence and provided summaries and gaps for prevention focused on the risk factors that are either unique to or more common in women than men. Some of the recommendations in this guideline were formerly associated with other prevention guidelines but have been assimilated because of the focus on women. In addition, we have summarized the data that sup- port the development of woman-specific stroke risk profiles, which might more accurately reflect a woman s future risk of stroke than some of the currently available stroke risk profiles. Prevention efforts for women would be enhanced if future epidemiological studies provided more detail on stroke sub- type, especially hemorrhagic stroke, in addition to accounting for age and sex. Similarly, it is important to improve stroke awareness and provide more rigorous education to women at younger ages, including childbearing ages, because of women s increased risk of stroke with age; the risks of stroke associated with pregnancy, gestational hypertension, and hor- monal contraception; and the onset of stroke risk factors such as obesity, hypertension, and diabetes mellitus, which occur at younger ages. Future research focused on risk profile devel- opment is urgently needed to appropriately tailor prevention strategies for women. There is a need for recognition of wom- en s unique sex-specific stroke risk factors, and a risk score that includes these factors would thereby identify women at risk. Until sex-specific risk is better understood, prevention and management of stroke and cardiovascular risk factors remains essentially the same for men and women. Disclosures Writing Group Disclosures Writing Group Member Employment Research Grant Other Research Support Speakers Bureau/ Honoraria Expert Witness Ownership Interest Consultant/ Advisory Board Other Cheryl Bushnell Wake Forest School of Medicine NIH/NINDS World Federation of Neurology None None None None None Louise D. McCullough University of Connecticut NIH/NINDS None Genentech* None None None None Issam A. Awad University of Chicago NIH/NINDS None None None None None None Monique V. Chireau Duke University Medical Center None None None None None None None Wende N. Fedder Alexian Brothers Health System None None None None None None None Karen L. Furie The Warren Alpert Medical School of Brown University/ Lifespan AHA ; NINDS None None None None UpToDate* JNNP Deputy Editor ; Stroke Vice Editor Virginia J. Howard University of Alabama at Birmingham NIH None None None None Spouse has relationship with Abbott Vascular*; spouse has relationship with Bayer* None Judith H. Lichtman Yale University AHA ; NINDS None None None None None None Lynda D. Lisabeth University of Michigan NIH None None None None None None Ileana L. Pi a Montefiore Medical Center None None None None None None None Mathew J. Reeves Michigan State University None None None None None None None Kathryn M. Rexrode Brigham and Women s Hospital NIH/NHLBI None None None None None None Gustavo Saposnik University of Toronto None None None None None Bayer* None Vineeta Singh University of California, San Francisco None None None None None None None Amytis Towfighi University of Southern California; Rancho Los Amigos National Rehabilitation Center AHA ; NIH/ NINDS None Boehringer Ingelheim* None None None None Viola Vaccarino Emory University None None None None None None None Matthew R. Walters University of Glasgow AstraZeneca*; GlaxoSmithKline*; Lundbeck*; Menarini*; Microtransponder, Inc*; Roche* None None None None Bayer*; Lundbeck*; UCB Pharma* None This table represents the relationships of writing group members that may be perceived as actual or reasonably perceived conflicts of interest as reported on the Disclosure Questionnaire, which all members of the writing group are required to complete and submit. A relationship is considered to be significant if (1) the person receives $10000 or more during any 12-month period, or 5% or more of the person s gross income; or (2) the person owns 5% or more of the voting stock or share of the entity, or owns $10000 or more of the fair market value of the entity. A relationship is considered to be modest if it is less than significant under the preceding definition. *Modest. Significant. Bushnell et al Guidelines for Prevention of Stroke in Women 1577 References 1. 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