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.


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.


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.


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.


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.


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.


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.


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.


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).


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).


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.


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.


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.


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.


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.


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).


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.


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.


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.


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. Go AS, Mozaffarian D, Roger VL, Benjamin EJ, Berry JD, Borden WB, Bravata DM, Dai S, Ford ES, Fox CS, Franco S, Fullerton HJ, Gillespie C, Hailpern SM, Heit JA, Howard VJ, Huffman MD, Kissela BM, Kittner SJ, Lackland DT, Lichtman JH, Lisabeth LD, Magid D, Marcus GM, Marelli A, Matchar DB, McGuire DK, Mohler ER, Moy CS, Mussolino ME, Nichol G, Paynter NP, Schreiner PJ, Sorlie PD, Stein J, Turan TN, Virani SS, Wong ND, Woo D, Turner MB; on behalf of the American Heart Association Statistics Committee and Stroke Statistics Subcommittee. Heart disease and stroke statistics 2013 update: a report from the American Heart Association [published corrections appear in Circulation. 2013;127:e841 and Circulation. 2013;127]. Circulation. 2013;127:e6 e245. 2. National Center for Health Statistics. Health, United States, 2011. Hyattsville, MD: US Department of Health and Human Services, Centers for Disease Control and Prevention, National Center for Health Statistics; 2012. http://www.cdc.gov/nchs/hus/contents2011.htm#031. Accessed December 31, 2012. 3. US Department of Health and Human Services, Administration on Aging. A profile of older Americans: 2011. http://www.aoa.gov/AoAroot/Aging_ Statistics/Profile/2011/docs/2011profile.pdf. Accessed March 6, 2013. 4. Reeves MJ, Bushnell CD, Howard G, Gargano JW, Duncan PW, Lynch G, Khatiwoda A, Lisabeth L. Sex differences in stroke: epidemiol- ogy, clinical presentation, medical care, and outcomes. Lancet Neurol.


Reeves MJ, Bushnell CD, Howard G, Gargano JW, Duncan PW, Lynch G, Khatiwoda A, Lisabeth L. Sex differences in stroke: epidemiol- ogy, clinical presentation, medical care, and outcomes. Lancet Neurol. 2008;7:915 926. 5. Kelly-Hayes M, Beiser A, Kase CS, Scaramucci A, D Agostino RB, Wolf PA.Theinfluenceofgenderandageondisabilityfollowingischemicstroke: the Framingham study. J Stroke Cerebrovasc Dis. 2003;12:119 126. 6. Seshadri S, Beiser A, Kelly-Hayes M, Kase CS, Au R, Kannel WB, Wolf PA. The lifetime risk of stroke: estimates from the Framingham Study. Stroke. 2006;37:345 350. 7. Gall SL, Tran PL, Martin K, Blizzard L, Srikanth V. Sex differences in long-term outcomes after stroke: functional outcomes, handicap, and quality of life. Stroke. 2012;43:1982 1987. 8. Gargano JW, Reeves MJ; Paul Coverdell National Acute Stroke Registry Michigan Prototype Investigators. Sex differences in stroke recovery and stroke-specific quality of life: results from a statewide stroke registry. Stroke. 2007;38:2541 2548. 9. Holroyd-Leduc JM, Kapral MK, Austin PC, Tu JV. Sex differences and similarities in the management and outcome of stroke patients. Stroke. 2000;31:1833 1837. 10. Kim JS, Lee KB, Roh H,Ahn MY, Hwang HW. Gender differences in the functional recovery after acute stroke. J Clin Neurol. 2010;6:183 188. 11. Paolucci S, Bragoni M, Coiro P, De Angelis D, Fusco FR, Morelli D, Venturiero V, Pratesi L. Is sex a prognostic factor in stroke rehabilitation? A matched comparison. Stroke. 2006;37:2989 2994. 12. Petrea RE, Beiser AS, Seshadri S, Kelly-Hayes M, Kase CS, Wolf PA. Gender differences in stroke incidence and poststroke disability in the Framingham Heart Study. Stroke. 2009;40:1032 1037. 13. Roquer J, Campello AR, Gomis M. Sex differences in first-ever acute stroke. Stroke. 2003;34:1581 1585. 14. Fish EN. The X-files in immunity: sex-based differences predispose immune responses. Nat Rev Immunol. 2008;8:737 744. 15. Pennell LM, Galligan CL, Fish EN. Sex affects immunity. J Autoimmun. 2012;38:J282 J291.


Pennell LM, Galligan CL, Fish EN. Sex affects immunity. J Autoimmun. 2012;38:J282 J291. 16. Rauch U. Gender differences in anticoagulation and antithrombotic ther- apy. Handb Exp Pharmacol. 2012:523 542. 17. Zuern CS, Lindemann S, Gawaz M. Platelet function and response to aspirin: gender-specific features and implications for female thrombotic risk and management. Semin Thromb Hemost. 2009;35:295 306. 18. Haast RA, Gustafson DR, Kiliaan AJ. Sex differences in stroke. J Cereb Blood Flow Metab. 2012;32:2100 2107. 19. Goldstein LB, Bushnell CD, Adams RJ, Appel LJ, Braun LT, Chaturvedi S, Creager MA, Culebras A, Eckel RH, Hart RG, Hinchey JA, Howard VJ, Jauch EC, Levine SR, Meschia JF, Moore WS, Nixon JV, Pearson TA; on behalf of the American Heart Association Stroke Council, Council on Cardiovascular Nursing, Council on Epidemiology and Prevention, Council for High Blood Pressure Research, Council on Peripheral Vascular Disease, and Interdisciplinary Council on Quality of Care and Outcomes Research. Guidelines for the primary prevention of stroke: a guideline for healthcare professionals from the American Heart Association/American Stroke Association [published correction appears in Stroke. 2011;42:e26]. Stroke. 2011;42:517 584.


Guidelines for the primary prevention of stroke: a guideline for healthcare professionals from the American Heart Association/American Stroke Association [published correction appears in Stroke. 2011;42:e26]. Stroke. 2011;42:517 584. Reviewer Disclosures Reviewer Employment Research Grant Other Research Support Speakers Bureau/ Honoraria Expert Witness Ownership Interest Consultant/ Advisory Board Other Jo-Ann Eastwood University of California Los Angeles AHA None Preventive Cardiovascular Nurses: Expert exchange* None None None None Michael D. Hill University of Calgary Covidien (money goes to institution); Hoffmann-La Roche Canada (money goes to institution) Heart & Stroke Foundation Alberta (money goes to institution); Alberta Innovates Health Solutions (money goes to institution) None None None Merck Ltd.* None Marian Limacher University of Florida NIH None None None None None None Virginia Miller Mayo Clinic None None None None None None None Latha Stead University of Florida None None None None None None None Greg Zipfel Washington University NINDS ; AHA ; Brain Aneurysm Foundation*; Hope Center for Neurological Disorders*; Pfizer None None None None Pfizer* None This table represents the relationships of reviewers that may be perceived as actual or reasonably perceived conflicts of interest as reported on the Disclosure Questionnaire, which all reviewers 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. 20.


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