Sex and Race Differences in the Association of Incident Ischemic Stroke With Risk Factors | Cardiology | JAMA Neurology | JAMA Network
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Table 1.  Baseline Characteristics of Reasons for Geographic and Racial Differences in Stroke (REGARDS) Cohort Members Without History of Stroke at Baseline (N = 25 789)
Baseline Characteristics of Reasons for Geographic and Racial Differences in Stroke (REGARDS) Cohort Members Without History of Stroke at Baseline (N = 25 789)
Table 2.  Crude Ischemic Stroke Incidence Rates and Incidence Rate Ratios Stratified by Age Group, Race, and Sex
Crude Ischemic Stroke Incidence Rates and Incidence Rate Ratios Stratified by Age Group, Race, and Sex
Table 3.  Multivariable Joint Associations of Risk Factors With Incident Ischemic Stroke by Sex in White and Black Individualsa
Multivariable Joint Associations of Risk Factors With Incident Ischemic Stroke by Sex in White and Black Individualsa
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Original Investigation
December 10, 2018

Sex and Race Differences in the Association of Incident Ischemic Stroke With Risk Factors

Author Affiliations
  • 1Department of Epidemiology, School of Public Health, University of Alabama at Birmingham
  • 2Department of Emergency Medicine, Alpert Medical School of Brown University, Providence, Rhode Island
  • 3Department of Neurology and Rehabilitation Medicine, University of Cincinnati College of Medicine, Cincinnati, Ohio
  • 4Department of Biostatistics, School of Public Health, University of Alabama at Birmingham
  • 5Epidemiological Cardiology Research Center, Department of Epidemiology and Prevention, Wake Forest University School of Medicine, Winston Salem, North Carolina
  • 6Department of Internal Medicine, Cardiology Section, Wake Forest University School of Medicine, Winston Salem, North Carolina
  • 7Department of Medicine, Weill-Cornell Medicine, New York, New York
  • 8Department of Health and Human Services, National Institute of Neurological Disorders and Stroke, National Institutes of Health, Bethesda, Maryland
  • 9Department of Epidemiology and Biostatistics, Dornsife School of Public Health, Drexel University, Philadelphia, Pennsylvania
  • 10Department of Medicine, Larner College of Medicine, Colchester, Vermont
JAMA Neurol. 2019;76(2):179-186. doi:10.1001/jamaneurol.2018.3862
Key Points

Question  Are there sex differences in ischemic stroke incidence among black and white individuals or race-sex differences in the association of risk factors with stroke?

Findings  In this cohort study, among 25 789 black and white individuals in the United States, the ratio of stroke incidence rates between women and men was similar for black and white individuals across age groups, with women having lower stroke risk than men between 45 and 64 years of age and 65 and 74 years of age but similar risk at 75 years and older. For white individuals but not black individuals, the association of hypertension, diabetes, and heart disease with stroke risk differed by sex.

Meaning  Sex-specific risk factor management to prevent stroke may be needed for white individuals but not black individuals.

Abstract

Importance  Race-specific and sex-specific stroke risk varies across the lifespan, yet few reports describe sex differences in stroke risk separately in black individuals and white individuals.

Objective  To examine incidence and risk factors for ischemic stroke by sex for black and white individuals.

Design, Setting, and Participants  This prospective cohort study included participants 45 years and older who were stroke-free from the Reasons for Geographic and Racial Differences in Stroke (REGARDS) cohort, enrolled from the continental United States 2003 through 2007 with follow-up through October 2016. Data were analyzed from March 2018 to September 2018.

Exposures  Sex and race.

Main Outcomes and Measures  Physician-adjudicated incident ischemic stroke, self-reported race/ethnicity, and measured and self-reported risk factors.

Results  A total of 25 789 participants (14 170 women [54.9%]; 10 301 black individuals [39.9%]) were included. Over 222 120 person-years of follow-up, 939 ischemic strokes occurred: 159 (16.9%) in black men, 326 in white men (34.7%), 217 in black women (23.1%), and 237 in white women (25.2%). Between 45 and 64 years of age, white women had 32% lower stroke risk than white men (incidence rate ratio [IRR], 0.68 [95% CI, 0.49-0.94]), and black women had a 28% lower risk than black men (IRR, 0.72 [95% CI, 0.52-0.99]). Lower stroke risk in women than men persisted at age 65 through 74 years in white individuals (IRR, 0.71 [95% CI, 0.55-0.94]) but not in black individuals (IRR, 0.94 [95% CI, 0.68-1.30]); however, the race-sex interaction was not significant. At 75 years and older, there was no sex difference in stroke risk for either race. For white individuals, associations of systolic blood pressure (women: hazard ratio [HR], 1.13 [95% CI, 1.05-1.22]; men: 1.04 [95% CI, 0.97-1.11]; P = .099), diabetes (women: HR, 1.84 [95% CI, 1.35-2.52]; men: 1.13 [95% CI, 0.86-1.49]; P = .02), and heart disease (women: HR, 1.76 [95% CI, 1.30-2.39]; men, 1.26 [95% CI, 0.99-1.60]; P = .09) with stroke risk were larger for women than men, while antihypertensive medication use had a smaller association in women than men (women: HR, 1.17 [95% CI, 0.89-1.54]; men: 1.61 [95% CI, 1.29-2.03]; P = .08). In black individuals, there was no evidence of a sex difference for any risk factors.

Conclusions and Relevance  For both races, at age 45 through 64 years, women were at lower stroke risk than men, and there was no sex difference at 75 years or older; however, the sex difference pattern may differ by race from age 65 through 74 years. The association of risk factors on stroke risk differed by race-sex groups. While the need for primordial prevention, optimal management, and control of risk factors is universal across all age, racial/ethnic, and sex groups, some demographic subgroups may require earlier and more aggressive strategies.

Introduction

While the age-adjusted incidence of stroke (primarily ischemic stroke) in men is approximately 30% higher than in women,1-4 a meta-analysis5 of age-stratified data from 44 studies across 19 countries showed heterogeneity by age, with the men-to-women incidence rate ratio (IRR) 45% higher from 45 through 64 years, 21% higher from 75 through 84 years, and only 9% higher at ages older than 85 years. While numeric estimates were not provided, graphical presentation of sex-specific incidence rates from both the Framingham Heart Study (involving white participants only)6 and the Northern Manhattan Stroke Study (involving white, black, and Hispanic participants)7 showed higher incidence of all stroke in men compared with women through age 74 years, but a higher incidence in women older than 74 years.

In the United States, the largest racial disparity in stroke risk is in black individuals compared with white individuals.8-10 For both men and women, black individuals between 45 and 64 years have a 3-fold higher risk of stroke compared with white individuals, but black-white differences in stroke risk dissipate by 85 years.2,11-13 While the difference between men and women in stroke risk is well described, we are not aware of studies evaluating whether the sex difference in stroke risk is similar in black individuals and white individuals. The lack of stroke data by sex, race/ethnicity, and age subgroups was called out as an important gap in knowledge in the first American Stroke Association (ASA) guidelines dedicated to stroke risk and prevention in women.14

Sex differences in the association of stroke risk factors with incident stroke have been examined, but some results have not been consistent across studies in different settings.14,15 Generally, the evidence supports a similar association between hypertension and stroke risk for men and women, a stronger association with diabetes and atrial fibrillation for women, and inconsistent results for smoking, with some studies suggesting smoking may be a stronger risk factor in women than men; however, a meta-analysis found no sex difference.15-17 A few studies have examined black-white differences in the association of risk factors with stroke,18-20 but we are unaware of studies examining sex-specific differences by race.

The objective of this investigation was to address these gaps in knowledge, specifically by (1) assessing whether black individuals share the same pattern as white individuals of a higher men-to-women incidence relative risk between the ages 45 and 64 years, a somewhat lower ratio between ages 65 and 74 years, and negligible differences in ages older than 75 years, and (2) assessing the joint effect of sex and race on the magnitude of the association of risk factors with ischemic stroke risk.

Methods
Study Design

The Reasons for Geographic and Racial Differences in Stroke (REGARDS) study is a prospective cohort study of 30 239 non-Hispanic black and white community-dwelling participants 45 years or older who are living in the 48 contiguous US states. Details of the study design and methods are available elsewhere.11,21 Briefly, participants were selected from a commercially available list and recruited by mail and telephone, with oversampling of black individuals and persons living in the southeastern United States, 2 groups with high stroke mortality. The institutional review boards of the participating institutions approved the study. All participants provided written informed consent.

Participants self-identified their race and sex. Medical history and risk factor information were obtained using a computer-assisted telephone interview and an in-home physical examinations. The examination included venipuncture, physical measurements, and an electrocardiogram. The cohort was enrolled between January 2003 and October 2007. Follow-up by computer-assisted telephone interview was performed at 6-month intervals to identify suspected stroke events (or proxy-reported events, in case of participant’s inability to respond).

Covariates

Covariates included measures of socioeconomic status defined by the participant’s education and annual household income and risk factors included in the original Framingham Stroke Risk Score22 (ie, systolic blood pressure, use of antihypertensive medications, cigarette smoking, diabetes, atrial fibrillation, left ventricular hypertrophy, and history of heart disease). Systolic blood pressure was defined as the average of 2 measurements taken after the participant had been seated for 5 minutes. Use of antihypertensive medications was determined by participant self-report. Diabetes was defined as a fasting glucose level of 126 mg/dL or greater (or 200 mg/dL or greater, if the participant failed to fast; to convert to mmol/L, multiply by 0.0555) or self-reported use of medications for glucose control. Current cigarette smoking was defined by participant self-report. Atrial fibrillation was defined by electrocardiographic evidence or self-reported physician diagnosis of atrial fibrillation. Left ventricular hypertrophy was defined using the Sokolow electrocardiographic criteria.23 Heart disease was defined by baseline electrocardiographic evidence of a myocardial infarction, self-reported physician diagnosis of myocardial infarction, or previous coronary artery bypass surgery, angioplasty, or coronary stenting. Measures of socioeconomic status included self-reported annual household income (<$20 000, $20 000 to $35 000, $35 000 to $75 000, $75 000 or greater, or declined to answer) and education (less than high school, high school graduate, some college, or college graduate or more).

Stroke Outcome

The REGARDS study methods of determination of incident stroke have been previously reported.11 Medical records were requested and examined for all individuals who had suspected strokes, including those identified via interviews with proxies after a report of death. A team of stroke experts (including D.O.K. and B.M.K.) reviewed the records to validate and classify potential strokes. The World Health Organization stroke definition was used,24 and events were classified as ischemic or hemorrhagic. This analysis included World Health Organization–defined, clinical and probable ischemic stroke through October 2016.

Statistical Analyses

Ischemic stroke event rates per 1000 person-years (and associated 95% CIs) were calculated using Poisson regression implemented with PROC GENMOD in SAS version 9.4 (SAS Institute). Race-and-sex–specific event rates were calculated within baseline age strata of 45 through 64 years, 65 through 74 years, and 75 years and older. The women-to-men IRRs were also calculated using Poisson regression, and the racial difference in these IRRs was assessed by an interaction term, with significance defined as a P value less than .10. As in other REGARDS analyses,11 using the approach of Rubin,25 multiple imputation was used for the outcome of potential stroke events for which medical records could not be retrieved or adjudication was still in progress (less than 10% of potential cases).26

For each race, sex-specific analyses of the association of risk factors with stroke were performed using Cox proportional hazards models (again using multiple imputation26). Hazard ratios (HRs) were calculated for each individual factor (after adjustment for age strata) and the joint effect of all the factors in a full multivariable model. The differential association of a risk factor in men vs women was assessed using an interaction term of sex and that risk factor, with significant interactions defined as those with P values less than .10.

Results

Of the 30 239 REGARDS participants, 4450 (14.7%) were excluded: 56 (0.2%) owing to anomalies in informed consent, 1930 (6.4%) because of a self-reported history of stroke at baseline, 2074 (6.9%) with missing data on 1 or more covariates, and 390 (1.3%) with missing follow-up data. This left 25 789 participants (85.3%) for this analysis.

The population is described in Table 1. Compared with white individuals, black individuals of both sexes had lower socioeconomic status and a generally worse risk factor profile than white individuals. For example, both black men and black women had systolic blood pressure levels approximately 4 mm Hg higher than their white counterparts (mean [SD] levels: black men, 131.8 [16.9] mm Hg; white men, 127.1 [15.3] mm Hg; black women, 129.7 [17.3] mm Hg; white women, 123.2 [15.8] mm Hg), and were more likely to be taking antihypertensive medications (black men: 2209 of 3883 [56.9%]; white men: 3261 of 7736 [42.2%]; black women: 4169 of 6418 [65.0%]; white women: 3211 of 7752 [41.4%]). The prevalence of diabetes was approximately twice as high for black participants than white participants (black men: 1176 [30.3%]; white men: 1342 [17.3%]; black women: 1838 [28.6%]; white women: 979 [12.6%]).

Black individuals were also more likely to have a high school education or less (black men: 1769 [45.5%]; white men: 2114 [27.3%]; black women: 3017 [47.0%]; white women: 2708 [34.9%]), and to have income less than $35 000 (black men: 1745 [44.9%]; white men: 2148 [27.8%]; black women: 3605 [56.2%]; white women: 3034 [39.1%]). Men of both races were more likely to have a history of heart disease than women (black men: 692 [17.8%]; white men: 1922 [24.8%]; black women: 746 [11.6%]; white women: 903 [11.6%]).

With a mean (SD) follow-up duration of 8.7 (3.6) years (median, 9.6 years; maximum, 14.1 years), with 222 120 person-years of follow-up, there were 939 ischemic stroke events. Of these, 159 (16.9%) occurred in black men, 326 (34.7%) occurred in white men, 217 (23.1%) occurred in black women, and 237 (25.2%) occurred in white women.

Table 2 provides the incidence rates for ischemic stroke by age group, race, and sex. For all race-sex groups, stroke incidence increased with increasing age. For participants ages 45 through 64 years, white women had a 32% lower stroke risk (IRR, 0.68 [95% CI, 0.49-0.94]), and black women had a 28% lower stroke risk (IRR, 0.72 [95% CI, 0.52-0.99]) than their male counterparts of the same race. There was no evidence of a black-white difference in the association of sex with stroke in this age group. For white individuals, the lower stroke risk in women compared with men persisted among participants aged 65 through 74 years (IRR 0.71 [95% CI, 0.55-0.94]); however, for black individuals in this age group, there was not a lower risk in women than men (IRR, 0.94 [95% CI, 0.68-1.30]). This racial difference was not statistically significant (P = .19). Finally, for those 75 years or older, there was no sex difference in stroke risk for either white individuals (IRR, 0.92 [95% CI, 0.70-1.22]) or black individuals (IRR, 0.95 [95% CI, 0.61-1.47]).

Table 3 describes the associations of risk factors with incident ischemic stroke in the fully adjusted model, stratified by race. For white individuals, most stroke risk factors, but not socioeconomic status factors, were associated with stroke risk. The associations of systolic blood pressure (women: hazard ratio [HR], 1.13 [95% CI, 1.05-1.22]; men: 1.04 [95% CI, 0.97-1.11]; P = .099), diabetes (white women: HR, 1.84 [95% CI, 1.35-2.52]; white men: 1.13 [95% CI, 0.86-1.49]; P = .02), and heart disease (white women: HR, 1.76 [95% CI, 1.30-2.39]; white men, 1.26 [95% CI, 0.99-1.60]; P = .09) with stroke risk were larger for women than men, while antihypertensive medication use had a smaller association in women than men (white women: HR, 1.17 [95% CI, 0.89-1.54]; white men: 1.61 [95% CI, 1.29-2.03]; P = .08). With an interaction P value of .02, the evidence for a sex difference was strongest for diabetes. Among white individuals, there was no evidence of a differential effect by sex in the association of other risk factors with stroke risk. For black individuals, systolic blood pressure (black women: HR, 1.10 [95% CI, 1.02-1.18]; black men: HR, 1.14 [95% CI, 1.04-1.24]), smoking (black women: HR, 1.44 [95% CI, 1.01-2.06]; black men: HR, 1.95 [95% CI, 1.37-2.78]), and heart disease (black women: HR, 1.59 [95% CI, 1.15-2.22]; black men: HR, 1.63 [95% CI, 1.14-2.33]) were associated with ischemic stroke risk for both women and men, while the association of antihypertensive medication use with stroke was only seen in women (HR, 1.50 [95% CI, 1.08-2.09]). There was no evidence of a difference by sex for any of the risk factors. Models for each individual risk factor adjusted for age only are provided in the eTable in the Supplement, where the magnitude of associations is generally larger than in the multivariable-adjusted results; however, the women-to-men ratio pattern is similar.

Discussion

In this national cohort study, the women-to-men IRR for stroke was similar for black individuals and white individuals at ages 45 through 64 years (with women having lower stroke risk than men) and at 75 years or older (with men and women having similar stroke risk). However, for individuals age 65 through 74 years, white women were at significantly lower stroke risk than white men, while there was no risk difference between black women and black men. The interpretation of this is complicated by the lack of a significant race-sex interaction in this age strata. It is well known that tests for interaction have low statistical power,27 and we interpret the lack of a significant interaction as an inability to conclusively establish this difference. As such, we call for other studies with sizable black and white populations to confirm this suggested racial difference in stroke risk between men and women age 65 through 74 years. Additionally, we found sex differences in the association of several risk factors with stroke incidence in white individuals, specifically diabetes, systolic blood pressure, use of antihypertensive medications, and heart disease; however, there was no evidence of a sex difference in the role of risk factors in black individuals. These are some of the first data we are aware of that have been able to address this in US black individuals, a group with high stroke mortality. These data fill an important gap highlighted by the American Stroke Association guidelines for stroke prevention in women: that studies should provide sex-specific, race/ethnicity–specific, and age-specific rates of stroke incidence, mortality, and case fatality, because age-adjusted rates mask important differences by age.14 Others have also called for cardiovascular epidemiologic studies to include different sex and racial/ethnic groups and design hypothesis-driven race/ethnicity–specific and sex-specific analyses.28,29

Others have reported women are at lower stroke risk than men through age 75 years, with equivalent or higher stroke risk at older ages, based on data primarily from white populations.5-7,30,31 However, among black participants in the REGARDS study, we found that the lower ischemic stroke rate in women dissipated at the earlier ages of 65 through 74 years old, with little difference in the stroke risk between women and men. While primordial and primary stroke prevention efforts are important to all individuals, a greater emphasis on these efforts at younger ages in black women may have a larger return.

There are only a few other studies that assessed age-specific and race/ethnicity–specific sex differences in stroke risk. The Brain Attack Surveillance in Corpus Christi Project is a population-based surveillance study of stroke in non-Hispanic white individuals and Mexican American individuals in Nueces County, Texas. For strokes that occurred between January 2000 and May 2007, this study found that in people 45 through 79 years old, in both ethnic groups, men were at higher risk of any stroke (ischemic and hemorrhagic) than women; however, after age 79 years, there was no sex difference.30 In the Northern Manhattan Stroke Study that included white individuals, black individuals, and Hispanic individuals, the joint effect of sex, race/ethnicity, and age was not reported, but age differences by race/ethnicity were reported. The study found an earlier age of stroke in black individuals and Hispanic individuals than in white individuals and sex differences by race/ethnicity.7

The current study is one of few reports to our knowledge that assess sex differences in the association of stroke risk factors within race and age strata. Our finding that the magnitude of the association between diabetes and stroke risk was larger in white women than in white men is largely supported by the literature.28,32,33 In a meta-analysis32 of 64 cohort studies from around the world, the sex-specific relative risk of total stroke attributable to diabetes was 2.28 (95% CI, 1.93-2.69) for women and 1.83 (95% CI, 1.60-2.08) for men. However, analyses of administrative health care data from 1.9 million residents of the United Kingdom found no sex difference in the association between type 2 diabetes and ischemic stroke.34 In a study restricted to persons with diabetes,35 the Louisiana State University Hospital-Based Longitudinal Study of 30 154 participants (of whom 17 509 [58.1%] were black individuals) reported a significant sex difference (P < .01) in the association between hemoglobin A1c (HbA1c) levels and stroke risk; in women, there was a 5% increased risk (HR, 1.05 [95% CI, 1.02-1.07]) of stroke for each 1% increase in HbA1c but only a 1% increased risk (HR, 1.01 [95% CI, 0.99-1.04]) in men. This significant association was observed in both black women (HR, 1.39 [95% CI, 1.15-1.67] in those with HbA1c levels >10.0 mmol/mol relative to those with HbA1c levels of 6.00-6.9 mmol/mol; P = .007 across 6 HbA1c levels ranging from <6.00 to >10.0 mmol/mol; to convert to proportion of total hemoglobin, multiply by 0.01) and white women (1.36 [95% CI, 1.06, 1.75] in those with HbA1c levels >10.0 mmol/mol relative to those with HbA1c levels of 6.0-6.9 mmol/mol; P = .03 across all 6 HbA1c levels) and was not observed in either black or white men.

The consensus in the literature is that there is no sex difference in the association between systolic blood pressure or hypertension with stroke risk but that additional data are needed to assess whether this observation is consistent in all race/ethnicity and age groups.16,36 A meta-analysis36 of 97 prospective cohort studies including 990 138 participants (43% women) and 20 752 stroke events found no evidence of a differential association between systolic blood pressure and stroke risk by sex (pooled ratio of relative risks, 0.98 [95% CI, 0.96-1.01]; P = .13). However the INTERSTROKE case-control study37 showed that among those with self-reported hypertension or measured blood pressure greater than 160/90 mm Hg, women had a higher odds ratio of stroke (odds ratio [OR], 4.89 [95% CI, 3.79-6.32]) than men (OR, 3.88 [95% CI, 3.22-4.68]). In addition, a recent article38 from China (reported after the meta-analysis reporting no differential effect by sex) suggested a stronger association between hypertension and stroke risk in older women (OR, 6.73 [95% CI, 2.14-21.15]) than older men (OR, 3.18 [95% CI, 1.65-6.14]).

In this analysis from REGARDS, we considered the joint effect of blood pressure level and use of antihypertensive medications on stroke risk, finding significant interactions with sex for white individuals but not black individuals. For white individuals, the finding is complex, because we observed a larger association of blood pressure with stroke risk in women than men but a smaller association with the use of antihypertensive treatment. Hence, while there appears to be a sex difference in the association of achieved levels of blood pressure and use of antihypertensive medications, this mixed message in which blood pressure appears more important for women than men but antihypertensive use more important for men than women makes comparisons with the literature difficult. In black individuals, there was no evidence of a significant difference by sex in the association of systolic blood pressure or the use of antihypertensive medications.

In this study, history of heart disease was associated with an increased risk of incident stroke in white women but not white men; however, there was no evidence of a similar sex difference in black individuals. We are not aware of other data assessing the difference between the sexes in the association of prevalent heart disease as a stroke risk factor.

It is unexplained why we observed differential effects of risk factors by sex in white individuals but not black individuals. It could be an issue of statistical power for factors such as diabetes, for which there was no association with incident stroke among black individuals. We also speculate that there may be racial differences in the severity and/or extent of control of risk factors that were not accounted for in our models but could affect stroke risk differentially by race. Additional study and confirmation of these findings is required.

In this era of personalized medicine, prevention is an important approach that focuses not only on genetics but also clinical data, environmental exposures, and lifestyle choices.39 Knowledge of differential susceptibility to risk factors informs the clinical management of patients to prevent the incidence and reduce the burden of diseases including stroke. For example, while blood pressure control is important for all individuals with hypertension, it is particularly crucial to focus additional efforts at control in the black population, for whom the risk of stroke is 3 times greater than in white individuals when blood pressure levels are elevated.19 We found a larger influence of both diabetes and heart disease on white women than for men, suggesting that, compared with white men, additional clinical attention should be focused on these factors in white women to reduce their stroke risk. While the findings for systolic blood pressure and use of antihypertensive medications are complex, the larger magnitude of association for systolic blood pressure suggests that increased attention to achieving blood pressure control in white women may also be particularly important. No risk factors appear to provide insights for differential clinical attention in black women compared with black men.

The strengths of this study include the large number of black and white women and men from across the continental United States and the large number of ischemic stroke events, which combined provide one of the few opportunities to assess sex-associated, race/ethnicity-associated, and age-associated differences in the incidence of stroke and differences in the association with stroke risk factors. In addition, physician adjudication of stroke events provides confidence in the definition of the study outcome and the classification of stroke.

Limitations

Limitations also merit discussion. Despite the large coverage of the cohort, participants may not be representative of the general population. As with any epidemiologic study, findings are vulnerable to misclassification and bias, but these should not influence men and women differently. As with all observational studies, we present associations, and causal inferences cannot be drawn. In addition, not all medical records for suspected stroke could be obtained, but this was addressed by using multiple imputation methods.

Conclusions

In this large national cohort study of black and white adults in the United States, we observed a lower risk of stroke in women aged 45 through 64 years for both black individuals and white individuals, and a similar risk of stroke for men and women aged 75 years or older for black individuals and white individuals. For individuals age 65 through 74 years, white women were at lower stroke risk than their white male counterparts, while the stroke risk of black men and women did not differ, suggesting that black women lose their protection from stroke at a younger age than white women. However, the loss of protection at an earlier age for black women needs to be interpreted with caution, because the sex-race interaction test failed to reach statistical significance. In white individuals, there were differences by sex in the associations of diabetes, blood pressure, antihypertensive use, and heart disease on stroke risk, while a differential association of risk factors by sex was not seen in black individuals. While prevention and management of these risk factors is important across all racial/ethnic and sex groups, sex-specific approaches may be warranted in white individuals.

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Article Information

Corresponding Author: Virginia J. Howard, PhD, Department of Epidemiology, School of Public Health, University of Alabama at Birmingham, 1720 2nd Ave South, Birmingham, AL 35294-0022 (vjhoward@uab.edu).

Accepted for Publication: October 5, 2018.

Published Online: December 10, 2018. doi:10.1001/jamaneurol.2018.3862

Author Contributions: Dr G. Howard had full access to all the data in the study and takes responsibility for the integrity of the data and the accuracy of the data analysis.

Concept and design: V. J. Howard, Madsen, Kleindorfer, Safford, Moy, G. Howard, Cushman.

Acquisition, analysis, or interpretation of data: V. J. Howard, Madsen, Kleindorfer, Judd, Rhodes, Soliman, Kissela, Safford, McClure, G. Howard, Cushman.

Drafting of the manuscript: V. J. Howard.

Critical revision of the manuscript for important intellectual content: All authors.

Statistical analysis: McClure, G. Howard.

Obtained funding: V. J. Howard, Kleindorfer, Safford, G. Howard, Cushman.

Administrative, technical, or material support: V. J. Howard, Judd, Rhodes, Soliman, Safford, Moy, Cushman.

Supervision: V. J. Howard, Madsen, Judd, Rhodes, Kissela, Safford, G. Howard.

Conflict of Interest Disclosures: Dr Kissela reports personal fees from Janssen and AbbVie, outside the submitted work. No other disclosures were reported.

Funding/Support: The Reasons for Geographic and Racial Differences in Stroke (REGARDS) research project is supported by a cooperative agreement from the National Institute of Neurological Disorders and Stroke and the National Institute on Aging, National Institutes of Health, Department of Health and Human Service (grant U01 NS041588). This study also received support from the National Heart, Lung, and Blood Institute (grant K23HL140081; Dr Madsen).

Role of the Funder/Sponsor: Dr Moy, an employee of the National Institutes for Neurological Disorders and Stroke, had a role in the design and conduct of the study; preparation, review, or approval of the manuscript; and decision to submit the manuscript for publication, but did not participate in the collection, management, analysis, and interpretation of the data.

Disclaimer: The content is solely the responsibility of the authors and does not necessarily represent the official views of the National Institute of Neurological Disorders and Stroke or the National Institutes of Health.

Additional Information: We thank the other investigators, the staff, and the participants of the REGARDS study for their valuable contributions. A full list of participating REGARDS investigators and institutions can be found at http://www.regardsstudy.org.

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