- Email: [email protected]
Healthy Lifestyle and Functional Outcomes from Stroke in Women
Accepted Manuscript Healthy Lifestyle and Functional Outcomes from Stroke in Women Pamela M. Rist, ScD, Julie E. Buring, ScD, Carlos S. Kase, MD, Tobias Kurth, MD, ScD PII:
S0002-9343(16)30176-0
DOI:
10.1016/j.amjmed.2016.02.002
Reference:
AJM 13379
To appear in:
The American Journal of Medicine
Received Date: 15 December 2015 Revised Date:
2 February 2016
Accepted Date: 3 February 2016
Please cite this article as: Rist PM, Buring JE, Kase CS, Kurth T, Healthy Lifestyle and Functional Outcomes from Stroke in Women, The American Journal of Medicine (2016), doi: 10.1016/ j.amjmed.2016.02.002. This is a PDF file of an unedited manuscript that has been accepted for publication. As a service to our customers we are providing this early version of the manuscript. The manuscript will undergo copyediting, typesetting, and review of the resulting proof before it is published in its final form. Please note that during the production process errors may be discovered which could affect the content, and all legal disclaimers that apply to the journal pertain.
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Healthy Lifestyle and Functional Outcomes from Stroke in Women
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Pamela M. Rist, ScD, Julie E. Buring, ScD, Carlos S. Kase, MD, Tobias Kurth, MD, ScD
From the Division of Preventive Medicine (P.M.R., J.E.B., T.K.), Department of Medicine, Brigham and Women’s Hospital, Harvard Medical School, Boston, MA; the Department of
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Epidemiology (P.M.R., J.E.B., T.K.), Harvard T.H. Chan School of Public Health, Boston, MA; Department of Neurology (C.S.K), Boston University School of Medicine, Boston, MA; Institute
Corresponding Author: Pamela M. Rist, ScD
Boston, MA 02215 Tel: (617) 278-0835
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Fax: (617) 731-3843
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900 Commonwealth Avenue, 3rd floor
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of Public Health (T.K.), Charité Universitätzmedizin, Berlin, Germany
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E-mail: [email protected]
Word count (not including title, abstract, acknowledgments, or references): 2999 Type of Manuscript: Clinical Research Study Running Head: Healthy Lifestyle and Functional Outcomes from Stroke Keywords: Epidemiology, stroke outcomes, lifestyle The authors report no conflicts of interest.
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All authors had access to the data and a role in writing the manuscript.
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Abstract Purpose: While a healthy lifestyle has been associated with reduced risk of developing ischemic stroke, less is known about its effect on stroke severity.
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Methods: We performed a prospective cohort study among 37,634 women without stroke or missing risk factor data at baseline. The healthy lifestyle index was composed of smoking, physical activity, body mass index, alcohol consumption, and diet (range 0-20, with 20
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representing healthiest lifestyle). Possible functional outcomes were no stroke or stroke with modified Rankin Scale (mRS) score of 0-1 (mild), 2-3 (moderate), or 4-6 (severe). Multinomial
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logistic regression was used to analyze the association between healthy lifestyle and functional outcomes from stroke.
Results: Over 17.2 years of follow-up, 867 total strokes were confirmed. Compared to the lowest category (0-4), the highest category (17-20) was associated with reductions in risk of total
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stroke with mild (OR=0.43; 95% CI: 0.20-0.90), moderate (OR=0.53; 95% CI: 0.27-1.06) and severe (OR=0.48; 95% CI: 0.20-1.18) functional outcomes. Even a modest healthy lifestyle index (5-8 points) was associated with significant decreases in total stroke with severe and
strokes.
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moderate functional outcomes. Similar results were seen for ischemic but not hemorrhagic
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Conclusions: Highest versus lowest scores on the healthy lifestyle index were associated with reductions in risk of total and ischemic strokes with mild, moderate, and severe functional outcomes among women. The evidence that even modest healthy lifestyle index scores reduced risks of total and ischemic stroke with moderate and severe functional outcomes suggests modest lifestyle changes may reduce risk of disabling stroke events.
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Introduction Stroke is a leading cause of morbidity and mortality worldwide.1,2 There is growing interest in determining whether a “healthy lifestyle” reduces the risk of stroke events. Previous
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studies among women have shown a decreased risk of the development of total and ischemic stroke with healthier lifestyles.3–6 However, research on healthy lifestyle and functional outcomes from stroke in initially healthy populations is limited. Most research on functional stroke
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outcomes has focused on the effect of single risk factors7–23 and has not considered how a combination of factors may interact to influence total and ischemic stroke functional
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outcomes. Given the morbidity and mortality consequences of stroke, it is important to determine if healthy lifestyles also decrease stroke severity.
Results for the effect of healthy lifestyle on hemorrhagic stroke are mixed. One study observed a decreased risk with healthier lifestyles6, while other studies have observed no
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association5 or suggested a U-shaped association where healthier lifestyle was associated with a non-significant increase in the risk of hemorrhagic stroke.3 None of these studies examined the impact of healthy lifestyle on functional outcomes from hemorrhagic stroke.
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To determine the associations between healthy lifestyle and the risks of functional outcomes from total, ischemic, and hemorrhagic stroke, we used data from the Women’s Health
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Study, a large prospective cohort of initially healthy women with available information on lifestyle factors and functional outcomes after incident stroke.
Methods
The Women’s Health Study (WHS) was a randomized, placebo controlled trial of the effects of low-dose aspirin and vitamin E in the primary prevention of cardiovascular disease and
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cancer. The design, methods, and main findings have been published.24,25 Briefly, at baseline (1992-1996), the study randomized 39,876 US female health professionals aged ≥45 years or older without a history of cardiovascular disease, cancer or other major illnesses to receive low
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dose aspirin and/or vitamin E (versus placebo) in a 2 by 2 factorial design. After the end of the trial in March 2004, women continue to be followed on an observational basis. Twice during the first year and yearly thereafter, women were sent follow-up questionnaires asking about
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demographic, lifestyle and health information, including the occurrence of stroke events.
The WHS was approved by the Institutional Review Board at Brigham and Women’s
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Hospital; all subjects provided written informed consent.
Exposure
We used a healthy lifestyle index previously developed in the WHS3, which contains
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similar components to other lifestyle indices associated with stroke risk4–6, to evaluate the relationship of healthy lifestyle with incident stroke. The healthy lifestyle index incorporates information from the baseline questionnaire on smoking, physical activity, body mass index
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(BMI), alcohol consumption, and diet. For each variable, we created five categories and assigned scores from 0 to 4 with higher scores indicating healthier behaviors. Smoking was
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categorized as: current smoker who smokes ≥15 cigarettes per day (0 points), current smoker who smokes <15 cigarettes per day (1 point), past smoker who smoked ≥20 pack-years (2 points), past smoker who smoked <20 pack-years (3 points), and never smoker (4 points). Physical activity was categorized based on frequency of strenuous exercise: rarely or never (0 points), <1 time per week (1 point), 1 time per week (2 points), 2 to 3 times per week (3 points), or ≥4 times per week (4 points). Body mass index was categorized as ≥35.0 kg/m2 (0 points),
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30.0-34.9 kg/m2 (1 point), 25.0-29.9 kg/m2 (2 points), 22.0-24.9 kg/m2 (3 points), and >22.0 kg/m2 (4 points). To reflect the J-shaped relationship between alcohol consumption and cardiovascular disease risk26, we assigned the least number of points to those who rarely or never
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drank alcohol and the highest number of points to those who consume light to moderate amounts of alcohol. Alcohol intake was categorized as never (0 points), <1 drink/week (1 point), 1 to 3 drinks/week (3 points), 4 to less than 10.5 drinks per week (4 points), and ≥10.5 drinks per week
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(2 points). The construction of our diet score has been described in detail previously.3 Briefly, women completed a 161-item standardized food frequency questionnaire at baseline.27 We
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examined intake of cereal fiber, folate, ratio of polyunsaturated to saturated fat, omega-3 fatty acids, trans fats, and glycemic load. Each item was grouped into deciles and scored from 0 (least healthy) to 9 (healthiest) (trans fat and glycemic load were scored inversely). The scores were summed to create a total diet score which was then grouped into quintiles. The lowest quintile
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(representing the least healthy diet) received 0 points while the highest quintile (representing the healthiest diet) received 4 points.
The individual scores from the five components were summed to create a total final
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healthy lifestyle index ranging from 0 to 20. We categorized the final score into five categories for our total and ischemic stroke analyses: 0 to 4 (least healthy category and the reference
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category), 5 to 8, 9 to 12, 13 to 16, and 17 to 20 (healthiest category). Due to the small number of hemorrhagic strokes among those with the lowest healthy lifestyle index scores, our exposure categories for our hemorrhagic stroke analyses were 0 to 8 (least healthy category and the reference category), 9 to 12, 13 to 16 and 17 to 20 (healthiest group).
Outcome Ascertainment
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If a woman reported a stroke on her follow-up questionnaire, we asked for permission to review her medical records. An Endpoints Committee of physicians, including a board-certified vascular neurologist (CSK) blinded to randomized treatment assignment, reviewed medical
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records and determined if the self-reported stroke was confirmed. A nonfatal stroke was defined as a focal neurologic deficit of sudden or rapid onset and vascular mechanism that lasted >24 hours. Fatal strokes were confirmed using all available sources, including death certificates and
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hospital records, to determine if there was evidence of a cerebrovascular mechanism. Strokes were classified according to major subtype (ischemic, hemorrhagic, or unknown) with excellent
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interobserver agreement (Cohen’s κ=0.96)28 and assigned a modified Rankin Scale (mRS) score based on the degree of impairment at hospital discharge. Only the first stroke event was used in our analyses.
The mRS is a measure of functional outcome from stroke and ranges from 0 (no
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symptoms) to 6 (death). We decided a priori to categorize the mRS score into three categories, similar to previous studies.29–32 Our possible outcomes are no stroke, stroke with mRS 0 to 1 (no symptoms or no significant disability), stroke with mRS 2 to 3 (slight to moderate disability),
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and stroke with mRS 4 to 6 (moderately severe disability to death). Due to the small number of hemorrhagic strokes, we collapsed mRS 2 to 3 and mRS 4 to 6 for the hemorrhagic stroke
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analyses.
Statistical Analysis
Of the 39,876 participants in the WHS, we excluded six women who reported a stroke
before the baseline questionnaire and 2,236 women missing information on the lifestyle factors that comprise the healthy lifestyle score, leaving 37,634 women eligible for our analyses. We
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used multinomial logistic regression to calculate age- and multivariable-adjusted odds ratios and 95% confidence intervals as a measure of the relative risk of the association between higher categories of healthy lifestyle index and functional outcomes from stroke compared with the
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lowest category of the healthy lifestyle index.
Multivariable-adjusted model 1 adjusted for potential confounders as well as randomized treatment assignment. These potential confounders included age, postmenopausal hormone use,
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ever use of oral contraceptives, family history of myocardial infarction before age 60 years, migraine, annual household income, highest level of education, location of residence, marital
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status, and ethnicity. Due to the smaller number of hemorrhagic strokes, our first multivariableadjusted model for hemorrhagic stroke did not adjust for race or education level. Multivariate model 2 adjusted for potential consequences of an unhealthy lifestyle in addition to all covariates included in the first multivariate model. These include self-report of
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history of diabetes mellitus, history of hypertension, antihypertensive treatment, and history of elevated cholesterol. For our hemorrhagic stroke analyses, we were not able to adjust for diabetes status because there were too few diabetics.
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In sensitivity analyses, we used multinomial logistic regression to explore the association between functional outcome from stroke and a healthy lifestyle index that did not include BMI as
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one of its components, as BMI may be considered a consequence of the other components of the healthy lifestyle index.
All analyses were performed with SAS version 9.3 (SAS Institute, Cary, NC). P-values
were two-tailed with p<0.05 considered statistically significant.
Results
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Table 1 shows the baseline characteristics of the WHS participants by healthy lifestyle index categories. As defined, those in the lowest category of the healthy lifestyle index were most likely to be current smokers who smoke ≥15 cigarettes per day, rarely or never perform
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physical activity, have a BMI ≥35 kg/m2, never consume alcohol, and have a diet score in the lowest quintile. As the healthy lifestyle index increased, there was a decreasing prevalence of hypertension, antihypertensive medication use, elevated cholesterol, family history of myocardial
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infarction, black ethnicity, household income <$50,000 per year, and having less than a
bachelor’s degree, and there was an increasing prevalence of current postmenopausal hormone
with ever use of oral contraceptives.
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use, being married, living in the west, and no history of migraine. There was no clear pattern
Over 17.2 years of follow-up, 867 total strokes were self-reported (707 ischemic, 156 hemorrhagic, and 4 unknown subtype). Compared with the lowest category of the healthy
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lifestyle index (0-4 points), higher healthy lifestyle index categories were associated with reductions in the risk of mild, moderate, and severe stroke outcomes (Table 2). Compared with the lowest category (0-4), the highest category (17-20) was associated with a significant
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reduction in risk of total stroke with mild functional outcomes (OR=0.43; 95% CI: 0.20, 0.90) and with non-significant reductions in the risk of total stroke with moderate (OR=0.53; 95% CI:
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0.27, 1.06) and severe (OR=0.48; 95% CI: 0.20, 1.18) functional outcomes. In other words, compared with those with a low healthy lifestyle index score (0 to 4), those with the highest healthy lifestyle index scores (17 to 20) had a 57% reduced risk of mild stroke outcomes, a 47% reduced risk of moderate stroke outcomes, and a 52% reduced risk of severe stroke outcomes. However, even those with a healthy index score of 5 to 8 had a significantly decreased risk of severe stroke (OR=0.54; 95% CI: 0.30, 0.99) and moderate stroke (OR=0.57; 95% CI: 0.36.
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0.92) and a non-significant decrease in the risk of mild score (OR=0.71; 95% CI: 0.45, 1.14) compared to women with a health index score of 0 to 4. Controlling for potential intermediates slightly attenuated the effect estimates and some
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results were no longer statistically significant (Table 2) suggesting that the health index impacts risk of functional outcomes from total stroke through pathways involving these potential
intermediates. However, the direction of the effects still indicated that compared to the lowest
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category of the healthy lifestyle index, higher categories of the healthy lifestyle index were
associated with reductions in the risk of mild, moderate, and severe functional outcomes from
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total stroke.
The overall pattern of results from functional outcomes from ischemic stroke was similar to total stroke. Compared to the lowest healthy lifestyle index category, higher healthy lifestyle index categories were associated with a decrease in the risk of mild, moderate, and severe
potential intermediates.
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ischemic stroke (Table 3). These results were slightly attenuated when we controlled for
Unlike the total and ischemic stroke analyses, those with the highest healthy lifestyle
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index scores had an increased risk of hemorrhagic stroke with mild outcome (RR=4.23, 95% CI: 1.20, 14.99) which persisted after adjustment for potential intermediates (RR=4.12, 95% CI:
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1.15, 14.72) (Table 4). Although there were a greater number of hemorrhagic strokes with moderate/severe outcomes, we did not see any significant decrease or increase in risk of hemorrhagic stroke with moderate/severe outcome for those in higher versus the lowest healthy lifestyle index categories.
When we excluded BMI from our healthy lifestyle index, the association between the modified healthy lifestyle index categories and functional outcomes from ischemic stroke
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followed a similar pattern to the original healthy lifestyle index, but the effects were attenuated. We did not observe a statistically significant association between the highest modified healthy lifestyle index category and mild functional outcomes from hemorrhagic
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stroke. This suggests that the inclusion of body mass index in our original healthy lifestyle index may have driven the statistically significant association between the highest category of the
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healthy lifestyle index and increased risk of hemorrhagic stroke with mild functional outcome.
Discussion
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Previous research in the WHS has shown that a healthy lifestyle is associated with a reduced risk of stroke.3 The present study expands upon these findings by demonstrating that higher scores on the healthy lifestyle index are associated with reductions in the risk of total and ischemic stroke with mild, moderate, and severe functional outcomes. Even modest scores on
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the healthy lifestyle index (5 to 8 points) were associated with a decreased risk of all functional outcomes, but this decrease was only statistically significant for moderate and severe outcomes. This suggests that maintaining a moderately healthy lifestyle may decrease the risk of a disabling
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ischemic stroke event among women. However, our healthy lifestyle index had little impact on the risk of moderate/severe hemorrhagic strokes.
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Although research on composite healthy lifestyle indices and functional outcomes from
stroke is limited, some research has examined the association between the individual components of the healthy lifestyle index and functional outcomes from stroke. Although smoking has been associated with the risk of both ischemic33 and hemorrhagic stroke34 among women, information on stroke outcomes is mixed.7–12 Some studies have shown beneficial effects of physical activity on functional outcomes from stroke or stroke severity13–15 while one study showed no significant
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effect.16 Previous studies on alcohol consumption have found either modest or no association between moderate alcohol consumption and stroke outcomes.17–19 Some studies have suggested that stroke patients who are overweight or obese may have better outcomes.20–22 However,
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limited evidence exists on the effect of BMI on stroke outcomes in initially healthy populations. Information on diet and stroke outcomes in initially healthy populations is limited. Patients with acute stroke and poor nutritional status have a higher risk of death than those without poor
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nutritional status.23 A prospective cohort study among women did not find significant
hemorrhagic, fatal, or nonfatal stroke.35
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associations between quintiles of the Mediterranean Diet score and incidence of ischemic,
Despite the mixed or weak evidence that these individual components independently influence stroke outcomes, our study shows that a combination of lifestyle factors may help reduce the risk of mild, moderate, and severe ischemic stroke. The majority of the women in this
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cohort had scores on the health index from 5 to 8 (26.3% of the cohort) or 9 to 12 (40.2% of the cohort). While these categories do not represent the healthiest lifestyle according to our index, we still observed reductions in the risk of mild, moderate, and severe ischemic stroke for these
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women compared to women in the lowest category. This suggests that adopting even a modestly healthy lifestyle may reduce the risk of risk of mild, moderate, and severe ischemic stroke. For
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example, someone could achieve 5 to 8 points on the healthy lifestyle index by being a past smoker, having a BMI between 25.0-29.9 kg/m2, exercising once per week, never consuming alcohol, and being in the second lowest quintile of the dietary score distribution. We observed a different pattern between the healthy lifestyle index and risk of
hemorrhagic stroke with mild or moderate/severe functional outcomes. Those in the highest category of the healthy lifestyle index had an increased risk of hemorrhagic stroke with a mild
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functional outcome. However, the small number of hemorrhagic strokes with mild outcomes (N=4) makes it difficult to definitively conclude that healthier lifestyles are associated with an increased risk of hemorrhagic stroke with mild outcome. In addition, this increase was no longer
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significant when BMI was removed from the healthy lifestyle index. This suggests that some of the association between the healthy lifestyle index and risk of mild hemorrhagic stroke is driven by BMI. Evidence on the association between BMI and hemorrhagic stroke risk is unclear.
39
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Some studies have shown an increased risk of hemorrhagic stroke among people who are lean36– while others found no association40–42 or a positive association with increasing BMI.43
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Information on the association between overweight or obesity and hemorrhagic stroke outcomes is limited. A study among men observed higher proportion of mild strokes with BMI ≥30 kg/m2 while the proportion of fatal strokes was greater in men with BMI <23 kg/m2.43 Strengths of the present study include available information on many lifestyle factors in a
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large number of participants, the higher number of outcome events which allowed us to explore outcomes from ischemic and hemorrhagic stroke separately, and high interobserver agreement on major stroke subtype classification. We used the mRS to measure of functional outcome from
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stroke, which is widely accepted for use in clinical trials, accounts for prestroke disability44, has strong test-retest reliability, interrater reliability and validity45, and does not exhibit a “ceiling
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effect”.46
Some limitations should be noted. First, we were unable to update the healthy lifestyle
index over time because not all factors included in the index were assessed at multiple time points. Second, we did not consider weighting the components of the healthy lifestyle index. Third, there is the potential for non-differential misclassification of self-reported risk factors
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which would bias our results towards the null. Fourth, all participants in WHS were female health professionals and were primarily white which may limit our generalizability. Data from this large prospective cohort study of women observed that the highest versus
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lowest scores on the healthy lifestyle index were associated with reductions in the risk of total and ischemic strokes with mild, moderate, and severe functional outcomes. The observation that even modest healthy lifestyle index scores reduced risks of total and ischemic stroke with
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translate into reductions in risk of a disabling stroke event.
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moderate and severe functional outcomes suggests that even modest lifestyle changes may
Acknowledgements/Study Funding: The WHS is supported by grants from the National Institutes of Health (CA047988, HL043851, HL080467, HL099355, UM1 CA182913). The funder played no role in the design and conduct of the study; collection, management, analysis,
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and interpretation of the data; and preparation, review, or approval of the manuscript; and
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decision to submit the manuscript for publication.
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in the Honolulu Heart Program and the Framingham Study: A comparison of incidence and
43. Kurth T, Gaziano JM, Berger K, et al. Body mass index and the risk of stroke in men. Arch
M AN U
Intern Med. 2002;162(22):2557-2562.
44. Van Swieten JC, Koudstaal PJ, Visser MC, Schouten HJ, van Gijn J. Interobserver agreement for the assessment of handicap in stroke patients. Stroke. 1988;19(5):604-607.
TE D
45. Banks JL, Marotta CA. Outcomes validity and reliability of the modified Rankin scale: implications for stroke clinical trials: a literature review and synthesis. Stroke. 2007;38(3):1091-1096.
Weimar C, Kurth T, Kraywinkel K, et al. Assessment of functioning and disability after
EP
46.
AC C
ischemic stroke. Stroke. 2002;33(8):2053-2059.
ACCEPTED MANUSCRIPT
Table 1. Baseline characteristics of participants by healthy lifestyle index score*. Healthy
Index (N= 37624) 5-8
(n = 1615;
(n = 9890;
4.3%)
26.3%)
13-16
17-20
(n = 15108;
(n = 9265;
(n = 1756;
40.15%)
24.6%)
4.7%)
Current >=15 cig/d
54.3
13.9
4.6
1.0
0
Current < 15 cig/d
12.0
7.5
4.3
2.2
0.2
Past >=20 pack-yrs
13.4
13.1
11.5
9.2
3.9
11.7
20.8
25.0
30.3
31.4
8.6
44.8
54.6
57.3
64.5
85.8
65.5
35.9
11.4
0
12.1
23.9
23.7
14.3
1.7
1 time/wk
1.6
5.9
12.1
12.5
5.2
2-3 times/wk
0.5
4.2
21.4
39.7
43.1
>=4 times/week
0
0.5
6.9
22.1
50.1
31.5
12.1
3.2
0.4
0
Never Physical activity, % Rarely or never
AC C
< 1 time/wk
EP
Past < 20 pack-yrs
TE D
Smoking, %
9-12
SC
0-4
M AN U
Characteristic
RI PT
Lifestyle
Body mass index, % >=35.0
ACCEPTED MANUSCRIPT
25.4
22.0
10.9
3.6
0.3
25.0-29.9
24.2
36.5
34.5
24.6
6.7
22.0-24.9
13.8
20.7
32.7
38.5
35.7
<22.0
5.2
8.8
18.7
33.0
57.4
< 1 drink/wk
86.2
70.7
44.8
17.6
0
1-3 drinks/wk
12.0
16.9
17.7
12.5
1.8
2 to <10.5 drinks/wk
0.9
5.6
16.4
24.9
21.6
>=10.5 drinks/wk
0.2
3.4
15.8
39.1
72.7
3.5
5.3
5.9
3.9
37.1
15.8
4.5
0
25.8
33.6
26.3
14.2
1.8
6.8
15.2
20.5
18.0
9.0
1.9
9.6
20.5
27.5
27.8
0.3
4.5
16.9
35.8
61.4
53.5 (6.2)
54.4 (6.9)
54.9 (7.2)
54.6 (7.1)
54.5 (7.1)
History of hypertension
37.1
32.4
25.3
19.3
14.5
Antihypertensive medication use, %
18.0
17.7
13.4
10.4
6.9
History of diabetes mellitus, %
5.6
4.0
2.2
1.2
0.9
History of elevated cholesterol
34.2
31.5
30.5
25.6
22.7
Alcohol consumption, %
Diet score quintile, % 65.3
TE D
1st
M AN U
0.7
2nd 3rd
5th
AC C
Age, mean (SE), y
EP
4th
SC
Never
RI PT
30.0-34.9
ACCEPTED MANUSCRIPT
Postmenopausal hormone use 55.2
53.1
49.2
47.3
44.9
Past
13.3
10.6
8.8
7.5
6.0
Current
31.3
36.1
41.8
45.1
49.0
Ever used oral contraceptives, %
71.2
67.9
68.0
72.1
75.2
Family history of MI before age 60
14.3
12.5
11.3
10.8
10.9
SC
RI PT
Never
years, %
White
94.4
Black
3.4
Other
2.2
M AN U
Ethnicity, % 93.5
94.0
95.5
96.9
2.7
2.3
1.4
0.9
3.8
3.8
3.1
2.2
61.9
53.3
43.7
33.9
26.9
30.3
35.3
39.6
41.9
39.5
3.2
6.4
10.6
18.3
28.3
77.1
65.9
55.8
45.2
37.9
Bachelor’s degree
13.7
19.1
23.4
26.3
28.2
Master’s degree or doctorate
7.4
13.2
19.2
26.8
32.3
Single
7.0
6.3
5.8
4.8
4.4
Married
62.0
68.8
72.3
73.8
74.9
TE D
Annual household income, % <$50,000 $50,000-$100,000
EP
>=$100,000 Highest level of education, %
AC C
Less than bachelor’s degree
Marital status, %
ACCEPTED MANUSCRIPT
Other
31.0
24.9
21.9
21.4
20.7
Northeast
20.5
19.3
19.0
20.2
17.9
Southeast
24.2
23.8
23.7
Midwest
41.1
39.9
36.0
West
14.2
16.7
21.0
No history of migraine
79.4
80.0
Past history of migraine
6.6
Migraine without aura
8.4
Migraine with aura
5.4
21.5
20.8
31.5
27.0
26.6
34.0
SC 81.7
M AN U
Migraine status, %
RI PT
Geographic location, %
83.1
84.1
5.7
5.3
5.2
5.6
8.5
7.9
6.8
5.0
5.6
5.0
4.8
5.2
Note: Numbers may not add to 100% due to missing data.
AC C
EP
consumption, and diet.
TE D
*The healthy lifestyle index includes information on smoking status, physical activity, BMI, alcohol
ACCEPTED MANUSCRIPT
Table 2. Age- and multivariable-adjusted relative risks of functional outcomes by modified Rankin scale (mRS) score after TOTAL stroke according to Healthy
RI PT
Lifestyle Index* categories in the Women’s Health Study (N=37,634). No mRS 0-1
mRS 2-3
(n=36,767)
(n=360)
(n=303)
mRS 4-6 (n=204)
SC
Stroke
RR
n
%
n
%
(95% CI)
HI 0-4
1556
4.2
22
6.1
HI 5-8
9644
26.2
101
28.6
TE D
M AN U
RR n
%
(95% CI)
n
%
(95% CI)
1.00
23
7.6
1.00
14
6.9
1.00
0.69
90
29.7
0.56
53
26.0
0.52
Ageadjusted
9086
40.1
24.7
150
41.7
AC C
HI 13-16
14759
EP
(0.43, 1.09)
HI 9-12
74
20.6
RR
0.63
115
(0.35, 0.88) 38.0
(0.40, 0.98) 0.51 (0.32, 0.83)
0.44
(0.29, 0.94) 84
41.2
(0.28, 0.69) 60
19.8
0.38 (0.24, 0.62)
0.50 (0.28, 0.88)
45
22.1
0.45 (0.25, 0.82)
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HI 17-20
1722
4.7
11
3.1
0.41
15
5.0
8
3.9
(0.26, 0.98)
0.43 (0.18, 1.02)
RI PT
(0.20, 0.84)
0.50
Multivariable-
SC
adjusted**
1556
4.2
22
6.1
1.00
23
7.6
1.00
14
6.9
1.00
HI 5-8
9644
26.2
101
28.6
0.71
90
29.7
0.57
53
26.0
0.54
(0.45, 1.14) HI 9-12
14759
40.1
150
41.7
0.66
HI 13-16
9086
24.7
74
20.6
(0.36, 0.92)
115
0.55
38.0
60
19.8
adjusted (with intermediates)***
4.7
11
3.1
AC C
Multivariable-
1722
EP
(0.33, 0.89)
HI 17-20
0.43
(0.20, 0.90)
0.47
(0.30, 0.99) 84
41.2
(0.29, 0.74)
TE D
(0.41, 1.04)
M AN U
HI 0-4
15
0.41
(0.30, 0.97) 45
22.1
(0.25, 0.68) 5.0
0.53 (0.27, 1.06)
0.54
0.51 (0.27, 0.95)
8
3.9
0.48 (0.20, 1.18)
ACCEPTED MANUSCRIPT
1556
4.2
22
6.1
1.00
23
7.6
1.00
14
6.9
1.00
HI 5-8
9644
26.2
101
28.6
0.74
90
29.7
0.59
53
26.0
0.56
(0.46, 1.18) 14759
40.1
150
41.7
0.72
(0.37, 0.94) 115
(0.45, 1.14) 9086
24.7
74
20.6
0.62 (0.38, 1.01)
HI 17-20
1722
4.7
11
3.1
0.49
84
(0.31, 1.02) 41.2
(0.32, 0.81)
60
19.8
0.47
(0.33, 1.06) 45
22.1
(0.28, 0.78)
15
5.0
0.64
0.59
0.58 (0.31, 1.08)
8
3.9
(0.33, 1.27)
0.56 (0.23, 1.37)
TE D
(0.23, 1.04)
0.51
M AN U
HI 13-16
38.0
SC
HI 9-12
RI PT
HI 0-4
*Healthy lifestyle index includes smoking, physical activity, body mass index, alcohol consumption, and diet. **Adjusted for age (squared term), postmenopausal hormone use (never, past, or current), ever use of oral contraceptives, family history of myocardial infarction
EP
before age 60 years, migraine status (no history, past history, active migraine with aura, or active migraine without aura), annual household income (<$50,000,
AC C
$50,000 to <$100,000, or ≥$100,000), highest level of education (less than a bachelor’s degree, bachelor’s degree, or master’s degree or doctorate), location of residence (Northeast, Southeast, Midwest, or West), marital status (single, married, or other), and ethnicity (white, black, or other). ***Adjusted for all covariates above in addition to history of diabetes mellitus, history of hypertension (defined as systolic blood pressure of ≥140 mm Hg, diastolic blood pressure of ≥90 mm Hg, or self-reported physician-diagnosed hypertension), antihypertensive treatment, and history of elevated cholesterol of ≥240 mg/dL (6.21 mmol/L).
ACCEPTED MANUSCRIPT
Note: Less than 100 women were missing information on diabetes, history of hypertension, antihypertensive treatment, history of high cholesterol, migraine status, location of residence, postmenopausal hormone use, history of oral contraceptive use, and were assigned to the most frequent category. More than 100
RI PT
women were missing information on annual household income, family history of myocardial infarction, education, and marital status and were assigned to a separate “missing” category. People missing information on ethnicity were included in the “other” category.
AC C
EP
TE D
M AN U
SC
HI = healthy lifestyle index score; mRS = modified Rankin scale; RR = relative risk; CI = confidence interval.
ACCEPTED MANUSCRIPT
Table 3. Age- and multivariable-adjusted relative risks of functional outcomes by modified Rankin scale (mRS) score after ISCHEMIC stroke according to
RI PT
Healthy Lifestyle Index* (HI) categories in the Women’s Health Study (N=37,474). No mRS 0-1
mRS 2-3
(n=36,767)
(n=329)
(n=269)
%
n
%
(95% CI)
HI 0-4
1556
4.2
22
6.7
HI 5-8
9644
26.2
96
29.2
(n=109)
RR
M AN U
RR n
mRS 4-6
SC
Stroke
n
%
(95% CI)
n
%
(95% CI)
1.00
20
7.4
1.00
8
7.3
1.00
0.64
77
28.6
0.54
32
29.4
0.51
Age-
TE D
adjusted
40.1
139
42.3
0.58
AC C
14759
EP
(0.40, 1.02)
HI 9-12
109
(0.33, 0.89) 40.5
(0.37, 0.91)
HI 13-16
9086
24.7
66
20.1
RR
0.46 (0.28, 0.74)
0.47
(0.23, 1.11) 43
39.5
(0.29, 0.76) 49
18.2
0.36 (0.21, 0.60)
0.40 (0.19, 0.87)
22
20.2
0.35 (0.16, 0.79)
ACCEPTED MANUSCRIPT
HI 17-20
1722
4.7
6
1.8
0.22
14
5.2
4
3.7
(0.27, 1.08)
0.34 (0.10, 1.15)
RI PT
(0.09, 0.55)
0.54
Multivariable-
SC
adjusted**
1556
4.2
22
6.7
1.00
20
7.4
1.00
8
7.3
1.00
HI 5-8
9644
26.2
96
29.2
0.65
77
28.6
0.56
32
29.4
0.56
(0.41, 1.04) HI 9-12
14759
40.1
139
42.3
0.59
HI 13-16
9086
24.7
66
20.1
(0.34, 0.92)
109
0.47
40.5
49
18.2
1722
4.7
6
EP
(0.29, 0.78) HI 17-20
1.8
0.23
Multivariableadjusted (with intermediates)***
AC C
(0.09, 0.56)
0.50
(0.25, 1.23) 43
39.5
(0.31, 0.82)
TE D
(0.37, 0.94)
M AN U
HI 0-4
14
0.38
(0.21, 1.01) 22
20.2
(0.22, 0.65) 5.2
0.57 (0.28, 1.16)
0.47
0.42 (0.18, 0.98)
4
3.7
0.42 (0.12, 1.45)
ACCEPTED MANUSCRIPT
1556
4.2
22
6.7
1.00
20
7.4
1.00
8
7.3
1.00
HI 5-8
9644
26.2
96
29.2
0.67
77
28.6
0.57
32
29.4
0.58
(0.42, 1.08) 14759
40.1
139
42.3
0.65
(0.35, 0.95) 109
(0.41, 1.03) 9086
24.7
66
20.1
0.54 (0.32, 0.89)
HI 17-20
1722
4.7
6
1.8
0.26
43
(0.26, 1.27) 39.5
(0.33, 0.89)
49
18.2
0.44
(0.23, 1.11) 22
20.2
(0.25, 0.75)
14
5.2
0.69
0.51
0.50 (0.21, 1.16)
4
3.7
(0.34, 1.40)
0.50 (0.15, 1.74)
TE D
(0.10, 0.66)
0.55
M AN U
HI 13-16
40.5
SC
HI 9-12
RI PT
HI 0-4
*Healthy lifestyle index includes smoking, physical activity, body mass index, alcohol consumption, and diet. **Adjusted for age (squared term), postmenopausal hormone use (never, past, or current), ever use of oral contraceptives, family history of myocardial infarction
EP
before age 60 years, migraine status (no history, past history, active migraine with aura, or active migraine without aura), annual household income (<$50,000,
AC C
$50,000 to <$100,000, or ≥$100,000), highest level of education (less than a bachelor’s degree, bachelor’s degree, or master’s degree or doctorate), location of residence (Northeast, Southeast, Midwest, or West), marital status (single, married, or other), and ethnicity (white, black, or other). ***Adjusted for all covariates above in addition to history of diabetes mellitus, history of hypertension (defined as systolic blood pressure of ≥140 mm Hg, diastolic blood pressure of ≥90 mm Hg, or self-reported physician-diagnosed hypertension), antihypertensive treatment, and history of elevated cholesterol of ≥240 mg/dL (6.21 mmol/L).
ACCEPTED MANUSCRIPT
Note: Less than 100 women were missing information on diabetes, history of hypertension, antihypertensive treatment, history of high cholesterol, migraine status, location of residence, postmenopausal hormone use, history of oral contraceptive use, and were assigned to the most frequent category. More than 100
RI PT
women were missing information on annual household income, family history of myocardial infarction, education, and marital status and were assigned to a separate “missing” category. People missing information on ethnicity were included in the “other” category.
AC C
EP
TE D
M AN U
SC
HI = healthy lifestyle index score; mRS = modified Rankin scale; RR = relative risk; CI = confidence interval.
ACCEPTED MANUSCRIPT
Table 4. Age- and multivariable-adjusted* relative risks of functional outcomes by modified Rankin scale (mRS) score after HEMORRHAGIC stroke according
RI PT
to Healthy Lifestyle Index categories in the Women’s Health Study (N=36,923). No mRS 0-1
mRS 2-6
(n=36,767)
(n=29)
(n=127)
SC
Stroke
n
%
n
%
(95% CI)
HI 0-8
11200
30.5
7
24.1
1.00
HI 9-12
14759
40.1
10
34.5
TE D
Age-adjusted
RR
M AN U
RR
1.08
n
%
(95% CI)
42
33.1
1.00
47
37.0
0.81
HI 17-20
9086
1722
24.7
4.7
8
27.6
1.41
AC C
HI 13-16
EP
(0.41, 2.85)
4
13.8
33
26.0
(0.51, 3.89)
3.71
(1.09, 12.69)
Multivariable-
(0.53, 1.23) 0.94 (0.60, 1.49)
5
3.9
0.76 (0.30, 1.93)
ACCEPTED MANUSCRIPT
adjusted* 11200
30.5
7
24.1
1.00
42
33.1
HI 9-12
14759
40.1
10
34.5
1.17
47
37.0
9086
24.7
8
27.6
1.57 (0.56, 4.41)
HI 17-20
1722
4.7
4
(0.55,1.27)
13.8
4.23
33
26.0
(0.63, 1.61)
5
3.9
(1.20, 14.99)
adjusted (with
11200
30.5
HI 9-12
14759
40.1
9086
24.7
7
24.1
AC C
HI 0-8
EP
intermediates)**
HI 13-16
0.81
(0.32, 2.09)
TE D
Multivariable-
1.00
M AN U
HI 13-16
0.83
SC
(0.44, 3.08)
1.00
RI PT
HI 0-8
10
8
34.5
27.6
1.00
42
33.1
1.00
1.15
47
37.0
0.86
(0.43, 3.04)
1.55
(0.57, 1.32) 33
26.0
1.06
ACCEPTED MANUSCRIPT
(0.55, 4.39) 1722
4.7
4
13.8
4.12
5
(1.15, 14.72)
3.9
0.88
RI PT
HI 17-20
(0.66, 1.71)
(0.34, 2.27)
*Healthy lifestyle index includes smoking, physical activity, body mass index, alcohol consumption, and diet.
SC
**Adjusted for age (squared term), postmenopausal hormone use (never, past, or current), ever use of oral contraceptives, family history of myocardial infarction
M AN U
before age 60 years, migraine status (no history, past history, active migraine with aura, or active migraine without aura), annual household income (<$50,000, $50,000 to <$100,000, or ≥$100,000), highest level of education (less than a bachelor’s degree, bachelor’s degree, or master’s degree or doctorate), location of residence (Northeast, Southeast, Midwest, or West), marital status (single, married, or other), and ethnicity (white, black, or other). ***Adjusted for all covariates above in addition to history of diabetes mellitus, history of hypertension (defined as systolic blood pressure of ≥140 mm Hg,
≥240 mg/dL (6.21 mmol/L).
TE D
diastolic blood pressure of ≥90 mm Hg, or self-reported physician-diagnosed hypertension), antihypertensive treatment, and history of elevated cholesterol of
Note: Less than 100 women were missing information on diabetes, history of hypertension, antihypertensive treatment, history of high cholesterol, migraine
EP
status, location of residence, postmenopausal hormone use, history of oral contraceptive use, and were assigned to the most frequent category. More than 100 women were missing information on annual household income, family history of myocardial infarction, education, and marital status and were assigned to a
AC C
separate “missing” category. People missing information on ethnicity were included in the “other” category.
HI = healthy lifestyle index score; mRS = modified Rankin scale; RR = relative risk; CI = confidence interval.
ACCEPTED MANUSCRIPT
Online Table 1. Multivariable-adjusted relative risks of functional outcomes by modified Rankin scale (mRS) score after ISCHEMIC stroke according to
No mRS 0-1
mRS 2-3
(n=36,767)
(n=329)
(n=269)
n
%
HI 0-4
5183
14.1
52
15.8
HI 5-8
15582
42.4
148
45.0
(95% CI)
n
%
(95% CI)
n
%
(95% CI)
1.00
49
18.2
1.00
22
20.2
1.00
0.93
109
40.5
0.73
47
43.1
0.69
Multivariableadjusted*
3092
35.1
8.4
114
34.7
AC C
HI 13-16
12910
EP
(0.68, 1.29)
HI 9-12
15
4.6
RR
TE D
%
(n=109)
RR
M AN U
RR n
mRS 4-6
SC
Stroke
RI PT
modified healthy lifestyle index* (HI) categories in the Women’s Health Study (N=37,474).
0.88
(0.52, 1.03) 90
33.5
(0.63, 1.23) 0.48 (0.27, 0.87)
0.74
(0.41, 1.16) 32
29.4
(0.52, 1.06) 21
7.8
0.72 (0.43, 1.23)
0.59 (0.34, 1.04)
8
7.3
0.64 (0.28, 1.48)
ACCEPTED MANUSCRIPT
Multivariable-
RI PT
adjusted (with intermediates)** 5183
14.1
52
15.8
1.00
49
HI 5-8
15582
42.4
148
45.0
0.93
109
HI 9-12
12910
35.1
114
34.7
0.90
40.5
90
33.5
(0.64, 1.27)
3092
8.4
15
4.6
0.51
TE D
HI 13-16
(0.27, 0.93)
1.00 0.72
22
20.2
1.00
47
43.1
0.67
(0.51, 1.02)
M AN U
(0.68, 1.29)
18.2
SC
HI 0-4
21
7.8
0.77
(0.40, 1.12) 32
29.4
(0.53, 1.10)
0.78
0.60 (0.34, 1.05)
8
(0.46, 1.32)
7.3
0.67 (0.29, 1.55)
*Modified healthy lifestyle index includes smoking, physical activity, alcohol consumption, and diet (maximum score of 16).
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**Adjusted for age (squared term), postmenopausal hormone use (never, past, or current), ever use of oral contraceptives, family history of myocardial infarction
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before age 60 years, migraine status (no history, past history, active migraine with aura, or active migraine without aura), annual household income (<$50,000, $50,000 to <$100,000, or ≥$100,000), highest level of education (less than a bachelor’s degree, bachelor’s degree, or master’s degree or doctorate), location of residence (Northeast, Southeast, Midwest, or West), marital status (single, married, or other), and ethnicity (white, black, or other). ***Adjusted for all covariates above in addition to history of diabetes mellitus, history of hypertension (defined as systolic blood pressure of ≥140 mm Hg, diastolic blood pressure of ≥90 mm Hg, or self-reported physician-diagnosed hypertension), antihypertensive treatment, and history of elevated cholesterol of ≥240 mg/dL (6.21 mmol/L).
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Note: Less than 100 women were missing information on diabetes, history of hypertension, antihypertensive treatment, history of high cholesterol, migraine status, location of residence, postmenopausal hormone use, history of oral contraceptive use, and were assigned to the most frequent category. More than 100
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women were missing information on annual household income, family history of myocardial infarction, education, and marital status and were assigned to a separate “missing” category. People missing information on ethnicity were included in the “other” category.
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HI = healthy lifestyle index score; mRS = modified Rankin scale; RR = relative risk; CI = confidence interval.
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Online Table 2. Multivariable-adjusted relative risks of functional outcomes by modified Rankin scale (mRS) score after HEMORRHAGIC stroke according to
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modified healthy lifestyle index* (HI) categories in the Women’s Health Study (N=36,923). No mRS 0-1
(n=36,766)
(n=29)
mRS 2-6 (n=127)
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Stroke
RR
n
%
n
%
(95% CI)
n
%
(95% CI)
Modified HI 0-8
20765
56.5
15
51.7
1.00
73
57.5
1.00
Modified HI 9-12
12910
35.1
10
34.5
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RR
1.14
47
37.0
1.06
Multivariableadjusted*
16
Multivariableadjusted (with
3092
8.4
4
13.8
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Modified HI 13-
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(0.51, 2.56) 1.92
(0.62, 5.92)
(0.73, 1.54) 7
5.5
0.58 (0.31, 1.49)
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intermediates)** 20765
56.5
15
51.7
1.00
73
57.5
Modified HI 9-12
12910
35.1
10
34.5
1.14
47
37.0
Modified HI 13-
3092
8.4
4
13.8
1.89
7
(0.61, 5.85)
5.5
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16
1.08
(0.74, 1.56)
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(0.51, 2.56)
1.00
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Modified HI 0-8
0.70 (0.32, 1.54)
*Modified healthy lifestyle index includes smoking, physical activity, alcohol consumption, and diet (maximum score of 16). **Adjusted for age (squared term), postmenopausal hormone use (never, past, or current), ever use of oral contraceptives, family history of myocardial infarction
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before age 60 years, migraine status (no history, past history, active migraine with aura, or active migraine without aura), annual household income (<$50,000, $50,000 to <$100,000, or ≥$100,000), highest level of education (less than a bachelor’s degree, bachelor’s degree, or master’s degree or doctorate), location of residence (Northeast, Southeast, Midwest, or West), marital status (single, married, or other), and ethnicity (white, black, or other).
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***Adjusted for all covariates above in addition to history of diabetes mellitus, history of hypertension (defined as systolic blood pressure of ≥140 mm Hg,
≥240 mg/dL (6.21 mmol/L).
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diastolic blood pressure of ≥90 mm Hg, or self-reported physician-diagnosed hypertension), antihypertensive treatment, and history of elevated cholesterol of
Note: Less than 100 women were missing information on diabetes, history of hypertension, antihypertensive treatment, history of high cholesterol, migraine status, location of residence, postmenopausal hormone use, history of oral contraceptive use, and were assigned to the most frequent category. More than 100 women were missing information on annual household income, family history of myocardial infarction, education, and marital status and were assigned to a separate “missing” category. People missing information on ethnicity were included in the “other” category.
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HI = healthy lifestyle index score; mRS = modified Rankin scale; RR = relative risk; CI = confidence interval.
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Clinical Significance •
Highest versus lowest scores on the healthy lifestyle index were associated with
functional outcomes among women.
The evidence that even a modest healthy lifestyle index scores reduced risks of total and ischemic stroke with moderate and severe functional outcomes suggests that modest
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lifestyle changes may translate to reductions in risk of a disabling stroke event.
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•
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reductions in risk of total and ischemic strokes with mild, moderate, and severe
S0002-9343(16)30176-0
DOI:
10.1016/j.amjmed.2016.02.002
Reference:
AJM 13379
To appear in:
The American Journal of Medicine
Received Date: 15 December 2015 Revised Date:
2 February 2016
Accepted Date: 3 February 2016
Please cite this article as: Rist PM, Buring JE, Kase CS, Kurth T, Healthy Lifestyle and Functional Outcomes from Stroke in Women, The American Journal of Medicine (2016), doi: 10.1016/ j.amjmed.2016.02.002. This is a PDF file of an unedited manuscript that has been accepted for publication. As a service to our customers we are providing this early version of the manuscript. The manuscript will undergo copyediting, typesetting, and review of the resulting proof before it is published in its final form. Please note that during the production process errors may be discovered which could affect the content, and all legal disclaimers that apply to the journal pertain.
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Healthy Lifestyle and Functional Outcomes from Stroke in Women
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Pamela M. Rist, ScD, Julie E. Buring, ScD, Carlos S. Kase, MD, Tobias Kurth, MD, ScD
From the Division of Preventive Medicine (P.M.R., J.E.B., T.K.), Department of Medicine, Brigham and Women’s Hospital, Harvard Medical School, Boston, MA; the Department of
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Epidemiology (P.M.R., J.E.B., T.K.), Harvard T.H. Chan School of Public Health, Boston, MA; Department of Neurology (C.S.K), Boston University School of Medicine, Boston, MA; Institute
Corresponding Author: Pamela M. Rist, ScD
Boston, MA 02215 Tel: (617) 278-0835
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Fax: (617) 731-3843
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900 Commonwealth Avenue, 3rd floor
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of Public Health (T.K.), Charité Universitätzmedizin, Berlin, Germany
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E-mail: [email protected]
Word count (not including title, abstract, acknowledgments, or references): 2999 Type of Manuscript: Clinical Research Study Running Head: Healthy Lifestyle and Functional Outcomes from Stroke Keywords: Epidemiology, stroke outcomes, lifestyle The authors report no conflicts of interest.
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All authors had access to the data and a role in writing the manuscript.
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Abstract Purpose: While a healthy lifestyle has been associated with reduced risk of developing ischemic stroke, less is known about its effect on stroke severity.
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Methods: We performed a prospective cohort study among 37,634 women without stroke or missing risk factor data at baseline. The healthy lifestyle index was composed of smoking, physical activity, body mass index, alcohol consumption, and diet (range 0-20, with 20
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representing healthiest lifestyle). Possible functional outcomes were no stroke or stroke with modified Rankin Scale (mRS) score of 0-1 (mild), 2-3 (moderate), or 4-6 (severe). Multinomial
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logistic regression was used to analyze the association between healthy lifestyle and functional outcomes from stroke.
Results: Over 17.2 years of follow-up, 867 total strokes were confirmed. Compared to the lowest category (0-4), the highest category (17-20) was associated with reductions in risk of total
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stroke with mild (OR=0.43; 95% CI: 0.20-0.90), moderate (OR=0.53; 95% CI: 0.27-1.06) and severe (OR=0.48; 95% CI: 0.20-1.18) functional outcomes. Even a modest healthy lifestyle index (5-8 points) was associated with significant decreases in total stroke with severe and
strokes.
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moderate functional outcomes. Similar results were seen for ischemic but not hemorrhagic
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Conclusions: Highest versus lowest scores on the healthy lifestyle index were associated with reductions in risk of total and ischemic strokes with mild, moderate, and severe functional outcomes among women. The evidence that even modest healthy lifestyle index scores reduced risks of total and ischemic stroke with moderate and severe functional outcomes suggests modest lifestyle changes may reduce risk of disabling stroke events.
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Introduction Stroke is a leading cause of morbidity and mortality worldwide.1,2 There is growing interest in determining whether a “healthy lifestyle” reduces the risk of stroke events. Previous
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studies among women have shown a decreased risk of the development of total and ischemic stroke with healthier lifestyles.3–6 However, research on healthy lifestyle and functional outcomes from stroke in initially healthy populations is limited. Most research on functional stroke
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outcomes has focused on the effect of single risk factors7–23 and has not considered how a combination of factors may interact to influence total and ischemic stroke functional
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outcomes. Given the morbidity and mortality consequences of stroke, it is important to determine if healthy lifestyles also decrease stroke severity.
Results for the effect of healthy lifestyle on hemorrhagic stroke are mixed. One study observed a decreased risk with healthier lifestyles6, while other studies have observed no
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association5 or suggested a U-shaped association where healthier lifestyle was associated with a non-significant increase in the risk of hemorrhagic stroke.3 None of these studies examined the impact of healthy lifestyle on functional outcomes from hemorrhagic stroke.
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To determine the associations between healthy lifestyle and the risks of functional outcomes from total, ischemic, and hemorrhagic stroke, we used data from the Women’s Health
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Study, a large prospective cohort of initially healthy women with available information on lifestyle factors and functional outcomes after incident stroke.
Methods
The Women’s Health Study (WHS) was a randomized, placebo controlled trial of the effects of low-dose aspirin and vitamin E in the primary prevention of cardiovascular disease and
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cancer. The design, methods, and main findings have been published.24,25 Briefly, at baseline (1992-1996), the study randomized 39,876 US female health professionals aged ≥45 years or older without a history of cardiovascular disease, cancer or other major illnesses to receive low
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dose aspirin and/or vitamin E (versus placebo) in a 2 by 2 factorial design. After the end of the trial in March 2004, women continue to be followed on an observational basis. Twice during the first year and yearly thereafter, women were sent follow-up questionnaires asking about
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demographic, lifestyle and health information, including the occurrence of stroke events.
The WHS was approved by the Institutional Review Board at Brigham and Women’s
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Hospital; all subjects provided written informed consent.
Exposure
We used a healthy lifestyle index previously developed in the WHS3, which contains
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similar components to other lifestyle indices associated with stroke risk4–6, to evaluate the relationship of healthy lifestyle with incident stroke. The healthy lifestyle index incorporates information from the baseline questionnaire on smoking, physical activity, body mass index
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(BMI), alcohol consumption, and diet. For each variable, we created five categories and assigned scores from 0 to 4 with higher scores indicating healthier behaviors. Smoking was
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categorized as: current smoker who smokes ≥15 cigarettes per day (0 points), current smoker who smokes <15 cigarettes per day (1 point), past smoker who smoked ≥20 pack-years (2 points), past smoker who smoked <20 pack-years (3 points), and never smoker (4 points). Physical activity was categorized based on frequency of strenuous exercise: rarely or never (0 points), <1 time per week (1 point), 1 time per week (2 points), 2 to 3 times per week (3 points), or ≥4 times per week (4 points). Body mass index was categorized as ≥35.0 kg/m2 (0 points),
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30.0-34.9 kg/m2 (1 point), 25.0-29.9 kg/m2 (2 points), 22.0-24.9 kg/m2 (3 points), and >22.0 kg/m2 (4 points). To reflect the J-shaped relationship between alcohol consumption and cardiovascular disease risk26, we assigned the least number of points to those who rarely or never
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drank alcohol and the highest number of points to those who consume light to moderate amounts of alcohol. Alcohol intake was categorized as never (0 points), <1 drink/week (1 point), 1 to 3 drinks/week (3 points), 4 to less than 10.5 drinks per week (4 points), and ≥10.5 drinks per week
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(2 points). The construction of our diet score has been described in detail previously.3 Briefly, women completed a 161-item standardized food frequency questionnaire at baseline.27 We
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examined intake of cereal fiber, folate, ratio of polyunsaturated to saturated fat, omega-3 fatty acids, trans fats, and glycemic load. Each item was grouped into deciles and scored from 0 (least healthy) to 9 (healthiest) (trans fat and glycemic load were scored inversely). The scores were summed to create a total diet score which was then grouped into quintiles. The lowest quintile
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(representing the least healthy diet) received 0 points while the highest quintile (representing the healthiest diet) received 4 points.
The individual scores from the five components were summed to create a total final
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healthy lifestyle index ranging from 0 to 20. We categorized the final score into five categories for our total and ischemic stroke analyses: 0 to 4 (least healthy category and the reference
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category), 5 to 8, 9 to 12, 13 to 16, and 17 to 20 (healthiest category). Due to the small number of hemorrhagic strokes among those with the lowest healthy lifestyle index scores, our exposure categories for our hemorrhagic stroke analyses were 0 to 8 (least healthy category and the reference category), 9 to 12, 13 to 16 and 17 to 20 (healthiest group).
Outcome Ascertainment
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If a woman reported a stroke on her follow-up questionnaire, we asked for permission to review her medical records. An Endpoints Committee of physicians, including a board-certified vascular neurologist (CSK) blinded to randomized treatment assignment, reviewed medical
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records and determined if the self-reported stroke was confirmed. A nonfatal stroke was defined as a focal neurologic deficit of sudden or rapid onset and vascular mechanism that lasted >24 hours. Fatal strokes were confirmed using all available sources, including death certificates and
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hospital records, to determine if there was evidence of a cerebrovascular mechanism. Strokes were classified according to major subtype (ischemic, hemorrhagic, or unknown) with excellent
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interobserver agreement (Cohen’s κ=0.96)28 and assigned a modified Rankin Scale (mRS) score based on the degree of impairment at hospital discharge. Only the first stroke event was used in our analyses.
The mRS is a measure of functional outcome from stroke and ranges from 0 (no
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symptoms) to 6 (death). We decided a priori to categorize the mRS score into three categories, similar to previous studies.29–32 Our possible outcomes are no stroke, stroke with mRS 0 to 1 (no symptoms or no significant disability), stroke with mRS 2 to 3 (slight to moderate disability),
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and stroke with mRS 4 to 6 (moderately severe disability to death). Due to the small number of hemorrhagic strokes, we collapsed mRS 2 to 3 and mRS 4 to 6 for the hemorrhagic stroke
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analyses.
Statistical Analysis
Of the 39,876 participants in the WHS, we excluded six women who reported a stroke
before the baseline questionnaire and 2,236 women missing information on the lifestyle factors that comprise the healthy lifestyle score, leaving 37,634 women eligible for our analyses. We
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used multinomial logistic regression to calculate age- and multivariable-adjusted odds ratios and 95% confidence intervals as a measure of the relative risk of the association between higher categories of healthy lifestyle index and functional outcomes from stroke compared with the
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lowest category of the healthy lifestyle index.
Multivariable-adjusted model 1 adjusted for potential confounders as well as randomized treatment assignment. These potential confounders included age, postmenopausal hormone use,
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ever use of oral contraceptives, family history of myocardial infarction before age 60 years, migraine, annual household income, highest level of education, location of residence, marital
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status, and ethnicity. Due to the smaller number of hemorrhagic strokes, our first multivariableadjusted model for hemorrhagic stroke did not adjust for race or education level. Multivariate model 2 adjusted for potential consequences of an unhealthy lifestyle in addition to all covariates included in the first multivariate model. These include self-report of
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history of diabetes mellitus, history of hypertension, antihypertensive treatment, and history of elevated cholesterol. For our hemorrhagic stroke analyses, we were not able to adjust for diabetes status because there were too few diabetics.
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In sensitivity analyses, we used multinomial logistic regression to explore the association between functional outcome from stroke and a healthy lifestyle index that did not include BMI as
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one of its components, as BMI may be considered a consequence of the other components of the healthy lifestyle index.
All analyses were performed with SAS version 9.3 (SAS Institute, Cary, NC). P-values
were two-tailed with p<0.05 considered statistically significant.
Results
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Table 1 shows the baseline characteristics of the WHS participants by healthy lifestyle index categories. As defined, those in the lowest category of the healthy lifestyle index were most likely to be current smokers who smoke ≥15 cigarettes per day, rarely or never perform
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physical activity, have a BMI ≥35 kg/m2, never consume alcohol, and have a diet score in the lowest quintile. As the healthy lifestyle index increased, there was a decreasing prevalence of hypertension, antihypertensive medication use, elevated cholesterol, family history of myocardial
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infarction, black ethnicity, household income <$50,000 per year, and having less than a
bachelor’s degree, and there was an increasing prevalence of current postmenopausal hormone
with ever use of oral contraceptives.
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use, being married, living in the west, and no history of migraine. There was no clear pattern
Over 17.2 years of follow-up, 867 total strokes were self-reported (707 ischemic, 156 hemorrhagic, and 4 unknown subtype). Compared with the lowest category of the healthy
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lifestyle index (0-4 points), higher healthy lifestyle index categories were associated with reductions in the risk of mild, moderate, and severe stroke outcomes (Table 2). Compared with the lowest category (0-4), the highest category (17-20) was associated with a significant
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reduction in risk of total stroke with mild functional outcomes (OR=0.43; 95% CI: 0.20, 0.90) and with non-significant reductions in the risk of total stroke with moderate (OR=0.53; 95% CI:
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0.27, 1.06) and severe (OR=0.48; 95% CI: 0.20, 1.18) functional outcomes. In other words, compared with those with a low healthy lifestyle index score (0 to 4), those with the highest healthy lifestyle index scores (17 to 20) had a 57% reduced risk of mild stroke outcomes, a 47% reduced risk of moderate stroke outcomes, and a 52% reduced risk of severe stroke outcomes. However, even those with a healthy index score of 5 to 8 had a significantly decreased risk of severe stroke (OR=0.54; 95% CI: 0.30, 0.99) and moderate stroke (OR=0.57; 95% CI: 0.36.
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0.92) and a non-significant decrease in the risk of mild score (OR=0.71; 95% CI: 0.45, 1.14) compared to women with a health index score of 0 to 4. Controlling for potential intermediates slightly attenuated the effect estimates and some
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results were no longer statistically significant (Table 2) suggesting that the health index impacts risk of functional outcomes from total stroke through pathways involving these potential
intermediates. However, the direction of the effects still indicated that compared to the lowest
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category of the healthy lifestyle index, higher categories of the healthy lifestyle index were
associated with reductions in the risk of mild, moderate, and severe functional outcomes from
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total stroke.
The overall pattern of results from functional outcomes from ischemic stroke was similar to total stroke. Compared to the lowest healthy lifestyle index category, higher healthy lifestyle index categories were associated with a decrease in the risk of mild, moderate, and severe
potential intermediates.
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ischemic stroke (Table 3). These results were slightly attenuated when we controlled for
Unlike the total and ischemic stroke analyses, those with the highest healthy lifestyle
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index scores had an increased risk of hemorrhagic stroke with mild outcome (RR=4.23, 95% CI: 1.20, 14.99) which persisted after adjustment for potential intermediates (RR=4.12, 95% CI:
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1.15, 14.72) (Table 4). Although there were a greater number of hemorrhagic strokes with moderate/severe outcomes, we did not see any significant decrease or increase in risk of hemorrhagic stroke with moderate/severe outcome for those in higher versus the lowest healthy lifestyle index categories.
When we excluded BMI from our healthy lifestyle index, the association between the modified healthy lifestyle index categories and functional outcomes from ischemic stroke
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followed a similar pattern to the original healthy lifestyle index, but the effects were attenuated. We did not observe a statistically significant association between the highest modified healthy lifestyle index category and mild functional outcomes from hemorrhagic
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stroke. This suggests that the inclusion of body mass index in our original healthy lifestyle index may have driven the statistically significant association between the highest category of the
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healthy lifestyle index and increased risk of hemorrhagic stroke with mild functional outcome.
Discussion
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Previous research in the WHS has shown that a healthy lifestyle is associated with a reduced risk of stroke.3 The present study expands upon these findings by demonstrating that higher scores on the healthy lifestyle index are associated with reductions in the risk of total and ischemic stroke with mild, moderate, and severe functional outcomes. Even modest scores on
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the healthy lifestyle index (5 to 8 points) were associated with a decreased risk of all functional outcomes, but this decrease was only statistically significant for moderate and severe outcomes. This suggests that maintaining a moderately healthy lifestyle may decrease the risk of a disabling
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ischemic stroke event among women. However, our healthy lifestyle index had little impact on the risk of moderate/severe hemorrhagic strokes.
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Although research on composite healthy lifestyle indices and functional outcomes from
stroke is limited, some research has examined the association between the individual components of the healthy lifestyle index and functional outcomes from stroke. Although smoking has been associated with the risk of both ischemic33 and hemorrhagic stroke34 among women, information on stroke outcomes is mixed.7–12 Some studies have shown beneficial effects of physical activity on functional outcomes from stroke or stroke severity13–15 while one study showed no significant
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effect.16 Previous studies on alcohol consumption have found either modest or no association between moderate alcohol consumption and stroke outcomes.17–19 Some studies have suggested that stroke patients who are overweight or obese may have better outcomes.20–22 However,
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limited evidence exists on the effect of BMI on stroke outcomes in initially healthy populations. Information on diet and stroke outcomes in initially healthy populations is limited. Patients with acute stroke and poor nutritional status have a higher risk of death than those without poor
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nutritional status.23 A prospective cohort study among women did not find significant
hemorrhagic, fatal, or nonfatal stroke.35
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associations between quintiles of the Mediterranean Diet score and incidence of ischemic,
Despite the mixed or weak evidence that these individual components independently influence stroke outcomes, our study shows that a combination of lifestyle factors may help reduce the risk of mild, moderate, and severe ischemic stroke. The majority of the women in this
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cohort had scores on the health index from 5 to 8 (26.3% of the cohort) or 9 to 12 (40.2% of the cohort). While these categories do not represent the healthiest lifestyle according to our index, we still observed reductions in the risk of mild, moderate, and severe ischemic stroke for these
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women compared to women in the lowest category. This suggests that adopting even a modestly healthy lifestyle may reduce the risk of risk of mild, moderate, and severe ischemic stroke. For
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example, someone could achieve 5 to 8 points on the healthy lifestyle index by being a past smoker, having a BMI between 25.0-29.9 kg/m2, exercising once per week, never consuming alcohol, and being in the second lowest quintile of the dietary score distribution. We observed a different pattern between the healthy lifestyle index and risk of
hemorrhagic stroke with mild or moderate/severe functional outcomes. Those in the highest category of the healthy lifestyle index had an increased risk of hemorrhagic stroke with a mild
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functional outcome. However, the small number of hemorrhagic strokes with mild outcomes (N=4) makes it difficult to definitively conclude that healthier lifestyles are associated with an increased risk of hemorrhagic stroke with mild outcome. In addition, this increase was no longer
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significant when BMI was removed from the healthy lifestyle index. This suggests that some of the association between the healthy lifestyle index and risk of mild hemorrhagic stroke is driven by BMI. Evidence on the association between BMI and hemorrhagic stroke risk is unclear.
39
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Some studies have shown an increased risk of hemorrhagic stroke among people who are lean36– while others found no association40–42 or a positive association with increasing BMI.43
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Information on the association between overweight or obesity and hemorrhagic stroke outcomes is limited. A study among men observed higher proportion of mild strokes with BMI ≥30 kg/m2 while the proportion of fatal strokes was greater in men with BMI <23 kg/m2.43 Strengths of the present study include available information on many lifestyle factors in a
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large number of participants, the higher number of outcome events which allowed us to explore outcomes from ischemic and hemorrhagic stroke separately, and high interobserver agreement on major stroke subtype classification. We used the mRS to measure of functional outcome from
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stroke, which is widely accepted for use in clinical trials, accounts for prestroke disability44, has strong test-retest reliability, interrater reliability and validity45, and does not exhibit a “ceiling
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effect”.46
Some limitations should be noted. First, we were unable to update the healthy lifestyle
index over time because not all factors included in the index were assessed at multiple time points. Second, we did not consider weighting the components of the healthy lifestyle index. Third, there is the potential for non-differential misclassification of self-reported risk factors
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which would bias our results towards the null. Fourth, all participants in WHS were female health professionals and were primarily white which may limit our generalizability. Data from this large prospective cohort study of women observed that the highest versus
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lowest scores on the healthy lifestyle index were associated with reductions in the risk of total and ischemic strokes with mild, moderate, and severe functional outcomes. The observation that even modest healthy lifestyle index scores reduced risks of total and ischemic stroke with
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translate into reductions in risk of a disabling stroke event.
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moderate and severe functional outcomes suggests that even modest lifestyle changes may
Acknowledgements/Study Funding: The WHS is supported by grants from the National Institutes of Health (CA047988, HL043851, HL080467, HL099355, UM1 CA182913). The funder played no role in the design and conduct of the study; collection, management, analysis,
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and interpretation of the data; and preparation, review, or approval of the manuscript; and
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decision to submit the manuscript for publication.
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18. Jørgensen HS, Reith J, Nakayama H, Kammersgaard LP, Raaschou HO, Olsen TS. What determines good recovery in patients with the most severe strokes? The Copenhagen Stroke
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Study. Stroke. 1999;30(10):2008-2012. 19. Sturm JW, Donnan GA, Dewey HM, Macdonell RAL, Gilligan AK, Thrift AG.
Determinants of handicap after stroke: the North East Melbourne Stroke Incidence Study
SC
(NEMESIS). Stroke. 2004;35(3):715-720.
20. Doehner W, Schenkel J, Anker SD, Springer J, Audebert HJ. Overweight and obesity are
M AN U
associated with improved survival, functional outcome, and stroke recurrence after acute stroke or transient ischaemic attack: observations from the TEMPiS trial. Eur Heart J. 2013;34(4):268-277.
21. Saini M, Saqqur M, Shuaib A, Collaborators V. Body mass index and acute ischemic stroke
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outcomes. Int J Stroke. 2014;9(5):618-623.
22. Zhao L, Du W, Zhao X, et al. Favorable functional recovery in overweight ischemic stroke
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survivors: findings from the China National Stroke Registry. J Stroke Cerebrovasc Dis. 2014;23(3):e201-e206.
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23. FOOD Trial Collaboration. Poor nutritional status on admission predicts poor outcomes after stroke: observational data from the FOOD trial. Stroke. 2003;34(6):1450-1456. 24. Lee I-M, Cook NR, Gaziano JM, et al. Vitamin E in the primary prevention of cardiovascular disease and cancer: the Women’s Health Study: a randomized controlled trial. JAMA. 2005;294(1):56-65.
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25. Ridker PM, Cook NR, Lee I-M, et al. A randomized trial of low-dose aspirin in the primary prevention of cardiovascular disease in women. N Engl J Med. 2005;352(13):1293-1304.
analysis. JAMA. 2003;289(5):579-588.
RI PT
26. Reynolds K, Lewis B, Nolen JDL, et al. Alcohol consumption and risk of stroke: a meta-
27. Willett WC, Sampson L, Browne ML, et al. The use of a self-administered questionnaire to
SC
assess diet four years in the past. Am J Epidemiol. 1988;127(1):188-199.
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28. Atiya M, Kurth T, Berger K, Buring JE, Kase CS, Women’s Health Study. Interobserver agreement in the classification of stroke in the Women’s Health Study. Stroke. 2003;34(2):565-567.
29. Rist PM, Buring JE, Kase CS, Schürks M, Kurth T. Migraine and functional outcome from
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ischemic cerebral events in women. Circulation. 2010;122(24):2551-2557. 30. Rist PM, Buring JE, Kase CS, Ridker PM, Kurth T. Biomarkers and functional outcomes from ischaemic cerebral events in women: a prospective cohort study. Eur J Neurol.
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2012;20(2):375-381.
AC C
31. Rist PM, Buring JE, Kase CS, Kurth T. Effect of low-dose aspirin on functional outcome from cerebral vascular events in women. Stroke. 2013;44(2):432-436. 32. Rist PM, Glymour MM, Orav EJ, et al. Non-steroidal anti-inflammatory drug use and functional outcome from ischemic cerebral events among women. Eur J Intern Med. 2014;25(3):255-258.
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33. Kawachi I, Colditz GA, Stampfer MJ, et al. Smoking cessation and decreased risk of stroke in women. JAMA. 1993;269(2):232-236.
RI PT
34. Kurth T, Kase CS, Berger K, Gaziano JM, Cook NR, Buring JE. Smoking and risk of hemorrhagic stroke in women. Stroke. 2003;34(12):2792-2795.
35. Fung TT, Rexrode KM, Mantzoros CS, Manson JE, Willett WC, Hu FB. Mediterranean diet
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Circulation. 2009;119(8):1093-1100.
SC
and incidence of and mortality from coronary heart disease and stroke in women.
36. Rexrode KM, Hennekens CH, Willett WC, et al. A prospective study of body mass index, weight change, and risk of stroke in women. JAMA. 1997;277(19):1539-1545. 37. Song Y-M, Sung J, Davey Smith G, Ebrahim S. Body mass index and ischemic and
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hemorrhagic stroke: a prospective study in Korean men. Stroke. 2004;35(4):831-836. 38. Thrift AG, McNeil JJ, Forbes A, Donnan GA, for the Melbourne Risk Factor Study (MERFS) Group. Risk Factors for Cerebral Hemorrhage in the Era of Well-Controlled
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Hypertension. Stroke. 1996;27(11):2020-2025.
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39. Kurth T, Gaziano JM, Rexrode KM, et al. Prospective study of body mass index and risk of stroke in apparently healthy women. Circulation. 2005;111(15):1992-1998. 40. Jood K, Jern C, Wilhelmsen L, Rosengren A. Body mass index in mid-life is associated with a first stroke in men: a prospective population study over 28 years. Stroke. 2004;35(12):2764-2769.
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41. Abbott RD, Behrens GR, Sharp DS, et al. Body mass index and thromboembolic stroke in nonsmoking men in older middle age. The Honolulu Heart Program. Stroke.
RI PT
1994;25(12):2370-2376. 42. Rodriguez BL, Agostino R D’, Abbott RD, et al. Risk of hospitalized stroke in men enrolled
risk factor effects. Stroke. 2002;33(1):230-236.
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in the Honolulu Heart Program and the Framingham Study: A comparison of incidence and
43. Kurth T, Gaziano JM, Berger K, et al. Body mass index and the risk of stroke in men. Arch
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Intern Med. 2002;162(22):2557-2562.
44. Van Swieten JC, Koudstaal PJ, Visser MC, Schouten HJ, van Gijn J. Interobserver agreement for the assessment of handicap in stroke patients. Stroke. 1988;19(5):604-607.
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45. Banks JL, Marotta CA. Outcomes validity and reliability of the modified Rankin scale: implications for stroke clinical trials: a literature review and synthesis. Stroke. 2007;38(3):1091-1096.
Weimar C, Kurth T, Kraywinkel K, et al. Assessment of functioning and disability after
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46.
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ischemic stroke. Stroke. 2002;33(8):2053-2059.
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Table 1. Baseline characteristics of participants by healthy lifestyle index score*. Healthy
Index (N= 37624) 5-8
(n = 1615;
(n = 9890;
4.3%)
26.3%)
13-16
17-20
(n = 15108;
(n = 9265;
(n = 1756;
40.15%)
24.6%)
4.7%)
Current >=15 cig/d
54.3
13.9
4.6
1.0
0
Current < 15 cig/d
12.0
7.5
4.3
2.2
0.2
Past >=20 pack-yrs
13.4
13.1
11.5
9.2
3.9
11.7
20.8
25.0
30.3
31.4
8.6
44.8
54.6
57.3
64.5
85.8
65.5
35.9
11.4
0
12.1
23.9
23.7
14.3
1.7
1 time/wk
1.6
5.9
12.1
12.5
5.2
2-3 times/wk
0.5
4.2
21.4
39.7
43.1
>=4 times/week
0
0.5
6.9
22.1
50.1
31.5
12.1
3.2
0.4
0
Never Physical activity, % Rarely or never
AC C
< 1 time/wk
EP
Past < 20 pack-yrs
TE D
Smoking, %
9-12
SC
0-4
M AN U
Characteristic
RI PT
Lifestyle
Body mass index, % >=35.0
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25.4
22.0
10.9
3.6
0.3
25.0-29.9
24.2
36.5
34.5
24.6
6.7
22.0-24.9
13.8
20.7
32.7
38.5
35.7
<22.0
5.2
8.8
18.7
33.0
57.4
< 1 drink/wk
86.2
70.7
44.8
17.6
0
1-3 drinks/wk
12.0
16.9
17.7
12.5
1.8
2 to <10.5 drinks/wk
0.9
5.6
16.4
24.9
21.6
>=10.5 drinks/wk
0.2
3.4
15.8
39.1
72.7
3.5
5.3
5.9
3.9
37.1
15.8
4.5
0
25.8
33.6
26.3
14.2
1.8
6.8
15.2
20.5
18.0
9.0
1.9
9.6
20.5
27.5
27.8
0.3
4.5
16.9
35.8
61.4
53.5 (6.2)
54.4 (6.9)
54.9 (7.2)
54.6 (7.1)
54.5 (7.1)
History of hypertension
37.1
32.4
25.3
19.3
14.5
Antihypertensive medication use, %
18.0
17.7
13.4
10.4
6.9
History of diabetes mellitus, %
5.6
4.0
2.2
1.2
0.9
History of elevated cholesterol
34.2
31.5
30.5
25.6
22.7
Alcohol consumption, %
Diet score quintile, % 65.3
TE D
1st
M AN U
0.7
2nd 3rd
5th
AC C
Age, mean (SE), y
EP
4th
SC
Never
RI PT
30.0-34.9
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Postmenopausal hormone use 55.2
53.1
49.2
47.3
44.9
Past
13.3
10.6
8.8
7.5
6.0
Current
31.3
36.1
41.8
45.1
49.0
Ever used oral contraceptives, %
71.2
67.9
68.0
72.1
75.2
Family history of MI before age 60
14.3
12.5
11.3
10.8
10.9
SC
RI PT
Never
years, %
White
94.4
Black
3.4
Other
2.2
M AN U
Ethnicity, % 93.5
94.0
95.5
96.9
2.7
2.3
1.4
0.9
3.8
3.8
3.1
2.2
61.9
53.3
43.7
33.9
26.9
30.3
35.3
39.6
41.9
39.5
3.2
6.4
10.6
18.3
28.3
77.1
65.9
55.8
45.2
37.9
Bachelor’s degree
13.7
19.1
23.4
26.3
28.2
Master’s degree or doctorate
7.4
13.2
19.2
26.8
32.3
Single
7.0
6.3
5.8
4.8
4.4
Married
62.0
68.8
72.3
73.8
74.9
TE D
Annual household income, % <$50,000 $50,000-$100,000
EP
>=$100,000 Highest level of education, %
AC C
Less than bachelor’s degree
Marital status, %
ACCEPTED MANUSCRIPT
Other
31.0
24.9
21.9
21.4
20.7
Northeast
20.5
19.3
19.0
20.2
17.9
Southeast
24.2
23.8
23.7
Midwest
41.1
39.9
36.0
West
14.2
16.7
21.0
No history of migraine
79.4
80.0
Past history of migraine
6.6
Migraine without aura
8.4
Migraine with aura
5.4
21.5
20.8
31.5
27.0
26.6
34.0
SC 81.7
M AN U
Migraine status, %
RI PT
Geographic location, %
83.1
84.1
5.7
5.3
5.2
5.6
8.5
7.9
6.8
5.0
5.6
5.0
4.8
5.2
Note: Numbers may not add to 100% due to missing data.
AC C
EP
consumption, and diet.
TE D
*The healthy lifestyle index includes information on smoking status, physical activity, BMI, alcohol
ACCEPTED MANUSCRIPT
Table 2. Age- and multivariable-adjusted relative risks of functional outcomes by modified Rankin scale (mRS) score after TOTAL stroke according to Healthy
RI PT
Lifestyle Index* categories in the Women’s Health Study (N=37,634). No mRS 0-1
mRS 2-3
(n=36,767)
(n=360)
(n=303)
mRS 4-6 (n=204)
SC
Stroke
RR
n
%
n
%
(95% CI)
HI 0-4
1556
4.2
22
6.1
HI 5-8
9644
26.2
101
28.6
TE D
M AN U
RR n
%
(95% CI)
n
%
(95% CI)
1.00
23
7.6
1.00
14
6.9
1.00
0.69
90
29.7
0.56
53
26.0
0.52
Ageadjusted
9086
40.1
24.7
150
41.7
AC C
HI 13-16
14759
EP
(0.43, 1.09)
HI 9-12
74
20.6
RR
0.63
115
(0.35, 0.88) 38.0
(0.40, 0.98) 0.51 (0.32, 0.83)
0.44
(0.29, 0.94) 84
41.2
(0.28, 0.69) 60
19.8
0.38 (0.24, 0.62)
0.50 (0.28, 0.88)
45
22.1
0.45 (0.25, 0.82)
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HI 17-20
1722
4.7
11
3.1
0.41
15
5.0
8
3.9
(0.26, 0.98)
0.43 (0.18, 1.02)
RI PT
(0.20, 0.84)
0.50
Multivariable-
SC
adjusted**
1556
4.2
22
6.1
1.00
23
7.6
1.00
14
6.9
1.00
HI 5-8
9644
26.2
101
28.6
0.71
90
29.7
0.57
53
26.0
0.54
(0.45, 1.14) HI 9-12
14759
40.1
150
41.7
0.66
HI 13-16
9086
24.7
74
20.6
(0.36, 0.92)
115
0.55
38.0
60
19.8
adjusted (with intermediates)***
4.7
11
3.1
AC C
Multivariable-
1722
EP
(0.33, 0.89)
HI 17-20
0.43
(0.20, 0.90)
0.47
(0.30, 0.99) 84
41.2
(0.29, 0.74)
TE D
(0.41, 1.04)
M AN U
HI 0-4
15
0.41
(0.30, 0.97) 45
22.1
(0.25, 0.68) 5.0
0.53 (0.27, 1.06)
0.54
0.51 (0.27, 0.95)
8
3.9
0.48 (0.20, 1.18)
ACCEPTED MANUSCRIPT
1556
4.2
22
6.1
1.00
23
7.6
1.00
14
6.9
1.00
HI 5-8
9644
26.2
101
28.6
0.74
90
29.7
0.59
53
26.0
0.56
(0.46, 1.18) 14759
40.1
150
41.7
0.72
(0.37, 0.94) 115
(0.45, 1.14) 9086
24.7
74
20.6
0.62 (0.38, 1.01)
HI 17-20
1722
4.7
11
3.1
0.49
84
(0.31, 1.02) 41.2
(0.32, 0.81)
60
19.8
0.47
(0.33, 1.06) 45
22.1
(0.28, 0.78)
15
5.0
0.64
0.59
0.58 (0.31, 1.08)
8
3.9
(0.33, 1.27)
0.56 (0.23, 1.37)
TE D
(0.23, 1.04)
0.51
M AN U
HI 13-16
38.0
SC
HI 9-12
RI PT
HI 0-4
*Healthy lifestyle index includes smoking, physical activity, body mass index, alcohol consumption, and diet. **Adjusted for age (squared term), postmenopausal hormone use (never, past, or current), ever use of oral contraceptives, family history of myocardial infarction
EP
before age 60 years, migraine status (no history, past history, active migraine with aura, or active migraine without aura), annual household income (<$50,000,
AC C
$50,000 to <$100,000, or ≥$100,000), highest level of education (less than a bachelor’s degree, bachelor’s degree, or master’s degree or doctorate), location of residence (Northeast, Southeast, Midwest, or West), marital status (single, married, or other), and ethnicity (white, black, or other). ***Adjusted for all covariates above in addition to history of diabetes mellitus, history of hypertension (defined as systolic blood pressure of ≥140 mm Hg, diastolic blood pressure of ≥90 mm Hg, or self-reported physician-diagnosed hypertension), antihypertensive treatment, and history of elevated cholesterol of ≥240 mg/dL (6.21 mmol/L).
ACCEPTED MANUSCRIPT
Note: Less than 100 women were missing information on diabetes, history of hypertension, antihypertensive treatment, history of high cholesterol, migraine status, location of residence, postmenopausal hormone use, history of oral contraceptive use, and were assigned to the most frequent category. More than 100
RI PT
women were missing information on annual household income, family history of myocardial infarction, education, and marital status and were assigned to a separate “missing” category. People missing information on ethnicity were included in the “other” category.
AC C
EP
TE D
M AN U
SC
HI = healthy lifestyle index score; mRS = modified Rankin scale; RR = relative risk; CI = confidence interval.
ACCEPTED MANUSCRIPT
Table 3. Age- and multivariable-adjusted relative risks of functional outcomes by modified Rankin scale (mRS) score after ISCHEMIC stroke according to
RI PT
Healthy Lifestyle Index* (HI) categories in the Women’s Health Study (N=37,474). No mRS 0-1
mRS 2-3
(n=36,767)
(n=329)
(n=269)
%
n
%
(95% CI)
HI 0-4
1556
4.2
22
6.7
HI 5-8
9644
26.2
96
29.2
(n=109)
RR
M AN U
RR n
mRS 4-6
SC
Stroke
n
%
(95% CI)
n
%
(95% CI)
1.00
20
7.4
1.00
8
7.3
1.00
0.64
77
28.6
0.54
32
29.4
0.51
Age-
TE D
adjusted
40.1
139
42.3
0.58
AC C
14759
EP
(0.40, 1.02)
HI 9-12
109
(0.33, 0.89) 40.5
(0.37, 0.91)
HI 13-16
9086
24.7
66
20.1
RR
0.46 (0.28, 0.74)
0.47
(0.23, 1.11) 43
39.5
(0.29, 0.76) 49
18.2
0.36 (0.21, 0.60)
0.40 (0.19, 0.87)
22
20.2
0.35 (0.16, 0.79)
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HI 17-20
1722
4.7
6
1.8
0.22
14
5.2
4
3.7
(0.27, 1.08)
0.34 (0.10, 1.15)
RI PT
(0.09, 0.55)
0.54
Multivariable-
SC
adjusted**
1556
4.2
22
6.7
1.00
20
7.4
1.00
8
7.3
1.00
HI 5-8
9644
26.2
96
29.2
0.65
77
28.6
0.56
32
29.4
0.56
(0.41, 1.04) HI 9-12
14759
40.1
139
42.3
0.59
HI 13-16
9086
24.7
66
20.1
(0.34, 0.92)
109
0.47
40.5
49
18.2
1722
4.7
6
EP
(0.29, 0.78) HI 17-20
1.8
0.23
Multivariableadjusted (with intermediates)***
AC C
(0.09, 0.56)
0.50
(0.25, 1.23) 43
39.5
(0.31, 0.82)
TE D
(0.37, 0.94)
M AN U
HI 0-4
14
0.38
(0.21, 1.01) 22
20.2
(0.22, 0.65) 5.2
0.57 (0.28, 1.16)
0.47
0.42 (0.18, 0.98)
4
3.7
0.42 (0.12, 1.45)
ACCEPTED MANUSCRIPT
1556
4.2
22
6.7
1.00
20
7.4
1.00
8
7.3
1.00
HI 5-8
9644
26.2
96
29.2
0.67
77
28.6
0.57
32
29.4
0.58
(0.42, 1.08) 14759
40.1
139
42.3
0.65
(0.35, 0.95) 109
(0.41, 1.03) 9086
24.7
66
20.1
0.54 (0.32, 0.89)
HI 17-20
1722
4.7
6
1.8
0.26
43
(0.26, 1.27) 39.5
(0.33, 0.89)
49
18.2
0.44
(0.23, 1.11) 22
20.2
(0.25, 0.75)
14
5.2
0.69
0.51
0.50 (0.21, 1.16)
4
3.7
(0.34, 1.40)
0.50 (0.15, 1.74)
TE D
(0.10, 0.66)
0.55
M AN U
HI 13-16
40.5
SC
HI 9-12
RI PT
HI 0-4
*Healthy lifestyle index includes smoking, physical activity, body mass index, alcohol consumption, and diet. **Adjusted for age (squared term), postmenopausal hormone use (never, past, or current), ever use of oral contraceptives, family history of myocardial infarction
EP
before age 60 years, migraine status (no history, past history, active migraine with aura, or active migraine without aura), annual household income (<$50,000,
AC C
$50,000 to <$100,000, or ≥$100,000), highest level of education (less than a bachelor’s degree, bachelor’s degree, or master’s degree or doctorate), location of residence (Northeast, Southeast, Midwest, or West), marital status (single, married, or other), and ethnicity (white, black, or other). ***Adjusted for all covariates above in addition to history of diabetes mellitus, history of hypertension (defined as systolic blood pressure of ≥140 mm Hg, diastolic blood pressure of ≥90 mm Hg, or self-reported physician-diagnosed hypertension), antihypertensive treatment, and history of elevated cholesterol of ≥240 mg/dL (6.21 mmol/L).
ACCEPTED MANUSCRIPT
Note: Less than 100 women were missing information on diabetes, history of hypertension, antihypertensive treatment, history of high cholesterol, migraine status, location of residence, postmenopausal hormone use, history of oral contraceptive use, and were assigned to the most frequent category. More than 100
RI PT
women were missing information on annual household income, family history of myocardial infarction, education, and marital status and were assigned to a separate “missing” category. People missing information on ethnicity were included in the “other” category.
AC C
EP
TE D
M AN U
SC
HI = healthy lifestyle index score; mRS = modified Rankin scale; RR = relative risk; CI = confidence interval.
ACCEPTED MANUSCRIPT
Table 4. Age- and multivariable-adjusted* relative risks of functional outcomes by modified Rankin scale (mRS) score after HEMORRHAGIC stroke according
RI PT
to Healthy Lifestyle Index categories in the Women’s Health Study (N=36,923). No mRS 0-1
mRS 2-6
(n=36,767)
(n=29)
(n=127)
SC
Stroke
n
%
n
%
(95% CI)
HI 0-8
11200
30.5
7
24.1
1.00
HI 9-12
14759
40.1
10
34.5
TE D
Age-adjusted
RR
M AN U
RR
1.08
n
%
(95% CI)
42
33.1
1.00
47
37.0
0.81
HI 17-20
9086
1722
24.7
4.7
8
27.6
1.41
AC C
HI 13-16
EP
(0.41, 2.85)
4
13.8
33
26.0
(0.51, 3.89)
3.71
(1.09, 12.69)
Multivariable-
(0.53, 1.23) 0.94 (0.60, 1.49)
5
3.9
0.76 (0.30, 1.93)
ACCEPTED MANUSCRIPT
adjusted* 11200
30.5
7
24.1
1.00
42
33.1
HI 9-12
14759
40.1
10
34.5
1.17
47
37.0
9086
24.7
8
27.6
1.57 (0.56, 4.41)
HI 17-20
1722
4.7
4
(0.55,1.27)
13.8
4.23
33
26.0
(0.63, 1.61)
5
3.9
(1.20, 14.99)
adjusted (with
11200
30.5
HI 9-12
14759
40.1
9086
24.7
7
24.1
AC C
HI 0-8
EP
intermediates)**
HI 13-16
0.81
(0.32, 2.09)
TE D
Multivariable-
1.00
M AN U
HI 13-16
0.83
SC
(0.44, 3.08)
1.00
RI PT
HI 0-8
10
8
34.5
27.6
1.00
42
33.1
1.00
1.15
47
37.0
0.86
(0.43, 3.04)
1.55
(0.57, 1.32) 33
26.0
1.06
ACCEPTED MANUSCRIPT
(0.55, 4.39) 1722
4.7
4
13.8
4.12
5
(1.15, 14.72)
3.9
0.88
RI PT
HI 17-20
(0.66, 1.71)
(0.34, 2.27)
*Healthy lifestyle index includes smoking, physical activity, body mass index, alcohol consumption, and diet.
SC
**Adjusted for age (squared term), postmenopausal hormone use (never, past, or current), ever use of oral contraceptives, family history of myocardial infarction
M AN U
before age 60 years, migraine status (no history, past history, active migraine with aura, or active migraine without aura), annual household income (<$50,000, $50,000 to <$100,000, or ≥$100,000), highest level of education (less than a bachelor’s degree, bachelor’s degree, or master’s degree or doctorate), location of residence (Northeast, Southeast, Midwest, or West), marital status (single, married, or other), and ethnicity (white, black, or other). ***Adjusted for all covariates above in addition to history of diabetes mellitus, history of hypertension (defined as systolic blood pressure of ≥140 mm Hg,
≥240 mg/dL (6.21 mmol/L).
TE D
diastolic blood pressure of ≥90 mm Hg, or self-reported physician-diagnosed hypertension), antihypertensive treatment, and history of elevated cholesterol of
Note: Less than 100 women were missing information on diabetes, history of hypertension, antihypertensive treatment, history of high cholesterol, migraine
EP
status, location of residence, postmenopausal hormone use, history of oral contraceptive use, and were assigned to the most frequent category. More than 100 women were missing information on annual household income, family history of myocardial infarction, education, and marital status and were assigned to a
AC C
separate “missing” category. People missing information on ethnicity were included in the “other” category.
HI = healthy lifestyle index score; mRS = modified Rankin scale; RR = relative risk; CI = confidence interval.
ACCEPTED MANUSCRIPT
Online Table 1. Multivariable-adjusted relative risks of functional outcomes by modified Rankin scale (mRS) score after ISCHEMIC stroke according to
No mRS 0-1
mRS 2-3
(n=36,767)
(n=329)
(n=269)
n
%
HI 0-4
5183
14.1
52
15.8
HI 5-8
15582
42.4
148
45.0
(95% CI)
n
%
(95% CI)
n
%
(95% CI)
1.00
49
18.2
1.00
22
20.2
1.00
0.93
109
40.5
0.73
47
43.1
0.69
Multivariableadjusted*
3092
35.1
8.4
114
34.7
AC C
HI 13-16
12910
EP
(0.68, 1.29)
HI 9-12
15
4.6
RR
TE D
%
(n=109)
RR
M AN U
RR n
mRS 4-6
SC
Stroke
RI PT
modified healthy lifestyle index* (HI) categories in the Women’s Health Study (N=37,474).
0.88
(0.52, 1.03) 90
33.5
(0.63, 1.23) 0.48 (0.27, 0.87)
0.74
(0.41, 1.16) 32
29.4
(0.52, 1.06) 21
7.8
0.72 (0.43, 1.23)
0.59 (0.34, 1.04)
8
7.3
0.64 (0.28, 1.48)
ACCEPTED MANUSCRIPT
Multivariable-
RI PT
adjusted (with intermediates)** 5183
14.1
52
15.8
1.00
49
HI 5-8
15582
42.4
148
45.0
0.93
109
HI 9-12
12910
35.1
114
34.7
0.90
40.5
90
33.5
(0.64, 1.27)
3092
8.4
15
4.6
0.51
TE D
HI 13-16
(0.27, 0.93)
1.00 0.72
22
20.2
1.00
47
43.1
0.67
(0.51, 1.02)
M AN U
(0.68, 1.29)
18.2
SC
HI 0-4
21
7.8
0.77
(0.40, 1.12) 32
29.4
(0.53, 1.10)
0.78
0.60 (0.34, 1.05)
8
(0.46, 1.32)
7.3
0.67 (0.29, 1.55)
*Modified healthy lifestyle index includes smoking, physical activity, alcohol consumption, and diet (maximum score of 16).
EP
**Adjusted for age (squared term), postmenopausal hormone use (never, past, or current), ever use of oral contraceptives, family history of myocardial infarction
AC C
before age 60 years, migraine status (no history, past history, active migraine with aura, or active migraine without aura), annual household income (<$50,000, $50,000 to <$100,000, or ≥$100,000), highest level of education (less than a bachelor’s degree, bachelor’s degree, or master’s degree or doctorate), location of residence (Northeast, Southeast, Midwest, or West), marital status (single, married, or other), and ethnicity (white, black, or other). ***Adjusted for all covariates above in addition to history of diabetes mellitus, history of hypertension (defined as systolic blood pressure of ≥140 mm Hg, diastolic blood pressure of ≥90 mm Hg, or self-reported physician-diagnosed hypertension), antihypertensive treatment, and history of elevated cholesterol of ≥240 mg/dL (6.21 mmol/L).
ACCEPTED MANUSCRIPT
Note: Less than 100 women were missing information on diabetes, history of hypertension, antihypertensive treatment, history of high cholesterol, migraine status, location of residence, postmenopausal hormone use, history of oral contraceptive use, and were assigned to the most frequent category. More than 100
RI PT
women were missing information on annual household income, family history of myocardial infarction, education, and marital status and were assigned to a separate “missing” category. People missing information on ethnicity were included in the “other” category.
AC C
EP
TE D
M AN U
SC
HI = healthy lifestyle index score; mRS = modified Rankin scale; RR = relative risk; CI = confidence interval.
ACCEPTED MANUSCRIPT
Online Table 2. Multivariable-adjusted relative risks of functional outcomes by modified Rankin scale (mRS) score after HEMORRHAGIC stroke according to
RI PT
modified healthy lifestyle index* (HI) categories in the Women’s Health Study (N=36,923). No mRS 0-1
(n=36,766)
(n=29)
mRS 2-6 (n=127)
SC
Stroke
RR
n
%
n
%
(95% CI)
n
%
(95% CI)
Modified HI 0-8
20765
56.5
15
51.7
1.00
73
57.5
1.00
Modified HI 9-12
12910
35.1
10
34.5
TE D
M AN U
RR
1.14
47
37.0
1.06
Multivariableadjusted*
16
Multivariableadjusted (with
3092
8.4
4
13.8
AC C
Modified HI 13-
EP
(0.51, 2.56) 1.92
(0.62, 5.92)
(0.73, 1.54) 7
5.5
0.58 (0.31, 1.49)
ACCEPTED MANUSCRIPT
intermediates)** 20765
56.5
15
51.7
1.00
73
57.5
Modified HI 9-12
12910
35.1
10
34.5
1.14
47
37.0
Modified HI 13-
3092
8.4
4
13.8
1.89
7
(0.61, 5.85)
5.5
M AN U
16
1.08
(0.74, 1.56)
SC
(0.51, 2.56)
1.00
RI PT
Modified HI 0-8
0.70 (0.32, 1.54)
*Modified healthy lifestyle index includes smoking, physical activity, alcohol consumption, and diet (maximum score of 16). **Adjusted for age (squared term), postmenopausal hormone use (never, past, or current), ever use of oral contraceptives, family history of myocardial infarction
TE D
before age 60 years, migraine status (no history, past history, active migraine with aura, or active migraine without aura), annual household income (<$50,000, $50,000 to <$100,000, or ≥$100,000), highest level of education (less than a bachelor’s degree, bachelor’s degree, or master’s degree or doctorate), location of residence (Northeast, Southeast, Midwest, or West), marital status (single, married, or other), and ethnicity (white, black, or other).
EP
***Adjusted for all covariates above in addition to history of diabetes mellitus, history of hypertension (defined as systolic blood pressure of ≥140 mm Hg,
≥240 mg/dL (6.21 mmol/L).
AC C
diastolic blood pressure of ≥90 mm Hg, or self-reported physician-diagnosed hypertension), antihypertensive treatment, and history of elevated cholesterol of
Note: Less than 100 women were missing information on diabetes, history of hypertension, antihypertensive treatment, history of high cholesterol, migraine status, location of residence, postmenopausal hormone use, history of oral contraceptive use, and were assigned to the most frequent category. More than 100 women were missing information on annual household income, family history of myocardial infarction, education, and marital status and were assigned to a separate “missing” category. People missing information on ethnicity were included in the “other” category.
ACCEPTED MANUSCRIPT
AC C
EP
TE D
M AN U
SC
RI PT
HI = healthy lifestyle index score; mRS = modified Rankin scale; RR = relative risk; CI = confidence interval.
ACCEPTED MANUSCRIPT
Clinical Significance •
Highest versus lowest scores on the healthy lifestyle index were associated with
functional outcomes among women.
The evidence that even a modest healthy lifestyle index scores reduced risks of total and ischemic stroke with moderate and severe functional outcomes suggests that modest
EP
TE D
M AN U
SC
lifestyle changes may translate to reductions in risk of a disabling stroke event.
AC C
•
RI PT
reductions in risk of total and ischemic strokes with mild, moderate, and severe