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the Departments of Neurology (S.S., M.K.H., C.S.K., R.A., P.A.W.) and Preventive Medicine (W.B.K.), School of Medicine, and the Department of Biostatistics, School of Public Health (A.B.), Boston University, Massachusetts.
Abstract
Background and Purpose— The lifetime risk (LTR) of stroke has not been reported for the United States population; such data would assist public education and health planning.
Methods— Framingham Original cohort participants (n=4897) who were stroke- and dementia-free at 55 years of age were followed biennially for up to 51 years (115 146 person years). We estimated the sex-specific 10-, 20-, and 30-year risks and LTR of developing a stroke by baseline age and blood pressure (BP) and compared it with the risk of developing Alzheimer disease (AD).
Results— A total of 875 participants (522 women) developed a first-ever stroke; 749 (448 women) had an ischemic stroke. LTR of stroke was high and remained similar at ages 55, 65, and 75 years, approximating 1 in 5 for women and 1 in 6 for men. Participants with a normal BP (<120/80 mm Hg) had approximately half the LTR of stroke compared with those with high BP (140/90 mm Hg). The LTR of AD at age 65 (292 participants; 211 women) approximated 1 in 5 for women and 1 in 10 for men. The LTR of developing either stroke or dementia approximated 1 in 3 in both sexes.
Conclusion— The LTR of stroke in middle-aged adults is 1 in 6 or more, which is equal to or greater than the LTR of AD. Women had a higher risk because of longer life expectancy. BP is a significant determinant of the LTR of stroke, and promotion of normal BP levels in the community might be expected to substantially reduce this risk.
Key Words: stroke epidemiology blood pressure Alzheimer disease
Introduction
The average life expectancy in the United States today is 77 years,1 so that most young adults should expect to grow old, and, as an unwelcome corollary, they will face the risk of developing diseases that are increasingly prevalent with age. The lifetime risk (LTR) of developing several of these conditions, such as dementia, coronary artery disease, and hip fractures, have been estimated,2–4 but the LTR of stroke has not been reported previously for the United States population. Estimation of the LTR of stroke is particularly important because stroke is a leading cause of mortality and the most common cause of neurological disability in older persons. Epidemiological studies have identified blood pressure (BP) as the single most important, modifiable stroke risk factor,5 and BP in middle age predicts the risk of stroke in older persons.6 Accordingly, we estimated the short- and intermediate-term risks and the LTR of developing stroke in the community-based Framingham cohort overall and also within BP categories defined by the Seventh Joint National Committee on the Prevention, Detection, Evaluation, and Treatment of High Blood Pressure (JNC 7) criteria.7 To put the LTR of stroke in perspective, we compared it with the LTR of dementia and Alzheimer’s disease (AD). We chose this comparison because dementia, largely attributable to AD, is the only other neurological condition listed among the 10 leading causes of total disease burden (based on disability, mortality, and societal costs) in developed countries,8 and these are the 2 most widely feared aging-related neurological diseases in the public perception.
Methods
Participants
The Framingham Heart Study is an ongoing cohort study that began in 1948 with the enrollment of 5209 participants into the Original cohort.9 These participants have been assessed biennially with medical histories, physical examinations, laboratory tests for vascular risk factors, and, at some examinations, by brain imaging studies. The present investigation, approved by the institutional board of Boston Medical Center, used 3 samples from the Framingham Original cohort: (1) 4897 participants who survived stroke-free up to 55 years of age and were followed for up to 51 years (115 146 person years) to estimate the LTR of first-ever stroke. (2) A dementia-free group of participants were identified in 1975 and have been under surveillance for the development of incident dementia.2 A total of 2794 persons from this group who reached 65 years of age free of dementia were followed for up to 29 years (42 233 person years) to estimate the LTR of dementia and AD. (3) Finally, 2711 participants who reached 65 years of age free of both stroke and dementia were followed for up to 29 years (39 985 person years) to estimate the LTR of developing either stroke or dementia.
Case Definition
Details of our stroke surveillance and protocol for determining the diagnosis and type of stroke have been published.5,10 Stroke was defined as an acute- onset focal neurological deficit of vascular etiology, persisting for >24 hours. Both ischemic and hemorrhagic stroke subtypes were included. Stroke subtypes were categorized based on pre-established criteria that include clinical features, imaging studies, and other laboratory criteria, noninvasive vascular studies, cardiac evaluations for a source of embolus, and, when available, information from autopsy studies. Ischemic stroke was diagnosed if a focal neurological deficit was documented and the imaging showed no hemorrhage, the imaging showed an ischemic infarct that correlated with the clinical deficit, or an ischemic infarct was documented at autopsy.
Screening techniques and procedures used to diagnose and categorize dementia have been described previously.2,11 Diagnostic and Statistical Manual of Mental Disorders, 4th edition, criteria were used to define dementia,12 but we additionally required that severity be at least "moderate" by Framingham criteria (1 on the Clinical Dementia Rating Scale)13 and that symptoms be present for 6 months. AD was defined using NINCDS-ADRDA criteria for definite, probable, or possible AD.14 All deaths were reviewed to assign a cause of death (stroke or an alternative etiology) and to determine whether dementia was present at the time of death.
Statistical Analysis
Participants were followed until they developed the outcome of interest (first-ever stroke or dementia), died, or until their most recent Framingham Study evaluation before December 2003. The estimation of cumulative incidence of diseases of the elderly is complicated by the competing risk of death. Subjects who die during the observation period are treated as censored observations in traditional survival analytic techniques, and their potential contribution to the probability of disease is distributed among subjects still at risk. However, the potential contribution of a subject who has died should be 0. Treating such subjects as censored inflates the estimate of cumulative incidence. We used a modified double-decrement survival analysis technique described previously,2,11 which adjusts the cumulative incidence for the competing risk of death, thereby providing an estimate of the actual risk of one developing the disease during his or her lifetime.
Sex-specific 10-, 20-, and 30-year risks, and the LTR of developing a first-ever stroke were defined for stroke-free participants at baseline ages 55, 65, 75, and 85 years (referred to as "index" ages) for all stroke, and specifically for ischemic stroke. Sex-specific 10-, 20-, and 30-year risks and the LTR of developing dementia and AD were estimated at ages 65, 75, and 85 years. In these event-specific analyses (considering either stroke or dementia), subjects were not censored when they developed the alternative event because the development of stroke did not preclude the development of dementia and vice versa. The combined risk of developing "either stroke or dementia" was also estimated, and for this analysis, only the first event (either stroke or dementia) was considered.
We further examined the risk of stroke and AD within BP categories defined using JNC 7 cut points (with the modification that we used actual BP levels, disregarding treatment). Participants were stratified by BP recorded at the last available examination before the index age (2 years earlier). We defined 4 categories using systolic BP (SBP) and diastolic BP (DBP) measured in mm Hg: SBP <120 and DBP <80; 120SBP<140 or 80DBP<90; 140SBP<160 or 90DBP<100 and SBP 160 or DBP 100. If categorization by SBP and DBP varied, participants were placed in the higher category; in >90%, classification into a higher category was based on SBP. In separate analyses, participants on antihypertensive therapy at index age were excluded. All statistical analyses were performed using SAS software (SAS Institute).
Results
Description of Participants
During a 51-year follow-up period, 18% (875 participants; 522 women) developed a first-ever stroke. Of these, 86% (749 participants; 448 women) developed an ischemic stroke. Over a 29-year follow-up period, 14% (400 participants; 270 women) developed dementia, and 73% of these (292 participants; 211 women) had AD.
LTR of Stroke
Table 1 displays the LTR of stroke, which remained relatively constant until 75 years of age, at 1 in 5 for women (20% to 21%) and approximately 1 in 6 for men (14% to 17%). The LTR at 85 years of age was lower (16% for women and 10% for men; P<0.05 compared with participants 55 to 75 years of age). Although the incidence rate of stroke increased with age, this was counterbalanced by a decreasing residual life expectancy (data not presented).
Short- and Intermediate-Term Risks of Stroke
Figure 1a and 1b plot the 10-, 20-, 30-year, and the LTR of stroke in women and men 65 years of age. Table 1 presents these risks for each index age. At 65 years of age, the 10-year risk was lower in women; by 75 years of age, women and men were at equal risk. At 85 years of age, the pattern was reversed, and 10-year risks were higher in women.
LTR, Short-Term, and Intermediate-Term Risks for Ischemic Stroke (Table 1; Figure 1a and 1b)
The LTR of ischemic stroke at 55 or 65 years of age was higher in women (18%) than in men (14% to 15%; P<0.01). As with overall stroke risk, the 10-year risk of ischemic stroke was lower in women than in men at <75 years of age but higher thereafter.
LTR, Short-Term, and Intermediate-Term Risks for Stroke by BP Category
There was a graded increase in stroke risk with increasing BP (Table 2; Figure 2). Participants with a normal BP (SBP <120 and DBP <80 mm Hg) had a significantly lower LTR of stroke than participants with a high BP (SBP 140 or DBP 90 mm Hg; P<0.01). In women, these risks were 1 in 6 (15%) and 1 in 4 (26%), respectively, whereas in men, they were 1 in 10 (10%) and 1 in 5 (21%). A similar risk gradient across the 4 BP categories was noted in younger (55 years of age) and in older participants (75 and 85 years of age), and the graded increase in risk with higher BP persisted when people on antihypertensive drugs were excluded (data not presented).
LTR of Dementia
The short-term, intermediate-term, and the LTR of dementia and AD are presented in Table 3 and Figure 1a and 1b. We observed a higher risk of dementia and AD in women (22% to 24% and 17% to 20%, respectively) compared with men (14% to 17% and 9% to 12%, respectively; P<0.01). Thus, >1 in 5 women and 1 in 6 men who reached 65 years of age developed dementia; 1 in 5 women and 1 in 10 men developed AD. These risks did not vary across BP categories (data not shown).
Combined Risk of Stroke or Dementia
Table 4 shows that the LTR of developing either stroke or dementia at age 65, 75, or 85 years is >1 in 3 (39% at 65 years and 38% at 85 years) for women and 1 in 4 for men (28% at 65 years and 24% at 85 years).
Comparison of Stroke and AD Risks
Figure 1a and 1b show that in 65-year-old participants, the 10- and 20-year risks of developing stroke were higher than the corresponding risk of AD. Men 65 to 75 years of age also had a higher LTR of stroke (1 in 6 for stroke; 1 in 10 for AD), whereas women at this age had an LTR of stroke approximately equal to their LTR of AD (1 in 5). At 85 years of age, the LTR of stroke was lower than the corresponding risk of AD in both sexes, but this difference was statistically significant only in women. The flattening of the LTR curves for stroke and AD in very old subjects (as shown in Figure 1a and 1b) is based on relatively small numbers and may, therefore, be attributable to chance.
Discussion
We observed that the LTR of stroke for middle-aged and "young-old" adults (55 to 75 years of age) was substantial at 1 in 6 or higher. This risk was higher in women (1 in 5) compared with men, largely because of the greater life expectancy in women, which increased their period at risk. For the oldest-old participants (>85 years of age), the LTR of stroke decreased, despite a continued rise in stroke incidence, because the remaining life expectancy decreased more rapidly than the risk of stroke increased.
Our estimates are based on simultaneously gathered data on both stroke incidence and mortality attributable to competing causes (the 2 key determinants of the LTR) in the same community-based cohort followed >5 decades. Estimates that combine stroke incidence collected in 1 population or time period with mortality data collected in another sample may yield biased estimates of LTR because a variety of risk factors that influence stroke risk (most notably hypertension) can also affect the risk of dying from other causes. There has been only 1 previous published report on the LTR of stroke; those estimates were based on a much shorter (6-year) follow-up of the Rotterdam Study sample and were similar to ours (21% for both men and women 55 years of age).15
Comparison of the LTR of Stroke With the LTR of AD
Our investigation presents the first available comparison of the LTR of stroke and AD in the same cohort. These estimates of the LTR of AD are higher than our previously published figure2 because they are based on extended observation of the same cohort with accrual of additional cases. We found that the LTR of stroke either equaled or was greater than the LTR of AD for most participants. Only in the oldest-old (>85 years of age) women was the LTR of stroke significantly lower than the LTR of AD. The combined LTR of developing either stroke or dementia was <30% in men but was nearly 40% in women (exceeding their LTR of developing symptomatic coronary artery disease).3
Strengths and Limitations
The strengths of our study include the use of a population-based cohort, the prospective ascertainment of end points using rigorous standardized and previously validated clinical diagnostic criteria that have not varied significantly over the 5 decades of follow-up, and the completeness of stroke and mortality ascertainment. These LTR estimates are population based, and therefore, although they serve as general guidelines, they have limited prognostic utility in a given individual in whom the LTR would depend on his or her own estimated life expectancy and level of exposure to various risk factors for stroke and dementia. The Framingham Original cohort is overwhelmingly white, so racial and ethnic differences need to be explored in other cohorts. Time period and birth cohort effects could limit the external validity of our results. We did not find a secular trend in the incidence of stroke in our population,10 but this issue needs to be addressed in additional studies. Temporal trends in life expectancy, risk factor prevalence and control, in disease awareness, and in the sensitivity of diagnostic tests could alter the LTR of stroke and dementia. Finally, these estimates describe the risk of overt stroke but do not address the risk of silent (covert) stroke, which may be substantial.16 Therefore, the stroke risks that we report, although high, are likely to be conservative estimates of the true population burden of cerebral vascular disease.
Public Health Significance
These LTR estimates are useful for public education because they are easier to comprehend than measures such as incidence, prevalence, or relative risk. A recent study using focus group discussions concluded that "patients preferred health risks to be framed in absolute terms, using bar graphs, and calculated over their expected lifetime."17 Health educators have also emphasized that while raising awareness of a health hazard, it is important to simultaneously provide data on modifiable risk factors because this increases receptivity and minimizes psychological distress.18 Our data can be used to generate simple bar graphs (supplemental Figure I, available online at http://stroke.ahajournals.org) showing, for example, that the LTR of stroke in a 65-year-old woman with BP <120/80 mm Hg is half that of a 65-year old woman with BP 140/90 mm Hg. Currently, two thirds of all hypertension remains undetected or inadequately treated.19 Although we cannot directly address the benefits of intervention in our observational data, education of middle-aged and older adults regarding their high LTR of stroke and the key contribution of high BP to this risk may be expected to motivate lifestyle modifications, thereby reducing mean population BP levels20 and, ultimately, the population burden of stroke.
Acknowledgments
Supported by grants from the National Institute of Neurological Disorders and Stroke (5R01-NS17950), the National Institute of Aging (5R01-AG08122 and 5R01-AG16495), the Boston University Alzheimer Disease Center P30 AG13846, and the National Heart, Lung and Blood Institute (NHLBI) Framingham Heart Study (National Institutes of Health/NHLBI Contract N01-HC-25195).
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