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(Stroke. 1996;27:819-824.)
© 1996 American Heart Association, Inc.

Articles

Age-Related Changes in Stroke Risk in Men With Hypertension and Normal Blood Pressure

J. David Curb, MD; Robert D. Abbott, PhD; Charles J. MacLean, PhD; Beatriz L. Rodriguez, MD; Cecil M. Burchfiel, PhD; Dan S. Sharp, MD, PhD; G. Webster Ross, MD Katsuhiko Yano, MD

From the John A. Burns School of Medicine, University of Hawaii at Manoa (J.D.C., B.L.R.), and The Honolulu Heart Program, Kuakini Medical Center (J.D.C., R.D.A., C.J.M., B.L.R., C.M.B., D.S.S., G.W.R., K.Y.), and Hawaii Department of Veteran's Affairs (G.W.R.), Honolulu, Hawaii; Division of Biostatistics, University of Virginia School of Medicine (Charlottesville) (R.D.A.); Department of Psychiatry, Medical College of Virginia (Richmond) (C.J.M.); and The National Heart, Lung, and Blood Institute, Bethesda, Md (C.M.B., D.S.S.).

Correspondence to J. David Curb, MD, Division of Clinical Epidemiology, Department of Medicine, John A. Burns School of Medicine, University of Hawaii, 347 N Kuakini St, Honolulu, HI 96817. E-mail curb@hhs.cba.hawaii.edu.

	Abstract

Top Abstract Introduction Subjects and Methods Results Discussion References

 
Background and Purpose Stroke is a major contributor to total morbidity and mortality in older individuals, and hypertension is an important risk factor for stroke. Relatively few data exist on whether this relationship changes with age.

Methods To examine age-related changes in the relationships between risk of stroke and hypertension, we examined the 6-year incidence of stroke among men aged 45 to 81 years using updated blood pressure data from three examinations of Japanese-American men from the Honolulu Heart Program.

Results Both the prevalence of hypertension (systolic blood pressure 160 mm Hg or diastolic blood pressure 95 mm Hg or the use of antihypertensive medication) and the 6-year incidence of stroke increased significantly with increasing age (P<.01). The increase in thromboembolic stroke incidence with age was more marked in those who were normotensive at baseline (2.7/1000 in those aged 45 to 54 years to 23.9/1000 in those 65 years; P<.001) than in hypertensive men (20.6/1000 in those aged 45 to 54 years to 33.5/1000 in those 65 years; P<.01). The age-related increase in risk of thromboembolic stroke among normotensive men resulted in a decrease in the percentage of strokes attributable to hypertension (50% in those aged 45 to 54 years to 18% in those 65 years; P<.05). Similar trends were seen for hemorrhagic stroke. There were no age-related changes in the relationships of other major atherosclerotic risk factors with stroke. The hypertension/stroke relationships were present after multivariate adjustment for age, smoking, cholesterol, and other factors.

Conclusions In view of the greater prevalence of hypertension and the proven efficacy of treatment in the elderly, these findings do not negate the value of aggressive screening and treatment of hypertension in this age group. However, it appears that other unidentified factors have an increasing role in the causation of stroke with advancing age.

Key Words: elderly • hypertension • risk factors • stroke

	Introduction

Top Abstract Introduction Subjects and Methods Results Discussion References

 
The incidence of stroke increases markedly with increasing age in our society.¹ For this reason stroke is a major contributor to total morbidity and mortality in older individuals. Hypertension is the single most powerful known risk factor for stroke at all ages.^{2 3 4} However, a relatively low relative risk for stroke related to hypertension at older ages noted in some studies^{5 6 7} may indicate that other age-related factors have greater importance as a population ages.

Most prospective studies of the association of risk factors and cerebrovascular accidents have focused on middle-aged populations. More recently, however, the possibility that age-related physiological changes might lead to changes in relationships between risk factors and atherosclerotic diseases has led to a number of investigations in older age groups.^{8 9} Despite this, little is known regarding whether the stroke risks associated with the classic atherosclerotic risk factors, such as hypertension, are different in older individuals than they are in younger persons.

To examine these relationships further, the data available from the 20-year follow-up of 8006 men enrolled in the Honolulu Heart Program were examined.

	Subjects and Methods

Top Abstract Introduction Subjects and Methods Results Discussion References

 
The Honolulu Heart Program is a prospective epidemiological study of cardiovascular disease initiated by the National Heart, Lung, and Blood Institute. Participants are 8006 men of Japanese ancestry living on the island of Oahu in 1965 and born between 1900 and 1919. At the time of the baseline examination (1965 to 1968), subjects were aged 45 to 68 years. Each participant was given a physical examination including an extensive cardiovascular evaluation. Initial screening included documentation of cardiac and neurological conditions to identify prevalent cases of coronary heart disease and stroke.^{10 11} This project was reviewed and approved by the Kuakini Medical Center Research and Institutional Review Committee. Written informed consent was obtained from each subject.

Information on cardiovascular events that occurred after the baseline examination has been obtained through a comprehensive surveillance of hospital discharges, death certificates, and autopsy records. In addition, data were gathered at repeated examinations given at 2 and 6 years of follow-up. As of 1990, 62 of the 8006 men in the original cohort had moved off the island of Oahu, resulting in an out-migration rate of approximately 1/1000 per year. Although there are indications of change in medical practice in Hawaii, during the periods of follow-up covered in these analyses (1965 to 1988), virtually all patients with suspected stroke were hospitalized. Validity studies have indicated that nearly 100% of hospital discharge episodes have been identified. The current survival status is unknown in only four men.

In this report, subjects were followed for the first occurrence of a fatal or nonfatal stroke. For a definite diagnosis of stroke, symptoms included neurological deficits that occurred suddenly and remained present for at least 2 weeks or until death. Definite stroke could usually be classified as thromboembolic or hemorrhagic based on clinical findings at hospitalization, surgery, through CT, or at autopsy. Subjects who had possible strokes or experienced neurological episodes attributed to other conditions, such as blood dyscrasias, neoplastic disease, head injury, surgical accident, meningoencephalitis, fat embolism, epilepsy, or cardiac arrest, were not included among the stroke victims. Since CT was not used in the diagnosis of stroke until later in the course of follow-up in Hawaii, an effect on the classification of stroke as thromboembolic or hemorrhagic could have been introduced when this technology first appeared. Studies of stroke patients in Japan¹² and autopsy data from the Honolulu Heart Program,¹³ however, indicate that the effect is small. Further details on the diagnosis of stroke are provided in earlier publications.^{11 13}

To assess the effects of hypertension on the incidence of stroke, Cox regression models were used, which allow for the effect of hypertension to change with age.¹⁴ Such models also permitted adjustments for cholesterol, smoking status, alcohol intake, and atrial fibrillation. The effects of hypertension were examined separately in men who were aged 45 to 54, 55 to 64, and 65 years and older.

Hypertension, age, and other variables were modeled as time-varying covariates, with two updates occurring in the course of follow-up. The first update occurred 6 years after the baseline exam (1971 to 1974). A second update occurred 10 years later (1980 to 1982) in a random sample of men who participated in a study of hyperlipidemia and coronary heart disease. To maintain uniform and nonoverlapping follow-up periods after each risk factor update (including the baseline assessment), follow-up after each exam was limited to 6 years. Follow-up was also restricted to men who were free of known coronary heart disease and stroke at the beginning of each 6-year period.

Hypertension was defined as systolic blood pressure greater than or equal to 160 mm Hg or diastolic greater than or equal to 95 mm Hg or the use of antihypertensive medication. The average of the last two of three blood pressures measured in the left arm with a standard mercury sphygmomanometer was used for these determinations. The first two blood pressures were measured by a nurse and the third by a physician during the course of the examination. Each was measured in a seated position after 5 minutes of rest. To be considered normotensive, the average blood pressure reading needed to be simultaneously less than 140 mm Hg for the systolic blood pressure and less than 90 mm Hg for the diastolic blood pressure. Men who were neither normotensive nor hypertensive were classified as having borderline hypertension.

Serum cholesterol (milligrams per deciliter), cigarette smoking (current/nonsmoker), alcohol intake (ounces per month), and atrial fibrillation (on electrocardiogram at examinations) were among the covariates examined at the various examinations; the methodologies for obtaining these data have been described elsewhere.^{11 15 16 17}

Based on the derived coefficients and standard errors from the Cox regression models, estimates of the relative risk of stroke for hypertensive compared with normotensive men were calculated along with 95% confidence intervals. Relative risks were calculated for specific age groups, and tests for the change in relative risk with age were based on Cox regression models with an age by hypertension interaction effect.

The percent attributable risk¹⁸ of stroke that could be attributed to hypertension was also calculated by age group, and tests for trend in the attributable risk of stroke with changes in age were conducted.¹⁹ The prevalence of hypertension and the 6-year incidence of stroke among normotensive men, men with borderline hypertension, and hypertensive men were also derived by age group. For the prevalence data, changes in the prevalence of hypertension with advancing age were assessed by logistic regression models.¹⁴

	Results

Top Abstract Introduction Subjects and Methods Results Discussion References

 
Shown in Table 1 are the number of men who participated in the baseline examination and who did not have a history of stroke or coronary heart disease at that examination and the number participating in the two subsequent examinations used for the updated analyses. The mean age and age range at the beginning of each examination are shown. The number of thromboembolic strokes occurring during the 6-year follow-up at each examination is also shown by age group. In addition, the mean systolic blood pressure and percentage of men on antihypertensive medication are shown for each examination.

View this table: [in this window] [in a new window]   Table 1. Characteristics of Japanese-American Men by Age Group at Each Examination of the Honolulu Heart Program1

As shown in Table 2, 267 incident cases of total stroke were observed across the three 6-year periods of follow-up: 63 hemorrhagic, 187 thromboembolic, and 17 of unknown type.

View this table: [in this window] [in a new window]   Table 2. Cox Regression Coefficients and Significance Levels for Relationship of Stroke to Selected Risk Factors by Stroke Type

The prevalence of hypertension increased with age, from 20.6% for men aged 45 to 54 years to 38.9% for those aged 65 years and older (Fig 1). The incidence of thromboembolic stroke also significantly increased over this age span (Fig 2). This increase was present, as expected, in those men classified as hypertensive at baseline, rising from 20.6/1000 in men aged 45 to 54 years to 33.5/1000 in men aged 65 years and older (P<.01). Among normotensive men, there was also a rise in the incidence of stroke, with an increase from 2.7/1000 in men aged 45 to 54 years to 23.9/1000 in men aged 65 years and older (P<.001). The rate of increase in incidence of stroke with age was significantly steeper in the normotensive group (P<.01). This corresponds to a decline from approximately seven times the risk of thromboembolic stroke in hypertensive men compared with normotensive men aged 45 to 54 years to less than a twofold (1.4) excess in men aged 65 years and older.

View larger version (25K): [in this window] [in a new window]   Figure 1. Mean percentage of Japanese-American men in Hawaii with hypertension or borderline hypertension at one of the three examinations in each of three age groups.

View larger version (26K): [in this window] [in a new window]   Figure 2. Six-year incidence of stroke by hypertensive status and age group in Japanese-American men in Hawaii. Values at top of figure are number of thrombotic events/6-year person intervals at risk.

Also shown in Table 2 are the results of the Cox proportional hazards analysis for total, hemorrhagic, and thromboembolic stroke as end points. In these models, covariates included age, serum cholesterol, smoking, alcohol consumption, atrial fibrillation, hypertension, and an interaction term (hypertensionxage) that permitted the effect of hypertension on stroke to change with age. The significant hypertensionxage term indicates that the risk of stroke associated with hypertension in older individuals was significantly less than that in younger individuals. Because of the relatively small number of hemorrhagic strokes, further analyses concentrated on thromboembolic strokes.

The observed relative risk of thromboembolic stroke for men with hypertension compared with those without hypertension declined markedly with increasing age (Fig 3). Superimposed on the bar graph is a linear representation of the change in relative risk with age and 95% confidence intervals for those estimates. These estimates are based on a Cox model with the age groups 45 to 54 years (ß [SE]=1.800 [0.332]), 55 to 64 years (ß=0.941 [0.222]), and 65 to 81 years (ß=0.476 [0.243]). Thus, the relative risk derived from these data declines with increasing age (P<.01). However, it is important to note that this decline is not driven by a decline in the magnitude of the risk for stroke associated with hypertension. As illustrated in Fig 2, the change is due to the increasing incidence of stroke in men with normal blood pressure.

View larger version (13K): [in this window] [in a new window]   Figure 3. Risk factor–adjusted 6-year relative risk of thromboembolic stroke for Japanese-American men in Hawaii with hypertension compared with those without hypertension by age, as well as a linear illustration of change in relative risk with age and 95% confidence limits (derived from the Cox model).

Although not illustrated here, the age-related trends for stroke risk associated with systolic and diastolic blood pressure among those not on antihypertensive medication showed a similar although less marked pattern of declining relative risk with increasing age. This indicates that the decline is not a treatment effect. Hypertension and systolic blood pressure were the only risk factors (including serum cholesterol, cigarette smoking, alcohol intake, and atrial fibrillation) that were age related in their effect on the risk of stroke. No significant age-related trend was seen for the other risk factors (data not shown here).

The attributable risk of thromboembolic stroke due to hypertension declined with increasing age (Fig 4). As with the decline in relative risk, this was due to the increase in stroke rates in those without hypertension with increasing age. The rate of stroke attributable to hypertension declined from 50% in men aged 45 to 54 years to less than 20% in men aged 65 years and older (P<.05).

View larger version (14K): [in this window] [in a new window]   Figure 4. Risk factor–adjusted percent attributable risk of thromboembolic stroke due to hypertension in Japanese-American men in Hawaii, as well as a linear illustration of change in attributable risk with age and 95% confidence limits (derived from the Cox model).

Although not shown here, analyses for hemorrhagic stroke revealed patterns similar to those presented for the incidence and relative risk of thromboembolic stroke, although with slightly weaker associations. In contrast to the findings for thromboembolic stroke, there was no significant trend to indicate change in the attributable risk for hemorrhagic stroke due to hypertension with increasing age.

	Discussion

Top Abstract Introduction Subjects and Methods Results Discussion References

 
In this population, hypertension remains a prominent risk factor for stroke, and as expected, the risk of stroke increases with age as it does in other populations. However, this increase in risk with age is most notable in those individuals without evidence of hypertension at the beginning of their follow-up period. Thus, while the risk of stroke rises with age in hypertensive men, the risk of stroke rises more rapidly with age in normotensive men. In contrast, no statistically significant change in the relative risk of stroke with increasing age was detected for atrial fibrillation, serum cholesterol, smoking, and alcohol consumption for total stroke or either stroke subtype. The percentage of strokes attributable to hypertension also significantly declined with age, again secondary to the increasing importance of stroke in men without hypertension. Thus, while hypertension remains an important risk factor for stroke in the elderly, it appears that other factors associated with aging have an increasing role in the causation of stroke in older individuals. There is other evidence to suggest that the relationship of hypertension and blood pressure with morbidity and mortality in older individuals may be complex.²⁰ Inverse, U- and J-shaped relationships between blood pressure and mortality have been reported in the elderly.^{21 22 23 24 25 26}

Previous Honolulu Heart Program analyses have indicated that the risk factor relationships seen in this population are similar to those seen in white populations.^{4 27} While the findings of the study reported here might be specific to Japanese-Americans, studies in other populations have previously indicated a decline in the relative risk of stroke associated with higher levels of blood pressure as age increases or have demonstrated a relationship that is relatively weak at older ages.^{5 6 7} Hypertension was associated with stroke mortality in upper-middle-class whites aged 65 to 74 years in a Southern California retirement community, but the relative risk of 1.8 is relatively low⁵ and similar to that in this report for individuals of similar age. In a Framingham Study investigation concentrating on another factor (the relationship of atrial fibrillation to stroke), data presented in their tables reveal a relative risk of stroke associated with hypertension of 3.5 in men aged 50 to 59 years, which dropped to 1.7 in men aged 70 to 79 years.⁶ Those data also indicate that the percentage of strokes attributable to hypertension declined with increasing age, from 48.8% in men aged 50 to 59 years to 33.4% in men aged 80 to 89 years. Although none of these trends were stressed in that report, the findings are notably similar to those presented here. More recent support for such a trend comes from an article describing a large meta-analysis using stroke death (age of stroke occurrence was not available) and diastolic blood pressure data from 45 prospective observational cohorts with follow-up of 5 to 30 years by the Prospective Studies Collaboration.⁷ Despite the inherent problems of between-study variability in methods and other factors, as well as the lack of data on many potential confounding variables in meta-analyses, the findings also demonstrate that the proportional difference in risk of stroke death was more extreme in middle age than in old age. The authors imply that attributable risk of stroke associated with blood pressure increases with age. However, there are no data on attributable risk presented in the report. There are apparently no data on antihypertensive treatment available, either at baseline or during the average 16-year follow-up period, for the cohorts. Thus, the authors were unable to note the phenomenon seen in the present study of increasing rates of stroke in normotensive individuals seen in the much shorter 6-year follow-up, during which intervening treatment and blood pressure changes are much less likely to become factors contributing to the relative incidence of stroke.

For example, some individuals who were normotensive at the beginning of follow-up could have subsequently become hypertensive during the 6-year follow-up. Such information was not generally available in this data set nor that of the Prospective Studies Collaboration.⁷ The probability of such a change in hypertension status would increase somewhat with increasing age, since the incidence of hypertension increases with age. Optimal treatment of hypertension should decrease the average individual risk of stroke to levels close to that associated with normal blood pressure. However, less than optimal treatment might result in those individuals with incident hypertension having somewhat increased risk of stroke, possibly increasing the apparent stroke rates in those who were normotensive at baseline. Such a bias might explain part of the effect seen here and in other studies. However, the follow-up of 6 years used in the present analysis is an extremely short time frame for an individual to progress clinically from normotension to hypertension to hypertension-related stroke at any age. This type of progression is normally associated with secondary hypertension, which is now known to account for a relatively small proportion of hypertension in the general population.^{28 29} Thus, rapid progression of hypertension seems unlikely to be a major contributor to the findings in this report. Similar changes with age in risk factor relationships with disease were not observed for any of the other major risk factors in this population nor with cholesterol levels in the Prospective Studies Collaboration.⁷

Selective mortality, leaving an older population less susceptible to hypertension-related stroke, may contribute to the findings presented in this and other reports. However, that would not lessen their importance in relation to treatment decisions in older individuals. It is possible that the trends that were observed in the Honolulu Heart Program could be affected by differing blood pressure treatment practices at different ages, most likely by increasing vigor of treatment and thus increasing efficacy as an individual ages. However, evidence indicates that in Hawaii, older individuals often have not been treated as vigorously as younger individuals.³⁰ In this cohort the number of individuals under treatment increased with age, but this change was not as rapid as the increase seen in the prevalence of hypertension, and the percentage of hypertensives treated actually decreased with age. The fact that a decrease was observed in the relative risk of stroke related to both systolic and diastolic blood pressure, after men on antihypertensive medication at baseline were excluded, would strengthen the argument that we are observing an underlying effect of the blood pressure and not solely a treatment effect.

In this population, as in others, the character of hypertension changes with age. Hypertension in younger age groups represents a mix of hypertensives who have mostly combined systolic/diastolic hypertension. Older age groups have an increasingly larger proportion of isolated systolic hypertension. Blood pressure variability also tends to increase with age. Associations between blood pressure and stroke risk that involve sufficient differences between systolic and diastolic hypertension or blood pressure variability and that change with age might result in differences in the hypertension/stroke-related relative risk with age. However, data from most studies, including the Framingham Study, indicate that elevations of both systolic and diastolic blood pressure measured at only one occasion are strong predictors of subsequent stroke.⁴ Older individuals may also have a longer duration of hypertension or other risk factor abnormalities before examination. The data available in this study are insufficient to detect whether duration is an important factor.

Blood pressure measured three times during one visit is used to determine hypertensive status in this analysis. A small proportion of those who would have had normal blood pressure after multiple measurements on multiple occasions could have been classified as having hypertension. Some truly hypertensive individuals were also undoubtedly classified as normal. However, such misclassification would be likely to weaken apparent relationships, making those that are seen more likely to be clinically significant. In addition, blood pressure measured at a single occasion has been shown to be strongly predictive of subsequent stroke.³¹

It should not be concluded from these data that older individuals should not be aggressively screened and treated for hypertension. Because of the increased prevalence of hypertension in older age groups, the absolute risk of stroke in older individuals in this and other populations attributable to hypertension remains large. In addition, recent results of the Systolic Hypertension in the Elderly Program indicate that treatment of isolated systolic hypertension reduced the risk of stroke by 36% in those older than 60 years.³² Subsequent analyses indicate that the greatest benefit may occur in those older than 80 years.³³

Although hypertension is the primary known risk factor for stroke, the results of these analyses indicate that other factors are increasingly important as an individual ages. Factors related to changes in cerebral vessel wall integrity may be important.³⁴ In this population other factors, such as physical inactivity, have been shown to be important risk factors for stroke in healthy nonhypertensive individuals.³⁵ However, the classic major risk factors do not seem to explain the increasing incidence of stroke in those without hypertension in this population. These and other factors not available in this study, such as impaired glucose tolerance and coagulation factors, may become increasingly important and may equal hypertension as stroke risk factors in older individuals. Thus, in the future, studies are needed of factors other than hypertension that may play a significant role in determining the risk of stroke as an individual ages.

	Acknowledgments

 
This study was supported by contract NO1-HC-05102 from the National Heart, Lung, and Blood Institute, Bethesda, Md.

Received December 14, 1995; revision received February 19, 1996; accepted February 19, 1996.

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