This Article Abstract Alert me when this article is cited Alert me if a correction is posted Citation Map Services Email this article to a friend Similar articles in this journal Similar articles in PubMed Alert me to new issues of the journal Download to citation manager Request Permissions Citing Articles Citing Articles via HighWire Citing Articles via Google Scholar Google Scholar Articles by Manolio, T. A. Articles by Price, T. R. Search for Related Content PubMed PubMed Citation Articles by Manolio, T. A. Articles by Price, T. R.

(Stroke. 1996;27:1479-1486.)
© 1996 American Heart Association, Inc.

Articles

Short-term Predictors of Incident Stroke in Older Adults

The Cardiovascular Health Study

Teri A. Manolio, MD, MHS; Richard A. Kronmal, PhD; Gregory L. Burke, MD, MS; Daniel H. O'Leary, MD; Thomas R. Price, MD for the CHS Collaborative Research Group

the Division of Epidemiology and Clinical Applications, National Heart, Lung, and Blood Institute, Bethesda, Md (T.A.M.); the Department of Biostatistics, University of Washington (Seattle) (R.A.K.); the Department of Public Health Sciences, Bowman Gray School of Medicine, Winston-Salem, NC (G.L.B.); the Department of Radiology, Tufts New England Medical Center, Boston, Mass (D.H.O'L.); and the Department of Neurology, University of Maryland (Baltimore) (T.R.P.).

Correspondence to Teri Manolio, MD, MHS, National Heart, Lung, and Blood Institute, 6701 Rockledge Dr, Rm 8160, Bethesda, MD 20892-7934.

	Abstract

Top Abstract Introduction Subjects and Methods Results Discussion References

 
Background and Purpose Risk factors for incident stroke have been examined in middle-aged persons, but less is known about stroke precursors in the elderly, who suffer the highest rates of stroke. Short-term risk factors for incident stroke were examined in a longitudinal, population-based study including extensive measures of subclinical disease.

Methods Prospective study of 5201 women and men aged 65 years and older was undertaken in the multicenter Cardiovascular Health Study.

Results During an average 3.31-year follow-up, 188 incident strokes occurred. Stroke incidence increased significantly with age and was similar in women and men. Factors associated with increased stroke risk in multivariate analysis included age, aspirin use, diabetes, impaired glucose tolerance, higher systolic blood pressure, increased time needed to walk 15 ft, frequent falls, elevated creatinine level, abnormal left ventricular (LV) wall motion and increased LV mass on echocardiography, ultrasound-defined carotid stenosis, and atrial fibrillation. Increased LV mass and carotid stenosis were associated with twofold and threefold increases in incidences of stroke, respectively (P<.001). Aspirin users had a 52% higher risk of stroke (relative risk, 1.52; 95% confidence interval, 1.1 to 2.0; P<.007) after adjustment for other factors. This association was present only among aspirin users without prior coronary disease, atrial fibrillation, claudication, or transient ischemic attack, who had an 84% higher risk (relative risk, 1.84; 95% confidence interval, 1.2 to 2.8).

Conclusions Short-term risk of stroke has a complex relationship with aspirin use and is strongly related to subclinical disease in this sample of older adults. These relationships should be considered in assessing stroke risk in the elderly, in whom recognized and subclinical cardiovascular disease is highly prevalent.

Key Words: aged • stroke, cerebrovascular disorders • epidemiology • risk factors

	Introduction

Top Abstract Introduction Subjects and Methods Results Discussion References

 
Stroke is the third leading cause of death in the United States and a leading cause of serious disability, particularly among the elderly. Stroke incidence rises sharply with advancing age, but most studies have examined stroke risk factors predominantly in middle age.^{2 3 4} Other than a report from the Framingham study,⁵ which focused on AF, studies assessing stroke risk in the elderly have been relatively small or limited to men.^{6 7 8}

Risk factors for stroke in middle-aged population samples have included age; male sex; hypertension; obesity; smoking; low vital capacity; ECG LV hypertrophy; prior heart disease; AF; increased alcohol intake; decreased physical activity; maternal history of stroke; and elevated levels of fibrinogen, uric acid, hematocrit, triglycerides, and fasting and postchallenge glucose. Some differences in risk factors for thromboembolic versus hemorrhagic stroke have been noted, particularly in the relationship of the latter with increased alcohol intake and low cholesterol levels.³ Relationships of cerebrovascular disease with established risk factors may also differ with increasing age, as has been suggested for such coronary disease risk factors as systolic blood pressure and total cholesterol.^{9 10}

The CHS cohort represents a large multicenter sample of older men and women followed up for the development of stroke and other cardiovascular diseases. Incident stroke data from an average follow-up of 3.31 years were analyzed to (1) determine the age- and sex-specific incidence of stroke and stroke subtypes among women and men aged 65 years and older, (2) compare baseline characteristics in women and men with and without incident stroke to identify bivariate associations with stroke incidence, and (3) determine the strength and independence of these risk factors in multivariate analysis.

	Subjects and Methods

Top Abstract Introduction Subjects and Methods Results Discussion References

 
CHS participants were recruited from a random sample of the Health Care Financing Administration Medicare eligibility lists in four US communities: Forsyth County, NC; Sacramento County, Calif; Washington County, Md; and Pittsburgh (Allegheny County), Penn. Details of design and methods have been published.^{1 11}

Ascertainment of Incident Stroke
Potential stroke events were identified during annual follow-up examinations and at interim 6-month phone contacts. The participant or his or her next of kin were interviewed shortly after the event about the surrounding circumstances. Hospital records for all reported strokes, as well as nonstroke hospitalizations with International Classification of Diseases, 9th Revision,¹² codes 430 through 438 identifying cerebrovascular disease, were abstracted for pertinent information and reviewed by a neurologist at each field center. Information on reported nonhospitalized stroke patients was obtained by physician questionnaire. This information was reviewed by a CHS neurologist at each field center, and any inconsistencies were reviewed with the participant's physician. When available, copies of CT and/or MRI scans were obtained and reviewed centrally; films were available in 70% of adjudicated strokes and hard-copy reports in an additional 17%. Potential stroke cases were adjudicated by a committee of neurologists, neuroradiologists, and internists using information from interviews, medical records, and available cerebral imaging studies. Adjudication decisions were usually unanimous in terms of presence of stroke, stroke subtype, and stroke as a cause of death.

Criteria for stroke were similar to those used in the Systolic Hypertension in the Elderly Program.¹³ Stroke was defined as a subarachnoid hemorrhage or a neurological deficit of rapid onset lasting more than 24 hours unless death supervenes or, if less than 24 hours, an appropriate lesion to explain the deficit was seen on brain imaging.

Strokes were classified as due to hemorrhage if there was evidence of blood in the subarachnoid space, ventricles, or parenchyma seen on cerebral imaging that did not appear consistent with hemorrhage into an infarction. Strokes were classified as hemorrhagic if there was bloody spinal fluid on lumbar puncture or evidence of hemorrhage at surgery or autopsy. Patients dying less than 24 hours after onset were assumed to have hemorrhage as a cause if they did not have lumbar puncture, cerebral imaging, or autopsy.

Strokes were classified as ischemic infarction if there was evidence of focal brain deficit without lumbar puncture or imaging, surgical, or autopsy evidence for primary hemorrhage. The stroke type was defined as unknown if information was insufficient to classify it as due to hemorrhage or ischemia. Methods of stroke classification and subtyping have been published.¹⁴

Statistical Analysis
Significance of differences between participants with and without stroke was assessed with ² tests for proportions and t tests for continuous variables. The log-rank test was used to test equality of event-rate curves.

All factors examined for associations with stroke incidence in bivariate analysis were entered into a forward stepwise proportional-hazards analysis to identify independent predictors of stroke. Variables that could be considered subsets of other variables, such as individual neurological symptoms or different antihypertensive medications, were presented to models only if the overall variable was significantly associated (P<.05) in stepwise analyses. Multivariate analyses were initially stratified by sex and then repeated for women and men combined because sex-specific results showed similar associations (model 1). All analyses were performed using the SPSS/Windows System.

Linearity of associations for ordinal variables significant in bivariate analysis was assessed by comparing stroke incidence at varying levels; if risk appeared to show a threshold at some distinct value, data were recorded as discrete variables above and below that threshold. This was particularly true for timed walking and number of days of aspirin use.

Potential nonlinear relationships of continuous variables were assessed using quintiles of these variables defined only in persons suffering stroke so as to yield an equal number of strokes in each "event-defined" quintile. Compared with quintiles defined in the entire population at risk, this method increases the ability to detect nonlinear relationships and provides a larger number of events in the lowest-risk quintile, which is usually used as a comparison group for estimating relative risk. Increased numbers of events in the "event-defined" lowest quintile enhances the stability of the incidence estimate in this group, thus decreasing the variability of risk estimates generated from it.

When a variable was a significant predictor of stroke both as a continuous variable and for the event-defined quintiles, and excess risk was clearly confined to the last category, it was dichotomized above and below the fifth-quintile cut point. When there was no evidence of nonlinear associations or nonlinear interactions with key variables, the variable was used in its continuous form.

Missing data were frequent for LV mass,¹⁵ so an imputation formula was calculated from the linear regression equation based on the best predictors of LV mass for the observed data. These predictors included sex, coronary disease, left atrial dimension, weight, ECG LV mass, diastolic and systolic blood pressures, maximum carotid diameter, presence of definite CHF, and resting heart rate. When any of these variables was missing, LV mass was imputed from sex, weight, and presence of major ECG abnormalities. Where missing data seemed likely to be associated with high-risk categories (timed walking, for instance, cannot be performed by disabled persons, and intimal-medial thickness cannot be measured in calcified plaque) and bivariate analyses of risk supported this supposition, missing data were replaced with the highest-risk category. Aspirin use, AF, and LV wall motion abnormalities were assumed to be absent if data were missing. Multivariate modeling was repeated with imputation for missing data (model 2). To permit comparison with published studies that did not conduct noninvasive testing, modeling was also repeated excluding echocardiographic and ultrasound variables (model 3).

	Results

Top Abstract Introduction Subjects and Methods Results Discussion References

 
Prior stroke was reported in 70 women and 114 men (total, 184) of whom 41 (22%) had a recurrent stroke. These 184 prevalent cases were excluded from analysis for incident stroke, leaving 5017 participants at risk during an average follow-up of 3.31 years (maximum, 4 years).

Ninety-four women and 94 men suffered an incident stroke during follow-up. Stroke incidence increased significantly with age in women and men (P<.0001) but did not differ significantly by sex after adjustment for age (Fig 1). Nonfatal strokes were further classified by stroke subtype. Of incident nonfatal strokes, 5% (n=18) were classified as due to hemorrhage (not including hemorrhagic infarctions) and 87% as ischemic, and 8% were unclassified. Hemorrhage was slightly more common in men and unclassified subtype in women, but these differences were not significant.

View larger version (44K): [in this window] [in a new window]   Figure 1. Incident stroke by age and sex.

Participants suffering a stroke during follow-up were older, more likely to have hypertension and higher systolic and diastolic blood pressures, and more often taking antihypertensive agents and aspirin at baseline than those not suffering a stroke (Table 1). They were also more likely to have diabetes; higher levels of fasting and 2-hour glucose, 2-hour insulin, creatinine, and factor VIII; lower levels of HDL cholesterol and factor VII; and greater chair-stand and 15-ft walk times. Because relationships with 15-ft walk and creatinine appeared distinctly nonlinear, these variables were also analyzed categorically. Participants with stroke were less likely to have creatinine levels 0.9 mg/dL and more likely to have creatinine levels 1.5 mg/dL than those without stroke. They were also more likely to have walk times of 8 seconds and to report neurological symptoms (especially dizziness, loss of balance, difficulty walking, and frequent falls). No relationships were noted with black race, hemoglobin, hematocrit, fibrinogen, LDL cholesterol, fasting insulin, fibrinogen, orthostatic hypotension, obesity or anthropometric measures, smoking, pack-years, alcohol intake, physical activity, total cholesterol, triglycerides, fasting insulin, uric acid, sibling history of stroke, loss of or changed speech, loss of or blurred vision, double vision, numbness/tingling, spinning sensation, paralysis/weakness, blackouts/fainting, or dizziness on standing.

View this table: [in this window] [in a new window]   Table 1. Bivariate Associations of Coronary Heart Disease Risk Factors and Neurological Symptoms With Incident Stroke

Subclinical disease (abnormalities detected on noninvasive testing that have not yet produced signs or symptoms) and clinical cardiovascular disease were also more common at baseline in participants subsequently suffering stroke (Table 2). Participants with incident stroke were nearly twice as likely as those without stroke to have qualitatively abnormal LV systolic function or abnormal LV wall motion on echocardiography. They were also more than three times as likely to have ECG LVH. They also had greater carotid wall thicknesses, more frequent and severe carotid stenosis, and lower ankle-arm indices and spirometric lung volumes. They were more likely to have reported a prior myocardial infarction at entry and more than three times as likely to have AF on baseline ECG. No associations were detected with LV diastolic dimension, prior CHF, prior TIA, echocardiographic LVH, or mitral stenosis.

View this table: [in this window] [in a new window]   Table 2. Bivariate Associations of Subclinical and Clinical Disease With Incident Stroke

Factors associated with stroke on stepwise proportional hazards analysis in women and men (sex-specific models did not differ, and no sex-interaction terms were significant) included aspirin use, diabetes, event-defined quintile of systolic blood pressure, increase in timed walk, frequent falls, serum creatinine, abnormal LV wall motion, carotid stenosis, LV mass >fifth event-specified quintile, and AF (Table 3, model 1).

View this table: [in this window] [in a new window]   Table 3. Hazard Ratios From Cox Proportional Hazards Regresson for Incident Stroke, Unadjusted and Adjusted, With and Without Imputation for Missing Data and Noninvasive Data

Inclusion of imputed data did not appreciably alter most of these relationships except for an attenuation of the risk associated with systolic blood pressure (model 2). Use of imputed data did lead to narrowing of many of the CIs around risk estimates and made age, impaired glucose tolerance, creatinine, and moderate carotid stenosis significant predictors. After excluding echocardiographic and carotid ultrasound variables, age was much stronger and male sex was significant, and ECG-LVH and definite CHF were added as independent predictors (model 3).

Stratification of the associations with systolic-pressure quintile by use of antihypertensive medications suggested an increased risk of low systolic pressure (127 mm Hg) compared with the next higher quintile (128 to 140 mm Hg) in users only (Table 4). Medication users in the second quintile had a 23% lower incidence of stroke compared with those in the lowest quintile. Incidence of stroke at blood pressures 127 mm Hg was 12.8 per 1000 person-years in medication users and 2.5 per 1000 person-years in nonusers, yielding a hazard ratio (after adjustment for factors in model 2) of 2.93 associated with medication use in this blood pressure category (95% CI, 1.41 to 6.10; P<.004). In the other four blood pressure quintiles, medication use was not associated with increased risk of stroke after adjustment for the same factors (data not shown).

View this table: [in this window] [in a new window]   Table 4. Stroke Risk by Quintile of Systolic Blood Pressure in Nonusers and Users of Antihypertensive Medications

Stratification of the association of aspirin use with stroke by history of coronary disease, TIA, or AF showed an 84% greater risk of stroke associated with aspirin use in subjects with none of these conditions (Table 5). Aspirin use was not associated with increased stroke risk in subjects with these conditions (Fig 2). Increased risk associated with aspirin use in nondiseased subjects was noted for nonhemorrhagic strokes (P<.003), as well as for the small number of hemorrhagic strokes (P<.003). Aspirin use was not associated with either category of stroke in diseased subjects (data not shown).

View this table: [in this window] [in a new window]   Table 5. Stroke Risk by Use of Aspirin in at Least 7 of Past 14 Days or by Prescription in Those Without (Nondiseased) and With (Diseased) Coronary Heart Disease, TIA, Claudication, or AF

View larger version (14K): [in this window] [in a new window]   Figure 2. Incident stroke by aspirin use and presence of clinical disease.

	Discussion

Top Abstract Introduction Subjects and Methods Results Discussion References

 
Incidence, Mortality, and Subtypes
Annual stroke incidence in the first 3.3 years of CHS follow-up was 9.82 cases per 1000 women and 13.4 cases per 1000 men, comparable with rates in similar age groups in other studies published since 1980.^{16 17} These lower rates are likely due to the relatively selective nature of the CHS cohort, since persons with serious disease and disability were excluded at entry or elected not to participate,¹⁸ and since persons with prior stroke at entry were excluded from this analysis.

Approximately 87% of strokes in CHS participants were classified as cerebral infarction, which was the highest proportion among several published population-based studies.^{16 17 19} CHS also had one of the lowest proportions of hemorrhagic stroke, particularly subarachnoid hemorrhage. These differences are likely due to the advanced age of CHS participants, since hemorrhagic stroke does not increase with age as rapidly as ischemic stroke, thus hemorrhages make up a smaller proportion of strokes with increasing age.²⁰ This supposition is supported by unpublished data from the Systolic Hypertension in the Elderly Program, in which 83% of strokes were classified as ischemic and 10.7% as hemorrhagic, proportions very similar to those seen in CHS (T.R. Price, personal communication).

Relationship of Incident Stroke to Age and Sex
Stroke incidence was more than three times higher in women aged 80 years and older than in women aged 65 to 74 in CHS, and nearly twice as high in men aged 80 years and older compared with those aged 65 to 74. Stroke incidence is known to be strongly related to age,^{3 21} and given the relatively small numbers of men at advanced ages and the possible impact of selective survival, the modest sex difference in strength of the age association is not surprising. Age was associated with slightly increased risk in multivariate analysis, which was significant in the model with imputed data. The age relationship was attenuated by adjustment for subclinical disease, as demonstrated in model 3 (excluding noninvasive measurements). The fact that the age relationship remained after adjustment for other risk factors that increase with age (such as blood pressure, diabetes, and subclinical disease) suggests either that age itself is somehow a risk factor for stroke, which seems unlikely,²² or that age is acting as a surrogate for other risk factors as yet unidentified or inadequately adjusted for. The advanced age range of the CHS cohort provides an excellent opportunity for identifying such factors, which will be an important focus of continued follow-up in this cohort.

Stroke incidence did not differ by sex in the full age range of CHS, although there was a borderline significant trend toward greater incidence in men aged 65 to 74 years than women of the same age (P<.03). Gender relationships with stroke incidence show little consistency with published data showing men at higher,²¹ similar,¹⁶ or lower²³ risk than women. Sex was not significantly associated with stroke in multivariate analysis, nor were significant interactions with gender detected in these models. The significant association of gender with stroke after excluding subclinical disease measures suggests that any sex differences in stroke incidence in these data are related to differences in subclinical disease between women and men.

Incident Stroke and Baseline Risk Factors
Because models with imputed data differed little (except in increased precision of point estimates) from models for subjects with complete data only, discussion will be limited to models with imputed data. Systolic blood pressure, aspirin use, diabetes, creatinine level, timed walking, and frequent falls retained their predictive relationships with stroke in multivariate analysis. Hypertension has long been known to be a major risk factor for stroke,²⁴ with systolic pressure appearing to be a stronger risk factor than diastolic.²⁵ The relation of low systolic blood pressure to stroke in medication users was somewhat surprising and was detected in a search for potential interaction between medication use and systolic pressure level. As has been pointed out,²⁶ ignoring the effect of antihypertensive medication use is similar to assuming that blood pressures attained after treatment in hypertensive patients confer risk equivalent to those that occur naturally (or without antihypertensive medication). Although antihypertensive treatment markedly reduces the increased risk of stroke associated with hypertension,²⁷ it may not be reasonable to assume that it eliminates this risk entirely, especially when treatment may have begun shortly before an event. Treated hypertensive patients with low blood pressure have been noted to be at increased risk of coronary heart disease and mortality,²⁸ presumably due to advanced end-organ damage impeding their ability to sustain higher pressure levels. To our knowledge, this is the first suggestion that treated hypertensive patients with low blood pressure may be at increased risk of stroke. CIs were overlapping, however, for stroke incidence estimates by systolic pressure category, so chance cannot be excluded as an explanation of these findings. Further follow-up of this cohort and extension of this analysis to other cohorts may help clarify these relationships, but a definitive answer on the appropriate level of target blood pressure in treated hypertensive patients probably awaits the results of clinical trials, one of which is currently under way.²⁹

Diabetes has shown strong and consistent relationships with stroke incidence,^{30 31} as was demonstrated in the present study. Less consistent associations have been demonstrated for impaired glucose tolerance,^{32 33} and few studies have included standard glucose tolerance testing as performed in the present study. Impaired glucose tolerance is common in elderly subjects and has been demonstrated to be associated with increased prevalence of cardiovascular disease and its risk factors.³⁴ The current data confirm prior evidence that asymptomatic hyperglycemia is not a benign condition in the elderly and that its previously demonstrated association with coronary disease³⁵ also extends to cerebrovascular disease.

Associations detected with timed walking and frequent falls have not been previously reported, perhaps because they were not included in prior investigations. Timed walking is a strong correlate of coronary disease, cardiovascular impairment, and disability^{36 37} and presumably reflects the known associations of these conditions with stroke.²¹ Frequent falls were assessed as a part of a questionnaire on TIA¹¹ and may simply be a marker for that condition, which is known to increase risk of completed stroke.³⁸ Falls have been associated with white matter abnormalities on CT³⁹ and with prior stroke⁴⁰ but not in and of themselves (and after adjustment for other factors) specifically with subsequent stroke.

Serum creatinine level was weakly related to incident stroke as detected in models with creatinine as a linear term. Categorizing creatinine into event-defined quintiles, however, showed almost all of the excess risk to be limited to the highest creatinine category. Although this might reflect some potential role of renal damage in the pathogenesis of stroke, it seems more likely to be a marker for severity or duration of hypertension and for individual susceptibility to end-organ damage not explained by systolic pressure and subclinical disease measures.

Participants reporting aspirin use in at least 7 of the 14 days preceding their baseline clinic visit (or having a prescription) were nearly twice as likely to have an incident stroke during follow-up than nonusers of aspirin. Although this may be consistent with aspirin being prescribed or taken preferentially by subjects with known cardiovascular disease, in whom it has been shown to reduce risk of myocardial infarction and stroke, stratification on presence of coronary disease, TIA, claudication, or AF suggested that the increased risk associated with aspirin was limited to subjects without these conditions. This association may be due to other indications (for which aspirin was prescribed or taken) also being associated with increased risk of stroke, but only 66 of the 1412 aspirin users had a prescription for it. History of arthritis was reported by 58% of all aspirin users (compared with 49% of nonusers), and arthritis was not associated with increased risk of stroke in this study (P=.6). Aspirin has been associated with modestly increased risk of stroke in healthy male physicians,⁴¹ elderly persons with AF,⁴² and unselected elderly persons,⁴³ but the mechanism for this association is not clear. Given the antiplatelet properties of aspirin, an increased risk of hemorrhagic stroke might be understandable in aspirin users, but both nonhemorrhagic and hemorrhagic stroke risk were increased in these studies, as well as the present one. Until larger numbers of events accrue, this relationship will remain difficult to understand, particularly in an observational nonrandomized study. A clinical trial is currently under way to assess the benefit of aspirin in primary prevention of stroke among women.⁴⁴

Incident Stroke and Baseline Subclinical Disease
Subclinical disease was also strongly related to incident stroke. Participants with echocardiographic abnormalities of LV wall motion at baseline were 50% more likely to suffer stroke during follow-up after adjustment for other factors, consistent with the known increased risk of stroke in persons with LV dysfunction.^{21 45} Abnormal wall motion (which was predominantly hypokinesis¹⁵ ) may be associated with a tendency to form clots that eventually cause embolic stroke. The greater strength of the relationship with subclinical LV dysfunction than with reported CHF may be due to improved and/or unbiased detection, since all CHS participants underwent echocardiography according to a standard protocol, and assessment of LV wall motion was possible in 99%.

Carotid stenosis of 50% to 74% was associated with a threefold increased risk of stroke in multivariate analysis, and all measures of carotid atherosclerosis were more common in bivariate analyses in incident stroke cases. This is not surprising because carotid disease has been shown to be associated with stroke in cross-sectional and longitudinal analyses.^{46 47} A lesser but still significant association was observed with milder degrees of carotid stenosis. Carotid atherosclerosis may be a marker for vascular disease at other sites closer to the brain but may also be a site for occlusion, embolization, or clot formation as a direct cause of stroke.

Inclusion of subclinical disease measures such as these in multivariate models may explain the loss of association of such established stroke risk factors as CHF and prevalent coronary disease. When these factors were excluded from analysis (model 3), ECG-LVH and CHF became significant, consistent with prior studies of these factors and stroke risk.⁴⁸

Conclusions
Short-term incidence of stroke was associated with age, aspirin use, diabetes, abnormal LV wall motion, systolic blood pressure, serum creatinine level, AF, 50% carotid stenosis, and prolonged timed walk in this large cohort of older adults. Inclusion of measures of subclinical disease such as echocardiography and carotid ultrasonography appears to have led to loss of relationships with many previously reported risk factors but did not account for lack of relationships with risk factors such as cholesterol and smoking. Increased risk associated with aspirin use was intriguing and deserves further follow-up, but it will be difficult to define in nonrandomized comparisons. Short-term stroke risk appears to be strongly related to noninvasive measures of subclinical cardiovascular disease, and such measures should be considered for use in identifying persons at increased risk of stroke.

	Selected Abbreviations and Acronyms

 

AF = atrial fibrillation CHF = congestive heart failure CHS = Cardiovascular Health Study CI = confidence interval ECG = electrocardiographic, electrocardiogram ECG-LVH = ECG-defined left ventricular hypertrophy LV = left ventricular TIA = transient ischemic attack

	Acknowledgments

 
This study was supported by contracts N01-HC-85079 through N01-HC-85086 from the National Heart, Lung, and Blood Institute.

	Footnotes

 
Participating institutions and principal staff have been previously published.¹

Received March 11, 1996; revision received May 31, 1996; accepted May 31, 1996.

	References

Top Abstract Introduction Subjects and Methods Results Discussion References

 

1. Manolio TA, Kronmal RA, Burke GL, Poirier V, O'Leary DH, Gardin JM, Fried LP, Steinberg EP, Bryan RN. Magnetic resonance abnormalities and cardiovascular disease in older adults: The Cardiovascular Health Study. Stroke. 1994;25:318-327.[Abstract]
2. Davis PH, Dambrosia JM, Schoenberg BS, Schoenberg DG, Pritchard DA, Lilienfeld AM, Whisnant JP. Risk factors for ischemic stroke: A prospective study in Rochester, Minnesota. Ann Neurol. 1987;22:319-327.[Medline] [Order article via Infotrieve]
3. Kagan A, Popper JS, Rhoads GG. Factors related to stroke incidence in Hawaii Japanese men: The Honolulu Heart Study. Stroke. 1980;11:14-21.[Abstract/Free Full Text]
4. Wolf PA. Risk factors for stroke. 1985; 16:359-360.
5. Wolf PA, Abbott RD, Kannel WB. Atrial fibrillation: A major contributor to stroke in the elderly. Arch Intern Med. 1987;147:1561-1564.[Abstract]
6. Welin L, Svardsudd K, Wilhelmsen L, Larsson B, Tibblin G. Analysis of risk factors for stroke in a cohort of men born in 1913. N Engl J Med. 1987;317:521-526.[Abstract]
7. Zeiler K, Siostrzonek P, Lang W, Gossinger H, Oder W, Ciciyasvilli H, Kollegger H, Mosslacher H, Deecke L. Different risk factor profiles in young and elderly stroke patients with special reference to cardiac disorders. J Clin Epidemiol. 1992;45:1383-1389.[Medline] [Order article via Infotrieve]
8. Woo J, Lau EM. Risk factors predisposing to stroke in an elderly Chinese population--a longitudinal study. Neuroepidemiology. 1990;9:131-134.[Medline] [Order article via Infotrieve]
9. Langer RD, Ganiats TG, Barrett-Connor E. Factors associated with paradoxical survival at higher blood pressures in the very old. Am J Epidemiol. 1991;134:29-38.[Abstract/Free Full Text]
10. Krumholz HM, Seeman TE, Merrill SS, Mendes de Leon CF, Vaccarino V, Silverman DI, Tsukahara R, Ostfeld AM, Berkman LF. Lack of association between cholesterol and coronary heart disease mortality and morbidity and all-cause mortality in persons older than 70 years. JAMA. 1994;272:1335-1340.[Abstract]
11. Fried LP, Borhani NO, Enright P, Furberg CD, Gardin JM, Kronmal RA, Kuller LH, Manolio TA, Mittelmark MB, Newman A, O'Leary DH, Psaty BM, Rautaharju P, Tracy RP, Weiler PG. The Cardiovascular Health Study: Design and rationale. Ann Epidemiol. 1991;1:263-279.[Medline] [Order article via Infotrieve]
12. World Health Organization. Manual of the International Classification of Diseases, Injuries, and Causes of Death. Vol. 1, 1975 revision. Geneva, 1977.
13. Systolic Hypertension in the Elderly Program (SHEP) Cooperative Research Group. Rationale and design of a randomized clinical trial on prevention of stroke in isolated systolic hypertension. J Clin Epidemiol. 1988;41:197-208.
14. Price TR, Psaty B, O'Leary D, Burke G, Gardin J. Assessment of cerebrovascular disease in the Cardiovascular Health Study. Ann Epidemiol. 1993;3:504-507.[Medline] [Order article via Infotrieve]
15. Gardin JM, Siscovick D, Anton-Culver H, Lynch JC, Smith VE, Klopfenstein HS, Bommer WJ, Fried LP, O'Leary DH, Manolio TA. Sex, age and disease affect echocardiographic left ventricular mass and systolic function in the free-living elderly: The Cardiovascular Health Study. Circulation. 1995;91:1739-1748.[Abstract/Free Full Text]
16. Bamford J, Sandercock P, Dennis M, Warlow C, Jones L, McPherson K, Vessey M, Fowler G, Molyneux A, Hughes T, Burn J, Wade D. A prospective study of acute cerebrovascular disease in the community: the Oxfordshire Community Stroke Project 1981-86. I. Methodology, demography and incident cases of first-ever stroke. J Neurol Neurosurg Psychiatry. 1988;51:1373-1380.[Abstract]
17. Jorgensen HS, Plesner AM, Hubbe P, Larsen K. Marked increase in stroke incidence in men between 1972 and 1990 in Frederiksberg, Denmark. Stroke. 1992;23:1701-1704.[Abstract/Free Full Text]
18. Tell GS, Fried LP, Hermanson BH, Manolio TA, Newman AB, Borhani NO. Recruitment of adults 65 years and older as participants in the Cardiovascular Health Study. Ann Epidemiol. 1993;3:358-366.[Medline] [Order article via Infotrieve]
19. Broderick JP, Phillips SJ, Whisnant JP, O'Fallon WM, Bergstralh EJ. Incidence rates of stroke in the eighties: the end of the decline in stroke? Stroke. 1989;20:577-582.[Abstract/Free Full Text]
20. Longstreth WT, Koepsell TD, Yerby MS, Van Belle G. Risk factors for subarachnoid hemorrhage. Stroke. 1985;16:377-385.[Free Full Text]
21. Kannel WB, Wolf PA, Verter J. Manifestations of coronary disease predisposing to stroke. JAMA. 1983;250:2942-2946.[Abstract]
22. Manolio TA, Furberg CD. Age as a predictor of outcome: What role does it play? American Journal of Medicine. 1992;92:1-6.[Medline] [Order article via Infotrieve]
23. D'Alessandro G, Di Giovanni M, Roveyaz L, Iannizzi L, Compagnoni MP, Blanc S, Bottacchi E. Incidence and prognosis of stroke in the Valle d'Aosta, Italy. Stroke. 1992;23:1712-1715.[Abstract/Free Full Text]
24. Kannel WB, Wolf PA, Verter J, McNamara P. Epidemiologic assessment of the role of blood pressure in stroke. JAMA. 1970;214:309-310.
25. Rutan GH, Kuller LH, Neaton JD, Wentworth DN, McDonald RH, Smith WM. Mortality associated with diastolic hypertension and isolated systolic hypertension among men screened for the Multiple Risk Factor Intervention Trial. Circulation. 1988;77:504-514.[Abstract/Free Full Text]
26. D'Agostino RB, Wolf PA, Belanger AJ, Kannel WB. Stroke risk profile: Adjustment for antihypertensive medication. Stroke. 1994;25:40-43.[Abstract]
27. SHEP Cooperative Research Group. Prevention of stroke by antihypertensive drug treatment in older persons with isolated systolic hypertension: final results of the Systolic Hypertension in the Elderly Program (SHEP). JAMA. 1991;265:3255-3264.[Abstract]
28. Berglund G. Goals of antihypertensive therapy. Is there a point beyond which pressure reduction is dangerous? Am J Hypertens. 1989;2:586-593.[Medline] [Order article via Infotrieve]
29. Amery A, Birkenhager W, Bulpitt C, et al. Syst-Eur: a multicentre trial on the treatment of isolated systolic hypertension in the elderly: objectives, protocol and organization. Aging. 1991;3:287-302.[Medline] [Order article via Infotrieve]
30. Aronow WS. Gutstein H, Lee NH, Edwards M. Three-year follow-up of risk factors correlated with new atherothrombotic brain infarction in 708 elderly patients. Angiology. 1988;39:563-566.
31. Wolf PA, Dawber TR, Thomas HE, Colton T, Kannel WB. Epidemology of stroke. In: Thompson RA, Green JR (eds), Stroke, Raven Press, New York, 1977, pp. 5-19.
32. Fuller JH, Shipley MJ, Rose G, Jarrett RJ, Keen H. Mortality from coronary heart disease and stroke in relation to degree of glycemia: the Whitehall study. Br Med J. 1983;287:867-870.
33. Burchfiel CM, Curb JD, Rodriguez BL, Abbott RD, Chiu D, Yano K. Glucose intolerance and 22-year stroke incidence. Stroke. 1994;25:951-957.[Abstract]
34. Savage PJ, Wahl WP, Tracy RP, Borhani NO, Ettinger WH. Association of abnormal glucose tolerance with coronary heart disease (CHD) in older men and women: the Cardiovascular Health Study (CHS). Circulation. 1991;84(suppl II):II-528.
35. Mykkanen L, Laakso M, Pyorala K. Asymptomatic hyperglycemia and atherosclerotic vascular disease in the elderly. Diabetes Care. 1992;15:1020-1030.[Abstract]
36. Guyatt GH, Sullivan MJ, Thompson PJ, Fallen EL, Pugsley SO, Taylor DW, Berman LB. The 6-minute walk: a new measure of exercise capacity in patients with chronic heart failure. Can Med Assoc J. 1985;132:919-923.[Abstract]
37. Fried LP, Ettinger WH, Hermanson BK, Newman AB, Gardin J. Physical disability in older adults: a physiological approach. J Gerontol. (in press)
38. Howard G, Evans GW, Crouse JR III, Toole FJ, Ryu JE, Tegeler C, Frye-Pierson J, Mitchell E, Sanders L. A prospective reevaluation of transient ischemic attacks as a risk factor for death and fatal or nonfatal cardiovascular events. Stroke. 1994;25:342-345.[Abstract]
39. Masdeu JC, Wolfson L, Lantos G, Tobin JN, Grober E, Whipple R, Amerman P. Brain white-matter changes in the elderly prone to falling. Arch Neurol. 1989;46:1292-1296.[Abstract]
40. Campbell AJ, Borrie MJ, Spears GF. Risk factors for falls in a community-based prospective study of people 70 years and older. J Gerontol. 1989;44:M112-7.[Medline] [Order article via Infotrieve]
41. Steering Committee of the Physicians' Health Study Research Group. Final report on the aspirin component of the ongoing Physicians' Health Study. N Engl J Med. 1989;321:129-135.[Abstract]
42. Stroke Prevention in Atrial Fibrillation Study Group Investigators. Preliminary report of the Stroke Prevention in Atrial Fibrillation Study. N Engl J Med. 1990;322:863-868.[Abstract]
43. Paganini-Hill A, Chao A, Ross RK, Henderson BE. Aspirin use and chronic diseases: a cohort study of the elderly. Br Med J. 1989;299:1247-1250.
44. Women's Health Study Research Group. The Women's Health Study: rationale and background. J Myocardial Ischemia. 1992;4:30-40.
45. The Stroke Prevention in Atrial Fibrillation Investigators. Predictors of thromboembolism in atrial fibrillation: II. Echocardiographic features of patients at risk. Annals Intern Med. 1992;116:6-12.
46. O'Leary DH, Polak JF, Kronmal RA, Kittner SJ, Bond MG, Wolfson SK, Bommer W, Price TR, Gardin JM, Savage PJ. Distribution and correlates of sonographically detected carotid artery disease in the Cardiovascular Health Study. Stroke. 1992;23:1752-1760.[Abstract/Free Full Text]
47. The Asymptomatic Carotid Atherosclerosis Study Group. Study design for randomized prospective trial of carotid endarterectomy for asymptomatic atherosclerosis. Stroke. 1989;20:844-849.[Abstract/Free Full Text]
48. Wolf PA, Dawber TR, Kannel WB. Heart Disease as a Precursor of Stroke. In: Schoenberg BS (ed): Adv Neurol, Vol. 19, Raven Press, New York, 1978, pp. 567-577.

This article has been cited by other articles:

				K. Tanaka, Y. Ishikawa, M. Yokoyama, H. Origasa, M. Matsuzaki, Y. Saito, Y. Matsuzawa, J. Sasaki, S. Oikawa, H. Hishida, et al. Reduction in the Recurrence of Stroke by Eicosapentaenoic Acid for Hypercholesterolemic Patients: Subanalysis of the JELIS Trial Stroke, July 1, 2008; 39(7): 2052 - 2058. [Abstract] [Full Text] [PDF]

				A. P. McGinn, R. C. Kaplan, J. Verghese, D. M. Rosenbaum, B. M. Psaty, A. E. Baird, J. K. Lynch, P. A. Wolf, C. Kooperberg, J. C. Larson, et al. Walking Speed and Risk of Incident Ischemic Stroke Among Postmenopausal Women Stroke, April 1, 2008; 39(4): 1233 - 1239. [Abstract] [Full Text] [PDF]

				S. Prabhakaran, C. B. Wright, M. Yoshita, R. Delapaz, T. Brown, C. DeCarli, and R. L. Sacco Prevalence and determinants of subclinical brain infarction: The Northern Manhattan Study Neurology, February 5, 2008; 70(6): 425 - 430. [Abstract] [Full Text] [PDF]

				C. Daly Is early chronic kidney disease an important risk factor for cardiovascular disease?: A Background Paper prepared for the UK Consensus Conference on Early Chronic Kidney Disease Nephrol. Dial. Transplant., September 1, 2007; 22(suppl_9): ix19 - ix25. [Full Text] [PDF]

				D. E. Weiner, H. Tighiouart, A. S. Levey, E. Elsayed, J. L. Griffith, D. N. Salem, and M. J. Sarnak Lowest Systolic Blood Pressure Is Associated with Stroke in Stages 3 to 4 Chronic Kidney Disease J. Am. Soc. Nephrol., March 1, 2007; 18(3): 960 - 966. [Abstract] [Full Text] [PDF]

				J. R. Crouse III Thematic review series: Patient-Oriented Research. Imaging atherosclerosis: state of the art J. Lipid Res., August 1, 2006; 47(8): 1677 - 1699. [Abstract] [Full Text] [PDF]

				L. B. Goldstein, R. Adams, M. J. Alberts, L. J. Appel, L. M. Brass, C. D. Bushnell, A. Culebras, T. J. DeGraba, P. B. Gorelick, J. R. Guyton, et al. Primary Prevention of Ischemic Stroke: A Guideline From the American Heart Association/American Stroke Association Stroke Council: Cosponsored by the Atherosclerotic Peripheral Vascular Disease Interdisciplinary Working Group; Cardiovascular Nursing Council; Clinical Cardiology Council; Nutrition, Physical Activity, and Metabolism Council; and the Quality of Care and Outcomes Research Interdisciplinary Working Group: The American Academy of Neurology affirms the value of this guideline. Circulation, June 20, 2006; 113(24): e873 - e923. [Abstract] [Full Text] [PDF]

				L. B. Goldstein, R. Adams, M. J. Alberts, L. J. Appel, L. M. Brass, C. D. Bushnell, A. Culebras, T. J. DeGraba, P. B. Gorelick, J. R. Guyton, et al. Primary Prevention of Ischemic Stroke: A Guideline From the American Heart Association/American Stroke Association Stroke Council: Cosponsored by the Atherosclerotic Peripheral Vascular Disease Interdisciplinary Working Group; Cardiovascular Nursing Council; Clinical Cardiology Council; Nutrition, Physical Activity, and Metabolism Council; and the Quality of Care and Outcomes Research Interdisciplinary Working Group: The American Academy of Neurology affirms the value of this guideline. Stroke, June 1, 2006; 37(6): 1583 - 1633. [Abstract] [Full Text] [PDF]

				T. S.M. Tsang, W. P. Abhayaratna, M. E. Barnes, Y. Miyasaka, B. J. Gersh, K. R. Bailey, S. S. Cha, and J. B. Seward Prediction of Cardiovascular Outcomes With Left Atrial Size: Is Volume Superior to Area or Diameter? J. Am. Coll. Cardiol., March 7, 2006; 47(5): 1018 - 1023. [Abstract] [Full Text] [PDF]

				S. L. Seliger, W.T. Longstreth Jr, R. Katz, T. Manolio, L. F. Fried, M. Shlipak, C. O. Stehman-Breen, A. Newman, M. Sarnak, D. L. Gillen, et al. Cystatin C and Subclinical Brain Infarction J. Am. Soc. Nephrol., December 1, 2005; 16(12): 3721 - 3727. [Abstract] [Full Text] [PDF]

				R. Vanholder, Z. Massy, A. Argiles, G. Spasovski, F. Verbeke, N. Lameire, and for the European Uremic Toxin Work Group (EUTox) Chronic kidney disease as cause of cardiovascular morbidity and mortality Nephrol. Dial. Transplant., June 1, 2005; 20(6): 1048 - 1056. [Abstract] [Full Text] [PDF]

				D. L. Tirschwell, N. L. Smith, S. R. Heckbert, R. N. Lemaitre, W. T. Longstreth Jr., and B. M. Psaty Association of cholesterol with stroke risk varies in stroke subtypes and patient subgroups Neurology, November 23, 2004; 63(10): 1868 - 1875. [Abstract] [Full Text] [PDF]

				J. S. Elkins, E. S. O'Meara, W. T. Longstreth Jr., M. C. Carlson, T. A. Manolio, and S. C. Johnston Stroke risk factors and loss of high cognitive function Neurology, September 14, 2004; 63(5): 793 - 799. [Abstract] [Full Text] [PDF]

				S. L. Seliger, D. S. Siscovick, C. O. Stehman-Breen, D. L. Gillen, A. Fitzpatrick, A. Bleyer, and L. H. Kuller Moderate Renal Impairment and Risk of Dementia among Older Adults: The Cardiovascular Health Cognition Study J. Am. Soc. Nephrol., July 1, 2004; 15(7): 1904 - 1911. [Abstract] [Full Text] [PDF]

				Th. Karapanayiotides, B. Piechowski-Jozwiak, G. van Melle, J. Bogousslavsky, and G. Devuyst Stroke patterns, etiology, and prognosis in patients with diabetes mellitus Neurology, May 11, 2004; 62(9): 1558 - 1562. [Abstract] [Full Text] [PDF]

				A. Arboix, M. Tarruella, L. Garcia-Eroles, M. Oliveres, C. Miquel, M. Balcells, and C. Targa Ischemic stroke in patients with intermittent claudication: a clinical study of 142 cases Vascular Medicine, February 1, 2004; 9(1): 13 - 17. [Abstract] [PDF]

				A. Scuteri, T. A. Manolio, E. K. Marino, A. M. Arnold, and E. G. Lakatta Prevalence of specific variant carotid geometric patterns and incidence of cardiovascular events in older persons: The cardiovascular health study (CHS E-131) J. Am. Coll. Cardiol., January 21, 2004; 43(2): 187 - 193. [Abstract] [Full Text] [PDF]

				M. J. Sarnak, A. S. Levey, A. C. Schoolwerth, J. Coresh, B. Culleton, L. L. Hamm, P. A. McCullough, B. L. Kasiske, E. Kelepouris, M. J. Klag, et al. Kidney Disease as a Risk Factor for Development of Cardiovascular Disease: A Statement From the American Heart Association Councils on Kidney in Cardiovascular Disease, High Blood Pressure Research, Clinical Cardiology, and Epidemiology and Prevention Hypertension, November 1, 2003; 42(5): 1050 - 1065. [Full Text] [PDF]

M. J. Sarnak, A. S. Levey, A. C. Schoolwerth, J. Coresh, B.