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(Circulation. 1995;92:720-726.)
© 1995 American Heart Association, Inc.

Articles

Subclinical Disease as an Independent Risk Factor for Cardiovascular Disease

L.H. Kuller, MD, DrPH; L. Shemanski, PhD; B.M. Psaty, MD, PhD; N.O. Borhani, MD; J. Gardin, MD; M.N. Haan, MD, DrPH; D.H. O'Leary, MD; P.J. Savage, MD; G.S. Tell, PhD; R. Tracy, PhD

From the Department of Epidemiology, Graduate School of Public Health (L.H.K.), University of Pittsburgh, Pittsburgh, Pa; School of Medicine (L.S., B.M.P., N.O.B.), University of Washington, (Seattle); Division of Cardiology (J.G.), University of California-Irvine (Davis); Department of Internal Medicine (M.N.H.), University of California-Sacramento; Division of Radiology (D.H.O'L.), Geisinger Medical Center, Danville, Pa; DECA (P.J.S.), National Heart, Lung, and Blood Institute, Bethesda, Md; Department of Public Health Sciences (G.S.T.), Bowman Gray School of Medicine, Winston-Salem, NC; and Department of Pathology-Biochemistry (R.T.), University of Vermont (Colchester).

Correspondence to Lewis H. Kuller, MD, DrPH, University of Pittsburgh, Department of Epidemiology, GSPH, 130 DeSoto St, Pittsburgh, PA 15261.

	Abstract

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Background The primary aim of the present study was to determine the relation between measures of subclinical cardiovascular disease and the incidence of clinical cardiovascular disease among 5201 adults 65 years of age or older who were participating in the Cardiovascular Health Study.

Methods and Results A new method of classifying subclinical disease at baseline examination in the Cardiovascular Health Study included measures of ankle-brachial blood pressure, carotid artery stenosis and wall thickness, ECG and echocardiographic abnormalities, and positive response to the Rose Angina and Claudication Questionnaire. Participants were followed for an average of 2.39 years (maximum, 3 years). For participants without evidence of clinical cardiovascular disease at baseline, the presence of subclinical disease compared with no subclinical disease was associated with a significant increased risk of incident total coronary heart disease including CHD deaths and nonfatal MI and angina pectoris for both men and women. For individuals with subclinical disease, the increased risk of total coronary heart disease was 2.0 for men and 2.5 for women, and the increased risk of total mortality was 2.9 for men and 1.7 for women. The increased risk changed little after adjustment for other risk factors, including lipoprotein levels, blood pressure, smoking, and diabetes.

Conclusions The measurement of subclinical disease provides an approach for identifying high-risk older individuals who may be candidates for more active intervention to prevent clinical disease.

Key Words: cardiovascular diseases • morbidity • mortality • risk factors • aging

	Introduction

Top Abstract Introduction Methods Results Discussion References

 
The goal of the present study was to describe the relation between prevalent subclinical cardiovascular disease at baseline and the risk of incident clinical cardiovascular disease in older men and women participating in the Cardiovascular Health Study (CHS).¹ Incident disease events were based on a maximum follow-up of 3 years and an average follow-up of 2.39 years. The specific methods of measurement of the various components of subclinical disease and other risk factors have been described in detail in previous CHS reports.^{2 3 4 5 6}

Epidemiological studies have documented that individuals with clinical cardiovascular disease related to one specific vascular bed (eg, intermittent claudication secondary to lower extremity arterial disease) are at a higher risk of clinical disease caused by atherosclerosis at another site, such as the heart or brain.^{7 8} Carotid artery stenosis is an important risk factor for both clinical stroke and CHD.^{9 10} ECG abnormalities with or without symptoms of coronary heart disease (CHD) are associated with an increased risk of clinical CHD.^{11 12 13} A positive response to the Rose Angina and Claudication Questionnaire is a predictor of subsequent CHD.^{14 15} The positive response is not diagnostic of angina pectoris and may be a marker of subclinical CHD.

Because of the systemic nature of atherosclerosis,^{16 17 18 19} an index of subclinical vascular disease based on measurements of several vascular beds combined with other markers of subclinical cardiovascular disease (CVD) may be better at predicting the risk of developing clinical CVD than the measurement of traditional risk factors or the measurement of atherosclerosis at a single vascular site.

Therefore, we developed an index of subclinical disease based on data from CHS.²⁰ This novel classification system for subclinical disease was based on a combination of ankle-brachial blood pressure, carotid artery stenosis and internal and common carotid artery wall thicknesses, ECG and echocardiographic abnormalities, and a positive response to the Rose questionnaire for angina pectoris (Table 1).

View this table: [in this window] [in a new window]   Table 1. Criteria for Clinical and Subclinical Disease in the Cardiovascular Health Study

The methods of developing the index of subclinical disease and some of the issues related to the selection of the measurements have been discussed, and the prevalence and risk factors related to subclinical disease have been given.²⁰ Our criteria are arbitrary. They were developed before the evaluation of any of the risk factors²⁰ or in the determination of the subsequent incidence and mortality and thus are unbiased.

One of the major goals was to evaluate individuals with a history of clinical CVD at baseline. The test results were then used to evaluate high- and low-risk groups among individuals without a history of clinical CVD. Some of the criteria, such as the Rose questionnaire, angina pectoris, and claudication, are very infrequently a unique component of the classification of subclinical disease. Approximately 2% of women and 1% of men with subclinical disease had a positive response to the Rose Questionnaire for symptoms of angina pectoris or claudication as the only criterion for subclinical disease, and the inclusion of the Rose angina or claudication criteria can therefore have no effect on the overall results of the study.

	Methods

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Baseline
The CHS was a longitudinal observational study of 5201 adults aged 65 or older; 2239 men and 2962 women were included at baseline.²¹ The participants were recruited from a defined sample of Medicare-eligible persons between April 1989 and May 1990. Participants were recruited from four US communities: Forsyth County, NC; Sacramento County, Calif; Washington County, Md; and Pittsburgh, Pa. A detailed description of the CHS has been published. The original sample of 5201 participants were primarily white; 148 (3%) were black women, and 96 (1.8%) were black men.

All of the CHS participants underwent a baseline clinical examination² and gave a medical history. At baseline examination, the CHS participants were classified according to the presence or absence of six preexisting CVDs that were identified before or at the baseline examination: myocardial infarction (MI), angina, congestive heart failure, stroke, transient ischemic attack (TIA), and claudication.²

Follow-up of Participants
Participants reported to the CHS clinical centers on subsequent hospitalizations and outpatient visits for specific cardiovascular diagnoses. Twice a year, the participants were queried about new diagnoses, hospitalizations, and procedures; follow-up alternated between clinic visits and telephone calls. Individuals who did not come to the clinic were visited at home or queried by telephone to obtain follow-up. To enhance the process, hospitalization data from the Health Care Financing Administration (HCFA) records were compared with the CHS events database to identify any missed hospitalizations. Hospitalizations were then reviewed and added to the CHS database. Only a few incident cardiovascular events were identified solely from the HCFA files. During the first 2 years of follow-up, only 3 of 145 incident MI and angina events (2.1%) were identified solely from HCFA data, whereas CHS surveillance identified 19 events (13.1%) that were not found in the HCFA files, and 123 events (82.8%) were identified from both CHS and HCFA data sources.

Classification of Events
Fatal events. Fatal CHD deaths were classified as definite fatal MI if there was no evidence of a nonatherosclerotic cause of death and there was evidence of a definite MI within 4 weeks of death, based on a combination of chest pain, enzyme values, and ECG changes. Definite fatal CHD death included no known nonatherosclerotic cause of death and one or both of the following: chest pain within 72 hours of death or prior evidence of chronic ischemic heart disease and the absence of valvular heart disease or nonischemic cardiomyopathy. Possible fatal CHD deaths included deaths with no known nonatherosclerotic cause and information consistent with the death certificate diagnosis of the underlying cause as CHD.

Nonfatal events. The nonfatal events discussed in this report included MI and angina pectoris. The identification of incident MI and angina pectoris was limited to CHS participants who did not have prevalent MI or angina pectoris at baseline. The diagnosis of MI was based on an algorithm that included a history of chest pain, increased enzyme values, and ECG changes similar to those for the fatal MI. All of the hospital records were reviewed by the Events Committee, and the ECGs were also read at the Electrocardiographic Reading Center for the CHS. The diagnosis of angina pectoris was based on a review of hospital records and clinical reports and included angiography, exercise tests, ECG, echocardiography, and the use of specific antianginal medications.²²

Statistical Analysis
Associations of event outcomes to prevalent subclinical and no CVD status and risk factors were assessed with the use of multivariate logistic regression. All analyses included an adjustment for age. Stepwise logistic procedures were used to assess whether any interaction was significant after including all main effects for the risk factors in the logistic model. In the presence of significant interactions, stratified analyses were performed to determine the magnitude of the effect of the interaction on the disease category comparisons. Associations were considered to be significant at P<.05. All analyses were performed with Statistical Analysis System software.²³

	Results

Top Abstract Introduction Methods Results Discussion References

 
With the use of the results of baseline examinations, we subdivided the CHS cohort into three groups based on their disease status: clinical CVD (1617), subclinical CVD (1942), and no subclinical or clinical CVD (1642). The criteria for clinical and subclinical disease are given in Table 1.²⁰

The initial analysis tested the hypothesis that individuals with subclinical disease but without clinical disease at baseline, as defined in Table 1, are at higher risk of developing incident clinical CHD or total mortality than are individuals with no subclinical disease. We then determined whether the possible increased risk of clinical CVD among individuals with prevalent subclinical disease was mediated by other risk factors (eg, lipid levels, blood pressure, cigarette smoking, and blood glucose level) measured at baseline. Finally, we evaluated whether these risk factors were predictors of incident clinical CHD among individuals with baseline prevalent subclinical disease.

The average follow-up was 2.39 years (maximum follow-up, 3 years). The specific events included in the analysis are given in Table 2. Deaths were classified as definite fatal CHD or MI; all CHD deaths, both definite or possible; and total mortality from all causes. Participants with clinical CHD at baseline were included in the analysis only if they died. Survivors were classified as having or not having an MI or angina pectoris. The patients who experienced angina as an end point included only those individuals who did not have an MI or did not die during the period of follow-up. The patients who had an MI as an end point were further subclassified according to those who survived the 3-year follow-up, experienced a nonfatal MI, or died from a fatal MI. The category of total CHD included all CHD deaths, definite and possible, as well as surviving subsets of participants who had either a nonfatal MI or angina pectoris.

View this table: [in this window] [in a new window]   Table 2. Distribution of Specific Events in the Cardiovascular Health Study: Men and Women by Category of Clinical Disease, Subclinical Disease, No Subclinical Disease, and Clinical Disease and Relative Risk

In this analysis, there were 544 men with no disease, 843 men with subclinical disease, 1098 women with no disease, and 1099 women with subclinical disease at baseline (852 men and 765 women had clinical disease at baseline). The rates for CHD deaths and total mortality were highest for participants with clinical disease at baseline, intermediate among those with subclinical disease, and lowest among those with no disease at baseline (Table 2). Subsequent analyses primarily focus on a comparison between participants with and those without subclinical disease and, except as noted, exclude all participants with clinical CHD at baseline as defined in Table 1.

For both men and women with subclinical disease at baseline, the age-adjusted incidence of total CHD was significantly higher than that for those without subclinical disease (Table 2). For women with subclinical disease at baseline, the incidence was significantly higher for total MI, nonfatal MI, and angina pectoris, whereas for men, there was little difference in the incidence of MI (fatal or nonfatal) between those with and those without subclinical disease (Table 2). Men had higher incidence rates of total CHD events than women. Women with subclinical disease had incidence rates that were close to the incidence rates for men with no subclinical disease. Women with no subclinical disease had very low incidence rates of clinical disease over the maximum 3 years of the follow-up (Table 2).

The definition of subclinical disease at baseline included major ECG abnormalities at rest based on the Minnesota Code.¹¹ ECG abnormalities are known predictors of clinical CHD events. To determine whether the higher incidence of events for participants with subclinical disease was primarily due to the inclusion of individuals with major ECG abnormalities, we analyzed the subclinical disease groups with and without major ECG abnormalities. A total of 325 men and 353 women with subclinical disease had major ECG abnormalities. There was little difference in the event rates according to whether ECG abnormalities were included in the subclinical disease category; this was true for both men and women. When participants with major ECG abnormalities were excluded, the number of events decreased along with the denominator of the rates, resulting in similar event rates. The men and women with subclinical disease, excluding those with ECG abnormalities, still had significantly higher total CHD event rates than did participants with no subclinical disease.

We next determined whether the presence of subclinical disease at baseline, compared with no subclinical disease, was an independent determinant of incident clinical disease after adjustment for other risk factors. We performed bivariate analysis comparing the age-adjusted rates of clinical disease by quartiles of risk factor levels based on cutoff points used in the CHS publication that compared risk factors and prevalent subclinical disease.²⁰ We evaluated LDL cholesterol, HDL cholesterol, and triglyceride levels and systolic and diastolic blood pressures. At all levels of risk factors, the incident clinical CHD rates were higher for those with subclinical than for those without subclinical disease. Multivariate analysis was then done with models that included LDL cholesterol, HDL cholesterol, and triglyceride levels; systolic and diastolic blood pressures; age; current and past cigarette smoking; weight; use of antihypertensive medications; use of lipid-lowering medications; and definite history of diabetes or hypertension.

Men had significantly higher total CHD rates than women (Table 2). Subclinical disease was a significant predictor of incident total CHD for both men and women combined and for men and women separately. The odds ratio (Table 3) for subclinical disease was very similar to the estimated relative risk (Table 2, without adjustment for other risk factors): 2.0 versus 1.8 for men and 2.5 versus 2.4 for women.

View this table: [in this window] [in a new window]   Table 3. Multivariate Assessment of Group Differences in Incident Clinical Cardiovascular Diseases: Subclinical Disease Compared With No Subclinical Disease Group1

The odds ratio for subclinical disease in regard to incident total MI for women was similar to that for total CHD (Table 3). For men and for both sexes combined, the odds ratio for total MI was less than that for incident total CHD.

For total mortality (Table 3), subclinical disease was a significant independent predictor in the multivariate model for men. Subclinical disease, however, was not an independent predictor of total mortality for women. This could be due to the relatively small number of CHD deaths in the subclinical (two) and no subclinical (none) disease categories among women. Only 5% of the total deaths among women compared with 25% of the total deaths among men were due to CHD.

Subclinical disease was a strong independent predictor of incident CHD. We next determined whether any other risk factors among individuals with subclinical disease improved the prediction of subsequent clinical disease—that is, for individuals with subclinical disease, did any of the risk factors predict clinical disease? In the multivariate model for men with subclinical disease, none of the risk factors (Table 3) were a significant independent predictor of incident total CHD; for women with subclinical disease, the only significant association was triglyceride level and incident total CHD.

In the final model, we evaluated the determinants of total mortality for the entire CHS cohort, including those with clinical disease (Table 4). For men and women combined, both subclinical disease and clinical disease were independent predictors of total mortality after adjustment for all other risk factors previously described. Men had significantly higher mortality rates than women. Subclinical disease was an independent predictor of total mortality in men but was not significant for women. Again, this was probably due to the smaller number of deaths among women and the smaller proportion of deaths due to CHD (Table 2). Sex, age, diabetes, and current smoking were significant predictors of total mortality (Table 4).

View this table: [in this window] [in a new window]   Table 4. Multivariate Assessment of Disease Group Differences in Total Mortality With Clinical Group Included

	Discussion

Top Abstract Introduction Methods Results Discussion References

 
Many older individuals (65 years of age or older) have subclinical disease that may substantially increase the risk of clinical heart disease.^{20 24 25 26 27 28 29 30}

We have documented that with an average follow-up of 2.3 years, the incidence of total clinical coronary artery disease was significantly increased among CHS participants with subclinical disease compared with those without subclinical disease and that this association is significant even after adjustment for age and other previously established CVD risk factors (Table 3).

The number of clinical cases was small and the length of follow-up was relatively short, so it remains difficult to evaluate specific subgroups at risk within the subclinical disease category. We have, however, shown that for men and women, even when participants with major ECG abnormalities are excluded, subclinical disease is a strong risk factor for incident clinical CHD compared with no subclinical disease. Abnormal ECG results alone were not the cause of the significantly higher risk associated with subclinical disease. The adjustment for major key risk factors such as lipoprotein levels and blood pressure had trivial effects on the significant association between subclinical disease and risk of incident CVD.

We estimated the population attributable risk percentage of incident total coronary heart disease for those with subclinical disease. The population attributable risk percentage for subclinical disease, excluding clinical disease, is the product of the attributable risk (defined as the difference in incidence between subclinical and no subclinical disease groups) and the prevalence of subclinical disease divided by overall incidence of disease. For men, the incidence of total CHD was 8.2% for subclinical disease and 4.2% for no subclinical disease, a 4% difference. The prevalence of subclinical disease was 61%, and the overall incidence was 6.63% (Table 2). The population attributable risk percentage was 36.8%. For women, the incidence of total CHD was 3.8% for subclinical disease and 1.5% for no subclinical disease (a difference of 2.3%). The prevalence of subclinical disease was 49%, and the overall incidence was 2.66%. The population attributable risk percentage was 42.5%. The attributable risk percentage, which represents the proportion of disease attributable to subclinical disease, is much higher than for most of the known risk factors or combination of risk factors and further documents the importance of subclinical disease as a contributor to subsequent incident clinical disease.

Men with subclinical disease continue to have a higher risk of incident clinical CHD than do women with subclinical disease. There are several possible reasons for this. First, men probably have had subclinical disease longer than women and therefore may have more extensive disease. Second, the risk of thrombosis or plaque changes may be higher for men than for women, given a similar degree of subclinical disease. Third, the extent of coronary artery disease or disease at another vascular site, which was not measured by our definition of subclinical disease, may be greater in men than in women with subclinical disease. These hypotheses are all testable in future studies.

There were some interesting and not completely explained differences in risk relations between prevalent subclinical disease and incident clinical CVD for men compared with women. For example, prevalent subclinical disease was an important predictor of total mortality in men (relative risk, 2.9; statistically significant), but this was not true for women (relative risk, 1.7). This finding could be due, as noted, to the relatively low frequency of CHD as a cause of death among women with subclinical or no clinical disease (4.5% [2 of 41] compared with 28% for men). On the other hand, women with subclinical disease had a much higher risk of MI (both fatal and nonfatal) than did women without subclinical disease (relative risk, 2.5), but we did not find such a relation for men (relative risk, 1.1). The risk relations between subclinical and no disease for angina pectoris were similar for men and women.

The treatment of traditional risk factors, such as elevated blood pressure, smoking, high LDL cholesterol, and low HDL cholesterol, is important.^{31 32 33 34 35 36 37 38} They are the major determinants of both subclinical and clinical disease. Treatment of these risk factors may prevent the development or progression of subclinical disease and subsequent clinical disease.^{33 36 37 39 40 41} Antiplatelet aggregating agents,⁴² such as aspirin, also reduce the risk of recurrent MI and stroke and may be beneficial even in primary prevention of MI in asymptomatic individuals.

The pathway from risk factors to clinical disease probably is through the development of subclinical disease. The identification of subclinical disease may therefore provide a very important marker of the effects of risk factors, such as lipoprotein levels, blood pressure, cigarette smoking, and diabetes, on the cardiovascular system among relatively asymptomatic individuals. It is possible that the risk of subclinical disease is a function of both current exposure and duration of exposure to a specific level or extent of a risk factor.

Many older individuals without subclinical disease, even those with increased risk factors such as high cholesterol level, are at low risk of developing clinical coronary artery disease and might not benefit from specific aggressive therapies. If such treatments are relatively costly, ie, drug therapy is expensive, or treatment may cause serious side effects, then the cost of such therapy may be greater than the benefits. The measurement of subclinical disease before the institution of aggressive therapies could focus therapeutic efforts on higher-risk individuals who are more likely to develop clinical disease within the next few years. After excluding those with clinical disease at baseline in the present study, there were 1098 women (approximately half of the women) and 544 men (39%) with no subclinical disease at baseline.²⁰ These groups had lower rates of both CHD mortality and morbidity during the 2.39-year follow-up and could be classified as a lower-risk population.

There may be additional significant unmeasured risk factors for incident clinical CHD among those with subclinical disease, in particular related to thrombosis, clotting, and changes in vessel wall morphology.^{43 44} Thus, markers of increased risk of clotting and thrombosis⁴⁵ and possible wall injury, such as measures of inflammation,^{43 46} may further identify individuals who are at even higher risk given that they have subclinical disease, especially over the short term. We are planning to evaluate this hypothesis within the CHS cohort. The measurement of subclinical disease has potentially very important implications for prevention and clinical medicine.

The measurement of subclinical disease in CHS can be done primarily by technicians (eg, carotid duplex scanning, ankle-brachial blood pressure, ECG, and echocardiography). These tests could be used to identify higher-risk individuals, especially older individuals. The costs of the various measures of subclinical disease are important in determining their usefulness in clinical practice to identify a subgroup of older individuals at high risk of clinical disease. Such information may lead to further referencing in guidelines for the identification and treatment of individuals with higher probability of a clinical cardiovascular event. The follow-up of the CHS cohort will provide the opportunity to determine the best combination of measures of subclinical disease for prediction of incident clinical disease and their relative costs.

Received February 16, 1995; accepted April 1, 1995.

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