(Circulation. 2000;101:e12.)
© 2000 American Heart Association, Inc.
AHA Scientific Statement |
Prevention Conference V
Beyond Secondary Prevention : Identifying the High-Risk Patient for Primary Prevention : Tests for Silent and Inducible Ischemia : Writing Group II
Key Words: AHA Conference Proceedings • ischemia • prevention • tests • risk factors • risk assessment
Writing Group II addressed the question of whether tests that assess silent ischemia or inducible ischemia add to prognostic information gained from standard risk factors in asymptomatic patients without known coronary disease. The tests reviewed included the exercise electrocardiogram (ECG), exercise and pharmacological (stress) echocardiogram (echo), exercise and pharmacological myocardial perfusion imaging, ambulatory ECG monitoring, and positron emission tomography.
These noninvasive tests detect myocardial ischemia
associated with obstructive coronary artery disease (CAD). To
date, their greatest application has been diagnostic, in
the evaluation of patients with symptoms of angina or a previous
clinical manifestation of coronary heart disease (CHD). One
limitation of the methods used to detect stress-induced (exercise or
pharmacological stress) myocardial ischemia is the dependence
of these methods on the presence of flow-limiting coronary
stenosis. As with all diagnostic studies, their
predictive value is dependent on the prevalence of disease in the
population tested. When used in a population with a low prevalence of
CHD, such as an asymptomatic population undergoing
cardiovascular screening, these tests are expected to
have low positive predictive value, and the majority of positive test
results represent false-positive responses
(Figure
). Also central to the
discussions of Writing Group II was the recognition that the majority
of future events among patients with CHD are related to severity of
obstruction, plaque instability, and total atherosclerotic
burden.1 Writing Group II was specifically concerned with
delineating the prognostic information available from these tests that
could contribute toward identifying patients at higher risk for major
CHD-related events.
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Exercise ECG Testing
The use of the exercise ECG to screen subjects who
are asymptomatic for CAD is historically a complex issue.
There may be poor predictive value in the nonselective use of the test,
and invalid abnormal responses (false-positive) may lead to
psychological and work disability as well as unnecessary medical
expense. Among asymptomatic individuals, there is evidence
that development of an ischemic ECG response at low workloads
of exercise testing is associated with a higher incidence of future
events such as angina pectoris, myocardial infarction, and sudden
death. More specifically, ST depression 
1 mm occurring within 6
minutes on the Bruce protocol (6 to 7 METs1) has been associated with
an increased relative risk of cardiovascular events in
men; however, the absolute risk of cardiac events in these populations
without associated cardiovascular risk factors remains
low.2 A study in which the Ellestad protocol was used in
asymptomatic men and women with known CHD3
found that ECG changes and exercise duration 
5 minutes correlated
with subsequent CHD in men >40 years old, but investigators concluded
that the exercise ECG was of limited value in women and in men 40
years of age.
With regard to subjects who are asymptomatic but
who also have risk factors for CHD, the results of exercise ECG testing
are prognostically useful. In the Seattle Heart Watch
Study,2 men with 1 risk factor (positive family history,
smoking, hypertension, blood pressure >140/90 mm Hg,
hypercholesterolemia [total
cholesterol >240 mg/dL]) and 2 abnormalities on exercise
testing (chest pain, exercise duration <6 minutes, ST depression
>1 mm, or <90% predicted heart rate) had a 30-fold increase in
5-year cardiac risk. Exercise testing had no predictive value in the
group with no risk factors. In the Lipid Research Clinics
Coronary Primary Prevention Trial, of 3775
asymptomatic hypercholesterolemic men, half
of whom were taking cholestyramine and half of whom were taking
placebo, there was a 5.7 times greater risk of death due to coronary
heart disease in the placebo group among those with a positive exercise
test result (1-mm ST-segment depression or elevation on exercise
testing) than among those with a negative test result. Overall, during
a mean follow-up period of 7.4 years, there was a 6.7% mortality rate
in the group with a positive test result versus 1.3% in the group with
a negative test result. Interestingly, a positive test result was not
significantly associated with nonfatal myocardial infarction. The
Multiple Risk Factor Intervention Trial (MRFIT)5 reported
a nearly 4-fold increase in the 7-year coronary mortality rate
among asymptomatic middle-aged men with elevated levels of
CHD risk factors and an abnormal exercise ECG and suggested that the
exercise ECG might serve to identify high-risk men who could benefit
from risk factor reduction.
There is a paucity of similar data regarding the use of the exercise ECG in women and the elderly (age >75 years). In this regard, the limitations of exercise ECG in these populations is reflected by the lower sensitivity and specificity of ST-segment alteration in women6 and the elderly.7 It is of interest that treadmill exercise capacity was recently shown to be the most accurate predictor of prognosis in both men and women in a study that also assessed the value of ST-segment changes.8
In 12 studies, investigators used the exercise test to screen
asymptomatic individuals for cardiovascular
risk and to predict subsequent events.4 9 10 11 12 13 14 15 16 17 18
Subjects were screened for silent heart disease and have been
monitored for cardiac events for 5 to 10 years. Considerably different
results have been obtained in these studies according to the end points
considered. When angina is included as an end point, nonspecific
symptoms in a subject with an abnormal test result are more likely to
be diagnosed as coronary disease during the follow-up period.
Hard end points, such as death or myocardial infarction, eliminated
this misclassification and are more appropriate for classifying
cardiovascular risk. The earliest exercise test studies
in asymptomatic people included angina as an end point,
whereas the 4 most recent studies used only hard end points such as
nonfatal myocardial infarction and coronary death. As shown in
the Table, the first studies tested 5526 subjects and ranged in size
from 113 to 1390 individuals. Sensitivity was 50%; specificity, 90%;
risk ratio, 9 times; and predictive value of a positive response, 25%.
This means that 1 of 4 subjects with abnormal test results eventually
had a cardiac event such as angina. The 4 most recent studies included
>12 000 subjects and monitored them only for hard end points. The
sensitivity of the exercise test was 
25%; specificity, 90%;
risk ratio, 4 times; and predictive value of a positive response, only
5%. In other words, in these studies, 1 of 20 people with an abnormal
test result eventually had a cardiac event such as death, and risk was
4-fold higher in those with positive test results than in those with
negative test results.
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Thus, routine use of the exercise ECG in completely unselected
asymptomatic populations before office screening
for risk cannot be recommended. In asymptomatic men >40
years old with 1 risk factor, exercise testing may provide useful
information as a guide to aggressive risk factor intervention or the
need to further evaluate the cause of myocardial ischemia. The
role of exercise testing in women and the elderly (>75 years of age)
as a guide to identifying the high-risk patient for primary prevention
requires further study.
Exercise and Pharmacological Stress Echocardiography
Stress echocardiography (SE) is based on the premise that myocardial ischemia leads to left ventricular dyssynergy that can be detected by 2-dimensional echo. Either exercise (treadmill or bicycle) or medication (usually dobutamine) is used as the stress modality. Although SE has been reported to increase the sensitivity and specificity of stress testing to detect CHD, most studies have focused on patients with known or suspected CHD who have a high pretest probability of disease. Few truly asymptomatic individuals have been evaluated for long-term prognosis.
Recent studies demonstrate that wall motion abnormalities at peak stress are among the most important predictors of an adverse outcome. These findings have been extended to include elderly patients19 and those with an intermediate pretest likelihood of disease.20 It is possible to ascertain low risk status through the use of SE. Several studies have examined the prognosis of patients after a normal exercise or pharmacological SE.21 22 23 Absence of an inducible wall motion abnormality is associated with an excellent prognosis. In a recent study of 1325 patients (28% of whom were asymptomatic), cardiac event–free survival after a normal exercise echocardiogram was 99%, 98%, and 97% at 1, 2, and 3 years, respectively.22 This favorable prognosis was observed even in subgroups with an intermediate or high pretest likelihood of disease. Predictors of subsequent cardiac events were age, workload achieved, angina, and left ventricular hypertrophy.
In conclusion, only limited data exist to support the use of SE as a screening tool or in combination with noninvasive risk factors to evaluate asymptomatic populations. Also, the addition of echocardiographic imaging to routine stress testing increases the cost and complexity of the examination. Although SE may be of value in assessing women and the elderly with increased risk factors, further studies are needed to define its role in identifying the high-risk patient for primary prevention.
Exercise and Pharmacological Myocardial Perfusion Imaging
Myocardial perfusion imaging has evolved as an important clinical tool in the evaluation of patients with known or suspected CHD, and numerous studies involving thousands of patients attest to its diagnostic and prognostic capabilities in such patients. Inducible ischemia by perfusion imaging identifies a high-risk subset when used in patients with known or suspected CHD, and the magnitude of risk is related to the magnitude of ischemic myocardium.24 Conversely, patients with normal myocardial perfusion images have a <1% risk per year of death or myocardial infarction.24 25
The development of perfusion defects with exercise or pharmacological stress is dependent on abnormal coronary vasodilator reserve; thus, myocardial perfusion imaging is potentially useful for detecting only those patients who have flow-limiting coronary artery stenosis. Therefore, perfusion imaging would be expected to have little or no practical value in the detection of patients with early coronary atherosclerotic disease who may be candidates for aggressive primary prevention strategies.
In high-risk asymptomatic populations such as those with a
positive family history of CHD (a sibling with CHD before age 60),
exercise thallium testing has been reported to identify an increased
relative risk of death or myocardial infarction if the stress ECG was
abnormal (relative risk [RR] 6.8), stress thallium was abnormal (RR
3.8), or both tests were abnormal (RR 61.3).26 Among 2104
patients without angina and without known CHD, 78% had normal
myocardial perfusion imaging, and the likelihood of death or myocardial
infarction was 0.3% per year, whereas the small subset (9% of
patients) with moderate to severe perfusion defects had an annual risk
of death of 5.6% and of myocardial infarction of 2.2%.24
These patients underwent perfusion imaging for clinical indications;
thus, these latter data may not be representative of
the results of screening an unselected asymptomatic
population. It is postulated that stress thallium
scintigraphy might be particularly useful in the risk
assessment of men 45 years old with a family history of premature
coronary disease. The available data suggest that myocardial
perfusion imaging should not be used broadly in screening unselected
asymptomatic populations27 but may be valuable
in selected populations considered at particularly high risk for
CHD.
Ambulatory ECG Monitoring
Because the majority of information about ambulatory ECG (Holter) monitoring for detection of ischemia was gained from studies in patients with known disease, its role as a tool to screen cardiovascular disease in healthy individuals, even those at increased risk, must be extrapolated from research that was not designed to answer that question. The sensitivity and specificity of ST-segment depression for angiographically proven CAD in patients with chest pain has been reported as 62% and 61%, respectively, which is less than the 67% and 75% specificity reported in the same population with treadmill ECG testing.28 Because of the low sensitivity and specificity of ambulatory ECG monitoring, published recommendations suggest that it is an inaccurate modality to exclude the presence of coronary disease. In the guidelines for use of ambulatory ECG published by the ACC/AHA Task Force,29 its use for detecting myocardial ischemia in asymptomatic individuals is considered a class III indication, ie, a condition for which there is general agreement that it is not a useful test.
Positron Emission Tomography
The basis for detecting CHD with positron emission tomography (PET), like conventional radionuclide methods, is detection of flow heterogeneity during maximal coronary hyperemia. In addition, PET may be used to quantify reduced regional myocardial blood flow reserve in regions subtended by diseased coronary arteries. With both of these methods, CHD is only detectable if coronary stenosis is hemodynamically significant. Because PET is insensitive for the detection of coronary stenoses of <50%, its use as a screening test for CHD and risk stratification of asymptomatic patients is not cost-effective.30
In patients with familial and secondary hypercholesterolemia, PET has revealed decreased myocardial blood flow reserve that correlated inversely with total plasma and LDL cholesterol.31 PET has also been used to quantify changes in the size and severity of myocardial perfusion abnormalities in patients with CHD after risk factor modifications.32 Thus, although significant issues surround the cost-effectiveness of PET in the evaluation of asymptomatic patients at risk for CHD, preliminary research suggests that there may be future applications of this technique in the detection of coronary endothelial dysfunction and the noninvasive monitoring of aggressive medical therapy and risk factor modification.
Conclusions
Data are quite limited regarding the prognostic utility of
noninvasive measures of inducing myocardial ischemia in
apparently asymptomatic persons. Very few prognostic
studies have included adequate numbers of asymptomatic
subjects. Therefore, conclusions about the role of such testing for the
purpose of risk assessment are limited. With the exception of exercise
ECG testing in asymptomatic men with increased
cardiovascular risk profiles, few data exist to support
the use of the noninvasive testing modalities discussed by Writing
Group II to screen asymptomatic populations for high-risk
subclinical CHD. Future research should investigate the role of these
techniques in association with global risk assessment (summarized by
Writing Group I) to further define prognosis, guide intensity of
therapy, and monitor the effectiveness of risk-intervention
strategies.
Footnotes
1 MET indicates metabolic equivalent, ie, 3.5 mL · kg-1 · min-1 of ventilatory oxygen consumption. 
In connection with Prevention Conference V, Writing Group I has published a complete report on "Medical Office Assessment" (Circulation. 2000;101:e3–e11), and Writing Group III has published a complete report on "Noninvasive Tests of Atherosclerotic Burden" (Circulation. 2000;101:e16–e22). In addition, the Executive Summary of "Prevention Conference V: Beyond Secondary Prevention: Identifying the High-Risk Patient for Primary Prevention" has been published in Circulation (Circulation. 2000;101:111–116).
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