(Circulation. 2001;103:2566.)
© 2001 American Heart Association, Inc.
Clinical Investigation and Reports |
Prediction of Mortality by Exercise Echocardiography
A Strategy for Combination With the Duke Treadmill Score
From the Department of Medicine (T.H.M., C.C., L.S.), University of Queensland, Brisbane, Australia; Cleveland Clinic Foundation (J.D.T.), Cleveland, Ohio; and Asheville Cardiology Associates (C.V., S.A.), Asheville, NC.
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Abstract |
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Background—In studies generally involving short follow-up, exercise echocardiography has been shown to predict composite end points. We sought to study the prediction of mortality with this test and to devise a strategy for combination with standard exercise testing.
Methods and Results—Clinical, exercise testing, and echocardiographic data were collected in 5375 patients (aged 54±14 years, 3880 men) undergoing exercise echocardiography. The Duke treadmill score was derived from the results of treadmill exercise testing. Resting left ventricular (LV) function and the presence and severity of ischemia were interpreted by expert observers. Follow-up at 10.6 years (mean 5.5±1.9 years) was complete in 5211 patients (97%). The Duke score classified 59% of patients as low risk, 39% as intermediate risk, and 2% as high risk. Resting LV dysfunction was present in 1445 patients (27%), and the exercise echocardiogram was abnormal in 2525 patients (47%). Death occurred in 649 patients (12%). Over the first 6 years of follow-up, those with normal exercise echocardiograms had a mortality of 1% per year. Ischemia was an independent predictor of mortality. In sequential Cox models, the predictive power of clinical data was strengthened by adding the Duke score, resting LV function, and the results of exercise echocardiography. Exercise echocardiography was able to substratify patients with intermediate-risk Duke scores into groups with a yearly mortality of 2% to 7%.
Conclusions—A normal exercise echocardiogram confers a low risk of death, and positive results are an independent predictor of death; ischemia is incremental to other data. This test may be particularly useful in patients with intermediate-risk Duke treadmill scores.
Key Words: exercise • echocardiography • coronary disease • mortality • prognosis
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Introduction |
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Exercise echocardiography is a routine test in patients with known or suspected coronary artery disease who have repolarization abnormalities that make the exercise ECG uninterpretable.1 Current exercise testing guidelines state that a standard exercise ECG should be the first investigation in patients with a diagnostic ECG who are able to exercise maximally.2 However, the accuracy of exercise echocardiography exceeds that of the exercise ECG, even when the ECG is interpretable.3 These guidelines would be supported if the relative prognostic implications of exercise echocardiography and exercise ECG were similar.
Although extensive outcome literature surrounds the use of pharmacological stress echocardiography,4 5 6 the outcome data available for exercise echocardiography are quite limited.7 8 9 10 11 12 Previous studies have suggested that the predictive value of a negative test is very high, although the predictive value of a positive test ranges from 17% to 35%. Echocardiographic identification of ischemia is an independent predictor of subsequent events, with these data being incremental to the prognostic information supplied by exercise testing.9 However, these previous studies are of relatively small size, generally have focused on composite end points, and have compared the results of exercise echocardiography with isolated exercise test characteristics. The latter approach does not account for the utility of standard exercise ECG testing as an excellent tool for allocation of risk when evidence of ischemia and exercise capacity are combined.13 Several schemes of combining these variables have been reported, but to date, none of these quantitative approaches has been compared with exercise echocardiography.
Thus, the purpose of the present study was to examine the ability of exercise echocardiography to predict mortality in patients with chronic stable coronary artery disease. We sought to define the predictive value of a negative test over prolonged follow-up and to explore the prognostic implications of a positive exercise echocardiogram, particularly in comparison with the Duke treadmill score.14
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Methods |
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Study Design
Exercise echocardiography was performed between 1988 and 1994 in 5375 consecutive patients with known or suspected coronary disease: 2416 at Asheville Cardiology Associates and 2959 at the Cleveland Clinic Foundation. Of the latter, 851 patients were involved in 2 previous studies that used separate end points.9 10 The clinical, exercise, and echocardiographic data of these patients were prospectively entered into separate databases, and follow-up was obtained from 1998 to 1999, after which the data were merged. Consent was obtained before testing, and the study was approved by the Institutional Review Board.
Clinical Evaluation
These patients were aged 54±14 years and included
3880 men (73%). The most frequent risk factor was hypertension (36%),
followed by smoking (12%) and diabetes (11%). The most common
indications for testing were diagnostic testing (2356
patients [44%]) and prognostic assessment (47%). Typical or
atypical chest pain was present in 3765 (70%) of the patients.
Coronary artery disease was known in 20% of the patients, 7%
of whom had experienced previous myocardial infarction and 11% of whom
had undergone previous bypass surgery. The pretest probability of
coronary artery disease was calculated on the basis of age,
sex, and symptom status15 in
those without known disease. A high probability (>85%) of
coronary artery disease was present in 34% of the
patients; 32% were at intermediate probability, and 34% were at low
probability (<15%). The likelihood of coronary artery disease
in the overall group was 31±25%. At the time of the study, 20% of
patients were treated with ß-adrenoceptor antagonists;
15%, with calcium antagonists; 17%, with ACE
inhibitors; 16%, with digitalis; and 5%, with
diuretics.
Exercise Testing
Patients were prepared for exercise testing in the
usual fashion.16 All
exercise testing involved maximal treadmill protocols selected in
accordance with the age and functional status of the patient; most
common were the Bruce (67%) and modified Bruce (22%)
protocols. Patients underwent continuous clinical and ECG monitoring
throughout the exercise test. Standard end points were used, and the
test was stopped for fatigue, severe ischemia (severe angina,
>2 mm ST depression), hypertension (systolic blood
pressure >220 mm Hg), hypotension (decrement of systolic
blood pressure >20 mm Hg), or arrhythmias.
Angina, ST-segment changes, hemodynamic response to exercise, and exercise capacity were archived for each patient. The Duke treadmill score14 was calculated from the exercise capacity, the maximum ST-segment deviation, and the presence of limiting or nonlimiting angina.
Echocardiography
A standard resting echocardiogram was captured
digitally into a quad-screen display. Because we sought to address the
prognostic value of the test in routine practice, this analysis
used the original interpretations of the studies by
echocardiographers trained in exercise
echocardiography (3 in Asheville and 10 in
Cleveland). Studies were interpreted independently of clinical,
exercise, or angiographic data, and results were made available to the
physicians responsible for the patients.
Resting LV function was evaluated as normal, mild, moderate, or severely reduced on the basis of qualitative assessment of the extent of abnormal wall motion. Exercise echocardiography was interpreted by comparison of rest and exercise images with use of the quad-screen digital display, with review of videotape if desired. A normal response was characterized by normal resting function, with no deterioration induced by exercise. Infarction was defined by akinesis or dyskinesis at rest. Ischemia was identified by new or worsening wall motion abnormalities. Myocardial segments were combined into vascular territories for the purpose of expressing the extent of ischemia as 1-, 2-, or 3-vessel coronary artery disease. The apex, anteroseptal, septal, and anterior walls were attributed to the left anterior descending coronary artery; the lateral wall, to the left circumflex artery; and the inferior and basal septal walls, to the right coronary artery. The posterior wall was attributed to the circumflex or right coronary artery if either was abnormal; in patients with isolated posterior wall abnormalities, these were ascribed to the left circumflex artery. Studies were designated as abnormal if >1 segment showed evidence of infarction or ischemia, and a normal study was characterized by a normal response in all segments. Because previous studies in the nuclear literature17 showed that the total extent of malperfused myocardium at peak stress is predictive of outcome, we produced an analogous "summed stress score" by counting the number of territories showing either rest or stress-induced changes.
Follow-Up
Follow-up data were gathered after 5.5±1.9 years
(range 0.7 to 10.6 years) by clinic review or telephone contact with
the patient or patient’s physician in 5211 patients (97%). The
primary end point was total mortality. Patients were censored at the
time of coronary bypass surgery or coronary
angioplasty, which were not identified as events.
Statistical Analysis
Descriptive statistics are expressed as mean±SD of
continuous variables and frequency and percentage of categorical
variables. Differences between Kaplan-Meier survival curves were
compared with the log-rank test. Cox proportional hazards models were
developed to investigate the effects of ischemia on outcome,
independent of clinical, exercise, and resting
echocardiographic variables in patients with
complete clinical data and to investigate the interaction of exercise
score, resting LV function, and ischemia in all patients. All
analyses were performed with the use of SPSS statistical
software (SPPS Inc), and a value of
P<0.05 was considered to be
statistically significant. In the situation of making multiple
comparisons, significant probability values were defined by the
Bonferroni method.
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Results |
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Exercise Response
A maximal exercise test was attempted by all patients; the average workload was 7.7±2.8 metabolic equivalents. A submaximal heart rate (<85% predicted for age) was achieved by 376 patients; the peak heart rate was 88±18% of that predicted. Angina was induced in 9% patients, and significant ST-segment changes were recorded in 1439 patients (27%). The Duke treadmill score identified 39% of the patients as being at intermediate risk (score 4 to -10), 2% as being at high risk (score -10 or less), and 59% as being at low risk (score
5).
Echocardiography
Echocardiographic images were
interpreted in all patients. Rest and stress images were considered
normal in 2829 patients (53%). Normal resting function was reported in
4352 patients (83%); in the remainder of the patients, the severity of
LV dysfunction was classified as mild (ejection fraction 40% to 50%)
in 11%, moderate (ejection fraction 30% to 39%) in 4%, and severe
(ejection fraction <30%) in 2%. Exercise-induced wall motion
abnormalities were reported in 1080 patients (20%), 472 of whom also
showed resting wall motion abnormalities.
Mortality During Follow-Up
Over a follow-up to 10 years (mean follow-up 5.5±1.9
years), 649 patients died (11%). Patients undergoing myocardial
revascularization (n=606, 11%) were censored from
follow-up at the time of this procedure.
Implications of Normal Exercise
Echocardiogram
The average yearly mortality associated with a normal
study was 1% per year for the first 6 years, with a small increase of
events after 6 years
(Figure 1
). In a multivariate model,
predictors of events in patients with a normal study included age,
smoking, submaximal exercise, an intermediate- or high-risk Duke score,
and digoxin therapy; ß-blocker therapy was protective against events
(Table 1).
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Prediction of Death
A low-risk Duke treadmill score was associated with a
94% five-year survival, compared with 85% and 76% survival with
intermediate- and high-risk scores
(Figure 2). Ischemia, scar, and especially both
ischemia and scar are also associated with death during
follow-up
(Figure 1
). In a model predicting death with the use of
clinical, exercise, and echocardiographic
variables, ischemia at exercise
echocardiography was found to be an independent
predictor of mortality
(Table 2). This model was developed at one center and
applied at the second site;
Figure 3 illustrates similar outcomes in the 2 populations
divided into quintiles of risk.
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Because not all patients presenting with known or
suspected coronary disease would have all investigations
performed in standard practice, we attempted to mimic this by a
sequence of models, initially evaluating clinical variables, then
exercise testing, and resting and exercise
echocardiography (Table 3). Each step in the
investigation produced a significant increment in the ability to
predict death.
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The risk associated with an abnormal test varied from 2% to
4% per year. Part of the incremental risk of a combination of both
scar and ischemia is that these patients have more extensive
disease; the impact of increasing disease extent is illustrated in
Figure 4. Another means of identifying a greater spectrum of
risk is to combine these variables. In a
multivariate model comprising exercise testing results,
resting LV function, and summed stress score, a high-risk Duke score
(relative risk [RR] 3.8, 95% CI 2.4 to 6.2; P<0.0001) or intermediate-risk Duke score (RR 2.4, 95% CI 2.0 to 2.8;
P<0.0001), resting LV dysfunction (RR 2.1, 95% CI 1.8 to 2.5;
P<0.0001), and multiple territory wall motion abnormalities (RR 1.9, 95% CI 1.5 to 2.4; P<0.0001) predicted death at 5
years. These factors may be combined to predict risk associated with
low-, intermediate-, and high-risk Duke scores
(Table 4). In the 2% of patients at high risk, the yearly
mortality (nearly 10% per year) justifies further evaluation and
possibly intervention without recourse to imaging. Conversely, in the
59% of the patients at low risk, although the extent of abnormality at
exercise echocardiography is able to differentiate
levels of risk, the numbers of patients with extensive abnormalities
are small, and the efficacy of more than resting imaging could be
questioned. Therefore, the greatest benefit of exercise
echocardiography is in the evaluation of the 39%
of patients at intermediate risk by the Duke score, in whom
subcategories of risk ranging from 2% to 7% can be identified. Thus,
the use of exercise echocardiography may be used to
focus further assessment on a small number of these patients.
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Discussion |
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Exercise echocardiography is a powerful tool for the prediction of death in patients with chronic stable coronary disease. The Duke treadmill score is predictive of outcome, and the greatest benefit of exercise echocardiography relates to those individuals having an intermediate-risk Duke score.
Assessment of Risk in Patients With Stable
Chronic Coronary Disease
The risk of mortality in stable coronary artery
disease is low.18
Nonetheless, the few patients with advanced or extensive disease are at
high risk of an event, which may be reduced by coronary
revascularization.13
However, although the evidence base favoring intervention is based on
the anatomic extent of coronary disease, most patients undergo
assessment with functional testing.
In patients who are unable to exercise, the expense of pharmacological stress imaging techniques is unavoidable, and a large evidence base has accumulated with respect to their value in prognostic assessment.4 5 6 In contrast, the additional cost has been more difficult to rationalize in patients who are able to exercise, because this test is an excellent tool for assessing risk in patients with coronary artery disease. In the Coronary Artery Surgery Study (CASS) registry, the presence of a positive test at low workload conferred a 5-fold increment of risk compared with a negative test at high workload.19 Similarly, the Duke database has been used to derive a treadmill score that confers a 5-fold increment of risk in high-risk compared with low-risk patients. Although intervention is appropriate for high-risk patients (5-year survival of 65%) and medical treatment is best for low-risk patients (5-year survival of 97%), the appropriate response to intermediate-risk patients is less clear, and angiographic assessment is often performed to identify extensive coronary artery disease.
A number of studies have shown the prognostic application of nuclear cardiology techniques17 20 21 to demonstrate low levels of risk (<1% per year) in the setting of a normal test. Scintigraphic studies have shown imaging data to be of independent and incremental prognostic value to standard investigations, and selective application of this modality in combination with standard risk variables22 may reduce expenditure on subsequent invasive investigations, while at the same time having no adverse impact on outcome.23
Previous studies with exercise echocardiography have indicated that the imaging component of this test adds incremental and independent information to the results of standard exercise testing.7 8 9 10 11 12 A normal exercise echocardiogram is associated with a risk of <1% per year over the first 6 years of follow-up, with a subsequent small increase that most likely reflects progressive coronary artery disease. Although the comparison with nuclear imaging results is difficult because of differences in the selection of patients, 2 studies that compared the techniques in the same patients have shown the prognostic implications to be similar. However, the event rate in patients with a positive study ranges from 18% to 35%, and many previous studies were limited by insufficient sample size, mandating the use of composite end points. No previous study has had sufficient mortality or follow-up to substratify positive test results. The results of the present study suggest that although exercise echocardiography offers incremental prognostic information in the group as a whole, this is of limited value in nearly 50% of the patients who are at high or low risk on the basis of the Duke score. In the remaining individuals at intermediate levels of risk, the results of exercise echocardiography are able to further stratify risk and may therefore reduce the cost of subsequent investigations.
Limitations of the Study
Earlier studies of stress
echocardiography have had the advantage of
assessing the performance of the test before it became used as
a clinical tool. The results in the present study reflect the
progressive acceptance of the test as a clinical tool.
Consequently, patients with positive tests tend to proceed to
angiography and thence to revascularization (and
removal from our analysis). Failure to censor patients at the
time of revascularization would have the effect of
improving the outcome of patients with positive test
results.
As currently performed, exercise echocardiography is interpreted subjectively. Although we sought to replicate "real life" by studying the performance of the test in a referral center and a large independent laboratory, the tests were interpreted by experts who have a similar approach to test interpretation, reflecting previous collaborative teaching and training activities. Nonetheless, an important limitation in the assessment of disease extent has been in the accordance of wall motion scoring between observers, and for this reason, disease extent was characterized on the number of coronary vascular territories involved. Indeed, the same approach has been used in multicenter nuclear cardiology studies.24 It is hoped that the development of a quantitative echocardiographic approach may facilitate a subtler means of assessing disease extent in the future.
Clinical Application
The findings of the present study apply to patients
with known or suspected coronary artery disease who are able to
exercise maximally and whose symptom status does not mandate
revascularization. The first step is to exclude
individuals at low risk on clinical grounds. The application of the
treadmill score is then able to identify almost 50% of the patients
who are either at low risk (in which case, further intervention would
not be necessary in most cases on prognostic grounds) or at high risk
(in which case, further stratification would in most instances be
deemed inappropriate). The remaining patients, who account for
approximately half of the total, merit further evaluation by exercise
echocardiography, which is able to substratify
patients. This investigative approach may potentially reduce the
performance of coronary angiography while at the same
time identifying patients at risk of subsequent cardiac events.
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Acknowledgments |
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This study was supported in part by the American Society of Echocardiography and the National Heart Foundation of Australia.
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Footnotes |
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Reprint requests to Prof T. Marwick, University Department of Medicine, Princess Alexandra Hospital, Brisbane, Qld 4102, Australia.
Received December 7, 2000; revision received March 12, 2001; accepted March 12, 2001.
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T. H Marwick, C. Case, L. Short, and J. D Thomas Prediction of mortality in patients without angina: Use of an exercise score and exercise echocardiography Eur. Heart J., July 1, 2003; 24(13): 1223 - 1230. [Abstract] [Full Text] [PDF]
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T.H. Marwick, L. Shaw, C. Case, C. Vasey, and J.D. Thomas Clinical and economic impact of exercise electrocardiography and exercise echocardiography in clinical practice Eur. Heart J., June 2, 2003; 24(12): 1153 - 1163. [Abstract] [Full Text] [PDF]
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R. Sicari, E. Pasanisi, L. Venneri, P. Landi, L. Cortigiani, E. Picano, and Echo Persantine International Cooperative (EPIC) a Stress echo results predict mortality: a large-scale multicenter prospective international study J. Am. Coll. Cardiol., February 19, 2003; 41(4): 589 - 595. [Abstract] [Full Text] [PDF]
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T. H Marwick Stress echocardiography Heart, January 1, 2003; 89(1): 113 - 118. [Full Text] [PDF]
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 T. H. Marwick, C. Case, S. Sawada, C. Vasey, L. Short, and M. Lauer Use of Stress Echocardiography to Predict Mortality in Patients With Diabetes and Known or Suspected Coronary Artery Disease Diabetes Care, June 1, 2002; 25(6): 1042 - 1048. [Abstract] [Full Text] [PDF]
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 T. H. Marwick, C. Case, S. Sawada, C. Vasey, and J. D. Thomas Prediction of Outcomes in Hypertensive Patients With Suspected Coronary Disease Hypertension, June 1, 2002; 39(6): 1113 - 1118. [Abstract] [Full Text] [PDF]
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 Combining Exercise Echocardiography with Traditional Exercise Testing to Predict Mortality Risk Journal Watch Cardiology, August 31, 2001; 2001(831): 10 - 10. [Full Text]
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