Prediction of mortality in patients without angina

Use of an exercise score and exercise echocardiography

Thomas H Marwicka,*, Colin Casea, Leanne Shorta and James D Thomasb

a University of Queensland,Brisbane, Australia
b Cleveland Clinic Foundation, Cleveland, OH, USA

* Correspondence to: Prof. T.H. Marwick, University Department of Medicine, Princess Alexandra Hospital, Brisbane, Qld 4102, Australia. Tel: +61-7-3240-5346; Fax: +61-7-3240-5399
E-mail address: tmarwick{at}medicine.pa.uq.edu.au

Received 10 October 2002; revised 17 February 2003; accepted 13 March 2003


    Abstract
 Top
 Abstract
 1. Introduction
 2. Methods
 3. Results
 4. Discussion
 5. Conclusion
 References
 
Background Exercise testing has limited efficacy for identifying coronary artery disease (CAD) in the absence of anginal symptoms. Exercise echocardiography is more accurate than standard exercise testing, but its efficacy in this situation has not been defined. We sought to identify whether the Duke treadmill score or exercise echocardiography (ExE) could be used to identify risk in patients without anginal symptoms.

Methods We studied 1859 patients without typical or atypical angina, heart failure, or a history or ECG evidence of infarction or CAD, who were referred for ExE, of whom 1832 (age 51±15 years, 944 men) were followed for up to 10 years. The presence and extent of ischaemia and scar were interpreted by expert reviewers at the time of the original study.

Results Exercise provoked significant (>0.1mV) ST segment depression in 215 patients (12%), and wall motion abnormalities in 137 (8%). Seventy-eight patients (4%) died before revascularization, only 17 from known cardiac causes. The independent predictors of death were age (RR 1.1, p<0.0001), smoking, Duke treadmill score (RR 0.9, p<0.0001) and resting LV dysfunction (RR 1.9, p<0.04), but did not include ischaemia at ExE. Echocardiography was not predictive of outcome in subgroups with an intermediate or high risk Duke score, nor in patients with two or more risk factors.

Conclusions Patients without anginal symptoms have a low mortality, especially from cardiac causes. If such individuals undergo exercise testing and a resting echocardiogram, exercise echocardiography does not offer additional prognostic information.

Key Words: Screening • Coronary artery disease • Exercise testing • Exercise echocardiography


    1. Introduction
 Top
 Abstract
 1. Introduction
 2. Methods
 3. Results
 4. Discussion
 5. Conclusion
 References
 
The initial presentation of a significant proportion of patients with coronary artery disease (CAD) is with sudden death.1 While some of these episodes may be related to plaque rupture in the absence of significant coronary lesions, others may relate to undiagnosed disease. It is now widely recognized that coronary disease may be present in the absence of angina in some patients, and that the presence of silent ischaemia does not appear related to the extent of coronary disease,2 nor does it carry different prognostic implications to disease marked by angina.3 However, the standard approach to the non-invasive evaluation of coronary disease, based on the assessment of pre-testprobability,4 would preclude investigation of these patients because the probability of disease is considered low in the absence of angina, irrespective of age and gender.5 Indeed, stress testing guidelines have identified exercise testing as having limited efficacy for screening patients withoutanginal symptoms.

Despite caution about the investigation of patients without angina, clinical suspicion of CAD, based on the presence of multiple risk factors, dyspnoea and other cardiac symptoms, or the performance of various occupations may lead to physicians referring patients for stress testing. In this situation, a more accurate stress imaging test is perceived as being more efficacious than the standard exercise test, although there are limited data to support this,6 and none with stress echocardiography. In this study, we evaluated the value of exercise echocardiography (ExE) for this approach in a group of individuals with no history of angina or preexistent coronary disease, and compared these findings with low-cost alternatives such as the ST segment response and Duke treadmill score.


    2. Methods
 Top
 Abstract
 1. Introduction
 2. Methods
 3. Results
 4. Discussion
 5. Conclusion
 References
 
2.1. Clinical characteristics
This study derived from a database of patients undergoing exercise echocardiography between 1988–94 at Cleveland Clinic Foundation. Patients were eligible for study if they lacked typical or atypical angina, heart failure, a history of infarction or CAD, or ECG evidence of infarction. The resulting group of 1859 patients had been referred because their physicians suspected an angina equivalent (dyspnoea or palpitations), because of multiple risk factors or the desire to exclude CAD due to their occupation. Clinical, exercise and echocardiographic data were gathered prospectively, and the patients were followed for up to 10 years (mean 4.7±1.8 years). Consent was obtained prior to testing and the study was approved by the Institutional Review Board.

Among the 1832 patients with complete follow-up, the mean age was 51±15 years; 10% were >70 years old, and men accounted for 994 patients (55%). The most frequent risk factors were smoking (41%, including 12% current), followed by hypertension (29%) and diabetes (6%). Mainly because of hypertension, patients were on treatment with either beta adrenoceptor antagonists (13%), calcium antagonists (11%) or angiotensin converting enzyme inhibitors (8%). Although decisions regarding drug therapy were left to the discretion of the patient's physician, drugs were not routinely discontinued before testing.

2.2. Exercise testing
All exercise tests were performed using maximal treadmill protocols selected in accordance with the age and functional status of the patient. A 12-lead ECG was performed with standard preparation,7 slightly modified to allow access to the echocardiographic windows – this generally involved positioning leads V2 and V5 one intercostal space lower than normal. Patients underwent continuous clinical and ECG monitoring during and after exercise. Standard end-points4 included severe ischaemia (severe angina, >2mm ST depression), hypertension (systolic blood pressure >220mmHg), hypotension (decrement of systolic blood pressure >20mmHg) or arrhythmias, but the most frequent end-point was fatigue.

The haemodynamic response to exercise, exercise capacity, symptom status and ECG changes with stress were noted in all patients. Age-predicted maximum heart-rate was defined using the formula 220-age. ST segments were assessed visually; for categorical analysis, significant ST displacement was defined as >0.1mV at 0.08s after the J point in any lead. Additionally, the exercise capacity (minutes of the Bruce protocol), maximum ST segment deviation (in mm) and angina score (2 for limiting and 1 for non-limiting angina) were used to calculate the Duke treadmill score, as previously described:8 Duke score=Exercise time-(5*max ST depression)–(4*angina score).

This score is used to allocate patients into high risk (below –10; major events in 7% per year), intermediate risk (4 to –10; 2–5% events per year) and low risk (above +5; <1% risk per year).

2.3. Echocardiography
A standard echocardiogram was performed at rest in all patients. Wall motion was scored at rest using the standard model of the American Society of Echocardiography.9 Myocardial segments were combined into vascular territories for the purpose of expressing the extent of ischaemia as one-, two- or three-vessel coronary artery disease. The apex, anteroseptal, septal and anterior walls were attributed to the left anterior descending, the lateral to the left circumflex, and the inferior and basal septal to the right coronary. The posterior wall was attributed to the circumflex or right coronary if either was abnormal; in patients with isolated posterior wall abnormalities, these were ascribed to the left circumflex. Resting LV function was evaluated as normal, mild, moderate or severely reduced, based on the number of territories involved. Exercise echocardiography was interpreted by comparison of rest and exercise images using the quad-screen digital display, and our standard approach was to supplement this with review of video-tape, although this was left to the discretion of the interpreting physician. A normal response was characterized by normal resting function, with no deterioration induced by exercise. Infarction was defined by resting wall motion abnormalities, and ischaemia was identified by new or worsening wall motion abnormalities. The criterion for an abnormal study was involvement of 1 segment by infarction or ischaemia. Finally, we expressed the total number of territories showing either rest or stress-induced changes as the ‘summed stress score'.10 Studies were interpreted independent of clinical, exercise or angiographic data, and results were made available to the physicians responsible for the patient.

2.4. Follow-up
Follow-up data were gathered after 4.7±1.8 years (median 4.5, range 0.1 to 10.4 years) by clinical review or telephone contact with the patient or patient's physician. The cause of death was identified from the patient's physician or medical records, and data were analysed for both total and cardiac mortality. However, we and others11 have reservations about the accuracy of designation of cardiac and non-cardiac mortality, so we chose total mortality as the primary end-point. Patients were censored at the time of coronary bypass surgery or coronary angioplasty, which were not identified as events.

The patients with incomplete follow-up were comparable to the overall group. The ages of those lost to follow-up and the overall group were similar (54±12 vs 51±15 years, p=0.51), as were their Duke treadmill scores (6±4 vs 5±6, p=0.14). The amount of ST depression was a little less in the group lost to follow-up (0.3±0.6 vs 0.5±0.9, p=0.05), and the number of patients with ischaemia were similar (10% vs 6%, p=0.90).

2.5. Statistical analysis
Descriptive statistics are expressed as frequency and percentage of categorical variables and mean and standard deviation of continuous variables. Cox proportional hazards models were developed to investigate the effects of ischaemia on outcome, independent of clinical, exercise and resting echocardiographic variables. The incremental value of various investigations was examined in a sequence of predictive models, based on clinical predictors of mortality, then adding the Duke treadmill score, resting LV function and finally LV function with stress. All analyses were performed using SPSS statistical software (SPPS Inc, Chicago, Ill); p values <0.05 were considered to be statistically significant except when making multiple comparisons, in which case the Bonferroni method was used to define significant p values.


    3. Results
 Top
 Abstract
 1. Introduction
 2. Methods
 3. Results
 4. Discussion
 5. Conclusion
 References
 
3.1. Exercise testing results
Patients exercised maximally, to an average workload of 9±3METS, and the peak heart-rate was 95±10% of the age-predicted maximum. Chest pain occurred during exercise testing in four patients (0.2%). Significant (0.1mV) ST segment depression occurred in 215 patients (12%). Based on combination of exercise capacity, ECG changes and chest pain responses into the Duke treadmill score, 1277 (70%) were classified as low risk, 535 (29%) as intermediate risk, and 20 patients (1%) as high risk.

Wall motion was normal at rest and during stress in 1695 patients (93%). Abnormal studies were limited to a single territory in 113 patients (6%), or multiple territories in 24 (1%). Wall motion at either rest or stress was abnormal in 137 patients; dysfunction was identified at rest in 47 patients (3%), 42 of whom had mild LV dysfunction and five had moderate dysfunction. Ischaemia was identified by ExE in 103 patients (6%), 90 of whom showed involvement of a single territory.

The results for the Duke treadmill score did not correlate well with either the extent of ischaemia (Kendall's tau –0.17, p<0.001), or scar (Kendall's tau –0.07, p<0.001). Similarly, the severity of resting LV dysfunction was not a good predictor of the extent of ischaemia (correlation 0.15, p<0.001).

3.2. Outcomes
There were 78 deaths (4%) from all causes before revascularization, giving an average annualized all-cause mortality of 0.9%. Cardiac causes of death were identified in 17 patients, giving an annualized cardiac mortality of 0.2%. Non-fatal myocardial infarction occurred in 17 patients. Myocardial revascularization was performed at any time in follow-up in 62 patients (3.4%), of whom 22 had ischaemia on the original test—17 of these had the revascularization procedure within 3 months of the test.

3.3. Predictors of mortality
Of the 78 patients that died, 30 were classified as low risk by the Duke score (2%), 43 were identified as being at intermediate risk (9%), and five as high risk patients (25%). Eight deaths occurred in 47 patients with LV dysfunction (17%), and 70 in patients without LV dysfunction (4%). Eight deaths occurred in 103 patients with ischaemia (8%), and 70 in patients without evidence of ischaemia (4%). Fig. 1summarizes the Kaplan–Meier survival curves of patients with and without ST depression, LV dysfunction, ischaemia and in each risk level of the Duke treadmill score. The annualized mortality of patients with an intermediate- to high-risk Duke treadmill score was 2%, compared with 0.4%/year in the low-risk patients. The annualized mortality in those with LV dysfunction was 3.2%, compared with 0.8% in those with normal LV function. Echo evidence of ischaemia was associated with a mortality of 1.6%, compared with 0.8% in those without ischaemia.



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Fig. 1 Kaplan–Meier survival curves of patients with and without ST depression, LV dysfunction, ischaemia and in each risk level of the Duke treadmill score.

 
The univariate and multivariate predictors of death are summarized in Table 1. For the whole group, age, risk factors, the Duke treadmill score (but not ST depression alone) and resting LV function were independent predictors of mortality. Although LV dysfunction with stress was associated with mortality as a univariate correlate, this was not independent of the other variables. The comparison of sequential models for clinical evaluation (age and smoking), exercise testing and resting echocardiography (Fig. 2) showed that each step of the sequential clinical evaluation added significant prognostic information. ExE was not a predictor of mortality, even if only the intermediate and high risk Duke score patients were subjected to this test.


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Table 1 Predictors of death in the group of patients with suspected coronary disease but without angina. Overall model chi-square was 176*

 


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Fig. 2 Statistical power of models (expressed as model chi-square) based on clinical analysis (age, smoking), exercise testing (age, smoking, Duke score), and echocardiography (age, smoking, Duke score, resting LV function) to show the incremental value of adding each level of data.

 
3.4. Predictors of mortality in patients with multiple risk factors
There were 300 asymptomatic patients who were screened because of the presence of two or more risk factors. Only 24 deaths occurred in this group, and age>70 (RR 1.6 [95%CI 0.4–7.4], p=0.02) and an intermediate or high-risk Duke score (RR 2.6 [95%CI 1.1–6.3], p=0.04) were independently associated with mortality. LV dysfunction at neither rest nor stress was predictive of outcome.


    4. Discussion
 Top
 Abstract
 1. Introduction
 2. Methods
 3. Results
 4. Discussion
 5. Conclusion
 References
 
The results of this study indicate that exercise testing may indeed be prognostically useful in selected patients when coronary disease is suspected in the absence of angina. However, while the Duke treadmill score and resting LV function was predictive of death in follow-up, exercise echocardiography was not independently associated with outcome. These findings run contrary to a widespread and expensive (but unsupported) practice of performing stress-imaging tests in the belief that the greater diagnostic accuracy of these tests also makes them superior to the exercise ECG as a prognostic tool in patients at low probability of CAD. Moreover, the annualized 2% risk in the highest risk group after exercise testing wouldrequire large numbers of treated patients to impart a survival benefit.

4.1. Investigation of coronary disease without angina
Although the current ACC/AHA guidelines for exercise testing4 have classified the exercise ECG to be inappropriate as a screening tool in the absence of angina, this is a heterogeneous group that includes individuals with absolutely no symptoms to those with nonspecific symptoms such as dyspnoea or palpitations. In patients with CAD risk factors, an abnormal stress test result increases the 5-year relative risk from 4 to 30-fold, depending on the positivity of the test.12–14 Exercise testing has also been shown to offer predictive value in patients with no risk factors, although this is less than in groups at higher levels of risk.15 In a recent review of four studies predicting hard events, although there was a relative risk of 4 between patients with positive and negative tests, only 5% of positive tests were associated with an event.16 Moreover, the value of screening in older patients and women is undefined. Unfortunately, as has often been the case with screening strategies, most diagnostic approaches for CAD have shown variable sensitivity, but significant problems have arisen withspecificity. False-positive studies risk inappropriate labelling of some individuals with coronary disease, or inappropriate diagnostic coronary angiography. The use of a more accurate test may reduce these risks of a false positive result.

While the ST segment response is the cornerstone of diagnostic testing for CAD, exercise capacity is an important prognostic marker.8 In this study, although the ST segment response was a univariate correlate of survival, use of the Duke treadmill score produced a more powerful model for prediction of death. This finding, which to our knowledge is the first with this score in a screening population, is consistent with the prognostic power of this tool in many other populations. In this study, although ischaemia at stress echocardiography was a univariate correlate of mortality, it was outweighed by the results of the Duke treadmill score. Nonetheless, while 48 of 555 patients with an intermediate- to high-risk Duke treadmill score died, the absolute number of deaths was only one and a half times the number who died after finding a low risk score.

While both exercise myocardial perfusion scintigraphy and exercise echocardiography have been shown to have prognostic value in symptomatic patients,10,17 there are few data regarding the application of these tests to screening. Myocardial perfusion imaging has been shown to be useful for the identification of disease in relatives of patients with premature CAD, especially in association with a positive exercise ECG.18 Likewise, a recent study of patients at low probability of coronary disease (but not asymptomatic subjects) using exercise echocardiography showed these results to be an independent predictor of adverse events over a shorter follow-up.19 However, previous comparisons with the exercise ECG have involved analysis of the ST segment response, rather than a multivariate score that includes other stress testingparameters.

Other imaging tests, including detection ofcarotid wall thickening and abnormal brachial reactivity, may have a role in screening for asymptomatic atherosclerosis, although their use to facilitate decision-making regarding risk reduction therapy is better validated.20 Electron-beam and multi-slice helical computed tomography have also recently been used to identify coronary calcification, although the value of this marker for the identification of coronary calcification in asymptomatic persons remains controversial.21 Certainly, individuals without evidence of calcification are at low risk of CAD, but although the extent of calcification can be used to stratify risk of CAD in patients with positive tests,22 this has been reported not to be a strong predictor of death. Additional non-invasive studies are often needed to identify whether sufficient risk is present to justify intervention.

4.2. End-points in studies of CAD screening
As recently discussed by Lauer,11 the identification of cardiac mortality is subjective and unreliable; it is likely that many patients who die of cardiac causes are not appropriately classified. For this reason, although most previous work in the field has focused on cardiac mortality or composite end-points, we attempted to predict total mortality. In our study, the cardiac mortality of 0.9% over an average 4.7 years of follow-up accounted for about 22% of total mortality. The annualized total mortality of 0.9% in this study compares with an annualized total mortality of 0.3% in a previous screening study examining all-cause mortality15—a difference likely explained on the basis of the average age being 15 years greater, with a greater prevalence of risk factors including twice the frequency of smoking in our study.

4.3. Limitations
A number of limitations pertain to this being an observational study. The investigators selected patients considered to lack anginal symptoms, but had no influence on the choice of patients for testing. The majority of these patients had some non-specific symptoms, but the presence or absence of symptoms was not predictive of outcome. Similarly, although we selected patients without electrocardiographic evidence of infarction, we did not obtain details of the electrocardiogram. In the patients selected in this study, we would anticipate that the majority of patients had a normal electrocardiogram, and the results are concordant with previous work showing that a stress-imaging protocol did not predict extensive coronary disease (and by inference, would be unlikely to predict outcome).23

As the test results were used by the physicians looking after the patients, the results may have been instrumental in the selection of patients for revascularization, thus reducing the apparentprognostic benefit of exercise echocardiography, because these patients with mainly positive tests may have gone on to have events. We do not think that this exerted a major influence on the results—only 22 patients (1%) showed ischaemia and proceeded to revascularization and of these, only 17 did so within 3 months (ie as a direct consequence of the test).

Finally, the original exercise echocardiograms were performed in the 1988–94 period, and imaging technology has clearly improved from this time, especially with respect to the development of harmonic imaging. Unfortunately, this phenomenon of ‘methodologic drift’ is an unavoidable issue in longitudinal studies of such a rapidly developing area as echocardiography. While the improvement of image quality has boosted the accuracy of stress echocardiography,24 we believe that an improvement sufficient to alter the results of this study would be improbable.


    5. Conclusion
 Top
 Abstract
 1. Introduction
 2. Methods
 3. Results
 4. Discussion
 5. Conclusion
 References
 
The results of this study confirm that the use of exercise testing in patients without anginal symptoms has limited value, with an event rate in the tested group that could not be improved by mechanical intervention. Moreover, while the physician might use the exercise test for other than prognostic reasons (eg. to reassure patients with nonspecific symptoms), there is no evidence thatexercise echocardiography is any more effective than the resting ejection fraction and Duke treadmill score in this situation.


    Acknowledgments
 
Supported in part by the American Society of Echocardiography and the National Heart Foundation of Australia.


    References
 Top
 Abstract
 1. Introduction
 2. Methods
 3. Results
 4. Discussion
 5. Conclusion
 References
 

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