Copyright © 2004, The European Society of Cardiology
Prognostic value of supine bicycle exercise stress echocardiography in patients with known or suspected coronary artery disease
aDepartment of Interventional Cardiology, G. Rummo Hospital, Benevento, Italy
bDepartment of Cardiology, Second University of Naples, Italy
cDepartment of Cardiology, Monaldi Hospital, Naples, Italy
Received 4 August 2004; received in revised form 1 November 2004; accepted after revision 4 November 2004.
* Corresponding author. Second University of Naples, Via G. Martucci 35, 80121 Naples, Italy. Tel.: +39081 7618525; fax: +39081 7145205. E-mail: adandrea@synapsis.it
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Aims To assess the prognostic significance of supine bicycle exercise stress echocardiography (ESE) for cardiac events, and the ESE additional role compared to other traditional clinical and echo variables, in patients with proven or suspected coronary artery disease (CAD).
Methods and results Clinical status and long-term outcome were assessed in 607 patients, for a mean period of 49.9±12.5 months. ESE was performed for the diagnosis of suspected CAD in 267 patients, and for the risk stratification in 340 patients. At baseline, the mean value of WMSI was 1.22±0.36, and the mean left ventricular ejection fraction was 58.2±10.9%. The ESE was positive for ischemia in 210 patients (34.9%), while the ECG was suggestive for ischemia in 157 patients. At peak effort, the mean WMSI was 1.38±0.46. Low work load was achieved by 158 patients (26.1%). During the follow-up period there were 222 events, including 48 cardiac deaths and 34 acute non-fatal myocardial infarction. By multivariable model, cigarette smoking, peak WMSI, positive ESE for ischemia and low work load were the only independent predictors of cardiac death. The cumulative 5-year mean survival rate according to ESE response was 95.9% in patients with negative ESE, and 81.7% in positive ESE (p<0.00001).
Conclusions In patients with known or suspected CAD able to perform a physical stress, bicycle ESE is able to stratify patients at higher risk of cardiac events. The final report of an ESE performed for prognostic purpose should include both the assessment of induced dyssinergy and the evaluation of indexes of the extent and the severity of myocardial ischemia.
Keywords: Bicycle exercise echocardiography; Prognosis; Coronary artery disease; Exercise capacity; Wall motion score index
Stress echocardiography, with either pharmacologic or exercise protocol, is a routinely accepted tool for both the diagnosis of coronary artery disease (CAD) and the evaluation of cardiac risk in different clinical settings.1
In patients who are unable to exercise, pharmacologic stress echo is widely used for diagnosis of CAD, and its efficacy for cardiac risk stratification has been tested in patients undergoing major vascular surgery, with impaired left ventricular (LV) function, with diabetes mellitus, and early after uncomplicated acute myocardial infarction (AMI).2–9 On the other hand, exercise stress echocardiography (ESE) is a routine test in patients able to perform a physical stress but with repolarization abnormalities that make the exercise ECG uninterpretable.10–15
Although several recent studies reported an excellent outcome in patients without evidence of stress-induced wall motion abnormalities, the ESE capacity to effectively identify patients at higher risk of cardiac events is less definite. In fact, many of the studies on this topic differ in follow-up duration, cardiac events considered (revascularization sometimes included), analysis of stress echo variables (often limited to stress-induced ischemia) and modalities (exercise, pharmacological).10–15 In addition, no study on the long-term prognostic value of supine bicycle ESE in a large population of patients has been reported to date, since most of the previous studies used post-treadmill stress echo analysis.
On this ground, the present study was undertaken to assess the long-term prognostic significance for late cardiac events of bicycle ESE, and the ESE additional role compared to other traditional clinical and rest echo variables, in a population of patients with proven or suspected CAD, followed up for 49.9±12.5 months.
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Patients' population
The initial cohort included 640 consecutive patients who underwent ESE clinically indicated from January 1998 to December 2003 for chest pain symptoms evaluation or for cardiac risk stratification.
In our echo laboratory we usually select the kind of stress on the basis of clinical findings and of known specific contraindications. Typical or atypical chest pain was present in 520 patients (85.6%). Patients were submitted to a bicycle ESE when able to perform physical stress but with repolarization abnormalities (due to left ventricular hypertrophy, use of digitalis, conduction disturbances, etc) that made the exercise ECG uninterpretable, or when treatment decisions were dependent on the site or the extent of ischemia.
Twenty-two patients who underwent coronary artery revascularization within 3 months from the ESE were censored. Eight patients were lost to follow-up (0.9%). Non-cardiac death occurred in 3 patients: 2 for malignant cancer and 1 for a car accident.
Patients' outcome and clinical status were finally assessed in 607 patients, for a mean period of 49.9±12.5 months (range: 4–60; median: 60; SE of arithmetic mean: 0.59; 25th percentile: 40.1; 75th percentile: 60). Exercise echo was performed for the diagnosis of suspected CAD in 267 patients (43.9%), and for the risk stratification of known CAD in 340 patients (56.1%).
At the time of the study, 32% of patients were treated with β-adrenoceptor antagonists; 15% with calcium antagonists; 17% with ACE inhibitors; 9% with digitalis and 8% with diuretics. Medical treatment if present was discontinued three days before the test.
Follow-up data were obtained from September 2003 to March 2004 through review of patient's hospital records, by periodical follow-up visit in our institution, or by phone interview with the patient. In case of death data were collected by phone contact with the same household family member.
Exercise stress echo
In our study patients performed exercise stress echo by bicycle ergometer in supine position using a standard Bruce protocol. After recording a resting 2-dimensional echocardiogram, the heart rate was continuously monitored and 12-lead electrocardiogram, echocardiographic images and blood pressure were recorded at every step. Criteria for test interruption were: achievement of maximal heart rate, onset of new or worsening wall motion abnormalities, severe chest pain, horizontal or down-sloping ST-segment depression
2mm, ST-segment elevation1.5mm, systolic blood pressure>220mmHg, diastolic blood pressure>120mmHg, reduction in systolic blood pressure30mmHg, supraventricular or ventricular tachyarrhythmias.
Two-dimensional images were obtained in 4 standard views (parasternal long-axis, parasternal short-axis, apical 4- and 2-chamber view) using Acuson Sequoia ultrasound systems (Mountain View, California – USA) at baseline, at each exercise step and during recovery, and recorded using a quad-screen cine-loop system.
Echocardiographic analysis
All examinations were reviewed by 2 independent observers with extensive experience in interpretation of stress echocardiograms and blinded to the clinical data. Disagreements were resolved by consensus.
For left ventricular (LV) wall motion analysis, standard 16-segment model of the LV of the American Society of Echocardiography was used,16 and wall motion was scored as 1=normal; 2=hypokinetic; 3=akinetic; 4=dyskinetic. LV wall motion score index (WMSI) was calculated at baseline and at the peak effort dividing the sum of individual segments scores by the number of considered segments. LV ejection fraction was measured at baseline (bEF) and at peak effort (pEF) using a commercially available software program that applied Simpson's rule on the 2- and 4-chamber views.
In patients with normal rest wall motion, the test was considered positive for myocardial ischemia in case of development of a transient regional dyssinergy. In case of development of regional dyssinergy limited to a single segment, the test was considered positive only in case of adequate visualization of the same segment in at least two different views. On the other hand, in patients with rest wall motion abnormalities the development of new or worsening wall motion abnormality, including a deterioration of wall motion after improvement at low work load, was considered indicative of residual myocardial ischemia. Furthermore, rest akinesia becoming dyskinesia was not considered a positive result.16
Low work load was defined as an achievement of <7 metabolic equivalents (METS) for men and <5 METS for women, because the expected treadmill time for men is, on an average, 2–3min longer than that for women (Bruce protocol).11,12 The ECG was indicative of myocardial ischemia if a horizontal or downsloping ST depression >1mm, 80ms after J point, developed with stress. However, electrocardiographic changes and chest pain were not considered per se as a positive response to stress test in the absence of induced or worsening wall motion abnormalities.
Follow-up
The definition of cardiac-related death required documentation of significant arrhythmias or cardiac arrest, or both, or death attributable to congestive heart failure or myocardial infarction in absence of any other precipitating factors.
Non-fatal myocardial infarction was defined as cardiac event requiring admission to the hospital, with elevation of biochemical markers of myocardial necrosis (Troponin) and with at least one of the following: (a) ischemic symptoms; (b) development of pathologic Q waves on the ECG; (c) ECG changes indicative of ischemia (ST-segment elevation or depression); (d) coronary artery intervention (coronary angioplasty).17
Statistical analysis
Descriptive statistics procedure were used to analyse the distribution of each variable. Patients groups were compared by Student's t-test for continuous variables and by 
2 test for categorical variables. Independent predictors of late cardiac events (death, hard events) were identified through univariable and multivariable Cox proportional-hazard regression models. The 0.05 probability level was adopted to consider the significance of the association between predictive variables and events. The risk associated with a given variable was expressed by a hazard ratio (HR) with corresponding 95% confidence intervals. Receiver operating characteristic (ROC) curve analysis was performed to select optimal cut-off values for echocardiographic measurements.
Inter- and intra-observer variability for echocardiographic measurements was examined using Bland–Altman analysis. Ninety-five percent confidence limits of a single estimate of the measurements were calculated as 2xSD/
2, and reported as a percent from the mean value.
In the multivariable analysis, an interactive stepwise procedure was adopted, where variables were included into the model in the same order as in the clinical practice. Therefore, clinical data were first analysed, and the global chi-square was calculated. Then, a second step was created after the addition of rest and stress echocardiography results to the independent predictors at the first step. The incremental prognostic value of the added variables was assessed by comparison of the global chi-square at each step. A p value 
0.1 was taken as the required level of significance for entering a variable into the model.
The cumulative probability of freedom from cardiac events was calculated by Kaplan–Meier life-table analysis and compared between groups by use of the Log-rank test.
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Study population
The final study population included 607 patients. An extensive analysis of cardiac risk factors was performed in all the patients (Table 1).
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Rest and exercise echocardiography
During ESE test, 9 tests (1.4%) were prematurely stopped because of the appearance of limiting side effects: non-sustained ventricular tachycardia in 3, severe chest pain in absence of new wall motion abnormalities in 3, severe hypertension in 3. All side effects were reversed by administration of methoprolol.
At baseline, the mean value of WMSI was 1.22±0.36, and the mean ejection fraction was 58.2±10.9%. Wall motion abnormalities were present in 365 patients (60.1%). The ESE was positive for ischemia in 210 patients (34.9%), while the ECG was suggestive for ischemia in 157 patients (25.8%). During the test only 97 patients (15.9%) experienced angina. At peak effort, the mean WMSI was 1.38±0.56, and EF was 62.3±9.8%. Low work load was achieved by 158 patients (26.1%). A submaximal heart rate (<85% predicted for age) was achieved by 32 patients (5.2%).
Inter-observer agreement was 95% for assessment of LV WMSI and 92% for analysis of positive response for ischemia. Intra-observer reproducibility was 96% and 94%, respectively.
Cardiac events
During the follow-up period there were 222 events (36.5%), including 48 cardiac deaths (7.9%), 34 acute non-fatal myocardial infarctions (5.6%), 82 composite endpoints (death or myocardial infarction) (13.5%). The other cardiac events were: angina pectoris in 30 patients (5%), acute heart failure in 16 (2.6%), PTCA in 72 (11.8%), CABG in 20 (3.4%).
By univariable analysis, the following variables resulted significant determinants for cardiac death (in descending order): positive ESE for ischemia, peak WMSI, low work load, rest WMSI, cigarette smoking, β-blocker therapy and age (Table 2). At multivariable analysis, utilizing an interactive stepwise procedure, the combination of clinical, rest and stress test variables identified positive ESE for ischemia, peak WMSI, low work load, and cigarette smoking as strongest independent predictors of cardiac death. The global 2 of this combined clinical and stress test model was 37.9 (p<0.00001) (Table 3).
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As for composite endpoint (death or non-fatal myocardial infarction), by univariable analysis the following variables resulted significantly predictive: positive stress test, peak WMSI, angina during the test, rest WMSI, hypercholesterolemia, submaximal heart rate and cigarette smoking (Table 2). However, multivariable analysis identified positive ESE, peak WMSI, angina during the test and hypercholesterolemia as only independent determinants of both the cardiac events. The global
2 of this combined clinical and stress test model was 39.8 (p<0.00001) (Table 3) (Fig. 1).
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The cumulative 5-year mean survival time free of cardiac events in patients with negative stress echo was 56.8 months versus 45.2 months in patients with positive test. The cumulative 5-year mean survival rate according to ESE response was 95.9% in patients with negative ESE, and 81.7% in positive ESE (p<0.00001).
Subgroup analyses
We performed further subgroup analyses on the basis of resting LV wall motion abnormalities (WMA). In case of negative ESE, both the patients with normal rest wall motion (survival rate: 96.7%; mean survival time: 58.1 months) and the patients with fixed WMA (survival rate: 95.4%; mean survival time: 57.2 months) showed a comparable long-term survival. On the other hand, patients with positive ESE were at higher risk of cardiac death both in presence of normal resting wall motion (survival rate: 82.5%; mean survival time: 46.7 months) and of WMA at baseline (survival rate: 78.7%; mean survival time: 44.6 months) (Log-rank=23.6; p<0.00001) (Fig. 2).
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On the other hand, ROC curve analyses selected cut-off values of peak work load<7 METS (AUC: 0.79; p<0.0001) and of peak WMSI
1.7 (AUC: 0.81; p<0.0001) as powerful predictors of cardiac mortality, in accordance with the previous authors.11,12,18 In particular, patients who achieved an exercise capacity of <7 METS were at higher risk of cardiac death than patients with peak exercise 7 METS (survival rate: 82.3% versus 95.7%, respectively) (Log-rank=13.4; p<0.0001) (Fig. 3).
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Discussion |
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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. However, recent studies with ESE have indicated that the imaging component of this test adds incremental and independent information to the results of standard ECG testing.10–15
European experience with ESE is very limited, while in the United States such stress modality is more popular than pharmacologic stress echo. When performed by experienced operators, ESE is a low-cost, easy-repeatable diagnostic technique, with high safety and feasibility (in our study: 98.6%), and therefore well accepted by the patient. Its diagnostic accuracy exceeds that of the exercise ECG, and is similar to that reported with nuclear imaging techniques.10–15,18 In addition, recent reports performing cost-effectiveness analyses of alternative strategies to investigate patients with chest pain, reported how, for patients with intermediate risk of CAD, ESE represented the best cost-effective proposal.19,20
To the best of our knowledge, this study is the first to provide data regarding the long-term prognostic usefulness of supine bicycle ESE to stratify patients with known or suspected CAD into high- and low-risk subsets for cardiac events. In fact, most of the previous studies are based on post-treadmill stress echo results, an approach which relies on imaging within a short time after the stress, a period when ischemia is resolving.10–15 In comparison, supine bicycle ESE has the advantage of imaging at baseline, at each exercise step and during recovery, and therefore during the development of ischemia and at its peak. Furthermore, supine bicycle ESE can achieve the maximum cardiovascular performance with lower values of heart rate. As a result, according to the previous reports, supine bicycle ESE could detect even small, quickly reversible wall motion abnormalities, while post-treadmill testing could loose important information about the existence, extension, and location of CAD.21–23
Previous studies have suggested that the predictive value of an ESE negative test is very high, while the predictive value of a positive test ranges from 17% to 35%.10–14
Our study confirms that the absence of ESE-induced myocardial dyssinergy provides a good long-term prognosis in a population with proven or suspected CAD and relatively preserved LV systolic function. Conversely, an ischemic pattern (i.e. new or worsening wall motion abnormalities) at ESE predicts a 4-fold higher cardiac mortality rate over a 5-year follow-up. In fact, by interactive stepwise multivariable analysis, a positive ESE result for ischemia in our study appeared to be the strongest independent predictor of cardiac-related death and of composite endpoint (Fig. 2). Moreover, our results emphasize that information obtained by ESE are additional and independent to that provided by clinical and rest echocardiographic data (Fig. 1).
Of note, in our population, although typical or atypical chest pain was present in 86% of patients, ESE was positive for ischemia only in 35%. This is in accordance with a recent report by Elhendy A. et al., which showed that only 50% of patients with classic angina pectoris had abnormal ESE, and confirmed that patients with angina and normal ESE have a low event rate and therefore can be exempted from invasive procedures during the 3 years after ESE.15
Among other stress echo variables, also indexes of the extent and the severity of stress-induced myocardial ischemia (peak WMSI) and of exercise capacity (low work load) appeared to be the significant predictors of cardiac death (Fig. 3), while angina during the test resulted as powerful predictor when both cardiac events were considered. This fact may be the consequence of the different physiological mechanisms implicated in the determination of different cardiac endpoints. In fact, some parameters (i.e. angina during stress) seem to be related to the degree of a single coronary stenosis, whereas other variables (i.e. impaired exercise capacity, high peak WMSI) presume an impaired global LV function secondary to a multivessel CAD, which is more related to the risk of cardiac death.24
Our findings are in accordance with the conclusions of the previous studies on the long-term prognostic value of exercise testing. In fact, poor exercise capacity, usually consequence of a multivessel involvement of the atherosclerotic process, showed a greater effect on survival than ST depression during exercise, and several studies have shown that patients who can exercise into stage four of the Bruce protocol (>8 METS) have a favorable outcome.12,25–27
In addition, peak WMSI, an integrated expression of both the amount and of the severity of wall motion abnormalities, carried out in our study had a strong predictive value of the same cardiac events, as previously pointed out in patient undergoing ESE for known or suspected CAD or with recent uncomplicated myocardial infarction.18
Multiple studies have also emphasized the prognostic role of indexes of global systolic function (rest and peak LV EF)5,7,28–29 while in our population these parameters were not predictive of cardiac events. This was most likely due to the fact that most of the patients in our study group had normal left ventricular systolic function, no significant valvular disease and capability of exercising.
Our findings, therefore, confirmed the prognostic role of recognized clinical risk factors and stress echo variables on cardiac events, emphasizing the usefulness of additional features of an ESE stress test in depicting the cardiac risk profile better than the sole use of the ischemic response to the stress.
Although extensive outcome of literature surrounds the use of pharmacological stress echocardiography,2–9 patients who are unable to exercise may have a particularly high event rate, which may not be representative of patients submitted to exercise testing. In addition, the additional cost of pharmacological stress imaging techniques is more difficult to rationalize in patients who are able to exercise, because exercise capacity evaluation is an excellent parameters for assessing risk in patients with known or suspected CAD.19–20
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As currently performed, exercise echocardiography is interpreted subjectively. An unsatisfactory intra- and inter-observer variability in stress echo interpretation has been previously reported.30 However, our tests were interpreted in a single centre by experts who have a similar approach to test interpretation, reflecting previous collaborative teaching and training activities. Furthermore, our inter- and intra-observer variability was examined using Bland–Altman analysis.
The routine implementation of second harmonic imaging of modern ultrasound systems, with and without contrast enhancement, improved the ability to detect mild form of CAD. This fact would have further increased the negative prognostic power of the stress echo.31
There is a controversy whether PTCA and CABG have to be considered as cardiac events. In fact, although they reflect the presence of a severe cardiac disease, the decision to undergo these procedures may be subjective and not by itself an adverse outcome. As a consequence, we preferred to not include these events among the endpoints of our study.
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Conclusions |
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In patients with known or suspected CAD, able to perform a physical effort and with uninterpretable resting ECG, supine bicycle ESE is able to stratify risk of long-term cardiac events, avoiding any additional cost of pharmacological stress imaging techniques. In such patients, an exercise stress test is always desirable, as the echocardiographic analysis may be correlated to the patient's symptoms, useful ST-segment data may be obtained and exercise capacity is prognostically important.
Therefore, the final report of an ESE performed for prognostic purpose should include not only the assessment of induced dyssinergy but also the evaluation of both the extent of induced myocardial ischemia (peak WMSI) and of peak exercise capacity (METS achieved).
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Acknowledgement |
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The authors are grateful to Miss Gemma D'Andrea for excellent technical support in preparing the manuscript.
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References |
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