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CLINICAL RESEARCH: CARDIAC IMAGING

Prediction of Mortality and Major Cardiac Events by Exercise Echocardiography in Patients With Normal Exercise Electrocardiographic Testing

Alberto Bouzas-Mosquera, MD^_*,_*, Jesús Peteiro, MD, PhD^_*, Nemesio Álvarez-García, MD^_*, Francisco J. Broullón, MS, Victor X. Mosquera, MD, Lourdes García-Bueno, MD^_*, Luis Ferro, MD^_* and Alfonso Castro-Beiras, MD, PhD^_*,

^_* Department of Cardiology, Hospital Universitario A Coruña, A Coruña, Spain
Department of Health Information Technology, Hospital Universitario A Coruña, A Coruña, Spain
Department of Cardiac Surgery, Hospital Universitario A Coruña, A Coruña, Spain
Red Temática de Investigación Cardiovascular (RECAVA)-Instituto de Salud Carlos III, Madrid, Spain

Manuscript received October 23, 2008; revised manuscript received January 6, 2009, accepted January 19, 2009.

^_* Reprint requests and correspondence: Dr. Alberto Bouzas-Mosquera, Department of Cardiology, Hospital Universitario A Coruña, As Xubias 84, 15006 A Coruña, Spain (Email: aboumos{at}canalejo.org).

Part of this study was presented during the Young Investigators' Award Session at the European Society of Cardiology Congress 2008, Munich, Germany, September 2008.

	Abstract

Top Abstract Methods Results Discussion Conclusions References

 
Objectives: We sought to assess the value of exercise echocardiography (EE) for predicting outcome in patients with known or suspected coronary artery disease and normal exercise electrocardiogram (ECG) testing.

Background: The prognostic value of EE in patients with normal exercise ECG testing has not been characterized.

Methods: We studied 4,004 consecutive patients (2,358 men, mean age [± SD] 59.6 ± 12.5 years) with interpretable ECG who underwent treadmill EE and did not develop chest pain or ischemic ECG abnormalities during the tests. Wall motion score index (WMSI) was evaluated at rest and with exercise, and the difference (WMSI) was calculated. Ischemia was defined as the development of new or worsening wall motion abnormalities with exercise. End points were all-cause mortality and major cardiac events (MACE).

Results: Overall, 669 patients (16.7%) developed ischemia with exercise. During a mean follow-up of 4.5 ± 3.4 years, 313 patients died, and 183 patients had a MACE before any revascularization procedure. The 5-year mortality and MACE rates were 6.4% and 4.2% in patients without ischemia versus 12.1% and 10.1% in those with ischemia, respectively (p < 0.001). In the multivariate analysis, WMSI remained an independent predictor of mortality (hazard ratio [HR]: 2.73, 95% confidence interval [CI]: 1.40 to 5.32, p = 0.003) and MACE (HR: 3.59, 95% CI: 1.42 to 9.07, p = 0.007). The addition of the EE results to the clinical, resting echocardiographic and exercise hemodynamic data significantly increased the global chi-square of the models for the prediction of mortality (p = 0.005) and MACE (p = 0.009).

Conclusions: The use of EE provides significant prognostic information for predicting mortality and MACE in patients with interpretable ECG and normal exercise ECG testing.

Key Words: exercise test • stress echocardiography • prognosis

Abbreviations and Acronyms   CAD = coronary artery disease   ECG = electrocardiogram   EE = exercise echocardiography   MACE = major adverse cardiac event(s)   WMA = wall motion abnormalities   WMSI = wall motion score index

Exercise echocardiography (EE) is another established technique for the diagnosis and risk stratification of patients with known or suspected CAD (3–10). It is well known that exercise-induced wall motion abnormalities (WMA) appear earlier in the ischemic cascade than angina or ST-segment changes, which are the end points of treadmill exercise ECG testing. On the other hand, EE may provide comparable information with nuclear imaging techniques at a significantly lower cost (11).

Patients with suspected CAD who do not develop chest pain or ischemic ECG abnormalities during exercise ECG testing may be deemed to be at low risk of cardiac events, but the lower sensitivity of this test for the detection of obstructive CAD may potentially translate into failure to identify some patients at risk. However, the prognostic value of EE in patients with normal exercise ECG testing has not been specifically evaluated. Thus, the purpose of this study was to assess the value of EE for predicting long-term mortality and cardiac events in patients with interpretable ECG and normal exercise ECG testing.

	Methods

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Patients.   Between March 1, 1995, and December 31, 2007, 5,740 patients with known or suspected CAD and interpretable resting ECG underwent EE at our institution. Of them, 1,736 patients (30.2%) developed chest pain and/or ischemic ECG abnormalities during the tests and were excluded; thus, 4,004 patients without any clinical or electrocardiographic evidence of myocardial ischemia during the tests were finally included in the study. All patients gave informed consent before testing, and the study was approved by the local research ethics committee.

Demographic and clinical data, as well as stress testing results, were entered in our prospective database at the time of the procedures. Patients referred for evaluation of chest pain were classified as having typical angina, probable angina, or nonischemic chest pain as previously described (12). A history of CAD was defined as previous myocardial infarction, previous coronary revascularization, or previous angiographic documentation of any significant (50%) coronary stenosis. In the subgroup of patients without a history of CAD, the pre-test probability of CAD was assessed according to a previously validated score (13). The resting ECG was considered interpretable in the absence of left bundle branch block, pre-excitation, paced rhythm, left ventricular hypertrophy, repolarization abnormalities, or treatment with digoxin.

Whenever possible, beta-blocker therapy was discontinued at least 48 h before testing. However, 5.9% of the patients were under the influence of beta-blocker drugs at the time of their tests.

Exercise treadmill testing.   Heart rate, blood pressure, and a 12-lead ECG were obtained at baseline and at each stage of the exercise protocol. Patients were encouraged to perform a treadmill exercise test (Bruce protocol 86.5%, modified Bruce 4.4%, modified Bruce for sportive people 7.9%, Naughton 1.2%) until they reached an end point. Exercise end points included physical exhaustion, significant arrhythmia, severe hypertension (systolic blood pressure >240 mm Hg or diastolic blood pressure >110 mm Hg), or severe hypotensive response (decrease >20 mm Hg in systolic blood pressure from baseline). Ischemic ECG abnormalities during the test were defined as the development of ST-segment deviation of 1 mm 80 ms after the J point; as indicated previously, these patients were excluded from the study. The Duke treadmill score was calculated as previously described (14,15).

EE.   Echocardiographic imaging was performed from the apical long-axis, apical 4- and 2-chamber, and parasternal long- and short-axis views, at rest, at peak exercise (16,17), and immediately after exercise. Peak imaging was performed with the patient still exercising, when signs of exhaustion were present or an end point was achieved. The patient was asked to walk quickly rather than run, to decrease body and respiratory movements. The transducer was firmly positioned on the apical and parasternal area by applying slight pressure to the patient's back with the left hand, so maintaining the patient between the transducer and the left hand, to avoid movement. Peak and post-exercise images were obtained with continuous imaging capture. Image acquisition was performed online and stored on an optical disk. The images corresponding to each view having the best quality at peak and post-exercise were chosen for comparison with rest images.

Echocardiographic analysis was performed on a digital quad-screen display system. Regional wall motion was evaluated with a 16-segment model of the left ventricle (18). Each segment was graded on a 4-point scale, with normal wall motion scoring = 1, hypokinetic = 2, akinetic = 3, and dyskinetic = 4. Wall motion score index (WMSI) was calculated at rest and at peak exercise as the sum of the scores divided by the number of segments. The change in WMSI from rest to peak exercise (WMSI) also was calculated.

Ischemia was defined as the development of new or worsening WMA with exercise, except worsening from akinesia to dyskinesia, which was not considered an ischemic response, and isolated hypokinesia of the inferobasal segment, which was not considered abnormal (19). Extensive ischemia was defined as the development of new or worsening WMA involving at least 3 myocardial segments. Multivessel ischemia was defined as ischemia involving at least 2 different coronary territories.

Patients with poor imaging quality were not excluded, and contrast was exceptionally administered (n = 7). The percentage of patients in whom 15 segments could be assessed was 3% at rest and 5.1% during and/or immediately after exercise. The feasibility and accuracy of peak versus immediate post-exercise imaging during treadmill EE have been reported previously (16,17).

Follow-up and end points.   Follow-up was obtained by review of hospital databases, medical records, and death certificates, as well as by telephone interviews when necessary. End points were all-cause mortality and major adverse cardiac events (MACE) (i.e., cardiac death and nonfatal myocardial infarction). Cardiac death was defined as death due to acute myocardial infarction, congestive heart failure, life-threatening arrhythmias, or cardiac arrest; unexpected, otherwise-unexplained sudden death also was considered cardiac death. Myocardial infarction was defined as the appearance of new symptoms of myocardial ischemia or ischemic ECG changes accompanied by increases in markers of myocardial necrosis. Revascularization procedures during follow-up were collected although they were not considered events as EE results may influence patients' management.

Statistical analysis.   Categorical variables were reported as percentages and comparison between groups based on the chi-square test. Continuous variables were reported as mean ± SD, and differences were assessed with the unpaired t test or Mann-Whitney U test as appropriate.

Cumulative event curves were estimated by the Kaplan-Meier method and compared by the log-rank test. Patients were censored at the time of a coronary revascularization procedure or noncardiac death for the MACE analysis, but not for the mortality analysis (20).

Univariable and multivariable associations of clinical, exercise, and EE variables with the end points were assessed with Cox's proportional hazards models. Variables were selected in a stepwise forward selection manner, with entry and retention set at a significance level of 0.05. Hazard ratios with 95% confidence intervals were estimated.

The incremental value of EE results over clinical, resting echocardiographic, and exercise treadmill testing variables was assessed in 4 modeling steps in the same order as in clinical practice. The first step was based on clinical data. Resting echocardiographic data were then added in the following step. The third step consisted of hemodynamic data obtained during exercise. In the final step the EE data were added. The chi-square value of each model and the incremental value of adding the different variables were estimated. A statistically significant increase in the global chi-square of the model defined incremental prognostic value (21). Statistical analyses were performed with the use of SPSS software (version 15.0, SPSS, Chicago, Illinois).

	Results

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Baseline and EE.   Mean age was 59.6 ± 12.5 years, and 2,358 patients (58.9%) were men. Clinical and demographic characteristics of the 4,004 patients are summarized in Table 1.

Patients with ischemia were older, were more likely to be male or to have a history of myocardial infarction or coronary revascularization, and presented more frequently with typical chest pain (Table 1); these patients also had lower workload and lower peak rate-pressure product than patients without ischemia (Table 2). The majority of patients had no previous history of CAD (n = 2,851, 71.2%). In this subgroup, 142 patients (5.0%) had resting WMA and 293 patients (10.3%) developed ischemia with exercise.

View larger version (10K): [in this window] [in a new window] [Download PPT slide]   Figure 1 Outcome of Patients According to Exercise Echocardiography Results (A) All-cause mortality and (B) major cardiac event curves in patients with versus without ischemia on exercise echocardiography.

View larger version (38K): [in this window] [in a new window] [Download PPT slide]   Figure 2 Outcome of Patients Stratified by Sex and Diabetes (A) Mortality and (B) major cardiac event curves in patients with versus without ischemia on exercise echocardiography stratified according to sex and diabetes.

View larger version (20K): [in this window] [in a new window] [Download PPT slide]   Figure 3 Major Cardiac Event Curves Stratified by the Pre-Test Likelihood of CAD Major cardiac event curves in patients without a history of coronary artery disease (CAD) stratified according to the pre-test probability of CAD and the development of ischemia on exercise echocardiography.

The presence of WMA at rest was also associated with a significantly worse outcome (Fig. 4). Patients with both resting WMA and ischemia had a greater 5-year mortality rate (16.3%) and 5-year MACE rate (13.2%). On the contrary, patients with neither resting WMA nor ischemia were at lower risk of events (5-year mortality rate 5.9% and 5-year MACE rate 3.2%). In the subgroup of patients without a history of CAD, the presence of resting WMA also identified a subset of patients with worse outcome (5-year mortality rate 19.5% vs. 5.7%, p < 0.001, and 5-year MACE rate 12.7% vs. 2.7%, p < 0.001).

View larger version (13K): [in this window] [in a new window] [Download PPT slide]   Figure 4 Outcome of Patients According to the Presence of Resting or Exercise Wall Motion Abnormalities (A) Mortality and (B) major cardiac event curves stratified according to the presence or absence of resting wall motion abnormalities (RWMA) and/or ischemia.

The global chi-square of the clinical model for predicting MACE was 83 (p < 0.001); after adding the resting WMSI, the global chi-square increased to 128 (p < 0.001); treadmill exercise data also added significantly to the model (chi-square test = 150, p < 0.001); finally, the addition of the EE results increased the global chi-square to 161 (p = 0.009).

	Discussion

Top Abstract Methods Results Discussion Conclusions References

 
To the best of our knowledge, the present study is the first to assess the prognostic implications of EE in a large cohort of patients with interpretable ECG and normal exercise ECG testing. This study shows that a significant proportion of patients with known or suspected CAD and normal exercise ECG testing develop new or worsening WMA during exercise, and these data provide significant prognostic information for the prediction of mortality and cardiac events in these patients.

Our results reflect the limitations of the negative predictive value of exercise ECG testing as compared with EE. In our study, 1 of 6 patients without chest pain or ischemic ECG abnormalities during the stress test developed new or worsening WMA. Furthermore, 2 of 3 patients with ischemia had extensive ischemia, and 1 of 3 had multivessel involvement.

The superior diagnostic accuracy of EE translates into better risk stratification. Although patients who do not develop chest pain or ischemic ECG abnormalities during exercise treadmill testing have an overall low risk of events, with the use of EE, we are able to identify a subset of patients at greater risk. In fact, the annualized mortality and MACE rates were >2% in the subgroup of patients with ischemia detected by EE; moreover, the mortality rate was almost twice as high as in the subgroup without ischemia, and the MACE rate was 2.4 times higher. On the contrary, a normal EE portends a good prognosis. The annualized rate of major cardiac events was 0.84% in patients without ischemia, and 0.64% in those with normal EE as defined by the American Society of Echocardiography (3) (i.e., normal left ventricular wall motion at rest and with exercise). These results are similar to those reported in a recent meta-analysis (22).

The prognostic value of EE has been previously well established (4–10). In particular, the value of ischemia on EE for predicting long-term mortality was evaluated by Marwick et al. (5) in a large cohort of patients with known or suspected CAD. These authors found that ischemia added incremental value to the results of exercise ECG testing for the prediction of death, and the greatest benefit of EE was found in the subgroup of patients with intermediate risk by the Duke score. Notably, although most patients in our study were at low risk according to the Duke score, ischemia was still strongly associated with worse outcome. Furthermore, the greatest differences in mortality and MACE rates in our study were found in the subgroup of patients without a history of CAD, which represents more than 70% of the population. The value of treadmill EE over the Duke score for the prediction of cardiac events in patients with interpretable ECG was also reported in a previous study by our group (10). However, patients who did not develop chest pain or ischemic ECG abnormalities during their tests were not specifically evaluated.

Current American Heart Association/American College of Cardiology practice guidelines (1,2,23) recommend exercise ECG testing as the preferred initial noninvasive test for the diagnosis and risk stratification of patients with normal resting ECG and suspected CAD in the absence of treatment with digoxin. The main argument against the routine performance of stress imaging procedures in patients with interpretable ECG is a higher cost and lower yield of such strategy (24,25). However, EE has lower cost than other noninvasive imaging techniques, and it is not clear whether the lower initial cost of exercise ECG testing translates into a lower overall cost of patient care. In this respect, some authors (26–28) have suggested that EE is a cost-effective technique, especially in populations in which exercise ECG testing has a high rate of false-positive results (3); in these patients, the greater specificity of EE may avoid the use of additional unnecessary diagnostic procedures. In addition, the prognostic implications of the greater negative predictive value of EE are also to be taken into account. Although we did not evaluate the cost-effectiveness of a strategy based on EE in the population included in our study, patients with abnormal results on EE might be misdiagnosed or stratified incorrectly on the basis of exercise ECG testing results, which might potentially preclude an appropriate management. Furthermore, the European Society of Cardiology (29) recommends the use of exercise stress with imaging techniques as an alternative to exercise ECG where facilities, costs, and personnel resources allow (Class IIa, Level of Evidence: B). However, it should be recognized that the relative yield of noninvasive imaging techniques in terms of avoiding false-negative results may be questionable in patients with low pre-test probability of CAD (30), in whom exercise ECG testing may maintain an acceptably high negative predictive value.

Study limitations.   First, this was an observational study and, hence, unmeasured confounding may account for at least part of the observed differences in outcomes. Given that the results of the tests were available to treating physicians, patients with ischemic results on EE may have been more likely to receive medical therapy and to undergo coronary revascularization procedures; thus, the actual prognostic value of EE may have been significantly underestimated, particularly in patients with extensive ischemia. In addition, the medication change after testing and its effect on outcome could not be assessed. On the other hand, the ascertainment of the cause of death may be susceptible to bias and misclassification (31). Finally, we routinely perform imaging acquisition during peak exercise in addition to post-exercise imaging because it has shown higher sensitivity (16,17); therefore, our results could have been different if we had used post-exercise imaging alone.

	Conclusions

Top Abstract Methods Results Discussion Conclusions References

 
A not-inconsiderable proportion of patients with suspected CAD and normal resting ECG, who do not have chest pain or ischemic ECG changes during treadmill stress testing, develop new or worsening WMA with exercise, and these data provide significant prognostic information for the prediction of mortality and major cardiac events. Patients with abnormal results on EE, who might be misdiagnosed or stratified incorrectly on the basis of exercise ECG testing results alone, might benefit from appropriate management.

	References

Top Abstract Methods Results Discussion Conclusions References

 
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