Author + information
- Received October 23, 2008
- Revision received January 6, 2009
- Accepted January 19, 2009
- Published online May 26, 2009.
- 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⁎,§
- ↵⁎Reprint requests and correspondence:
Dr. Alberto Bouzas-Mosquera, Department of Cardiology, Hospital Universitario A Coruña, As Xubias 84, 15006 A Coruña, Spain
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 (ΔWMSI) 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, ΔWMSI 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.
The American Heart Association/American College of Cardiology practice guidelines (1,2) recommend exercise electrocardiogram (ECG) testing as the preferred initial noninvasive test for the diagnosis and risk stratification of patients with suspected coronary artery disease (CAD) and interpretable resting ECG in the absence of treatment with digoxin.
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.
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).
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 (ΔWMSI) 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.
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 ttest or Mann-Whitney Utest 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).
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.
There were no major complications as a result of the tests. The Duke treadmill score was ≥5 (low risk) in 3,501 patients (87.4%). Overall, 715 patients (17.9%) had resting WMA and 669 (16.7%) developed ischemia with exercise; of them, 438 patients (10.9%) had extensive ischemia and 219 patients (5.5%) developed multivessel ischemia.
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.
During a mean follow-up of 4.5 ± 3.4 years, 313 deaths occurred. Five-year mortality rate was 6.4% in the group of patients without ischemia versus 12.1% in the group with ischemia (p < 0.001) (Fig. 1A).Overall, 380 patients underwent revascularization procedures during follow-up (percutaneous coronary intervention in 313 [7.8%] patients and coronary artery bypass grafting in 67 [1.7%] patients). A total of 183 patients experienced a MACE before any revascularization procedure, including 63 cardiac deaths and 120 nonfatal myocardial infarctions. Five-year MACE rate was 4.2% in the nonischemic group versus 10.1% in the ischemic group (p < 0.001) (Fig. 1B). Patients with extensive ischemia or multivessel ischemia were at greater risk of events (5-year mortality rate of 13.3% and 15.9%, and 5-year MACE rate of 12.1% and 16.2%, respectively).
The association of ischemia during EE with events remained significant in the subgroup of patients without a history of myocardial infarction (5-year mortality rate 12.9% in patients with ischemia vs. 6.1% in patients without ischemia, p < 0.001, and 5-year MACE rate 8.8% vs. 3.3%, p < 0.001), in those without a history of coronary revascularization (5-year mortality rate 12.5% vs. 6.3%, p < 0.001, and 5-year MACE rate 9.4% vs. 3.7%, p < 0.001), and in those without any history of CAD (5-year mortality rate 13.3% vs. 5.7%, p < 0.001, and 5-year MACE rate 7.8% vs. 2.7%, p < 0.001). Patients with a low-risk Duke score who developed ischemia on EE also had a greater 5-year mortality rate (9.5% vs. 4.5%, p < 0.001) and 5-year MACE rate (12.7% vs 2.7%, p < 0.001) as compared with patients without ischemia. Figure 2shows mortality and MACE curves stratified according to sex and diabetes.
The subgroup of patients without a history of CAD was further stratified according to their pre-test probability of CAD (low pre-test probability: n = 492 patients; intermediate pre-test probability: n = 1,873 patients; high pre-test probability: n = 486 patients). As shown in Figure 3,MACE rate was consistently and significantly greater in patients with ischemia as compared with those without ischemia in all subgroups according to their pre-test likelihood of CAD. The association of ischemia with mortality was highly significant in the subgroup of patients with intermediate pre-test probability of CAD (5-year mortality rate 13.4% in patients with ischemia vs. 6.1% in patients without ischemia, p < 0.001). Although there was a trend toward a greater mortality rate in the subgroups of patients with low and high pre-test probability of CAD who developed ischemia as compared with those who did not (5-year mortality rate 7.1% vs. 1.9% for patients with low pre-test probability of CAD and 11.8% vs. 6.1% for patients with high pre-test probability of CAD, respectively), these differences did not reach statistical significance.
On the other hand, patients with a history of CAD who developed ischemia had a nonsignificant trend toward greater mortality and MACE rates as compared with those without ischemia (5-year mortality rate 11.4% vs. 8.4% and 5-year MACE rate 11.7% vs. 8.8%, respectively, p > 0.05 for both comparisons).
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).
Predictors of outcome and incremental value of EE
Univariate associations with mortality and MACE are listed in Table 3.In multivariate analysis, resting WMSI and ΔWMSI remained independent predictors of both total mortality and MACE (Tables 4 and 5).⇓
The global chi-square of the clinical model for predicting all-cause mortality was 170 (p < 0.001); the addition of resting echocardiographic data (resting WMSI) increased the global chi-square to 231 (p < 0.001); the inclusion of hemodynamic variables during exercise added significantly to the model (chi-square test = 398, p < 0.001); the subsequent addition of the EE results (ΔWMSI) to the clinical, resting echocardiographic, and treadmill exercise data also provided incremental information for predicting mortality (chi-square test = 408, p = 0.005).
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).
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.
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.
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.
Part of this study was presented during the Young Investigators' Award Session at the European Society of Cardiology Congress 2008, Munich, Germany, September 2008.
- Abbreviations and Acronyms
- coronary artery disease
- exercise echocardiography
- major adverse cardiac event(s)
- wall motion abnormalities
- wall motion score index
- Received October 23, 2008.
- Revision received January 6, 2009.
- Accepted January 19, 2009.
- American College of Cardiology Foundation
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