Outcome by Exercise Echocardiography in Patients with Low Pretest Probability of Coronary Artery Disease


Recommendations for testing in patients with low pretest probability of coronary artery disease differ in guidelines from no testing at all to different tests. The aim of this study was to assess the value of exercise echocardiography (ExE) to define outcome in this population.


A retrospective analysis was conducted of 1,436 patients with low pretest probability of coronary artery disease (<15%) who underwent initial ExE. Overall mortality, major adverse cardiac events (MACEs), defined as cardiac death or nonfatal myocardial infarction, and revascularization during follow-up, were assessed. Ischemia (development of new wall motion abnormalities with exercise) and fixed wall motion abnormalities were measured.


The mean age was 50 ± 12 years. Resting wall motion abnormalities were seen in 13 patients (0.9%) and ischemia in 108 (7.5%). During follow-up, 38 patients died, 10 of cardiac death (annualized death rate, 0.39%); 20 patients had MACEs (annualized MACE rate, 0.21%); and 48 patients (29 with ischemia) underwent revascularization (annualized revascularization rate, 0.51%). The number and percentage of MACEs in the abnormal and normal ExE groups were similar (two [1.7%] vs 18 [1.4%], P = .70), as was the annualized MACE rate (0.31% vs 0.21%, P = .50). Peak left ventricular ejection fraction exhibited a nonsignificant trend for predicting MACEs ( P = .11). The number of studies needed to detect an abnormal finding was 12.6 and to detect a patient with extensive ischemia was 26.1.


ExE offers limited prognostic information in patients with low pretest probability of coronary artery disease. The small number of abnormal findings on ExE and low event rates and the large number of studies needed to detect an abnormal finding limit further the value of imaging in this population.

Although functional noninvasive imaging has the highest reach in patients with intermediate pretest probability of coronary artery disease (CAD), there remains an important number of patients with low pretest probability (LPP) of the disease and clinical symptoms. Recommendations for testing in these patients differ in current guidelines from no testing at all in those with probabilities <15% according to European Society of Cardiology guidelines or <10% according to National Institute for Health and Care Excellence guidelines to exercise electrocardiography, stress echocardiography, or computed tomography according to American guidelines. Also, stress echocardiography has been proposed in some guidelines for the assessment of chest pain with any pretest probability in case of wide availability and also for the assessment of atypical chest pain in women. Overall, although the small number of cardiac events when the pretest probability of CAD is low is well known, as well as the large number of false-positive results resulting from diagnostic testing in this population, clinicians may still choose imaging techniques to study these patients. This might be true particularly if the pretest probability is not taken into account before ordering the test, if the referring clinician is not aware of the limited performance of these tests in these patients, and if these techniques are widely available. We aimed to review our stress echocardiography database for patients with LPP of CAD to investigate if exercise echocardiography (ExE) has any value to define outcomes. We hypothesized that adverse event rates would be low for these patients and that higher event rates in those with abnormal results would be driven by revascularization, not by cardiac death or nonfatal myocardial infarction (MI).


Collected data from the University of A Coruña stress echocardiography laboratory data bank were retrospectively analyzed.


Data were obtained from 1,436 patients with LPP of CAD (<15%) who underwent initial treadmill ExE at our institution during a 20-year period from March 1995 to January 2015. Data were extracted from a database of 18,031 patients, with initial ExE performed in 14,906 patients. Patients with left ventricular (LV) dysfunction, defined as LV ejection fraction (LVEF) < 52% for men and < 54% for women, were excluded ( n = 155), as were patients with congenital heart disease ( n = 5), moderate or severe valvulopathies ( n = 49), and hypertrophic cardiomyopathy ( n = 281). The pretest probability of CAD was determined retrospectively by an investigator who was blinded to the results of ExE.

Demographic and clinical data, as well as stress testing results, were entered into our database at the time of the procedures. Data were taken from the original ExE reports of the patients. The pretest probability of CAD was assessed according to Genders et al . Clinicians referred these patients for ExE, instead of exercise ECG testing, because of the high availability of the former at our institution.

Whenever possible, β-blocker therapy was discontinued for ≥48 hours before testing. However, 6% of patients were still under the influence of β-blockers at the time of their tests.

Exercise Electrocardiography

Heart rate, blood pressure, and electrocardiography were obtained at baseline and at each stage of exercise. Patients were encouraged to perform a treadmill exercise test (Bruce protocol in 78.8%, Bruce protocol for fitness patients in 19%, modified Bruce protocol in 1.6%, Naughton protocol in 0.6%). Exercise end points included physical exhaustion, significant arrhythmia, severe hypertension (systolic blood pressure > 240 mm Hg or diastolic blood pressure > 110 mm Hg), severe hypotensive response (decrease > 20 mm Hg), and symptoms during exercise. Ischemic electrocardiographic (ECG) results were defined as the development of ST-segment deviation ≥ 1 mm that was horizontal or down-sloping away from the isoelectric line 80 ms after the J point in at least two leads, in patients with normal baseline ST segments. ECG results were considered nondiagnostic in the presence of left bundle branch block, preexcitation, paced rhythm, repolarization abnormalities, or treatment with digoxin. In patients with diagnostic ECG results, the Duke treadmill score (DTS) was calculated. Positive exercise test results were defined as chest pain during the test and/or ischemic ECG abnormalities in patients with diagnostic ECG results. A maximal test was defined as the achievement of ≥85% of the mean age-predicted heart rate; otherwise the test was considered submaximal. All patients gave informed consent.

Exercise Echocardiography and Echocardiographic Analysis

Echocardiography was performed in three apical views (long-axis, four-chamber, and two-chamber) and two parasternal views (long-axis and short-axis) at baseline, at peak exercise, and in the immediate postexercise period. Peak exercise imaging on the treadmill has been previously described by our group. It is performed with the patient still exercising, when signs of exhaustion are present or an end point is achieved. If the patient is running, he or she is asked to walk fast instead of running during acquisition. In addition, it may be necessary to keep steady the velocity of the treadmill. The transducer is firmly positioned on the apical and then parasternal area by applying pressure to the patient’s back with the left hand, maintaining the patient between the transducer and the left hand, in order to diminish body and respiratory movements. A continuous imaging acquisition system is used. We have demonstrated higher heart rates during acquisition with peak than with postexercise imaging, and also higher sensitivity and prognostic value.

Regional wall motion abnormalities (WMAs) were evaluated with a 16-segment model of the left ventricle. Each segment was graded on a four-point scale: normal wall motion = 1, hypokinetic = 2, akinetic = 3, dyskinetic = 4, and nonvisualized = 0. However, isolated hypokinesia of the basal inferior or inferoseptal segments was not considered abnormal. Wall motion score index (WMSI) and visually estimated LVEF were calculated at rest, peak exercise, and postexercise.

WMSI was calculated as the sum of scores divided by the number of visualized segments. The worst WMSI and LVEF obtained on peak exercise or postexercise imaging were considered definitive values. The change in WMSI from rest to exercise was calculated. Ischemia was defined as the development of new or worsening WMA with exercise and a fixed WMA as a WMA that remained the same with exercise. Extensive ischemia was defined as new or worsening WMA involving three or more segments in the same or different coronary artery distribution territories. Abnormal results on ExE were defined as ischemia or fixed WMAs.

Follow-up and End Points

Follow-up in the entire study cohort of 1,436 patients was obtained by review of hospital databases, medical records, and death certificates, as well as by telephone interviews when necessary. We had complete access to the electronic health care system of our community and also electronic access to general practitioner consults. In case of death outside a hospital, the cause of death was provided by the mortality registry of our community. No patients were lost during follow-up.

Considered end points were overall mortality and major adverse cardiac events (MACEs). MACEs were considered in case of cardiac death or nonfatal MI. MI was defined as the appearance of new symptoms of myocardial ischemia or ischemic ECG changes accompanied by increases in markers of myocardial necrosis. Cardiac death was defined as death due to acute MI, congestive heart failure, life-threatening arrhythmias, or cardiac arrest. Unexpected sudden death without an identified cardiac cause was also considered cardiac death. Revascularization procedures during follow-up were identified, although they were not considered events, as the results of ExE might have influenced patient management. Coronary angiograms during follow-up were collected. Significant CAD was considered by the catheterization laboratory team in case of luminal narrowing in a main coronary artery or major branch of ≥70% or by visual assessment or ≥50% of the left main coronary artery. Posttest risk by exercise ECG testing was defined as low in case of negative clinical and ECG findings, intermediate in case of either clinical or ECG positivity, and high in case of both clinical and ECG positivity. In patients with diagnostic ECG results, the DTS risk categories (low, intermediate, and high) were also used to assess outcomes. Posttest risk by ExE was defined as low in case of normal findings, intermediate in case of mild ischemia, and high in case of extensive ischemia, fixed WMAs, or combined ischemia and resting WMAs.

Statistical Analysis

Categorical variables are reported as percentages, and comparisons between groups were based on χ 2 tests. Continuous variables are reported as mean ± SD, and intergroup differences were assessed using unpaired Student’s t tests or Mann-Whitney U tests, as appropriate. P values < .05 were considered to indicate statistical significance.

Patients were censored at the time of coronary revascularization procedures for the analysis of MACEs but not for the analysis of overall mortality. Annualized event rates were calculated by dividing the number of events by the total number of person-years at risk. Survival free of the end point of interest was estimated by the Kaplan-Meier method, and survival curves were compared using the log-rank test.

Univariate and multivariate associations of the different variables with outcomes were assessed with the Cox proportional hazards model. Variables were selected in a stepwise forward selection manner, with entry and retention set at P = .05. Hazard ratios with 95% CIs were estimated.

The incremental value of exercise echocardiographic results over clinical, resting echocardiographic, and exercise treadmill testing variables was assessed in steps. The first step was based on clinical data. Resting echocardiographic data and exercise ECG data were then added in the following step. The third step consisted of echocardiographic data obtained during exercise. A statistically significant increase in the global χ 2 defined incremental prognostic value. Statistical analysis was performed using SPSS version 15.0 (SPSS, Chicago, IL).


Clinical Baseline Characteristics and Test Results

The clinical baseline characteristics of the overall group and of patients classified as having normal or abnormal results on ExE are shown in Table 1 . Table 2 shows the exercise ECG results, and Table 3 shows the results of ExE. As expected, patients with positive results were older and had a higher prevalence of coronary risk factors and abnormal resting ECG findings. Exercise ECG and echocardiographic testing also showed more abnormalities in these patients, particularly clinical or ECG positivity and decrease in LVEF with exercise.

Table 1

Clinical baseline characteristics in the overall group and in patients with and without abnormal results on ExE

Variable All ( n = 1,436) Normal results on ExE ( n = 1,322) Abnormal results on ExE ( n = 114) P
Female 1,307 (91) 1,196 (90.4) 111 (97.4) .01
Age (y) 50 ± 12 49 ± 12 53 ± 9 <.001
Current smokers 255 (17.8) 234 (17.7) 21 (18.4) .90
Diabetes 155 (10.8) 136 (10.3) 19 (16.7) .04
Hypertension 576 (40.1) 517 (39.1) 59 (51.8) .008
Hypercholesterolemia 531 (37) 473 (35.8) 58 (50.9) .001
Atypical/probable angina 184 (12.8) 157 (11.9) 27 (23.7) <.001
Nonanginal chest pain 873 (60.8) 826 (62.5) 47 (41.2) <.001
Dyspnea 136 (9.5) 127 (9.6) 9 (7.9) .60
Atrial fibrillation 16 (1.1) 14 (1.1) 2 (1.8) .40
Abnormal resting ECG results 200 (13.9) 175 (13.2) 25 (21.9) .01
β-blocker use the day of ExE 60 (4.2) 51 (3.9) 9 (7.9) .04
Nitrates 97 (6.8) 89 (6.7) 8 (7) .90
Calcium channel blockers 71 (4.9) 68 (5.1) 3 (2.6) .40
ACE inhibitors/ARAs 279 (19) 255 (19.3) 24 (21) .60
Digoxin 9 (0.6) 7 (0.5) 2 (1.7) .10
Diuretics 48 (3.3) 41 (3.1) 7 (6.1) .08

ACE , Angiotensin-converting enzyme; ARA , angiotensin receptor antagonist.

Data are expressed as number (percentage) or as mean ± SD.

Table 2

Exercise testing variables in the overall group and in patients with and without abnormal results on ExE

Variable All ( n = 1,436) Normal results on ExE ( n = 1,322) Abnormal results on ExE ( n = 114) P
Systolic blood pressure (mm Hg)
Rest 128 ± 19 127 ± 19 132 ± 18 .01
Peak 163 ± 29 163 ± 29 164 ± 29 .7
Heart rate (beats/min)
Rest 83 ± 15 83 ± 15 82 ± 14 .7
Peak 161 ± 18 161 ± 18 154 ± 19 .001
Rate-pressure product (1,000 mm Hg × beats/min)
Rest 10.6 ± 2.5 10.5 ± 2.5 11.0 ± 2.5 .2
Peak 26.2 ± 5.5 26.3 ± 5.4 25.4 ± 5.8 .1
Achieved workload (METs) 10.3 ± 3.3 10.4 ± 3.4 8.9 ± 2.6 <.001
% achieved of MAPHR 94 ± 9 94 ± 9 92 ± 11 .08
Angina during the test 113 (7.9) 83 (6.3) 30 (26) <.001
Positive ECG results 113 (7.9) 82 (6.2) 31 (27) <.001
Positive exercise testing 199 (13.9) 152 (11.5) 47 (41) <.001

MAPHR , Mean age-predicted heart rate; METs , metabolic equivalents.

Data are expressed as mean ± SD or as number (percentage).

Defined as clinical or ECG positivity, regardless of echocardiographic results.

Table 3

Results of ExE in the overall group and in patients with and without abnormal results on ExE

Variable All ( n = 1,436) Normal results on ExE ( n = 1,322) Abnormal results on ExE ( n = 114) P
Rest 1.00 ± 0.02 1.00 1.02 ± 0.05 <.001
Peak 1.03 ± 0.12 1.00 1.32 ± 0.28 <.001
LVEF (%)
Rest 62 ± 4 62 ± 4 60 ± 3 <.001
Peak exercise 70 ± 6 70 ± 5 60 ± 9 <.001
Change in LVEF 8 ± 5 9 ± 3 −1 ± 8 <.001

Data are expressed as mean ± SD.

Of the 1,436 patients, 114 patients had abnormal results on ExE (7.9%). The results on ExE were categorized as ischemia in 101 patients, fixed WMAs in six, and mixed ischemia and resting WMAs in seven. Among the ischemic patients, extensive ischemia was seen in 55 (51%). Of the 13 patients with resting WMAs, these WMAs were observed in the left anterior descending coronary artery distribution territory in two and in the right coronary artery and left circumflex coronary artery distribution territories in 11. The involved territories in the 114 patients with abnormal results on ExE were the right coronary artery and left circumflex coronary artery distribution territories in 21 patients (27%), the left anterior descending coronary artery distribution territory in 62 patients (54%) (in these cases, WMAs were restricted to two segments in 38 subjects), and three coronary artery distribution territories in 31 patients (27%).

Relationship between Exercise ECG Testing and ExE

Abnormal results on ExE were more frequent among the 199 patients who had clinical symptoms and/or any exercise ECG abnormalities (47 of 199 [24%]) than in those without. These abnormal exercise echocardiographic findings were detected in 14 of 27 patients with clinical symptoms plus exercise ECG abnormalities (52%), in 33 of 172 patients with either clinical symptoms or exercise ECG abnormalities (19%), and in 67 of 1,237 patients with completely normal results on exercise ECG testing (5.4%). Among subjects with diagnostic electrocardiograms, DTS risk was low in 1,014 (82%), intermediate in 221 (17.9%), and high in one (0.1%). Again, the results of ExE were more frequently abnormal in patients with intermediate- or high-risk DTS than in those with low-risk DTS (20% vs 4%, P < .001).

Angiography during Follow-up

A total of 165 patients (11.5%) underwent coronary angiography during follow-up; in 114 of these 165 patients (69%), angiographic findings were either normal or demonstrated nonsignificant lesions. Among the 114 patients with abnormal results on ExE, 76 underwent angiography (67%) and 29 had significant lesions (38%), whereas among the 1,322 patients with normal results on ExE, 89 were referred to angiography (7%) and significant lesions were found in 22 (25%). The frequency of true-positive results was higher among patients with extensive ischemia. Of 55 patients with extensive ischemia, 47 underwent coronary angiography (85.5%), which detected significant CAD in 24 (51%). The majority of patients with positive angiographic results underwent revascularization (48 of 51 [94%]).


During a mean follow-up period of 6.7 ± 5.2 years, 38 patients died (cardiac death in 10), and 20 patients had MACEs, including 12 patients with MIs. A total of 48 patients (29 with ischemia on ExE) underwent revascularization. Table 4 shows the annualized revascularization, MI, MACE, and overall mortality rates. Figure 1 depicts the Kaplan-Meier curves for overall mortality and MACEs in patients with and without ischemia and in patients with and without an abnormal results on ExE, and Figure 2 shows the Kaplan-Meier curves for MI and revascularization. Tables 5 and 6 show the univariate and multivariate predictors of MACEs and overall mortality, respectively. Clinical or ECG positivity during the test was not predictive of MACEs or overall mortality. The DTS was a univariate predictor of mortality, although it was not of MACEs. Exercise echocardiographic variables were not independent predictors of MACEs or overall mortality, although there was a nonsignificant trend for peak LVEF for predicting MACEs ( P = .11). Among the 12 patients with MIs, only one had abnormal results on ExE (8%), whereas among the 1,424 patients without MIs, abnormal results on ExE were found in 113 (8%) ( P = 1.00). Among the 20 patients with MACEs, only two had abnormal results on ExE (17%), which was again similar to the percentage of patients with abnormal results on ExE who did not have MACEs during follow-up (8%) ( P = .70). Finally, among the 38 patients who died, eight had abnormal results on ExE (21%), whereas among living patients, 106 had abnormal findings on ExE (7.6%) ( P = .002). The positive predictive values of abnormal results on ExE for MACEs and for overall mortality were as low at 1.8% and 7%, respectively; those for ischemia were 1.8% and 6.5%. In contrast, the negative predictive values of abnormal results on ExE for MACEs and for overall mortality were 92.1% and 92.5%. The negative predictive values of ischemia were similar (92.4% for MACEs and 92.8% for overall mortality). The number of studies needed to detect an abnormal finding was 12.6, to detect ischemia 13.9, and to detect extensive ischemia 26.1.

Table 4

Annualized revascularization, mortality rates, and MACEs in the overall group and in patients with and without abnormal results on ExE

Variable All ( n = 1,436) Normal results on ExE ( n = 1,322) Abnormal results on ExE ( n = 114) P
Annualized revascularization rate (%) 0.51 0.22 4.54 <.001
Annualized mortality rate (%) 0.39 0.34 0.98 .005
Annualized MI rate (%) 0.13 0.13 0.16 .81
Annualized MACE rate (%) 0.21 0.21 0.31 .54

Figure 1

Kaplan-Meier curves for MACEs (top) and for overall mortality (bottom) in patients with and without ischemia (left) and in patients with and without positive findings on ExE (right) .

Figure 2

Kaplan-Meier curves for MI (left) and for revascularization (right) in patients with and without positive findings on ExE.

Table 5

Univariate and multivariate predictors of MACEs

Variable Univariate Multivariate
HR 95% CI P HR 95% CI P
Clinical variables
Nonanginal chest pain 0.40 0.16–1.00 .049 0.37 0.15–0.94 .04
Nitrites 4.37 1.67–11.41 .003 3.83 1.45–10.11 .007
Exercise ECG testing
Achieved workload (METs) 0.82 0.72–0.97 .02 0.85 0.73–0.99 .035
Peak ExE
Peak LVEF 0.94 0.88–0.99 .03 0.95 0.88–1.01 .12
Change in LVEF 0.93 0.87–1.00 .05

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Apr 17, 2018 | Posted by in CARDIOLOGY | Comments Off on Outcome by Exercise Echocardiography in Patients with Low Pretest Probability of Coronary Artery Disease

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