Background
Stress echocardiography is an established technique for diagnosis, risk stratification, and prognosis in patients with known or suspected coronary artery disease. The ability of stress echocardiography to predict clinical outcomes, such as coronary angiography and revascularization, has not been reported previously. The purpose of this study was to evaluate the clinical outcomes of coronary angiography, revascularization, and cardiac events in patients undergoing stress echocardiography.
Methods
A total of 3121 patients (mean age, 60 ± 13 years; 48% men) undergoing stress echocardiography (41% treadmill, 59% dobutamine) were assessed. Follow-up (mean, 2.8 ± 1.1 years) for subsequent coronary angiography, revascularization (percutaneous coronary intervention [PCI] or coronary artery bypass grafting [CABG]), and confirmed hard events (nonfatal myocardial infarction or cardiac death) was obtained.
Results
Stress echocardiographic results were normal (peak wall motion score index [pWMSI], 1.0) in 66% and abnormal (pWMSI > 1.0) in 34% of patients. The pWMSI effectively risk-stratified patients into low-risk (pWMSI, 1.0; 0.8% per year), intermediate-risk (pWMSI, 1.1-1.7; 2.6% per year), and high-risk (pWMSI >1.7; 5.5% per year) groups for future cardiac events ( P < .0001). Early coronary angiography (30 days following stress echocardiography) was performed in only 35 patients (1.7%) with normal stress echocardiographic results and 267 patients (25.5%) with abnormal stress echocardiographic results ( P < .0001). Late coronary revascularization (2 years following stress echocardiography) occurred in 80 patients (PCI, 2.8%; CABG, 1.1%) with pWMSI values of 1.0, 123 patients (PCI, 13.5%; CABG, 7.3%) with pWMSI values of 1.1 to 1.7, and 102 patients (PCI, 12.7%; CABG, 9.6%) with pWMSI values > 1.7. Multivariate logistic regression analysis identified pWMSI as a predictor of coronary angiography (relative risk, 2.04; 95% confidence interval, 1.67-2.5), revascularization (relative risk, 1.91; 95% confidence interval, 1.68-2.17), and cardiac events (relative risk, 2.45; 95% confidence interval, 2.09-2.88) (all P values < .0001). Patients with markedly abnormal stress echocardiographic results (pWMSI > 1.7) had a significantly higher cardiac event rate in those who did not undergo coronary revascularization (9.6% per year vs 2.9% per year, P < .05).
Conclusions
Stress echocardiography is an effective gatekeeper for coronary angiography and revascularization. Stress echocardiographic results influence clinical decision making in higher risk patients with significantly increased referral to coronary angiography and revascularization. Patients with markedly abnormal stress echocardiographic results (pWMSI > 1.7) were most likely to benefit from coronary revascularization.
Stress echocardiography is routinely used for diagnosis, risk stratification, and prognosis in patients with known or suspected coronary artery disease (CAD). Because coronary angiography is invasive and carries a potential risk for leading to inappropriate coronary revascularization, noninvasive testing strategies that could influence the decision to perform coronary angiography might prove to be cost effective. As such, stress echocardiography can be proposed as a gatekeeper to coronary angiography and coronary revascularization. This concept would be valid if patients with normal stress echocardiographic results are deemed at low risk with an acceptably low cardiac event rate, and few such patients are referred to coronary angiography. Numerous studies have demonstrated that patients with normal stress echocardiographic results have a benign prognosis, with a cardiac event rate < 1% per year.
The objectives of the present stress echocardiographic study were 4-fold: (1) to reaffirm the prognostic value of stress echocardiography to risk-stratify patients into low-risk (<1% per year), intermediate-risk (1%-5% per year), and high-risk (>5% per year) risk groups for cardiac events; (2) to characterize patients and determine the component variable(s) of stress echocardiography that best predict outcomes of coronary angiography, revascularization, and cardiac events; (3) to evaluate the post–stress echocardiography use of coronary angiography and revascularization as an effective gatekeeper in a large patient population with follow-up; and (4) to examine the influence of stress echocardiographic results on the decision to refer for coronary revascularization and its subsequent impact on cardiac events and prognosis.
Methods
Study Population
We identified 3121 nonconsecutive patients referred for exercise or pharmacologic stress echocardiography between March 21, 2000, and December 31, 2007, to St Luke’s-Roosevelt Hospital Center (New York, NY). Successful follow-up (100%) for cardiac events ≥1 year after testing was obtained. Patients with nonischemic cardiomyopathy were excluded (n = 35).
Exercise Echocardiographic Protocol
Exercise was the preferred stress modality in patients who were able to exercise to an adequate workload (≥85% of age-adjusted maximal predicted heart rate and 5 metabolic equivalents). Maximal exercise treadmill testing was performed using a standard Bruce protocol. Patients exercised to general fatigue, with premature termination for severe angina, ventricular tachycardia, hemodynamically significant arrhythmias, or hemodynamic instability. Postexercise echocardiographic images were acquired within 30 to 60 seconds after the termination of treadmill exercise.
Dobutamine Echocardiographic Protocol
Dobutamine was administered intravenously beginning at a dose of 5 to 10 μg/kg/min and increased by 10 μg/kg/min every 3 minutes up to a maximum of 40 μg/kg/min, or until a study end point was achieved. The end points for termination of the dobutamine infusion included the development of new segmental wall motion abnormalities, the attainment of >85% of age-predicted maximum heart rate, or the development of significant adverse effects related to the dobutamine infusion. Atropine was administered intravenously in 0.25-mg to 0.5-mg increments up to a maximum dose of 2.0 mg if a study end point was not achieved.
During both types of stress, transthoracic echocardiographic images were obtained using standard views with commercially available ultrasound equipment (Acuson Sequoia, Siemens Medical Solutions USA, Inc, Mountain View, CA; Sonos 5500, Hewlett-Packard Corporation, Andover MA). Echocardiographic images were acquired at baseline, with each increment of dobutamine infusion (if pharmacologic stress), and during the recovery phase.
Echocardiographic Image Analysis
The left ventricle was divided into 16 segments, as recommended by the American Society of Echocardiography, and a score was assigned to each segment at baseline, with each stage of stress (dobutamine only), and during recovery. Each segment was scored as follows: 1 = normal, 2 = mild to moderate hypokinesis (reduced wall thickening and excursion), 3 = severe hypokinesis (markedly reduced wall thickening and excursion), 4 = akinesis (no wall thickening and excursion), and 5 = dyskinesis (paradoxical wall motion away from the center of the left ventricle during systole). All echocardiograms were interpreted by two experienced echocardiographers who were blinded to patients’ treatment and outcomes. Stress echocardiographic studies of poor image quality (<13 of 16 left ventricular [LV] segments visualized) were excluded (approximately 5%). Contrast (Definity; Lantheus Medical Imaging, North Billerica, MA) was used in approximately 13% of stress echocardiographic studies for endocardial border delineation both at rest and during stress.
A normal response to stress was defined as normal wall motion at rest, with increases in wall thickening and excursion during stress. An abnormal (ischemic) response to stress was defined as (1) an LV wall segment that did not increase in thickening and excursion during stress (lack of a hyperdynamic wall motion response) or (2) a deterioration in LV wall segment thickening and excursion during stress (increase in wall-motion score of ≥1 grade) and (3) a biphasic response with dobutamine stress. Maximal severity was the score of the LV wall segment(s) with the greatest value (worst wall motion grade) at postexercise stress (range, 0-5). Peak wall motion score index (pWMSI) following stress was derived from the cumulative sum score of 16 LV wall segments divided by the number of visualized segments. Resting ejection fraction used in the study analysis was an average visual estimation from two experienced echocardiographers.
Patient Follow-Up
Follow-up was obtained in all patients by means of physician-directed telephone interviews using a standardized questionnaire. Early coronary angiography was defined as occurring <3 months after the stress echocardiographic study. Late coronary revascularization was defined as occurring <2 years after the stress echocardiographic study. Coronary angiography and revascularization reports were reviewed in detail and obtained from outside institutions when known. The hard endpoints of the study were nonfatal myocardial infarction (MI) or cardiac death. Nonfatal MI was documented when diagnostic changes in cardiac enzymes (troponin) were accompanied by appropriate clinical symptoms, electrocardiographic findings, or both. Cardiac death was confirmed by review of hospital medical records, death certificate, or both. Autopsy records were reviewed when available. The adjudication of MI and cardiac death was done by physicians who were blinded to clinical and stress echocardiographic results of the patients.
Statistical Analysis
Continuous data are expressed as the mean ± SD. Differences in categorical variables among groups were assessed using χ 2 analysis. Multiple comparisons of continuous variables were made using single-factor analysis of variance, and when significant, differences between pairs were tested using Bonferroni’s correction for the confidence limit. Univariate analysis was performed to determine the relationship between clinical and echocardiographic variables separately with coronary angiography and coronary revascularization. Univariate variables that were separately predictive of coronary angiography and coronary revascularization were considered in multivariate logistic regression analysis. Statistical significance was defined as P < .05. All analyses were performed using commercially available statistical software (SPSS for Windows version 10.0.5; SPSS, Inc, Chicago, IL).
Results
Patient Characteristics and WMSI
From the entire study cohort of 3121 patients, 1293 (41%) underwent treadmill exercise, and 1828 (59%) underwent pharmacologic stress. The patient characteristics and stress echocardiographic results are listed in Table 1 . Patients with abnormal stress echocardiographic results (pWMSI, 1.1-1.7 or >1.7) more often were older and male; had histories of MI; had undergone percutaneous coronary intervention (PCI) or coronary artery bypass grafting (CABG); and had hypertension, diabetes, greater numbers of cardiac risk factors, abnormal rest electrocardiographic results, higher pWMSI values, greater numbers of new ischemic wall motion abnormalities, lower ejection fractions, and higher cardiac event rates compared with patients with pWMSI values of 1.0. Patients with abnormal stress echocardiographic results and pWMSI values > 1.7 more often were male; had histories of MI; and had diabetes, abnormal rest electrocardiographic results, lower achieved percentage maximal heart rate, higher pWMSI values, greater numbers of new ischemic wall motion abnormalities, and lower ejection fractions compared with patients with pWMSI values of 1.1 to 1.7.
| Stress echocardiographic results (WMSI) | |||
|---|---|---|---|
| Normal | Abnormal | ||
| Variable | 1.0 (n = 2072) | 1.1-1.7 (n = 593) | >1.7 (n = 456) |
| Age (y) | 58 ± 13 | 63 ± 12 ∗ | 63 ± 12 ∗ |
| Men | 879 (43%) | 301 (51%) ‡ | 314 (69%) ‡ |
| History of MI | 170 (8%) | 125 (21%) ‡ | 215 (47%) ‡ |
| History of PCI | 18 (5%) | 57 (12%) ∗ | 65 (16%) ∗ |
| History of CABG | 60 (4%) | 69 (15%) ∗ | 79 (20%) ∗ |
| History of hypertension | 1304 (64%) | 425 (72%) ∗ | 316 (70%) † |
| History of diabetes | 446 (23%) | 171 (31%) § | 174 (40%) § |
| Number of cardiac risk factors | 1.8 ± 1.1 | 2 ± 1.1 ∗ | 2.1 ± 1.2 ∗ |
| Abnormal rest electrocardiographic results | 743 (37%) | 280 (49%) ‡ | 324 (74%) ‡ |
| % maximal heart rate (beats/min) | 92 ± 11 | 90 ± 10 | 81 ± 15 † |
| pWMSI | 1.0 | 1.3 ± 0.2 ‡ | 2.7 ± 0.6 ‡ |
| Number of new ischemic wall motion abnormalities | 0 | 3.5 ± 2 ‡ | 8.5 ± 3.9 ‡ |
| Ejection fraction (%) | 58 ± 4.7 | 54 ± 7.7 ‡ | 32 ± 14 ‡ |
| MI | 33 (0.6%) | 24 (1.5%) ∗ | 19 (1.5%) ∗ |
| Cardiac death | 13 (0.2%) | 19 (1.1%) ∗ | 51 (4.0%) ∗ |
∗ P < .0001 versus normal stress echocardiographic results.
† P < .05 versus normal stress echocardiographic results.
‡ P < .0001 versus both groups.
Stress Echocardiography and Follow-Up Cardiac Events
Patients were followed for up to 5 years (mean, 2.8 ± 1.1 years), and 100% were followed for ≥1 year. Among the total study cohort of 3121 patients, 159 coronary events (5.1%) occurred during the follow-up period. These included 76 nonfatal MIs (2.4%) and 83 cardiac deaths (2.7%). There were 23 cardiac events among patients who underwent treadmill stress and 136 events among patients who underwent dobutamine stress (1.8% per year vs 7.4% per year, P < .0001).
Characteristics of Patients With and Without Cardiac Events
Descriptive patient characteristics and exercise and stress echocardiographic variables in patients with and without cardiac events on follow-up are shown in Table 2 . Patients with cardiac events on follow-up were older; had more frequent histories of MI, hypertension, and diabetes; had abnormal rest electrocardiographic results; and were less likely to undergo treadmill exercise compared with those without cardiac events. With respect to echocardiographic variables, patients with cardiac events had higher pWMSI values, greater numbers of new ischemic wall motion abnormalities, and lower ejection fractions.
| Cardiac events | No events | ||
|---|---|---|---|
| Variable | (n = 159) | (n = 2962) | P |
| Age (y) | 67 ± 12 | 60 ± 13 | .0001 |
| Men | 86 (54%) | 1413 (48%) | .07 |
| History of MI | 62 (39%) | 446 (15%) | .0001 |
| History of hypertension | 120 (77%) | 1929 (66%) | .002 |
| History of diabetes | 69 (45%) | 804 (28%) | .0001 |
| Abnormal rest electrocardiographic results | 52 (33%) | 513 (17%) | .0001 |
| Treadmill exercise | 23 (14%) | 1272 (67%) | .0001 |
| pWMSI | 1.9 ± 1 | 1.3 ± 0.6 | .0001 |
| Number of new ischemic wall motion abnormalities | 4.7 ± 3.5 | 1.7 ± 1.7 | .0001 |
| Ejection fraction (%) | 43 ± 19 | 54 ± 11 | .0001 |
pWMSI and Cardiac Event Rate
The annual cardiac event rate increased as a function of the extent and severity of wall motion abnormalities during stress and increasing pWMSI ( Figure 1 ). Normal stress echocardiographic results (pWMSI, 1.0) were associated with a benign prognosis (0.8% per year), whereas mild to moderate (pWMSI, 1.1-1.7) and markedly abnormal (pWMSI > 1.7) stress echocardiography results were associated with higher cardiac event rates (2.6% per year and 5.5% per year, respectively, P < .0001 vs normal stress echocardiographic results).
Characteristics of Patients With and Without Coronary Angiography and Revascularization
The characteristics of patients who underwent coronary angiography and revascularization are listed in Table 3 . Patients who underwent coronary angiography and revascularization more often were older and male; had histories of PCI or CABG; and had hypertension, diabetes, greater numbers of cardiac risk factors, and lower achieved percentage maximal heart rate. With respect to echocardiographic variables, patients with cardiac events had higher pWMSI values, greater numbers of new ischemic wall motion abnormalities, and lower ejection fractions.
| Coronary angiography | Coronary revascularization | |||||
|---|---|---|---|---|---|---|
| Variable | No (n = 2581) | Yes (n = 540) | P | No (n = 2817) | Yes (n = 304) | P |
| Age (y) | 59 ± 14 | 62 ± 11 | .0001 | 60 ± 13 | 63 ± 11 | .0001 |
| Men | 1167 (45%) | 332 (62%) | .0001 | 1301 (46%) | 198 (65%) | .0001 |
| History of MI | 343 (13%) | 70 (13%) | .30 | 392 (16%) | 119 (42%) | .0001 |
| History of PCI | 141 (7%) | 71 (15%) | .0001 | 143 (6%) | 68 (27%) | .0001 |
| History of CABG | 137 (7%) | 72 (16%) | .0001 | 137 (6%) | 71 (28%) | .0001 |
| History of hypertension | 383 (72%) | 1666 (66%) | .003 | 1832 (66%) | 217 (72%) | .01 |
| History of diabetes | 668 (27%) | 209 (40%) | .0001 | 684 (26%) | 109 (38%) | .0001 |
| Number of cardiac risk factors | 1.9 ± 1.1 | 2.3 ± 1 | .0001 | 1.8 ± 1.1 | 2.3 ± 1.1 | .0001 |
| Abnormal rest electrocardiographic results | 805 (31%) | 236 (44%) | .0001 | 934 (33%) | 107 (35%) | .50 |
| % maximal heart rate (beats/min) | 91 ± 12 | 87 ± 13 | .0001 | 91 ± 12 | 87 ± 13 | .0001 |
| pWMSI | 1.2 ± 0.5 | 1.7 ± 0.8 | .0001 | 1.3 ± 0.6 | 1.7 ± 0.8 | .0001 |
| Number of new ischemic wall motion abnormalities | 1.3 ± 2 | 4.8 ± 4.4 | .0001 | 1.6 ± 1.2 | 4.7 ± 3.4 | .0001 |
| Ejection fraction (%) | 55 ± 10 | 48 ± 14 | .0001 | 54 ± 11 | 50 ± 13 | .0001 |
Post–Stress Echocardiography Referral for Coronary Angiography and Coronary Revascularization
Referral to early coronary angiography increased as a function of the extent and severity of abnormal wall motion response during stress and increasing pWMSI ( Figure 2 A). Normal stress echocardiographic results (pWMSI, 1.0) were associated with low referral to coronary angiography (1.7%), whereas mild to moderate (pWMSI, 1.1-1.7) and markedly abnormal (pWMSI > 1.7) stress echocardiographic results were associated with higher referral to coronary angiography (22.9% and 41.9%, respectively, P < .0001 vs normal stress echocardiographic results).
