This study evaluates the prognostic value of stress echocardiography (Secho) in short-term (10 years) and lifetime atherosclerotic cardiovascular disease risk–defined groups according to the American College of Cardiology/American Heart Association 2013 cardiovascular risk calculator. The ideal risk assessment and management of patients with low-to-intermediate or high short-term versus low (<39%) or high (≥39%) lifetime CV risk is unclear. The purpose of this study was to evaluate the prognostic value of Secho in short-term and lifetime CV risk–defined groups. We evaluated 4,566 patients (60 ± 13 years; 46% men) who underwent Secho (41% treadmill and 59% dobutamine) with low-intermediate short-term (<20%) risk divided into low (<39%, n = 368) or high (≥39%, n = 661) lifetime CV risk and third group with high short-term risk (≥20%, n = 3,537). Follow-up (3.2 ± 1.5 years) for nonfatal myocardial infarction (n = 102) and cardiac death (n = 140) were obtained. By univariate analysis, age (p <0.001) and ≥3 new ischemic wall motion abnormalities (WMAs, p <0.001) were significant predictors of cardiac events. Cumulative survival in patients was significantly worse in patients with ≥3 WMA versus <3 WMA in low-intermediate short-term and low (3.3% vs 0.3% per year, p <0.001) or high (2.0% vs 0% per year, p <0.001) lifetime risk and also in those with high short-term CV risk group (3.5% vs 1.0% per year, p <0.001). Multivariate Cox proportional hazards analysis identified ≥3 new ischemic WMAs as the strongest predictor of cardiac events (hazard ratio 3.0, 95% confidence interval 2.3 to 3.9, p <0.001). In conclusion, Secho results (absence or presence of ≥3 new ischemic segments) can further refine risk assessment in patients with low-intermediate or high short-term versus low or high lifetime cardiovascular risk. Event rate with normal Secho is low (≤1% per year) but higher in patients with high short-term CV risk by the American College of Cardiology/American Heart Association 2013 cardiovascular risk calculator.
Stress echocardiographic results can effectively risk-stratify patients with known or suspected coronary artery disease (CAD) into low, intermediate, and high-risk groups. A normal stress echocardiographic study confers a benign short-term prognosis. The 2013 American College of Cardiology/American Heart Association (ACC/AHA) Guidelines on the assessment of cardiovascular risk released a new gender-specific algorithm CV risk estimator to enable health care providers and patients to estimate short-term (10 years) and lifetime risk for atherosclerotic CV disease. The present study evaluates the prognostic value of stress echocardiography (Secho) to further substratify risk in patients previously evaluated by CV risk estimator into 3 short-term (10 years) and lifetime risk groups.
Methods
We identified 4,566 patients who were referred for exercise or pharmacologic Secho from March 21, 2000, to December 31, 2012 (Mount Sinai St. Luke’s and Mount Sinai Roosevelt Hospitals, New York, New York). Follow-up (100%) for cardiac events ≥1 year was obtained in all patients.
As suggested by the 2013 ACC/AHA 2013 cardiovascular risk calculator, we entered age, gender, race, serum levels of total and high-density lipoprotein cholesterol, smoking, blood pressure, and treatment for hypertension to estimate the short-term and lifetime risk of atherosclerotic disease. Low-intermediate short-term risk was defined as an estimated 10-year risk <20% of fatal or nonfatal coronary heart disease. Patients with low-intermediate short-term CV risk (<20%) were divided into low (<39%; group I, n = 368) or high (≥39%; group II, n = 661) lifetime risk. A third group with high short-term risk (group III, n = 3,537) was defined as an estimated 10-year risk ≥20%. All patients with diabetes or established CAD (history of myocardial infarction [MI], percutaneous coronary intervention, or coronary bypass) were included in high short-term risk group III.
Maximal symptom-limited treadmill exercise testing was performed using the standard Bruce protocol. Patients exercised to general fatigue, with premature termination for severe angina, ventricular tachycardia, hemodynamically significant arrhythmias, or hemodynamic instability. Post-exercise echocardiographic images were acquired within 30 to 60 seconds after termination of treadmill exercise.
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 development of new segmental WMAs, 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 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, Mountain View, California, and Hewlett Packard Sonos 5500, Andover, Massachusetts). Echocardiographic images were acquired at baseline, with each increment of dobutamine infusion (if pharmacologic stress) and during the recovery phase.
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 LV during systole). All echocardiograms were interpreted by experienced echocardiographers who were blinded to patient’s treatment and outcome. Contrast (Definity; Lantheus Medical Imaging, N. Billerica, MA) was used in ∼13% of stress echocardiographic studies for endocardial border delineation both at rest and stress.
A normal response to stress was defined as normal wall motion at rest with increase 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. Peak wall motion score index after stress was derived from the cumulative sum score of 16 LV wall segments divided by the number of visualized segments. Resting left ventricular ejection fraction used in the study analysis was visual estimated by experienced echocardiographers who were blinded to patient’s treatment and outcome. Interobserver and intraobserver variabilities of Secho wall motion and ejection fraction estimation were both <5%.
Follow-up was obtained in all patients by means of physician-directed telephone interviews using a standardized questionnaire. The hard end points of the study were nonfatal 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, and autopsy records when available.
All analysis was carried out using SPSS for Windows, version 13.0 (SPSS, Inc., Chicago, Illinois). Continuous variables are expressed as mean ± SD. Patient groups were compared using Student’s t tests and single-factor analysis of variance. Differences in categorical variables among groups were assessed using the chi-square analysis. Univariate Cox proportional hazards analysis was performed to determine the relation between clinical and echocardiographic variables and cardiac events. Univariate predictors of cardiac events were considered in multivariate logistic regression analysis. Kaplan-Meier cumulative survival analysis with stratification by normal or abnormal stress echocardiographic test results was performed. The comparison of survival between groups was made using the Mantel-Cox test (log-rank test). Statistical significance was defined as p <0.05.
A forward conditional (Wald) Cox proportional hazards model with all assumptions tested was used to determine the incremental prognostic value of stress echocardiographic variables over the ACC/AHA 2013 cardiovascular risk calculator, decreased left ventricular ejection fraction, pharmacologic stress test, and ≥3 new ischemic segments. The incremental prognostic value of the added variables was determined by comparison of the global chi-square calculated at each step. The stepwise selection or removal of variables for inclusion was based on clinical judgment and univariate statistical significance.
Results
In the study cohort of 4,566 patients, 1,892 (41%) underwent treadmill exercise and 2,674 (59%) underwent pharmacologic stress. The study indications were 56% chest pain (27% with typical angina), 25% CAD risk assessment, 6% dyspnea, 5% preoperative, and 8% other. The patient characteristics and stress echocardiographic results in defined CV risk groups are characterized in Table 1 . In the high short-term risk group III, there were 34% with diabetes, 19% with previous MI, 12% with previous PCI, and 10% with previous bypass surgery.
| Variable | Low-intermediate short-term | High short-term | P value | |
|---|---|---|---|---|
| I.-Low Lifetime (n = 368) | II-High lifetime (n = 661) | III.-High lifetime (n = 3537) | ||
| Age (years) | 49 ± 11 | 47 ± 10 | 64 ± 12 | <0.001 |
| Men | 59 (16%) | 239 (36%) | 1797 (51%) | <0.001 |
| Systemic hypertension | 108 (29%) | 335 (51%) | 2571 (73%) | <0.001 |
| Hyperlipidemia | 33 (9%) | 133 (20%) | 1785 (51%) | <0.001 |
| Smoker | 64 (17%) | 109 (17%) | 1290 (37%) | <0.001 |
| Number of cardiac risk factors | 0.7 ± 0.7 | 1.5 ± 0.9 | 2.2 ± 1.1 | <0.001 |
| Previous percutaneous coronary intervention | 0 | 0 | 423 (12%) | <0.001 |
| Previous coronary bypass | 0 | 0 | 336 (10%) | <0.001 |
| Abnormal rest electrocardiogram | 109 (30%) | 188 (28%) | 1608 (46%) | <0.001 |
| Exercise stress echocardiogram | 241 (66%) | 403 (61%) | 1248 (35%) | <0.001 |
| ≥ 3 ischemic segments | 29 (7.9%) | 48 (7.3%) | 750 (21%) | <0.001 |
| Peak wall motion score index | 1.1 ± 0.4 | 1.1 ± 0.4 | 1.3 ± 0.6 | <0.001 |
| Ejection fraction (%) | 57 ± 8 | 57 ± 8 | 53 ± 12 | <0.001 |
| Cardiac events | 8 (2.2%) | 8 (1.2%) | 226 (6.4%) | <0.001 |
Patients were followed for up to 5 years (mean 3.2 ± 1.5 years), and all patients were followed for ≥1 year. The mean age of the overall cohort was 60 ± 13 years and consisted of 2,095 men (46%).
Among the study cohort of 4,566 patients, there were a total of 242 cardiac events during the follow-up. These included 102 nonfatal MI and 140 cardiac deaths. There were 202 of 2,674 cardiac events (7.6%) in patients who underwent pharmacologic stress test and 40 of 1,892 cardiac events (2.1%) in patients who underwent treadmill stress echocardiogram (2.5% vs 0.75% per year, p <0.0001; Table 2 ). All variables listed in Table 1 were considered in the univariate analysis. Significant univariate predictors of cardiac events are listed in Table 3 . Clinical and echocardiographic variables significant on univariate analysis were considered in multivariate analysis.
| Variable | No events (n = 4324) | Cardiac events (n = 242) | p Value |
|---|---|---|---|
| Age (years) | 60 ± 13 | 67 ± 12 | <0.001 |
| Men | 1965 (45%) | 130 (54%) | 0.01 |
| Systemic hypertension | 2824 (65%) | 190 (79%) | <0.001 |
| Diabetes mellitus | 1285 (30%) | 105 (43%) | <0.001 |
| Hyperlipidemia | 1839 (43%) | 112 (46%) | 0.25 |
| Smoker | 1375 (32%) | 88 (36%) | 0.14 |
| Number of cardiac risk factors | 1.9 ± 1.2 | 2.3 ± 1.1 | <0.001 |
| Previous myocardial infarction | 594 (14%) | 85 (35%) | <0.001 |
| Previous percutaneous coronary intervention | 395 (9%) | 28 (12%) | 0.20 |
| Previous coronary bypass | 305 (7%) | 31 (13%) | 0.001 |
| Abnormal rest electrocardiogram | 1746 (40%) | 159 (66%) | <0.001 |
| % maximum age-predicted heart rate | 91 ± 12 | 86 ± 13 | <0.001 |
| Exercise stress echocardiogram | 1852 (43%) | 40 (17%) | <0.001 |
| ≥ 3 ischemic segments | 720 (17%) | 107 (44%) | <0.001 |
| Peak wall motion score index | 1.2 ± 0.5 | 1.8 ± 0.9 | <0.001 |
| Ejection fraction (%) | 55 ± 10 | 44 ± 18 | <0.001 |
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