Stress echocardiography and major cardiac events in patients with normal exercise test

Calasans, Flávia Ricci; Santos, Bruno Fernandes de Oliveira; Silveira, Débora Consuelo Rocha; Araújo, Ana Carla Pereira de; Melo, Luiza Dantas; Barreto-Filho, José Augusto; Sousa, Antônio Carlos Sobral; Oliveira, Joselina Luzia Menezes

doi:10.5935/abc.20130124

Abstracts

BACKGROUND: Exercise test (ET) is the preferred initial noninvasive test for the diagnosis and risk stratification of coronary artery disease (CAD), however, its lower sensitivity may fail to identify patients at greater risk of adverse events. OBJECTIVE: To assess the value of stress echocardiography (SE) for predicting all-cause mortality and major cardiac events (MACE) in patients with intermediate pretest probability of CAD and a normal ET. METHODS: 397 patients with intermediate CAD pretest probability , estimated by the Morise score, and normal ET who underwent SE were studied. The patients were divided into two groups according to the absence (G1) or presence (G2) of myocardial ischemia on SE .End points evaluated were all-cause mortality and MACE, defined as cardiac death and nonfatal acute myocardial infarction (AMI). RESULTS: G1 group was comprised of 329 (82.8%) patients. The mean age of the patients was 57.37 ± 11 years and 44.1% were male. During a mean follow-up of 75.94 ± 17.24 months, 13 patients died, three of them due to cardiac causes, and 13 patients suffered nonfatal AMI. Myocardial ischemia remained an independent predictor of MACE (HR 2.49; [CI] 95% 1.74-3.58). The independent predictors for all-cause mortality were male gender (HR 9.83; [CI] 95% 2.15-44.97) and age over 60 years (HR 4.57; [CI] 95% 1.39-15.23). CONCLUSION: Positive SE for myocardial ischemia is a predictor of MACE in the studied sample, which helps to identify a subgroup of patients at higher risk of events despite having normal ET.

Coronary Artery Disease; Exercise Test; Echocardiography; Stress

FUNDAMENTO: O teste ergométrico (TE), inicialmente indicado para diagnóstico e estratificação de risco da doença arterial coronariana (DAC), apresenta baixa sensibilidade, o que pode implicar em falha na detecção de pacientes com risco aumentado de eventos adversos. OBJETIVO: Avaliar a ecocardiografia sob estresse físico (EEF) na predição de eventos cardíacos maiores (ECM) e óbitos por todas as causas em pacientes com probabilidade pré-teste intermediária de DAC e TE normal. MÉTODO: Trata-se de estudo retrospectivo em que foram estudados 397 pacientes, com probabilidade pré-teste intermediária de DAC pelo método de Morise e TE normal, submetidos à EEF. Dividiu-se em dois grupos: EEF negativo (G1) ou positivo (G2) para isquemia miocárdica. Os desfechos avaliados foram mortalidade por qualquer causa e ECM, definidos como óbito cardíaco e infarto agudo do miocárdio (IAM) não fatal. RESULTADOS: O grupo G1 constituiu-se de 329 (82,8%) pacientes. A idade média foi de 57,37 ± 11 anos e 44,1% eram do gênero masculino. Durante o seguimento médio de 75,94 ± 17,24 meses, ocorreram 13 óbitos, dentre eles três por causas cardíacas (IAM), além de 13 IAM não fatais. Isquemia miocárdica permaneceu como preditor independente de ECM (RR 2,49; [IC] 95% 1,74-3,58). As variáveis preditoras de mortalidade por qualquer causa foram gênero masculino (RR 9,83; [IC] 95% 2,15-44,97) e idade > 60 anos (RR 4,57; [IC] 95% 1,39-15,23). CONCLUSÃO: A EEF positiva é preditora de ECM na amostra estudada, o que auxilia na identificação de um subgrupo de pacientes sob maior risco de eventos adversos, apesar de apresentarem TE normal.

Doença da Artéria Coronariana; Teste de Esforço; Ecocardiografia sob Estresse

^IUniversidade Federal de Sergipe, Aracaju, SE

^IILaboratório de Ecocardiografia da Clínica e Hospital São Lucas - ECOLAB, Aracaju, SE - Brazil

Mailing Address

ABSTRACT

BACKGROUND: Exercise test (ET) is the preferred initial noninvasive test for the diagnosis and risk stratification of coronary artery disease (CAD), however, its lower sensitivity may fail to identify patients at greater risk of adverse events.

OBJECTIVE: To assess the value of stress echocardiography (SE) for predicting all-cause mortality and major cardiac events (MACE) in patients with intermediate pretest probability of CAD and a normal ET.

METHODS: 397 patients with intermediate CAD pretest probability , estimated by the Morise score, and normal ET who underwent SE were studied. The patients were divided into two groups according to the absence (G1) or presence (G2) of myocardial ischemia on SE .End points evaluated were all-cause mortality and MACE, defined as cardiac death and nonfatal acute myocardial infarction (AMI).

RESULTS: G1 group was comprised of 329 (82.8%) patients. The mean age of the patients was 57.37 ± 11 years and 44.1% were male. During a mean follow-up of 75.94 ± 17.24 months, 13 patients died, three of them due to cardiac causes, and 13 patients suffered nonfatal AMI. Myocardial ischemia remained an independent predictor of MACE (HR 2.49; [CI] 95% 1.74-3.58). The independent predictors for all-cause mortality were male gender (HR 9.83; [CI] 95% 2.15-44.97) and age over 60 years (HR 4.57; [CI] 95% 1.39-15.23).

CONCLUSION: Positive SE for myocardial ischemia is a predictor of MACE in the studied sample, which helps to identify a subgroup of patients at higher risk of events despite having normal ET.

Keywords: Coronary Artery Disease; Exercise Test; Echocardiography, Stress.

Introduction

Coronary artery disease (CAD) is the most common cause of morbidity and mortality in Western countries¹. The availability of effective treatment options from the medical, interventional and surgical point of view becomes important in identifying patients at increased risk of cardiovascular events². Thus, the assessment of prognosis is essential to select the appropriate management of patients with suspected or known CAD³. Although the gold standard for the diagnosis of CAD is coronary angiography, noninvasive techniques play an important role in directing invasive diagnostic and therapeutic procedures, and are associated with lower morbidity and cost⁴.

Exercise test (ET) plays an important role in the diagnosis and risk stratification of patients with known or suspected CAD^5-8 . Among noninvasive tests, it continues to be the most commonly used method for diagnostic and prognostic evaluation of CAD, with recognized value particularly in patients with intermediate pretest probability⁹. However, it is established in the literature that left ventricle wall motion abnormalities detected by Stress Echocardiography (SE) appear earlier in the ischemic cascade than angina or ST segment changes¹⁰.

It has been well documented that ischemia resulting from coronary obstruction may occur without clinically recognizable signs, such as electrocardiographic changes or symptoms, such as angina^11,12, which underlines the need for early recognition and treatment, with the objective to reduce subsequent risk^13,14. Patients who do not develop angina or electrocardiographic abnormalities on ET may have a low risk for cardiac events and deaths; however, the lower sensitivity of this test in detecting obstructive CAD may potentially result in failure to identify patients at higher risk¹⁵.

Previous studies have clearly indicated the role of SE in predicting cardiovascular events and mortality in various clinical settings^16-23; however, there are no studies in the literature addressing the prognostic value of SE in patients with intermediate pretest probability for CAD and normal ET. The objective of this study is to assess the value of SE in predicting cardiac events and deaths from all causes in this subgroup of patients.

Methods

Patients

A total of 397 consecutive patients with suspected CAD, normal ET and intermediate pretest probabilities of CAD were included. Pretest probability was estimated in accordance with Morise's score^24,25. These patients were referred to the Clinical Echocardiography Laboratory at Hospital São Lucas (Aracaju, Sergipe) to undergo SE in the period from January, 2001 to December, 2005. The exclusion criteria were defined as: a) low or high pretest probability of CAD; b) prior diagnosis of CAD; c) positive ET for myocardial ischemia; d) presence of left bundle branch block (LBBB) of the His bundle, e) refusal to participate in the research; and f) inability to establish telephone contact during follow-up. The ethical principles governing human experimentation were carefully followed and all patients signed an informed consent form. The study was approved by the Ethics and Research Committee of the Federal University of Sergipe (CAAE 1818.0.000.107-06).

The protocol consisted of complete clinical research, in which previous symptoms were recorded, such as chest pain or dyspnea, and risk factors for cardiovascular disease were evaluated, followed by 12-lead electrocardiogram (ECG) and resting echocardiogram. Also included was a physical exertion test using a treadmill and, following, we proceeded back to the acquisition of echocardiography images. Clinical and demographic data, as well as the results of the stress tests, were recorded in our database.

Exercise test

Patients were examined in the postprandial period after a light meal and were instructed to avoid any excessive physical activity on the day the examination was conducted. The investigation was conducted with the person breathing room air, with the testing room at a constant temperature (20º C to 24º C). Bruce protocol was followed in conducting the ET. During the test, the subjects were monitored continuously by a three-lead ECG and were encouraged to reach their peak physical effort.

The ET was considered positive for myocardial ischemia when ST segment elevation or horizontal or descending negative deflection equal to or higher than one millimeter for at least 60-80 milliseconds from the J⁹ point was noted.

Stress Echocardiography

Echocardiography was carried out with a Hewlett Packard/Phillips SONOS 5500, observing the technical aspects classically described by Schiller et al²⁶. The two-dimensional echocardiography images were obtained in the parasternal and apical acoustic windows during rest and immediately after exercise, with the patient in the left lateral decubitus position and electrocardiographic recordings captured simultaneously. The images were recorded on a VCR or digital video display (DVD).

The wall motion was assessed by experienced level III echocardiographers, as recommended by the American Society of Echocardiography. The segmental parietal thickening of the LV (left ventricle) was quantitatively evaluated at rest and after exercise by using the 16-segment model, ranked at: 1, normal; 2, hypokinetic, 3, akinetic and 4, dyskinetic. The left ventricular wall motion score index (LVWMSI) was calculated at rest and during exercise as the sum of the scores given to each of the 16 segments, divided by the number of segments evaluated at a given time. An LVWMSI equal to one corresponds to normal, from 1.1 to 1.6 represents a mild disorder; from 1.61 to 2 indicates moderate dysfunction. Values greater than 2 represent significant dysfunction²⁶. The difference between the LVWMSI under stress and at rest is known as ΔLVWMSI. The development of new alterations in parietal motility or the worsening of existing dyssynergia (ΔLVWMSI ≠ 0) was considered indicative of myocardial ischemia.

Follow-up and outcomes

Patient follow-up was performed through structured interviews obtained by telephone contact. Contact was also made with the assisting physician and a revision of medical records was performed. Deaths from all causes and major cardiac events (MACE), defined as cardiac death and non-fatal acute myocardial infarction, were considered as outcomes of the study.

Statistical Analysis

Categorical variables were presented as percentages and analyzed using the chi-square or Fisher's exact test. Continuous variables were represented as mean +/- SD and compared with the aid of the unpaired t test or Mann-Whitney U test, whichever was appropriate. The cumulative event curves were estimated by the Kaplan-Meier method and compared using the long-rank test. Patients were censored at the time of myocardial revascularization for analysis of major cardiac events, but not for general mortality.

To evaluate the risk factors for MACE and deaths from all causes, Cox regression was utilized (univariate and multivariate). The variables included in the multivariate model were all those with p < 0.1 in the univariate analysis. Multicolinearility problems were solved before variables were inserted into the model. The method used was forward variable selection. The variables that remained in the model were tested for possible interactions. The assumption of proportional risk was tested through waste by Schoenfield for each of the variables that remained in the final model. The values of p < 0.05 were considered significant. The statistical analyses were processed by means of the Statistical Package for the Social Sciences (SPSS) program, version 17.0 (Chicago, IL).

Results

Clinical characteristics of the study population

Among the 397 patients with intermediate pretest probability of CAD and normal ET undergoing SE, 175 (44.1%) were male and the mean age was 57.4 ± 11 years. Group G1 was comprised of 329 (82.8%) patients with negative results and group G2 contained 68 (17.2%) patients who tested positive for myocardial ischemia by SE. Group G2 had a higher average age, but there was no difference between groups in relation to gender and presence of precordialgia. The two groups (G1 and G2) showed similar frequencies of comorbidities such as dyslipidemia, systemic arterial hypertension, diabetes mellitus, and family history of CAD (Table 1).

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Hemodynamic and echocardiography parameters

Patients with ischemia on SE had a lower mean double product when compared to the group without ischemia. In addition, the averages of the chronotropic rate and peak cardiac rate were also lower in Group G2. In terms of the average of the ejection fraction, Group G2 (0.62 ± 0.07) had a lower ejection fraction in relation to Group G1 (0.67 ± 0.05). It was noted that the patients from Group G2 were more prone to developing arrhythmias (Table 2).

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Follow-up and Outcomes

During the mean follow-up of 75.94 ± 17.24 months, there were 13 deaths (nine in G1 and four in G2), including three deaths from cardiac causes (AMI), as well as 13 non-fatal AMIs. Of the 16 MACE, eleven occurred in G1 and five in G2. In the univariate analysis, the variables male gender, age, double product at peak exercise and positive SE for myocardial ischemia were associated with mortality. Variables associated with the development of MACE in the univariate analysis were age, double product at peak exercise, wall motion abnormalities at rest, positive SE for myocardial ischemia and ΔLVWMSI (Table 3). In the final model of the multivariate analysis, only the ΔLVWMSI continued to show significance as an independent predictor of MACE (HR 2.49; [CI] 95% 1,74-3,58). The variables predicting mortality from any cause were male gender (HR 9,83; [CI] 95% 2,15-44,97) and age older than or equal to 60 years (HR 4,57; [CI] 95% 1,39-15,23) (Table 4). Kaplan-Meier curve for all-cause death and MACE are represented in Figures 1 and 2, respectively.

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Discussion

This study shows that a significant proportion of patients with intermediate pretest probability of CAD and normal ET presents myocardial ischemia detected on SE. It was shown that one in six patients had changes indicative of myocardial ischemia on SE. The results reflect the limitations of the negative predictive value of ET when compared to SE in the population where ET has its value primarily recognized in the intermediate pretest probability of CAD.

For the diagnosis of myocardial ischemia, when interpreting the results of ET one should take into account the pretest probability of CAD, since the predictive values are related to the prevalence of the disease in the population considered. The clinical value of ET is recognized mainly in patients with intermediate pretest probability of CAD. This is due to the fact that many false positive results are expected in asymptomatic groups and a high rate of future cardiac events can already be expected in patients with high pretest probability of CAD, regardless of the outcome of ET⁹.

The variability of ET diagnostic accuracy was previously studied by two meta-analyses^27,28. In these studies, patients underwent both procedures (ET and coronary angiography). The approximate sensitivity and specifity of ST segment rectified or descending depression > 1.0mm was 50% and 90%, respectively^29-31. The SE shows good accuracy in the detection of CAD, with higher sensitivity and specificity for diagnosis in relation to electrocardiogram ET and echocardiogram at rest, and presents additional value in the localization and quantification of myocardial ischemia³².

Furthermore, the extent of ischemia and severity of myocardial wall motility disorders, measured at the peak of the SE exercise protocol, are considered independent and cumulative predictors of prognosis in patients with known or suspected CAD, providing additional prognostic information to the standard ET¹⁹. Studies show that the extent and severity of ischemia induced by exercise are strong predictors of AMI and cardiac death^18,33,34, which confirms the results of this study in which myocardial ischemia, estimated by ΔLVWMSI, has been a predictor of adverse cardiac events.

It is clear, therefore, that echocardiography variables that reflect the extent and severity of CAD are superior for risk assessment of subsequent events, as observed by Arruda and colleagues. In a cohort of 5,798 patients with known or suspected CAD, the LVWMSI had significant prognostic value for MACE and was more reliable than the variable ischemia, defined in the study as the development of a new change in parietal motility or worsening of existing dyssynergia.

The presence of myocardial ischemia detected by SE was previously described as a predictor of adverse cardiac events and mortality from any cause in patients with normal ET. In the study of a Spanish cohort that included 4004 patients, of whom 16.7% had ischemia on SE, the ΔLVWMSI was an independent predictor of mortality and MACE¹⁵. In the present study, ΔLVWMSI was able to predict the development of adverse cardiac events; however, it was not a predictor of mortality from all causes. Importantly, the Spanish cohort included patients at high risk for CAD who were excluded from the study in order to evaluate a population that typically generates doubts in terms of the diagnostic approach.

The importance of SE in predicting mortality and adverse cardiac events overcomes the limitations inherent in the ET, and can even be observed in patients with inconclusive tests, just as in patients with LBBB. During the follow-up of 609 patients with LBBB (average follow up of 4.6 ± 3.4 years), five-year mortality and cardiac events were twice as high in patients who had ischemia on SE³⁵. In a study of a Brazilian population with LBBB, the SE was also a predictor of major cardiac events³⁶.

In this study, it was observed that SE confers a good prognosis in patients with normal results on echocardiography. This evidence was first described by Sawada et al³⁷ and was later confirmed by other studies. In a cohort of 1,325 patients whose coronary status was unknown, the prognosis after a normal SE was considered excellent. The rate of survival free of cardiac events over one, two and three years was 99.2%, 97.8% and 97.4%, respectively, with a favorable prognosis even in patients with intermediate pretest or high³⁸ probability. According to a study involving 437 patients with angina and no previous history of AMI or myocardial revascularization, patients with normal tests have a low rate of occurrence of events and may be exempted from invasive procedures for three years following a normal test¹⁹.

The favorable prognostic implications of negative SE for myocardial ischemia are consistent with a recent published meta-analysis in which the negative predictive value of SE for AMI and cardiac death was 98.4% ([95% CI] 97.9 to 98.9) over 33 months of follow-up, a value similar to that of myocardial perfusion scintigraphy, which was found to be 98.8% ([CI 95%] 98.5 - 99.0), over 36 months of follow-up³⁹.

With regard to the limitations of the study, we highlight the limitation inherent in observational studies, in which non-measured variables can corroborate the difference in prognosis between groups.

Although currently recommended as the initial test for evaluation of CAD compared to SE, ET has limitations regarding its negative predictive value. Through SE it was possible to identify a subgroup of patients at higher risk for developing adverse cardiac events, although they presented with a normal ET. However, additional studies of cost-effectiveness are needed to determine whether the increase in prognostic value provided by SE justifies its use as an initial test. This strategy could involve reducing potential costs through the proper selection of therapeutic strategies to enable appropriate referral for coronary angiography for patients at higher risk.

Conclusion

A positive SE for myocardial ischemia is a predictor of MACE in the sample studied, which helps to identify a subgroup of patients at higher risk of adverse events, despite presenting a normal ET.

Author contributions

Conception and design of the research, Acquisition of data, Analysis and interpretation of the data, Statistical analysis, Writing of the manuscript, Critical revision of the manuscript for intellectual content: Calasans FR, Santos BFO, Silveira DCR, Araújo ACP, Melo LD, Barreto-Filho JA, Sousa ACS, Oliveira JLM.

Potential Conflict of Interest

No potential conflict of interest relevant to this article was reported.

Sources of Funding

There were no external funding sources for this study.

Study Association

This study is not associated with any post-graduation program.

References

1. Lloyd-Jones D, Adams R, Carnethon M, De Simone G, Ferguson TB, Flegal K, et al; American Heart Association Statistics Committee and Stroke Statistics Subcommittee. Heart disease and stroke statistics-2009 update: a report from the American Heart Association Statistics Committee and Stroke Statistics Subcommittee. Circulation. 2009;119(3):480-6.
2. Jahnke C, Nagel E, Gebker R, Kokocinski T, Kelle S, Manka R, et al. Prognostic value of cardiac magnetic resonance stress tests: adenosine stress perfusion and dobutamine stress wall motion imaging. Circulation. 2007;115(13):1769-76.
3. Pundziute G, Schuijf JD, Jukema JW, Boersma E, de Roos A, van der Wall EE, et al. Prognostic value of multislice computed tomography coronary angiography in patients with known or suspected coronary artery disease. J Am Coll Cardiol. 2007;49(1):62-70.
4. Scanlon PJ, Faxon DP, Audet AM, Carabello B, Dehmer GJ, Eagle KA, et al. ACC/AHA guidelines for coronary angiography. A report of the American College of Cardiology/American Heart Association Task Force on practice guidelines (Committee on Coronary Angiography). Developed in collaboration with the Society for Cardiac Angiography and Interventions. J Am Coll Cardiol. 1999;33(6):1756-824.
5. Roger VL, Jacobsen SJ, Pellikka PA, Miller TD, Bailey KR, Gersh BJ. Prognostic value of treadmill exercise testing: a population-based study in Olmsted County, Minnesota. Circulation. 1998;98(25):2836-41.
6. Goraya TY, Jacobsen SJ, Pellikka PA, Miller TD, Khan A, Weston SA, et al. Prognostic value of treadmill exercise testing in elderly persons. Ann Intern Med. 2000;132(11):862-70.
7. Ellestad MH, Wan MK. Predictive implications of stress testing: follow-up of 2700 subjects after maximum treadmill stress testing. Circulation. 1975;51(2):363-9.
8. Mark DB, Shaw L, Harrell FE Jr, Hlatky MA, Lee KL, Bengtson JR, et al. Prognostic value of a treadmill exercise score in outpatients with suspected coronary artery disease. N Engl J Med. 1991;325(12):849-53.
9. Gibbons RJ, Balady GJ, Bricker JT, Chaitman BR, Fletcher GF, Froelicher VF, et al; American College of Cardiology/American Heart Association Task Force on Practice Guidelines. Committee to Update the 1997 Exercise Testing Guidelines. ACC/AHA 2002 guideline update for exercise testing: summary article. A report of the American College of Cardiology/American Heart Association Task Force on Practice Guidelines (Committee to Update the 1997 Exercise Testing Guidelines). J Am Coll Cardiol. 2002;40(8):1531-40.
10. Picano E; American College of Cadiology; American Heart Association. Stress echocardiography for the diagnosis of coronary artery disease. Indian Heart J. 2003;55(3):223-7.
11. Geft IL, Fishbein MC, Ninomiya K, Hashida J, Chaux E, Yano J, et al. Intermittent brief periods of ischemia have a cumulative effect and may cause myocardial necrosis. Circulation. 1982;66(6):1150-3.
12. Gottlieb SO, Weisfeldt ML, Ouyang P, Mellits ED, Gerstenblith G. Silent ischemia as a marker for early unfavorable outcomes in patients with unstable angina. N Engl J Med. 1986;314(19):1214-9.
13. Beller GA. Myocardial perfusion imaging for detection of silent myocardial ischemia. Am J Cardiol. 1988;61(12):22F-28F.
14. Kaul S, Senior R, Firschke C, Wang XQ, Lindner J, Villanueva FS, et al. Incremental value of cardiac imaging in patients presenting to the emergency department with chest pain and without ST-segment elevation: a multicenter study. Am Heart J. 2004;148(1):129-36.
15. Bouzas-Mosquera A, Peteiro J, Alvarez-Garcia N, Broullon FJ, Mosquera VX, Garcia-Bueno L, et al. Prediction of mortality and major cardiac events by exercise echocardiography in patients with normal exercise electrocardiographic testing. J Am Coll Cardiol. 2009;53(21):1981-90.
16. Arruda AM, Das MK, Roger VL, Klarich KW, Mahoney DW, Pellikka PA. Prognostic value of exercise echocardiography in 2,632 patients > or = 65 years of age. J Am Coll Cardiol. 2001;37(4):1036-41.
17. Arruda AM, McCully RB, Oh JK, Mahoney DW, Seward JB, Pellikka PA. Prognostic value of exercise echocardiography in patients after coronary artery bypass surgery. Am J Cardiol. 2001;87(9):1069-73.
18. Arruda-Olson AM, Juracan EM, Mahoney DW, McCully RB, Roger VL, Pellikka PA. Prognostic value of exercise echocardiography in 5,798 patients: is there a gender difference? J Am Coll Cardiol. 2002;39(4):625-31.
19. Elhendy A, Mahoney DW, Burger KN, McCully RB, Pellikka PA. Prognostic value of exercise echocardiography in patients with classic angina pectoris. Am J Cardiol. 2004;94(5):559-63.
20. Oliveira JL, Barreto-Filho JA, Oliveira CR, Santana TA, Anjos-Andrade FD, Alves EO, et al. Prognostic value of exercise echocardiography in diabetic patients. Cardiovasc Ultrasound. 2009;7:24.
21. Yao S, Bangalore S, Ahuja A, Chaudhry FA. Stress echocardiography: risk stratification, prognosis, patient outcomes and cost-effectiveness. Minerva Cardioangiol. 2009;57(3):315-31.
22. Oliveira JL, Goes TJ, Santana TA, Travassos TF, Teles LD, Anjos-Andrade FD, et al. Chronotropic incompetence and a higher frequency of myocardial ischemia in exercise echocardiography. Cardiovasc Ultrasound. 2007;5:38.
23. McKeogh JR. The diagnostic role of stress echocardiography in women with coronary artery disease: evidence based review. Curr Opin Cardiol. 2007;22(5):429-33.
24. Morise AP, Jalisi F. Evaluation of pretest and exercise test scores to assess all-cause mortality in unselected patients presenting for exercise testing with symptoms of suspected coronary artery disease. J Am Coll Cardiol. 2003;42(5):842-50.
25. Morise AP, Haddad WJ, Beckner D. Development and validation of a clinical score to estimate the probability of coronary artery disease in men and women presenting with suspected coronary disease. Am J Med. 1997;102(4):350-6.
26. Schiller NB, Shah PM, Crawford M, DeMaria A, Devereux R, Feigenbaum H, et al. Recommendations for quantitation of the left ventricle by two-dimensional echocardiography. American Society of Echocardiography Committee on Standards, Subcommittee on Quantitation of Two-Dimensional Echocardiograms. J Am Soc Echocardiogr. 1989;2(5):358-67.
27. Detrano R, Gianrossi R, Froelicher V. The diagnostic accuracy of the exercise electrocardiogram: a meta-analysis of 22 years of research. Prog Cardiovasc Dis. 1989;32(3):173-206.
28. Gianrossi R, Detrano R, Mulvihill D, Lehmann K, Dubach P, Colombo A, et al. Exercise-induced ST depression in the diagnosis of coronary artery disease: a meta-analysis. Circulation. 1989;80(1):87-98.
29. DelCampo J, Umann T, McGowan V, Froning J, Froelicher V. Comparison of computerized and standard visual criteria of exercise ECG for diagnosis of coronary artery disease. Ann Noninvasive Electrocardiol. 1996;1(4):430-42.
30. Froelicher VF, Lehmann KG, Thomas R, Goldman S, Morrison D, Edson R, et al. The electrocardiographic exercise test in a population with reduced workup bias: diagnostic performance, computerized interpretation, and multivariable prediction. Veterans Affairs Cooperative Study in Health Services #016 (QUEXTA) Study Group. Quantitative Exercise Testing and Angiography. Ann Intern Med. 1998;128(12 Pt 1):965-74.
31. Morise AP. Comparison of the Diamond-Forrester method and a new score to estimate the pretest probability of coronary disease before exercise testing. Am Heart J. 1999;138(4 Pt 1):740-5.
32. Cheitlin MD, Armstrong WF, Aurigemma GP, Beller GA, Bierman FZ, Davis JL, et al. ACC/AHA/ASE 2003 Guideline Update for the Clinical Application of Echocardiography: summary article. A report of the American College of Cardiology/American Heart Association Task Force on Practice Guidelines (ACC/AHA/ASE Committee to Update the 1997 Guidelines for the Clinical Application of Echocardiography). J Am Soc Echocardiogr. 2003;16(10):1091-110.
33. Olmos LI, Dakik H, Gordon R, Dunn JK, Verani MS, Quinones MA, et al. Long-term prognostic value of exercise echocardiography compared with exercise 201Tl, ECG, and clinical variables in patients evaluated for coronary artery disease. Circulation. 1998;98(24):2679-86.
34. D'Andrea A, Severino S, Caso P, Liccardo B, Forni A, Fusco A, et al. Prognostic value of supine bicycle exercise stress echocardiography in patients with known or suspected coronary artery disease. Eur J Echocardiogr. 2005;6(4):271-9.
35. Bouzas-Mosquera A, Peteiro J, Alvarez-Garcia N, Broullon FJ, Garcia-Bueno L, Ferro L, et al. Prognostic value of exercise echocardiography in patients with left bundle branch block. J Am Coll Cardiol. 2009;2(3):251-9.
36. Vasconcelos Fde L, Santos BF, Santana Nde O, Faro GB, Rocha Rde O, Leal VV, et al. Prognostic value of exercise stress echocardiography in patients with left bundle branch block. Arq Bras Cardiol. 2011;97(6):478-84.
37. Sawada SG, Ryan T, Conley MJ, Corya BC, Feigenbaum H, Armstrong WF. Prognostic value of a normal exercise echocardiogram. Am Heart J. 1990;120(1):49-55.
38. McCully RB, Roger VL, Mahoney DW, Karon BL, Oh JK, Miller FA Jr, et al. Outcome after normal exercise echocardiography and predictors of subsequent cardiac events: follow-up of 1,325 patients. J Am Coll Cardiol. 1998;31(1):144-9.
39. Metz LD, Beattie M, Hom R, Redberg RF, Grady D, Fleischmann KE. The prognostic value of normal exercise myocardial perfusion imaging and exercise echocardiography: a meta-analysis. J Am Coll Cardiol. 2007;49(2):227-37.