Accepted Manuscript Reframing the Interpretation and Application of Exercise Electrocardiography Albert J. Sinusas, MD Erica S. Spatz, MD, MHS PII:
S0735-1097(14)00280-0
DOI:
10.1016/j.jacc.2013.12.026
Reference:
JAC 19747
To appear in:
Journal of the American College of Cardiology
Received Date: 13 December 2013 Accepted Date: 18 December 2013
Please cite this article as: Sinusas AJ, Spatz ES, Reframing the Interpretation and Application of Exercise Electrocardiography, Journal of the American College of Cardiology (2014), doi: 10.1016/ j.jacc.2013.12.026. This is a PDF file of an unedited manuscript that has been accepted for publication. As a service to our customers we are providing this early version of the manuscript. The manuscript will undergo copyediting, typesetting, and review of the resulting proof before it is published in its final form. Please note that during the production process errors may be discovered which could affect the content, and all legal disclaimers that apply to the journal pertain.
ACCEPTED MANUSCRIPT
Editorial Comments Reframing the Interpretation and Application of Exercise Electrocardiography Albert J. Sinusas, MD and Erica S. Spatz, MD, MHS
RI PT
Section of Cardiovascular Medicine, Department of Medicine Yale University School of Medicine
Address for correspondence: Albert J. Sinusas, MD, FACC Section of Cardiovascular Medicine
PO Box 8017, DANA 3 New Haven, CT 06520
(203) 737-1026 (fax)
EP
203-785-5005
TE D
Yale University School of Medicine
M AN U
Brief Title: Application of Exercise Electrocardiography
SC
New Haven, CT 06520
AC C
Email: [email protected]
No conflicts.
Key Words: exercise testing, downstream testing, imaging
1
ACCEPTED MANUSCRIPT
Guidelines recommend that most patients being evaluated for ischemic heart disease (IHD) undergo exercise electrocardiography (ECG), provided they are able to exercise.[1] Yet despite over three decades of data and experience, the test continues to vex interpreting
RI PT
physicians and referring providers alike. While recognized as providing valuable information, ambivalence arises in estimating the likelihood of disease based on a test with a reported
sensitivity of only 68% and specificity of 77%, far below the test performance of most other
SC
cardiovascular imaging modalities.
Inherent to the interpretation of the exercise ECG is the application of Bayes' theorem, or
M AN U
the process of probabilistic reasoning. Simply stated, the predictive value of any test result is conditional on the pretest probability of disease. These concepts were illustrated in Diamond and Forrester’s landmark paper of 1979, demonstrating the likelihood of coronary artery disease based on an individual’s age, sex, and symptoms, as well as the magnitude of ST depression with
TE D
exercise. In the ensuing 35 years, researchers have leveraged other data associated with the exercise ECG to improve the accuracy for detection of IHD, assess severity of disease, and inform risk stratification, including the evaluation of hemodynamic changes, exercise time, and
EP
symptoms. For example, the presence of angina and duration of exercise, captured in the Duke Treadmill Score, have been demonstrated to correlate with risk of future events.[2] Many other
AC C
electrocardiographic indices, beyond simple analysis of ST segment depressions, have been proposed for detection of IHD (e.g., heart rate recovery; heart rate adjustment for ST segment depression; QRS duration and amplitude), although none of these indices have been as widely applied as the analysis of discrete ST depressions. These other previously established, more sensitive or specific ECG indices are rarely reported and it is not clear that they would change clinical practice.[3, 4]
2
ACCEPTED MANUSCRIPT
In this issue of the Journal of the American College of Cardiology, Christman and colleagues examine specific exercise ECG findings, and their association with utilization of additional diagnostic cardiovascular imaging tests as well as cardiovascular outcomes.[1] From a
RI PT
10,000-foot view, scoping the diagnostic evaluation of adults suspected of IHD is incredibly helpful for: (1) observing referral patterns, (2) discovering knowledge gaps, and (3) identifying areas for quality improvement; it is indeed the feedback every health system should be
SC
providing. Unfortunately, the overview engenders more questions than conclusions. For
example, it is impossible to judge whether the diagnostic referral patterns observed in this study
M AN U
are the result of probabilistic reasoning, or the interpretation of test findings in isolation. Without considering the patient’s pretest probability of disease and risk of future events, only limited conclusions can be drawn about the diagnostic utility of exercise ECG and the appropriateness of downstream testing. With respect to new knowledge, while the study adds to the literature
TE D
regarding the performance of specific exercise ECG findings in detecting disease, there continue to be salient questions about our ability to integrate test findings into calculations of disease probability and decisions around next steps. Given these limitations, the study’s impact may be
EP
greatest in identifying areas for improvement. Questions around test performance and the appropriateness of downstream testing are increasingly relevant for the cardiovascular imaging
AC C
community, particularly in light of the recent advances in non-invasive diagnostic testing modalities that have further expanded options for test selection. It may be that interpreting physicians need to reconsider their role in informing Bayesian decision-making. Outcomes following the diagnostic evaluation of IHD of 3,345 individuals referred for exercise ECG to a high-volume, academic stress lab were reviewed. The exercise ECG was reported as positive for ischemia in 3.7% of individuals; most were negative (67.7%) or
3
ACCEPTED MANUSCRIPT
inconclusive (28.5%). Additional downstream testing was performed in approximately 1 in 10 adults, reflecting the myriad of diagnostic modalities available for evaluating ischemia: nuclear myocardial perfusion imaging (obtained in 65% of individuals referred for a downstream test),
RI PT
stress echocardiogram (10%), coronary CTA (4%), stress MRI (1%), and coronary angiography (20%). Despite the increased sensitivity of more advanced diagnostic modalities, downstream testing yielded relatively few positive test results, especially among individuals with negative
SC
and inconclusive test findings, perhaps suggesting referring providers’ overestimation of disease probability or the limitations of all diagnostic tests. Moreover, as expected in this ambulatory
M AN U
population, the combined event-free survival from coronary revascularization, myocardial infarction, and cardiovascular death was low. These data provide important feedback; at the margins, the exercise ECG remains a useful initial strategy for the risk stratification of individuals suspected of IHD.
TE D
A second aim of the study was to determine whether new insights may be gained from reevaluating the reasons for inconclusive test findings, which generated the bulk of downstream testing. The authors found that individuals with inconclusive tests because of ‘rapid recovery of
EP
ECG changes’ unanimously had normal findings on subsequent diagnostic imaging tests, whereas those with inconclusive tests because of ‘typical angina but no ECG changes’ frequently
AC C
had a positive downstream test. These findings are consistent with prior studies showing that transient ECG changes and chest pain that occur with exercise ECG testing are important diagnostic and prognostic indices. The presence of chest pain was shown to be an important independent predictor of coronary artery disease along with outcomes in the 1970s, and is a risk factor in the Duke Treadmill Score used for prognosis.[5, 6] The clinical value of analyzing the time to recovery of ST depressions has also been established in earlier studies.[4] In fact, these
4
ACCEPTED MANUSCRIPT
earlier studies suggested that it was necessary to perform a heart rate (HR) adjustment for the recovery of exercise-induced ST depressions, and that change in ST/HR index or evaluation of the ST rate-recovery loop during exercise testing improved the prognostic value. [4]
RI PT
Nonetheless, conclusions about the utility of specific exercise ECG findings in the
‘inconclusive’ group must be interpreted with caution. For example, suppose only individuals with a high pretest probability were referred for additional testing, then individuals with low-
SC
probability of disease are not accounted for when assessing the yield of inconclusive test
findings. This differential assessment leads to ‘verification bias,’ or the inability to verify disease
M AN U
in all subjects (since not everyone had a downstream test).[7] Hence, the finding that 21% of individuals with ‘angina but no ECG changes’ had a positive downstream test may be an overestimation of the true utility of this finding.
Another limitation in validating specific exercise ECG findings with non-invasive
TE D
cardiovascular imaging tests is that most of the downstream tests performed in this study are not considered gold standards of coronary artery disease. All non-invasive imaging tests are inherently subject to delivering false positive and negative results, and cannot be used to verify
EP
exercise ECG findings. This can be appreciated if we consider the clinical significance of exertional angina. As outlined above, the presence of angina during a physiologic test to increase
AC C
myocardial oxygen demand has long been recognized as a predictor of outcomes, independent of ECG findings.[5, 8] Similarly, angina without perfusion defects or wall motion defects is also associated with adverse events. These tests were designed to detect obstructive coronary artery disease. However, microvascular disease or epicardial endothelial dysfunction may result in angina with normal ECG, imaging, and even coronary catheterization findings. Indeed, women with angina or other evidence of ischemia but no obstructive coronary disease have poor
5
ACCEPTED MANUSCRIPT
outcomes.[9, 10] As such, one must wonder whether patients were harmed by receiving a negative downstream test result. Developments in quantitative dynamic positron emission tomography (PET) imaging
RI PT
may help advance our understanding of this paradox. For example, diminished coronary flow reserve, a marker of microvascular disease, has been demonstrated using dynamic PET in
patients with chest pain and normal epicardial arteries.[11] These and other developments have
SC
the potential to transform test interpretation and risk assessment, however, they need to be correlated with patient outcomes.
M AN U
Indeed, as the field of advanced cardiac imaging grows, it is increasingly more complex to determine the optimal diagnostic work-up for patients suspected of IHD. Test selection and interpretation requires knowing more than just the pretest probability of disease and the reported sensitivity and specificity of the test.[12] Consideration must be given to the local quality of the
TE D
test (both in its administration and interpretation), the test’s performance in specific populations, and how the test would affect patient management and/or outcomes. Patient preferences must also be taken into account. These aspects of test selection are nuanced for each patient, and need
EP
to be considered when inferring the appropriateness of any downstream test, whether the optimal
testing.
AC C
imaging modality was selected, or whether patients benefited (or were harmed) by additional
How can we improve the yield of diagnostic tests and referral patterns to investigate IHD? The cardiovascular imaging community may be uniquely positioned to help shape the diagnostic landscape. To do so, however, cardiovascular imaging specialists may need to reconsider the reporting of test interpretations and their role in influencing disease management. For example, a more expanded reporting framework may consider questions, such as: What is
6
ACCEPTED MANUSCRIPT
the patients’ baseline risk for IHD? What are the specific test findings and what do they indicate, even if discordant? What are the options for next steps? What is at stake? Are there any risks in further testing? How might downstream testing affect management? What do the guidelines
RI PT
offer? What is the cost? Ideally, the consultation would serve as a clinical guide, facilitating more informed, patient-centered discussions and decisions regarding next steps. It would also serve as a roadmap for future investigative work and technology, identifying gaps in knowledge
SC
and opportunities for advancement. In this context, specific findings from the exercise ECG may
AC C
EP
TE D
M AN U
prompt more thoughtful decision-making, actually improving their diagnostic yield.
7
ACCEPTED MANUSCRIPT
References: 1. Fihn, S.D., et al., 2012 ACCF/AHA/ACP/AATS/PCNA/SCAI/STS Guideline for the Diagnosis and Management of Patients With Stable Ischemic Heart Disease: A Report of the American
RI PT
College of Cardiology Foundation/American Heart Association Task Force on Practice Guidelines, and the American College of Physicians, American Association for Thoracic Surgery, Preventive Cardiovascular Nurses Association, Society for Cardiovascular
SC
Angiography and Interventions, and Society of Thoracic Surgeons. J Am Coll Cardiol 2012;60:e44 -164.
M AN U
2. Mark, D.B., et al., Exercise treadmill score for predicting prognosis in coronary artery disease. Ann Intern Med, 1987. 106(6): p. 793-800.
3. Kligfield, P. and M.S. Lauer, Exercise electrocardiogram testing: beyond the ST segment. Circulation, 2006. 114(19): p. 2070-82.
TE D
4. Kligfield, P., O. Ameisen, and P.M. Okin, Heart rate adjustment of ST segment depression for improved detection of coronary artery disease. Circulation, 1989. 79(2): p. 245-55. 5. Cole, J.P. and M.H. Ellestad, Significance of chest pain during treadmill exercise:
EP
correlation with coronary events. Am J Cardiol, 1978. 41(2): p. 227-32. 6. Weiner, D.A., et al., The predictive value of anginal chest pain as an indicator of coronary
AC C
disease during exercise testing. Am Heart J, 1978. 96(4): p. 458-62. 7. Punglia, R.S., et al., Effect of verification bias on screening for prostate cancer by measurement of prostate-specific antigen. N Engl J Med, 2003. 349(4): p. 335-42. 8. Diamond, G.A., A clinically relevant classification of chest discomfort. J Am Coll Cardiol, 1983. 1(2 Pt 1): p. 574-5.
8
ACCEPTED MANUSCRIPT
9. Humphries, K.H., et al., Angina with "normal" coronary arteries: sex differences in outcomes. Am Heart J, 2008. 155(2): p. 375-81. 10. Johnson, B.D., et al., Prognosis in women with myocardial ischemia in the absence of
RI PT
obstructive coronary disease: results from the National Institutes of Health-National Heart, Lung, and Blood Institute-Sponsored Women's Ischemia Syndrome Evaluation (WISE). Circulation, 2004. 109(24): p. 2993-9.
SC
11. Geltman, E.M., et al., Increased myocardial perfusion at rest and diminished perfusion
Cardiol, 1990. 16(3): p. 586-95.
M AN U
reserve in patients with angina and angiographically normal coronary arteries. J Am Coll
12. Fryback, D.G. and J.R. Thornbury, The efficacy of diagnostic imaging. Med Decis Making,
AC C
EP
TE D
1991. 11(2): p. 88-94.
9
S0735-1097(14)00280-0
DOI:
10.1016/j.jacc.2013.12.026
Reference:
JAC 19747
To appear in:
Journal of the American College of Cardiology
Received Date: 13 December 2013 Accepted Date: 18 December 2013
Please cite this article as: Sinusas AJ, Spatz ES, Reframing the Interpretation and Application of Exercise Electrocardiography, Journal of the American College of Cardiology (2014), doi: 10.1016/ j.jacc.2013.12.026. This is a PDF file of an unedited manuscript that has been accepted for publication. As a service to our customers we are providing this early version of the manuscript. The manuscript will undergo copyediting, typesetting, and review of the resulting proof before it is published in its final form. Please note that during the production process errors may be discovered which could affect the content, and all legal disclaimers that apply to the journal pertain.
ACCEPTED MANUSCRIPT
Editorial Comments Reframing the Interpretation and Application of Exercise Electrocardiography Albert J. Sinusas, MD and Erica S. Spatz, MD, MHS
RI PT
Section of Cardiovascular Medicine, Department of Medicine Yale University School of Medicine
Address for correspondence: Albert J. Sinusas, MD, FACC Section of Cardiovascular Medicine
PO Box 8017, DANA 3 New Haven, CT 06520
(203) 737-1026 (fax)
EP
203-785-5005
TE D
Yale University School of Medicine
M AN U
Brief Title: Application of Exercise Electrocardiography
SC
New Haven, CT 06520
AC C
Email: [email protected]
No conflicts.
Key Words: exercise testing, downstream testing, imaging
1
ACCEPTED MANUSCRIPT
Guidelines recommend that most patients being evaluated for ischemic heart disease (IHD) undergo exercise electrocardiography (ECG), provided they are able to exercise.[1] Yet despite over three decades of data and experience, the test continues to vex interpreting
RI PT
physicians and referring providers alike. While recognized as providing valuable information, ambivalence arises in estimating the likelihood of disease based on a test with a reported
sensitivity of only 68% and specificity of 77%, far below the test performance of most other
SC
cardiovascular imaging modalities.
Inherent to the interpretation of the exercise ECG is the application of Bayes' theorem, or
M AN U
the process of probabilistic reasoning. Simply stated, the predictive value of any test result is conditional on the pretest probability of disease. These concepts were illustrated in Diamond and Forrester’s landmark paper of 1979, demonstrating the likelihood of coronary artery disease based on an individual’s age, sex, and symptoms, as well as the magnitude of ST depression with
TE D
exercise. In the ensuing 35 years, researchers have leveraged other data associated with the exercise ECG to improve the accuracy for detection of IHD, assess severity of disease, and inform risk stratification, including the evaluation of hemodynamic changes, exercise time, and
EP
symptoms. For example, the presence of angina and duration of exercise, captured in the Duke Treadmill Score, have been demonstrated to correlate with risk of future events.[2] Many other
AC C
electrocardiographic indices, beyond simple analysis of ST segment depressions, have been proposed for detection of IHD (e.g., heart rate recovery; heart rate adjustment for ST segment depression; QRS duration and amplitude), although none of these indices have been as widely applied as the analysis of discrete ST depressions. These other previously established, more sensitive or specific ECG indices are rarely reported and it is not clear that they would change clinical practice.[3, 4]
2
ACCEPTED MANUSCRIPT
In this issue of the Journal of the American College of Cardiology, Christman and colleagues examine specific exercise ECG findings, and their association with utilization of additional diagnostic cardiovascular imaging tests as well as cardiovascular outcomes.[1] From a
RI PT
10,000-foot view, scoping the diagnostic evaluation of adults suspected of IHD is incredibly helpful for: (1) observing referral patterns, (2) discovering knowledge gaps, and (3) identifying areas for quality improvement; it is indeed the feedback every health system should be
SC
providing. Unfortunately, the overview engenders more questions than conclusions. For
example, it is impossible to judge whether the diagnostic referral patterns observed in this study
M AN U
are the result of probabilistic reasoning, or the interpretation of test findings in isolation. Without considering the patient’s pretest probability of disease and risk of future events, only limited conclusions can be drawn about the diagnostic utility of exercise ECG and the appropriateness of downstream testing. With respect to new knowledge, while the study adds to the literature
TE D
regarding the performance of specific exercise ECG findings in detecting disease, there continue to be salient questions about our ability to integrate test findings into calculations of disease probability and decisions around next steps. Given these limitations, the study’s impact may be
EP
greatest in identifying areas for improvement. Questions around test performance and the appropriateness of downstream testing are increasingly relevant for the cardiovascular imaging
AC C
community, particularly in light of the recent advances in non-invasive diagnostic testing modalities that have further expanded options for test selection. It may be that interpreting physicians need to reconsider their role in informing Bayesian decision-making. Outcomes following the diagnostic evaluation of IHD of 3,345 individuals referred for exercise ECG to a high-volume, academic stress lab were reviewed. The exercise ECG was reported as positive for ischemia in 3.7% of individuals; most were negative (67.7%) or
3
ACCEPTED MANUSCRIPT
inconclusive (28.5%). Additional downstream testing was performed in approximately 1 in 10 adults, reflecting the myriad of diagnostic modalities available for evaluating ischemia: nuclear myocardial perfusion imaging (obtained in 65% of individuals referred for a downstream test),
RI PT
stress echocardiogram (10%), coronary CTA (4%), stress MRI (1%), and coronary angiography (20%). Despite the increased sensitivity of more advanced diagnostic modalities, downstream testing yielded relatively few positive test results, especially among individuals with negative
SC
and inconclusive test findings, perhaps suggesting referring providers’ overestimation of disease probability or the limitations of all diagnostic tests. Moreover, as expected in this ambulatory
M AN U
population, the combined event-free survival from coronary revascularization, myocardial infarction, and cardiovascular death was low. These data provide important feedback; at the margins, the exercise ECG remains a useful initial strategy for the risk stratification of individuals suspected of IHD.
TE D
A second aim of the study was to determine whether new insights may be gained from reevaluating the reasons for inconclusive test findings, which generated the bulk of downstream testing. The authors found that individuals with inconclusive tests because of ‘rapid recovery of
EP
ECG changes’ unanimously had normal findings on subsequent diagnostic imaging tests, whereas those with inconclusive tests because of ‘typical angina but no ECG changes’ frequently
AC C
had a positive downstream test. These findings are consistent with prior studies showing that transient ECG changes and chest pain that occur with exercise ECG testing are important diagnostic and prognostic indices. The presence of chest pain was shown to be an important independent predictor of coronary artery disease along with outcomes in the 1970s, and is a risk factor in the Duke Treadmill Score used for prognosis.[5, 6] The clinical value of analyzing the time to recovery of ST depressions has also been established in earlier studies.[4] In fact, these
4
ACCEPTED MANUSCRIPT
earlier studies suggested that it was necessary to perform a heart rate (HR) adjustment for the recovery of exercise-induced ST depressions, and that change in ST/HR index or evaluation of the ST rate-recovery loop during exercise testing improved the prognostic value. [4]
RI PT
Nonetheless, conclusions about the utility of specific exercise ECG findings in the
‘inconclusive’ group must be interpreted with caution. For example, suppose only individuals with a high pretest probability were referred for additional testing, then individuals with low-
SC
probability of disease are not accounted for when assessing the yield of inconclusive test
findings. This differential assessment leads to ‘verification bias,’ or the inability to verify disease
M AN U
in all subjects (since not everyone had a downstream test).[7] Hence, the finding that 21% of individuals with ‘angina but no ECG changes’ had a positive downstream test may be an overestimation of the true utility of this finding.
Another limitation in validating specific exercise ECG findings with non-invasive
TE D
cardiovascular imaging tests is that most of the downstream tests performed in this study are not considered gold standards of coronary artery disease. All non-invasive imaging tests are inherently subject to delivering false positive and negative results, and cannot be used to verify
EP
exercise ECG findings. This can be appreciated if we consider the clinical significance of exertional angina. As outlined above, the presence of angina during a physiologic test to increase
AC C
myocardial oxygen demand has long been recognized as a predictor of outcomes, independent of ECG findings.[5, 8] Similarly, angina without perfusion defects or wall motion defects is also associated with adverse events. These tests were designed to detect obstructive coronary artery disease. However, microvascular disease or epicardial endothelial dysfunction may result in angina with normal ECG, imaging, and even coronary catheterization findings. Indeed, women with angina or other evidence of ischemia but no obstructive coronary disease have poor
5
ACCEPTED MANUSCRIPT
outcomes.[9, 10] As such, one must wonder whether patients were harmed by receiving a negative downstream test result. Developments in quantitative dynamic positron emission tomography (PET) imaging
RI PT
may help advance our understanding of this paradox. For example, diminished coronary flow reserve, a marker of microvascular disease, has been demonstrated using dynamic PET in
patients with chest pain and normal epicardial arteries.[11] These and other developments have
SC
the potential to transform test interpretation and risk assessment, however, they need to be correlated with patient outcomes.
M AN U
Indeed, as the field of advanced cardiac imaging grows, it is increasingly more complex to determine the optimal diagnostic work-up for patients suspected of IHD. Test selection and interpretation requires knowing more than just the pretest probability of disease and the reported sensitivity and specificity of the test.[12] Consideration must be given to the local quality of the
TE D
test (both in its administration and interpretation), the test’s performance in specific populations, and how the test would affect patient management and/or outcomes. Patient preferences must also be taken into account. These aspects of test selection are nuanced for each patient, and need
EP
to be considered when inferring the appropriateness of any downstream test, whether the optimal
testing.
AC C
imaging modality was selected, or whether patients benefited (or were harmed) by additional
How can we improve the yield of diagnostic tests and referral patterns to investigate IHD? The cardiovascular imaging community may be uniquely positioned to help shape the diagnostic landscape. To do so, however, cardiovascular imaging specialists may need to reconsider the reporting of test interpretations and their role in influencing disease management. For example, a more expanded reporting framework may consider questions, such as: What is
6
ACCEPTED MANUSCRIPT
the patients’ baseline risk for IHD? What are the specific test findings and what do they indicate, even if discordant? What are the options for next steps? What is at stake? Are there any risks in further testing? How might downstream testing affect management? What do the guidelines
RI PT
offer? What is the cost? Ideally, the consultation would serve as a clinical guide, facilitating more informed, patient-centered discussions and decisions regarding next steps. It would also serve as a roadmap for future investigative work and technology, identifying gaps in knowledge
SC
and opportunities for advancement. In this context, specific findings from the exercise ECG may
AC C
EP
TE D
M AN U
prompt more thoughtful decision-making, actually improving their diagnostic yield.
7
ACCEPTED MANUSCRIPT
References: 1. Fihn, S.D., et al., 2012 ACCF/AHA/ACP/AATS/PCNA/SCAI/STS Guideline for the Diagnosis and Management of Patients With Stable Ischemic Heart Disease: A Report of the American
RI PT
College of Cardiology Foundation/American Heart Association Task Force on Practice Guidelines, and the American College of Physicians, American Association for Thoracic Surgery, Preventive Cardiovascular Nurses Association, Society for Cardiovascular
SC
Angiography and Interventions, and Society of Thoracic Surgeons. J Am Coll Cardiol 2012;60:e44 -164.
M AN U
2. Mark, D.B., et al., Exercise treadmill score for predicting prognosis in coronary artery disease. Ann Intern Med, 1987. 106(6): p. 793-800.
3. Kligfield, P. and M.S. Lauer, Exercise electrocardiogram testing: beyond the ST segment. Circulation, 2006. 114(19): p. 2070-82.
TE D
4. Kligfield, P., O. Ameisen, and P.M. Okin, Heart rate adjustment of ST segment depression for improved detection of coronary artery disease. Circulation, 1989. 79(2): p. 245-55. 5. Cole, J.P. and M.H. Ellestad, Significance of chest pain during treadmill exercise:
EP
correlation with coronary events. Am J Cardiol, 1978. 41(2): p. 227-32. 6. Weiner, D.A., et al., The predictive value of anginal chest pain as an indicator of coronary
AC C
disease during exercise testing. Am Heart J, 1978. 96(4): p. 458-62. 7. Punglia, R.S., et al., Effect of verification bias on screening for prostate cancer by measurement of prostate-specific antigen. N Engl J Med, 2003. 349(4): p. 335-42. 8. Diamond, G.A., A clinically relevant classification of chest discomfort. J Am Coll Cardiol, 1983. 1(2 Pt 1): p. 574-5.
8
ACCEPTED MANUSCRIPT
9. Humphries, K.H., et al., Angina with "normal" coronary arteries: sex differences in outcomes. Am Heart J, 2008. 155(2): p. 375-81. 10. Johnson, B.D., et al., Prognosis in women with myocardial ischemia in the absence of
RI PT
obstructive coronary disease: results from the National Institutes of Health-National Heart, Lung, and Blood Institute-Sponsored Women's Ischemia Syndrome Evaluation (WISE). Circulation, 2004. 109(24): p. 2993-9.
SC
11. Geltman, E.M., et al., Increased myocardial perfusion at rest and diminished perfusion
Cardiol, 1990. 16(3): p. 586-95.
M AN U
reserve in patients with angina and angiographically normal coronary arteries. J Am Coll
12. Fryback, D.G. and J.R. Thornbury, The efficacy of diagnostic imaging. Med Decis Making,
AC C
EP
TE D
1991. 11(2): p. 88-94.
9
