INTRODUCTION — The diagnosis of coronary heart disease (CHD) as the cause of chest discomfort (or other anginal-type symptoms of cardiac origin) starts with a careful clinical history and resting electrocardiogram (ECG), and often requires additional investigation. Invasive coronary angiography is considered the "gold standard" for the diagnosis of CHD involving the epicardial coronary vessels, but it is limited by its invasive nature, attendant risks, inability to assess the microcirculation, and cost. Invasive angiography is therefore rarely indicated as the first diagnostic test for stable CHD, and is appropriate only in select, high-risk patient populations [1,2]. Computed tomography coronary angiography (CTCA), which can noninvasively image the epicardial coronary vessels, has a lower risk than invasive angiography but shares many limitations of invasive angiography (eg, radiation exposure, inability to assess the microcirculation, or to assess the functional significance of coronary stenoses), and has additional limitations of its own (eg, artifact). (See "Cardiac imaging with computed tomography and magnetic resonance in the adult".)
The evaluation of patients presenting with chest discomfort or other symptoms suggestive of CHD usually relies upon stress testing. Several types of stress tests are available clinically that vary in accuracy, availability, and cost. The optimal testing strategy, including the possible use of more than one test, differs according to the patient population [3,4]. (See "Selecting the optimal cardiac stress test".)
The use of stress testing for the diagnosis of obstructive CHD will be reviewed here. The overall approach to the patient who presents with chest discomfort, including those with known or suspected CHD, the advantages and limitations of the different stress testing modalities, and the use of stress testing to assess prognosis or guide management are discussed separately. (See "Outpatient evaluation of the adult with chest pain" and "Selecting the optimal cardiac stress test" and "Prognostic features of stress testing in patients with known or suspected coronary disease".)
OUR APPROACH TO DIAGNOSTIC STRESS TESTING — Our approach to diagnostic stress testing varies with the pretest probability of disease, which is the estimate of the likelihood of coronary heart disease (CHD) prior to stress testing based upon the patient's age, gender, symptom characteristics, and clinical history, including standard cardiac risk factors. Because pre-test probability of disease strongly influences post-test likelihood of disease (figure 2B), clinical assessment of pretest probability, based upon data from large studies, is essential prior to testing (table 1). This estimate of pretest probability of CHD can then be used to determine the need for and the optimal initial diagnostic approach to testing in the patient with known or suspected CHD.
Estimating pretest probability — Several studies with varying methodologies have contributed to estimation of the pretest probability of CHD [5-11]. As examples:
●In the classic analysis from the Coronary Artery Surgery Study (CASS), 1465 men and 580 women with complaints of chest pain underwent treadmill exercise testing prior to invasive coronary angiography, and were categorized into three groups based on chest pain symptoms :
•Definite or classic angina – Substernal chest discomfort characterized by all of the following characteristics: a typical quality and duration, provocation by exertion or emotional stress, and relief by rest or nitroglycerin
•Probable or atypical angina – Chest pain with two of the three above characteristics
•Nonanginal or nonischemic chest pain – Chest pain with one or none of the above characteristics
The pretest probability (figure 1) of CHD varied between 5 and 89 percent based upon gender and chest pain characteristics. Within each of these subgroups, the frequency of CHD increased with age, while women with the same symptoms were less likely to have CHD than men of the same age (table 1) [5-7,12]. The higher false-positive rate on exercise ECG testing in women compared with men can be largely explained by the lower prevalence of CHD in women [1,2].
●Male gender, older age, diabetes mellitus, and hyperlipidemia were identified as independent predictors of the likelihood of CHD in an analysis of nearly 400,000 patients from the American College of Cardiology National Cardiovascular Data Registry who underwent invasive coronary angiography . Elective noninvasive testing (some form of stress testing in most cases) was performed prior to angiography in 84 percent of patients, and patients with an abnormal noninvasive test result were significantly more likely to have obstructive CHD (41 versus 35 percent).
●Patient age, sex, and symptom type were independent predictors of the probability of CHD in a multi-center registry of over 14,000 patients with suspected CHD who underwent CT coronary angiography . The overall prevalence of CHD was lower in this cohort of patients who did not undergo invasive coronary angiography than in earlier studies that required referral to cardiac catheterization to document anatomic CHD. (See "Noninvasive testing and imaging for diagnosis in patients at low to intermediate risk for acute coronary syndrome".)
Using the pretest probability — The interpretation of the stress test result (as with any diagnostic test) is strongly influenced by the pre-test probability of disease (ie, prevalence). The probability of disease in a patient with a positive test result (positive predictive value), and probability of no disease in a patient with a negative test result (negative predictive value), depends directly on the pretest probability of disease. Major differences between studies in the apparent accuracy of noninvasive testing are explained, at least in part, by this factor.
Stress testing is most useful for the diagnosis of CHD in patients with an intermediate pretest probability (variably defined as between 25 and 75 percent or between 10 and 90 percent) (table 1). Positive tests in these patients are more likely to be true positives due to the predictive accuracy of the test . Stress testing is less useful for the diagnosis of CHD in patients with either a high or a low pretest probability. Asymptomatic patients without diabetes have a low pretest probability of significant CHD, and generally should not be screened by use of stress testing. In asymptomatic patients, the risk of developing symptomatic CHD over the next 10 years can be estimated using one of many validated risk scores. (See "Screening for coronary heart disease" and "Screening for coronary heart disease in patients with diabetes mellitus" and "Cardiovascular disease risk assessment for primary prevention: Risk calculators".)
In special situations, such as those who have high-risk occupations (eg, airline pilots, bus drivers), asymptomatic patients may be considered for stress testing or CCTA. (See 'Summary and recommendations' below and "Screening for coronary heart disease".)
Posttest probability — The pretest probability, in conjunction with the sensitivity and specificity of the test, is used to determine the posttest probability of CHD (figure 2A-B).
Among patients with a very high pretest probability, a positive stress test is highly predictive of CHD, but a negative stress test does not exclude CHD. Conversely, among patients with a very low pretest probability, a positive stress test is likely to be a false-positive result, while a negative stress test is highly predictive of the absence of CHD.
Once the decision to perform a stress test has been made, the choice of the optimal test will depend upon clinical information. The ability to exercise adequately and a normal resting ECG are necessary for performing an exercise ECG without imaging for CHD. Stress imaging options have different advantages and disadvantages in different patient groups. Local expertise and availability may also affect the choice of imaging modality for stress testing. This is also discussed in greater detail separately. (See "Selecting the optimal cardiac stress test".)
Test accuracy — For patients in whom all of the tests can be performed, accuracy, radiation exposure, local expertise in performance and interpretation of the test, and cost are all important factors in choosing a test.
Sensitivity and specificity — The accuracy of noninvasive tests for CHD is determined by their sensitivity and specificity (figure 1). (See "Glossary of common biostatistical and epidemiological terms", section on 'Measures of diagnostic test performance'.)
●Sensitivity reflects the probability of a positive test among patients with disease. A high sensitivity increases a test's ability to "rule out" disease if the test is negative.
●Specificity reflects the probability of a negative test among patients without disease. A high specificity increases a test's ability to "rule in" disease if the test is positive.
●Predictive accuracy is the percentage of test responses (both positive and negative) that are true; this measure depends upon both test characteristics and disease prevalence in the tested population.
The sensitivity of the stress testing for diagnosing CHD depends upon the population studied, the definition of coronary disease used (≥70 and ≥50 percent diameter stenosis are common definitions), and the extent of coronary disease. There are also procedure-specific factors. With exercise ECG testing, for example, test performance can be affected by exercise end points, the number of ECG leads monitored, and most importantly by the ECG criteria used for a positive test (table 2). (See "Exercise ECG testing: Performing the test and interpreting the ECG results".)
The sensitivity and specificity of a given test vary reciprocally upon the threshold used to define a positive result. As an example, if ST segment depression with exercise is used as the test endpoint, a cutoff of 1 mm of ST segment depression is more sensitive but less specific than a cutoff of 2 mm of ST segment depression to define a positive test. In general, the application of more stringent criteria for a positive result decreases sensitivity and increases specificity, while the application of less stringent criteria increases sensitivity and decreases specificity.
Epicardial disease versus microcirculatory disease — For decades, CHD was diagnosed by identifying a significant stenosis in an epicardial coronary artery, and it was felt that patients with angina but no obstructive epicardial CHD must have a non-cardiac etiology for their symptoms. This approach also affected the sensitivity and specificity of various diagnostic tests, with epicardial CHD seen (or not seen) on coronary angiography used as the gold standard. However, functional changes at the site of epicardial vessels and/or at the microcirculatory level may, in some individuals, lead to true myocardial ischemia, resulting in symptoms, wall motion abnormalities on stress echocardiography, and perfusion defects on rMPI, even in the absence of severely obstructive coronary artery disease (CAD). It is now more common for trials to include combined anatomic (eg, invasive coronary angiography) and functional (eg, assessment of myocardial ischemia) reference standards for the determination of test sensitivity and specificity. (See "Microvascular angina: Angina pectoris with normal coronary arteries".)
Post-test referral (verification) bias — The majority of studies evaluating diagnostic accuracy of stress testing determine sensitivity and specificity used invasive coronary angiography as the gold standard. Because patients are generally referred for angiography due to abnormal test results, this leads to artificially increased sensitivity and decreased specificity. This poses challenges in determining the true accuracy of stress testing for the diagnosis of CHD. The few studies that have corrected for verification bias then reported lower sensitivity and higher specificity.
Challenges in women — While women present some diagnostic challenges for identifying ischemia related to obstructive CHD, the choice of diagnostic test is rarely made based on gender but rather on the clinical scenario. However, women are less likely to present with (or report during treadmill testing) typical angina and false positive test results during exercise ECG testing are more common in women . The diagnostic value of the exercise ECG testing alone in women is limited by a lower specificity of ST segment changes compared with men and a lower sensitivity for diagnosing ischemia compared with stress imaging [14,15]. Some of the important causes of this lower predictive accuracy in women are:
●A lower prevalence of coronary disease than in men of the same age [5,16].
●A higher prevalence of nonobstructive CAD and microvascular disease which, while not associated with obstructive disease on angiography, can cause symptoms and are associated with future cardiac events .
●A modestly higher incidence of false-positive ST segment depression during exercise [5,18].
The optimal diagnostic strategy, from a standpoint of both accuracy and cost effectiveness, is not yet known in women with suspected CHD. The WOMEN trial randomized 824 women with an intermediate pre-test probability of CHD to either an exercise ECG or exercise myocardial perfusion imaging. The study found that the exercise ECG strategy led to more abnormal initial tests, and thus required more follow-up testing, but had lower overall costs and equivalent clinical outcomes . The consensus statement of the American Heart Association recommends using a similar diagnostic approach in women and men .
AVAILABLE NON-INVASIVE TESTS — A variety of noninvasive tests are available to establish the diagnosis of coronary heart disease (CHD). The performance of each modality listed below is usually defined by comparing the noninvasive test results with invasive coronary angiography as the gold standard. The following tests are available for the non-invasive diagnosis of coronary heart disease:
●Exercise ECG, generally using a treadmill and standardized protocols.
●Radionuclide myocardial perfusion imaging using either exercise or pharmacologic stress and imaging with either single photon emission computed tomography (SPECT) or positron emission tomography (PET). (See "Overview of stress radionuclide myocardial perfusion imaging".)
●Coronary computed tomography angiography (CCTA) and CT perfusion and perfusion reserve. (See "Cardiac imaging with computed tomography and magnetic resonance in the adult".)
●Cardiac magnetic resonance imaging. (See "Cardiac imaging with computed tomography and magnetic resonance in the adult".)
●Hybrid imaging using either SPECT/CT, PET/CT, or PET/MR.
Noninvasive tests can be classified according to the manifestation of CHD they aim to detect: anatomic coronary artery disease, reversible myocardial ischemia, or prior myocardial infarction. Tests for myocardial ischemia can be further classified according to the method used to detect ischemia (ECG changes, perfusion defects, or wall motion abnormalities) and the method used to induce ischemia (exercise or pharmacologic stress). The different noninvasive tests vary in their diagnostic discrimination (sensitivity, specificity, and frequency of nondiagnostic results). The sensitivity of stress testing with imaging (SPECT 87 percent, echocardiography 86 percent) is generally higher than that of exercise ECG testing without imaging (68 percent), whereas values for specificity are similar [20-22]. The tests also vary with respect to prognostic accuracy, relative cost, and interobserver variability. (See "Selecting the optimal cardiac stress test", section on 'Comparison of different imaging techniques'.)
The extent of ischemia identified with stress testing can be estimated or quantified by each of the methods above, but the severity of ischemia is better graded by stress imaging techniques. More extensive and more severe ischemia indicates a worse prognosis and the likely need for more aggressive management, including coronary angiography. Ischemia can also be localized by imaging but is not localized accurately by ST segment depression on the exercise ECG . A more extensive discussion of the choice between available tests is presented separately. (See "Selecting the optimal cardiac stress test".)
Exercise ECG testing — Exercise ECG testing, most often based on treadmill exercise, is the most commonly used stress test because it is simple, inexpensive, and well validated. The performance and interpretation of this test are described in detail separately. (See "Exercise ECG testing: Performing the test and interpreting the ECG results".)
Advantages of exercise testing — As a general rule, exercise stress testing provides more information than pharmacologic stress testing for the following reasons (see "Selecting the optimal cardiac stress test", section on 'Exercise'):
●Exercise testing is more physiologic and mimics the conditions under which the patient's usual symptoms may be replicated. Symptoms induced by pharmacologic stress testing are often nonspecific side effects of the drug.
●Exercise documents the workload that induces symptoms and ischemia. (See "Exercise ECG testing: Performing the test and interpreting the ECG results", section on 'Common exercise protocols'.)
●Exercise capacity and hemodynamic responses are predictors of prognosis independent of ischemia. (See "Prognostic features of stress testing in patients with known or suspected coronary disease", section on 'Exercise ECG'.)
●Symptoms and ischemia at a low workload indicates a greater likelihood of severe disease and a worse prognosis than does the same degree of ischemia at a high workload. Furthermore, the inability to exercise is itself associated with increased cardiovascular risk.
In addition to obtaining the physiologic information related to exercise, exercise ECG testing has several advantages:
●Widely available and accessible
●No requirements for intravenous access or radiation exposure
●Relatively inexpensive, particularly compared with stress testing with imaging
Limitations of exercise ECG testing — While exercise ECG testing is a valuable test for many patients, it is not feasible for patients who either are unable to exercise to an adequate level, or may be nondiagnostic for ischemia in those patients who have certain baseline ECG abnormalities.
To maximize the sensitivity of exercise ECG testing, the patient must be able to exercise adequately. Failure to achieve at least 85 percent of the maximal predicted heart rate reduces the sensitivity for diagnosing ischemic heart disease. (See "Exercise ECG testing: Performing the test and interpreting the ECG results", section on 'Limitations to exercise ECG testing'.)
The exercise ECG cannot be interpreted for the development of ischemia in the presence of certain baseline ECG abnormalities, including:
●Left bundle branch block
●Paced ventricular rhythm
●Left ventricular hypertrophy with repolarization abnormalities
●ST-segment depression ≥1 mm
Other conditions that may affect test accuracy include digoxin use and electrolyte abnormalities with associated ST-T abnormalities.
For patients who cannot exercise, who have baseline ECG abnormalities that preclude exercise ECG interpretation, or in whom a previously performed exercise ECG test was nondiagnostic due to an inadequate heart rate response, a number of alternative noninvasive tests are available and discussed separately. (See "Selecting the optimal cardiac stress test".)
Radionuclide myocardial perfusion imaging — Stress testing with radionuclide myocardial perfusion imaging (rMPI; either SPECT or PET) is a well-validated option for the evaluation of patients with symptoms suggestive of obstructive coronary heart disease (CHD). Stress rMPI can be performed using either exercise or pharmacologic stress (with vasodilators or dobutamine), and can be performed with a number of radioisotopes. rMPI is generally more sensitive and specific for the diagnosis of CHD than exercise ECG testing alone. The performance and interpretation of this test is described in detail separately. (See "Overview of stress radionuclide myocardial perfusion imaging".)
Advantages of rMPI stress testing — Stress testing with rMPI provides information regarding the extent, severity, and location of the ischemic territory that is not acquired from exercise ECG testing alone. The information about myocardial perfusion defects increases the sensitivity and specificity for the diagnosis of CHD over clinical characteristics and exercise test results. Stress rMPI also provides measurements of left ventricular volumes and global and regional function. Pharmacologic stress testing with rMPI is an option for patients who are unable to exercise to an adequate level (by substituting a vasodilator or dobutamine as the stress agent), as well as those with resting ECG abnormalities that preclude exercise ECG testing alone. Vasodilator rMPI is typically performed for the majority of patients who are unable to exercise adequately; dobutamine stress rMPI is an option when vasodilator effects are likely to be attenuated (ie, recent caffeine or theophylline use), or when vasodilators are contraindicated, because dobutamine can be safely given to patients with reactive airway disease . A practical advantage of rMPI with SPECT is the ability to perform delayed imaging post stress. Another major advantage of stress rMPI is its prognostic value . In 2016, the American Society of Nuclear Cardiology and Society of Nuclear Medicine and Molecular Imaging published a joint position paper recommending the use of PET MPI as a first-line preferred test for patients with known or suspected CHD who meet appropriate criteria for a stress imaging test and are unable to complete a diagnostic-level exercise stress imaging study . (See 'Advantages of stress echocardiography' below and "Overview of stress radionuclide myocardial perfusion imaging".)
Limitations of rMPI stress testing — While stress testing with rMPI offers advantages over exercise ECG testing alone, there are also some potential limitations. rMPI is more costly than the exercise ECG alone. Stress testing with rMPI also exposes the patient to radiation; the exposure level with PET MPI is lower than with SPECT MPI. In addition, interpretation of rMPI with SPECT can be affected by attenuation artifacts related to soft tissue overlying the heart (eg, sub-diaphragmatic tissues, chest wall, breasts, adipose) or extracardiac radioisotope (eg, liver or gastrointestinal uptake which may be adjacent to the heart). (See "Radiation dose and risk of malignancy from cardiovascular imaging" and "Overview of stress radionuclide myocardial perfusion imaging".)
Stress echocardiography — Stress echocardiography is another well-validated option for the evaluation of patients with symptoms suggestive of obstructive coronary heart disease (CHD). It can be performed with either exercise or pharmacologic stress (most commonly dobutamine, vasodilators in some settings) and does not expose the patient to radiation. Stress echocardiography is generally more sensitive and specific for the diagnosis of CHD than exercise ECG testing alone, although more costly. The performance and interpretation of this test is described in detail separately. (See "Overview of stress echocardiography".)
Advantages of stress echocardiography — Stress echocardiography documents myocardial function and regional wall motion, which provide information regarding the global left ventricular function, ischemic territory, and extent of ischemia that is not available from exercise ECG testing alone. This information increases the sensitivity and specificity for the diagnosis of CHD. As with rMPI, the accuracy of stress echocardiography is dependent upon the degree of stenosis and the amount of myocardium at risk.
Stress echocardiography is an option for patients who are unable to exercise to an adequate level (by substituting dobutamine or a vasodilator as the stress agent), as well as those with resting ECG abnormalities that preclude exercise ECG testing alone. In contrast to stress testing with rMPI and post-treadmill exercise stress echocardiography, dobutamine stress echocardiography allows images to be obtained at increasing levels of stress and during peak stress. Other considerations in choosing between dobutamine echocardiography and pharmacologic rMPI include feasibility (rMPI is preferred if acoustic windows are suboptimal), cost (generally higher for rMPI), concern for radiation exposure (with rMPI), local availability, and expertise [3,27]. (See 'Advantages of rMPI stress testing' above.)
There are several other advantages of stress echocardiography, including:
●Shorter patient time commitment than rMPI, similar to exercise ECG testing
●No radiation exposure
●Additional information on cardiac structures (valves, ascending aorta, pericardial space)
●Readily available and less technically demanding than rMPI
Limitations of stress echocardiography — While stress echocardiography offers some advantages over other stress modalities, it also has potential limitations. One limitation is the potential for rapid resolution of ischemia prior to image acquisition post-exercise. Additionally, a hypertensive response to exercise may be associated with a greater likelihood of a false positive exercise stress echocardiogram. Suboptimal images limit the interpretation in a small percentage of echocardiographic studies, thereby impairing the assessment of segmental and global LV systolic function . Suboptimal imaging during exercise stress echocardiography can also be exacerbated by respiratory motion due to heavy breathing post-exercise and patient positioning following the transition from treadmill to imaging table. Echocardiographic contrast administration during stress echocardiography can help to define the endocardial borders and identify wall motion abnormalities in patients with suboptimal acoustic windows. This is discussed in greater detail separately. (See "Contrast echocardiography: Clinical applications", section on 'Stress echocardiography'.)
Stress cardiac magnetic resonance imaging — Pharmacologic stress testing, using either a vasodilator or dobutamine, can be combined with cardiac magnetic resonance (CMR) imaging to assess for myocardial ischemia. Stress CMR with dobutamine or adenosine appears to have at least equivalent, and possibly superior, sensitivity and specificity for diagnosing coronary heart disease (CHD) when compared with stress rMPI or stress echocardiography [29,30]. Due to technical considerations related to CMR imaging, however, exercise stress is not an option with this technique, which limits the amount of physiologic information acquired during the stress test. In addition, the technique is not available in most centers.
TEST SELECTION — Once the decision has been made to pursue a stress test, the major questions to be addressed in selecting one or more of the available diagnostic tests are:
●Can the patient exercise adequately? (see "Exercise ECG testing: Performing the test and interpreting the ECG results")
●Is the resting ECG normal? (see 'Limitations of exercise ECG testing' above)
●Does the patient have large body habitus or lung disease?
●Is there local expertise in performing and interpreting the test?
●What is the test performance? (see 'Test accuracy' above)
●What is the pre-test likelihood of disease? (see 'Estimating pretest probability' above)
●What are the costs and effects on health outcomes of each test?
●Are there contraindications to the test?
A more extensive discussion of stress test selection is presented separately. (See "Selecting the optimal cardiac stress test".)
Comparison of stress testing options — In general, all stress testing modalities have sensitivities and specificities for the diagnosis of obstructive CHD in the 70 to 90 percent range, with stress imaging modalities typically being more sensitive than exercise ECG testing alone (table 3). However, no study has compared the diagnostic accuracy of all available types of stress tests in the same group of patients and there are few studies that compare results of even two noninvasive tests in the same patients. Consequently, the relative performance of alternative tests is based upon the synthesis of multiple studies of variable design. (See "Selecting the optimal cardiac stress test", section on 'Comparison of different imaging techniques'.)
SOCIETY GUIDELINE LINKS — Links to society and government-sponsored guidelines from selected countries and regions around the world are provided separately. (See "Society guideline links: Chronic coronary syndrome" and "Society guideline links: Multimodality cardiovascular imaging appropriate use criteria" and "Society guideline links: Stress testing and cardiopulmonary exercise testing".)
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SUMMARY AND RECOMMENDATIONS
●Stress testing is useful for the evaluation of selected patients with known or suspected coronary heart disease (CHD). In general, exercise stress is preferred for patients who are able to exercise, and pharmacologic stress is reserved for those unable to complete an exercise stress test. (See 'Introduction' above.)
●The major questions to be addressed before selecting one or more of the available diagnostic tests include the patient's pretest probability of CHD, accuracy of the available tests, effects of the test on health outcomes, and special considerations (both patient- and test-related) which may result in a preference for a specific choice. (See 'Test selection' above.)
●Our approach to diagnostic stress testing varies with the pretest probability of disease. We strongly recommend that a specific clinical assessment of pretest probability be made prior to testing, based upon objective data (table 1). Once the decision to perform a stress test has been made, the choice of the optimal stress test will depend upon clinical information. (See 'Our approach to diagnostic stress testing' above and "Selecting the optimal cardiac stress test".)
•In the patient with a high pretest probability of CHD, noninvasive testing is generally not necessary to establish the diagnosis, and a negative test result is likely to be a false negative. However, stress testing may be important in determining prognosis and guiding management.
•In the patient with an intermediate pretest probability of CHD, in whom the main objective is to clarify the diagnosis, we generally recommend exercise ECG testing, with the addition of imaging when clinically indicated and appropriate.
•In the patient with a low pretest probability of CHD, we do not recommend stress testing for most patients because a positive result is likely to be a false positive.
●Exercise ECG testing, stress testing with radionuclide myocardial perfusion imaging (rMPI), and stress echocardiography are all well-validated options for stress testing to diagnose CHD (table 3), with each test offering a variety of strengths and drawbacks relative to the other available tests. (See 'Available non-invasive tests' above.)
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