Cardiac Stress Testing in the Emergency Department
Authors: Preeti Jois-Bilowich, MD, Clinical Assistant Professor, Department of Emergency Medicine, University of Florida, Gainesville; and Jonathan Glauser, MD, MBA, Institute Chairman, Emergency Services Institute, Cleveland Clinic, Cleveland, OH.
Peer Reviewer: Robert F. McCarron, MD, Assistant Professor of Emergency Medicine, University of Massachusetts Medical School, Medical Director, Cardiac Decision Unit, University of Massachusetts Memorial Medical Center, Worcester, MA.
A few years ago, cardiac stress testing would not have been an important subject for emergency physicians. With the growth of observation units run by emergency physicians, however, more of us are ordering these tests and then acting on the results. Even in departments where there is no formal observation unit, many patients are ruled out for myocardial infarction and scheduled for functional stress testing as an outpatient. These tests are likely ordered by the emergency physician with or without consultation with a cardiologist or primary physician. Therefore, the modern emergency physician needs to be familiar with the limitations and restrictions of the common tests available.
There is another, and perhaps more important, reason to have a sound knowledge of stress testing. During nearly every shift a patient presents with chest pain and the history of a negative cardiac stress test. Admitting the patient for another rule-out is expensive; therefore, understanding the sensitivity and specificity of each different type of test will help emergency physicians determine the risk profile for the patient.
Sandra M. Schneider, MD, FACEP, Editor
Introduction
The Agency for Healthcare Research and Quality (AHRQ) reports that Americans made approximately 110 million individual visits to the emergency department (ED) in 2005. Of those, nearly 84 million were adult patients (18 years of age or older). Six of the 10 most common conditions requiring admission to the hospital from the ED involved diseases of the circulatory systemcongestive heart failure, coronary artery disease, heart attack, and problems with heart rhythm.1
Overall, death rates from cardiovascular disease are decreasing. However, it remains the major cause of death in the United States, with roughly 288 deaths per 100,000 people per year. These statistics highlight the fact that cardiovascular disease still poses challenges for both the public health and economic sectors. Proposed costs of care for patients with cardiovascular disease are estimated to be around $450 billion.2
Overview
Stress testing is an important modality in the clinical practice of emergency medicine for the evaluation of patients with known or suspected coronary artery disease (CAD). With the use of exercise or pharmacologic testing in emergency department chest pain centers and clinical decision units (CDUs), emergency physicians may provide rapid and efficient risk stratification and management for chest pain patients believed to possibly have CAD. In addition, stress testing is useful for identifying patients with recurrent ischemia after revascularization with either coronary artery bypass graft (CABG) or percutaneous coronary intervention (PCI).
Coronary angiography is considered the "gold standard" for diagnosis, but it is invasive and costly, and considered inappropriate as an initial diagnostic study in most instances.3 The main indications for performing a stress test are for risk assessment and stratification during initial evaluation of suspected ischemic chest pain and in patients with a significant change in cardiac symptoms.4 For patients with stable angina, the main indications for stress testing are at initial evaluation and when there is significant change in cardiac symptoms. Risk stratification may lead to a decision to refer the patient for revascularization. In the case of coronary disease, the existence of 50-70% stenosis has been cited as the severity warranting intervention. Similarly, in diagnosing re-stenosis after previous revascularization, at least a 50-70% diameter stenosis is needed to produce a hemodynamically significant reduction in flow under conditions of stress.5 Guidelines on clinical competence for physicians performing exercise testing have been published by the American College of Physicians and the American College of Cardiology.6,7
In general, stress testing for diagnosis is warranted in those with an intermediate (25-75%) pretest probability of disease.8 Patients at high pretest probability will have a high rate of false negative tests, while those with a low pretest probability will have a high rate of false positive tests. (See Table 1.)9 For example, in patients with a low (5%) pretest probability of CAD, the positive predictive value (post-test probability) of a positive test is only 21%, assuming a test sensitivity of 50% and specificity of 90%. Therefore, if 1000 such patients are tested, 120 will have a positive result, of which 95 will not have significant CAD. In patients with a high pretest probability (90%) of CAD, a negative result lowers the probability only to 83%.3 This supports the statement that stress testing for prognosis in patients with suspected CAD should be performed in those at intermediate or high pretest probability. The results of such testing can identify patients at variable degrees of mortality risk.10 For patients at high risk, performing coronary angiography without prior non-invasive testing may be cost-effective. Any stress test should be symptom-limited: ataxia, near-syncope, moderate to severe angina, signs of poor perfusion, or subject's desire to stop.11 (See Table 2.)
 |
 |
The limited value of stress testing in patients with a low pretest probability of disease was borne out in one study of 1618 low-risk patients evaluated by exercise echocardiography. After a median follow-up of 3 years, only 9 of 346 patients (2.6%) with an abnormal exercise echocardiogram sustained a cardiac event; conversely, only 9 of 19 patients who had a cardiac event had an abnormal test.12
Pathophysiology
In the normal, or healthy, coronary artery, increased myocardial oxygen demand is matched by increased coronary blood flow. Natural physiologic mechanisms exist to allow for this supply-demand match-up; increased oxygen demand causes the endothelium to release nitric oxide, which in turn creates arterial vasodilation, and subsequently increases blood flow. The rate of blood flow depends on the driving pressure gradient and the resistance of the vascular bed. (See Figure 1.) The dynamic pressure drop across a stenosis is inversely proportional to the fourth power of the radius (of the stenosis).13 To illustrate this concept: if the lumen of the artery is reduced by half, then blood flow through that artery decreases by 16 times.
 |
In healthy coronary arteries, the rate of resting myocardial blood flow is approximately 1 mL/g/min. With exercise, there is a subsequent increase of heart rate, contractility, and blood pressure, creating an increase in myocardial demand. This demand, in healthy arteries, leads to an increased rate of flow up to 3 times the resting rate. However, in areas perfused by stenotic coronary arteries, increased myocardial demand reveals physiologic problems in the forms of: ischemic electrocardiogram (ECG) changes, symptomatic chest pain, perfusion defects, and regional wall motion abnormalities.14-16
Options for Stress Testing
Stress tests vary by features. Some entail exercise. (See Table 3.) For patients who cannot exercise, vasodilators (dipyridamole and adenosine) may be employed for nuclear imaging, or dobutamine or, less frequently, dipyridamole may be employed for echocardiography. (See Table 4.) Ischemia may be assessed by ECG changes, with perfusion defects with myocardial perfusion imaging (MPI) utilizing nuclear agents, or by wall motion abnormalities on echocardiography. The degree of ischemia can be graded semi-quantitatively using each of these modalities, although the exercise ECG will not localize ischemia. Noninvasive tests can be classified according to the manifestation of CAD they aim to detect: anatomic CAD, reversible myocardial ischemia, or prior myocardial infarction. Although the sensitivity and specificity for detection of CAD varies by test, all are highly sensitive for the detection of CAD that will benefit from revascularization.17
 |
 |
It is notable that the American Heart Association/American College of Cardiology guidelines recommend exercise stress testing with nuclear imaging or echocardiography in patients who have undergone PCI or CABG.4 In these patients with known prior CAD, the ability to identify ischemia is significantly lower with exercise ECG testing as compared to imaging after revascularization. There is also a need to document both the site and extent of ischemia, something exercise ECG testing alone cannot do.18
Exercise ECG Testing Without Imaging
The exercise test plays an important role in diagnosis of CAD because it is readily available, inexpensive, and easily performed. It does not require injections, and does not involve exposure to radiation. Since it does not accurately localize the site or extent of myocardial ischemia, it is less useful in patients who have undergone revascularization, in whom other forms of stress testing are recommended.
Exercise places major demands on the cardiopulmonary system; thus, it can be considered the most practical test of cardiac perfusion and function. Myocardial oxygen consumption can be reasonably estimated by the product of heart rate and systolic blood pressure. This is valuable clinically since exercise-induced angina often occurs at the same myocardial oxygen demand.11 Symptom-limited treadmill or bicycle exercise is the preferred form of stress because it provides information concerning patient symptoms, cardiovascular function, and hemodynamic response during activity. Ischemia at a low workload indicates a greater likelihood of severe disease and a worse prognosis than the same degree of ischemia at a high workload.3 It is to be expected that the following groups of patients would be unable to exercise: those with leg claudication, deconditioning, arthritis, or pulmonary disease. Many observation/chest pain units perform stress testing after a second troponin (8-12 hours after pain) is negative. If such testing is planned, the patient with chest pain should make arrangements to have appropriate clothing and footwear (sneakers, socks) brought to the emergency department.
The adaptations that occur during an exercise test allow the body to increase its resting metabolic rate up to 20 times, during which cardiac output can increase up to 6 times.11 Predicted maximal heart rate varies by individual, but has been cited as 220 minus patient age.4,8 The patient must be able to exercise to goal levels; failure to achieve at least 85% of predicted maximal heart rate is considered inadequate if the test is otherwise negative. Monitoring should continue for at least 5 minutes after exercise or until and ST-segment changes stabilize.
The inability to perform an exercise test is, in itself, a negative prognostic factor in patients with CAD. For this reason, patients who require pharmacologic stress testing have a higher risk of subsequent events than those who undergo exercise testing, even if the stress test is normal.19 Exercise-induced angina, abnormally low systolic blood pressure (< 130 mmHg), or a fall in systolic blood pressure during exercise all constitute bad prognostic signs regardless of the stress test employed. Low exercise capacity and abnormal systolic blood pressure response have been associated with poor outcome.20
Exercise capacity is generally measured in METS. The common measure of total body work is the oxygen uptake, which is usually expressed as a rate in liters per minute. The usual measure of the capacity of the body to deliver and use oxygen is the maximal oxygen consumption (VO2 max), which is the product of the maximal cardiac output and the maximal arteriovenous oxygen difference.11 One MET, or metabolic equivalent, representing the resting metabolic rate, is roughly 3.5 mL of O2/kg/minute. A MET value achieved from an exercise test is a multiple of the resting metabolic rate. Clinically meaningful METS for exercise and maximal performance are listed. (See Table 5.) An exercise capacity of < 6 METS was an independent predictor of death in patients undergoing exercise testing after angioplasty.5 Each 1 MET increase in exercise capacity equates with a 10-25% improvement in survival in populations studied.11 In some studies of exercise testing, exercise capacity or workload was the strongest predictor of mortality and cardiovascular events.19,21
 |
The Duke Treadmill score is commonly used for prognosis, and is the most popular validated treadmill score. Originally based upon data from 2758 consecutive patients from 1969 through 1980, subsequent data was used to validate the result in patients who underwent both exercise treadmill testing and coronary angiography.22 The formula is derived as follows: Duke score = METS – 5 x (mm exercise-induced ST depression) – 4 x (TM AP index). The TM AP index equals 0 if no angina is produced during the test, 1 if angina occurred during the test, and 2 if angina was the reason for stopping.18 A moderate risk Duke prognostic score ranges from –10 through +4. Patients who have a strongly positive exercise test (Duke treadmill score <–11) are at high risk for mortality: five-year survival of 97% in patients with low-risk Duke treadmill scores, 65% five-year survival in patients with high-risk Duke treadmill scores.20 Angiography has been recommended for patients with a yearly mortality of > 4% per year (high-risk Duke treadmill score), or those with a yearly mortality risk of 2-3% per year (moderate-risk Duke score) and left ventricular dysfunction. (Table 6 summarizes treadmill scores.)4
 |
The two major components of cardiac output are heart rate and stroke volume. Of these, heart rate is responsible for most of the increase in cardiac output during exercise. The heart rate response to exercise is influenced by several factors, such as medication use, the presence of heart disease, fitness, and type of activity, but the most important factor is age. A significant decline in maximal heart rate occurs with increasing age. Age-related maximal heart rate estimates are, however, a relatively poor index of maximal effort. Exercise, therefore, should be symptom-limited, and not targeted on achieving a certain heart rate such as 85% of age-predicted maximal heart rate.11
There are other vital sign changes monitored during stress testing in addition to maximal heart rate. Total peripheral resistance is reduced by vasodilatation, so that mean arterial pressure increases only moderately despite even a fivefold increase in cardiac output. During recovery, the parasympathetic system is re-activated. A delay in heart rate recovery has been used as a marker of autonomic dysfunction.23 Exertional hypotension has been shown to predict severe CAD and is associated with a poor prognosis. While the definition of exertional hypotension varies, a drop in systolic blood pressure below pre-exercise values is an ominous criterion.11
Pretest Preparation
The patient should be instructed not to eat, drink, or smoke for at least 2 hours prior to the test, and to dress for exercise. Patients should be pain-free, and should have either a normal or non-diagnostic ECG prior to stress testing. There should be a normal set of initial cardiac markers. The physical examination should concentrate on the presence of a loud systolic murmur, as patients with aortic stenosis may develop severe cardiovascular complications. Contraindications to exercise testing are listed. (See Table 7.) A diagnostic test that fails to achieve at least 85% of the patient's predicted maximal heart rate is considered inadequate to exclude ischemic heart disease, even if the test is otherwise negative.24 For this reason, patients generally should withhold anti-anginal medications prior to the test. Withholding beta-blockers and other anti-ischemic drugs for 4-5 half-lives typically translates to 48 hours for scheduled stress tests when possible.4 If the patient is to be tested off beta-blockers, it has been proposed that they not be stopped abruptly.11
 |
Patients generally exercise on a bicycle ergometer or on a treadmill. The bicycle ergometer costs less, makes less noise, and takes up less space. Individuals generally perform more work on a treadmill because a greater muscle mass is involved. Maximal oxygen uptake is up to 25% higher during treadmill exercise as opposed to the upright cycle ergometer.11
Exercise Testing: Specific Parameters
The American College of Cardiology guidelines for the use of the standard exercise test state that it is appropriate for testing of adult patients with less than 1 mm of ST depression, including those with right bundle-branch block who have an intermediate probability of coronary artery disease based upon gender, age, and symptoms.4
ST depression is a representation of global subendocardial ischemia and does not localize coronary artery lesions. A positive exercise test has been defined as at least 1 mm ST depression, or upsloping ST-segment depression/ ST-segment elevation for at least 0.08 seconds compared with the baseline ECG. ST depression in the inferior leads (2, 3, aVF) may be false positive unless more than 1 mm. ST depression in the precordial lead V5 along with V4 and V6 more accurately reflects ischemia. In patients with right bundle-branch block, ECG changes in leads V1-V3 are non-diagnostic. (See Figure 2.) Other measures have corrected ST depression by dividing by the exercise-induced increase in heart rate (ST/HR index).4
 |
Exercise-induced ventricular dysrthymias have an independent association with death in patients with coronary artery disease. Premature ventricular contractions are not of concern in otherwise healthy individuals, but are certainly of concern in patients with the following: history of syncope or sudden death, physical examination with a large heart or murmurs, heart failure, or prolonged QT interval.11
Exercise-induced ST-depression is not diagnostic in a variety of conditions: left bundle-branch block (LBBB), Wolf-Parkinson-White syndrome, electronically paced rhythm, intraventricular conduction defects with T wave inversion, patients taking digoxin, patients with more than 1 mm resting ST depression, or in patients with left ventricular hypertrophy even if they have less than 1 mm of ST depression.4 Patients with LBBB have an appreciable incidence of transient defects in the anteroseptal and septal regions in the absence of a lesion in the left anterior descending artery. In these cases, pharmacologic testing with a vasodilator (dipyridamole or adenosine) is preferred.25
There is prognostic importance of an abnormal heart rate recovery pattern after exercise testing. Defined as a change in heart rate from peak exercise to heart rate measured 2 minutes later, a rate decline of less than 12 beats per minute was predictive of all-cause mortality at 6 years in one report.26 Another report demonstrated that a ratio of greater than 1 for systolic blood pressure 3 minutes after recovery divided by systolic blood pressure 1 minute after recovery was associated with a worse prognosis.27
There is a higher false-positive rate on exercise ECG testing in women compared to men, possibly explainable by the lower prevalence of CAD in women.8 Another consideration for lower predictive accuracy in women may be inadequate exercise capacity to induce ischemia, especially in older women. Because of its simplicity and low cost, the standard exercise treadmill ECG is still the most reasonable exercise test to select in men with a normal resting ECG who are able to exercise. In patients unable to exercise, a perfusion imaging or dobutamine echocardiography study is recommended.4
One large meta-analysis reported overall sensitivity and specificity of exercise ECG testing in patients who underwent coronary angiography to be 68% and 77%, respectively.28 The limitations of exercise ECG testing in patients who have undergone revascularization should be emphasized. The sensitivity of the exercise ECG alone was 54% in identifying re-stenosis after PTCA, while the sensitivity of stress echocardiography has been given at 82% in these patients.18
Exercise Echocardiography
Stress two-dimensional transthoracic echocardiography can be used to demonstrate the presence of coronary disease by showing inducible wall motion abnormalities. (See Figure 3.) The main prognostic variable is the extent and severity of exercise-induced ventricular dysfunction. The stress may be pharmacologic or exercise induced. The choice as to the type of stress test is based upon the patient's ability to perform exercise, the presence of baseline electrocardiographic abnormalities, and whether it is important to localize ischemia or assess myocardial viability. This test is recommended as an initial stress test for patients who can exercise but have baseline ECG (such as ST-T) abnormalities.29 Indications for stress echocardiography recently have been issued as a joint statement from multiple societies representing emergency medicine, cardiology, and cardiology imaging. It is useful in the re-evaluation of medically managed patients with previous abnormal catheterization or abnormal prior stress imaging.30 The diagnostic accuracy of exercise echocardiography seems to be high in patients with left ventricular hypertrophy, in particular. When a treadmill exercise is used, images are obtained immediately after exercisingpreferably within 60-90 secondssince imaging during exercise is not generally feasible. Ischemia may resolve rapidly, however, and wall motion abnormalities may rapidly reverse. Imaging during treadmill stress has been reported.31 Exercise testing has been performed in a semi-supine position on a tilting table, permitting continuous echocardiographic imaging.32
 |
One meta-analysis compared the performance of different stress tests for sensitivity and specificity in the detection of significant coronary heart disease, as defined generally by stenosis on angiography of > 50% or > 70%. The sensitivity and specificity of exercise ECG testing were 68% and 77%, respectively, in 132 studies of more than 24,000 patients, while those of stress echocardiography were 76% and 88%, respectively, in six studies of 206 patients.3 Sensitivity may be higher in detecting left anterior descending artery and multivessel disease.31 Pharmacologic stress testing with dobutamine has a better combination of sensitivity and specificity than does vasodilator (dipyridamole or adenosine) echocardiography, which is infrequently performed.33 It appears that stress echocardiography is more accurate than stress thallium myocardial perfusion imaging in patients with left ventricular hypertrophy. Stress echocardiography has the additional advantage of providing important information regarding valvular function such as mitral or aortic regurgitation, as well as information regarding left ventricular mass, chamber size, left ventricular function, and ejection fraction.29 Ultimately, the choice of stress test may hinge on factors such as local availability and expertise, as echocardiography interpretation can be subjective. From the perspective of risk stratification, a meta-analysis of studies that evaluated event-free survival, the negative predictive value for MI and cardiac death was 99% and 97% after 33 months, respectively, for exercise echocardiography.34
Limitations of any echocardiographic study include the need for an adequate acoustic window. Patients may have obesity or obstructive pulmonary disease, which confound the search for a suitable window up to 15% of the time. Echocardiography is dependent upon the sonographer's skill as well.35 The specificity of stress echocardiography is reduced in patients with a prior myocardial infarction, and the test may be difficult to interpret in patients with irregular cardiac rhythms.18
There appears to be an enhanced predictive value of exercise echocardiography when study findings were combined with the Duke treadmill score. In patients with chronic stable coronary disease, and an intermediate Duke treadmill score (score 4 to -10), echocardiography was able to identify subcategories of risk of death ranging from 2.4% to 7% after a follow-up of 10.6 years. A normal echocardiogram with a low-risk Duke treadmill score was associated with a risk of death < 1% per year over the first six years of follow-up. Among patients with a high-risk Duke treadmill score, the yearly mortality in the group with echocardiographic evidence of ischemia in multivessel territory was 12%. High-risk patients (five-year survival of 65%) by Duke treadmill score generally required invasive intervention, while low-risk patients who had a five-year survival of 97% could be managed medically, making the intermediate-risk group the one most likely to derive benefit from exercise echocardiography.36 Long-term survival is lowest in patients with wall-motion abnormalities on stress echocardiography, which are extensive, involve multiple territories, or are associated with a stress-induced decrease in ejection fraction or increase in left ventricular cavity size.10
Real-time three-dimensional echocardiography has been employed more recently, with shorter acquisition times, and shows similar sensitivity and specificity (93% and 75%, respectively) to two-dimensional echocardiography.37
Dobutamine Echocardiography
This technique is based upon the premise that the contractile function of myocardial regions perfused by arteries with significant stenosis will be impaired when regional ischemia is induced by the chronotropic and inotropic effects of dobutamine. The onset of action is within 1-2 minutes of intravenous infusion; at a dose of 20 mg/kg/min there is a mean increase in blood pressure of approximately 12 mmHg, and at 40 mg/kg/min the mean heart rate is 120-125 beats/minute.29
The accuracy of dobutamine echocardiography is dependent upon the degree of stenosis and the amount of myocardium at risk. The positive predictive value increased with the number of segments in which wall motion deteriorated and with the severity of wall motion deterioration.38 The test accurately screens for coronary disease in patients unable to exercise. It cannot assess functional capacity, and results depend upon obtaining good echocardiographic windows, as with exercise echocardiography. Dobutamine can cause ventricular dysrhythmias, especially in patients with poor left ventricular function or severe CAD; side effects may necessitate discontinuing the infusion or administering a beta-blocker.39
In one report of 103 patients who underwent both coronary angiography with angioplasty and dobutamine echocardiography, dobutamine-induced wall motion abnormalities were noted in only 38% of the myocardial segments supplied by the re-stenotic coronary arteries. Dobutamine echocardiography showed no induced wall motion abnormalities in 79% of the segments without re-stenosis. In this study, dobutamine echocardiography demonstrated low sensitivity and high specificity for the diagnosis of re-stenosis.40 Its overall diagnostic accuracy in the diagnosis of coronary stenosis approximates 81%.29 Dipyridamole and adenosine have been used as well for echocardiography, but dobutamine has been shown to yield the highest combination of sensitivity (80%) and specificity (84%) overall, making it the preferred agent for echocardiography in patients who cannot exercise.33 With a normal test, annual cardiac death rates after a normal dobutamine stress echocardiogram approximate 0.6%; with an abnormal test, annual cardiac death rates approximate 2.8%, with annual cardiac event rates of 6.9%.29 ST elevation during dobutamine echocardiographic testing was a marker of severe disease and high risk in one recent report, with a 40% death rate at 2.6-year follow-up.41
Among patients who are unable to exercise, dobutamine echocardiography has a role for diagnosis in patients with an intermediate pretest probability of coronary artery disease, and for prognosis to identify the extent, severity, and location of ischemia in patients who do not have paced rhythm or a paced ventricular rhythm.8
Nuclear Stress Testing
Nuclear perfusion tests use radioactive tracers to qualitatively assess myocardial tissue perfusion at rest and under stress. Myocardial perfusion is obtained using positive emission tomography (PET) or single photon emission computed tomography (SPECT). Myocardial "stress" is induced either by exercise or with pharmacologic agents, similar to those used in stress echocardiography. The hallmark value of nuclear stress testing is in the identification of a "reversible perfusion defect": a perfusion defect that is seen on stress imaging, but which is not present during rest imaging. (See Insert, Figure 4.)
 |
Tracers. Radioactive tracers were first used in humans by Blumgart in 1925 to study blood circulation time.48,49 He is rightly called the father of nuclear medicine, envisioning the need for an appropriate indicator and an appropriate detector. Multiple adaptations, investigations, and subsequent refinements have led us from that initial introduction to current modalities of nuclear stress testing.
In the United States, myocardial perfusion tracers used for SPECT include: thallium 201 (TI-201), technetium 99-m sestamibi (Tc-99m sestamibi/ Cardiolite), and technetium-99m tetrofosmin (Tc-99m tetrofosmin/ Myoview).
Thallium 201( TI-201). TI-201 is a monovalent action analog of potassium. It has a high first-pass extraction, active membrane transport into the myocyte, and redistribution after 10-15 minutes of injection. Redistribution, or washout, depends on initial myocyte tracer concentration and on myocardial blood flow. TI-201 is renally cleared.
A standard dose (usually 2.5 to 4.0 mCi [millicurie]; determined by nuclear cardiology protocols) is injected at peak exercise stress or at peak onset of pharmacologic vasodilation. A SPECT image is obtained 10-15 minutes later. Rest imaging, which looks at redistribution of the tracer, is done approximately 3 hours later.50
Tc-99m Tracers. Both sestamibi and tetrofosmin fall into this category, owing to their similar characteristics: lipid-soluble, less first pass-extraction than TI-201, and virtually negligible washout/redistribution. Their uptake and retention is dependent on transmembrane energy potentials and on blood flow. They are excreted into the gastrointestinal system after extraction by the hepatobiliary system.50
Because there is no redistribution, sestamibi and tetrofosmin require separate dose injections at stress and at rest.51 After injection of Tc-99m sestamibi at peak exercise, image acquisition is delayed approximately 15-20 minutes; after pharmacologic vasodilation, the delay is 60 minutes; and at rest, images are obtained 45-60 minutes after tracer injection. For Tc-99m tetrofosmin, images are acquired 10-15 minutes after peak exercise; 45 minutes after peak pharmacologic vasodilation; and 30-45 minutes after injection at rest.52
Ideally, stress and rest SPECT images using Tc-99m tracers are performed on two separate days to avoid contamination of rest images by any residual activity from the stress portion of the test. However, due to logistical and throughput issues, most centers use a one-day protocol for Tc-99m tracer tests. Overlapping information due to residual activity is avoided by using a low dose of tracer for the first study (typically one-quarter of the total dose [8-12 mCi]), and then a higher dose (or the remaining three-quarters of the total dose) for the rest images. In the one-day protocol, the time between the stress and the rest images is roughly 4 hours. This accounts for the increased blood flow and tracer extraction during the stress phase.
Reversible Defects. As discussed before, reversible defects are perfusion defects that are seen on imaging during stress but not at rest. These defects correlate well with degree of stenosis in the coronary vessel. Several findings portend a higher likelihood of future cardiac events: extensive inducible ischemia, including multiple perfusion defects in territories supplied by different coronary arteries; large perfusion defects in a territory supplied by one coronary artery; post-stress left ventricular ejection fraction (LVEF) of less than 40%. On the contrary, patients who have a normal perfusion scan, whether pharmacologic or exercise, have an event rate of less than 1% per year, comparable with the general population without evidence of CAD.51,54,55
Value of Nuclear Stress Testing. When discussing the value of a test, as it applies to patients presenting to an ED with chest pain, it is important to realize that the term has different implications. For the patient, the value lies in the negative predictive value (NPV) of the test; or otherwise stated, the "this means I won't die from heart disease in X number of months/years" factor. For the EP, the value of a test lies in all its statistical aspects: sensitivity, specificity, positive predictive value (PPV), and NPV. But, perhaps for the EP evaluating a patient with non-ACS chest pain, the NPV does become the important asset; otherwise known as the "Well, patient, I can tell you that you won't die from coronary artery disease in X days/weeks/months/years" aspect of the test.
The diagnostic and prognostic value of the nuclear stress test has been studied extensively in this regard. The 2002 Taskforce for Guideline Update for the Management of Patients with Chronic Stable Angina from the ACC/AHA performed an exhaustive review of exercise and pharmacologic nuclear stress tests. The sensitivity of exercise SPECT with TI-201 ranges between 89-90%, and the specificity is 70-76%. For pharmacologic TI-201 SPECT the sensitivity and specificity are 90% and 70%, respectively.56 A recent meta-analysis showed NPV of normal exercise myocardial perfusion imaging for myocardial infarction and cardiac death over the next 36 months to be approximately 98%, with the same prognosis regardless of gender.34
The Future: Computed Tomography (CT) and Magnetic Resonance Imaging (MRI)
Screening for coronary artery disease has been proposed with the promotional concept of atherosclerotic burden. Electron-beam computed tomography (EBCT) has received publicity, but has not been shown to have test characteristics superior to standard exercise testing.
Newer CT scanners offer the possibility of non-invasive coronary angiography. However, the small dimensions and the rapid motion of the coronary arteries pose tremendous challenges for non-invasive imaging. Based on clinical considerations, this will most likely be beneficial for symptomatic patients who are not at high risk for CAD.42) The current industry standard is 64-slice CT with rotation times between 330 and 420 milliseconds. One manufacturer has chosen to increase the number of simultaneously acquired slices through a 256-slice system, allowing coverage of the entire heart in one single rotation. In theory, this would make CT more amenable to use in patients with dysrhythmias such as atrial fibrillation.43 Sixty-four multislice computed tomographic angiography (CTA) has shown 98% sensitivity and 74% specificity in determining CAD. Patients were pre-treated with beta-blockers to achieve heart rates of < 65 beats per minute.44 The sensitivity of CT has ranged between 86% and 100%, with specificity between 91% and 100% and negative predictive value of 95% to 100%, generally when studied in populations in which the prevalence of CAD was low.42 Because the study takes less time than standard stress testing, CTA may be useful for emergency department patients at low or moderate risk for CAD. The study is problematic in patients with significant renal insufficiency, or who are unable to perform a 10-second breath hold. As well, high heart rates, the presence of atrial fibrillation, contrast allergy, or severe calcification make the study contraindicated. The quality of the image is not as high as with invasive angiography. There is an issue of excessive dye load for patients who may have severe disease and require an emergency cardiac angiogram. However, its negative predictive value is high, making the study valuable in ruling out stenosis in patients with low or intermediate pretest likelihood of disease.45
The diagnostic accuracy of adenosine stress cardiac magnetic resonance imaging (86%) over standard exercise tolerance testing (48%) in detecting coronary stenosis has been demonstrated in patients following an ST-elevation myocardial infarction.46 This figure is similar to that found in an earlier study comparing cardiac stress MRI to stress echocardiography, in which stress MRI was both 86% sensitive and specific, versus 74% and 70%, respectively, for echocardiography. Nearly 9% could not undergo MRI because of claustrophobia or obesity.47 While exercise testing has not generally been recommended in the evaluation of the patient with known CAD, MRI has the advantage of acquiring an image without operator dependence.35
Summary: What Does It Mean for the Emergency Physician?
This paper provides a detailed synopsis of stress testing. What it does not provide is a "one-for-all" protocol. Each institution should create a steering committee, if one doesn't already exist, to evaluate the protocols and pathways to evaluate patients presenting to the ED with chest pain. It is important that the committee involve emergency physicians, radiologists, and cardiologists, as all three fields will have direct input on patient care in this setting. Ideally, quality measurements will allow the department to evaluate the efficacy of its protocols in terms of time and throughput as well as with patient outcomes. A sample protocol used by an observation unit to evaluate patients presenting with chest pain is included. (See Insert, Figure 5.)
 |
Lastly, there is a distinct dilemma that arises when a patient who has recently undergone a negative stress work-up returns to the ED with chest pain. It is an especially intriguing quandary for the EP, who does not have the added comfort of schedule follow-up, well-established rapport, or the liability of a "less-than-perfect" treatment standard. To date, there are no clear-cut answers from studies examining this question. It seems logical to re-evaluate the patient, starting with history and physical examination and concluding with risk stratification and appropriate ED testing (ECG, biomarkers, etc).
In a field that is fraught with complicated situations and difficult decisions, it is probably best to formulate a large differential diagnosis concerning the patient's re-visit to the ED with chest pain. If the EP feels strongly that there is another, more plausible etiology for chest pain, then the patient likely does not need to undergo further cardiac evaluation. However, based on pre-test probabilities (risk factors, lifestyle, family history, etc.), the EP should always feel comfortable obtaining a cardiology consult or admitting the patient for further work-up and evaluation. This scenario lends further strength to the notion of a well-formulated multi-disciplinary approach to the patient with chest pain; it will allow better collaboration among the specialities and will create better patient care and outcomes.
Conclusions
The emergency physician now has a variety of non-invasive cardiac tests available to screen for coronary disease in patients deemed to be at risk. In the future, technology will afford more options for such testing, as imaging becomes more sensitive. Adherence to diagnostic guidelines has the potential to be cost-saving in terms of avoidance of hospitalization and should enhance patient safety.
References
1. Merrill C, Owens P, Stocks C. Emergency department visits for adults in community hospitals from selected states. Statistical brief #47. The Agency for Healthcare Research and Quality. 2008: 1-12.
2. Rosamond W, Flegal K, Furie K, et al. Heart disease and stroke statistics 2008 update: A report from the American Heart Association Statistics Committee and Stroke Statistics Subcommittee. Circulation 2008;117:e25-e146.
3. Garber AM, Hlatky MA. Stress testing for the diagnosis of coronary heart disease. UpToDate at http://www.uptodateonline.com/utd/content/topic.do?topicKey=chd/59850&view accessed 2/25/08.
4. Gibbons RJ, Balady GJ, Bricker JT, et al. ACC/AHA guideline update for exercise testing: summary article: A report of the American College of Cardiology/American Heart Association Task Force on Practice Guidelines. Circulation 2002;106:1883-1892.
5. Lauer MS. Role of stress testing and cardiac imaging in patients who have undergone previous coronary revascularization. Cardiol Rev 2000;8:158-165.
6. American College of Cardiology. COCATS guidelines: Guidelines for training in adult cardiovascular medicine. Core Cardiology Training Symposium. J Am Coll Cardiol 1995;25:1-34.
7. Schlant RC, Freisinger GC, Leonard JJ. Clinical competence in exercise testing. A statement for physicians from the ACP/ACC/AHA Task Force on Clinical Privileges in Cardiology. J Am Coll Cardiol 1990;16:1061-1065.
8. Gibbons RJ, Abrams J, Chatterjee K, et al. ACC/AHA 2002 guideline update for the management of patients with chronic stable angina. At: www.acc.org/qualityandscience/clinical/statements.htm.
9. Pryor DB, Shaw L, McCants CB, et al. Value of the history and physical in identifying patients at increased risk for coronary artery disease. Ann Intern Med 1993;118:81-90.
10. Weiner DA. Stress testing to determine prognosis and management of patients with known or suspected coronary heart disease. UpToDate at: http://www.uptodateonline.com/online/content/topic.do?topicKey=chd/32147&view. Accessed 4/25/2008.
11. Engel G, Froelicher VF. ECG Exercise Testing. In: Fuster V, O'Rourke RA, Walsh RA, et al, eds. Hursts's The Heart, 12th ed. New York: McGraw-Hill; 2008:324-339.
12. Elhendy A, Shub C, McCully RB, et al. Exercise echocardiography for the prognostic stratification of patients with low pretest probability of coronary artery disease. Am J Med 2001;111:18-23.
13. Spaan JAE, Piek JJ, Hoffman JIE, et al. Physiological basis of clinical used coronary hemodynamic indices. Circulation 2006;113:446-455.
14. Gould KL, Lipscomb K. Effects of coronary stenosis on coronary flow reserve and resistance. Am J Cardiol 1974;34:89-92.
15. Feil H, Siegel M. Electrocardiographic changes during attacks of angina pectoris. Am J Med Sci 1928;175:255-260.
16. Heinicke N, Benesch B, Kaiser T, et al. Mechanisms of regional wall motion abnormalities in contrast-enhanced dobutamine stress echocardiography. Clin Res Cardiol 2006;95:650-656.
17. Garber AM, Solomon NA. Cost-effectiveness of alternative test strategies for the diagnosis of coronary artery disease. Ann Intern Med 1999;130:719-28.
18. Papaioannou GI, Manning WJ, Heller GV. Role of stress testing after coronary revascularization. UpToDate at: http://www.uptodateonline.com/online/content/topic.do?topicKey=chd/33230 accessed 4/25/08.
19. Navare SM, Mather JF, Shaw LJ, et al. Comparison of risk stratification with pharmacologic and exercise stress myocardial perfusion imaging: A meta-analysis. J Nucl Cardiol 2004;11:551-561.
20. Shaw LJ, Peterson ED, Shaw LK, et al. Use of a prognostic treadmill score in identifying diagnostic coronary disease subgroups. Circulation 1998;98: 1622-1630.
21. Spin JM, Prakash M, Froelicher VF, et al. The prognostic value of exercise testing in elderly men. Am J Med 2002;112:453.
22. Mark DB, Hlatky MA, Harrall FE Jr, et al. Exercise treadmill score for predicting prognosis in coronary artery disease. Ann Intern Med 1987;106:793.
23. Fletcher GF, Balady GJ, Amsterdam EA, et al. Exercise standards for testing and training: A statement for health care professionals from the American Heart Association. Circulation 2001;104:1694-1740.
24. Hlatky MA, Pryor DB, Harrell FE, et al. Factors affecting sensitivity and specificity of exercise electrocardiography. Multivariate analysis. Am J Med 1984;77:64-71.
25. Vagduganathan P, He ZX, Raghavan C, et al. Detection of left anterior descending coronary artery stenosis in patients with left bundle branch block: Exercise, adenosine, or dobutamine imaging? J Am Coll Cardiol 1996;28:543.
26. Cole CR, Blackstone EH, Pashkow FJ, et al. Heart-rate recovery immediately after exercise as a predictor of mortality. N Engl J Med 1999;341: 1351-1357.
27. McHam SA, Marwick TH, Pashkow FJ, et al. Delayed systolic blood pressure recovery after graded exercise: An independent correlate of angiographic coronary disease. J Am Coll Cardiol 1999;34: 754-759.
28. Gianrossi R, Detrano R, Mulvihill D, et al. Exercise-induced ST depression in the diagnosis of coronary artery disease: A meta-analysis. Circulation 1989;80:87-98.
29. Manning WJ. Stress echocardiography in the diagnosis and prognosis of coronary heart disease. UpToDate February 11,2008 at: http://www.uptodateonline.com/online/content/topic.do?topicKey=noninvas/13131. Accessed 4/25/2008.
30. Douglas PS, Khandheria B, Stainback RF, et al. ACCF/ASE/ACEP/AHA/ ASNC/SCAI/SCCT/SCMR 2008 Appropriateness criteria for stress echocardiography. Circulation 2008;117:1478-1497.
31. Peteiro J, Garrido I, Monserrat L, et al. Comparison of peak and postexercise treadmill echocardiography with the use of continuous harmonic imaging acquisition. J Am Soc Echocardiogr 2004;17:1044-1049.
32. Lancellotti P, Hoffer EP, Pierard LA. Detection and clinical usefulness of a biphasic response during exercise echocardiography early after myocardial infarction. J Am Coll Cardiol 2003;41:1142-1147.
33. Kim C, Kwok YS, Haegerty P, et al. Pharmacologic stress testing for coronary disease prognosis: A meta-analysis. Am Heart J 2001;142:934-944.
34. Metz LD, Beattie M, Horn R, et al. The prognostic value of normal exercise myocardial perfusion imaging and exercise echocardiography: a meta-analysis. J Am Coll Cardiol 2007;49:227-237.
35. Kasprzak JD, Paelinck B, Ten Cate FJ, et al. Comparison of native and contrast-enhanced harmonic echocardiography for visualization of left ventricular endocardial border. Am J Cardiol 1999;83:211-217.
36. Marwick TH, Case C, Vasey C, et al. Prediction of mortality by exercise echocardiography. Circulation 2001;103:2566-2571.
37. Eroglu E, D'hooge J, Herbots L, et al. Comparison of real-time tri-plane and conventional 2D dobutamine stress echocardiography for the assessment of coronary artery disease. Eur Heart J 2006;27:1719-1724.
38. Bartunek J, Marwick TH, Rodrigues ACT, et al. Dobutamine-induced wall motion abnormalities: Correlations with myocardial fractional flow reserve and quantitative coronary angiography. J Am Coll Cardiol 1996;27: 1429-1436.
39. Weiner DA. Advantages and limitations of different stress testing modalities. UpToDate at: http://www.uptodateonline.com/online/content/topic.do?topicKey=chd/34293 Accessed 4/25/08.
40. Heinle SK, Lieberman EB, Ancukiewicz M, et al. Usefulness of dobutamine echocardiography for detecting restenosis after percutaneous transluminal coronary angioplasty. Am J Cardiol 1993;72:1220-1225.
41. Arruda AL, Barretto RB, Shub C, et al. Prognostic significance of ST-segment elevation during dobutamine stress echocardiography. Am Heart J 2006;151:744.e1-744.e6.
42. Aschenbach S. Developments in coronary CT angiography. Curr Cardiol Rep 2008;10:51-59.
43. Kido T, Kurata A, Higashino H, et al. Cardiac imaging using 256-detector row four-dimensional CT: Preliminary clinical report. Radiat Med 2007;25: 38-44.
44. Rivipati G, Aronow WS, Lai H, et al. Comparison of sensitivity, specificity, positive predictive value, and negative predictive value of stress testing versus 64-multislice coronary computed angiography in predicting obstructive coronary artery disease diagnosed by coronary angiography. Am J Cardiol 2008;101:774-775.
45. Hendel RC, Patel MR, Kramer CM, et al. ACCF/ACR/SCCT/SCMR/ ASNC/NASCI/SCAI/SIR 2006 appropriateness criteria for cardiac computed tomography and cardiac magnetic resonance imaging. J Am Coll Cardiol 2006;48:1475-1497.
46. Greenwood JP, Younger JF, Ridgway JP, et al. Safety and diagnostic accuracy of stress cardiac magnetic resonance imaging vs. exercise tolerance testing early after acute ST elevation myocardial infarction. Heart 2007;93: 1363-1368.
47. Nagel E, Lehmkuhl HB, Bocksch W, et al. Noninvasive diagnosis of ischemia-induced wall motion abnormalities with the use of high-dose dobutamine stress MRI: Comparison with dobutamine stress echocardiography. Circulation 1999;99:763-770.
48. Blumgart HL, Yens OC. Studies on the velocity of blood flow. J Clin Invest 1926;4:1-13.
49. Patton DD. The birth of nuclear medicine instrumentation: Blumgart and Yens 1925. J Nucl Med 2003;44:1362-1365.
50. Henzlova MJ, Cerqueira MD, Mahmarian JJ, et al. Stress protocols and tracers. J Nucl Cardiol 2006;13:e80-90.
51. Chua SC, Ganatra RH, Green DJ et al. Nuclear cardiology: Myocardial perfusion imaging with SPECT and PET. Imaging 2006;18:166-177.
52. Nakajima K, Taki J, Shuke N, et al. Myocardial perfusion imaging and dynamic analysis with technetium-99m tetrofosmin. J Nucl Med 1993;34:1478-1484.
53. Jain D, Wackers FJ, Mattera J, et al. Biokinetics of technetium-99m tetrofosmin myocardial perfusion imaging agent: Implications for a one-day imaging protocol. J Nucl Med 1993;34:1254-1259.
54. Ladenheim ML, Pollock BH, Rozanski A, et al. Extent and severity of myocardial hypoperfusion as predictors of prognosis in patients with suspected coronary artery disease. J Am Coll Cardiol 1986;7:464-471.
55. Shaw LJ, Hendel R, Borges-Nato S, et al. Prognostic value of normal exercise and adenosine 99mTc-tetrofosmin SPECT imaging: Results from the multicenter registry of 4728 patients. J Nucl Med 2003;44:134-139.
56. Gibbons JR, Antman ME, Alpert JS et al. for the TaskForce. ACC/AHA guideline update for the management of patients with chronic stable angina. American College of Cardiology. 2002; 1-125.
A few years ago, cardiac stress testing would not have been an important subject for emergency physicians. With the growth of observation units run by emergency physicians, however, more of us are ordering these tests and then acting on the results.You have reached your article limit for the month. Subscribe now to access this article plus other member-only content.
- Award-winning Medical Content
- Latest Advances & Development in Medicine
- Unbiased Content