Marwa A. Sabe and Julie C. Huang
ESSENTIAL FACTS
1. With few exceptions, exercise stress testing is the test of choice for initial evaluation of suspected coronary artery disease (CAD).
2. Diagnosis of CAD using exercise stress testing is limited by verification bias and an uncertain “gold standard.”
3. Exercise capacity is the most important prognostic factor derived from exercise stress testing; Duke treadmill score (DTS), heart rate recovery (HRR), chronotropic response, and ventricular ectopy during recovery also provide important prognostic information.
4. Exercise stress testing is most useful for intermediate-risk patients.
ESSENTIAL EVIDENCE/CURRENT GUIDELINES
The exercise electrocardiographic (ECG) stress test is one of the most commonly performed diagnostic tests in modern medicine and is the test of choice for the initial evaluation of suspected CAD. Its advantages include its low cost, general safety, noninvasive nature, and its usefulness in providing information regarding functional capacity. With the wide proliferation of imaging techniques, the “plain old treadmill test” has become increasingly underappreciated, despite its ability to predict short- and long-term risks. In fact, if a patient is able to exercise, has not been previously revascularized, and has a baseline ECG that is considered interpretable, ECG stress testing is the test of choice for the evaluation of suspected CAD.
Traditionally, the primary goal of exercise stress testing is the diagnosis of obstructive CAD and myocardial ischemia in patients with symptoms of angina or risk factors for heart disease. This goal, however, is hampered by verification bias; because the majority of patients who undergo coronary angiography to confirm the diagnosis of CAD have had a positive stress test, it cannot be known for certain how sensitive or specific the stress test is—those who had a negative stress test are not evaluated similarly with angiography. Furthermore, the use of coronary angiography as the gold standard for the diagnosis of CAD is increasingly questioned, as more recent studies have suggested that, because of arterial remodeling, an angiographically normal-appearing artery can actually have a significant amount of atherosclerotic disease upon evaluation by other methods such as intravascular ultrasound. For these reasons, some cardiologists discourage the notion of exercise stress testing as a “diagnostic” tool, but instead consider it a “prognostic” tool.
Safety
Exercise treadmill testing is generally considered to be very safe, but can rarely be associated with serious complications. These may include myocardial infarction (3.5/10,000 tests), serious arrhythmias (4.8/10,000), and death (0.5/10,000). Exercise testing after myocardial infarction is also safe at as early as 3 to 5 days, though is usually limited to submaximal testing using endpoints of 70% age-predicted maximal heart rate (rather than the 85% on a standard exercise stress test) or a peak work level of 5 METs.
Indications and Contraindications to Exercise ECG Stress Testing
Most commonly, exercise stress testing is ordered for the diagnosis of obstructive or flow-limiting CAD; it is most useful in patients with an intermediate pretest probability based on age, gender, and description of chest pain. In a patient with a high pretest probability of CAD (e.g., a middle-aged male with typical anginal symptoms and multiple cardiac risk factors), a negative stress test does not sufficiently preclude a diagnosis of CAD and is more likely to be a false negative result. In contrast, in a patient with a low pretest probability of CAD (e.g., a young woman with atypical symptoms and no significant risk factors), a positive stress test is more likely to be a false positive result. The sensitivity and specificity of testing is therefore highest in patients with intermediate pretest probability. Patients must also have a baseline ECG in which ST segments and subsequent changes are interpretable.
Patients with left bundle branch block, paced rhythms, >1 mm of resting ST depression (e.g., digoxin therapy or left ventricular hypertrophy with strain pattern), and Wolff–Parkinson–White syndrome are therefore not recommended for exercise ECG testing without adjunctive imaging due to the difficulty in assessing ECG changes in these patients. In patients with underlying left bundle branch block on ECG, pharmacologic stress is preferred over exercise stress due to the risk of diagnosing false positive septal ischemia.
Stress testing can also be used to assess prognosis in patients with known or suspected CAD. It is recommended after myocardial infarction for activity or exercise prescription, entrance into cardiac rehabilitation, and evaluation of medical therapy: and after revascularization to evaluate symptoms and as periodic monitoring of high-risk, asymptomatic patients. In patients with valvular heart disease, stress testing is used for evaluation of exercise capacity and may be very useful in determining the appropriate timing of surgery. Use of stress testing is also indicated for adjustment of pacemaker settings, assessment of suspected exercise induced arrhythmias, and evaluation of therapy in patients with suspected exercise-induced arrhythmias. Before a patient returns to work, testing may provide a comparison of peak workload achieved to that required in employment.
There are no class I indications for testing of asymptomatic patients, and routine screening is classified as a class III indication. However, patients who are asymptomatic but have multiple risk factors, those planning to start vigorous exercise or are engaged in occupations that may affect public safety (e.g., pilots, bus drivers), and those who are at high risk of cardiovascular disease because of comorbidities such as diabetes mellitus can still be referred for exercise stress testing though these are listed as class II indications (see Table 10.1 for class I indications for exercise stress testing).
TABLE
10.1 Class I Indications for Exercise Stress Testing
Adapted from Gibbons RJ, Balady GJ, Bricker JT, et al. ACC/AHA 2002 guideline update for exercise testing: summary article: a report of the American College of Cardiology/American Heart Association Task Force on Practice Guidelines (Committee to Update the 1997 Exercise Testing Guidelines). Circulation. 2002;106:1883–1892.
Contraindications to exercise stress testing (Table 10.2) include testing of extremely low-risk patients and those with recent myocardial infarction (within 2 days), unstable angina or dynamic ECG changes, active or unstable arrhythmias or congestive heart failure, aortic dissection, severe aortic stenosis, or other acute cardiac or systemic processes. Relative contraindications are at the discretion of the physician: testing may proceed if the benefit outweighs the risk.
TABLE
10.2 Contraindications to Exercise Testing
MI, myocardial infarction; SBP, systolic blood pressure; DBP, diastolic blood pressure; AV, atrioventricular.
(Adapted from Gibbons RJ, Balady GJ, Beasley JW, et al. ACC/AHA guidelines for exercise testing: executive summary: a report of the American College of Cardiology/American Heart Association Task Force on Practice Guidelines (Committee on Exercise Testing). Circulation. 1997;96:345–354.)
Methods of Testing
Ideally, the exercise stress test should last 8 to 12 minutes; this provides a reasonable compromise for assessment of functional capacity without fatigue and attainment of anaerobic threshold. It is therefore important to choose the appropriate exercise protocol to suit the patient’s projected ability to perform the test. For instance, the widely used Bruce protocol may be an appropriate test for most patients, but is likely too difficult for an elderly patient undergoing risk stratification before hospital discharge. A truncated test provides a less accurate assessment of functional capacity.
Although bicycle protocols allow for a more precise measurement of work capacity, most patients in the United States have more familiarity with treadmill methods and treadmill is therefore more commonly used. The disadvantage of treadmill is that work is only estimated and tends to be overestimated, depending on the degree of reliance (leaning) on handrails.
Placement of electrodes for ECG measurement differs in exercise testing compared to standard 12-lead ECG and may result in rightward axis shift and false positive or negative inferior Q waves. Lead V5 is often the best for assessment of ST changes. ECGs are obtained at rest, during each stage of exercise, at peak exercise, and every 1 to 2 minutes for at least 5 minutes of recovery. Other data obtained during testing include cardiac rhythm, heart rate, blood pressure, symptoms, and the patient’s rating of perceived exertion. The test is completed when the patient attains 85% of the age-predicted maximum heart rate or cannot proceed because of symptoms. The age-predicted maximum heart rate is calculated as 220 minus the age in years.
Absolute indications for termination of stress testing (Table 10.3) include symptoms, drop in systolic blood pressure, sustained ventricular arrhythmias, and the development of ST elevation in leads without q waves. Relative indications for termination of testing are also listed.
TABLE
10.3 Indications for Termination of ECG Stress Testing
SBP, systolic blood pressure; VT, ventricular tachycardia; IVCD, intraventricular conduction defect; DBP, diastolic blood pressure.
(Adapted from Gibbons RJ, Balady GJ, Beasley JW, et al. ACC/AHA guidelines for exercise testing: executive summary: a report of the American College of Cardiology/American Heart Association Task Force on Practice Guidelines (Committee on Exercise Testing). Circulation. 1997;96:345–354.)
Diagnostic Interpretation
Interpretation of the ECG stress test primarily involves evaluation of the ST segment. The classic positive finding is ≥1 mm of horizontal or down-sloping ST-segment depression 80 ms after the J point, though many labs also consider up-sloping ST-segment depression ≥1.5 mm a positive finding. Ischemic changes tend to occur in leads I and V4-V6; the more widespread the ECG changes, usually the more severe the disease. ST-segment depression does not localize ischemia; however, ST-segment elevation in leads without Q waves does localize the distribution of ischemia and is an absolute indication for termination of the test. Markers of severe CAD during testing include a drop in systolic blood pressure below resting value, exercise-limiting angina, poor exercise capacity <5 METs, down-sloping ST depression in recovery, and ST depression at low work load.
Prognostic Interpretation
Of as much importance as evaluation of ST segments during stress testing is the contribution of other markers of risk to overall prognosis. Exercise capacity is the most important prognostic variable; it is widely accepted that patients able to perform >10 METs are in general at low risk for cardiovascular events (Table 10.4). The heart rate recovery (HRR), the difference in heart rate from peak exercise to 1 minute recovery, is known to be a very strong prognostic indicator. HRR of 12 beats or less predicts an increased relative risk of sudden cardiac death and all cause mortality independent of CAD severity. Normally, withdrawal of the sympathetic nervous system and reactivation of the parasympathetic nervous system lead to a drop in heart rate after exercise, that is, HRR > 12 beats. A reduction in vagal activity, which may be the mechanism of a low HRR, has been previously shown to have an adverse effect on mortality and may be the reason a poor HRR predicts mortality.
TABLE
10.4 Age and Gender Estimated Functional Capacity
The Duke treadmill score (DTS), a composite of exercise capacity and angina, also provides important information. It is calculated as:
DTS = minutes of Bruce protocol – 5 × ST deviation – 4 × angina index
where the angina index is 0 = no angina, 1 = angina, but not test limiting, and 2 = test-limiting angina. DTS interpretation is as follows:
Low (≥ + 5): mortality risk <1% per year
Intermediate (–10 to +4): mortality risk 1% to 3% per year
High (<–10): mortality risk >3% per year
The use of beta-blockers during stress testing may affect certain variables such as chronotropic incompetence and peak heart rate but has little if any effect on the DTS and its prognostic implications. The presence of ventricular ectopy during exercise recovery is a significant negative prognostic indicator.
Exercise ECG Stress Testing in Women
Women represent a special population when choosing stress test modality. Because of the lower prevalence of obstructive CAD in women, diagnostic tests that detect focal areas of stenosis, such as ECG exercise stress testing, are less sensitive and specific in women. One of the reasons for the decreased accuracy of the ECG exercise stress test in women is the difference of accuracy of ST-segment depression in men and women. Women are more likely to have ST and T-wave changes on baseline ECG and more ST depression with exercise testing that does not provide prognostic value. It has been proposed that estrogen may have a digoxin-like effect on ST segments during exercise as ST depression is more likely to vary with the menstrual cycle in premenopausal women, and postmenopausal women taking estrogen supplements are more likely to have ST depression during exercise than women not taking these supplements. However, despite the decreased accuracy of exercise ECG stress testing in women, the 2005 Guidelines for the Role of Noninvasive Testing in the Clinical Evaluation of Women with Suspected Coronary Artery Disease recommends exercise ECG stress testing as the first diagnostic test of choice in intermediate risk, symptomatic women with normal baseline ECGs. In women who are asymptomatic, other parameters gained from the exercise stress test such as poor exercise capacity, low HRR, and failure to reach the target heart rate are more predictive of outcome than ECG changes associated with exercise.
Metabolic Gas-Exchange Analyses
Metabolic stress testing is indicated for the evaluation of exercise capacity and response to therapy in patients with heart failure being considered for heart transplantation as well as for differentiation of cardiac from pulmonary causes of exercise intolerance. It may also be used for the evaluation of exercise capacity when subjective measurement is unreliable, for the assessment of responses to specific therapeutic interventions, and for the determination of exercise intensity for a cardiac rehabilitation program. It is not indicated for routine evaluation of exercise capacity.
Several standard measurements are made in metabolic stress testing in addition to the above-mentioned variables used in routine ECG testing. The peak Vo2 (oxygen uptake) defines the patient’s aerobic capacity and is proportional to the cardiac output; a peak Vo2 of <14 mL/kg/min identifies high-risk patients who are reasonable candidates for cardiac transplant despite ambulatory status. The respiratory exchange ratio (RER), calculated as Vco2/Vo2, where Vco2 is the production of carbon dioxide, identifies the adequacy of the test, with RER > 1.09 suggesting adequate effort for reliable analysis of the test. Other important variable measurements include Vo2 at anaerobic threshold, the VE (minute ventilation)/MVV (maximal voluntary ventilation) (proportion of ventilatory), and Vo2 pulse or Vo2/HR (measure of stroke volume).
SUMMARY
In modern medical practice with its large array of available diagnostic testing, there is still a role for exercise ECG testing in the evaluation of suspected ischemic heart disease. It should be used primarily for evaluation of symptoms, but it is also important for risk stratification in certain patients, as well as in evaluation of the effectiveness of therapy. In its use as a tool for diagnosis of CAD, it is best used in patients with an intermediate pretest probability based on patient characteristics and symptomatology. In this situation the sensitivity and specificity of the test are highest, generally reported as 68% and 77%, though these values are hampered by verification bias.
The prognostic information gained from stress testing is just as important, and includes exercise capacity, HRR, chronotropic competence, and the DTS.
SUGGESTED READINGS
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.
Diaz LA, Brunken RC, Blackstone EH, et al. Independent contribution of myocardial perfusion defects to exercise capacity and heart rate recovery for prediction of all-cause mortality in patients with known or suspected coronary heart disease. J Am Coll Cardiol.2001;37(6):1558–1564.
Froelicher VF, Lehmann KG, Thomas R, et al. The electrocardiographic exercise test in a population with reduced workup bias: diagnostic performance, computerized interpretation, and multivariable prediction. Veterans Affairs Cooperative Study in Health Services #016 (QUEXTA) Study Group. Quantitative Exercise Testing and Angiography. Ann Intern Med. 1998;128: 965–974.
Frolkis JP, Pothier CE, Blackstone EH, Lauer MS. Frequent ventricular ectopy after exercise as a predictor of death. N Engl J Med. 2003;348(9):781–790.
Gibbons RJ, Balady GJ, Beasley JW, et al. ACC/AHA guidelines for exercise testing. A report of the American College of Cardiology/American Heart Association Task Force on Practice Guidelines (Committee on Exercise Testing). J Am Coll Cardiol. 1997;30(1):260–311.
Gibbons RJ, Balady GJ, Bricker JT, et al. ACC/AHA 2002 guideline update for exercise testing: summary article. A report of the American College of Cardiology/American Heart Association Task Force on Practice Guidelines (Committee to Update the 1997 Exercise Testing Guidelines). J Am Coll Cardiol. 2002;40(8): 1531–1540.
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QUESTIONS AND ANSWERS
Questions
1. A 40-year-old asymptomatic man with no risk factors undergoes stress testing as part of an “Executive Physical” program. His resting electrocardiography (ECG) is normal and he is taking no medications. He has an exercise capacity of 14 METs (13.5 minutes on the Bruce protocol), no angina, a peak heart rate of 180, and 1 mm of down-sloping ST-segment depression noted in lead V5. His Duke treadmill score (DTS) is:
a. 9
b. 8.5
c. 7.5
d. 3.5
e. 2
2. Given these test results, the next most appropriate step is:
a. No further cardiac testing
b. A stress imaging study
c. A repeat stress test in 1 year
d. Coronary angiography
3. A 55-year-old woman presents with intermittent substernal chest pain that radiates to the left arm. The pain is not clearly exertional and is not clearly relieved with rest. There is no history of gastrointestinal problems; her symptoms are not related to meals or body position. Her resting ECG is normal and she is taking no medications. She is referred for an exercise test and is found to have ST-segment depression. Assuming that the true, unbiased sensitivity of exercise ST-segment changes is 45% and the specificity is 85%, the likelihood that she has at least one 50% coronary artery stenosis is:
a. 0.25
b. 0.50
c. 0.75
d. 0.80
e. 0.90
4. A 60-year-old man with chronic obstructive pulmonary disease (COPD) (FEV1 1.25) and chronic ischemic cardiomyopathy (EF 30%) is referred for metabolic stress testing, which shows the following: peak Vo2 15 mL/kg/min, peak Vco2 18 mL/kg/min, Vo2 at anaerobic threshold 10 mL/kg/min, peak VE 45 L/min. Which of the following is true?
a. The test was submaximal.
b. The primary limitation to exercise is cardiac.
c. The primary limitation to exercise is pulmonary.
d. The patient should be referred for cardiac transplantation.
e. It is not possible to differentiate cardiac from pulmonary limitations to exercise in this patient.
5. A 60-year-old man presents with exertional pressure-like chest discomfort that is relieved with rest and that often radiates to the left arm and jaw. His resting ECG is normal. He is taking no medications. Which of the following is true?
a. The patient should be referred for coronary angiography.
b. The patient should have an exercise test to determine whether obstructive coronary artery disease (CAD) is present.
c. The patient should be referred for an exercise imaging study.
d. The patient should have an exercise test to determine his short- and long-term prognosis.
e. The patient need not have any test; he should be started on a beta-blocker, aspirin, and a lipidlowering agent and then followed.
6. In which of the following patients is an exercise ECG stress test recommended by class I indications?
a. A 45-year-old man with a past medical history of hypertension who presents with postprandial abdominal discomfort for the past few weeks
b. A 65-year-old female with a history of inferior myocardial infarction, status post percutaneous coronary intervention with stent placement in the right coronary artery and hypertension, who presents with worsening exertional, substernal chest pain for the past month, relieved with rest and nitroglycerin
c. A 50-year-old man with a family history of early CAD who presents for a routine physical exam and is noted to have left bundle branch block on resting ECG
d. A 60-year-old female with a history of 40-packyear smoking, hyperlipidemia, and diabetes mellitus, who presents with new symptoms of chest discomfort brought on with exertion for the past 2 weeks. Symptoms are relieved with rest. Her resting ECG has a right bundle branch block.
e. An 85-year-old man with exertional chest pain and shortness of breath. He has a harsh systolic murmur at the right upper sternal border with radiation to the carotids and a soft P2 on exam.
7. A 55-year-old woman with a history of hypertension and hyperlipidemia presents to the ER with symptoms of substernal chest pain radiating to the left arm that started 2 days prior to presentation. ECG reveals no abnormalities and she is chest pain free after two sublingual nitroglycerin tablets. She is ruled out for acute myocardial infarction by three sets of biomarkers 8 hours apart. What is the next recommended step?
a. Refer to the catheterization lab for immediate PCI.
b. Order an exercise ECG stress test.
c. Order a Persantine nuclear stress test because the exercise ECG test will likely show false positive ST depressions in female patients.
d. Send the patient home with no further testing.
8. The patient in Question 7 undergoes an ECG exercise stress test with the following results:
She completes 8 minutes of a modified Bruce protocol. She reaches a heart rate of 160 bpm, which decreases to 152 bpm after 1 minute of recovery. She has mild, nontest-limiting angina during the exam. Her ECG has no ST changes but does show occasional premature ventricular complexes (PVC’s).
Which of the following is a true statement based on these results?
a. Based on her DTS score, she has a mortality risk of <1% per year.
b. Her results cannot be interpreted because of the poor sensitivity and specificity of exercise ECG stress testing in women.
c. She has an increased risk of mortality based on her heart rate recovery (HRR).
d. PVCs have no prognostic value in stress testing.
e. Her stress test should have been immediately terminated when she experienced symptoms of angina.
9. All of the following patients have contraindications to ECG exercise stress testing except:
a. A 70-year-old man who had chest pain 48 hours prior to presenting to the ER. He is currently chest pain free. His ECG shows new q waves in V1-V3 that were not present on an ECG 1 month prior.
b. A 45-year-old woman with postpartum cardiomyopathy who presents with decompensated heart failure.
c. A 65-year-old man who presents with chest pain for the past few days brought on by exertion and deep breaths and relieved with rest. He was discharged 1 week prior after undergoing a right total knee replacement.
d. A 55-year-old man with a history of hypertension who presents with complaints of exertional chest pain for the past month. His resting blood pressure is 160/100 and he has a heart rate of 65 with first degree AV block on resting ECG.
e. An 85-year-old woman with recent history of syncope. On exam, she has a systolic ejection murmur with radiation to both carotid arteries. Her carotid pulses are delayed.
10. Which of the following parameters is a marker of severe CAD?
a. Up-sloping ST depression in recovery
b. 1-mm ST elevations in leads with q waves
c. Exercise capacity of <6 METS
d. ST depressions in leads V1-V3 in a patient with underlying RBBB
e. A drop in systolic blood pressure below resting value during testing
Answers
1. Answer B: DTS = 13.5 minutes – 5 × 1 mm of ST depression – 4 × 0 angina = 8.5.
2. Answer A: A DTS ≥ 5.5 implies low risk of death (≤1% per year) and therefore no further testing is needed.
3. Answer C: This is the positive predictive value, where PPV = (Sens)(Prev)/[(Sens)(Prev) + (1 – Spec) (1 – Prev)]. The patients has atypical angina, and given her age and gender therefore has an intermediate-risk (0.50) pretest likelihood. Substituting values, the PPV is 0.75.
4. Answer C: The MVV is 40 × 1.25 = 50. Given his VE of 45, he used up 90% of his breathing reserve.
5. Answer D: The patient has typical angina and a very high pretest likelihood of disease. Exercise testing is appropriate to assess prognosis. If he is found to be at low risk, medical management will be appropriate.
6. Answer D: Class I indications for exercise ECG testing include patients with an intermediate pretest probability of CAD based on sex, age, and symptoms. These include patients with RBBB. Class II indications include patients with low (the 45-year-old man) or high risk of CAD. Class III indications include patients with baseline ECG that is not interpretable (LBBB, LVH with strain pattern, 1-mm ST depressions at rest, preexcitation, and paced rhythms), documented myocardial infarction, or established diagnosis of CAD based on angiography. The 85-year-old man likely has severe symptomatic aortic stenosis, which is a contraindication to exercise stress testing.
7. Answer B: This patient has an intermediate risk of CAD based on age, sex, and symptoms, thus an exercise ECG test is indicated. Although in this woman, false positive ST depressions are possible, this is not a reason to order a pharmacologic stress test before an exercise ECG test in a patient who can exercise and has an interpretable baseline ECG.
8. Answer C: Her DTS score is 8 – (5 × 0) – (4 × 1) = 4. A DTS score of −10 to +4 predicts a mortality risk of 1% to 4% per year. Although exercise ECG stress testing has a lower sensitivity and specificity in women, it is still recommended as the first test of choice to assess CAD in women with an interpretable ECG who can exercise. Her HRR is calculated as 160 – 152 = 8; HRR < 12 is predictive of an increased risk of mortality. Ventricular ectopy during testing is also a significant adverse prognostic indicator. Mild angina is not a reason to terminate testing; stress testing should be terminated for moderate to severe angina.
9. Answer D: Contraindications to exercise ECG stress testing include the following: MI in the past 2 days, recent significant change in resting ECG, uncontrolled heart failure, acute pulmonary embolus, and severe aortic stenosis.
10. Answer E: Markers of severe CAD during testing include a drop in systolic blood pressure below resting value, exercise-limiting angina, poor exercise capacity <5 METS, down-sloping ST depression in recovery, and ST depression at low work load. ST elevation in leads with preexisting q waves is not predictive of disease severity. ECG changes in leads V1-V3 in patients with RBBB are not interpretable.