Role of Standard Treadmill Exercise Testing in CAD Diagnosis and risk stratification

General description of procedure, equipment, technique

Exercise testing provides both electrocardiographic and nonelectrocardiographic information that is useful for the diagnosis of coronary heart disease (CHD) and for the prognosis. Exercise protocols aim to assess exercise capacity. Perhaps the best measure of exercise capacity is maximum oxygen consumption (VO_2max), defined as the maximal amount of oxygen a subject can take in from inspired air during dynamic exercise and an estimator of cardiac output. While the optimal protocol will vary by patient, exercise protocols with progressive incremental increases in workload tend to estimate VO_2max more accurately. The most commonly employed exercise methods are treadmill or bicycle ergometry, with treadmill tests tending to demonstrate 10% to 15% higher VO_2max, 5% to 20% higher peak heart rate, and more frequent ST segment changes.

While the Bruce protocol is the most commonly used treadmill protocol in the U.S., with a large amount of published data, the relatively large increments in work between stages can make VO_2max estimation less accurate and cause some patients to terminate exercise before VO_2max is achieved. Ramp protocols targeting an exercise duration of 6 to 12 minutes tend to estimate VO_2max more accurately, constantly increasing work by increasing the incline at set brief intervals and increasing ramp speed based on estimated functional capacity. However, these protocols are limited by the need to accurately predict a patient’s functional capacity.

Indications and patient selection

Due to the wealth of prognostic information that nonelectrocardiographic test parameters provide (detailed below), exercise testing is recommended as a first-line test for the diagnosis of CHD in patients who are able to exercise, with two notable exceptions. Due to the combination on an uninterpretable ECG for ischemia and a high rate of false positive imaging findings with exercise, vasodilator myocardial perfusion imaging is recommended as the first-line test to diagnose CHD in patients with either: (1) a paced ventricular rhythm, or (2) a left bundle branch block. Exercise stress testing with imaging (myocardial perfusion imaging or echocardiography) should be employed as a first-line test in patients with greater than 1 mm resting ST segment depression, preexcitation (Wolff-Parkinson-White syndrome), and prior coronary revascularization (PCI or CABG).

Routine exercise testing is not currently recommended for detection of CHD in asymptomatic adults, although guidelines do allow for exercise testing in individuals with risk factors prior to starting a vigorous exercise program other than walking and in individuals in certain high-risk occupations. While stress-induced imaging abnormalities in this population demonstrate additional prognostic value in some, but not all, studies, absolute event rates were consistently low (even in subjects with abnormal tests) and the sensitivity was too low to justify cost-effective use of these tests for screening.

Contraindications

Any patient with evidence of clinical or hemodynamic instability should not undergo exercise testing until stabilized. Specific absolute contraindications, as outlined in ACC/AHA Exercise Testing Guidelines, include: acute myocardial infarction within the past 2 days, high-risk unstable angina, uncontrolled arrhythmia with symptoms or hemodynamic compromise, symptomatic severe aortic stenosis, decompensated heart failure, acute pulmonary embolism, acute myocarditis or pericarditis, and acute aortic dissection. Relative contraindications include: known left main coronary stenosis, moderate valvular stenosis, dynamic left ventricular outflow tract obstruction, severe hypertension (systolic blood pressure >200 mm Hg and/or diastolic blood pressure >110 mm Hg), tachy- or bradyarrhythmias, high-degree atrioventricular block, and significant electrolyte derangement.

Details of how the procedure is performed

Exercise testing should be performed at facilities with trained personnel with knowledge of the indications, contraindications, risks, and complications of exercise stress testing, including the normal and abnormal hemodynamic and electrocardiographic responses to exercise, and certification to perform cardiopulmonary resuscitation. A physician should be readily available. Typically, patients are asked not to eat for at least 3 hours prior to exercise testing. Following a brief history, physical examination, and an explanation of the procedure to the patient, ECG leads are placed and a standard 12-lead ECG performed along with measurement of resting heart rate and blood pressure. The exercise protocol is then initiated, with regular monitoring of heart rate, blood pressure, ECG, and patient symptoms during exercise until a testing endpoint is achieved. Monitoring is then continued until vital signs and ECG return to resting values, typically for 6 to 8 minutes.

Exercise testing should be terminated if the patient expresses a desire to stop or develops findings of severe ischemia, significant arrhythmia, or hemodynamic compromise. Specific absolute indications to terminate an exercise stress test, as outlined in ACC/AHA Exercise Testing Guidelines, include: drop in systolic blood pressure of >10 mm Hg from baseline despite increasing workload with associated evidence of ischemia; moderate or severe angina; dizziness or near-syncope; evidence of poor perfusion; ≥ 1.0 mm ST elevation in leads without diagnostic Q waves (other than V₁ or aVR); sustained ventricular tachycardia; subject’s desire to stop; and technical difficulties accurately monitoring the ECG or blood pressure.

Additional relative indications to stop a test include: drop in systolic blood pressure of >10 mm Hg without additional evidence of ischemia, >2 mm of horizontal or downsloping ST segment depression, arrhythmias other than ventricular tachycardia, development of LBBB or interventricular conduction delay that cannot be distinguished from VT, increasing angina, and a hypertensive blood pressure response (systolic blood pressure >250 mm Hg and/or diastolic blood pressure >115 mm Hg).

Interpretation of results

Diagnosis: Interpretation of electrocardiographic response

Electrocardiographic manifestations of exercise-induced myocardial ischemia focuses on ST segment deviation, measured relative to the P-Q junction. Ischemic ST segment depression is horizontal or downsloping, ≥ 0.10 mV (1 mm) in magnitude, and lasts for ≥ 80 msec, with downsloping ST segment depression more specific for ischemia than horizontal or upsloping ST segment depression. Importantly, comparable diagnostic significance is associated with ischemic ST segment depression occurring only during the recovery phase of an exercise test compared to ST segment depression occurring during exercise.

The development of exercise-induced ST segment elevation in subjects without preexisting Q waves is a high-risk marker associated with transmural ischemia and reliably localizing the area of ischemia. It is rare, occurring in an estimated 0.1% of patients in a clinical laboratory. ST elevation is not infrequent in leads with preexisting Q waves and is of unclear significance among patients with prior MI.

Prognosis

Duke treadmill score

Both exercise capacity and the presence of exercise-induced myocardial ischemia, generally reflected in ST segment deviation and/or anginal symptoms, are powerful prognostic parameters obtained during the exercise stress. The most widely used risk score that integrates these prognostic measures is the Duke treadmill score (DTS), which is based on three prognostic variables: ST segment depression, exercise time on Bruce protocol, and Duke angina index (0 = no angina, 1 = typical angina occurred, and 2 = angina was reason for test termination). The DTS is calculated as:

DTS = Exercise time (in minutes) – (5 x ST deviation in mm) – (4 x Duke angina index).

This score effectively stratifies subjects in terms of risk of death or MI, including unselected outpatients, in whom the 4-year survival rate among low-risk patients (DTS (≥ +5) was 99%, while among high-risk patients (score ≤ -11) it was 79%. An important limitation of the DTS is its limited discrimination in elderly subjects.

Exercise capacity

Exercise capacity is the most powerful prognostic parameter from an exercise test. Exercise capacity is commonly measured in metabolic equivalents (METs), where one MET is the basal oxygen uptake during quiet sitting and is equal to 3.5 mL/kg/min. Nomograms exist to estimate age-predicted exercise capacity among men (18.0 – [0.15 × age]) and women (14.7 – [0.13 × age]).

Chronotropic incompetence

Chronotropic incompetence refers to an inability to achieve the expected increase in heart rate with exercise. It is thought to reflect sympathetic sensitivity and has been consistently associated with increased risk of all-cause and cardiovascular mortality, beyond demographics, standard risk factors, and findings on perfusion imaging. Chronotropic incompetence can be measured by:

(1) The proportion of age-predicted maximal heart rate achieved during the stress test:

peak HR/220-age;

(2) The proportion of heart rate reserve used:

([peak HR – rest HR]/[maximum age-predicted HR – rest HR]) × 100;

(3) The chronotropic index which incorporates data regarding both resting HR and physical fitness:

[(METs_stage– METs_rest)/(METs_peak – METs_rest)]/ [HR_peak –HR_rest]/[ HR_{max predicted} –HR_rest].

Of note, the prognostic relevance of chronotropic incompetence in patients on beta-blocker therapy at the time of the exercise test is unclear, as the majority of studies excluded these patients.

Heart rate recovery

Heart rate recovery is the rate of decrease in heart rate postexercise, and is calculated as:

Heart rate recovery = heart rate_{peak exercise} – heart rate_{1 or 2 minutes postexercise}

with impaired commonly defined as a ≤ 12 bpm decrease within the first minute postexercise or a <22 bpm decrease at 2 minutes postexercise. Heart rate recovery likely reflects parasympathetic reactivation and autonomic balance, with impaired heart rate recovery associated with an increased risk of death, even after adjustment for patient demographics, standard risk factors, and perfusion abnormalities on nuclear imaging. This relationship is also independent of exercise capacity and peak chronotropic response. Like chronotropic incompetence, the prognostic utility of heart rate recovery in patients on beta-blockers is unclear. Among asymptomatic individuals, both exercise capacity and heart rate recovery appear to add important prognostic information beyond the Framingham risk score, particularly among those with low to intermediate risk.

Blood pressure responses

Exercise is normally characterized by a steady rise in systolic blood pressure with little change in diastolic blood pressure, with a resulting increase in pulse pressure. Exercise-induced hypotension, defined as an initial increase in blood pressure followed by a 20 mm Hg decrease during exercise or by a decrease during exercise >10 mm Hg below standing rest blood pressure, is associated with an increased prevalence of 3-vessel disease or left main coronary artery disease and with an up to 3-fold increased risk in death at 2 year follow-up.

An exaggerated systolic blood pressure response to exercise (commonly defined as peak systolic blood pressure >200 to 220 mm Hg) appears associated with an increased risk of subsequent hypertension. Studies investigating the relationship with cardiovascular outcomes of both systolic and diastolic blood pressure measured at low level and maximal exercise have been conflicting, particularly with respect to their association independent of resting blood pressure.

Ventricular arrhythmias

Frequent ventricular ectopy is generally defined as an increased frequency of premature ventricular contractions (e.g. >7 per minute or >10% of beats in a 30-second period), ventricular bigeminy or trigeminy, couplets or triplets, or ventricular tachycardia. Data regarding the prognostic role of exercise-induced ventricular ectopy is conflicting. Recent studies in largely asymptomatic population-based cohorts and among referral populations suggest that exercise-induced frequent ventricular ectopy is associated with increased long-term, all-cause, and cardiac mortality. However, further data is needed to clarify this association, as the strength and magnitude of this relationship likely varies with the definition of frequent ventricular ectopy employed, the phase of exercise test when measured (exercise versus recovery), and the population being assessed (asymptomatic screening versus referral versus known CHD).

Performance characteristics of the procedure (applies only to diagnostic procedures)

Sensitivity defines the probability that a patient with disease will have a positive test and specificity defines the probability that a patient without disease will have a negative test. Estimates of the diagnostic accuracy of ECG-exercise stress testing for the diagnosis of significant coronary disease vary widely. However, many studies suffer from important methodological limitations that may inflate estimates of ST segment depression sensitivity, including (1) inclusion of subjects with high probability of having disease (e.g. prior MI), and (2) inclusion of subjects based on the results of the test being evaluated,( i.e. only subjects undergoing both stress testing and coronary angiography are included, although the decision to pursue angiography is influenced by the results of the exercise test (workup bias). A large meta-analysis of 147 studies involving 24,074 patients reported a mean sensitivity and specificity of 68% and 78%, respectively, although in studies that avoided workup bias and included more patients without a high pretest probability of disease, ischemic ST segment depression demonstrated a sensitivity of 50% and a specificity of 90%.

The clinically relevant information in interpreting the results of any given patient’s test is the likelihood that a positive result is truly indicative of disease (positive predictive value) and that a negative result truly excludes disease (negative predictive value). These parameters are dependent both on the test and the prevalence of disease in the population (i.e. the pretest probability). Bayes’ theorem states that the probability of disease after a diagnostic test is equal to the pretest probability of disease multiplied by the probability of a true positive result from the test. A corollary is that the chances of a positive result truly reflecting disease (i.e., positive predictive value) will be higher in high prevalence populations and lower in low prevalence populations. Age, gender, and chest pain history have consistently been shown to be the most powerful predictors of CHD. As outlined in the ACC/AHA Exercise Testing Guidelines, together these variables are commonly used to assess the pretest probability of CHD as either high (>90%), intermediate (10% to 90%), low (5% to 10%), and very low (<5%). The results of exercise testing will have the greatest effect on posttest probability of CHD in subjects with intermediate pretest probabilities.

Outcomes (applies only to therapeutic procedures)

N/A

Alternative and/or additional procedures to consider

Indications for testing with imaging

Exercise testing with imaging is only recommended as an initial test to diagnose CHD in situations in which baseline ECG abnormalities make interpretation of ischemic ST segment deviation unreliable: (1) preexcitation syndrome (Wolff-Parkinson-White), (2) electrically paced ventricular rhythm, (3) greater than 1 mm resting ST segment depression, and (4) complete left bundle branch block. Subjects with ventricular-paced rhythms and complete left bundle branch block in particular should undergo vasodilator stress perfusion studies due to the increased false-positive rate associated with exercise stress and echocardiographic imaging.

Complications and their management

Exercise stress testing is a safe procedure. Recognized serious complications of exercise testing include myocardial infarction (MI), malignant ventricular arrhythmias, and sudden death. Large survey studies have reported acute myocardial infarction in 0.9 to 3.6 per 10,000 tests, serious arrhythmias in 0.3 to 4.8 per 10,000 tests, and death in 0 to 0.5 per 10,000 tests. The risk of adverse events is higher in post-MI patients and patients undergoing evaluation for malignant ventricular arrhythmias. Although rare, given the potential for serious risks, clinical judgment is essential in selecting patients appropriate for stress testing, as is careful monitoring by appropriately trained staff before, during, and after testing.

What’s the evidence?

Gibbons, RJ, Balady, GJ, Bricker, JT. “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. vol. 106. 2002. pp. 1883-92. (Key guideline including recommendations and evidence review for indication, performance, and interpretation of exercise stress testing.)

Fletcher, GF, Balady, GJ, Amsterdam, EA, Chaitman, B, Eckel, R, Fleq, J, Froelicher, VF, Leon, AS, Pina, IL, Rodney, R, Simons-Morton, DA, Williams, MA, Bazzarre, T. “Exercise standards for testing and training: a statement for healthcare professionals from the American Heart Association”. . vol. 104. 2001. pp. 1694-1740. (Key statement reviewing the details of exercise stress test patient selection, study performance, and results interpretation, including a comprehensive literature review.)

Schlant, RC, Friesinger, 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. vol. 16. 1990. pp. 1061-5. (Statement of the key skills necessary to perform, supervise, and interpret exercise stress tests.)

Gianrossi, R, Detrano, R, Mulvihill, D. “Exercise-induced ST depression in the diagnosis of coronary artery disease. A meta-analysis”. Circulation. vol. 80. 1989. pp. 87-98. (Large meta-analysis of 147 studies (n = 24,074) comparing the performance of exercise-induced ST segment depression to coronary angiography in diagnosing coronary artery disease.)

Rywik, TM, Zink, RC, Gittings, NS. “Independent prognostic significance of ischemic ST-segment response limited to recovery from treadmill exercise in asymptomatic subjects”. Circulation. vol. 97. 1998. pp. 2117-22. (Study of 825 healthy volunteers demonstrating similar adverse prognostic implication for incident coronary events of ischemic ST segment changes developing during exercise and those developing only during recovery.)

Mark, DB, Hlatky, MA, Harrell, FE, Lee, KL, Califf, RM, Pryor, DB. “Exercise treadmill score for predicting prognosis in coronary artery disease”. Ann Intern Med. vol. 106. 1987. pp. 793-800. (Initial development and validation of the Duke Treadmill Score in 2,842 referral patients with chest pain who underwent both treadmill exercise testing and coronary angiography.)

Mark, DB, Shaw, L, Harrell, EF. “Prognostic value of a treadmill exercise score in outpatients with suspected coronary artery disease”. N Engl J Med. vol. 325. 1991. pp. 849-53. (Validation of the Duke Treadmill Score in 613 unselected outpatients referred for exercise testing.)

Kwok, JM, Miller, TD, Hodge, DO, Gibbons, RJ. “Prognostic value of the Duke treadmill score in the elderly”. J Am Coll Cardiol. vol. 39. 2002. pp. 1475-81. (Study demonstrating limited prognostic utility of the Duke Treadmill Score among 247 elderly patients ≥ 75 years old.)

Morris, CK, Myers, J, Froelicher, VF, Kawaguchi, T, Ueshima, K, Hideg, A. “Nomogram based on metabolic equivalents and age for assessing aerobic exercise capacity in men”. J Am Coll Cardiol. vol. 22. 1993. pp. 175-82. (Derivation of a nomogram to predict normal exercise capacity based on age and activity level among men.)

Gulati, M, Black, HR, Shaw, LJ. “The prognostic value of a nomogram for exercise capacity in women”. N Engl J Med. vol. 353. 2005. pp. 468-75. (Derivation and validation of a nomogram to predict normal exercise capacity based on age among women. )

Ekelund, LG, Haskell, WL, Johnson, JL, Whaley, FS, Criqui, MH, Sheps, DS. “Physical fitness as a predictor of cardiovascular mortality in asymptomatic North American men. The Lipid Research Clinics Mortality Follow-up Study”. . vol. 319. 1988. pp. 1379-84.

Blair, SN, Kohl, HW, Barlow, CE, Paffenbarger, RS, Gibbons, LW, Macera, CA. “Changes in physical fitness and all-cause mortality. A prospective study of healthy and unhealthy men”. JAMA. vol. 273. 1995. pp. 1093-8.

Myers, J, Prakash, M, Froelicher, V, Do, D, Partington, S, Atwood, JE. “Exercise capacity and mortality among men referred for exercise testing”. N Engl J Med. vol. 346. 2002. pp. 793-801.

Blair, SN, Kohl, HW, Paffenbarger, RS, Clark, DG, Cooper, KH, Gibbons, LW. “Physical fitness and all-cause mortality. A prospective study of healthy men and women”. . vol. 262. 1989. pp. 2395-2401.

Lauer, MS, Francis, GS, Okin, PM, Pashkow, FJ, Snader, CE, Marwick, TH. “Impaired chronotropic response exercise stress testing as a predictor of mortality”. JAMA. vol. 281. 1999. pp. 524-9. (Hospital-based cohort study of 2,953 persons referred for treadmill thallium testing, demonstrating a significant association between chronotropic incompetence and all-cause mortality independent of potential confounders including age, gender, and thallium perfusion defects.)

Cole, CR, Blackstone, EH, Pashkow, FJ, Snader, CE, Lauer, MS. “Heart-rate recovery immediately after exercise as a predictor of mortality”. N Engl J Med. vol. 341. 1999. pp. 1351-7. (Hospital-based cohort study of 2,428 persons referred for exercise thallium testing, demonstrating a significant association between heart rate recovery and all-cause mortality independent of potential confounders including workload achieved and thallium perfusion defects.)

Nishime, EO, Cole, CR, Blackstone, EH, Pashkow, FJ, Lauer, MS. “Heart rate recovery and treadmill exercise score as predictors of mortality in patients referred for exercise ECG”. JAMA. vol. 284. 2000. pp. 1392-8. (Hospital-based cohort study of 9,454 persons referred for exercise testing, demonstrating a significant association between both heart rate recovery and Duke Treadmill Score and all-cause mortality independent of potential clinical confounders.)

Stuart, RJ, Ellestad, MH. “National survey of exercise stress testing facilities”. Chest. vol. 77. 1980. pp. 94-7. (Survey of 518,448 exercise stress tests, including the incidence and types of complications, performed at 1,375 centers.)

Myers, J, Voodi, L, Umann, T, Froelicher, VF. “A survey of exercise testing: methods, utilization, interpretation, and safety in the VAHCS”. J Cardiopulm Rehab. vol. 20. 2000. pp. 251-8. (Survey of 75,828 exercise stress tests performed at 72 Veterans Affairs Medical Centers, including the incidence and types of complications.)

Senaratne, MP, Smith, G, Gulamhusein, SS. “Feasibility and safety of early exercise testing using the Bruce protocol after acute myocardial infarction”. J Am Coll Cardiol. vol. 35. 2000. pp. 1212-20. (Study of 300 acute myocardial infarction patients without rest angina, heart failure, or significant arrhythmia demonstrating the safety of exercise stress testing with Bruce protocol within 3 days of admission.)

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