Chapter 26: ECG Exercise Testing

Exercise electrocardiography testing has been a valuable noninvasive tool for many decades in the evaluation of patients with suspected or known coronary artery disease (CAD) and remains widely utilized. The primary goals of noninvasive stress testing are to aid in the diagnosis of obstructive CAD and to provide risk stratification in an attempt to estimate the probability of myocardial infarction (MI) or death. Although cardiac stress imaging can improve the diagnostic yield and enhance risk stratification beyond exercise electrocardiogram (ECG) variables alone, the standard exercise ECG stress test should play a key role in the evaluation of patients with suspected CAD. The exercise ECG continues to be of great value, especially as the CAD paradigm has shifted from an emphasis on diagnosis to the importance of risk stratification.

It is beyond the scope of this chapter to review the instrumentation, patient preparation, technical considerations, detailed instructions, and interpretation of exercise ECG testing; much of this material is discussed in Chapter 8. Additional information is available for review in prior publications from the American Heart Association.^1–4 As a general rule, exercise testing is most commonly performed on a treadmill using a standardized protocol that incrementally increases both the speed and grade of the treadmill in an attempt to achieve maximal cardiac stress. A variety of exercise protocols have been developed, with the Bruce protocol being the most commonly used. Despite the strong clinical validation of the Bruce protocol, the use of a singular protocol for all patients is not appropriate.

Exercise testing is generally a safe and well-tolerated procedure, yet clinical judgment and appropriate supervision should be employed. Death or MI may occur in up to 1 per 2500 tests.^2,5 Absolute and relative contraindications to exercise testing and indications for the termination of exercise testing are summarized in Chapter 8.²

The standard criterion of an abnormal exercise ECG response is ST-segment depression (horizontal or down-sloping) ≥1 mm 80 ms after the J-junction. Using the standard 12-lead ECG, ST-segment depression in lead V₅ has the greatest diagnostic value for CAD, whereas ST-segment depression confined only to the inferior leads is of little value. ST-segment depression does not localize areas of ischemia. ST-segment elevation in leads without Q waves occurs infrequently. This finding represents transmural ischemia and, as a result, localizes ischemia and the culprit vessel. Exercise-induced ST-segment elevation in lead aVR has been utilized to improve detection of left main or ostial left anterior descending artery disease.⁶

It is well recognized that certain drugs (beta-blockers and nitrates) reduce test sensitivity, and resting baseline ECG abnormalities (left ventricular hypertrophy with strain, digoxin effect, and ST-segment depression) reduce test specificity and should be taken into consideration for test interpretation. Bayes' theorem states that the greatest yield of testing for diagnostic purposes occurs in patients who have intermediate (10–90%) pretest probability of CAD. Individuals at the extremes of pretest probability, either very low (younger women with atypical chest pain) or very high (older men with typical angina), derive little benefit from testing. The ACC/AHA Exercise Test guidelines² recommend against performing an exercise test for diagnostic purposes in these patient subsets. The ACC/AHA guidelines as well as other organizations generally discourage exercise testing with our without imaging in asymptomatic patients.^7,8

There are multiple meta-analyses reviewing the diagnostic accuracy of exercise treadmill testing.^2,9–11 Sensitivity is generally in the range of 65% and specificity 80%. It is important to appreciate that these apparent values for sensitivity and specificity have not been corrected for referral bias (also called verification bias). Referral bias is a concept that addresses the preferential referral of patients with positive test results to coronary angiography, the subset of patients in whom sensitivity and specificity are determined. The net impact of referral bias is to artificially inflate test sensitivity and to artificially decrease test specificity. Approaches to overcome referral bias include catheterizing the entire population of patients who undergo evaluation for CAD¹² or adjusting the sensitivity and specificity values by applying mathematical corrections.¹³ Posttest referral bias alters not only standard exercise treadmill test (ETT) results, but also stress imaging results.^14,15

A multitude of valuable prognostic information can be obtained during an exercise ECG test. Variables obtained through the ETT may reflect overall cardiovascular and physical fitness as well as function of the autonomic nervous system. Exercise variables that have been shown to predict outcome include: exercise duration, chronotropic incompetence, heart rate recovery, exercise hypotension, exercise hypertension, and ventricular ectopy.^16,17 Exercise ST-segment depression contains prognostic information but generally is a weaker parameter than these other variables. Exercise duration has been demonstrated in many studies to be the strongest prognostic variable (Fig. 26-1).^2,18–23 Several studies have demonstrated the relationship of exercise duration to myocardial ischemia and subsequent events. Patients achieving ≥10 metabolic equivalents (METS) have demonstrated a lower prevalence of myocardial ischemia by stress SPECT compared to patients achieving <7 METS and also low rates of nonfatal myocardial infarct (0.7%/year) or cardiac death (0.1%/year).^24,25 Available data on whether exercise hypertension (commonly defined as a systolic blood pressure during exercise >190–220 mm Hg) corresponds to an increased risk of cardiac events are unclear,^26,27 whereas exercise hypotension has been associated with an increased (threefold higher) risk of future cardiovascular events over a 2-year period.²⁸ Chronotropic incompetence is the failure of the heart rate to increase appropriately with exercise (defined as <80% of the predicted value) and the proportion of heart rate reserve used during exercise can be calculated by the formula: (heart rate^peak − heart rate^rest)/(220 − age − heart rate^rest).¹⁷ Chronotropic incompetence has been shown to predict all-cause mortality and cardiac death.^29,30 Impairment of heart rate recovery and heart rate variability have also been shown to predict all-cause mortality and cardiovascular events.^31,32 While sustained episodes of ventricular arrhythmias are uncommon and can be mediated by ischemia, shorter periods of ventricular ectopy (isolated ventricular premature complexes, couplets, or nonsustained ventricular tachycardia) during exercise or in the recovery period occur more often. The prognostic importance of these "short" episodes of ventricular ectopy is uncertain.³³ The relationship between exercise-induced ventricular ectopy, myocardial ischemia, and left ventricular systolic function remains ill defined.

Many prognostic scores have been developed and subsequently validated using combinations of the variables described above. The most commonly used score is the Duke treadmill score that is calculated using three exercise parameters (exercise duration, ST-segment depression, and angina). The Duke treadmill score = exercise time (minutes based on the Bruce protocol) − (5 × maximum ST-segment deviation [in millimeters]) − (4 × exercise angina [0 = none, 1 = non-limiting, and 2 = exercise limiting]). The Duke treadmill score stratifies patients into low-risk (score ≥+5, annual cardiovascular mortality 0.25%), intermediate-risk (score +4 to −10, annual cardiovascular mortality 1.25%), or high-risk (score <−10, annual cardiovascular mortality 5%) categories (Fig. 26-2).^34,35 This score was initially developed using the Duke University treadmill database and has subsequently been validated by several other investigators.^36,37 Applying all available prognostic information and not just the three variables that comprise the Duke score enhances the accuracy of risk stratification.³⁸

Comparison of ECG–ETT with Stress Imaging

The standard ETT and stress imaging study each has advantages compared to the other (Table 22-1). The major advantage of ETT is lower cost. The charge for an exercise stress SPECT study is approximately five to seven times higher than a standard ETT. Stress imaging does have several advantages over the standard ETT. In patients with significant abnormalities on the resting ECG (left bundle branch block, paced ventricular rhythm, ventricular pre-excitation, and ST-segment depression ≥1 mm), the stress ECG will be either uninterpretable or inaccurate. Patients with percutaneous coronary intervention (PCI) and/or coronary artery bypass graft surgery (CABG) are more likely to have significant resting ECG abnormalities. In these patients another important clinical issue is localization of ischemia if further revascularization is being considered. Finally, the sensitivity of the stress ECG in patients who undergo pharmacologic stress, especially vasodilator stress, is very low. In these patients pharmacologic stress needs to be combined with imaging. The ACC/AHA guidelines^2,39 acknowledge these issues and recommend that stress imaging preferentially be performed instead of standard ETT as the initial stress modality in the following patients: (1) high pretest probability of CAD; (2) inability to exercise; or (3) significant resting ECG abnormalities.

Many studies have demonstrated that stress imaging also has higher sensitivity⁴⁰ and provides incremental prognostic accuracy^36,41–45 compared to the standard ETT. However, these studies did not indicate which subsets of patients benefit or what percentage of the population can be more accurately risk stratified. An important question is whether the standard ETT can identify a subset of patients whose event rate is so low that imaging fails to add additional prognostic information or is not cost effective.

To address this issue, several studies have compared the ability of an approach using just clinical and exercise ECG variables versus an approach using clinical, exercise ECG, and nuclear imaging variables to identify patients with severe (left main and/or three-vessel) CAD at angiography and to predict clinical outcome.^46–49 The study populations were restricted to patients with a normal resting ECG. The rationale for studying only patients with a normal resting ECG was twofold: (1) the majority of patients with a normal resting ECG have normal left ventricular ejection fraction (LVEF) and (2) the exercise ECG is more accurate if the resting ECG is normal. Approximately 95% of patients with a normal resting ECG undergoing evaluation for CAD have a normal LVEF when directly measured by a variety of imaging techniques.^50–53 In addition, in patients with a normal resting ECG, the specificity of the exercise ECG is much higher compared to those with resting ST-T abnormalities.²

In a study of 411 patients with a normal resting ECG who underwent exercise SPECT followed by coronary angiography within 6 months,⁴⁶ the clinical–exercise ECG–SPECT model correctly reclassified only an additional 14 patients (3% of the study population) for the presence or absence of severe angiographic CAD compared to the clinical–exercise ECG model alone (Fig. 26-3). Importantly, the addition of SPECT failed to identify more patients as high risk who had angiographic severe CAD. A cost-effectiveness analysis employing a conservative approach of Medicare RVUs revealed that the cost of each of these correctly reclassified patients exceeded $20,000. In addition, the follow-up component of this study revealed no difference in event rates between patients categorized as low or high risk by each model. These results are consistent with earlier studies comparing the clinical–exercise ECG-only approach to an approach using clinical–exercise ECG–exercise gated equilibrium radionuclide imaging.^47,49

A very small number of patients with a normal resting ECG who have a low-risk treadmill score will have a subsequent event (a "false-negative" prognostic treadmill score). To determine if these patients can be identified by SPECT, 1461 patients with these characteristics (normal resting ECG and low-risk Duke treadmill score) who underwent exercise SPECT were followed up for 7 ± 1 years.⁴⁸ To further risk stratify this population, a clinical risk score previously demonstrated to predict a patient's risk of both severe angiographic CAD and clinical outcome^54–56 and different from the Diamond–Forrester method that assesses pretest probability of any CAD was applied. The majority (79%) of the population characterized as low risk by the clinical score had good clinical outcome (annual risk of cardiac death <0.5%), regardless of the SPECT image results (Fig. 26-4 [top panel]). In the minority (21%) of the population characterized as high risk by the clinical score, SPECT summed stress score (SSS) prognostic categories could risk stratify these patients. Those with low- or intermediate-risk SSS had annual cardiac mortality <1%, whereas in those with high-risk SSS annual cardiac mortality approached 3% (Fig. 26-4 [bottom panel]).

The results of these studies are generally in agreement with other studies examining this issue.^43,45,57 In a study using SPECT imaging, patients with normal gated SPECT LVEF were at low risk (annual cardiac death rate <1%), even if their SSS was severely abnormal.⁵⁷ In a more recent study, SPECT imaging could risk stratify 1136 patients with a normal resting ECG who had a low-risk Duke treadmill score.⁴³ The annual cardiac death/MI rate in patients with normal SPECT was 0.5% versus 2.9% for mildly abnormal SPECT and 3.5% for moderately severely abnormal SPECT. For patients with a low pretest probability of CAD, however, the cost-effectiveness analysis revealed that the cost per hard event detected by applying SPECT was $211,470.

Other studies suggest that certain patient subsets who are at higher risk on clinical grounds, which includes the "older" elderly (age ≥75 years), might be more effectively risk stratified by using stress SPECT instead of standard ETT.⁵⁸ Age is a major determinant of both pretest probability of CAD and risk of experiencing a clinical event. National guidelines recommend that high-risk patients preferentially undergo stress imaging as the initial stress modality.³⁹ However, specific recommendations addressing age have yet to be incorporated into national guidelines. More work in this field is necessary to clarify if such an approach is cost effective. Women represent an additional patient subset of interest as a result of lower test accuracy of the standard treadmill test, which in part is due to a lower prevalence of CAD in women compared to men. The WOMEN (What is the Optimal Method for Ischemia Evaluation in Women) trial randomized symptomatic women with an intermediate likelihood of CAD to standard ETT or exercise SPECT.⁵⁹ The cumulative costs were lower in women randomized to the standard ETT and importantly, the survival free of major adverse events was not significantly different between the groups (98% for ETT vs. 97.7% for exercise SPECT; p = 0.59) over 2 years of follow-up.

Additional cost savings may also be possible through using newer stress protocols with SPECT imaging performed as needed. As mentioned earlier, patients achieving ≥10 METS have demonstrated a lower prevalence of myocardial ischemia by stress SPECT compared to patients achieving <7 METS and also low rates of nonfatal myocardial infarct (0.7%/year) or cardiac death (0.1%/year).^24,25 Using the strategy of beginning with a standard ETT in select patients and avoiding SPECT imaging in those patients who achieve ≥10 METS, a satisfactory cardiac workload (usually defined as ≥85% maximal age-predicted heart rate, and without ischemic ST changes during exercise) may result in considerable cost savings when compared to exercise SPECT.²⁴ If patients were unable to achieve ≥10 METS, had worrisome exercise-related symptoms, or ECG findings during exercise (i.e., ischemic ST changes or complex ventricular ectopy) then a strategy of SPECT imaging "on-demand" could be utilized with injection of the isotope during exercise followed by a decision regarding the need for subsequent resting SPECT images.

Appropriate Use Criteria and ECG–ETT

The American College of Cardiology Foundation Appropriate Use Criteria (AUC) Task Force in conjunction with the American Heart Association and other societal organizations published appropriateness criteria for noninvasive testing modalities for the diagnosis of or evaluation for stable ischemic heart disease.⁶⁰ This multimodality AUC document assigns AUC ratings for exercise ECG as well as adjunct stress imaging modalities for the detection and risk assessment of stable ischemic heart disease patients. The ETT appropriate ratings for a variety of clinical scenarios evaluated in the AUC document are shown in Table 26-2. These AUC are partially consistent with the ACC/AHA Guideline Update for Exercise Testing² that address the use of standard ETT versus stress SPECT (Table 26-3). For patients at low pretest probability of CAD with a normal resting ECG who can adequately exercise, the appropriateness criteria document assigns an indication of rarely appropriate for SPECT imaging, based on the rationale that such patients should be evaluated with the standard ETT. For the patient at intermediate or high pretest probability of CAD and otherwise the same characteristics, the appropriateness criteria document assigns SPECT imaging a rating of appropriate.

The available literature suggests that the standard ETT can effectively detect or exclude the presence of CAD in a large number of patients, as well as successfully identify patients who are at low clinical risk. Numerous studies have demonstrated that annual event rates in these patients who have a low-risk ETT score are well below 1%. SPECT imaging in these patients either fails to identify additional patients who subsequently experience events or the cost of using SPECT to identify the small number of higher-risk patients missed by the standard ETT is prohibitive. Many patients being evaluated for CAD will have low-risk treadmill scores and can be appropriately reassured and will not require additional testing. The very small percentage of patients (most studies suggest <5%) with high-risk treadmill scores are candidates for proceeding directly to coronary angiography. The subset of patients classified as intermediate risk by the treadmill score will often require additional testing, which could include SPECT,⁴² for refinement of risk stratification. In these patients this two-step approach of standard ETT followed by SPECT is less convenient than if only SPECT had been performed as the initial test. However, applying the standard ETT in the entire population initially may be a more cost-effective strategy overall, as most patients will be classified as low risk and will not require additional testing. The standard ETT should continue to play a major role in the initial stratification of CAD patients, especially in an area of increasingly constrained financial resources.