Exercise Stress Testing

Exercise stress testing without adjunct noninvasive imaging is frequently used as the initial screening test in patients without known coronary artery disease who present with chest pain syndromes or symptoms suggestive of ischemia. The premise of exercise stress testing is that the increased myocardial oxygen demand during exercise will produce clinical signs of ischemia (angina, ECG changes) in the setting of a flow-limiting stenosis that impairs myocardial blood supply. The diagnostic performance of this test varies greatly depending on the pretest likelihood of the population being studied. In patients with an intermediate pretest probability of CAD on the basis of symptoms and risk factors, exercise treadmill testing is useful as an initial screening test. However, the overall sensitivity of treadmill exercise testing is approximately 70%. A meta-analysis of more than 24,000 patients undergoing exercise stress testing and coronary angiography observed a mean sensitivity of 68% and a mean specificity of 77%. Accuracy was greatest in patients with multivessel coronary disease and those with left main or three-vessel coronary artery disease.⁶

Exercise Stress Myocardial Perfusion Imaging

Because exercise treadmill testing relies on changes in the 12-lead ECG as a surrogate of ischemia, the accuracy of the test is highly dependent on the baseline electrocardiogram. Abnormalities such as previous myocardial infarction (Q waves or left bundle branch block) or ST-T wave changes resulting from left ventricular hypertrophy or therapy with digoxin, hamper the ability to interpret ischemic changes accurately during exercise. In patients with an abnormal ECG, myocardial perfusion imaging adds significant diagnostic accuracy to the treadmill test for detecting CAD. Large studies have consistently shown that SPECT myocardial perfusion imaging with technetium-labeled agents, such as sestamibi, yields a greater than 90% sensitivity for the detection of coronary artery disease.^7–9 False-negative scans tend to occur in the setting of single-vessel disease (particularly in the left circumflex artery distribution), a mild degree of stenosis (<70% occluded), or when the patient is unable to achieve the target heart rate or is taking antianginal therapy. These studies have also observed that the specificity of stress SPECT imaging is in the range of 68%. The less optimal specificity can be attributed to both referral bias (performing angiography in only those patients with abnormal scans), as well as false-positive scans with defects resulting from artifacts produced by soft tissue attenuation (diaphragm, breast) or patient motion.

Contemporary imaging techniques that employ ECG gating have facilitated the simultaneous assessment of myocardial perfusion and function. Examination of regional wall motion and thickening enhances the evaluation of a suspect area of hypoperfusion by providing the ability to distinguish true myocardial scarring from attenuation. Specificity can also be enhanced with the use of attenuation correction. These algorithms incorporate additional data obtained from an external radioactive source or computed tomography to create a soft tissue attenuation image of the chest, and then adjust the regional counts on the emission scan to correct for the loss of counts resulting from attenuation from overlying breast, diaphragm, and chest wall structures.¹⁰

Pharmacologic Stress Myocardial Perfusion Imaging

As many patients are unable to perform physical exercise to a workload adequate for a diagnostic exercise stress test, myocardial perfusion imaging performed after pharmacologic stress is used frequently as an alternative. This is typically performed after the intravenous infusion of a vasodilator, such as dipyridamole, adenosine, or regadenoson, or after administration of the inotrope dobutamine. Dipyridamole stimulates the release of endogenous adenosine in the distal coronary vasculature, which then binds adenosine receptors in the vasculature, producing the desired effect of coronary artery vasodilation, as well as undesirable effects such as flushing, bronchospasm, headache, and even transient heart block. This vasodilation of the resistance vessels increases myocardial blood flow, mimicking the effects of physical exercise.

Dipyridamole is typically administered intravenously as a bolus injection over a period of 4 minutes, with peak effect occurring at 8 minutes, at which time the radiotracer is injected.¹¹ A 4- to 6-minute continuous infusion of intravenous adenosine is now used more commonly.^12,13 Both agents are equally effective in increasing myocardial blood flow threefold to fivefold over rest, which is similar to that produced by exercise. Although adenosine tends to achieve maximal flow in more patients than dipyridamole, side effects are more common with adenosine. Regadenoson is a new adenosine A_2A receptor agonist that selectively increases coronary blood flow without producing side effects, such as hypotension, atrioventricular block, chest pain, and flushing, which are common with adenosine and dipyridamole.^14–16 Regadenoson can be used as an alternative stressor in patients with lung disease, because its receptor selectivity may avoid the bronchospasm that can occur with other vasodilators.^17,18

An intravenous infusion of dobutamine is also effective for pharmacologic stress. It is typically used as an alternative to vasodilator stress in patients with bronchospasm and pulmonary disease. The dobutamine infusion produces increased myocardial oxygen demand by increasing heart rate, blood pressure, and myocardial contractility.¹⁹

All of the currently used pharmacologic stress agents have similar abilities to produce flow heterogeneity and corresponding perfusion defects in the presence of a significant (>50% to 70%) stenosis of a coronary artery. A meta-analysis of dipyridamole SPECT imaging demonstrated a sensitivity of 89% and specificity of 65% for the detection of coronary artery disease. Dipyridamole and adenosine tests had essentially similar sensitivities and specificities. The sensitivity of dobutamine SPECT imaging in detecting CAD is approximately 80%, which is slightly lower than that of the vasodilator agents.²⁰

Stable Angina

The goals of stress testing extend beyond the detection of coronary artery disease alone. For stress testing information to be useful, results must reliably identify patients of sufficiently low risk that further evaluation or intervention can be safely avoided, while also providing additional information to the clinical risk assessment when results are abnormal. The ability of both exercise and pharmacologic MPI to add incremental prognostic information to the clinical risk assessment in patients with known CAD has been evaluated in thousands of patients.²¹ Several large studies of patients with known or suspected CAD, including both men and women, have demonstrated the incremental prognostic value of a normal MPI.^22–26

Perhaps of greatest clinical usefulness is that these studies have consistently shown that patients with a normal MPI have a subsequent annual rate of cardiac death and nonfatal myocardial infarction (MI) of less than 1%, even patients with known CAD.^27,28 When the results are abnormal, the SPECT scan provides incremental prognostic information beyond that obtained by clinical, ECG, and stress testing combined. Moreover, the value of SPECT MPI in determining prognosis is such that the information obtained from subsequent coronary angiography does not provide any incremental prognostic information beyond that obtained by the SPECT results.^29,30 The increase in the risk of hard events increases in proportion to the severity and extent of the perfusion defect when assessed by semiquantitative methods or automated quantitative approaches. The degree of ischemia on SPECT is associated with an increase in the short-term incidence of nonfatal MI, whereas scar size is more predictive of cardiac death.²⁸ Important stress MPI variables that are predictive of future cardiac events include defects in more than one vascular territory (multivessel disease), transient left ventricular cavity dilation during stress,³¹ and increased pulmonary uptake of radiotracer^32,33 (suggesting increased LV filling pressures), as well as other parameters outlined in Box 54-1. The prognostic ability of stress MPI is also enhanced by inclusion of ECG-gated SPECT, which permits assessment of LV global systolic performance, the most potent predictor of event-free survival, as well as analysis of regional wall motion and LV volumes.^34–36

Medical Therapy versus Revascularization

One of the most important contributions of stress MPI in the clinical evaluation of patients with known or suspected CAD is the ability to provide prognostic information that can be used to guide further testing and therapies. Because the extent and severity of ischemia on a stress MPI study is directly proportional to the risk of future cardiac events, this information can be incorporated into the decision-making process concerning medical or revascularization therapies for a given patient. Patients with mild ischemic defects that are not high risk can generally be safely treated medically, whereas higher-risk findings (transient ischemic dilation, multivessel disease pattern, large territory at risk) should be strongly considered for more invasive evaluation and a lower threshold for revascularization. A 3-year follow-up study of patients with mild to moderate defects on stress SPECT myocardial perfusion imaging treated with medical therapy noted a 2% incidence of cardiac death or nonfatal infarction and less than a 5% rate of revascularization, suggesting that SPECT imaging is highly useful in identifying patients with CAD who have a sufficiently low risk for events that revascularization is not necessary.³⁷

In contrast, the benefit of revascularization over medical therapy has been characterized in patients with high-risk stress SPECT MPI findings. Hachamovitch and colleagues²⁸ followed 5183 patients after stress MPI for a mean of 2 years, and found that the rates of MI and cardiac death did not differ substantially between patients treated with medical therapy or revascularization after a normal or mildly abnormal scan. However, patients with severely abnormal scans had a significantly higher annualized cardiac death rate when treated medically (4.6% deaths per year) compared with those referred for revascularization (1.3% per year) (Fig. 54-3). Patients with a greater ischemic burden on imaging were also found to benefit more from revascularization than medical therapy, with serial imaging studies showing a greater reduction in reversible defect size in those treated with revascularization. A subsequent observational study of 10,627 consecutive patients with no prior infarct or revascularization demonstrated a survival advantage in patients with no or mild ischemia treated with medical therapy, with revascularization having prognostic benefit beyond medical therapy in patients with moderate to severe ischemia.³⁸ More recently, the Clinical Outcomes Utilizing Revascularization and Aggressive Drug Evaluation (COURAGE) trial³⁹ showed no difference in the incidence of death or myocardial infarction in 2287 patients with stable angina randomized to optimal medical therapy or percutaneous revascularization. A substudy of this trial showed that the addition of percutaneous revascularization to optimal medical therapy resulted in more effective reduction of ischemia than medical therapy alone, with less angina.⁴⁰ Moreover, regardless of treatment assignment, the degree of residual ischemia on follow-up perfusion imaging was proportional to the risk of subsequent cardiac events. Thus, it appears that revascularization can be employed selectively in patients with CAD based on the extent and severity of the ischemic burden. Patients with low-risk findings can be treated medically, whereas more extensive ischemia is best treated with more aggressive interventions.

Figure 54–3 SPECT myocardial perfusion imaging and prognosis. This large retrospective analysis of patients undergoing stress SPECT myocardial perfusion imaging demonstrates the incremental prognostic information obtained with the imaging results. The annualized incidence of cardiac death (A) and myocardial infarction (MI) (B) is displayed for patients treated medically (solid columns) and those undergoing revascularization (gray columns) with respect to the myocardial perfusion image result. Annualized cardiac events were low (<1%) in both groups with normal SPECT studies. However, event rates increased with respect to the degree of SPECT abnormality. Survival was significantly improved in those with severely abnormal scans who underwent revascularization. ∗P < .01 compared with patients undergoing revascularization early after nuclear testing; †P < .001 compared with patients treated with medical therapy after nuclear testing; Abnl, abnormal; Nl, normal.

(Reprinted with permission from Hachamovitch R, Berman DS, Shaw LJ, et al. Circulation 97:535-43, 1998.)

These principles have been shown to have a favorable impact in terms of both patient outcomes and cost when applied clinically. Several large studies have focused on the clinical use of stress MPI to guide patient management and have shown that referral for coronary angiography is accordingly low (about 3.5%) after a normal stress MPI, but referrals increase to 60% when the stress MPI is moderately to severely abnormal.^28,41,42 This demonstrates that clinicians can incorporate MPI into their practice appropriately, particularly when deferring further invasive evaluation when the MPI is normal. The use of stress MPI to guide patient management has also been demonstrated to be cost effective.

An “ischemia-guided” approach to managing patients with CAD has been shown to optimize the use of angiography and subsequent revascularization procedures.⁴³ The Economics of Noninvasive Diagnosis (END) study^44,45 compared differences in cost for 11,372 consecutive patients referred for either stress MPI or cardiac catheterization as the initial approach. Not only were the rates of subsequent myocardial infarction the same in the two groups, costs were significantly higher for the direct cardiac catheterization group as compared with the MPI ischemia-guided approach. Moreover, patients sent directly to cardiac catheterization were more likely to be treated with coronary revascularization in all subsets of risk when compared with those undergoing stress MPI initially. The ischemia-guided approach to stable angina was found to be less costly, with less interventions and similar cardiac event rates. These cost differences can be directly attributed to a decrease in apparently unnecessary procedures in patients with negative MPI results.

Preoperative Evaluation for Noncardiac Surgery

Perioperative cardiac events are an important cause of morbidity and mortality during and after noncardiac surgery, and they occur in more than 2% of patients undergoing these procedures. Much of this risk can be assessed preoperatively via clinical evaluation (a history of coronary artery or cerebrovascular disease, congestive heart failure, renal insufficiency, insulin-requiring diabetes, or high-risk surgical procedure) to identify patients at high risk for cardiac complications who might benefit from risk-reduction strategies (specific perioperative medical therapy or revascularization) and patients having sufficiently low risk that further evaluation before surgery is not necessary.⁴⁶ However, patients with an intermediate risk for cardiac complications may benefit from further noninvasive testing to identify ischemia and provide further risk stratification prior to surgery.⁴⁷ Provocative testing for ischemia is typically performed in such patients. However, exercise testing is not always feasible for patients with pulmonary disease or low exercise capacity, and in particular for those undergoing orthopedic or vascular surgery. Pharmacologic stress MPI has been shown to add significant information to preoperative risk stratification.⁴⁸ It is recommended for those patients with intermediate clinical risk predictors (prior MI, diabetes, renal insufficiency), for those who have poor functional capacity, and for those undergoing a high-risk surgical procedure (emergent surgery, aortic or peripheral vascular surgery, prolonged procedures with anticipated large blood loss or volume shifts). When results of stress MPI are normal, the incidence of perioperative cardiac events has been shown to be approximately 1% for all procedures, including major vascular surgery.⁴⁹ Although the severity and extent of ischemia remains an important predictor of adverse cardiac events during and after surgery, recent studies have shown that revascularization before noncardiac surgery does not appear to affect later outcome in terms of death and nonfatal myocardial infarction.⁵⁰