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Harvey S. Hahn, MD, FACC, Director, Cardiovascular Fellowship Training Program and Co-Director KPN CV Quality, Kettering Medical Center, Associate Professor of Clinical Medicine, Wright State University/Boonshoft School of Medicine, Kettering, OH, and Loma Linda University, Loma Linda, CA
Erik Poldemann, MD, Cardiology Fellow, Kettering
Medical Center, Kettering, OH
Jeffrey W. Morgan, DO, MA, FACOI, CS, Dean, School of Osteopathic Medicine in Arizona, Mesa, AZ
This article addresses specifics of the cardiac testing options, considering their appropriate indications, choices of approach, risks, and costs.
• Electrocardiography provides fast, crucial information on several life-threatening conditions, including arrythmias, electrolyte derangements and myocardial ischemia or infarction. It is among the most commonly performed diagnostic procedures in the United States, with sensitivity of detecting an ST-elevation MI low (30-70%) and the specificity in detecting STEMI a respectable 70-100%.
• Coronary artery calcium scoring is a reliable, reproducible, and cost-effective means of measuring a patient’s atherosclerotic plaque burden and aids in predicting risk of major cardiovascular events. Recent data have demonstrated scoring is limited in that age, statin use, and increased exercise levels are all associated with increasing scores but not event rates. A very low score, although portending an excellent prognosis, does not guarantee freedom from coronary artery disease.
• Echocardiography is safe, easily obtainable, and can evaluate the effects of ischemic heart disease, ejection fraction, left ventricular size and filling pressures, and arguably may be the most prognostic test in cardiology.
• A variety of exercise testing, including standard treadmill, exercise myocardial perfusing imaging, stress echo, dobutamine stress echocardiography, pharmacologic PET, and coronary computed tomographic angiography, are discussed with their respective pros and cons.
Part 1 of this two-part series focused on the theory of ordering tests and strategies to minimize unecssary testing. Part 2 looks at when and how to select each individual test given the patient's clinical scenario.
In the process of working up a patient with a cardiac complaint, a clinician has a seemingly endless number of testing options. The most appropriate choice depends first and foremost on the patient’s complaint, the history of the present illness, past medical history, body habitus, functional capacity, and costs of the test. (See Figure 1.) It is also important to factor into the decision the associated risks of a test.
As a clinician, the first thing to ask once the decision has been made to order a test is, “What is the question I am trying to answer?” Establishing the clinical question to be answered by the test will guide the physician to the ideal test. (See Table 1.) Most of the testing options outlined in this article focus on the evaluation of chest pain and ischemic heart disease.
There are more costs to a test than just financial strain on the medical system; there is also a financial cost to the patient, as well as costs of time and radiation exposure. (See Table 2.)
History is still the first cardiac test. A complete history and physical exam are the foundation of an accurate assessment of a cardiac patient. The information gathered from a meticulously executed history and physical exam helps guide a skillful clinician toward the judicious use of diagnostic tests.
A patient’s perception of the quality of the care he or she receives also can be associated with the clinician’s performance of a history and physical exam.1 Eliciting a careful cardiovascular history requires direct communication with the patient; an abundance of information and insight into a condition can be gleaned from direct interaction.1 Time constraints, without doubt, have imposed limits on the clinician’s ability to obtain a careful history and physical exam. The authors believe a proper and focused history and physical examination of the cardiovascular patient can help determine disease severity and prognosis accurately.
The classic article by Diamond and Forrester estimated the probability of coronary artery disease (CAD) based on gender, age, and type of symptoms.2 Using a 50-year-old man as an example, nonanginal chest pain had a disease prevalence of 21.5%; atypical chest pain, 58.9%; and typical angina, 92.0%. Males were more likely to have CAD in all age groups, and prevalence increased with age in both genders.
The exam also is prognostic. Positive findings of murmurs, bruits, and diminished pulses all are important findings to diagnose cardiovascular disease. Blood pressure, heart rate, and fluid status are therapeutic targets to normalize with medical therapy. Abnormal findings on exam, especially those related to heart failure, are extremely prognostic. Killip and Kimball initially described their findings in a post-infarct population in 1967. The researchers showed that with more findings of heart failure (Killip class I, no heart failure findings; Killip class II, S3 gallop or bibasilar rales; Killip class III, pulmonary edema; or Killip class IV, shock), mortality increased in a stepwise fashion.3
Patients with no signs of heart failure had a 6% mortality, although patients with pulmonary edema had a mortality of 38% and those with shock had a mortality of 81%. A follow-up study looked at all-cause mortality in four randomized clinical trials based on the original Killip classification and found that this pattern persisted in modern medicine.4
The practice of clinical electrocardiography - and clinical correlation of the findings from this methodology - has evolved over more than a century.5 Although there have been numerous advances in cardiac imaging in recent years, the electrocardiogram (ECG) still provides crucial information in just minutes regarding the electrical properties of the heart in several life-threatening conditions, including bradyarrhythmias and tachyarrhythmias, electrolyte derangements, and, most of all, myocardial ischemia or infarction.5
Although electrocardiography is an age-old technology, it is still among the most commonly performed diagnostic tests in the United States.6 The sensitivity of a 12-lead ECG in detecting an ST-elevation myocardial infarction (STEMI) is low, and ranges from 30-70%. However, the specificity of ECG in detecting STEMI is more respectable and approaches 70-100%.7 According to the American Board of Internal Medicine and American Academy of Family Physicians, the average cost of an ECG is around $50.8 At the individual patient level, the cost of an ECG may seem a small price to pay to detect cardiac disease; however, this does not take into account the hundreds, or even thousands, of dollars downstream from resulting testing and referrals.
Limited attention has been paid to the appropriate clinical indications for an ECG, likely because of its ease of use, simplicity, and low cost.5 There is value in having a “baseline” ECG, mostly for comparison and to look for acute ischemic changes. It is almost impossible to argue against a routine, baseline ECG.
After the history and physical exam, there are other ways to assess a patient's risk before ordering more advanced cardiac testing. The most common practice is to combine the clinical assessment with the ECG and biomarkers to stratify patients into different risk categories. This has been done most commonly in the emergency department with point-of-care troponin assays.
The ADAPT trialists looked to an accelerated two-hour diagnostic protocol to assess patients with acute chest pain. Using the Thrombolysis in Myocardial Infarction (TIMI) score, ECG, and two troponin values, the researchers identified 20% of their study population that was low risk and did not need admission or further testing. Of that group, only a single patient had a major adverse cardiac event (MACE), giving the protocol a negative predictive value (NPV) of 99.7%.9
A larger study again used clinical assessment with ECG and troponin evaluation. This study of three community teaching hospitals involved more than 45,000 patients. Of those, 11,230 had two normal troponin values. There were only 20 events for a MACE rate of 0.18%.10 If patients with abnormal vital signs or an abnormal ECG were excluded, there were four events, for a MACE rate of 0.06%. Of those four events, two were non-cardiac and possibly iatrogenic - again making the case for less is more.
One of the most common risk scores is the history, ECG, age, risk factors, and troponin (HEART) score. A recent meta-analysis of the HEART score demonstrated an NPV of 96%.11 Stopyra et al looked at not only MACE rates, but further healthcare utilization after using the HEART Pathway - an electronic health record clinical decision support tool - scoring compared to usual care.13 They found that MACE was not different at one year, but that downstream, cardiac testing was actually higher in the group that used the HEART Pathway.12 Initially, there was less testing in the HEART Pathway group, but by one year there was more testing overall in that group.
The study by Stopyra et al was a small randomized controlled trial of 282 patients.13 A much larger, cohort-designed study of more than 8,400 patients looked at MACE, admissions, and downstream testing for one year before implementing the HEART Pathway, and then for one year after its implementation. In this study, the researchers identified 30.7% of patients as low risk. MACE and death rates were unchanged in the two time periods. There was a 6% decrease in admission for chest pain; early discharges increased from 37% to 43%; and stress testing and angiography decreased a small but significant relative 11%.14
Before selecting a specific cardiac test, the final question to be asked is, “Does this patient even need a test?” A mentor of one of the authors used to ask, “Do you need to know, or is it neat to know?” The question had to be answered before the mentor would agree to a testing strategy. Physicians need to ask the patient if he or she needs to know. As discussed earlier, many patients do not need more reassurance than their doctor’s opinion, which they trust. The National Academy of Medicine’s 2017 report stressed engaging the patient and family in shared decision-making.15 Also, one of the three pillars of evidence-based medicine is “patient values and expectations.”16 Physicians cannot know these unless they talk and listen to their patients. Not only are many tests inappropriate, but so is the old paternalistic model of medicine.
Coronary artery calcium (CAC) scoring is a reliable, reproducible, cost-effective means of measuring a patient’s atherosclerotic plaque burden and aids in predicting an individual’s risk of a variety of major cardiovascular events.17 CAC scoring, or the quantification of coronary artery calcium, is a non-contrast-enhanced image acquisition technique obtained during a single breath-hold. The scan is obtained in about 10 minutes, is gated by the ECG, and does not require the administration of a beta-blocker to lower the heart rate.18 Computed tomographic (CT) scanners for CAC scoring are readily available and expose a patient to about 1 mSv of radiation without the need for contrast.
Recent studies using coronary angiography, intracoronary ultrasound, and histological studies have demonstrated that CAC quantification by scores correlates well with atherosclerotic plaque burden, but is not associated with the luminal area of a vessel.19 Initial studies showed that progression of CAC was associated with advancement of CAD.20 However, more recent data have demonstrated that CAC scoring is limited in that age,21 statin use,22 and increased exercise level23 all are associated with increasing CAC scores, but not event rates. This limits the use of CAC to monitor disease progression or status serially.
Several methods have been suggested for implementing a CAC in guiding primary prevention strategies. Use of CAC scoring, in a modified approach combined with the atherosclerotic cardiovascular disease (ASCVD) risk estimate, can reclassify a patient’s risk and potentially could influence a significant clinical decision, such as starting statin therapy.24
Although a very low CAC score, or even a score of zero, portends an excellent prognosis, it does not guarantee freedom from CAD. In an interesting study, researchers examined only patients with a CAC of zero and found that 16% had reversible defects consistent with ischemia on PET scanning.25 This is most likely a result of the fact that many coronary lesions, especially the more vulnerable ones, are soft plaques and not calcified.
Echocardiography is the most commonly used cardiac imaging modality to assess the structure and function of the heart.26 The benefit of transthoracic echocardiography (TTE) is that it can be performed relatively quickly, can be transported and done at the bedside, and can be done with little to no risk to the patient. Although TTE is painless, it can lead to further testing downstream and should be ordered rarely in a patient with no symptoms or signs of cardiovascular disease.27 It is rarely appropriate to obtain a transthoracic echocardiogram as a part of “routine surveillance” of left ventricular function with no change in the clinical status of the patient and if the patient has had a TTE within the last year.27
Although TTE is relatively safe and is easily obtainable, in most cases its use should be limited to patients with a change to their clinical status or cardiac exam. A TTE may lead to further unnecessary consultations and to more invasive procedures, which can increase the financial cost to the patient further and can expose him or her to a number of procedural-related complications.28
Echocardiogram is arguably the most prognostic test in cardiology since it provides measurement of several variables that have been independently and reproducibly shown to predict mortality. These include ejection fraction (EF), left ventricular size, right ventricular function, filling pressures (by the E/e’ estimate), Doppler patterns, and pulmonary artery pressures.
Although it has many advantages, TTE can look only at the effects of ischemic heart disease, such as an old myocardial infarction. It cannot detect ischemia unless added to a stress test, which will be discussed later.
It is helpful to think of cardiac stress testing as a combination of two components: a stressing agent (i.e., treadmill, bicycle, or pharmacological) and an imaging agent (ECG, echocardiography, or radionucleotide tracer).29 Determining the ideal combination of stressing agent and imaging agent establishes the appropriateness of the test and is a large part of the art of medicine.
Exercise stress testing or exercise electrocardiography is an important diagnostic tool in the evaluation and management of patients with known or suspected CAD. Myocardial ischemia occurs when the supply of oxygenated blood to myocardial cells is inadequate to meet the delicate balance of supply and demand.
Exercise electrocardiography capitalizes on this principle by stressing this relationship in a controlled environment, where the physiological response of the patient is closely observed.30 Exercise stress testing is relatively safe and effective for detecting significant CAD. According to the American College of Cardiology, exercise electrocardiography has a sensitivity of 68% and specificity of 77% for detecting CAD.31 Exercise stress testing is appropriate in the initial evaluation of patients with suspected or known CAD who present with chest pain and who have an intermediate pre-test probability for CAD.
Prior to ordering an exercise electrocardiography test, a few questions must be asked. First, is the patient physically able to exercise and will the person's exercise capacity allow him or her to achieve the target of 85% of the maximum predicted heart rate? Second, does the patient’s baseline ECG have abnormalities that may interfere with the interpretation of an ECG stress test? These abnormalities include ventricular pre-excitation, ventricular paced rhythms, left bundle branch block, digoxin use with ST-T wave changes, and significant left ventricular hypertrophy with secondary ST-T wave changes. These baseline ECG findings typically preclude a patient from undergoing plain exercise electrocardiographic testing.
Exercise should be the preferred stress modality when it is obvious that the patient has the ability to exercise - or even when it is uncertain. If the target heart rate or metabolic equivalent of task (MET) level is not achieved, then vasodilator stress MPI can be performed.32 Even if the target heart rate is not reached, important physiologic and symptomatic information still can be gleaned: Did the patient develop chest pain? Does the person have a hypertensive response to exercise? Does the patient have chronotropic (heart rate) reserve?
Clinicians should note that most exercise stress tests in patients without known coronary artery disease are performed best by holding cardioactive medications on the day of the stress test (i.e., beta-blockers and calcium channel blockers) to allow for a better detection of the ischemia.30
Exercise stress testing evaluates a patient’s symptoms, exercise capacity, and ECG changes under physiological stress. The ability to produce symptoms is the most important diagnostic portion of the test. Exercise capacity is quantified by METs or exercise time. One MET is defined as the energy expended by sitting quietly, or body oxygen consumption of 3.5 mL/kg of body weight per minute for the average adult.33
Exercise capacity alone is a powerful predictor of cardiovascular events.34 In one study of 6,213 men, some healthy and some with cardiovascular disease, the peak exercise capacity achieved was found to be a stronger predictor of an increased risk of death than clinical variables or established risk factors like hypertension, smoking, and diabetes mellitus.33
Patients in this group whose exercise capacity was < 5 METs had nearly twice the risk of death from any cause as patients whose exercise capacity was > 8 METs.33
The researchers also suggested that for every 1 MET increase in treadmill performance, there was a 12% improvement in overall survival.33 Because poor exercise capacity is a modifiable risk factor, studies also have suggested that exercise capacity improvements over time translate to improved overall prognosis. In another study of nearly 10,000 men, researchers observed a nearly 8% reduction in mortality for every one-minute increase in the time the subject spent on the treadmill.35 Several studies have suggested that patients at intermediate risk for CAD or who have known CAD who achieve ≥ 10 METs on exercise stress ECG testing have a very low prevalence of cardiac mortality, nonfatal myocardial infarction, and late revascularization, regardless of the heart rate they achieve during the test.36 METs are also the most important component of the commonly used Duke treadmill score.37
Before imaging technology allowed for the assessment of myocardial perfusion and function, symptom-limited exercise ECG stress testing was the lone noninvasive method of detecting significant CAD.32 To increase the sensitivity and specificity of a treadmill stress test and to quantify or localize areas of ischemic myocardium, clinicians now can add myocardial perfusion imaging (MPI) to an exercise stress test. The added benefit of exercise MPI is that it provides an assessment of wall motion and ejection fraction as well. Numerous studies have demonstrated that the combination of MPI with symptom-limited exercise enhances the diagnostic and prognostic value of exercise stress testing beyond the measurements obtained from exercise stress ECG testing.32 In one study, the sensitivity of MPI for detecting a coronary artery stenosis ≥ 70% was 86% in male diabetic patients compared with 88% in male nondiabetic patients. The sensitivity of MPI for detecting a coronary artery stenosis ≥ 70% was 93% in female diabetic patients and 86% in nondiabetic patients,38 although the specificity of MPI for detecting significant coronary artery stenosis ranged from 55-64%.38
The major disadvantages of stress MPI using single photon emission computed tomography (SPECT) is the time required to obtain the resting and stress images (up to four hours to obtain both sets of pictures) and radiation exposure to the patient. The average radiation exposure to the patient ranges from 10 to 20 mSv39; for comparison, the average dose of radiation from diagnostic angiography is about 3-4 mSv. MPI also is prone to attenuation artifacts from either breast tissue or the diaphragm, which can lead to equivocal or false-positive findings.
For patients who are unable to achieve ≥ 85% of their maximum predicted heart rate for age or who have physical limitations precluding them from performing exercise stress testing, pharmacological stress testing is a reasonable option. Adenosine, dipyridamole, and regadenoson are the most commonly used pharmacologic stress agents. These are excellent vasodilator stressing agents because they produce coronary vasodilation and increase myocardial blood flow three to five times that of resting myocardial blood flow.40 When a significant coronary artery stenosis is present and there is flow-limited obstruction, there is a relative difference in radiotracer uptake in the area supplied by the stenotic coronary artery, which appears as a perfusion defect when compared with the resting myocardium.41 The choice of a pharmacological stress agent depends on multiple factors; regadenoson is the primary vasodilator agent used for pharmacological stress MPI because of its ease of use and better tolerability by patients.42 Overall, the sensitivity and specificity of pharmacological stress MPI for detecting significant obstructive CAD ranges from 80-90%.43
Dobutamine, which increases the heart rate and the contractility of the heart, also can be used as a stressing agent for MPI. This increase in heart rate and contractility, in turn, increases the myocardial oxygen demand to a level that is comparable to exercise.41 Dobutamine is generally well-tolerated and safe as a stressing agent for MPI. The target for dobutamine MPI is the 85% age-predicted maximum heart rate. Once this target heart rate is achieved, the radionucleotide is injected over a 10-second period and allowed to circulate for 60 seconds or more.44
Even though pharmacologic agents represent an excellent alternative to exercise stress testing, the inability to exercise is a poor prognostic sign. In a large series of patients, regardless of EF or perfusion results, the one-year mortality was four times higher in the pharmacologic group than in the exercise group.45 This most likely reflects comorbid conditions that affect not only cardiovascular health, but overall health, such as COPD, amputations due to peripheral artery disease, or severe disability.
Stress echocardiography is another well-validated method of evaluating for ischemic heart disease. Like other stress tests, it is used best in patients with an intermediate pretest probability for CAD. The advantages of echocardiography are that it is readily available, generally inexpensive, and images are acquired without any radiation exposure to the patient. Additionally, stress echocardiography provides an assessment of wall motion, EF, and valvular and diastolic function. Images are acquired at rest and then immediately after peak stress. The hallmark of myocardial ischemia during stress echocardiography is the presence of reduced systolic wall thickening when myocardial oxygen demand exceeds myocardial blood supply.46 The advantage is that these changes to myocardial contraction are detectable on echocardiography prior to the patient experiencing chest pain or the appearance of ST-T wave changes on the ECG.46 Another advantage of stress echocardiography is the relatively short duration of the test; on average, most stress echocardiographic studies can be obtained and interpreted within one hour, potentially increasing the efficiency with which a clinician can decide patient disposition.
Stress echocardiography also is an appropriate test in patients who have abnormalities in their ECG at baseline that preclude interpretation of exercise ECGs.26 Although the sensitivity of stress echocardiography is slightly less than that of stress MPI studies for detection of single-vessel disease, its overall specificity is higher on average.47 The sensitivity of stress echocardiography to detect significant CAD (> 50% coronary artery stenosis by angiography) averages 88%, although the sensitivity is around 83%.26 Image quality during stress echocardiography is greatly affected by a patient’s body habitus; therefore, stress echocardiography may be difficult in obese individuals with poor acoustic windows and may need to be performed with contrast. The quality of the test also greatly depends on local expertise and the experience of the operator obtaining the images.48
Stress echocardiography also has excellent prognostic value, and a normal stress echocardiogram translates to a good prognosis.48 In one study of 1,325 patients who were followed after a normal stress echocardiography study, researchers found that one- and three-year cardiac event-free survival rates were 99% and 97%.49 This suggests that a normal exercise echocardiography study confers a favorable prognosis.
When performing stress echocardiography in patients who are unable to exercise, pharmacological agents, including dobutamine and dipyridamole, can be employed. Dobutamine is administered in a graded infusion to achieve the target heart rate. The advantage of pharmacological stress echocardiography is that echocardiographic imaging can be obtained at the exact time of peak stress.78 The procedure itself is very safe, and the risks associated with dobutamine stress echocardiography are relatively low. For dobutamine stress echocardiography, the overall rate of life-threatening events is one per 1,000 tests, or 0.18%.50 This testing modality also is used frequently to assess low-flow aortic stenosis and to evaluate for myocardial viability.
Positron emission tomography (PET) is a powerful imaging modality that is used to evaluate myocardial perfusion noninvasively.51 PET stress tests have numerous advantages over SPECT stress imaging. PET stress tests provide higher-resolution images; expose the patient to less radiation than a SPECT scan; and require only 30 minutes to perform. The major disadvantage of PET MPI is the inability to perform the test with exercise as the stressing agent, because of the short half-life of the radioisotopes used. The sensitivity of PET perfusion imaging for detecting angiographic stenosis of ≥ 50% is 91% and specificity is 89%.52 The diagnostic accuracy of PET is also significantly higher than SPECT MPI in all populations, including obese patients, estimated to be 89% vs. 79%.53 Overall, the diagnostic accuracy of MPI with PET imaging is better than SPECT MPI. This can be attributed to PET’s superior temporal resolution and ability to correct for attenuation artifact. Also, several studies in recent years have verified that a normal PET stress test has excellent prognostic value.54,55 Despite its increased cost, PET is emerging as an excellent option for MPI because of its high diagnostic accuracy, ability to correct for soft tissue attenuation artifact, and ability to provide prognostic information.
Coronary computed tomographic angiography (CCTA) is also known as multidetector CT (MDCT), multislice CT (MSCT), 3D CT, and dual source CT. CCTA provides a noninvasive anatomical assessment of the coronaries, which allows clinicians to quantify CAD accurately.56 CCTA images are acquired quickly (in a single breath hold) and can provide information such as EF, wall motion, and images of the aorta to evaluate for dissection. For detecting significant coronary artery plaques, CCTA has a reported sensitivity of 90%
and a specificity of 95%.57
The major limitations of CCTA are radiation exposure, the need for contrast, and the necessity to achieve a slow, regular heart rate.57 Current generation CT scanners expose the patient to much lower radiation doses than previous scanners; 320 detector and dual source scanners typically deliver 1 mSv of radiation to the patient,58 which is the same dose as a CAC score. Slower heart rates improve image quality, and therefore beta-blockers may need to be used in patients with heart rates above 65 beats per minute.59
Many recent studies have verified the prognostic utility of CCTA. A study of 1,559 patients who underwent CCTA found that a negative CCTA had a NPV of 99.3% in excluding major adverse cardiac events for 30 days after the initial presentation.60 Similarly, disease burden obtained by CCTA has similar prognostic value as that of invasive catheterization.61 Furthermore, CCTA not only shows the lumen, but also shows the whole vessel and lesion composition. Low attenuation plaque (soft plaque) is mostly lipid and more likely to rupture and lead to acute coronary syndromes.62 This is in direct contrast to what CAC measures - hard, calcified plaque, which is much more stable. CCTA can predict by their appearance high-risk lesions more likely to rupture. Lesions that exhibit positive remodeling (remember the Glagov phenomena mentioned in Part 1), disrupted plaque, ulcerations or intraplaque dye penetration,62 or the “napkin ring” sign63 all are at high-risk of rupturing and causing ischemic symptoms.
Recently, the Prospective Multicenter Imaging Study for Evaluation of Chest Pain (PROMISE) trial examined the initial strategy of CCTA vs. functional stress testing in stable diabetic patients with symptoms suggestive of CAD. The PROMISE trial found that in diabetic patients with stable chest pain, a CCTA strategy resulted in fewer adverse cardiovascular outcomes than an initial functional stress testing strategy.64
To choose the best and most appropriate test for the patient, keep these points in mind:
Financial Disclosure: To reveal any potential bias in this publication, and in accordance with Accreditation Council for Continuing Medical Education guidelines, Dr. Wise (editor) reports he is involved with sales for CNS Vital Signs and Clean Sweep. Dr. Hahn (author), Dr. Poldemann (author), Dr. Morgan (peer reviewer), Mr. Schneider (editor), Ms. Mark (executive editor), Ms. Coplin (editorial group manager), and Ms. Johnson (accreditations manager) report no financial relationships with companies related to the field of study covered by this CME activity.