The Challenge of Noninvasive Test Selection for Stable Chest Pain
The prevalence of angina is high in the general population and increases with age in both sexes, from approximately 3% to 4% in patients aged 40–59 years to 10% to 11% in those older than 80 years old. New-onset stable chest pain among patients without known coronary artery disease (CAD) is a common clinical problem that results in approximately 4 million outpatient stress tests annually in the United States. An initial evaluation always includes a full history and physical examination as well as basic ancillary studies, which should be sufficient for the physician to generate a hypothesis regarding the etiology of the chest pain (including cardiac vs. noncardiac). As described in more detail later, this initial evaluation should determine the patient’s risk factors for atherosclerotic coronary disease and classify symptoms as typical, atypical, or noncardiac chest pain, which, in combination with age, can be used to quantify the pretest probability of underlying coronary disease. Important ancillary studies include fasting lipids, a resting 12-lead electrocardiogram, and possibly a chest x-ray. In addition to implementing any needed risk factor modification, empiric treatment with aspirin, β-blockers, and/or nitroglycerin may be considered in a patient who has an intermediate-to-high likelihood of obstructive coronary artery disease while awaiting an outpatient diagnostic test. Decisions then need to be made regarding testing, i.e.:
- 1.
who to test (and who should not be tested)
- 2.
if testing is chosen, which initial test to perform, including the type of noninvasive test or an invasive strategy.
Goals of Testing for the Diagnosis of CAD
While test selection for the diagnosis of CAD has the immediate goal of trying to determine if obstructive CAD accounts for the patient’s symptoms, there are many other potential and salient goals that are both patient specific and system specific ( Fig. 15.1 ). Related short-term patient-centric goals include determining the presence, severity, and extent of CAD, lifestyle and medical treatment optimization, risk stratification, and referral for invasive angiography or possible revascularization, if necessary. The overall long-term goal is to improve clinical outcomes for both individual patients and the overall population. Additional longer-term patient-centric goals include safety, such as reducing radiation exposure to prevent adverse sequelae, while goals for the healthcare system include maximizing efficiency and minimizing cost.
However, selection of patients for testing and selecting initial tests for the diagnosis of CAD are not always straightforward. Major US and European guidelines differ fairly substantially in their basic approaches to determining both the pretest probability of CAD in symptomatic patients and how to proceed with test selection. This may be related to a variation in features at presentation and regional preferences for diagnostic strategies and may be influenced by differences in healthcare systems, access to testing technologies, and risk tolerance. Importantly, limited information on health-related outcomes exists in this stable as-yet-undiagnosed population, and there is little consensus about which test is preferable or even when one is required. The discrepancies between guidelines differ significantly from other areas in cardiology (i.e., therapy for acute coronary syndromes or chronic heart failure), in which general consensus exists largely based on the availability of randomized clinical trial data. To date, current guidelines for imaging stable chest pain of suspected cardiac etiology have not yet incorporated the results of recent, large, randomized trials comparing functional versus anatomic testing strategies.
Complicating the uncertainty are several potential adverse downstream consequences associated with noninvasive tests. These include patient-centered outcomes of false-positive testing such as discomfort during cardiac catheterization, procedural complications, and the effects of radiation, as well as the impact of changes in medical therapy after test result findings and cost. Recent reports of high rates of finding nonobstructive CAD on angiography may speak to the quality of clinical assessment, including the crucial step of patient selection for noninvasive testing. The majority of studies on outpatients with a clinical syndrome of possible ischemia show that, in contrast to past data, at present up to 90% of such tests are normal and approximately 99% of those patients will not experience an untoward clinical event. The risks of false-negative testing include those of a missed diagnosis and failure to treat CAD or risk factors properly. The high incidence of normal noninvasive testing and weak correlations between noninvasive testing results and the presence of obstructive CAD provide further impetus to improve patient selection for noninvasive testing. These issues have important implications for healthcare utilization as well as for the individual patient.
In addition, the fundamental concepts about how we define “significant” CAD have been recently evolving, contributing to the uncertainty of how to best evaluate specific patient populations with chest pain. Recent evidence has found that the association between angiographically defined coronary stenosis and ischemia is variable, as many patients have no ischemia despite the presence of significant stenosis and others may have ischemia with no severe stenosis. Furthermore, the extent to which routine revascularization to treat ischemia reduces death or myocardial infarction (MI), or improves quality of life in patients with stable ischemic heart disease, remains one of the most fundamental uncertainties in cardiology today.
Therefore, decisions regarding noninvasive test use and selection remain common but challenging for many clinicians and a controversial topic for practice guidelines. This chapter reviews important patient characteristics that influence noninvasive test selection for the diagnosis of CAD, including an emphasis on comparing major guideline recommendations and evaluating very recent data, including promising technologies. We review contemporary considerations in cardiovascular imaging, such as how best to evaluate special populations, and appropriate use, including the consequences of noninvasive testing that are sometimes overlooked, such as radiation and cost. Finally, we present a step-by-step practical proposal for a unified approach, incorporating the latest trial evidence, to optimize test selection for both functional and anatomic strategies.
Overview: Patient Selection for Noninvasive Testing
The current discussion applies specifically to stable, symptomatic patients with suspected ischemic heart disease on the basis of a thorough history, physical examination, and laboratory data. First, angina is both a continuum and a collection of disparate symptoms, ranging from atypical pain or angina equivalent to typical angina to low-risk unstable angina; delineating these categories can be difficult but the implications for testing and prognosis are significant. While new-onset angina is generally regarded as unstable angina, if the chest pain first occurs with heavy exertion—such as prolonged or fast running (Canadian Cardiovascular Society I)—the patient with new-onset angina may instead fall under the definition of stable, rather than unstable, angina. Further confusing the issue is the fact that research is often conducted on the basis of location of care (e.g., office, rapid access chest pain center, or emergency department) rather than solely on symptom type, such that differences in healthcare systems or access to care may obscure differences in clinical presentation. Second, the physical examination, while often normal, should help to exclude other causes of chest pain (e.g., chest wall tenderness or pericarditis), including life-threatening causes (e.g., aortic stenosis, aortic dissection, or pulmonary embolism). The resting 12-lead electrocardiogram (ECG) is also usually normal or has only minor abnormalities, and patients undergoing assessment should have negative or minimally abnormal cardiac biomarkers, if measured. Thus, in addition to patient-specific considerations such as suitability for revascularization, the next critical step for consideration of noninvasive testing is determination of the pretest probability of obstructive CAD.
Clinical Classification of Chest Pain and the Pretest Probability of Obstructive CAD
Classically, chest pain symptoms are categorized as typical, atypical, or noncardiac chest, which in combination with age can be used to quantify the pretest probability of underlying coronary disease ( Table 15.1 ). This must be distinguished from other tools such as the Framingham Risk Score or newer atherosclerotic cardiovascular disease (ASCVD) score, which are helpful in evaluating overall risk burden and prognosis using baseline clinical characteristics, but are not designed to evaluate the likelihood of obstructive CAD in the presence of symptoms. While the Coronary CT Angiography Evaluation for Clinical Outcomes: An International Multicenter (CONFIRM) registry risk score provides incremental prognostic information from plaque burden and stenosis found on coronary computed tomographic angiography (CCTA), it was derived in a mixed population of patients (asymptomatic and symptomatic) and requires noninvasive testing by definition, and thus does not aid in the decision to test or in test selection itself.
| Typical angina (definite) | Meets all three of the following characteristics:
|
| Atypical angina (probable) | Meets two of these characteristics |
| Nonanginal chest pain | Lacks or meets only one or none of the characteristics |
The Diamond and Forrester algorithms represent the gold standard for prediction of obstructive CAD in symptomatic patients. However, calculation of pretest probability using this score differs depending on which guideline is followed, as each country or region has adopted a different modification. In the United States, current guidelines recommend use of a Diamond and Forrester likelihood score combined with data from the Coronary Artery Surgery Study risk score ( Table 15.2 ). The UK National Institute for Health and Care Excellence (NICE) guidelines advocate calculating CAD likelihood using another modified Diamond and Forrester clinical prediction rule by Pryor et al. This score incorporates the additional high-risk features of diabetes, smoking, hyperlipidemia, and resting ECG changes. More recently, a clinical prediction rule by Genders et al., which aimed to validate, update, and extend the Diamond and Forrester model to a more contemporary population and especially women, had the effect of reclassifying 16% of men and 64% of females. This revised risk score has been incorporated into the European Society of Cardiology (ESC) guidelines (see Table 15.2 ). For example, the pretest probability of obstructive CAD in a 55-year-old female with typical angina differs depending on whether the score used is based on the American College of Cardiology (ACC)/American Heart Association (AHA) guidelines (73%), ESC guidelines (47%), or NICE guidelines (38–92%). A discussion of the impact of diagnostic testing in specific subgroups is discussed subsequently (see “Noninvasive Diagnostic Testing Considerations for Special Populations” ).
| Males | |||||||||
|---|---|---|---|---|---|---|---|---|---|
| Nonanginal Chest Pain | Atypical Angina | Typical Angina | |||||||
| Guideline | ACC/AHA a | ESC b | Nice c | ACC/AHA | ESC | Nice | ACC/AHA | ESC | Nice |
| Age 30–39 | 4 | 18 | 3–35 | 34 | 29 | 8–59 | 76 | 59 | 30–88 |
| 40–49 | 13 | 25 | 9–47 | 51 | 38 | 21–70 | 87 | 69 | 51–92 |
| 50–59 | 20 | 34 | 23–59 | 65 | 49 | 45–79 | 93 | 77 | 80–95 |
| 60–69 | 27 | 44 | 49–69 | 72 | 59 | 71–86 | 94 | 84 | 93–97 |
| 70–79 | 54 | 69 | 89 | ||||||
| > 80 | 65 | 78 | 93 | ||||||
| Females | |||||||||
|---|---|---|---|---|---|---|---|---|---|
| Nonanginal Chest Pain | Atypical Angina | Typical Angina | |||||||
| Guideline | ACC/AHA | ESC | Nice | ACC/AHA | ESC | Nice | ACC/AHA | ESC | Nice |
| Age 30–39 | 2 | 5 | 1–19 | 12 | 10 | 2–39 | 26 | 28 | 10–78 |
| 40–49 | 3 | 8 | 2–22 | 22 | 14 | 5–43 | 55 | 37 | 20–79 |
| 50–59 | 7 | 12 | 4–25 | 31 | 20 | 10–47 | 73 | 47 | 38–92 |
| 60–69 | 14 | 17 | 9–29 | 51 | 28 | 20–51 | 86 | 58 | 56–84 |
| 70–79 | 24 | 37 | 68 | ||||||
| > 80 | 32 | 47 | 76 | ||||||
a ACC/AHA uses combined Diamond and Forrester and Coronary Artery Surgery Study risk score. Each value represents the percent with obstructive CAD on catheterization. Modified from Fihn SD, Gardin JM, Abrams J, et al. 2012 ACCF/AHA/ACP/AATS/PCNA/SCAI/STS guideline for the diagnosis and management of patients with stable ischemic heart disease: a report of the American College of Cardiology Foundation/American Heart Association Task Force on Practice Guidelines, and the American College of Physicians, American Association for Thoracic Surgery, Preventive Cardiovascular Nurses Association, Society for Cardiovascular Angiography and Interventions, and Society of Thoracic Surgeons. J Am Coll Cardiol. 2012;60:e44–e164.
b ESC uses updated Diamond and Forrester prediction score. Modified from Genders TS, Steyerberg EW, Alkadhi H, et al. A clinical prediction rule for the diagnosis of coronary artery disease: validation, updating, and extension. Eur Heart J. 2011;32:1316–1330.
c NICE uses modified Diamond and Forrester prediction score. Modified from Pryor DB, Shaw L, McCants CB, et al. Value of the history and physical in identifying patients at increased risk for coronary artery disease. Ann Intern Med. 1993;118:81–90. A range is provided for each estimate from “Low” to “High” risk depending on the presence of the additional factors of diabetes, smoking, and hyperlipidemia (total cholesterol > 6.4 mmol/L).
Pretest Probabilities and the Degree of Obstructive CAD
While all of these adapted Diamond and Forrester scores are easily implemented at the bedside, mounting evidence demonstrates that they largely overestimate the degree of obstructive CAD. Estimates based on a contemporary CCTA registry, as well as recent clinical trials, have found that the prevalence of obstructive epicardial CAD in patients with typical or atypical angina is much lower than that predicted by Diamond and Forrester in 1979, or any subsequent modification. There are also increasing questions about the need to predict other coronary abnormalities besides severe stenoses. Several studies have found that high rates of nonobstructive CAD are routinely identified during elective coronary angiography, with a significant variation in the rate of nonobstructive CAD between centers. Plaque burden and location each carries incremental prognostic value above traditional obstructive stenosis. Therefore, while we continue to rely on likelihood scores to predict pretest probability of CAD based mainly on age and symptoms alone, improved strategies for likelihood of CAD, risk stratification, and subsequent test selection are warranted and have been proposed or are in development (see “Noninvasive Imaging Integrating Functional and Anatomical Strategies” ). Validation in other populations may encourage future adoption.
Quantifying “Intermediate” Pretest Probability of CAD
Determination of pretest probability also impacts the performance of the available diagnostic methods (the likelihood that this patient has obstructive disease if the test is positive, or does not have disease if the test is negative). Diagnostic testing is most valuable when the pretest probability of ischemic heart disease (IHD) is intermediate, since the application of a test result using Bayesian analysis drives the posttest probability sufficiently lower (negative test) or higher (positive test) to inform future decision-making—usually whether or not the patient should proceed to cardiac catheterization.
Nevertheless, there remains no universal definition of intermediate pretest probability. The definition of 10% to 90%, first advocated in 1980, has been applied in several studies and is the current definition used in the ACC/AHA guidelines for stable IHD ( Table 15.3 ). Low and high pretest probabilities are thus less than 10% and greater than 90%, respectively. This risk stratification scheme is also used by the most recent ACC/AHA Appropriate Use Criteria Task Force. In contrast, the current ESC guidelines using the Genders et al .– modified Diamond and Forrester clinical prediction rule stratifies patients into four groups: less than 15%, 15–65%, 66–85%, and greater than 85%. In comparison to the US guidelines, the intermediate group is defined by a pretest probability of 15% to 85% by combining the two mid-risk groups. Based on these four groups, the ESC guidelines recommend specific test strategies (see later). Finally, the UK NICE guidelines differ compared to both the ACC/AHA and ESC guidelines, identifying an intermediate pretest probability as 30% to 60%.
| Sensitivity | Specificity | |||
|---|---|---|---|---|
| ACC/AHA 2012 | ESC 2013 | ACC/AHA 2012 | ESC 2013 | |
| Exercise ECG | 0.68 | 0.45–0.50 | 0.77 | 0.85–0.90 |
ECHO
| ||||
| 0.76 | 0.88 | |||
| 0.80–0.85 | 0.80–0.88 | |||
| 0.79–0.83 | 0.82–0.86 | |||
SPECT
| ||||
| 0.88 | 0.77 | |||
| 0.73–0.92 | 0.63–0.87 | |||
| 0.90–0.91 | 0.75–0.84 | |||
PET
| ||||
| 0.91 | 0.82 | |||
| 0.81–0.97 | 0.74–0.91 | |||
| CMR | ||||
| 0.79–0.88 | 0.82–0.86 | ||
| 0.67–0.94 | 0.61–0.85 | ||
| CCTA | 0.95–0.99 | 0.64–0.93 | ||
ACC/AHA 2012 estimates were modified from Garber AM, Solomon NA. Cost-effectiveness of alternative test strategies for the diagnosis of coronary artery disease. Ann Intern Med . 1999;130:719–728.
ESC 2013 estimates were collated from multiple studies and modified from Montalescot G, Sechtem U, Achenbach S, et al. 2013 ESC guidelines on the management of stable coronary artery disease. Eur Heart J . 2013;34:2949–3003.
Is There a Role for Watchful Waiting in Patients with Stable Chest Pain?
Due to low event rates in stable chest pain populations undergoing imaging or ECG testing, and the similar outcomes with medical treatment and coronary revascularization in trials such as Clinical Outcomes Utilizing Revascularization and Aggressive Drug Evaluation (COURAGE), some have recommended that a strategy of deferred testing may be preferable to performing any test at all. In this scenario, a patient with a sufficiently low pretest probability of obstructive CAD as the cause of their stable chest pain would not undergo any initial noninvasive cardiac testing, would be monitored clinically, and would be treated according to primary prevention strategies. This is on a background of the explosive growth in cardiac imaging in the United States, which has become central to discussions surrounding the high cost of healthcare, including a rapid escalation of costs for testing (twice that of other physician services). However, there is as yet no direct clinical trial evidence to support a deferred testing strategy. This is in contrast to the robust evidence now available that supports a testing strategy with either functional testing or CCTA as being safe and effective (see “A New Standard for Pragmatic, Imaging Trials: PROMISE and SCOT-HEART” ).
Another important aspect in the decision regarding whether to defer testing is first considering whether the patient would benefit from revascularization. If the patient has significant comorbidities or their quality of life is not expected to benefit from revascularization, then optimizing medical therapy may be a more reasonable approach than testing.
General Approach to Choosing a Noninvasive Test
Following identification of a symptomatic patient with no prior history of CAD and an intermediate pretest probability of CAD, the clinician is generally advised to consider a functional or, more rarely, an anatomic strategy. The NICE guidelines are an exception to this rule; they recommend an anatomic strategy for lower pretest probabilities (<30%).
Approach to Choosing a Functional Test
For functional testing, the choice of stress must first be considered (exercise vs. pharmacologic) and, if exercise is employed, consideration must also be given to whether or not additional imaging should be performed. Several stress imaging modalities currently exist, each with their advantages and disadvantages ( Table 15.4 ). These include radionuclide stress myocardial perfusion imaging (MPI) using single photon emission computed tomography (SPECT) or positron emission tomography (PET), stress echocardiography, and stress cardiac magnetic resonance (CMR). SPECT, PET, and echocardiography may be coupled to either exercise or pharmacologic stress, whereas stress CMR is only performed with pharmacologic stress.
| Technique | ADVANTAGES | Disadvantages |
|---|---|---|
| Echocardiography |
|
|
| SPECT |
|
|
| PET |
|
|
| CMR |
|
|
| CCTA |
|
|
In the absence of contraindications, symptom-limited exercise with an exercise treadmill test (ETT) or bicycle ergometer is the preferred stress-testing modality (over pharmacologic stress) since it provides information concerning reproducibility of symptoms, cardiovascular function, exercise capacity, ECG changes, and the hemodynamic response during usual forms of activity. Exercise capacity alone is a powerful predictor of mortality. Furthermore, a score such as the Duke Treadmill Score when applied to data generated by the ETT can improve diagnostic certainty in addition to its prognostic implications. However, a patient may be unable to exercise due to one or more noncardiac reasons. These include obesity, orthopedic limitations, balance issues, pulmonary limitations, frailty, or limb dysfunction as a result of paraplegia from a prior cerebrovascular event. A detailed discussion on the various forms of exercise modalities (treadmill, or upright or supine bicycle) and protocols (Bruce, Modified Bruce, Naughton) is presented elsewhere (see Chapter 10 ). If absolute contraindications exist, then pharmacologic stress should be used; if relative contraindications exist, pharmacologic stress should be considered.
In addition to considering exercise capacity, several conditions interfere with the ability to make an ECG diagnosis of ischemia (e.g., left bundle branch block, right ventricular pacing, resting ST depression > 1 mm) and may result in an uninterpretable exercise ECG. When such conditions are present, imaging should be used regardless of the stress modality.
If the patient is unable to exercise to sufficient workload, then pharmacologic stress is required. The decision regarding which imaging modality to use will depend on patient factors including suitability of the stress agents for that purpose as well as patient tolerance; ischemic endpoints may vary accordingly. If MPI is used, vasodilators are the preferred pharmacologic stress agents, and perfusion is assessed. If echocardiography is performed, inotropic agents are the most commonly used (although this can vary by country), and wall motion is assessed. For CMR, either inotropes or vasodilators can be used with corresponding endpoints. However, as for exercise testing, contraindications to vasodilator stress agents (adenosine, dipyridamole, and the selective A2A receptor agonists, including regadenoson, binodenoson, and apadenoson) or inotropic agents (typically dobutamine) should be taken into account in selecting the test modality.
If the patient is not a candidate for exercise or pharmacologic stress testing, an anatomic strategy with coronary artery calcium (CAC) scoring or CCTA should be considered. Moreover, based on recently published trial data, an anatomic-first strategy may be a reasonable alternative in selected patients (see “A New Standard for Pragmatic Imaging Trials: PROMISE and SCOT-HEART” ) as discussed later.
Diagnostic Accuracy of Functional Testing Strategies
There are distinct strengths and weaknesses associated with each imaging modality (see Table 15.4 ), and test selection ultimately depends on many factors, including local availability, local expertise, existence and relevance of prior imaging data, cost, the patient’s body habitus (e.g., morbid obesity), radiation exposure, and the need for concomitant assessment of hemodynamic function or valvular disease. Diagnostic performance should be considered when multiple options exist, ideally based on local laboratory performance rather than the literature. Since such detailed data are often not available, a cost-effectiveness meta-analysis by Garber and Solomon may be used. This analysis includes information on diagnostic accuracy of individual tests and is cited by the ACC/AHA guidelines as evidence for differing diagnostic accuracy between modalities (see Table 15.3 ). PET is the most sensitive noninvasive functional test, and exercise ECG is the least sensitive. SPECT is nearly as sensitive as and somewhat less specific than PET (specificity, 0.77 [range in individual studies: 0.53–0.96] for SPECT and 0.82 [0.73–0.88] for PET). Echocardiography is more specific than PET (0.88 [0.80–0.95] compared with 0.82 [0.73–0.88]) but less sensitive (0.76 [0.40–1.00] compared with 0.91 [0.69–1.00]). The Clinical Evaluation of Magnetic Resonance Imaging in Coronary Heart Disease (CE-MARC) study directly and prospectively compared CMR to SPECT. Compared to SPECT, CMR had greater sensitivity (0.87 [95% CI 0.82–0.90] compared with 0.67 [0.60–0.72]) and similar specificity (0.83 [0.80–0.87 for CMR]; 0.83 [0.79–0.86 for SPECT]). CE-MARC2 is a three-arm trial that is ongoing and will provide valuable insights by comparing outcomes following CMR-guided care, positron emission tomography–computed tomography (PET-CT)-guided care (according to ACC/AHA appropriate-use criteria), and NICE guideline-based management.
The ESC guidelines use multiple primary studies to summarize test performance. A major difference between the reference data used by each guideline is the lower sensitivity of the exercise ECG reported in the ESC guidelines—only 50% (despite an excellent specificity of 90%). The marked differences in these values are at least partially, if not fully, explained by the ESC’s use of data obtained from studies avoiding verification bias; ACC/AHA guidelines do not restrict data to studies avoiding verification bias. Because this lower sensitivity means that the number of incorrect test results will become higher than the number of correct test results in populations with a pretest probability of greater than 65%, the ESC does not recommend employing the exercise stress test without imaging in such higher-risk populations for diagnostic purposes. In general, it may be more appropriate to employ more specific testing for patients with a low-intermediate pretest probability of CAD and reserve more sensitive testing for those with high-intermediate pretest probabilities. Therefore the precision of pretest probability estimates to impact the choice the optimal noninvasive test is important even within the intermediate ranges.
Guideline Recommendations for Choosing a Functional Test
ACC/AHA 2012 Guideline
Among patients who can exercise, there are strong recommendations for nonimaging ETT for patients with an intermediate pretest probability of CAD, and exercise stress with nuclear MPI or echocardiography for those with an intermediate-to-high pretest probability of CAD who have an uninterpretable ECG (Class I). The remaining Class I recommendation is for pharmacologic stress with nuclear MPI or echocardiography for patients who are unable to exercise. The guideline recommends against the use of pharmacologic stress with nuclear MPI, echocardiography, or CMR for patients who can exercise with interpretable ECGs, or amongst patients who can exercise with an interpretable ECG and who have only a low pretest probability of IHD (< 10%; Class III). The other testing strategies fall within the IIa or IIb classes of recommendations. While no specific recommendations are provided for patients with a pretest probability greater than 90%, it is reasonable to consider cardiac catheterization as the initial test, which is supported by the ACC/AHA 2012 diagnostic angiography appropriate use criteria.
ACC Multimodality Appropriate Use Criteria 2014
The ACC Appropriate Use Criteria (AUC) document development process uses an independent technical panel to rate each testing modality as either appropriate, may be appropriate, or rarely appropriate for given symptomatic target populations. The following appropriate functional testing situations are summarized here and in further detail in Table 15.5 :
- •
Exercise ECG
- •
Patients who are able to exercise with a low-to-intermediate pretest probability of CAD and an interpretable ECG
- •
- •
Stress radionuclide imaging or stress echocardiography
- •
All patient groups are appropriate, with the exception of those with a low pretest probability of CAD who are able to exercise and have an interpretable ECG, for whom stress echocardiography may be appropriate but stress MPI is rarely appropriate
- •
- •
Stress CMR
- •
Patients with an intermediate pretest probability of CAD who are unable to exercise or have an uninterpretable ECG
- •
Patients with a high pretest probability of CAD, irrespective of their ability to exercise or whether their ECG is interpretable
- •
| Target Population | Exercise ECG | Stress RNI | Stress ECHO | Stress CMR | CAC | CCTA |
|---|---|---|---|---|---|---|
| Low pretest probability of CAD ECG interpretable AND able to exercise | A | R | M | R | R | R |
| Low pretest probability of CAD ECG uninterpretable OR unable to exercise | A | A | M | R | M | |
| Intermediate pretest probability of CAD ECG interpretable AND able to exercise | A | A | A | M | R | M |
| Intermediate pretest probability of CAD ECG uninterpretable OR unable to exercise | A | A | A | R | A | |
| High pretest probability of CAD ECG interpretable AND able to exercise | M | A | A | A | R | M |
| High pretest probability of CAD ECG uninterpretable OR unable to exercise | A | A | A | R | M |
Notably, in this most recent AUC guidance document, ratings for stress CMR were more often in accord with the ratings for stress radionuclide imaging (RNI), stress echo, and exercise treadmill testing. This may reflect the simultaneous rating of modalities, the growing body of evidence supporting the utility and accuracy of stress CMR, and its increasing use in the community.
Despite guidance that exercise treadmill testing without imaging may be routinely used in many patients, the practice of stress imaging still dominates the US testing landscape for both symptomatic and asymptomatic patients. Among intermediate-risk patients with chest pain assigned to the functional arm of the Prospective Multicenter Imaging Study for Evaluation of Chest Pain (PROMISE) trial, only 10.2% of patients received exercise testing without imaging as a prespecified test. Furthermore, in 2012, the Choosing Wisely campaign ( http://www.choosingwisely.org ) brought together nine leading medical organizations (including the ACC and the American Society of Nuclear Cardiology [ASNC]) to each pick five tests which they viewed as overused. The cardiac tests felt to be most overused by both the ACC and ASNC for the testing of CAD were all imaging-based modalities in patients with few symptoms: stress imaging in patients without symptoms or high-risk markers for diabetes, regular stress cardiac imaging in asymptomatic patients during routine follow-up after treatment, and stress cardiac imaging during preoperative assessment. Therefore, the practice of US providers does not appear to reflect current US guideline recommendations.
ESC 2013 Guideline
In patients able to exercise and who have an evaluable ECG, exercise treadmill testing is recommended as the initial test for establishing a diagnosis of CAD in patients with symptoms of angina and intermediate pretest probability of CAD of 15% to 65% (Class I). Furthermore, stress imaging (echocardiography, CMR, SPECT, or PET) is strongly recommended as the initial option if local expertise and availability permit (Class I). Exercise ECG without imaging in patients with an ST depression greater than or equal to 0.1 mV on resting ECG or taking digitalis is not recommended for diagnostic purposes (Class III). An imaging stress test is recommended as the initial test for diagnosing CAD with a high-intermediate pretest probability between 66% and 85% or if the left ventricular ejection fraction is less than 50% in patients without typical angina (Class I). While there are no specific recommendations for pharmacologic stress, exercise is recommended over pharmacologic testing whenever possible (Class I). A pretest probability of greater than 85% establishes a presumptive diagnosis of CAD, at which point risk stratification should be performed. In patients with severe symptoms or a clinical constellation suggesting high-risk coronary anatomy, clinicians are advised to initiate guideline-directed medical therapy and consider invasive catheterization as the initial test. In patients who have mild symptoms, noninvasive testing for risk stratification should be considered only if there is agreement to proceed to revascularization in the event of high-risk test findings.
UK 2010 NICE Guideline
For patients with chest pain and an estimated pretest probability of 30% to 60% the clinician is advised to offer noninvasive functional imaging for myocardial ischemia as the first-line test. In contrast to the other guidelines, NICE incorporates an anatomic strategy as the front-line test for patients with a low-intermediate pretest probability. If the pretest probability is 10% to 29%, a “rule out” CAD strategy was felt to be best achieved with initial CAC scoring (and then CCTA if the CAC score is 1–400) and is justified based on cost-effectiveness and low radiation doses. Alternatively, patients with a high CAC score may be investigated by functional assessment, depending on the score and patient factors (see next section), or invasive angiography. If the estimated pretest probability is 61% to 90%, the clinician should offer invasive coronary angiography as the first-line diagnostic investigation. Notably, exercise testing without imaging is never recommended in the investigative pathway for patients with no prior history of established CAD, representing a significant change to current practice and in contrast with other major guidelines. This is based on the evidence of poorer diagnostic accuracy of exercise testing compared to the other tests and supported by a cost-effectiveness model derived specifically for these guidelines.
Approach to Choosing an Anatomic Test Using CAC or CCTA
Until recently, the use of an anatomic strategy using CAC or CCTA has not generally been considered first-line in the diagnosis of CAD in intermediate pretest probability patients with stable chest pain (apart from the NICE guidelines for low-intermediate pretest probability patients, discussed previously), and receives weak, if any, recommendations in current ACC/AHA and ESC guidelines as well as the AUC (see later section). However, two recent randomized controlled trials (PROMISE and Scottish Computed Tomography of the Heart [SCOT-HEART]) directly comparing anatomic and functional testing in the setting of low-risk chest pain provide potential support for its inclusion as a reasonable choice in selected patients (see later discussion).
Patient Selection for CAC
While CAC imaging has been mostly used for risk stratification in asymptomatic individuals, some studies have evaluated the use of CAC in the diagnostic work-up of patients with suspected CAD (by excluding CAD). Data from a high-risk symptomatic population suggest a non-negligible rate of obstructive CAD (i.e., 20% of patients with a high pretest probability of CAD) in the absence of detectable calcium. In contrast, data from lower-risk cohorts have demonstrated that among patients with a negative calcium scan, severe CAD requiring percutaneous coronary intervention (PCI) or coronary artery bypass grafting (CABG) occurs in less than or equal to 1% of patients. The Computed Tomography vs. Exercise Testing in Suspected Coronary Artery Disease (CRESCENT) randomized controlled trial assessed the effectiveness and safety of a tiered cardiac CT protocol, consisting of a calcium scan and selective performance of CCTA if CAC was present. It found that this tiered approach offered an effective and safe alternative to functional testing while lowering diagnostic expenses and radiation exposure. Patients in the CRESCENT trial had a pretest probability of approximately 45% per Diamond–Forrester criteria. Therefore, incorporation of CAC into stepwise CCTA imaging protocols may be beneficial in symptomatic patients, provided they have a low-to-intermediate pretest probability of CAD, although further studies are required for confirmation. One caveat is that this could lead to a higher false-negative rate in younger patients, who may have CAD without detectable CAC, since atherosclerotic calcification increases with age. This may also be seen in women and ethnic minorities.
Patient Selection for CCTA
As with functional testing, the clinician must first consider whether the patient is a good candidate for CCTA. According to a report from the 2014 Society of Cardiovascular Computed Tomography Guidelines Committee, only patients with adequate breath-holding capabilities, without severe obesity (body mass index [BMI] >39 kg/m 2 ), with sinus rhythm and with a heart rate less than or equal to 60 beats per minute (BPM), and with normal or near-normal renal function should be considered for CCTA. If necessary, the patient should be able to tolerate use of short-acting β-blockers or other heart rate–lowering medication to achieve target heart rates. State-of-the-art multidetector scanners reduce radiation exposure and may obviate the need for adjunctive medications in many patients, as they allow accurate imaging with higher heart rates. Absolute contraindications must also be ruled out and include definite acute coronary syndromes, glomerular filtration rate (GFR) of less than 30 mL/min per 1.73m 2 unless on chronic dialysis, previous anaphylaxis after iodinated contrast administration, previous episode of contrast allergy after adequate steroid/antihistamine preparation, inability to cooperate (including inability to raise arms), or pregnancy or uncertain pregnancy status in premenopausal women. Finally, one constraint is that CCTA accuracy may be limited with a high CAC score (Agatston score > 400 U), which can only be determined once the image acquisition has started.
Diagnostic Accuracy of CCTA
Multicenter studies evaluating the diagnostic accuracy of 64-slice multidetector CCTA for detection of significant (at least 50% stenosis) CAD on quantitative invasive coronary angiography have found sensitivities of between 85% and 99% and specificities between 64% and 90%, although newer equipment and scan protocols may improve the diagnostic accuracy. The Assessment by Coronary Computed Tomographic Angiography of Individuals Undergoing Invasive Coronary Angiography (ACCURACY) trial found that specificity was reduced significantly in the presence of coronary artery calcium. In contrast, negative predictive values for CCTA have generally been high (95–100%). This has garnered significant interest in using CCTA in scenarios to “rule out” coronary artery stenosis, or patients with lower pretest probability. Three randomized controlled trials have found a CCTA strategy to provide superior efficiency in the emergency department for low- to intermediate-risk chest pain to “rule out” acute coronary syndromes while providing excellent event-free survival similar to usual care, with no increase in costs or radiation exposure (see Chapter 13 ).
Guideline Recommendations for Choosing an Anatomic Test with CAC and CCTA
ACC/AHA 2012 Guideline
There are currently no strong (Class I) recommendations for CAC or CCTA as the initial test. CCTA may be considered for patients who cannot exercise or for those patients who have a prior normal functional test but ongoing symptoms, have an inconclusive functional test, or are unable to undergo stress MPI or echocardiography (all Class IIa).
ACC Multimodality Appropriate Use Criteria 2014
As in the preceding section, the document rated each testing modality as either appropriate, may be appropriate, or rarely appropriate for given symptomatic target populations. The following anatomic testing situations are summarized here and in further detail in Table 15.4 :
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CAC
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Rarely appropriate for a symptomatic population of patients with chest pain
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CCTA
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Appropriate only for symptomatic patients with an intermediate pretest probability of CAD and an uninterpretable ECG or unable to exercise
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ESC 2013 Guideline
Similar to the ACC/AHA 2012 guideline, there are no strong recommendations (Class I) for CAC or CCTA as the initial test. It is a Class IIa recommendation that CCTA should be considered as an alternative to stress imaging techniques for ruling out CAD in patients with a low-intermediate pretest probability (15–65%) who have an inconclusive exercise ECG or stress imaging test or who have contraindications to stress testing. This recommendation includes patients who can exercise, but excludes the highest range of pretest probability to improve accuracy by selecting patients less likely to have significant coronary calcium, which decreases diagnostic accuracy (discussed previously). Class III recommendations include using CCTA for patients with prior coronary revascularization (not applicable to this population) or as a “screening” test in asymptomatic individuals.
UK 2010 NICE Guideline
In contrast to the ESC guidelines, NICE recommends CAC scoring as the first-line test in patients with an estimated pretest probability of CAD of 10% to 29%. Further management depends on the calcium score: if 0, consider other causes of chest pain; if 1–400, offer 64-slice (or greater) CCTA or imaging stress testing; and if higher than 400, offer invasive coronary angiography. If this is not clinically appropriate or acceptable to the person and/or revascularization is not being considered, offer noninvasive functional imaging.
Major differences between guideline recommendations for the diagnosis of CAD in patients with stable chest pain have several notable differences and are summarized in Table 15.6 .
