D i a g n o s i n g C o ro n a r y A r t e r y

D i s e a s e i n th e P a t i e n t
P res entin g wi t h St ab l e I sch e m i c
Heart Disease
The Role of Anatomic versus Functional Testing

a,b, a
Michelle D. Kelsey, MD *, Anita M. Kelsey, MD, MBA

KEYWORDS
 Stable ischemic heart disease  Stress testing
 Coronary computed tomographic angiography

KEY POINTS
 There are many options for diagnostic evaluation of individuals presenting with symptoms
of stable ischemic heart disease.
 Both functional and anatomic diagnostic tests can be useful to identify ischemic or
obstructive coronary artery disease and risk stratify patients.
 The choice between diagnostic testing modalities depends on individual patient
characteristics.

INTRODUCTION/HISTORY/DEFINITIONS/BACKGROUND

The management of patients presenting with suspected stable coronary artery disease
(CAD) can be challenging. The evaluation of such an individual includes assessment of
his or her pretest probability, with a clinical history, followed by diagnostic testing where
appropriate, to further risk stratify and define the extent of disease. This work-up re-
quires identifying both the categorical classification of coronary disease (present vs
absent) and, if coronary disease is present, the graded finding of functional disease
severity. There are several options for evaluation, including functional stress testing
with a variety of imaging modalities, or anatomic testing using diagnostic coronary angi-
ography or coronary computed tomographic angiography (CCTA). In this article, we will

a
Division of Cardiology, Department of Medicine, Duke University, 2301 Erwin Road, Durham,
NC 27710, USA; b Duke Clinical Research Institute, 300 West Morgan Street, Durham, NC
27701, USA
* Corresponding author. 300 West Morgan Street, Durham, NC 27701.
E-mail address: [email protected]
Twitter: @MDKelseyMD (M.D.K.); @AnitaKelseyMD (A.M.K.)

Med Clin N Am 108 (2024) 427–439

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428 Kelsey & Kelsey

review the characteristics of both functional and anatomic testing, the risks and benefits
of both categories, and the principles of selecting the most appropriate test for the
individual patient.

Clinical Presentation
The first essential step in the evaluation of a patient presenting with stable chest pain is
a careful clinical history and a resting electrocardiogram (ECG).1 This precedes all
consideration of diagnostic evaluation, as a thoughtful clinical assessment with esti-
mation of pre-test probability is the foundation of this work-up. There are several vali-
dated scores which use a variety of clinical information to predict pre-test probability
of disease.2–4 Some guidelines also recommend incorporating information on coro-
nary artery calcium burden to enhance pre-test probability estimates.1 Regardless
of methodology used, this part of the work-up guides all further steps in the diag-
nosis—both the need for additional testing and the choice of that specific test.

Observation/Assessment/Evaluation
Once pre-test probability has been established, there are many diagnostic imaging
modalities to choose from for the work-up of CAD. While each test has unique advan-
tages and disadvantages, ultimately the optimal test depends on local availability and
the ability to achieve high quality images with expert interpretation.1

Functional tests
Functional testing for CAD can be performed with or without imaging and uses exer-
cise or pharmacologic agents to induce or mimic stress on the heart and vasculature.
In general, functional tests are designed to detect myocardial ischemia as a surrogate
marker for obstructive CAD. Exercise is typically preferred over use of pharmacologic
agents in functional stress testing (in patients who do not otherwise have a contrain-
dication).5 Exercise ECG is recommended by the American College of Cardiology
(ACC)/American Heart Association (AHA) as a first line test for low-risk individuals to
exclude myocardial ischemia, and is considered reasonable for intermediate to high
risk individuals with no known CAD.1 Patients must have an interpretable ECG (without
baseline ST-T wave abnormalities, pacing, left bundle branch block, or pre-excitation)
and be able to exercise to a satisfactory workload.6 Although the diagnostic accuracy
of exercise ECG is lower than other forms of stress testing, the data gathered from this
test provide useful prognostic information—as lower exercise capacity with earlier
ECG changes suggests higher risk.7,8 Exercise ECG may also be economically reason-
able. When studied as a part of tiered testing with selective stress echocardiography,
exercise ECG was shown to be cost-effective for the level of diagnostic accuracy
offered.9
Functional testing with imaging has improved sensitivity and specificity compared
with exercise ECG for the diagnosis of obstructive CAD. Stress testing with echocardi-
ography, cardiac magnetic resonance imaging (CMR), single-photon emission comput-
erized tomography (SPECT) or positron-emission tomography (PET) myocardial
perfusion imaging (MPI) are all deemed effective for the diagnosis of myocardial
ischemia in intermediate-high risk patients who present with stable angina.1 The perfor-
mance characteristics of these tests are relatively similar. In comparison to quantitative
coronary angiography for the diagnosis of obstructive CAD (>50% stenosis), stress
echocardiography has a sensitivity of 0.85 (0.80–0.89) and specificity of 0.82 (0.72–
0.89); CMR has a sensitivity of 0.90 (0.83–0.94) and specificity of 0.80 (0.69–0.88);
SPECT has a sensitivity of 0.87 (0.83–0.90) and specificity of 0.70 (0.63–0.76); and
PET has a sensitivity of 0.90 (0.78–0.96) and specificity 0.85 (0.78–0.90).10,11

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 The Role of Anatomic versus Functional Testing 429

While these tests perform relatively equally in the diagnosis of obstructive CAD,
there are some circumstances in which one is favored over another. In general, PET
MPI (when available) is preferred over SPECT for those with and without known
obstructive CAD presenting with stable chest pain.1 PET has been shown to have bet-
ter diagnostic accuracy than SPECT12 and can also provide quantitative assessment
of myocardial blood flow which adds prognostic information.13 Stress echocardiogra-
phy also provides useful prognostic data, and can lend insight into hemodynamic
changes with stress (eg, changes in diastolic function or pulmonary artery pressure
response).14,15 CMR has shown to be as useful as MPI in the work-up of stable chest
pain, and also provides highly accurate assessment of left ventricular function and
other changes to myocardial tissue (eg, scarring, inflammation, etc.).16,17 In terms of
radiation exposure, neither stress echocardiography nor CMR use radiation. The
average radiation exposure for SPECT and PET MPI depend on the imaging protocol
and radio-tracer used. In general, the average dose for PET is 3 mSv when Rubidium-
82 is used and the average dose for SPECT in 10 mSv when Technetium-99m is
used.18
Beyond the binary diagnosis of obstructive CAD, each functional test modality of-
fers important prognostic information that can help guide further management of the
patient presenting with stable angina symptoms. Exercise ECG provides a wealth of
data on exercise capacity and heart rate and blood pressure response to exercise,
which have been associated with longer-term risk. In particular, individuals with
reduced exercise capacity on exercise ECG testing have been shown to have
increased all-cause mortality.19,20 Similarly, abnormal heart rate response to exercise
(ie, inability to achieve 85% of the age-predicted maximum heart rate with activity)
and abnormal heart rate recovery after exercise (ie, a smaller fall in heart rate at
1 minute after stopping activity) have been associated with increased cardiovascular
(CV) and all-cause mortality.21–23 Other variables, such as a fall in systolic blood
pressure with exercise,24 ventricular ectopy during recovery,25 or exercise-induced
left bundle branch block,26 have also been associated with increased risk. Some
of these factors have been combined into risk scores, such as the Duke treadmill
score (which combines exercise time, ST segment deviation with activity, and degree
of angina), in order to predict both severity of obstructive CAD and downstream
survival.7,27
Functional tests with imaging also offer important prognostic information, in addi-
tion the data derived from exercise parameters. On myocardial perfusion imaging, the
extent of ischemia, presence of large fixed perfusion defect, reduced left ventricular
function, and left ventricular cavity dilation have been associated with increased risk
for CV events.28–30 Similarly, on stress echocardiography, left ventricular size and
function and the number and degree of left ventricular wall motion abnormality with
stress, as well as ischemic ECG changes in the absence of regional wall motion ab-
normalities, have been associated with higher risk.14,31–33 Finally, on stress CMR,
stress-induced wall motion abnormality, extent of perfusion defects and degree of
late gadolinium enhancement (suggestive of scarring), are associated with increased
risk for major CV events.34 While exercise stress testing is generally preferred over
pharmacologic stress testing (when able), these tests can also provide prognostic
information.5,32
It is critical to integrate these prognostic variables in the interpretation of stress
testing results, beyond simply diagnosing obstructive CAD. The spectrum of findings
from a stress test can help guide revascularization decisions, and should be used to
tailor preventive care, to optimize CV risk factor control particularly among individuals
with high risk features.

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430 Kelsey & Kelsey

Anatomic tests
CCTA is used to visualize the coronary arteries and directly evaluate atherosclerotic
plaque. CCTA is recommended for evaluation of intermediate-high risk individuals
without known CAD who present with stable chest pain.1 CCTA can also be used
for individuals with known history of CAD who have already undergone revasculariza-
tion, who present with stable chest pain, to assess stent or bypass graft patency.1
CCTA not only offers percent stenosis of each coronary artery, but also can provide
details on atherosclerotic plaque characteristics. Certain radiographic features (low
attenuation plaque, positive remodeling) have been associated with higher risk pla-
que.35,36 Fractional flow reserve (FFR-CT) can be calculated from CT angiographic
data and can estimate ischemia or a specific stenotic lesion within the vessel or
flow at the distal end of the vessels.37 Individuals undergoing CCTA are often pre-
treated with beta blockers to ensure heart rates are low and stable, and are given nitro-
glycerin to increase the size of the arteries for better visualization. Individuals with
contraindications to either of these agents, or with heart rates that are variable due
to arrhythmia, may not be appropriate for CCTA imaging.38 Patients undergoing
CCTA must also be able to cooperate during the scan (hold their breath at certain
times) to optimize image acquisition.38 Finally, significant calcification in the coronary
arteries can impact the ability to see vessel details. Depending on the distribution of
calcification, this can decrease diagnostic accuracy.10 The average radiation dose
from CCTA is 3 to5 mSv.39
Invasive coronary angiography has long been considered the gold standard for the
diagnosis of CAD. Beyond visual assessment, there are many tools available to quan-
tify stenosis and to characterize coronary atherosclerotic lesions. Intravascular ultra-
sound and optical coherence tomography can be used to visualize intraluminal
coronary structure. Instantaneous wave-free ratio (iFR) and fractional flow reserve
(FFR) can be used for intracoronary physiologic assessment, to understand the hemo-
dynamic significance of a stenotic region.40 These techniques are performed at the
time of the procedure using specialized equipment. There are also methods of quan-
titative coronary angiography using software to analyze angiographic images to
compute a more exact percent stenosis.41 These technologies improve the accuracy
of invasive coronary angiography and help to select the most appropriate patients for
revascularization.40
Though invasive coronary angiography remains the gold standard for the diagnosis
of CAD, there are risks associated with this procedure. Major complications are rare,
occurring less than 2% of the time in modern practice. Other risks include the
following: infection (<1%), contrast induced nephropathy (3.3%–16.5%), cholesterol
emboli (<2%), local vascular injury (0.7%–11.7%), hematoma requiring blood transfu-
sion (2.8%), retroperitoneal bleeding (0.3%), arrhythmia (1.3%–2.5%), or death
(<1%).42 Invasive coronary angiography also carries radiation exposure of approxi-
mately 8 to 10 mSv.43
Though invasive coronary angiography has been considered the gold standard for
the diagnosis of obstructive CAD, it is no longer routinely recommended as a first test
in the work-up of stable chest pain (unless very high clinical likelihood).1 Multiple ran-
domized trials suggest that CCTA or other functional stress testing can be used safely
for first-line evaluation in the majority of individuals. This allows for appropriate triaging
of patients, higher yield invasive coronary angiography, and lower rates of procedural
complications.44,45
Similar to functional testing, anatomic tests also provide prognostic information,
which should be integrated into the evaluation of patients presenting with stable angina.
On CCTA, the presence of any stenosis, higher degree of stenosis, and proximal

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 The Role of Anatomic versus Functional Testing 431

location of stenosis have been associated with increased CV risk.46,47 Lower FFR-CT
values have also been associated with higher risk of subsequent events including
myocardial infarction or unplanned revascularization.48 Similarly, invasive coronary ar-
tery flow measures, using iFR or FFR, have also demonstrate an association between
positive (obstructive) values and increased risk for adverse CV events.49,50 As with func-
tional testing, these prognostic variables should be incorporated into the overall
assessment of individuals presenting with stable angina, in order to guide revasculari-
zation decisions and optimize preventive care for individuals at high risk.

Current Evidence
The ACC/AHA guidelines offer slightly different recommendations for anatomic versus
functional testing in the work-up of patients with stable chest pain (Table 151,52).1
Notably, among intermediate-high risk individuals without known CAD, anatomic eval-
uation with CCTA has a Class 1, level of evidence A indication, while other functional
stress imaging has Class 1, but slightly lower level of evidence B-R.1
There is a growing body of evidence of head-to-head comparison studies between
functional and anatomic testing in the evaluation of stable angina. The results of these
comparisons are variable, depending on the outcome measure selected and the pop-
ulation studied (Table 2). Among the largest, were the Prospective Multicenter Imag-
ing Study for Evaluation of Chest Pain (PROMISE) trial, published in 2015, and the
Scottish Computed Tomography of the Heart (SCOT-HEART) trial, published in
2018. PROMISE randomized outpatients with stable symptoms suggestive of CAD
to CCTA or functional testing with SPECT, stress echo or exercise ECG. After a me-
dian follow-up of 25 months, there were similar event rates (a composite of death,
myocardial infarction, hospitalization for unstable angina, or major procedural compli-
cation) between the functional and anatomic testing arms.53 SCOT-HEART random-
ized outpatients with stable symptoms suggestive of CAD to CCTA with standard of
care (most commonly exercise ECG) or CCTA alone. At 5 years of follow-up, there
were lower rates of CV death or myocardial infarction in the CCTA with standard of
care arm.54
Anatomic testing with CCTA typically leads to more refined selection of patients for
invasive coronary angiography. In both PROMISE and SCOT-HEART, when invasive
coronary angiography was pursued, participants were more likely to have obstructive
CAD at the time of catheterization.53–55 This suggests a higher yield selection for inva-
sive testing after anatomic evaluation. Similarly, in both PROMISE and in SCOT-
HEART, there was increased coronary revascularization in the CCTA arms, likely a
downstream consequence of increased catheterization with obstructive CAD.53–55
Anatomic testing also leads to more changes in preventive medications than func-
tional testing. In SCOT-HEART, there were increased prescriptions of anti-platelet
agents and statins after anatomic evaluation.55 As CCTA can diagnose both obstruc-
tive and non-obstructive CAD, it often prompts more changes in medical therapy.
Ultimately, one must consider individual patient characteristics to select the most
appropriate diagnostic imaging modality for work-up of stable chest pain. CCTA is
more often recommended in those at lower clinical risk, as it has higher diagnostic ac-
curacy among patients with lower pre-test probability or disease.56 Conversely, func-
tional testing is often recommended for those at higher risk, as it can be more helpful
to rule-in obstructive coronary disease, and guide subsequent revascularization deci-
sions.4 Along these lines, there is some evidence to suggest that functional testing
may have more prognostic utility among older adults over 65 years of age; while
anatomic testing with CCTA better risk stratified those under 65 years.57 CCTA may
have particular utility in women, as some evidence suggests that anatomic testing

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Kelsey & Kelsey

Table 1
Selected randomized trials of anatomic vs. functional testing for stable coronary artery disease51–54,61

Randomized Trial (Year) Patient Population (N) Diagnostic Testing Modalities Primary Endpoint Result
Min et al,51 2012 Outpatients with stable CCTA vs SPECT Angina-specific health Change in angina stability
CAD symptoms (N 5 180) status CCTA 30  37.0 vs SPECT
22.9  30.1, P 5 .11
CAPP,52 2014 Troponin-negative stable CCTA vs ETT Composite of all-cause ETT: 1 death, 2 NSTEMI
chest pain, without known mortality, STEMI/NSTEMI, CCTA: 1 death, 1 NSTEMI
CAD (N 5 500) HF admission, stroke
PROMISE,53 2015 Outpatients with stable CAD CCTA vs Functional testing Composite of death, MI, aHR 1.04 (95% CI: 0.83–1.29),
symptoms (N 5 10,003) (SPECT, stress echo, ETT) unstable angina, major P 5 .75
procedural complication
SCOT-HEART,54 2018 Outpatients with stable CAD Standard of care and CCTA vs Composite of CV death HR 0.59 (95% CI: 0.41–0.84),
symptoms (N 5 4,146) standard of care (ETT or SPECT) or MI P 5 .004
PRECISE,61 2023 Outpatients with stable CAD CCTA with FFR-CT vs Functional Composite of death, MI and aHR 0.29 (95% CI: 0.20–0.31),
symptoms (N 5 2,103) testing (SPECT, stress echo, ETT, catheterization without P < .001
MRI) or ICA obstructive CAD

Abbreviations: aHR, adjusted hazard ratio; CAD, coronary artery disease; CCTA, coronary compute tomographic angiography; CI, confidence interval; Echo, echo-
cardiography; ETT, exercise treadmill testing; FFR-CT, fractional flow reserve computed tomography; HF, heart failure; HR, hazard ratio; MI, myocardial infarction;
ICA, invasive coronary angiography; NSTEMI, non-ST elevation myocardial infarction; SPECT, single-photon emission computerized tomography; STEMI, ST eleva-
tion myocardial infraction.
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Table 2
American college of cardiology/american heart association guideline recommendations for anatomic vs. functional testing in patients with stable chest pain

Anatomic Testing Recommendations COR, LOE Functional Testing Recommendations COR, LOE
Low-risk Patients without known CAD CAC testing is reasonable as first line to 2a, B-R Exercise testing without imaging is 2a, B-NR
identify low risk patients reasonable as first line
Intermediate-High Risk without known CCTA is effective for diagnosis of CAD 1, A Stress imaging (stress echo, PET/SPECT 1, B-R
CAD MPI or CMR) is effective for diagnosis of
ischemia
Sequential Testing in Intermediate-High If CCTA is inconclusive, stress imaging is 2a, B-NR After inconclusive or abnormal exercise 2a, B-NR
Risk reasonable 2a, B-NR ECG or stress imaging, CCTA is

The Role of Anatomic versus Functional Testing

If coronary stenosis of 40%–90% in reasonable
proximal or middle vessel segment on
coronary CCTA, FFR-CT can be used
Known non-obstructive CAD CCTA is reasonable to determine plaque 2a, B-NR Stress imaging (stress echo, PET/SPECT 2a, C-LD
burden and progression to obstructive MPI or CMR) is reasonable for the
disease diagnosis of ischemia
Known obstructive CAD CCTA is reasonable to evaluate bypass 2a, B-NR For chest pain despite optimal medical 1, B-NR
graft anatomy or stent patency (for therapy, stress testing (PET/SPECT MPI,
stents  3 mm) CMR or stress echo) is recommended
Prior CABG Surgery If suspected myocardial ischemia, CCTA is 2a, C-LD If suspected myocardial ischemia, stress 2a, C-LD
reasonable testing is reasonable

Abbreviations: CABG, coronary artery bypass grafting; CAC, coronary artery calcium; CAD, coronary artery disease; CCTA, coronary computed tomographic angi-
ography; CMR, cardiac magnetic resonance imaging; COR, class of recommendation; ECG, electrocardiogram; FFR-CT, fractional flow reserve computed tomog-
raphy; LOE, level of evidence; MPI, myocardial perfusion imaging; PET, positron emission tomography; SPECT, single-photon emission computerized tomography.

433
434 Kelsey & Kelsey

may provide more prognostic information among this demographic.58 Thus, individual
patient characteristics and pre-test probability of disease must be considered in order
to select the optimal test to evaluate for obstructive CAD.

Emerging Therapies/Emerging Treatment

While both functional and anatomic testing can be useful in the work-up of suspected
CAD, there may be some individuals who do not require any such evaluation. Both the
ESC guidelines on the diagnosis of chronic coronary syndromes,4 and the ACC/AHA
guideline on the evaluation and diagnosis of chest pain1 suggest that testing can be
deferred in individuals who have a low pretest probability for obstructive coronary dis-
ease and who have an overall favorable prognosis. The ESC guidelines specifically
recommend deferring testing in those with a pre-test probability less than or equal
to 5%, and it can also be considered in those with a pre-test probability of 5% to
15%. This is because clinical outcomes are favorable in this populations and testing
may be low-yield unless there is some other compelling reason to pursue (eg, limiting
symptoms or need for additional clarification).59,60
This strategy of deferred testing among low risk patients was tested prospectively in
the Prospective Randomized Trial of the Optimal Evaluation of Cardiac Symptoms and
Revascularization trial.61 In this pragmatic randomized control trial, patients present-
ing with stable anginal symptoms were randomized to a precision strategy vs. usual
testing for work-up of suspected CAD. Every participant was risk stratified using the
PROMISE Minimal Risk Score (PMRS). The PMRS was derived from the PROMISE
trial dataset and was designed to identify individuals at very low risk of obstructive
CAD with likewise low risk of CV events. Participants in the precision strategy arm
who were deemed low risk were not immediately offered testing, and instead offered
reassurance and medical therapy. Low risk individuals randomized to usual care were
offered functional testing or coronary angiography, based on their clinician preference.
Importantly, in this study, individuals randomized to the precision strategy with de-
ferred testing had no CV events at 1 year (no death, no myocardial infarction) and
64% never received subsequent testing.62 There was similar improvement in angina
symptoms between low risk precision strategy and low risk usual care arms. The re-
sults of this study support guideline recommendations and offer additional reassur-
ance that testing may be safely deferred in low risk individuals.

DISCUSSION

The evaluation of individuals presenting with stable chest pain can be challenging. The
first step in this work-up includes a careful clinical history in order to determine pre-test
probability of disease. This clinical information and baseline risk are then used to guide
the selection of an appropriate diagnostic test (if any). There are many diagnostic tests
available to evaluate for the presence of obstructive CAD. There are both functional
tests and anatomic tests, which have very different indications and contraindications
and provide slightly different diagnostic and prognostic information. The choice of
the optimal diagnostic test depends first on the local availability and expertise to
accurately acquire and interpret the clinical data. Provided this is available, the deci-
sion between functional testing and anatomic testing depends on individual patient
characteristics. Anatomic testing with CCTA can be useful in lower risk populations,
to rule out obstructive CAD. This testing performs particularly well in younger individ-
uals and in women, and leads to more downstream initiation of preventive therapies,
which can have long term clinical benefit. Functional testing can be useful among
higher risk individuals. When ischemia is detected, functional testing can help to guide

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 The Role of Anatomic versus Functional Testing 435

revascularization decisions. Both anatomic and functional testing offer unique advan-
tages and disadvantages, and the choice between the 2 depends heavily on the clinical
scenario at hand.

SUMMARY

The evaluation of patients who presents with stable chest pain suspicious for obstruc-
tive CAD starts with an assessment of pre-test probability using clinical history. There
are both functional and anatomic tests available for those that would benefit from addi-
tional diagnostic evaluation. The decision between these testing modalities depends on
individual patient characteristics.

CLINICS CARE POINTS

 Assessment of pre-test probability is an essential first step in the evaluation of patients

present with stable chest pain.
 Anatomic testing has particular utility among younger individuals and women
 Functional testing can be helpful to rule-in ischemia and guide revascularization decisions
 Low risk individuals presenting with stable angina may not require any further diagnostic
testing, given low diagnostic yield of tests in this population and overall low clinical event
rates.
 Selection of the most appropriate test (or deferred test) should be individualized to the
patient and clinical scenario.

DISCLOSURE

M D. Kelsey reports consultation/advisory panels for Bayer, Heartflow. The remaining

authors report nothing to disclose.

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