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357
characteristics (Fig. 20.12 Dey). Automated assessment of
plaque characteristics (Autoplaq®; Cedars-Sinai Medical
Center, Los Angeles, California) has been shown by Dey
et al. to correlate highly with measurements by intravascular
ultrasound [ 41 ]. More recently, Diaz-Zamudio, Dey and
associates have shown these automated plaque measurements to be predictive of abnormal FFR and more predictive
than stenosis grading in intermediate coronary lesions, with
total, noncalcifi ed, and low-attenuation being signifi cant predictors of ischemia [ 42 ]. The automated assessments have
the potential of becoming practical clinical tools that could
augment the assessment of coronary stenosis by CCTA.
Beyond the anatomic assessments of plaque and stenosis,
CCTA acquisitions can be used to assess physiologic processes. Two major developments have been recently reported
in this regard. The fi rst is the assessment of myocardial perfusion with CT (CT perfusion or CTP). CTP has its origins
in digital subtraction angiography initially evaluated in the
1970s. With cardiac CT, it has now been applied to assess
perfusion defects at rest and during vasodilator stress, providing assessments of regional hypoperfusion. The approach
has recently been assessed in two large multicenter trials.
The CORE64 study evaluated rest/adenosine CTP using the
combination of stenosis ≥50 % on ICA and SPECT myocardial perfusion defect as the comparator of hypoperfusion. A
high receiver operating characteristic (ROC) curve area was
reported [ 43 ]. Comparable accuracy for detection of ICA
stenosis was subsequently reported in the trial between adenosine CTP and pharmacologic SPECT assessments. In
another multicenter trial, Cury et al. reported a high ROC
curve area for the assessment of perfusion defect comparing
regadenoson CTP to regadenoson SPECT [ 44 ]. These reports
suggest that CCTA might effectively be used clinically for
assessment of vasodilator stress myocardial perfusion and
Fig. 20.9 Illustration of F-18 NaF uptake superimposed on CCTA
( right ) and corresponding culprit lesions on invasive coronary angio-
grams ( left ) in a patient with recent anterior ST elevation MI ( top ) and
non-ST elevation MI ( bottom ). Intense uptake of F-18 NaF ( orange/
red ) is seen at the site of the culprit plaques ( red arrows ). A bystander
lesion in the left circumfl ex coronary artery that was stented but was not
the culprit vessel had no increase in uptake of F-18 NaF ( white arrows ,
lower panel ) (Reprinted from Joshi et al. [ 35 ] with permission under a
Creative Commons Attribution license)
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coronary plaque and stenosis. Potentially, this combination
could allow adjudication of borderline stenoses with respect
to their hemodynamic signifi cance without need for a second
stress test on a separate occasion.
An exciting even more recent development has been that
of estimating FFR from a resting CCTA study FFRCT. This
approach uses computational fl uid dynamics, assessing the
CCTA studies through the use of an off-site supercomputer.
The method does not require a second acquisition with its
attendant radiation and work-fl ow complexity, and has no
additional contrast or radiation, since it uses the standardly
acquired CCTA study (Fig. 20.13 ). Three large multicenter
trials have demonstrated the high accuracy of this method in
predicting FFR by ICA [ 45 – 47 ]. In the NXT study, the accu-
racy of FFRCT exceeded that of coronary stenosis measured
by ICA in prediction of FFR [ 47 ] (Fig. 20.14 ; Courtesy
NXT). This promising technique could be of high value to
interventionalists in determining the need for revasculariza-
tion and potentially allowing them to reduce the need for
FFR measurements in the catheterization laboratory as well
as to reduce the proportion of times that ICA is performed
and revascularization is not needed. How well the approach
will perform in standard clinical practice is currently undergoing evaluation.
Value-Based Imaging
All of these assessments now available due to the technologic assessments must now be addressed in terms of how
they will fi t in with the migration to value-based imaging. In
this section, we address consideration of the “value proposition” in four different settings in which CAD is considered or
being evaluated: prevention, detection/assessment of ACS,
assessment of patients with suspected or known SIHD, and
patients with heart failure related to CAD.
Fig. 20.10 CCTA (volume rendering, right; curved multiplanar reconstruction ( middle ) and ICA showing adverse plaque characteristics
associated with moderate stenosis in a culprit left anterior descending
coronary artery lesion in a 40-year-old male patient presenting with
acute coronary syndrome. The blue arrow on ICA shows the site of
maximal luminal obstruction. On CCTA the plaque is seen to be large,
with positive remodeling ( yellow arrows ; remodeling index 1.43) and to
have a low attenuation component ( red arrow ), consistent with lipid in
necrotic core (Reprinted from Motoyama et al. [36] with permission
from Elsevier)
D.S. Berman et al.
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Fig. 20.11 Case examples
illustrating the relationship of
coronary stenosis on CCTA
( top ) to ischemia on
SPECT-MPI polar maps
( bottom ) in patients with high
grade coronary stenosis by
quantitative coronary analysis
( QCA ). The patient on the left
had an 81 % stenosis,
associated with a plaque
without adverse features
( green arrow ) and had no
evidence of ischemia. The
patient on the right had a
70 % stenosis by QCA,
associated with a plaque with
adverse characteristics of
large volume, positive
remodeling ( yellow arrow )
and low attenuation plaque
( red arrow ) and demonstrated
clear evidence of ischemia
(Reprinted from Shmilovich
et al. [
38 ] with permission
from Elsevier)
Fig. 20.12 Features which
can be assessed by automated
quantitative plaque
characterization (AutoPlaq®;
Cedars-Sinai Medical Center;
Los Angeles, California).
NCP non-calcifi ed plaque,
CP calcifi ed plaque
(Reprinted from Dey et al.
[ 41 ] copyright RNSA® with
permission from the
Radiological Society of North
America)
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Prevention
More lives could be saved by appropriate implementation
of preventive therapies such as the use of statin and aspirin
than through the use of revascularization. Yet the manner
in which prevention strategies are chosen is imprecise.
Increasingly, modern concepts are that medicine is migrating toward “precision medicine,” in which the therapy for a
patient is chosen based on the characteristics of that individual. The standard guidelines for implementation of
aggressive prevention strategies employ the use of global
risk scores, such as the Framingham Risk Score (FRS) to
place patients into treatment groups. These scores are
based on risk factors that are known in populations to be
independently associated with atherosclerotic cardiovascular disease (ASCVD) [ 48 ]. The current ACC/AHA guide-
lines from 2014 essentially result in nearly 100 % of men
over age 55 having a recommendation for being on statin
and aspirin therapy [ 48 , 49 ]. There are multiple limitations
in the use of global risk scores in the individual patient.
They do not take into account individual variations of the
biologic effects of the risk factor, the chronicity of the factor, and cannot account for all risk factors. On the other
hand, the CT CAC score is a marker of CAD in an individual patient, representing the integrated effect of all risk
factors on the individual’s coronary vasculature. It thus
overcomes the imprecision of the global risk scores. Recent
analysis of patients from the Multi-Ethnic Subclinical
Atherosclerosis (MESA) study has shown that the new
AHA-ACC-ASCVD score overestimated risk by 25–115 %,
with substantial implications for individual patients and the
health care system [ 50 ].
Hundreds of studies have evaluated the prognostic value
of the CAC in asymptomatic subjects. They have consistently documented that CAC score provides incremental
Fig. 20.13 Illustration of CCTA ( left ) ICA ( middle ) and FFR CT ( right )
in: a patient with a moderate coronary stenosis ( top ) associated with a
reduced FFR and FFR
CT
( top ) and a patient with a higher grade coro-
nary stenosis associated with a normal FFR and FFR
CT
( bottom ). Note
the correspondence between the FFR and the FFR
CT
measurements and
the discordance with the visually appreciated degree of stenosis ( red
arrows ) (Reprinted from Min et al. [ 45 ] with permission from the
American Medical Association)
D.S. Berman et al.
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361
information over a global risk scores, mainly the FRS. Among
most important of these studies to date are the MESA study
[ 51 ] and the Heinz-Nixdorf Recall study [ 52 ]. These were
large, population based studies in which CAC and multiple
other tests were compared to global risk scores for assessing
patient prognosis. The results of the trials were very similar.
They showed strong incremental value of CAC over the FRS,
and a high net reclassifi cation index (NRI). Each trial has
had numerous substudies reported. In a recent report from
the MESA trial, the CAC score was the only assessment of
many including CRP to add to the FRS in assessment of
prognosis [ 53 ]. Further interesting work from the MESA
trial has been to show that the CAC score could be used to
more effectively target statin and aspirin therapy than the
FRS. With respect to aspirin, Miedema et al. [ 54 ] demon-
strated from MESA that in patients with a low FRS (<10 %),
the use of aspirin would result in net patient harm, whereas
the use of aspirin in patients with CAC >100 would be associated with patient benefi t. Similarly, regarding statin therapy, it was projected that it is both cost-saving and more
effective to scan intermediate-risk patient for CAC and to
treat those with CAC ≥1 with a statin than basing treatment
on standard risk- assessment guidelines [ 55 ].
The CAC scan can affect the degree to which the patient
adopts heart healthy behaviors including improvement in
risk factor profi le [ 56 ], intensifi cation of Rx [ 57 ], better
adherence to Rx [ 58 ], dietary modifi cations [ 58 ], and
increased exercise [ 59 ]. Interesting work from MESA
demonstrated that improvement in healthy lifestyle behavior
including regular exercise, healthy diet, smoking avoidance,
and weight maintenance was associated with lower coronary
calcium incidence, slower calcium progression, and lower
all-cause mortality over 7.6 years [ 60 ].
The largest randomized trial to date assessing the value of
CAC scanning is the Early Identifi cation of Subclinical
Atherosclerosis by Noninvasive Imaging Research (EISNER)
trial [ 56 ]. It was designed to test the primary hypothesis that
performing CAC scanning would lead to a benefi cial sustained 4-year effect on individuals’ CAD risk factors—using
the FRS as a composite of these—as a surrogate for improved
outcomes. Secondarily, we assessed the impact of CAC
scanning on downstream medical resource utilization and
healthcare costs. The trial involved assigning 2137 volunteers
to groups that did versus did not undergo CAC scanning
before risk factor counseling (2:1 scan/control randomization). Compared to the no-scan group, the scan group showed
a net favorable change in systolic blood pressure (p = 0.02),
LDL-cholesterol (p = 0.04), waist circumference for those
with increased abdominal girth (p = 0.01), and tendency to
weight loss among overweight subjects (p = 0.07). While
mean FRS rose in the no-scan group, it remained static in the
scan group (0.7 ± 5.1 versus 0.002 ± 4.9, p = 0.003). Within
the scan group, increasing baseline CAC score was associated with a dose–response improvement in systolic and diastolic blood pressure (p <0.001), total cholesterol (p <0.001),
LDL- cholesterol (p <0.001), triglycerides (p <0.001), weight
(p <0.001) and FRS (p = 0.003). Downstream medical testing
and costs in the scan group were comparable versus the noscan group, balanced by lower and higher resource utilization for those with normal CAC scans and CAC scores ≥400,
100
90
81
65
64
84
83
86
60
51
61
95
92
93
46
33
91
80
70
60
50
40
30
20
10
0
FFR
CT
£.80cv
CT≥50
ICA≥50
NXT: Per-Vessel Prediction of Invasive FFR:
FFRCT vs. CT and ICA:
FFR
CT
diagnostic accuracy superior to both CT and ICA stenosis
N=484
Accuracy Sensitivity Specificity PPV NPV
Fig. 20.14 Accuracy,
sensitivity, and specifi city of
FFR
CT
( red ) and percent
diameter stenosis [ black :
CCTA; pink : ICA] in
prediction of invasive FFR
(Reprinted with permission
from Nørgaard et al. [ 47 ]
with permission from
Elsevier)
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respectively. Improvement in the global risk score, associated with no increase in overall costs, provided evidence that
there is value in testing this population at intermediate risk.
Of note, this study had several components that were acting
to underestimate the potential of the CAC scan to improve
outcomes. The only difference between the control and treatment groups was a one-time counselling session in which the
patients in the scan group were shown their scans and a nurse
practitioner discussed the scan implications (those that were
known at that early time) along with the patients risk factor
profi le with the patient, while the control group patients
received the risk factor counseling alone. There were no
treatments recommended by the nurse practitioner; specifi cally, the only treatment guidelines that were discussed were
those of the NCEP III—with no specifi c recommendation for
change in treatment based on scanning. Subsequently,
patients were sent by mail an anonymized report of their
study; however, their physicians were not sent reports.
Application in Diabetes
Assessment of the asymptomatic patient with diabetes is an
important subgroup with generally a higher risk of cardiac
events than patients in most other asymptomatic groups.
Comparing the potential value of the various noninvasive
tests in these patients casts further light on their effectiveness
in the asymptomatic patient population. CAC scanning may
be of value in this application.
Extensive data has shown that a CAC score of 0 is found
in a high proportion of adult asymptomatic diabetics—38 %
in the MESA study [ 61 ]. The possibility that this fi nding
might improve patient outcomes, particularly in the psychologic well being of the diabetic patient, if of interest in this
regard. There is a greater increase of risk of events in every
category of increased CAC score when compared to the nondiabetic population. CAC scanning has the potential of defi ning a high risk group that might benefi t from ischemia
testing.
Randomized clinical trials (RCTs) have suggested that
routine SPECT-MPI in the asymptomatic diabetic patient
may not be of value. In the Detection of Ischemia in
Asymptomatic Diabetics (DIAD) study [ 62 ], 1143 asymp-
tomatic diabetics were randomized to either a screening
approach using SPECT-MPI (n = 522), or a non- imaging
regimen. The patients were not selected to be high risk. Over
a 4.8 year follow-up, the cardiac event rates were low and
there was no outcome benefi t in the group undergoing
SPECT-MPI. While the prevalence of any perfusion or LV
function abnormality was 22 %, a moderate-to-large perfusion defect was present in ischemia only 6 %. In the small
group that did have moderate-to-large perfusion defects, the
event rate was elevated. The Basel Asymptomatic High-risk
Diabetes Outcome (BARDOT) trial [ 63 ] studied 400 patients
with type 2 diabetes who had no history or symptoms of
CAD, but who were defi ned as high risk. Baseline SPECT-
MPI was abnormal in 22 %, concordant with the results of
the DIAD study. Major adverse cardiac events (MACE,
defi ned as cardiac death, myocardial infarction, or symptomdriven coronary revascularization) occurred in 2.9 % of
patients with normal baseline SPECT- MPI compared to
9.8 % of patients with an abnormal MPI (p = 0.011). Patients
with abnormal SPECT-MPI were randomized to an approach
of catheterization with intended revascularization vs noninvasive management; there was no difference in outcomes in
those randomized to medical therapy only vs combined
medical therapy and revascularization. Overall, the fi ndings
suggest a lack of outcome benefi t of stress testing of asymptomatic diabetic patients. Whether such testing might have
been benefi cial if the defi nition of high-risk had been based
on elevated CAC levels would be of interest.
A recent multicenter RCT has evaluated the application of
CCTA in the high risk asymptomatic diabetic patient. In this
regard, the FACTOR-64 trial evaluated whether routine coronary CTA screening of high risk asymptomatic diabetics
affects changes in treatment that leads to a reduction in cardiac events [ 64 ]. Nine hundreds patients were randomized to
CT screening (n = 452) with protocol specifi c recommendations for management after testing or standard care (n = 448).
CCTA showed no CAD in 31 %, mild plaque <50 % stenosis
in 46 %, moderate stenosis in 12 %, and severe stenosis in
11 % of the patients. CCTA prompted a stress test in 14 % of
the cases, and angiography in 8 %, of whom 53 % underwent
subsequent PCI and 19 % underwent coronary artery bypass
graft (CABG). There was a trend for a lower rate of events in
the CT group: for the primary composite endpoint of death,
MI, or hospitalization for unstable angina, the rate was 6.2 %
in the CT arm vs. 7.6 % in the standard care group (HR 0.80,
95 % CI 0.49–1.32, p = 0.38). At the end of the trial, the CT
group showed improvements in statin use and intensity, lipid
fractions, and blood pressure levels. The composite primary
end point was less than half of expected and there was a nonsignifi cant trend toward lower composite events. While not
yet proven statistically in this trial, the results suggest that a
strategy based on screening high risk asymptomatic diabetics using CCTA might be of value.
Value of Noninvasive Imaging for Prevention
Given the plethora of CAC studies demonstrating the adverse
prognosis of a high CAC score, it is questionable whether a
suffi ciently powered randomized clinical trial demonstrating
that CAC improves outcomes be performed. Nonetheless, a
vast amount of consistent observational data suggest that
CAC scanning in the appropriate asymptomatic patient at low
to intermediate risk would result in improved outcomes that
would outweigh any increase in costs associated with the test
and downstream testing and treatments, thus providing value
(Fig. 20.15 ). The possibility that coronary CTA or stress
myocardial perfusion imaging might prove of value in very
high risk asymptomatic patients has not been fully explored.
D.S. Berman et al.
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363
Evaluation of the Symptomatic Patient
In the symptomatic patient without known CAD, the fi rst
question that arises addresses what is the cause of the
symptoms (i.e., establishing the diagnosis) and, after it is
answered, what is the appropriate treatment, which involves
assessment of short term as well as long term risk. While
use of 50 % stenosis on ICA for establishing diagnosis of
CAD as the cause of symptoms is questioned, it has been
the usual standard for establishing the presence of “signifi cant” CAD—a standard that might be common to assessment of the patients with either acute or stable chest pain
syndromes. In this regard, the sensitivity and specifi city for
detection of “angiographically signifi cant” CAD has long
been a standard for test assessment. Extensive evidence has
shown that direct visualization of the coronary stenosis
with CCTA is superior to all other forms of noninvasive
testing, on a per patient, per vessel, and per segment basis
[ 65 – 68 ]. Beyond detection of stenosis, CCTA has been
studied extensively in risk prediction and effect on patient
outcomes.
Evaluation of Patient with Acute Chest Pain
Almost eight million individuals are evaluated each year for
acute chest pain in the emergency department (ED) [ 69 ].
Despite standardized protocols and high vigilance, between
2 and 6 % of patients are erroneously discharged with missed
myocardial infarction [ 70 ] with higher mortality rates than
patients who are hospitalized. For patients with normal or
nondiagnostic initial ECGs and troponin levels on presentation to the ED, an important clinical problem is to distinguish
those with acute coronary syndromes requiring hospital
admission from those who may be safely discharged. It is
now standard in many EDs and chest pain centers to evaluate
such patients with a “rule-out myocardial infarction” strategy followed by stress testing and/or cardiac imaging; however, it has been estimated that the diagnosis of acute ED
chest pain costs $10–$12 billion annually in the United
States [ 69 ].
Use of SPECT-MPI in the Evaluation of Acute
Chest Pain
Noninvasive imaging has become part of the standard of
care in assessing patients with low to intermediate risk of an
ACS in the ED. A common approach is to use rest or rest/
stress Tc-99m sestamibi or tetrofosmin SPECT-MPI for this
purpose. A 99 % negative predictive value of rest SPECTMPI, when the radiopharmaceutical is injected during or
shortly after chest pain, has been reported [ 69 ]. A prospec-
tive, randomized, controlled multicenter trial examined
whether incorporating acute rest SPECT-MPI into an ER
evaluation strategy of patients presenting with suspected
acute ischemia improved initial ER triage [ 71 ]. A signifi -
cant reduction in hospitalization was noted in patients with
normal SPECT-MPI studies. When the radiopharmaceutical
is injected after pain has subsided and the SPECT-MPI
study is normal, stress SPECT- MPI studies or stress only
SPECT-MPI protocols are common and have been shown to
be effective [ 72 ]. The comparative use of SPECT-MPI to
CCTA is discussed below. Below, evidence that CCTA may
be superior in this application will be presented; however,
there are settings in which CCTA would be expected to be
nondiagnostic in which SPECT-MPI might be preferred.
These include patients with known dense coronary calcifi cation, elderly patients in whom dense coronary calcifi cations are likely, patients with prior bypass surgery, possibly
with prior percutaneous coronary intervention (PCI), and
known ischemic cardiomyopathy, and with contraindications to CCTA.
Use of CCTA in the Evaluation of Acute
Chest Pain
Three large randomized clinical trials have evaluated the
application of CCTA to patients in with suspected ACS in the
emergency department in comparison to a standard of care
approach (SOC). In all of these studies, the patients evaluated were defi ned as being in a low to intermediate group
regarding the likelihood of having an ACS at the time of their
ED visit. The fi rst of these was the CT-STAT trial comparing
CCTA to rest/stress SPECT-MPI [ 73 ]. In 16 centers, 699
patients were randomly assigned to CCTA (n = 361) or MPI
(n = 338) as the index noninvasive test. CCTA resulted in a
54 % reduction in time to diagnosis (2.9 h vs. 6.3 h)
compared with MPI (p <0.0001). Costs of care were 38 %
lower (p <0.0001). The diagnostic strategies had no difference in major adverse cardiac events after normal index testing (0.8 % in the CCTA arm vs. 0.4 % in the MPI arm,
p = 0.29). The ACRIN-PA trial [ 74 ] evaluated 1392 low-to-
intermediate risk patients (TIMI score 0–2) presenting to the
ED to CCTA or the physician elected traditional approach to
standard care in a 2:1 ratio. Patients evaluated with coronary
Fig. 20.15 Hypothesized value of using CAC scanning for prevention
in patients with an intermediate risk of ASCVD
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CTA had a shorter mean hospital stay and were also discharged more rapidly (total length of stay 18 vs 25 h; p
<0.0001) and more frequently (50 vs 23 %) than patients
undergoing the standard care evaluation. Of 640 patients
with a negative CCTA examination, none died or had a myocardial infarction within 30 days [ 74 ]. The ROMICAT II trial
[ 75 ] randomly assigned patients 40–74 years of age with
symptoms suggestive of acute coronary syndromes but without ischemic electrocardiographic changes or an initial positive troponin test to early CCTA or to standard evaluation in
the emergency department. The rate of acute coronary syndromes among 1000 patients with a mean (±SD) age of
54 ± 8 years (47 % women) was 8 %. Compared with standard evaluation, in the CCTA group, the mean length of hospital stay was reduced by 7.6 h (p <0.001). Fifty percent of
the patients in the CCTA arm were discharged by 8.6 vs
26.7 h in the standard ED evaluation arm (p <0.001). A
higher proportion of patients were discharged directly from
the emergency department (47 vs. 12 %, p <0.001). Sixtytwo percent of patients were in the ED for 12 h or less in the
CCTA arm vs 21 % in the control arm. There were no signifi cant differences in major adverse cardiovascular events at 28
days. The cumulative mean cost of care was similar in the
CCTA group and the standard-evaluation group ($4289 and
$4060, respectively; p = 0.65).
The CT-COMPARE trial [ 76 ] was a single center large
randomized trial comparing CCTA to exercise ECG testing
(ExECG) in 562 patients with low-intermediate risk chest
pain subjects. ACS occurred in 24 (4 %) patients. Despite
higher odds of downstream testing in the CCTA arm (OR
2.0), 30 day per-patient cost was signifi cantly lower in the
CCTA group ($2193 vs $2704, p < 0.001). The length of stay
of patients in the CCTA arm was signifi cantly shorter
(p < 0.0005). No patient had post-discharge cardiovascular
events at 30 days.
Value of CCTA in the Patient with Suspected ACS
How might the results of these four trials be interpreted with
respect to “value”? In aggregate, the results are consistent
with respect to the major fi ndings. Overall, both CCTA and
standard of care approaches are successful in assuring a low
risk of missed events or of early events after discharge.
Regarding outcomes, while “hard outcomes” of death or
myocardial infarction were not different, improved outcomes
would include the patient benefi t of rapid discharge and the
effect of their rapid discharge on improved care of other
patients in a busy ED environment. An effect that has not yet
been adequately assessed is the potential of the CCTA
approach to reduce both short term and long term costs.
Since extensive data has now shown that patients with completely normal CCTA studies have an extremely low rate of
subsequent ACS over a prolonged period of time, there may
be fewer repeat visits to the ED by patients with normal studies, who might be less concerned about their recurrent chest
symptoms. In this regard, the downstream long term effects
of knowledge about the presence of non-obstructive CAD—
if effectively explained to the patient—may have the effect
of increasing preventive treatment and improving outcomes.
Thus, the “value proposition” for the use of CCTA in the ED
is likely to be positive for application in the correctly selected
patient (Fig. 20.16 ). It is of great interest, however, that as of
2015, the largest insurance carrier in the United States—
Wellpoint—has a national medical policy (with effective
date 10/08/2013) that the use of CCTA “is considered investigational and not medically necessary for…diagnosis of
CAD, in individuals with acute or non-acute symptoms” [ 77 ]
(reference “Anthem; Medical Policy #: RAD 00035 Last
Review Date: 02/05/2015”).
Evaluation of the Symptomatic Patient
with Suspected Stable Ischemic Heart Disease
(SIHD)
Chest discomfort or other symptoms raising the possibility
of angina are among the most common problems confronting
primary care physicians and cardiologists. While stress
testing, usually with imaging, is the most common manner in
which patients with suspected SIHD are evaluated, the use of
CCTA is rapidly growing in this setting. In these patients, the
reason for testing is twofold: (1) establishing the diagnosis
explaining the symptoms so as to institute the appropriate
medical therapy and (2) assessing potential benefi t from
revascularization. Despite the youth of the method—with
CCTA being introduced with 64 slice scanners only in
2005—an impressive body of evidence has been accumulated
documenting the effectiveness of CCTA not only for establishing the diagnosis but in assessing the risk of events.
As noted above, CCTA has higher sensitivity and speci-
fi city for angiographically signifi cant disease noted above
Fig. 20.16 Hypothesized value of using CCTA in patients with acute
chest pain. ED emergency department
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when compared to other forms of testing. Regarding risk of
cardiac events, strong prognostic power of CCTA has been
consistently demonstrated. A large number of manuscripts
have been published from the CONFIRM registry, which as
of 2015 was comprised of more than 32,000 patients evaluated in six countries, in whom comprehensive clinical, scan,
and outcome data were recorded [ 78 ]. Data elements
included risk factors, symptom type, CCTA results interpreted in 16 coronary segments for plaque, plaque type, and
stenosis severity (0 = normal; 1 = 1 to <50 % stenosis; 2 = 50
to <70 % stenosis, and 3 = ≥70 % stenosis). The number of
vessels with ≥50 % stenosis, a modifi ed Duke score which
added the location of the stenosis, a segment involvement
score (SIS)—the number from 0 to 16 of segments with
plaque, and a summed severity score (SSS), accounting for
the severity of stenosis and the number of segments involved,
ranging from 0 to 48. In the seminal article from CONFIRM,
Min et al. reported analysis of 23,854 patients without known
CAD who underwent a 2.3 year follow-up [ 78 ]. This early
study demonstrated that the mortality rate in patients with
entirely normal CCTA studies was extremely low, and that
with every degree of increasing abnormality, mortality rate
increased. Importantly, there was signifi cant increase in mortality in the patients with non-obstructive CAD progressively
increasing according to anatomic extent and severity of nonobstructive CAD (Fig. 20.17 ). This increase was noted for
the number of vessels with greater than 50 % stenosis, the
modifi ed Duke score, the SIS, and the SSS. These increases
in mortality with each increasing degree of anatomic abnormality were observed in men and women. Since this publication, consistent fi ndings have been reported from CONFIRM
across multiple patient subgroups, ranging from patients
with no risk factors [ 79 ] to patients with abnormal left ven-
tricular function [ 80 ]. In a group of 15,187 patients from
CONFIRM in whom MACE events were recorded (death,
myocardial infarction, and late revascularization), this
graded relationship between events and observed degree of
CAD by CCTA was also seen [ 81 ]. A long “warranty period”
for patients with a normal has been described: the annual
event rate of patients with a normal CCTA study has been
reported in multiple studies to be less than 0.25 %.
Two large randomized clinical trials comparing CCTA to
a SOC approach have recently been reported. The Scot-Heart
Trial [ 82 ] examined 4138 patients aged 18–75 presenting to
12 rapid access chest pain centers in Scotland who were randomized to CCTA vs a SOC approach. The median follow up
time was 1.7 years. Of note, 85 % of the patients had already
had stress ECG testing at the time of randomization. The primary endpoint was certainty of the diagnosis of angina secondary to coronary heart disease at 6 weeks. From 2010 to
2014, the study randomized 4146 (42 %) of 9849 patients
who had been referred for assessment of suspected angina
due to CHD. At baseline, 47 % of participants had a clinic
diagnosis of CHD and 36 % were considered to have angina
due to CHD. At 6 weeks, CTCA reclassifi ed the diagnosis of
CHD in 558 (27 %) patients and the diagnosis of angina due
to CHD in 481 (23 %) patients (p <0.0001). Regarding the
presence of CHD, physician certainty increased (p < 0.0001)
and the frequency of CHD increased (p = 0·0172). Regarding
diagnosis of angina due to CHD, the certainty increased (p
< 0.0001). The fi ndings changed planned investigations (in
15 vs 1 %; p <0.0001) and treatments (23 vs 5 %; p <0.0001)
(Fig. 20.18 ), but did not affect 6-week symptom severity or
subsequent admittances to hospital for chest pain. After
1.7 years, CTCA was associated with a 38 % reduction in
fatal and non-fatal myocardial infarction (26 vs 42, HR 0.62,
95 % CI 0.38–1.01; p = 0.053), close to, but missing, statistical signifi cance (Fig. 20.18 ). The overall conclusion of the
trial was the CCTA changed and clarifi ed diagnosis in one of
four patients, altered subsequent investigations in one of six,
changed treatment in one of four and showed a trend toward
reduction of fatal and non-fatal MI.
The PROMISE trial [ 83 ] evaluated 10,003 symptomatic
patients (60.8 ± 8.3 years, 52.7 % were women, 87.7 %
symptomatic) with no prior CAD who were referred for
noninvasive testing, randomizing them to CCTA (n = 4686)
or functional testing (n = 4692) with stress nuclear (67.3 %),
stress echo (22.5 %), or stress ECG alone (10.2 %). The
composite primary end point was death, myocardial infarction, hospitalization for unstable angina, or major procedural
complication. Secondary end points included invasive cardiac catheterization that did not show obstructive CAD and
radiation exposure. The mean pretest likelihood of obstructive CAD by the Diamond-Forrester classifi cation was
53.3 ± 21.4 %. However, the observed prevalence of ≥50 %
stenosis on CCTA in the CCTA arm was only 11.3 %.
Over a median follow-up period of 25 months, a primary
Prognostic Value of CCTA CAD Extent / Severity
23,854 patients w/o known CAD (57±13 years), 2.3 year f/u
1.00
0.98
0.96
0.94
0.92
Survival Probability
0.90
0.0 0.5 1.0 1.5
Survival Time (Years)
2.0 2.5 3.0
3-Vessel/Left Main
p<0.0001
p<0.001
p<0.0001
2-Vessel
1-Vessel
CAD
CAD
Normal
Non-Obstructive
p<0.0001
Fig. 20.17 Unadjusted All-Cause Kaplan-Meier Survival by the presence, extent, and severity of CAD by CCTA. Note the dose- response
relationship of mortality to increasing numbers of vessels with obstructive coronary artery disease ( CAD ). f/u follow-up (Reprinted from Min
et al. [ 78 ] with permission from Elsevier)
20 Value Based Imaging for Coronary Artery Disease: Implications for Nuclear Cardiology and Cardiac CT
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366
end-point event occurred in 3.3 % of the CCTA group and
3.0 % in the functional-testing group (p = ns). No signifi cant
difference was also shown in subsequent death or non-fatal
MI. While invasive coronary angiography was more common within 90 days after testing in the CCTA group (12.2 vs.
8.1 %), CCTA was associated with fewer catheterizations
showing no obstructive CAD than was functional testing (3.4
vs. 4.3 %, P = 0.02). Although the trial was not powered for
non-inferiority, this large trial suggests that a strategy of initial CCTA is not inferior to the more commonly employed
functional strategy with respect to short term cardiac events
in a relatively low risk, symptomatic population.
The infl uence of CCTA on subsequent management is
illustrated in case examples on Fig. 20.19 . When the fi ndings
of CCTA are completely normal, treatment and subsequent
testing is clear. The very high negative predictive value—the
defi nitive ability to rule out CAD and the associated long
“warranty period”—is a principal driving force in the
application of CCTA. As with CAC scanning, the fi nding of
non-obstructive CAD may prompt the use of aggressive
preventive measures, which is likely to ultimately improve
long term outcomes. When a proximal high grade stenosis is
found, direct referral for invasive coronary angiography
would likely follow. Stress imaging after CCTA may be
useful in guiding the decisions in patients with borderline
coronary stenosis (50–69 %), non-diagnostic CCTA results,
and possibly patients with signifi cant but not critical stenosis
to evaluate the presence and extent and severity of ischemia
as a guide to potential benefi t from revascularization. As discussed above, FFRCT is an alternative approach to assessment of lesions associated with diagnostic uncertainty. An
approach to the symptomatic patient with an intermediate
pretest likelihood of CAD, based on using CCTA as the initial test is shown schematically in Fig. 20.20 .
Value of CCTA and Stress Imaging in the Patient
with Suspected Stable Ischemic Heart Disease
How might the results of these the current evidence be interpreted with respect to “value” of CCTA and stress imaging in
suspected SIHD? A conceptual approach to the symptomatic
patient with an intermediate pretest likelihood of CAD,
based on using CCTA as the initial test, is shown in Fig. 20.21 .
The value will likely depend on the correct selection of
patients for testing. Consistent large registry data provide
evidence of excellent risk stratifi cation by CCTA. The ScotHeart trial suggested a possible benefi t with respect to outcomes, and important changes in confi dence of diagnosis
and changes in therapy. The PROMISE trial provided evidence that CCTA has similar outcomes compared to a functional approach in a patient group with a low prevalence of
CAD. It is reasonable to hypothesize that in the low-intermediate likelihood of obstructive CAD group, there may be an
outcome benefi t as suggested by Scot-Heart, or outcomes
might be unchanged as suggested by PROMISE. CCTA
strategy will likely be less costly than a functional strategy,
despite an increase in the rate of revascularization
(Fig. 20.21 ). The greatest cost savings might be in patients
with entirely normal studies—as the benign prognosis associated with the completely normal study, commonly seen in
the patients being sent for testing, becomes more widely
appreciated. In these patients, it is likely that the frequency
repeat functional tests will be lower than with the functional
CTCA and Clinical Outcome
1.7 Years of Follow-up
CHD Death, Non-Fatal MI
and Non-fatal Stroke
CHD Death and Non-Fatal MI
HR 0.64 [0.41-1.01], P=0.056
HR 0.62 [0.38-1.01], P=0.053
0123
Follow up
(years)
0123
Follow up
(years)
Proportion of patients
with an event (%)
Proportion of patients
with an event (%)
CTCA
Standard Care
Standard Care 2073 1550 837 316 Standard Care 2073 1547 835 315
Standard Care
CTCA CTCA 2073 1569 851 3212073 1571 853 323
CTCA
5
4
3
2
1
0
5
4
3
2
1
0
Fig. 20.18 Results of the
Scot Heart Trial. KaplanMeier curves for CHD death
and myocardial infarction
( left ) and CHD death,
myocardial infarction, and
stroke ( right ) in patients
assigned to CTCA ( blue ) and
standard care ( red ) (Adapted
with permission from the
Newby et al. Lancet , 2015
under a Creative Commons
Attribution license)
D.S. Berman et al.
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