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Coronary Computed Tomography Angiography (CCTA), Including Noninvasive Fractional Flow Reserve (FFR)
Medical Policies
Pending Policies - Radiology
Coronary Computed Tomography Angiography
(CCTA), Including Noninvasive Fractional Flow Reserve
(FFR)
Number: RAD604.007
Effective Date:
12-01-2017
Coverage:
*CAREFULLY CHECK STATE REGULATIONS AND/OR THE MEMBER CONTRACT*
Contrast-Enhanced Coronary Computed Tomography Angiography
Contrast-enhanced coronary computed tomography angiography (CCTA) for evaluation of
individuals without known coronary artery disease (CAD) who present with acute chest pain in
the emergency room or emergency department setting may be considered medically
necessary.
Contrast-enhanced CCTA for evaluation of symptomatic individuals with suspected ischemic
heart disease, who meet guideline criteria for a noninvasive test in the outpatient setting may
be considered medically necessary (refer to NOTE 1 below).
NOTE 1: A noninvasive test should be performed on individuals with at least intermediate risk
for coronary artery disease (10%-90% risk by standard risk prediction instruments/pre-test
probability assessments). The choice of test will depend on:
1. Interpretability of the electrocardiogram; and
2. Ability to exercise; and
3. Presence of comorbidities.
(Class I recommendation from the 2012 American College of Cardiology Foundation/American
Heart Association Task Force on use of noninvasive testing in patients with suspected stable
ischemic heart disease. See the Description section for definitions, guidelines, and pre-test
probability assessment identified by the Task Force.)
Contrast-enhanced CCTA for evaluation of anomalous (native) coronary arteries in individuals in
whom abnormal coronary arteries are suspected may be considered medically necessary.
CCTA, with or without contrast enhancement, as an adjunct to other testing, may be
considered medically necessary for the evaluation of cardiac structure and function to:
• Assess complex congenital heart disease, including anomalies of coronary circulation, great
vessels, and cardiac chambers and valves; OR
• Assess suspected arrhythmogenic right dysplasia, left ventricular function when
cardiomyopathy is suspected or established, and right ventricular function when right ventricular
dysfunction is suspected in individuals with technically limited images from echocardiography
(ECG), magnetic resonance imaging (MRI), or transesophageal echocardiography (TEE); OR
• Assess suspected or established dysfunction of prosthetic cardiac valves in individuals with
technically limited images from ECG, MRI, or TEE; OR
• Assess coronary arteries in individuals with new onset heart failure when ischemia is the
suspected etiology and cardiac catheterization and nuclear stress test are not planned; OR
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• Assess a cardiac mass (suspected tumor or thrombus) in individuals with technically limited
images from ECG, MRI, or TEE; OR
• Assess a pericardial condition (such as, pericardial mass, constrictive pericarditis, pericardial
effusion, or complications of cardiac surgery in patients) with technically limited images from
ECG, MRI, or TEE; OR
• Perform non-invasive coronary vein mapping prior to placement of a biventricular pacemaker;
OR
• Perform non-invasive coronary arterial mapping, including internal mammary artery prior to
repeat cardiac surgical revascularization; OR
• Evaluate pulmonary vein anatomy prior to invasive radiofrequency ablation for atrial
fibrillation; OR
• Evaluate cardiac aneurysm and pseudoaneurysm; OR
• Evaluate thoracic aortic aneurysm (TAA) (such as suspected aneurysm in individuals who
have not undergone computed tomography (CT) or MRI within the preceding 60 days,
confirmed TAA in individuals with new or worsening symptoms, or suspected aortic dissection
(with or without worsening symptoms or pre-operative planning); OR
• Assess coronary arteries in asymptomatic patients scheduled for open heart surgery for
valvular heart disease in lieu of invasive coronary arteriography.
CCTA, with or without contrast enhancement, for coronary artery evaluation is considered
experimental, investigational and/or unproven for all other indications, including but not
limited to:
• Screening asymptomatic individuals for CAD; OR
• Evaluating asymptomatic individuals with cardiac risk factors in lieu of cardiac evaluation and
standard non-invasive cardiac testing; OR
• Evaluating individuals for any other indication not listed above, including but not limited to
high or low pretest probability (low risk defined as <10% and high risk as >90%) of CAD.
CCTA performed using a multi-detector row CT scanner with less than 64-slice scanner is
considered experimental, investigational and/or unproven.
Noninvasive Fractional Flow Reserve Computed Tomography
The use of noninvasive fractional flow reserve (FFR) following a positive CCTA may be
considered medically necessary to guide decisions about the use of invasive coronary
angiography in patients with stable chest pain at intermediate risk (refer to NOTE 1 above) of
CAD (i.e., suspected or presumed stable ischemic heart disease).
The use of noninvasive FFR computed tomography (FFR
) simulation not meeting the criteria
CT
above is considered experimental, investigational and/or unproven.
NOTE 2: If CT imaging is done of the blood vessels it is not necessarily a CCTA. A CCTA must
include reconstruction post-processing of the angiographic images and interpretations, which is
a key distinction between a CCTA and conventional CT. If the reconstruction post-processing is
not done, it is not considered a CCTA study.
NOTE 3: For any CT to detect coronary artery calcification, see policy RAD604.009.
Description:
Contrast-enhanced coronary computed tomography angiography (CCTA) is a noninvasive
imaging test that requires the use of intravenously administered contrast material and high-
resolution, high-speed computed tomography (CT) machinery to obtain detailed volumetric
images of blood vessels. It is a potential diagnostic alternative to current tests for cardiac
ischemia (i.e., noninvasive stress testing and/or invasive coronary angiography [ICA]).
Background
Contrast-Enhanced Coronary Computed Tomography Angiography
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A variety of noninvasive tests are used to diagnose coronary artery disease (CAD). They can be
broadly classified as those that detect functional or hemodynamic consequences of obstruction
and ischemia (exercise treadmill testing, myocardial perfusion imaging [MPI], stress
echocardiography with or without contrast), and others that identify the anatomic obstruction
itself (CTA, coronary magnetic resonance imaging [MRI]). (1) Functional testing involves
inducing ischemia by exercise or pharmacologic stress and detecting its consequences.
However, not all patients are candidates. For example, obesity or obstructive lung disease can
make obtaining echocardiographic images of sufficient quality difficult. Conversely, the presence
of coronary calcifications can impede detecting coronary anatomy with CTA.
Some tests will be unsuitable for particular patients. The presence of dense arterial calcification
or an intracoronary stent can produce significant beam-hardening artifacts and may preclude a
satisfactory imaging. The presence of an uncontrolled rapid heart rate or arrhythmia hinders the
ability to obtain diagnostically satisfactory images. Evaluation of the distal coronary arteries is
generally more difficult than visualization of the proximal and mid-segment coronary arteries
due to greater cardiac motion and the smaller caliber of coronary vessels in distal locations.
Evaluation of obstructive CAD involves quantifying arterial stenoses to determine whether
significant narrowing is present. Lesions with stenosis more than 50% to 70% in diameter
accompanied by symptoms are generally considered significant. It has been suggested that
CCTA may help rule out CAD and avoid ICA in patients with a low clinical likelihood of
significant CAD. Also of interest is the potential important role of non-obstructive plaques (i.e.,
those associated with <50% stenosis) because their presence is associated with increased
cardiac event rates. (2) CCTA also can visualize the presence and composition of these
plaques and quantify plaque burden better than conventional angiography, which only visualizes
the vascular lumen. Plaque presence has been shown to have prognostic importance.
Congenital coronary arterial anomalies (i.e., abnormal origin or course of a coronary artery) that
lead to clinically significant problems are relatively rare. Symptomatic manifestations may
include ischemia or syncope. Clinical presentation of anomalous coronary arteries is difficult to
distinguish from other more common causes of cardiac disease; however, an anomalous
coronary artery is an important diagnosis to exclude, particularly in young patients who present
with unexplained symptoms (e.g., syncope). There is no specific clinical presentation to suggest
a coronary artery anomaly.
Levels of radiation delivered with current generation scanners using reduction techniques
(prospective gating and spiral acquisition) have declined substantially - typically to under 10
mSv. For example, an international registry developed to monitor CCTA radiation exposure
recently reported a median of 2.4 mSv (interquartile range, 1.3-5.5). (3) By comparison,
radiation exposure accompanying rest-stress perfusion imaging ranges varies by isotope used -
approximately 5 mSv for rubidium-82 (positron emission tomography [PET]), 14 mSv for
fluorodeoxyglucose fluorine 18 (PET), 9 mSv for sestamibi (single-photon emission computed
tomography [SPECT]), and 41 mSv for thallium; during diagnostic invasive coronary
angiography, approximately 7 mSv is delivered. (4) Electron beam computed tomography
(EBCT) using electrocardiogram (ECG) triggering delivers the lowest dose (0.7-1.1 mSv with 3-
mm sections). Any cancer risk due to radiation exposure from a single cardiac imaging test
depends on age (higher with younger age at exposure) and sex (greater for women). (5-7)
Empirical data have suggested that every 10 mSv of exposure is associated with a 3% increase
in cancer incidence over 5 years. (8)
American College of Cardiology (ACC) and American Heart Association (AHA) Guidelines and
Definitions:
In 1999, the ACC and the AHA released a joint scientific statement describing the assessment
of cardiovascular or coronary heart disease (CHD) risk to categorize patients for selection of
appropriate interventions (available in the ACC website <http://www.acc.org>). (24) The
statement defines CHD, as derived from the Framingham Heart Study, to include angina
pectoris, unstable angina or coronary insufficiency, and unrecognized myocardial infarction (MI)
(defined by EKG). The ACC/AHA scientific statement further states, “The first step in
determining the patient’s risk is to calculate the number of Framingham points for each risk
factor”, by using the Framingham Global Risk Assessment Scoring:
Table 1. Framingham Global Risk Assessment Scoring and Calculating Final Score
Risk Factor
Risk Points
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Men
Women
Age by year:
Less than 34
-1
-9
35 - 39
0
-4
40 - 44
1
0
45 - 49
2
3
50 - 54
3
6
55 - 59
4
7
60 - 64
5
8
65 - 69
6
8
70 - 74
7
8
Total Cholesterol, mg/dL*:
Less than 160
-3
-2
169 - 199
0
0
200 - 239
1
1
240 - 279
2
2
Greater than or equal to 280
3
3
HDL cholesterol, mg/dL*:
Less than 35
2
5
35 - 44
1
2
45 - 49
0
1
50 - 59
0
0
Greater than or equal to 60
-2
-3
Systolic blood pressure, mm Hg**:
Less than 120
0
-3
120 - 129
0
0
130 - 139
1
1
140 - 159
2
2
Greater than 160
3
3
Diabetes:
No
0
0
Yes
2
4
Smoker:
No
0
0
Yes
2
2
Adding Up the Points
Age:
Cholesterol:
HDL - C:
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Blood Pressure:
Diabetes:
Smoker:
Total Points:
Table Key:
* mg dL = milligrams/deciliter
** mm Hg = millimeter of mercury as it relates to a unit of pressure equal to 0.001316
atmosphere.
Additionally, the 1999 ACC/AHA scientific statement explained the following tables as
demonstrating the relative and absolute risk estimates for CHD in men and women as
determined for Framingham scoring, including this explanation for table information, “Relative
risk estimates for each age range are compared with baseline risk conferred by age alone (in
the absence of other major risk factors).” (24) Additionally, described was, “Average risk refers
to that observed in the Framingham population. Absolute risk estimates are given in the two
right hand columns. Absolute risk is expressed as the percentage likelihood of developing CHD
per decade. Total CHD risk equates to all forms of clinical CHD, whereas hard CHD includes
clinical evidence of MI and coronary death. Hard CHD estimates are approximated from
published Framingham data.”
In the following grids, the intermediate risk estimates (classified as moderately above average
risk) will be identified as bolded and high risk as underlined. Following the last grid (for
women), the keys for these symbols “*”, “#”, “++”, and “**” will be defined below the last table.
Table 2. Intermediate Risk Estimates for Men and Women
MEN
Age
30-
35-39
40-44
45-49
50-54
55-
60-
65-69
70-74
34
59
64
Low
(2%
(3%)
(3%)
(4%)
(5%)
(7%)
(8%)
(10%)
(13%)
Absolute
Absolute
Risk
Risk
Risk ++
Level*
Points#
Total
Hard
CHD++
CHD**
0
1.0
2%
2%
1
1.5
1.0
1.0
3%
2%
2
2.0
1.3
1.3
1.0
4%
3%
3
2.5
1.7
1.7
1.3
1.0
5%
4%
4
3.5
2.3
2.3
1.8
1.4
1.0
7%
5%
5
4.0
2.6
2.6
2.0
1.6
1.1
1.0
8%
6%
6
5.0
3.3
3.3
2.5
2.0
1.4
1.3
1.0
10%
7%
7
6.5
4.3
4.3
3.3
2.6
1.9
1.6
1.3
1.0
13%
9%
8
8.0
5.3
5.3
4.0
3.2
2.3
2.0
1.6
1.2
16%
13%
9
10.0
6.7
6.7
5.0
4.0
2.9
2.5
2.0
1.5
20%
16%
10
12.5
8.3
8.3
6.3
5.0
3.6
3.1
2.5
1.9
25%
20%
11
15.5
10.3
10.3
7.8
6.1
4.4
3.9
3.1
2.3
31%
25%
12
18.5
12.3
12.3
9.3
7.4
5.2
4.6
3.7
2.8
37%
30%
13
22.5
15.0
15.0
11.3
9.0
6.4
5.6
4.5
3.5
45%
35%
>14
26.5
>17.7
>17.7
>13.3
>10.6
>7.6
>6.6
>5.3
>4.1
>53%
>45%
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WOMEN
Age
40-44
45-49
50-54
55-59
60-64
65-69
70-74
Low
(2%)
(3%)
(5%)
(7%)
(8%)
(8%)
(8%)
Absolute
Absolute
Risk
Risk
Risk ++
Level*
Points#
Total
Hard
CHD++
CHD**
0
1.0
2%
1%
1
1.0
2%
1%
2
1.5
1.0
3%
2%
3
1.5
1.0
3%
2%
4
2.0
1.3
4%
2%
5
2.0
1.3
4%
2%
6
2.5
1.7
1.0
5%
2%
7
3.0
2.0
1.2
6%
3%
8
3.5
2.3
1.4
1.0
7%
3%
9
4.0
2.7
1.6
1.1
1.0
1.0
1.0
8%
3%
10
5.0
3.3
2.0
1.4
1.3
1.3
1.3
10%
4%
11
5.5
3.7
2.2
1.6
1.4
1.4
1.4
11%
7%
12
6.5
4.3
2.6
1.9
1.6
1.6
1.6
13%
8%
13
7.5
5.0
3.0
2.1
1.9
1.9
1.9
15%
11%
14
9.0
6.0
3.6
2.6
2.3
2.3
2.3
18%
13%
15
10.0
6.7
4.0
2.9
2.5
2.5
2.5
20%
15%
16
12.0
8.0
4.8
3.4
3.0
3.0
3.0
24%
18%
>17
>13.5
>9.0
>5.4
>3.9
5.4
5.4
5.4
>27%
>20%
Table Key:
* Low absolute risk level = 10-year risk for CHD end points for the person the same age, blood
pressure less than 120 mm Hg systolic and less than 80 mm Hg diastolic, serum total
cholesterol - 160 to 199 mg/dL, LDL-C - 100 to 129 mg/dL (LDL = low-density lipoprotein), HDL-
C - greater or equal to 45 mg/dL in men and greater or equal to 55 mg/dL in women,
nonsmoker, and no diabetes mellitus. Percentages show 10-year absolute risks for total CHD
endpoints.
# Points = number of points estimated from the Framingham Global Risk Assessment Scoring.
++ 10-year absolute risk for total CHD end points estimated from the Framingham data
corresponding to the Framingham (Global Risk Assessment Scoring) points.
** 10-year absolute risk for hard CHD end points approximated from the Framingham data
corresponding to the Framingham (Global Risk Assessment Scoring) points.
In 2010, the ACC and the AHA released a joint scientific report describing the appropriate use
criteria for CCTA. (57) Within the joint report, ACC/AHA defined the following risk and probability
terminology:
• Absolute risk - the probability of developing CHD, including myocardial infarction (MI) or CHD
death over a given period of time. The National Heart, Lung, and Blood Institute specifies
absolute risk for CHD as being over the next 10 years, referring to 10-year risk for any hard-
cardiac event.
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• CHD Risk-Low - the age-specific risk level that is below average. In general, low risk will
correlate with a 10-year absolute CHD risk <10%.
• CHD Risk-Intermediate - the age-specific risk level that is average or above average. In
general, moderate risk will correlate with a 10-year absolute CHD risk ranging from 10% to
20%. Among women and younger men, an expanded intermediate risk range of 6% to 20%
may be appropriate.
• CHD Risk-High - the presence of diabetes mellitus in a patient ≥ 40 year of age, peripheral
artery disease or other coronary risk equivalents, or the 10-year absolute CHD risk of > 20%.
• Pretest probability - the likelihood of the presence of a condition before a diagnostic test.
• Very low pretest probability - < 5% pretest probability of CAD.
• Low pretest probability - < 10% pretest probability of CAD.
• Intermediate pretest probability - Between 10% and 90% pretest probability of CAD.
• High pretest probability - > 90% pretest probability of CAD.
• Typical angina (definite) - substernal chest pain, or ischemic equivalent discomfort that is
provoked by exertion or emotional stress AND relieved by rest and/or nitroglycerin.
• Atypical angina (probable) - chest pain or discomfort with two characteristics of definite or
typical angina.
• Non-anginal chest pain - chest pain or discomfort that meets one or none of the typical
anginal characteristics.
• Acute coronary syndrome - includes those patients whose clinical presentations covering the
following range of diagnoses: unstable angina, MI without ST-elevation, and MI with ST-
elevation.
• EKG (uninterpretable) - EKG with resting ST-segment depression, complete left bundle-
branch block, pre-excitation (Wolff-Parkinson-White syndrome), or paced rhythm.
• Able to exercise - able to complete a diagnostic exercise treadmill examination.
The ACC/AHA also provided clinicians, within the 2010 guidelines, a pretest probability of CAD
by age, sex, and symptoms table to make their assessments, using the pretest categories of
very low, low, intermediate, and high as defined just above (10):
Table 3. Pretest Probability of Coronary Artery Disease
Age
Sex
Typical/Definite
Atypical/Probable
Non-Anginal
Asymptomatic
Angina Pectoris
Pain
Angina Pectoris
< 39
Men
Intermediate
Intermediate
Low
Very Low
< 39
Women
Intermediate
Very Low
Very Low
Very Low
40-
Men
High
Intermediate
Intermediate
Low
49
40-
Women
Intermediate
Low
Very Low
Very Low
49
50-
Men
High
Intermediate
Intermediate
Low
59
50-
Women
Intermediate
Intermediate
Low
Very Low
59
> 60
Men
High
Intermediate
Intermediate
Low
> 60
Women
High
Intermediate
Intermediate
Low
Regulatory Status
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Coronary Computed Tomography Angiography (CCTA), Including Noninvasive Fractional Flow Reserve (FFR)
Multidetector-row helical CT (MDCT) or multi-slice CT scanning is a technologic evolution of
helical CT, which uses CT machines equipped with an array of multiple x-ray detectors that can
simultaneously image multiple sections of the patient during a rapid volumetric image
acquisition. MDCT machines currently in use have 64 or more detectors. CCTA is performed
using MDCT, and multiple manufacturers have been cleared for marketing by the U.S. Food and
Drug Administration (FDA) 510(k) clearance process. Current machines are equipped with at
least 64 detector rows. Lower detector row machines are no longer used for CCTA. Intravenous
iodinated contrast agents used for CCTA also have received FDA approval.
Noninvasive Fractional Flow Reserve Computed Tomography
A noninvasive imaging test, performed prior to ICA as a gatekeeper, that can distinguish
candidates who may benefit from early revascularization (e.g., patients with unprotected left
main stenosis ≥50% or hemodynamically significant disease) from those unlikely to benefit
could avoid unnecessary invasive procedures and their potential adverse consequences.
Gatekeepers to ICA
Imposing an effective noninvasive gatekeeper strategy with one or more tests before planned
ICA to avoid unnecessary procedures is compelling. The most important characteristic of a
gatekeeper test is its ability to accurately identify and exclude clinically insignificant disease
where revascularization would offer no potential benefit. From a diagnostic perspective, an
optimal strategy would result in few false-negative tests while avoiding an excessive false-
positive rate, it would provide a low posttest probability of significant disease. Such a test would
then have a small and precise negative likelihood ratio and high negative predictive value. An
effective gatekeeper would decrease the rate of ICA while increasing the diagnostic yield
(defined by the presence of obstructive CAD on ICA). At the same time, there should be
no increase in major adverse cardiac events. A clinically useful strategy would satisfy these
diagnostic performance characteristics and impact the outcomes of interest. Various tests have
been proposed as potentially appropriate for a gatekeeper function prior to planned ICA,
including CCTA, MRI, SPECT, PET, and stress echocardiography (SECHO). More recently,
adding noninvasive measurement of fractional flow reserve (FFR) using CCTA has been
suggested, combining functional and anatomic information.
Fractional Flow Reserve
Invasive FFR is rarely used in the U.S. to guide percutaneous coronary intervention (PCI). For
example, using the National Inpatient Sample, Pothineni et al. (2016) reported that 201,705
PCIs were performed in 2012, but just 21,365 FFR procedures. (66) Assuming the intention of
FFR is to guide PCI, it would represent just 4.3% of PCI procedures. Whether noninvasively
obtained FFR will influence decisions concerning ICA, over and above anatomic considerations,
is therefore important to empirically establish.
Randomized controlled trials (RCTs) and observational studies have demonstrated that FFR-
guided revascularization can improve cardiovascular outcomes, reduce revascularizations, and
decrease costs. (67) For example, the Fractional Flow Reserve versus Angiography for Multi-
Vessel Evaluation (FAME) trial randomized 1005 patients with multi-vessel disease and planned
PCI. (65, 68) At 1 year, compared with PCI guided by angiography alone, FFR-guided PCI
reduced the number of stents placed by approximately 30% - followed by lower rates (13.2%
versus 18.3%) of major cardiovascular adverse events (myocardial infarction, death, repeat
revascularization) and at a lower cost. The clinical benefit persisted through 2 years, although
by 5 years events rates were similar between groups. (69)
European guidelines (2013) for stable CAD have recommended that FFR be used “to identify
hemodynamically relevant coronary lesion(s) when evidence of ischaemia is not available”
(class Ia), and “[r]evascularization of stenoses with FFR <0.80 is recommended in patients with
angina symptoms or a positive stress test.” (70) Guidelines (2014) have also recommended
using “FFR to identify haemodynamically relevant coronary lesion(s) in stable patients when
evidence of ischaemia is not available” (class Ia recommendation). (71) U.S. guidelines (2012)
have stated that an FFR of 0.80 or less provides level Ia evidence for revascularization for
“significant stenoses amenable to revascularization and unacceptable angina despite guideline
directed medical therapy.” (24) In addition, the importance of FFR in decision making appears
prominently in the 2017 appropriate use criteria for coronary revascularization in patients with
stable ischemic heart disease (SIHD). (72)
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Measuring FFR during ICA can be accomplished by passing a pressure-sensing guidewire
across a stenosis. Coronary hyperemia (increased blood flow) is then induced and pressure
distal and proximal to the stenosis is used to calculate flow across it. FFR is the ratio of flow in
the presence of a stenosis to flow in its absence. FFR levels less than 0.75 to 0.80 are
considered to represent significant ischemia while those 0.94 to 1.0 normal. Measurement is
valid in the presence of serial stenoses, is unaffected by collateral blood flow, (73) and
reproducibility is high. (74) Potential complications include adverse events related to catheter
use such as vessel wall damage (dissection); the time required to obtain FFR during a typical
ICA is less than 10 minutes.
FFR using CCTA requires at least 64-slice CCTA and cannot be calculated when images lack
sufficient quality (75) (11% to 13% in recent studies from Koo et al., 2011; Min et al., 2012;
Nakazato et al., 2013; Nørgaard et al., 2014 [76-79]), e.g., in obese individuals (e.g., body mass
index, >35 kg/m2). The presence of dense arterial calcification or an intracoronary stent can
produce significant beam-hardening artifacts and may preclude satisfactory imaging. The
presence of an uncontrolled rapid heart rate or arrhythmia hinders the ability to obtain
diagnostically satisfactory images. Evaluation of the distal coronary arteries is generally more
difficult than visualization of the proximal and mid-segment coronary arteries due to greater
cardiac motion and the smaller caliber of coronary vessels in distal locations.
FFR can be modeled noninvasively using images obtained during CCTA (80) - “so-called
fractional flow reserve using coronary computed tomography angiography” (FFR
; HeartFlow
CT
software termed FFR
; Siemens cFFR) using routinely collected CCTA imaging data. The
CT
process involves constructing a digital model of coronary anatomy and calculating FFR across
the entire vascular tree using computational fluid dynamics. FFRCT can also be used for “virtual
stenting” to simulate how stent placement would be predicted to improve vessel flow. (81)
Only the HeartFlow FFRCT software has been cleared by the FDA. Imaging analyses require
transmitting data to a central location for analysis, taking 1 to 3 days to complete. Other
prototype software is workstation-based with onsite analyses. FFRCT requires at least 64-slice
CCTA and cannot be calculated when images lack sufficient quality (82) (11% to 13% in recent
studies [76-79]), e.g., in obese individuals (e.g., body mass index, >35 kg/m2).
Regulatory Status
In November 2014, FFRCT simulation software (HeartFlow, Inc., Redwood City, California) was
cleared for marketing by the FDA through the de novo 510(k) process (class II, special controls;
FDA product code: PJA). In January 2016, the FFRCT v2.0 device was cleared through a
subsequent 510(k) process.
HeartFlow FFRCT post-processing software is cleared “for the clinical quantitative and
qualitative analysis of previously acquired Computed Tomography [CT] DICOM [Digital Imaging
and Communications in Medicine] data for clinically stable symptomatic patients with coronary
artery disease. It provides FFR
[fractional flow reserve using coronary computed tomography
CT
angiography], a mathematically derived quantity, computed from simulated pressure, velocity
and blood flow information obtained from a 3D computer model generated from static coronary
CT images. FFRCT analysis is intended to support the functional evaluation of coronary artery
disease. The results of this analysis [FFR
] are provided to support qualified clinicians to aid in
CT
the evaluation and assessment of coronary arteries. The results of HeartFlow FFRCT are
intended to be used by qualified clinicians in conjunction with the patient’s clinical history,
symptoms, and other diagnostic tests, as well as the clinician’s professional judgment.” (82)
Rationale:
This policy was created in 2007 and has been updated regularly with searches of peer reviewed
scientific literature in the MedLine database. The most recent literature search was done
through October 17, 2017. The following is a summary of the key literature.
Contrast-Enhanced Coronary Computed Tomography Angiography
The policy was originally based on a literature search from MedLine and the May 2005 Blue
Cross Blue Shield Association (BCBSA) Technology Evaluation Center (TEC) Assessment. (9)
The policy also contains several joint reports and guidelines from the American College of
Cardiology Foundation (ACCF), which includes key specialty and subspecialty societies. (57,
58, 59, 60) Additional BCBSA TEC Assessments in 2006 and 2011 were included in the review
of the key literature to date. (10, 11)
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NOTE 4: The societies represented within the task force are: the American College of
Cardiology (ACC), the American Heart Association (AHA), the American College of Radiology
(ACR), the Society of Cardiovascular Computed Tomography (SCCT), the American Society of
Echocardiography (ASE), the American Society of Nuclear Cardiology (ASNC), the North
American Society of Cardiovascular Imaging (NASCI), the Society of Cardiovascular
Angiography (SCA), and the Society of Cardiovascular Magnetic Resonance (SCMR). Within
this medical policy, reference to these reports and guidelines will be shown as ACC/AHA.
The objective of the 2005 BCBSA TEC Assessment was to evaluate the clinical effectiveness of
CTA using either electron beam computed tomography (EBCT) or multi-detector-row computed
tomography (MDCT) as a noninvasive alternative to invasive coronary angiography (ICA),
particularly in patients with a low probability of significant coronary artery stenosis. (9)
Evaluation of the coronary artery anatomy and morphology was the most frequent use of
cardiac CTA and primary focus of the TEC Assessment. The Assessment considered multiple
indications, but computed tomography (CT) technology used in studies reviewed is now
outdated (studies employed 16-slice scanners). The TEC Assessment concluded that the use of
contrast-enhanced cardiac CTA for screening or diagnostic evaluation of the coronary arteries
did not meet TEC criteria.
The 2006 BCBSA TEC Assessment was undertaken to determine the usefulness of cardiac
CTA as a substitute for ICA for 2 indications: in the diagnosis of coronary artery stenosis and in
the evaluation of acute chest pain in the emergency department (ED). (10) Seven studies in the
ambulatory setting and utilizing 40- to 64-slice scanners were identified. Two studies performed
in the ED used 4- or 16-slice scanners. Evidence was judged insufficient to form conclusions.
Available studies at the time were inadequate to determine the effect of cardiac CTA on health
outcomes for the diagnosis of coronary artery stenosis in patients referred for angiography or
for evaluation of acute chest pain in the ED.
Three major indications for cardiac or coronary CTA (CCTA) are considered in the current
policy:
1. Patients with acute chest pain without known coronary disease presenting in the ED setting,
2. Evaluation of stable patients with signs and symptoms of coronary artery disease (CAD) in
the non-ED setting, and
3. Evaluation of anomalous coronary arteries.
In 2016, the Agency for Healthcare Research and Quality (AHRQ) published a comparative
effectiveness review on noninvasive testing for CAD. (12) The review found that:
• After CCTA, clinical outcomes for patients with an intermediate pretest risk:
o Were similar when compared with usual care or functional testing (low-to-moderate strength
of evidence).
o Were similar when compared with single-photon emission computed tomography (SPECT)
(low strength of evidence).
• After CCTA, referral for ICA and revascularization:
o Was more common than after functional testing (high strength of evidence).
o Was similar compared with SPECT and usual care (low strength of evidence).
• After CCTA, additional testing in the ED setting:
o Was less common compared with usual care (moderate strength of evidence).
o Was more common than after SPECT (high strength of evidence).
• After CCTA, hospitalization:
o Was less common compared to usual care in the ED setting (moderate to low strength of
evidence).
o Was similar to functional testing in the outpatient setting (moderate strength of evidence).
Overall, the AHRQ review found no clear differences between strategies for clinical or
management outcomes, although CCTA may lead to a higher frequency of referral for ICA and
revascularization.
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In August 2016, noninvasive fractional flow reserve (FFR) using CTA (FFR
) was added to this
CT
medical policy and was based on literature search assessing the technical performance,
diagnostic accuracy, effect of FFRCT on patient outcomes, and postadoption studies.
Patients with Acute Chest Pain Presenting to the Emergency Setting: CCTA
Diagnostic Validity
The diagnostic characteristics of CCTA have not been directly assessed in patients in the ED
setting. Because patients who test negative on CCTA are discharged from care and their
disease status is unknown, there is verification bias and diagnostic characteristics of CCTA
cannot be determined. The diagnostic characteristics of CCTA, previously established in other
studies, were assumed to apply to patients in the ED setting and were tested in randomized
trials to establish clinical utility.
Effect on Health Outcomes
A 2011 BCBSA TEC Assessment examined evidence on patients with acute chest pain and
without known CAD. (11) Randomized controlled trials (RCTs) and prospective observational
studies were identified. RCTs of CCTA procedures conducted in ED settings are described in
Table 1.
A 2007 RCT by Goldstein et al. randomized 197 patients from a single center without evidence
of acute coronary syndromes to CCTA (n=99) or usual care (n=98). (13) Over a 6-month follow-
up, no cardiac events occurred in either arm. ICA rates were somewhat higher in the CCTA
arm. Diagnosis was achieved more quickly after CCTA.
The CT-STAT RCT evaluated a similar sample of 699 patients from 16 centers. (14) Over a 6-
month follow-up, there were no deaths in either arm; there were 2 cardiac events in the CCTA
arm and 1 in the perfusion imaging arm. ICA rates were similar in both arms. A second
noninvasive test was obtained more often after CCTA (10.2% versus 2.1%), but cumulative
radiation exposure in the CCTA arm (using retrospective gating) was significantly lower (mean,
11.5 mSv versus 12.8 mSv [millisievert]). Time to diagnosis was shorter and estimated ED costs
lower with CCTA.
A 2012 RCT (AC RIN-PA) by Litt et al. also evaluated the safety of CCTA in patients in the ED.
(15) Although the trial was a randomized comparison with traditional care, the principal outcome
was safety after negative CCTA examinations. No patients who had negative CCTA
examinations (n=460) died or had a myocardial infarction (MI) within 30 days. Compared with
traditional care, patients in the CCTA group had higher rates of discharge from the ED (49.6%
versus 22.7%), shorter lengths of stay, and higher rates of detection of coronary disease.
A 2012 RCT (ROMICAT II) by Hoffmann et al. compared length of stay and outcomes in
patients evaluated with CCTA versus usual care. (16) For patients in the CCTA arm, mean
length of hospital stay was reduced by 7.6 hours, and more patients were discharged directly
from the ED (47% versus 12%). There were no undetected coronary syndromes or differences
in adverse events at 28 days. However, in the CCTA arm, there was more subsequent
diagnostic testing and higher cumulative radiation exposure. Cumulative costs of care were
similar between groups.
A 2014 RCT (CT-COMPARE) by Hamilton-Craig et al. assessed length of stay and patient costs
in 562 patients presenting to the ED with low-to-intermediate risk chest pain who received
CCTA or exercise stress testing. (17) Costs within 30 days of presentation were significantly
lower in the CCTA group (mean, $2193) than in the exercise testing group (mean, $2704;
p<0.001). Length of stay was significantly reduced in the CCTA patients compared with the
exercise testing patients. Clinical outcomes at 30 days and at 12 months did not differ.
In 2015, Linde et al. reported long-term follow-up from the CATCH trial. (18, 19) This trial
randomized 600 patients to a CCTA-guided strategy or to standard of care (SOC). For the
CCTA-guided strategy, referral for ICA required coronary stenosis greater than 70%. This trial
differed in design from the other trials, because patients had been discharged from the ED, and
if there was intermediate stenosis (50%-70%) on CCTA, a stress test was used. The referral
rate for ICA was 17% for the CCTA strategy versus 12% with SOC (p=NS [not significant]). At a
median 18.7-month follow-up, a major cardiac event was observed in 5 patients in the CCTA-
strategy arm compared to 14 in the SOC group (hazard ratio [HR], 0.36; 95% confidence
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interval [CI], 0.16 to 0.95; p=0.04). Three other follow-up studies reported no cardiac events
after a negative CCTA in the ED after 12 (N=481), (20) 24 (N=368), (21) or 47 months (N=506).
(22)
Table 4. RCTs Comparing CCTA to SOC in the Evaluation of Acute Chest Pain
Study (year)
N
Study
FU,
MI in Neg
LOS,
ICA (CTA* vs
Design
mo
CTA* arm
Control)
h (p)
Goldstein et al.
197
CTA*
6
0
3.4 versus 15
12.1% versus
versus
7.1%
(2007) (13)
SPECT
Goldstein et al.
699
CTA*
6
0
2.9 versus
7.2% versus
versus
6.3
6.5%
(2011) (14)
SPECT
Litt et al.
1370
CTA*
1
0
18 versus 24
9.0% versus
versus
3.5%
(2012) (15)
SOC
Hoffmann et al.
1000
CTA*
1
0
23.2 versus
11% versus 7%
versus
30.8
(2012) (16)
SOC
Hamilton-Craig et al.
562
CTA*
12
0
13.5 versus
8.0% versus
versus
20.7
3.8%
(2014) (17)
SOC
(Adapted from Marcus et al. [2016]. [23])
Table Key:
SOC: standard of care;
N: number;
FU: follow-up;
mo: months;
MI: myocardial infarction;
Neg: negative;
CTA*: coronary computed tomography angiography;
LOS: length of stay;
h (p): hours, p-value;
ICA: invasive coronary angiography;
vs: versus;
SPECT: single-photon emission computed tomography.
Section Summary: Acute Chest Pain Presenting to the Emergency Setting: CCTA
The high negative predictive value (NPV) of CCTA in patients presenting to the ED with chest
pain permits ruling out coronary disease with high accuracy. The efficiency of the workup is
improved, because patients are safely and quickly discharged from the ED with no adverse
outcomes among patients with negative CCTA examinations.
Other important outcomes that require consideration in comparing technologies include ICA
rates, use of a second noninvasive test, radiation exposure, and follow-up of any incidental
findings. Some studies have shown that subsequent invasive testing is more frequent in
patients who received CCTA. Studies have differed over which treatment strategies result in
higher overall radiation exposure. Incidental findings after CCTA are common and lead to
further testing, but the impact of these findings on subsequent health outcomes is uncertain.
Stable Patients with Angina and Suspected CAD: CCTA
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Before use of CCTA, the initial noninvasive test in a diagnostic strategy was always a functional
test. Current practice guidelines recommend a noninvasive test be performed in patients with
intermediate risk of CAD. The choice of functional test is based on clinical factors such the
predicted risk of disease, electrocardiogram (ECG) interpretability, and ability to exercise. When
disease is detected, treatment alternatives include medical therapy or revascularization
(percutaneous coronary intervention [PCI] or coronary artery bypass graft [CABG] surgery). If
revascularization is indicated, patients undergo ICA to confirm the presence of stenosis. Which
approach to adopt is based on the extent of anatomic disease, symptom severity, evidence of
ischemia from functional testing, and, more recently, fractional flow reserve (FFR) obtained
during invasive angiography. Many studies have shown that only a subset of anatomically
defined coronary lesions are clinically significant and benefit from revascularization. Other
studies have shown only limited benefits of treating coronary stenoses in stable patients. Thus
an assessment of the diagnostic characteristics of CCTA alone is insufficient to establish clinical
utility. A difficulty in evaluating a noninvasive diagnostic test for CAD is that patient outcomes
depend not only on the test results, but also the management and treatment strategy. The most
convincing evidence of clinical utility compares outcomes after anatomic-first (CCTA) and
functional-first (e.g., perfusion imaging, stress echocardiography) strategies.
Relevant studies reviewed here include those comparing diagnostic performance of CCTA with
angiography, studies of outcomes of patients undergoing CTA versus alternative tests, and
studies of incidental findings and radiation exposure.
Diagnostic Accuracy
There is a fairly large body of evidence evaluating the diagnostic characteristics of CCTA for
identifying coronary lesions. The best estimate of the diagnostic characteristics of CCTA can be
obtained from recent meta-analyses and systematic reviews. Table 2 shows ranges of
sensitivity and specificity for functional noninvasive tests from studies of the diagnosis and
management of stable angina reviewed by Fihn et al. (24) Sensitivities tended to range between
70% and 90%, depending on the test and study, and specificities ranged between 70% and
90%.
For CCTA, estimates of sensitivity from various systematic reviews are considerably higher (see
Table 3). The guideline statement from Fihn et al. cited studies reporting sensitivities between
93% and 97%. (24) A meta-analysis by Ollendorf et al. of 42 studies showed a summary
sensitivity estimate of 98% and a specificity of 85%. (25) A meta-analysis of 8 studies
conducted by the Ontario Health Ministry showed a summary sensitivity estimate of 97.7% and
a specificity of 79%. (26) In the meta-analysis by Nielsen et al., sensitivity of CCTA varied
between 98% and 99% (depending on the analysis group). (27)
Table 5: Summary of Estimates of Sensitivity and Specificity of Functional Noninvasive
Tests from Recent Guideline Statement (Fihn et al. [24])
Noninvasive Test
Sensitivity (Range
Specificity (Range
or Single Estimates
or Single Estimate
Exercise electrocardiography
61%
70%-77%
Pharmacologic stress echocardiography
85%-90%
79%-90%
Exercise stress echocardiography
70%-85%
77%-89%
Exercise myocardial perfusion imaging
82%-88%
70%-88%
Pharmacologic stress myocardial perfusion
88%-91%
75%-90%
imaging
Table 6: Estimates of Sensitivity and Specificity of CCTA from Guidelines and Meta-
Analyses
Study
Sensitivity (Range
Specificity (Range
or Single Estimates
or Single Estimate
Fihn et al. (2012) guideline statement (24)
93%-97%
80%-90%
Ollendorf et al. (2011) meta-analysis (25)
98%
85%
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Health Quality Ontario (2010) meta-
97.7%
79%
analysis (26)
Nielsen et al. (2014) meta-analysis (27)
98%-99%
82%-88%
Effect on Health Outcomes - Randomized Controlled Trials
For patients at intermediate risk of CAD, 3 major RCTs were identified comparing net health
outcomes following a CCTA strategy with outcomes from other noninvasive testing strategies.
The PROMISE (PROspective Multicenter Imaging Study for Evaluation of Chest Pain) trial
randomized 10,003 patients to CCTA or exercise ECG, nuclear stress testing, or stress
echocardiography (as determined by physician preference) as the initial diagnostic evaluation.
(28) For the composite end point of death, MI, hospitalization for unstable angina, or major
procedural complication, the outcome rates between the 2 groups showed no statistically
significant difference (HR=1.04; 95% CI, 0.83 to 1.29). CCTA also did not meet prespecified
noninferiority criteria compared with alternative testing. Some clinical outcomes assessed at 12
months favored CCTA, but the differences were nonsignificant. Coronary catheterization rates
and revascularization rates were higher in the CCTA group.
In the SCOT-HEART (Scottish COmputed Tomography of the HEART) trial, 4146 patients were
randomized to CCTA or SOC. (29) The primary end point was the change in the proportion of
patients with a more certain diagnosis (presence or absence) of angina pectoris. Secondary
outcomes included death, MI, revascularization procedures, and hospitalizations for chest pain.
Analysis of the primary outcome showed that patients who underwent CCTA had an increase in
the certainty of their diagnosis relative to those in usual care (relative risk, 1.79; 95% CI, 1.62 to
1.96). Regarding health outcomes, the rates of heart disease death and MI were lower with
CCTA (1.3% versus 2.0%; HR=0.62; p=0.053), but results were of marginal statistical
significance.
The CAPP (Cardiac CT for the Assessment of Pain and Plaque) trial randomized 500 patients
with stable chest pain to CCTA or exercise stress testing. (30) The primary outcome was the
change difference in scores of Seattle Angina Questionnaire domains at 3 months. Patients
were also followed for further diagnostic tests and management. In the CCTA arm, 15.2% of
subjects underwent revascularization. In the exercise stress testing arm, 7.7% underwent
revascularization. For the primary outcome, angina stability and quality of life showed
significantly greater improvement in the CCTA arm than in the exercise stress testing arm.
Effect on Health Outcomes - Nonrandomized Controlled Trials
Nonrandomized studies comparing outcomes of patients following a CCTA strategy with
outcomes following other noninvasive testing strategies were also identified. Some studies have
emphasized downstream utilization of diagnostic testing and procedures rather than patient
outcomes.
Nielsen et al. conducted an observational trial comparing patients who underwent CCTA or
exercise stress testing. (31) Patients had a low-to-intermediate pretest probability of CAD and
presented with suspected angina. Patients were followed for 12 months after the initial test, and
assessed for occurrence of major adverse events (e.g., cardiac death, nonfatal MI). Subsequent
utilization of cardiovascular tests and therapy were also compared between groups. Clinical
outcomes were not compared formally because there were few clinical events. No deaths were
reported during the follow-up period. Three patients in the exercise testing group had MIs within
12 months. For downstream test utilization, the exercise test group had greater subsequent use
of perfusion imaging (9% versus 4%, p=0.03) and greater mean total 1-year costs (€1777
versus €1510, p=0.03). Rates of ICA and revascularization did not differ significantly.
Shreibati et al. used Medicare claims data to compare all-cause mortality, subsequent utilization
of several cardiac tests, treatment, and total costs in patients who underwent initial noninvasive
testing with CCTA, stress echocardiography, myocardial perfusion imaging (MPI), or exercise
ECG. (32) In this study, patients undergoing CCTA had higher rates of several types of
utilization subsequent to their tests than patients undergoing MPI. The study also presented
outcomes for both stress echocardiography and exercise electrocardiography, but they tended
not to differ from outcomes for MPI. There were increased rates of ICA (22.9% versus 12.1%)
and revascularization (11.4% versus 4.6%). Total spending and CAD-related spending were
also higher for CCTA than for MPI. There was no significant difference in all-cause mortality
between CCTA and MPI. Although the mortality rate for CCTA (1.05%) was slightly lower than
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the mortality rate for MPI (1.28%), the adjusted odds ratio (OR) showed a higher risk of
mortality, which may be due to unusual confounding. However, there was a slightly lower
likelihood of hospitalization for MI (adjusted OR=0.60; p=0.04).
In Min et al. (2008), costs and clinical outcomes for patients undergoing initial CCTA were
compared with patients undergoing initial MPI. (33) The data source for this study was a
proprietary claims database from 2 regional health plans. Utilization of medical care was lower
after CCTA. Overall costs were lower, the proportion receiving ICA was lower, and the
proportion receiving revascularization was lower after CCTA. In terms of clinical outcomes, the
proportion with a hospitalization for angina was lower in the CCTA group. The CCTA group also
had a lower rate of a combined outcome of angina or MI hospitalization (HR=0.70; 95% CI, 0.55
to 0.90).
In 2825 patients evaluated for stable angina and suspected CAD in Japan, Yamauchi et al.
examined outcomes after initial CCTA (n=625), MPI (n=1205), or angiography (n=950). (34)
Average follow-up was 1.4 years. In a Cox proportional hazards model adjusted for potential
confounders, the relative hazard rates of major cardiac events after MPI or CCTA were lower
than after angiography; annual rates were 2.6%, 2.1%, and 7.0%, respectively.
Revascularization rates were higher after CCTA than MPI (OR=1.6; 95% CI, 1.2 to 2.2).
Incidental Findings
A number of studies using scanners using 64 or more detector rows were identified. (35-43)
Incidental findings were frequent (26.6%-68.7%) with pulmonary nodules typically the most
common and cancers rare (»5/1000 or less). Aglan et al. (2010) compared the prevalence of
incidental findings when the field of view was narrowly confined to the cardiac structures with
that when the entire thorax was imaged. (35) As expected, incidental findings were less
frequent in the restricted field (clinically significant findings in 14% versus 24% when the entire
field was imaged).
Radiation Exposure
Exposure to ionizing radiation increases lifetime cancer risk. (44) Three studies have estimated
excess cancer risks due to radiation exposure from CCTA. (6, 7, 45) Assuming a 16-mSv dose,
Berrington de Gonzalez et al. (2009) estimated that the 2.6 million CCTAs performed in 2007
would result in 2700 cancers or approximately 1 per 1000. (45) Smith-Bindman et al. (2009)
estimated that cancer would develop in 1 of 270 women and 1 of 600 men age 40 undergoing
CCTA with a 22-mSv dose. (7) Einstein et al. (2007) employed a standardized phantom to
estimate organ dose from 64-slice CCTA. (6) With modulation and exposures of 15 mSv in men
and 19 mSv in women, calculated lifetime cancer risk at age 40 was 7 per 1000 men (1/143)
and 23 per 1000 women (1/43). However, estimated radiation exposure used in these studies
was considerably higher than received with current scanners - now typically under 10 mSv and
often less than 5 mSv with contemporary machines and radiation reduction techniques. For
example, in the 47-center PROTECTION I (Prospective Multicenter Study on Radiation Dose
Estimates of Cardiac CT Angiography) study enrolling 685 patients, the mean radiation dose
was 3.6 mSv, using a sequential scanning technique. (46) In a 2012 study of patients
undergoing an axial scanning protocol, mean radiation dose was 3.5 mSv, and produced
equivalent ratings of image quality compared with helical scan protocols, which had much
higher mean radiation doses of 11.2 mSv. (47)
Section Summary: Stable Angina and Suspected CAD: CCTA
A number of studies have evaluated the diagnostic accuracy of CTA for diagnosing CAD in an
outpatient population. In general, these studies have reported high sensitivity and specificity,
although there is some variability in these parameters across studies. Meta-analysis of these
studies have shown that, for detection of anatomic disease, CCTA has a sensitivity greater than
95%, which is superior to all other functional noninvasive tests. Specificity is at least as good as
other noninvasive tests. However, the link between improved diagnosis and health outcomes is
not as clear, and thus outcome studies are necessary to demonstrate the clinical utility of CCTA.
Direct clinical trial evidence comparing CCTA and other strategies in the diagnostic
management of stable patients with suspected CAD has not demonstrated the superiority of
CCTA in any of the single clinical trials. Clinical trials demonstrated greater utilization of ICA and
subsequent revascularization procedures after CCTA. An important problem of interpreting the
clinical trials is that the comparator strategies differ: in the PROMISE trial, the CAPP trial, and
Min et al. (2012), CCTA was compared with an alternative noninvasive test; in other studies,
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CCTA was supplement to usual care (which may or may not have included a noninvasive test).
This design difference in the clinical trials is likely a reflection of how CCTA is used in clinical
practice - either as a substitute for another noninvasive test or as an addition to other
noninvasive tests. The PROMISE trial explicitly compared CCTA with an alternative functional
test as the initial diagnostic test. Although the trial did not show the superiority of CCTA and did
not meet pre-specified criteria for noninferiority, examination of some secondary clinical
outcomes supports a conclusion of “at least” noninferiority. The results of the other randomized
trials are consistent with noninferiority of CCTA with other established noninvasive tests. Thus,
the randomized studies indicate that outcomes of patients are likely to be similar with CCTA
versus other noninvasive tests.
The non-randomized studies of CCTA have several methodologic shortcomings including
reliance on administrative data and inability to fully assess and adjust for potential confounding.
The findings generally show little difference in patient outcomes between diagnostic strategies.
Downstream utilization of medical care showed variable findings.
Although studies of incidental findings and radiation exposure raise issues regarding the
potential for adverse effects of CCTA, there is not sufficient evidence that the magnitude of
these effects is important for ascertaining the net benefit or risk of CCTA in this setting.
Suspected Anomalous Coronary Arteries
Anomalous coronary arteries are an uncommon finding during angiography, occurring in
approximately 1% of coronary angiograms completed for evaluation of chest pain. However,
these congenital anomalies can be clinically important depending on the course of the
anomalous arteries. A number of case series have consistently reported that CCTA is able to
delineate the course of these anomalous arteries, even when conventional angiography cannot.
(48-51) However, none of the studies reported results when the initial reason for the study was
to identify these anomalies, nor did any of the studies discuss impact on therapeutic decisions.
Given the uncommon occurrence of these symptomatic anomalies, it is unlikely that a
prospective trial of CCTA could be completed.
Other Diagnostic Uses of CCTA
Given its ability to define coronary artery anatomy, there are many other potential diagnostic
uses of CCTA including patency of coronary artery bypass grafts, in-stent restenosis, screening,
and preoperative evaluation:
• Evaluating patency of vein grafts is generally less of a technical challenge due to vein size
and lesser motion during imaging. In contrast, internal mammary grafts may be more difficult to
image due to their small size and presence of surgical clips. Finally, assessing native vessels
distal to grafts presents difficulties, especially when calcifications are present, due to their small
size. For example, a 2008 meta-analysis including results from 64-slice scanners, reported high
sensitivity 98% (95% CI, 95 to 99; 740 segments) and specificity 97% (95% CI, 94 to 97). (52)
Other small studies have reported high sensitivity and specificity. (53, 54) Lacking are
multicenter studies demonstrating likely clinical benefit, particularly given the reasonably high
disease prevalence in patients evaluated.
• Use of CCTA for evaluation of in-stent restenosis presents other technical challenges -
motion, beam hardening, and partial volume averaging. Whether these challenges can be
sufficiently overcome to obtain sufficient accuracy and impact outcomes has not been
demonstrated.
• Use for screening a low-risk population was recently evaluated in 1000 patients undergoing
CCTA compared with a control group of 1000 similar patients. (55) Findings were abnormal in
215 screened patients. Over 18 months of follow-up, screening was associated with more
invasive testing, statin use, but without difference in cardiac event rates.
CCTA for preoperative evaluation before noncardiac surgery has been suggested, but
evaluated only in small studies and lacking demonstrable clinical benefit.
Ongoing and Unpublished Clinical Trials: CCTA
Some currently unpublished trials that might influence this review are listed in Table 7.
Table 7. Summary of Key Trials
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NCT Number
Title
Enrollment
Completion
Date
Ongoing
NCT01384448
Stress Echocardiography and Heart
400
Feb 2017
Computed Tomography (CT) Scan in
Emergency Department Patients With
Chest Pain
NCT01559467
The Supplementary Role of Non-
300
May 2017
invasive Imaging to Routine Clinical
Practice in Suspected Non-ST-
elevation Myocardial Infarction
(CARMENTA)
NCT01283659
IMAGE-HF Project I-C: Computed
250
Jun 2017
Tomographic Coronary Angiography
for Heart Failure Patients (CTA-HF)
NCT02400229
Diagnostic Imaging Strategies for
3546
Sep 2019
Patients with Stable Chest Pain and
Intermediate Risk of Coronary Artery
Disease (DISCHARGE)
NCT01083134
The Correlation of Heart
100
Mar 2020
Hemodynamic Status Between 320
Multi-detector Computed
Tomography, Echocardiography and
Cardiac Catheterization in Patients
With Coronary Artery Disease
Unpublished
NCT00991835
Plaque Registration and Event
2015
Dec 2014
Detection In Computed Tomography
(unknown)
(PREDICT)
NCT02291484
Comprehensive Cardiac CT Versus
250
May 2016
Exercise Testing in Suspected
(completed)
Coronary Artery Disease (2)
(CRESCENT2)
Table Key:
NCT: National Clinical Trial.
Practice Guidelines and Position Statements: CCTA
American College of Cardiology Foundation (ACCF) et al.
The ACCF and several other medical societies (American Heart Association, American College
of Physicians, American Association for Thoracic Surgery, Preventive Cardiovascular Nurses
Association, Society for Cardiovascular Angiography and Interventions, and Society of Thoracic
Surgeons, known as the AHA/ACP/AATS/PCNA/SCAI/STS) issued joint guidelines for
management of patients with stable ischemic heart disease in 2012 (see Table 8). (24)
Table 8. Joint Guidelines on Management of Stable Ischemic Heart Disease
Diagnosis
Recommendation
Class
LOE
Unknown
Able to Exercise
“Coronary CTA might be reasonable for patients with an
IIb
B
intermediate pretest probability of IHD [ischemic heart
disease] who have at least moderate physical functioning
or no disabling comorbidity.”
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Unable to Exercise
“Coronary CTA is reasonable for patients with a low to
IIa
B
intermediate pretest probability of IHD who are incapable
of at least moderate physical functioning or have
disabling comorbidity.”
“Coronary CTA is reasonable for patients with an
IIa
C
intermediate pretest probability of IHD who a) have
continued symptoms with prior normal test findings, or b)
have inconclusive results from prior exercise or
pharmacological stress testing, or c) are unable to
undergo stress with nuclear MPI or echocardiography.”
Known Coronary Disease
Able to Exercise
“Coronary CTA may be reasonable for risk assessment
IIb
B
in patients with SIHD (stable ischemic heart disease)
who are able to exercise to an adequate workload but
have an uninterpretable ECG.”
Able to Exercise
“Pharmacological stress imaging (nuclear MPI,
III
B
echocardiography, or CMR) or coronary CTA is not
recommended for risk assessment in patients with SIHD
who are able to exercise to an adequate workload and
have an interpretable ECG.”
Unable to Exercise
“Pharmacological stress CMR is reasonable for risk
IIa
B
assessment in patients with SIHD who are unable to
exercise to an adequate workload regardless of
interpretability of ECG.”
“Coronary CTA can be useful as a first-line test for risk
IIa
C
assessment in patients with SIHD who are unable to
exercise to an adequate workload regardless of
interpretability of ECG.”
Unable to Exercise
“A request to perform either a) more than 1 stress
III
C
imaging study or b) a stress imaging study and a
coronary CTA at the same time is not recommended for
risk assessment in patients with SIHD.”
Regardless of Patients’ Ability to Exercise
“Coronary CTA might be considered for risk assessment
IIb
C
in patients with SIHD unable to undergo stress imaging
or as an alternative to invasive coronary angiography
when functional testing indicates a moderate- to high-risk
result and knowledge of angiographic coronary anatomy
is unknown.”
Table Key:
LOE: level of evidence;
CCTA: coronary computed tomography angiography;
IHD: ischemic heart disease;
MPI: myocardial perfusion imaging;
SIHD: stable ischemic heart disease;
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ECG: electrocardiography;
CMR: cardiac magnetic resonance.
Appropriate use criteria (57, 58) and expert consensus documents (59) published jointly by
ACCF/ACR/AHA/NASCI/SAIP/SCAI/SCCT addresses CCTA in the emergency setting: “In the
context of the emergency department evaluation of patients with acute chest discomfort,
currently available data suggest that CCTA may be useful in the evaluation of patients
presenting with an acute coronary syndrome (ACS) who do not have either acute
electrocardiogram (ECG) changes or positive cardiac markers. However, existing data are
limited, and large multicenter trials comparing CTA with conventional evaluation strategies are
needed to help define the role of this technology in this category of patients.”
In 2013, ACCF/AHA/ASE/ASNC/HFSA/HRS/SCAI/SCCT/SCMR/STS published appropriate
use criteria for detection and risk assessment of stable ischemic heart disease. (60) CCTA was
considered appropriate for:
• Symptomatic patients with intermediate (10%-90%) pre-test probability of CAD and
uninterpretable ECG or inability to exercise;
• Patients with newly diagnosed systolic heart failure;
• Patients who have had a prior exercise ECG or stress imaging study with abnormal or
unknown results;
• Patients with new or worsening symptoms and normal exercise ECG.
National Institute for Health and Care Excellence (NICE)
The NICE considers CCTA indicated for patients with stable chest pain and Agatston coronary
artery calcium score less than 400, when the pretest likelihood is between 10% and 29%. (61)
U.S. Preventive Services Task Force (USPSTF) Recommendations
No USPSTF recommendations screening asymptomatic individuals using CCTA have been
identified.
Summary of Evidence: Coronary Computed Tomography Angiography
For individuals who have acute chest pain and suspected coronary artery disease (CAD) in the
emergency setting, at intermediate to low risk, who receive coronary computed tomography
angiography (CCTA), the evidence includes several randomized controlled trials. Relevant
outcomes are overall survival, morbid events, and resource utilization. Trials have shown similar
patient outcomes, with faster patient discharges from the emergency department (ED), and
lower short-term costs. The evidence is sufficient to determine that the technology results in a
meaningful improvement in the net health outcome.
For individuals who have stable chest pain, intermediate risk of CAD, meeting guideline criteria
for noninvasive testing (i.e., intermediate risk) who receive CCTA, the evidence includes studies
of diagnostic accuracy of CCTA, randomized trials comparing CCTA with alternative diagnostic
strategies, and observational studies comparing CCTA with alternative diagnostic strategies.
Relevant outcomes are overall survival, test accuracy, morbid events, and resource utilization.
Studies of diagnostic accuracy have shown that CCTA has higher sensitivity and similar
specificity to alternative noninvasive tests. Although randomized trials have not shown the
superiority of CCTA over other diagnostic strategies, results are consistent with noninferiority
(i.e., similar health outcomes) to other diagnostic strategies. The evidence is sufficient to
determine that the technology results in a meaningful improvement in the net health outcome.
For individuals who have suspected anomalous coronary arteries who receive CCTA, the
evidence includes case series. Relevant outcomes are overall survival, test accuracy, morbid
events, and resource utilization. Series have shown that CCTA can detect anomalous coronary
arteries missed by other diagnostic modalities. Anomalous coronary arteries are rare, and
formal studies to assess clinical utility are unlikely to be performed. In most situations, these
case series alone would be insufficient to determine whether the test improves health
outcomes. However, in situations where patient management will be affected by CCTA results
(e.g., with changes in surgical planning), an indirect chain of evidence indicates that health
outcomes are improved. The evidence is sufficient to determine that the technology results in a
meaningful improvement in the net health outcome.
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Noninvasive Fractional Flow Reserve Computed Tomography
The literature reviewed assessed the potential impact of noninvasive imaging, particularly
focusing on use of coronary computed tomography angiography (CCTA) and noninvasive
fractional flow reserve (FFR), to guide use of invasive coronary angiography (ICA) in patients
with stable chest pain at intermediate risk of coronary artery disease (CAD; i.e., suspected or
presumed stable ischemic heart disease [SIHD]) being considered for ICA. Assessment of a
diagnostic technology typically focuses on 3 categories of evidence: 1) its technical
performance (test-retest reliability or interrater reliability); 2) diagnostic accuracy (sensitivity,
specificity, and positive and negative predictive value) in relevant populations of patients; and 3)
clinical utility demonstrating that the diagnostic information can be used to improve patient
outcomes.
CCTA with Selective Noninvasive FFR
Clinical Context and Test Purpose
The purpose of selective noninvasive FFR using CCTA (FFR
) in patients with stable chest
CT
pain who have suspected SIHD and who are being considered for ICA is to select patients who
may be managed safely with observation only, instead of undergoing ICA in the short term.
Technical Performance
Data supporting technical performance derive from the test-retest reliability of FFRCT and
invasively measured FFR (reference standard). Other technical performance considerations
were summarized in the U.S. Food and Drug Administration (FDA) documentation. (75, 82)
Johnson et al. (2015) reported on the repeatability of invasive FFR. (83) Data from 190 paired
assessments were analyzed (patients measured twice over 2 minutes). The test-retest
coefficient of variation of 2.5% (r2=98.2%) was reported using a “smart minimum” in the
analyses (“the lowest average of 5 consecutive cardiac cycles of sufficient quality within a run of
9 consecutive quality beats”). Hulten and Di Carli (2015) noted that based on the Johnson
results, an FFR of 0.8 would have a 95% confidence interval (CI) of 0.76 to 0.84. (84) Gaur et
al. (2014) analyzed data from 28 patients (58 vessels) with repeated FFRCT and invasive FFR
measurements. (85) They reported coefficients of variation of 3.4% (95% CI, 1.5% to 4.6%) for
FFRCT and 2.7% (95% CI, 1.8% to 3.3%) for invasive FFR. Although reproducibility was
acceptable, whether test-retest reliability over time might be similar is unclear.
The ability to obtain FFRCT measurements is directly related to the quality of imaging data and
values are not calculated for small vessels (<1.8 mm). Nitrate administration is recommended
(generally standard practice unless contraindicated) for vasodilatation, and a lack of nitrates can
affect FFRCT results. In addition, the FDA de novo summary lists factors that can adversely
impact FFRCT results, including: imaging data quality, incorrect brachial pressure, myocardial
dysfunction and hypertrophy, and abnormal physiology (e.g., congenital heart disease).
Coronary calcium might also impact measurements. (86)
Section Summary: Technical Performance
Reported results have indicated that the test-retest reliability is acceptable and other known
factors can impact variability of FFRCT results.
Diagnostic Accuracy
Studies Included in FFRCT Systematic Reviews: Per-Patient Diagnostic Accuracy
Twenty-six studies have contributed patient-level results to a 2015 meta-analysis that examined
5 non-FFRCTimaging modalities (see Table 9). (87) Five studies contributed results to 2 meta-
analyses, Wu et al. (2016) (88) and Danad et al. (2017), (89) evaluating the diagnostic accuracy
of FFRCT using patients as the unit of analysis. Only the FDA-cleared HeartFlow software has
been evaluated prospectively across multiple sites. Two small retrospective studies have
reported per-patient performance characteristics for the prototype Siemens workstation-based
software. (90, 91) The 3 HeartFlow FFRCT studies used successive software versions with
reported improvement in specificity (from 54% to 79%) between versions 1.2 and 1.4. (76, 72,
92) The NXT (HeartFlow Analysis of Coronary Blood Flow Using Coronary CT Angiography
[HFNXT]) Trial, the basis for device clearance by the FDA, was conducted at 11 sites in 8
countries (Canada, EU [European Union], Asia). (79) Although not examined in the 2 included
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meta-analyses, subgroup analyses suggested little variation in results by sex and age. (93)
Effectively, the entirety of the data was obtained in patients of white or Asian decent; almost all
patients were appropriate for testing according to FDA clearance.
Danad et al. (2017) included 23 studies published between January 2002 and February 2015
evaluating the diagnostic performance of CCTA, FFR
, single-photon emission computed
CT
tomography (SPECT), stress echocardiography (SECHO), magnetic resonance imaging (MRI),
or ICA compared with an invasive FFR reference standard. (89) The 3 included FFRCT studies
used the HeartFlow software and had performed FFR in at least 75% of patients. A cutoff of
0.75 defined significant stenosis in 8 (32%) studies and in the remainder 0.80 (the current
standard used in all FFRCT studies). Per-patient and per-vessel meta-analyses were performed.
Study quality was assessed using QUADAS-242; no significant biases were identified in FFR
CT
studies but a high risk of biased patient selection was judged in 10 (43.4%) of other studies.
HeartFlow funded publication Open Access; 1 author was a consultant to, and another a
cofounder of, HeartFlow.
On the patient level, MRI had the highest combined sensitivity (90%; 95% CI, 75% to 97%) and
specificity (94%; 95% CI, 79% to 99%) for invasive FFR, but were estimated from only 2 studies
(70 patients). FFRCThad similar sensitivity (90%; 95% CI, 85% to 93%), but lower specificity
(71%; 95% CI, 65% to 75%), and accordingly a lower positive likelihood ratio (3.34; 95% CI,
1.78 to 6.25) than MRI (10.31; 95% CI, 3.14 to 33.9). The negative likelihood ratios were low
(lower is better) for both FFR
(0.16; 95% CI, 0.11 to 0.23) and MRI (0.12; 95% CI, 0.05 to
CT
0.30); however, the confidence interval is more narrow for FFRCT due to larger sample for
FFRCT. CCTA had a slightly higher negative likelihood ratio (0.22; 95% CI, 0.10 to 0.50).
Results for the per-vessel area under the summary receiver operating characteristic curve were
similar except for CCTA where per-patient results were considerably worse (e.g., C statistic of
0.57 versus 0.85). Reviewers noted heterogeneity in many estimates (e.g., CCTA sensitivity,
I
=80%). Finally, pooled results for some imaging tests included few studies.
2
In 2016, Wu et al. identified 7 studies (833 patients, 1377 vessels) comparing FFRCT with
invasively measured FFR from searches of PubMed, Cochrane, EMBASE, Medion, and
meeting abstracts through January 2016. (88) Studies included patients with established or
suspected SIHD. In addition to the 3 FFRCTstudies pooled by Danad et al., (89) 1 additional
study using HeartFlow technique (44 patients; 48 vessels) and 3 additional studies (180
patients; 279 vessels) using Siemens cFFR software (not FDA approved or cleared) were
identified. An invasive FFR cutoff of 0.80 was the reference standard in all studies. Per-patient
results reported in 5 studies were pooled and reported in Table 9. All studies were rated at low
risk of bias and without applicability concerns using the QUADAS-2 tool. (94) Appropriate
bivariate meta-analyses (accounting for correlated sensitivity and specificity) were used.
As expected given study overlap, FFRCT performance characteristics were similar to those
reported by Danad et al., (89) but with a slightly higher specificity (see Table 9). The pooled per-
vessel C statistic was lower (0.86) than the per-patient result (0.90). No evidence of publication
bias was detected, but the number of studies was too small to adequately assess. Reviewers
noted that, in 2 studies, FFRCTresults were uninterpretable in 12.0% (79) and 8.2% (95) of
participants.
Takx et al. (2015) identified studies reporting on the ability of perfusion CT, MRI,
SECHO, PET, and SPECT to detect hemodynamically significant CAD as measured by ICA with
invasive FFR. (87) Studies published through May 2014 were eligible for inclusion; PubMed,
EMBASE, and Web of Science were searched. QUADAS-2 was used to assess study quality
(94); studies generally rated poorly on blinding of the index test result from the assessor and
study population selection. Reviewers designated the negative likelihood ratio as the diagnostic
characteristic of interest (i.e., ability to exclude disease) noting that myocardium perfusion scan
(MPI) (e.g., MRI, SPECT, PET, or CT) has been proposed to be a gatekeeper to ICA. No
funding was obtained for the review and the study was registered on PROSPERO (96) (the 2
other meta-analyses were not).
The pooled negative likelihood ratios for MRI, PET, and perfusion CT were similar in magnitude
(0.12 to 0.14; see Table 9) although the confidence interval for PET was wide. Heterogeneity
among studies included in the pooled patient-level results was considered high for PET
2
(I
=84%), moderate for CT (I2=70%) and SPECT (I2=55%), and low for MRI (I2=0%) and
SECHO (I2=0%). Publication bias, when able to be assessed, was not suspected. With respect
to ability to detect hemodynamically significant ischemia, reviewers concluded that “MPI with
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MRI, CT, or PET has the potential to serve as a gatekeeper for invasive assessment of
hemodynamic significance by ICA and FFR.” Studies of FFRCT were not included in the
analysis.
Table 9. Pooled Per-Patient Pooled Diagnostic Performance of Noninvasive Tests for
Invasive FFR
Test
Studies
N
Sensitivity
Specificity
C
LR+
LR-
(95% CI)
(95% CI)
(95% CI)
(95% CI)
Danad et al. (2017) (89)
MRI
2
70
90%
94%
0.94
10.3
0.12
(75 to 97)
(79 to 99)
(3.14 to
(0.05 to
33.9)
0.30)
FFR
CT
3
609
90%
71%
0.94
3.3
0.16
(85 to 93)
(65 to 75)
(1.78 to
(0.11 to
6.25)
0.23)
CTA
4
694
90%
39%
0.57
1.5
0.22
(86 to 93)
(34 to 44)
(1.25 to
(0.10 to
1.90)
0.50)
SECHO
2
115
77%
75%
0.82
3.0
0.34
(61 to 88)
(63 to 85)
(1.94 to
(0.17 to
4.65)
0.66)
SPECT
3
110
70%
78%
0.79
3.4
0.40
(59 to 80)
(68 to 87)
(1.04 to
(0.19 to
11.1)
0.83)
ICA
2
954
69%
67%
0.75
2.5
0.46
(65 to 75)
(63 to 71)
(1.25 to
(0.39 to
5.13)
0.55)
Wu et al. (2016) (88)
FFR
CT
5
683
89%
76% (64 to
0.90
3.7
0.14
84)
(85 to 93)
(2.41 to
(0.09 to
5.61)
0.21)
Takx et al. (2015) (87)
MRI
10
798
89%
87%
0.94
6.3
0.14
(86 to 92)
(83 to 90)
(4.88 to
(0.10 to
8.12)
0.18)
PCT
5
316
88%
80%
0.93
3.8
0.12
(82 to 92)
(73 to 86)
(1.94 to
(0.04 to
7.40)
0.33)
SECHO
4
177
69%
84%
0.83
3.7
0.42
(56 to 79)
(75 to 90)
(1.89 to
(0.30 to
7.15)
0.59)
SPECT
8
533
74%
79%
0.82
3.1
0.39
(67 to 79)
(74 to 83)
(2.09 to
(0.27 to
4.70)
0.55)
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PET
2
224
84%
87%
0.93
6.5
0.14
(75 to 91)
(80 to 92)
(2.83 to
(0.02 to
15.1)
0.87)
Table Key:
N: number;
CI: confidence interval;
C: C-statistic;
LR: likelihood ratio;
CT: computed tomography;
MRI: magnetic resonance imaging;
FFR
: fractional flow reserve computed tomography;
CT
CTA: computed tomography angiography;
SECHO: stress echocardiography;
SPECT: single photon emission computed tomography;
PCT: perfusion computed tomography;
ICA: invasive coronary angiography.
Section Summary: Diagnostic Accuracy
Three studies including 609 patients have evaluated diagnostic accuracy of the FDA-cleared
HeartFlow software. Software used in successive studies was also revised to improve
performance characteristics, particularly specificity. For example, using an earlier software
version, the DeFACTO (DEtermination of Fractional Flow Reserve by Anatomic Computed
TOmographic Angiography)Trial reported a specificity of 54%. (97) Accordingly, pooled results
from the Danad systematic review must be interpreted carefully. (89) In addition, there is some
uncertainty in the generalizability of results obtained in these studies conducted under likely
controlled conditions (e.g., data from the NXT Trial [79] forming the basis for FDA clearance).
Given the purpose to avoid ICA, the negative likelihood ratio, or how a negative result might
dissuade a clinician from proceeding to ICA, is of primary interest - i.e., excluding a patient with
vessels having a high FFR from ICA. While confidence intervals are relatively wide and
overlapping, the negative likelihood ratio estimates of FFRCT for excluding physiologically
significant coronary stenoses tended to be lower (i.e., better) than CCTA alone, SECHO,
SPECT, and ICA. Only MRI yielded a similarly low or lower negative likelihood ratio than FFR
CT
Clinical Utility
Indirect Evidence
Diagnostic performance can offer indirect evidence of clinical utility, assuming providers act
according to a test result. As previously noted, an effective gatekeeper strategy must be able to
decrease the probability of disease (rule out) sufficiently that a planned ICA would not be
performed. Ruling out disease is a function of the negative likelihood ratio that defines the
degree to which a negative test decreases the posttest odds (and probability) of disease.
Table 10 illustrates how a negative test would lower the probability of a hemodynamically
significant obstruction from pretest probabilities of 0.25, 0.50, or 0.75 for the various tests
examined in the meta-analyses. For example, according to the results of Danad et al., if the
pretest probability was 0.50, following a negative CCTA study the posttest probability would be
0.18 (95% CI, 0.09 to 0.33); and following a negative SECHO, 0.25 (95% CI, 0.15 to 0.40) or
SPECT, 0.29 (95% CI, 0.16 to 0.45). (89) In contrast, beginning with a pretest probability of
0.50, a negative FFRCT would yield a posttest probability of 0.14 (95% CI, 0.10 to 0.19) (Danad
et al., [89]) and 0.12 (95% CI, 0.08 to 0.17) (Wu et al., [88]). Overall, the negative likelihood
ratios and posttest probability estimates for FFRCT are slightly better than CCTA as well as
SECHO and SPECT.
Table 10. Change in Disease Probability Following a Negative Test
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Posttest Probability (95% CI) After Negative Test
Study
Modality
Negative LR
Pretest
Pretest
Pretest
Probability
Probability
Probability
(95% CI)
0.75
0.25
0.50
Danad et al. (2017) (89)
MRI
0.12
0.04
0.11
0.26
(0.05 to
(0.02 to 0.09)
(0.05 to 0.23)
(0.13 to 0.47)
0.30)
FFR
CT
0.16
0.05
0.14
0.32
(0.11 to
(0.04 to 0.07)
(0.10 to 0.19)
(0.25 to 0.41)
0.23)
CTA
0.22
0.07
0.18
0.40
(0.10 to
(0.03 to 0.14)
(0.09 to 0.33)
(0.23 to 0.60)
0.50)
SECHO
0.34
0.10
0.25
0.50
(0.17 to
(0.05 to 0.18)
(0.15 to 0.40)
(0.34 to 0.66)
0.66)
SPECT
0.40
0.12
0.29
0.55
(0.19 to
(0.06 to 0.22)
(0.16 to 0.45)
(0.36 to 0.71)
0.83)
ICA
0.46
0.13
0.32
0.58
(0.39 to
(0.12 to 0.15)
(0.28 to 0.35)
(0.54 to 0.62)
0.55)
Wu et al. (2016) (88)
FFR
CT
0.14
0.04
0.12
0.30
(0.09 to
(0.03 to 0.07)
(0.08 to 0.17)
(0.21 to 0.39)
0.21)
Takx et al. (2015) (87)
MRI
0.14
0.04
0.12
0.30
(0.10 to
(0.03 to 0.06)
(0.09 to 0.15)
(0.23 to 0.35)
0.18)
PCT
0.12
0.04
0.11
0.26
(0.04 to
(0.01 to 0.10)
(0.04 to 0.25)
(0.11 to 0.50)
0.33)
SECHO
0.42
0.12
0.30
0.56
(0.30 to
(0.09 to 0.16)
(0.23 to 0.37)
(0.47 to 0.64)
0.59)
SPECT
0.39
0.12
0.28
0.54
(0.27 to
(0.08 to 0.15)
(0.21 to 0.35)
(0.45 to 0.62)
0.55)
PET
0.14
0.04
0.12
0.30
(0.02 to
(0.01 to 0.22)
(0.02 to 0.47)
(0.06 to 0.72)
0.87)
Table Key:
CI: confidence interval;
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LR: likelihood ratio;
CT: computed tomography;
MRI: magnetic resonance imaging;
FFR
: fractional flow reserve computed tomography;
CT
CTA: computed tomography angiography;
PET: positron emission tomography;
SECHO: stress echocardiography;
SPECT: single photon emission computed tomography;
PCT: perfusion computed tomography;
ICA: invasive coronary angiography.
One study was identified (Curzen et al., 2016) that examined 200 consecutive individuals
selected from the NXT trial population “to reproduce the methodology of the invasive RIPCORD
[Does RoutIne Pressure Wire Assessment Influence Management Strategy at CORonary
Angiography for Diagnosis of Chest Pain?] study” with elective management of stable chest
pain. (98) All subjects received CCTA including FFR
“in at least 1 vessel with diameter ≥ 2
CT
mm and diameter stenosis ≥ 30%” as well as ICA within 60 days of CCTA. Three experienced
interventional cardiologists reviewed the CCTA results (initially without the FFRCT results) and
selected a management plan from the following 4 options: “1) optimal medical therapy (OMT)
alone; 2) PCI [percutaneous coronary intervention] + OMT; 3) coronary artery bypass graft +
OMT; or 4) more information about ischemia required - they committed to option 1 by
consensus.” Following the initial decision, results from the FFRCT were shared with the same
group of interventional cardiologists who again made a decision by consensus based on the
same 4 options. A cutoff of 0.80 or less was considered significant on FFRCT. A stenosis was
considered significant on CCTA or ICA with 50% or more diameter narrowing. Change in
management between the first decision based on CCTA only and the second decision based on
CCTA plus FFRCT was the primary end point of this study. Secondary end points included
analysis of the vessels considered to have significant stenosis based on CCTA alone versus
CCTA plus FFRCT as well as vessels identified as targets for revascularization based on CCTA
alone versus CCTA plus FFR
CT
NOTE 5: This study was conducted by investigators in the United Kingdom and Denmark.
Funding was provided by HeartFlow and multiple authors reported receiving fees, grants, and/or
support from HeartFlow.
Results for the primary end-point (see Table 11) yielded a change in management category for
72 of 200 (36%) individuals. For the 87 individuals initially assigned to PCI based on CCTA
alone, the addition of the FFRCT results shifted management for 26 of 87 (30%) to OMT (i.e., no
ischemic lesion on FFR
) and an additional 16 (18%) individuals remained in the PCI category
CT
but FFRCT identified a different target vessel for PCI. These findings provide supportive
information that the improved diagnostic accuracy of FFRCT in particular related to its better
negative likelihood ratio compared to CCTA alone would likely lead to changes in management
that would be expected to improve health outcomes.
Table 11. Summary of Overall Changes to Management in Patients Using CCTA versus
CCTA + FFR
CT
Management Category
CCTA Alone,
CCTA Plus
Strategy
Consensus
FFR
CT
,
Change
a
n (%)
Decision
n (%)
(95% CI)
More data required
38 (19.0%)
0
-
Optimal medical therapy
67 (33.5%)
113 (56.5%)
23%
(18% to 29%)
Percutaneous coronary
87 (43.5%)
78 (39.0%)
-5%
intervention
(-2% to -8%)
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Coronary artery bypass graft
8 (4.0%)
9 (4.5%)
0.5%
surgery
(0.1% to 3%)
Table Key:
CT: computed tomography;
CTA: computed tomography angiography;
FFR
: fractional flow reserve computed tomography;
CT
CI: confidence interval;
n: number;
a
: p<0.001 for between-group change, CCTA alone versus CCTA plus FFR
CT
Direct Evidence
Two prospective comparative studies were identified, including 1 prospective nonrandomized
study that compared an FFRCT strategy (CCTA with noninvasive FFR measurement when
requested or indicated) with ICA and 1 RCT that examined CCTA as a gatekeeper to ICA (see
Tables 12 and 13). In addition, 1 prospective cohort study and 2 retrospective cohort studies
were identified, in which patients were referred for CCTA, which included FFRCT evaluation.
The PLATFORM (Prospective LongitudinAl Trial of FFR
: Outcome and Resource IMpacts)
CT
Study compared diagnostic strategies with or without FFRCT in patients with suspected stable
angina but without known CAD. (99, 100) The study was conducted at 11 EU sites. All testing
was nonemergent. Patients were divided into 2 strata, according to whether the test planned
prior to study enrollment was: 1) noninvasive or 2) ICA (the patient population of interest in this
evidence review). Patients were enrolled in consecutive cohorts, with the first cohort undergoing
a usual care strategy followed by a second cohort provided CCTA with FFRCT performed when
requested (recommended if stenoses ≥30% were identified). Follow-up was scheduled at 90
days and 6 and 12 months after entry (99.5% of patients had 1-year follow-up data).
NOTE 6: Funding was provided by HeartFlow and multiple authors reported receiving fees,
grants, and/or support from HeartFlow. Data analyses were performed by the Duke Clinical
Research Institute.
ICA without obstructive disease at 90 days was the primary end-point in patients with planned
invasive testing - “no stenosis ≥ 50% by core laboratory quantitative analysis or invasive FFR <
0.80.” Secondary end-points included ICA without obstructive disease following planned
noninvasive testing, and 1) Major adverse cardiovascular events (MACE) at 1 year defined as a
composite of all-cause mortality, myocardial infarction (MI), and urgent revascularization and 2)
MACE and vascular events within 14 days. Quality of life (QOL) was evaluated using the
Seattle Angina Questionnaire, and EQ-5D (5-item and 100-point visual analog scale). CCTA
studies were interpreted by site investigators; quantitative coronary angiography measurements
were performed at a central laboratory, as was FFRCT. Cumulative radiation was also assessed.
A sample size of 380 patients in the invasive strata yielded a 90% power to detect a 50%
decrease in the primary end point given a 30% event rate (ICA without obstructive disease) with
a usual care strategy and a dropout rate up to 10%.
ICA was planned in 380 participants, of whom 193 (50.8%) had undergone prior noninvasive
testing. The mean pretest probability in the planned ICA strata was approximately 50% (51.7%
and 49.4% in the 2 groups). FFRCT was requested in 134 patients and successfully obtained in
117 of 134 (87.3%) in the FFRCT group. At 90 days, 73.3% of those in the usual care group had
no obstructive findings on ICA compared with 12.4% in the FFRCT group based on core
laboratory readings (56.7% and 9.3% based on site readings). The difference was similar in a
propensity-matched analysis of a subset of participants (n=148 from each group or 78% of the
entire sample). Prior noninvasive testing did not appear associated with non-obstructive
findings. MACE rates were low and did not differ between strategies. Mean level of radiation
exposure though 1 year was also similar in the usual care group (10.4 mSv) and the planned
ICA group (10.7 mSv). No differences in QOL were found between groups. (101)
Results of the PLATFORM study support the notion that, in patients with planned ICA, FFR
CT
can decrease the rate of ICAs and unnecessary procedures (finding no significant obstructive
disease) and that FFRCT may provide clinically useful information to physicians and patients.
Study limitations include a nonrandomized design; high rate of no obstructive disease with a
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usual care strategy (73.3%), which was higher than the 30% rate assumed in the sample size
estimates; and a sample size that was small with respect to evaluating adverse cardiac events.
Although finding a large effect in patients with planned invasive testing, the nonrandomized
design limits causal inferences and certainty that the magnitude of effect. The propensity-
matched analysis (in a matched subset) offers some reassurance, but the sample size was
likely too small to provide robust results.
Dewey et al. (2016) conducted the Coronary Artery Disease Management (CAD-Man) Trial, a
single-center, parallel-group assignment trial examining CCTA as a gatekeeper to ICA in
patients with atypical angina or chest pain and suspected CAD who were indicated for ICA.
(102) Patients were randomized to direct ICA or to ICA only if a prior CCTA was positive (a
stenosis ≥70% stenosis in any vessel or ≥50% in the left main coronary artery). The trialists
reported that when obstructive disease was suspect following CCTA, late enhancement MRI
was performed to evaluate the extent of viable myocardium (completed in 17 patients) to guide
revascularization; however, the study protocol clarified that MRI was not used for decisions to
proceed to ICA. A major procedural complication (death, stroke, MI, or event requiring >24-hour
hospitalization) within 24 hours was the primary outcome; secondary outcomes included ICA
with obstructive CAD (diagnostic yield), revascularizations, and MACE during long-term follow-
up. The trial was performed in Germany. Patients were excluded if they had evidence of
ischemia or signs of MI and just over half (56.5%) were inpatients at the time of enrollment.
Obstructive disease was defined as “at least one 50% diameter stenosis in the left main
coronary artery or at least one 70% diameter stenosis in other coronary arteries.” Allocation
concealment appeared adequate, but the trial was unblinded owing to the nature of the
intervention. In addition, the mean pretest probability of CAD at baseline was higher in the ICA-
only arm (37.3% versus 31.3%; see Table 12). The research was supported by public funding.
ICAs were reduced by 85.6% in the CCTA arm and by 80.9% for ICA with no obstructive
disease. A major procedural complication (the primary outcome) occurred in a single patient
undergoing CCTA. PCIs were less frequent when CCTA was performed - 9.6% versus 14.2%
(p<0.001). Over a median follow-up of 3.3 years, MACE rates were similar in the trial arms
(4.2% in the CCTA group versus 3.7% with ICA; adjusted hazard ratio [HR], 0.90; 95% CI, 0.30
to 2.69). In the CCTA arm, there was 1 death, 2 patients with unstable angina, and 6
revascularizations; in the ICA arm there was 1 MI, 1 stroke, and 5 revascularizations.
The trial demonstrated that CCTA as a gatekeeper to planned ICA can avoid a large number of
procedures, a corresponding increase in the diagnostic yield, and fewer revascularizations. Of
note, the prevalence of obstructive CAD found on ICA in this study population was 13% (43/334
eligible for primary outcome analysis), which is lower than the prevalence of obstructive CAD in
the PLATFORM population (26.7%). Thus, the subset of individuals who went onto ICA
following CCTA findings of obstructive CAD was 20 (12%) of 167 eligible for primary outcome
analysis and only 3 (1.7%) were found to have no obstructive CAD on ICA. MACE rates did not
differ between arms. The trial was powered neither to detect a difference nor to assess
noninferiority - implications of the absence of a difference are limited. Finally, although the
patient population included those scheduled for elective ICA, it was heterogeneous, including
those with recent onset and longer standing chest pain. The single-center nature of the trial is
an additional limitation; a subsequent multicenter Diagnostic Imaging StrateGies for Patients
with Stable CHest Pain And Intermediate Risk of Coronary Artery DiseasE Trial (DISCHARGE)
is ongoing.
Table 12. Characteristics of Comparative Studies
Characteristics
Nonrandomized
Randomized
PLATFORM
CAD-Man
ICA
FFR
CT
ICA
CCTA
(n=187)
(n=193)
(n=162)
(n=167)
Age (Standard Deviation),
63.4
(10.9)
60.7
(10.2)
60.4
(11.4)
60.4
(11.3)
years
Female, n (%)
79 (42.2%)
74 (38.3%)
88 (52.7%)
78 (48.1%)
Race/ethnic minority, n (%)
2 (1.1%)
1 (0.5%)
-
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Pretest probability
51.7%
49.4%
37.3%
31.3%
obstructive CAD, %
(17.2%)
(24.8%)
Angina (%)
-
-
-
-
• Typical
52 (27.8%)
45 (23.3%)
-
-
• Atypical
122 (65.2%)
142 (73.6%)
79 (48.8%)
65 (38.9%)
• Non-cardiac
12 (7.0%)
5 (2.6%)
80 (49.4%)
97 (58.1%)
Other chest discomfort
-
-
3 (1.8%)
5 (3.0%)
• Prior noninvasive testing,
92 (49.2%)
101 (52.3%)
84 (50.3%)
92 (56.8%)
n (%)
• Diabetes, n (%)
36 (19.3%)
30 (15.5%)
30 (18.5%)
15 (9.0%)
Current smoker
-
-
34 (21.0%)
41 (24.5%)
• Current or past smoker
103 (55.1%)
101 (52.3%)
85 (52.4%)
88 (52.6%)
Table Key:
PLATFORM: Prospective Longitudinal Trial of FFR
: Outcome And Resource Impacts Study;
CT
CAD-MAN: Coronary Artery Disease Management Trial;
CAD: coronary artery disease;
CT: computed tomography;
CTA: computed tomography angiography;
FFR
: fractional flow reserve computed tomography;
CT
ICA: invasive coronary angiography;
n: number.
Table 13. Results of Comparative Studies
Outcomes
Nonrandomized
Randomized
PLATFORM
CAD-Man
ICA
FFR
CT
ICA
CCTA
(n=187)
(n=193)
(n=162)
(n=167)
Noninvasive FFR
CT
-
-
-
-
• Requested, n (%)
-
134 (69.4%)
-
-
-
117 (60.1%)
-
-
• Successfully performed, n
(%)
ICA no obstructive disease,
137 (73.3%)
24 (12.4%)
137 (84.5%)
6 (3.6%)
n (%)
• Absolute difference (95%
60.8% (53.0% to 68.7%)
80.9% (74.6% to 87.2%)
CI), %
ICA, n (%)
187 (100%)
76 (39.4%)
162 (100%)
24 (14.4%)
60.6% (53.7% to 67.5%)
85.6% (80.3% to 90.9%)
• Absolute difference (95%
CI), %
Revascularization, n (%)
-
-
-
-
• PCI
49 (26.2%)
55 (28.5%)
-
-
• CABG
18 (9.6%)
10 (5.2%)
-
-
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• Any
67 (35.8%)
65 (33.7%)
23 (14.2%)
16 (9.6%)
1-year outcomes, n (%)
-
-
-
-
• MACE
a
2 (1.1%)
2 (1.0%)
-
-
b
-
-
6 (3.7%)
7 (4.2%)
• MACE
Table Key:
PLATFORM: Prospective Longitudinal Trial of FFR
: Outcome And Resource Impacts Study;
CT
CAD-MAN: Coronary Artery Disease Management Trial;
CAD: coronary artery disease;
CT: computed tomography;
CTA: computed tomography angiography;
FFR
: fractional flow reserve computed tomography;
CT
ICA: invasive coronary angiography;
n: number
CI: confidence interval;
PCI: percutaneous coronary intervention;
CABG: coronary artery bypass grafting;
MACEa: major adverse cardiovascular events, Death, myocardial infarction, unplanned urgent
revascularization;
MACEb: major adverse cardiovascular events, Cardiac death, myocardial infarction, stroke,
unstable angina, any revascularization.
Møller Jensen et al. (2017) reported on a single-institution study of 774 consecutive individuals
with suspicion of CAD referred for nonemergent ICA or CCTA. (103) Subjects were analyzed in
2 groups: a low-intermediate-risk group accounting for 76% of patients with mean pretest
probability of CAD 31% and a high-risk group accounting for 24% of patients with mean pretest
probability of CAD 67%. Among the 745 who received CCTA, FFRCT was selectively ordered in
28% of patients overall (23% in the low-intermediate-risk group, 41% in the high-risk group).
CCTA was considered inconclusive in 3% of subjects and among those with conclusive CCTA,
FFRCT yielded few inconclusive results, with less than 3% of cases. During a minimum 90-day
follow-up, the combined testing strategy of selective FFRCT following CCTA resulted in avoiding
ICA in 91% of low-intermediate-risk and 75% of high-risk individuals. None of the patients who
avoided ICA based on CCTA with selective FFRCT were associated with serious clinical adverse
events over an average of 157 days of follow-up.
Nørgaard et al. (2017) reported on results from symptomatic patients referred for CCTA at a
single center in Denmark from May 2014 to April 2015. (104) All data were obtained from
medical records and registries; the study was described as a “review” of diagnostic evaluations
and apparently retrospectively conducted. Follow-up through 6 to 18 months was ascertained.
From 1248 referred patients, 1173 underwent CCTA; 858 received medical therapy, 82
underwent ICA, 44 MPI, and 189 FFR
(185 [98%] obtained successfully). Of the 185
CT
individuals who successfully obtained FFR
, FFRCT demonstrated values of 0.80 or less in 1
CT
or more vessels in 57 (31%) patients and 49 (86%) went on to ICA; whereas of the 128 with
higher FFRCT values, only 5 (4%) went on to ICA. Assuming ICA was planned for all patients
undergoing FFR
, these results are consistent with FFRCT being able to decrease the rate of
CT
ICA. However, implications are limited by the retrospective design, performance at a single
center, and lack of a comparator arm including one for CCTA alone.
Lu et al. (2017) retrospectively examined a subgroup referred to ICA (105) from the completed
PROspective Multicenter Imaging Study for Evaluation of Chest Pain (PROMISE) trial.
PROMISE was a pragmatic trial comparing CCTA with functional testing for the initial evaluation
of patients with suspected SIHD. (106) Of 550 participants referred to ICA within 90 days, 279
were not considered for the analyses due to CCTA performed without nitroglycerin (n=139),
CCTA not meeting slice thickness guidelines (n=90), or Non-diagnostic studies (n=50). Of the
remaining 271 patients, 90 scans were inadequate to obtain FFR
, leaving 181 (33%) of those
CT
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referred to ICA for analysis. Compared with those excluded, patients in the analytic sample
were less often obese, hypertensive, diabetic, minority, or reported a CAD equivalent symptom.
The 2 groups had similar pretest probabilities of disease, revascularization rates, and MACE,
but the distribution of stenoses in the analytic sample tended to be milder (p=0.06). FFR
CT
studies were performed in a blinded manner and not available during the conduct of PROMISE
for decision making.
Severe stenoses (≥70%) or left main disease (≥50%) were present in 110 (66%) patients by
CCTA result and in 54% by ICA. Over a 29-month median follow-up, MACE (death, nonfatal MI,
hospitalization for unstable angina) or revascularization occurred in 51% of patients (9% MACE,
49% revascularization). A majority (72%) of the sample had at least 1 vessel with an FFR
CT
≤0.80, which was also associated with a higher risk of revascularization but with a wide
confidence interval (HR = 5.1; 95% CI, 2.6 to 11.5). If reserved for patients with an FFRCT of
0.80 or less, ICAs might have been avoided in 50 patients (i.e., reduced by 28%) and the rate of
ICA without 50% or more stenosis from 27% (calculated 95% CI, 21% to 34%) to 15%
(calculated 95% CI, 10% to 23%). If the 90 patients whose images sent for FFRCT but were
unsatisfactory proceeded to ICA - as would have occurred in practice - the rate of ICA might
have decreased by 18% and ICA without significant stenosis from 31% to 25%.
The authors suggested that when CCTA is used as the initial evaluation for patients with
suspected SIHD, adding FFRCT could have decreased the referral rate to ICA in PROMISE
from 12.2% to 9.5%, or close to the 8.1% rate observed in the PROMISE functional testing arm.
They also noted similarity of their findings to PLATFORM and concluded, “In this hypothesis-
generating study of patients with stable chest pain referred to ICA after [coronary]CTA, we
found that adding FFRCT may improve the efficiency of referral to ICA, addressing a major
concern of an anatomic [coronary]CTA strategy. FFRCT has incremental value over anatomic
[coronary]CTA in predicting revascularization or major adverse cardiovascular events.”
This retrospective observational subgroup analysis from PROMISE suggests that when CCTA is
the initial noninvasive test for the evaluation of suspected SIHD, FFRCT prior to ICA has the
potential to reduce unnecessary ICAs and increase the diagnostic yield. However, study
limitations and potential generalizability are important to consider. First, analyses included only
a third of CCTA patients referred to ICA and some characteristics of the excluded group differed
from the analytic sample. Second, conclusions assume that an FFRCT greater than 0.80 will
always dissuade a physician from recommending ICA and even in the presence of severe
stenosis (e.g., ≥70% in any vessel or ≥50% in the left main) - or almost half (46%) of patients
with an FFRCT greater than 0.80. Finally, estimates including patients with either non-diagnostic
coronary studies (n=50) or studies inadequate for calculating FFR
(n=90) are more
CT
appropriate because most likely those patients would proceed in practice to ICA. Accordingly,
the estimates are appropriately considered upper bounds for what might be seen in practice. It
is also important to note that in strata of the PLATFORM trial enrolling patients for initial
noninvasive testing (not planned ICA), ICA was more common following CCTA and contingent
FFRCT than following usual care (18.3% versus 12.0%) and ICA, with no obstructive disease
more frequent in the FFRCT arm (12.5% versus 6.0%).
Section Summary: Clinical Utility
The evidence on the diagnostic performance characteristics, particularly showing higher
specificity of FFRCT and better negative likelihood ratio as compared to CCTA alone, may be
combined with indirect evidence that CCTA with a selective FFRCT strategy would likely lead to
changes in management that would be expected to improve health outcomes, particularly by
limiting unnecessary invasive coronary angiography testing. Moreover, there is direct evidence,
provided by 2 prospective and 2 retrospective studies, that compares health outcomes
observed during 90-day to 1-year follow-up for strategies using CCTA particularly in
combination with selective FFRCT with strategies using ICA or other noninvasive imaging tests.
The available evidence provides support that use of CCTA with selective FFRCT is likely to
reduce the use of ICA in individuals with stable chest pain who are unlikely to benefit from
revascularization by demonstrating the absence of functionally significant obstructive CAD. In
addition, the benefits are likely to outweigh potential harms given that rates of revascularization
for functionally significant obstructive CAD appear to be similar and cardiac-related adverse
events do not appear to be increased following a CCTA with selective FFRCT strategy. While
individual studies are noted to have specific methodologic limitations and some variation is
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noted in the magnitude of benefit across studies, in aggregate the evidence provides
reasonable support that the selective addition of FFRCT following CCTA results in a meaningful
improvement in the net health outcome.
Ongoing and Unpublished Clinical Trials: FFR
CT
Some currently unpublished trials that might influence this review are listed in Table 14.
Table 14. Summary of Key Trials
NCT Number
Title
Enrollment
Completion
Date
Ongoing
NCT02173275
Computed Tomographic Evaluation
618
Jul 2017
of Atherosclerotic Determinants of
Myocardial Ischemia
NCT02400229
Diagnostic Imaging Strategies for
3546
Sep 2019
Patients with Stable Chest Pain and
Intermediate Risk of Coronary Artery
Disease: Comparative
Effectiveness Research of Existing
Technologies) - A Pragmatic
Randomised Controlled Trial of CT
versus ICA
NCT02973126
Assessment of Fractional Flow
270
Oct 2020
Reserve Computed Tomography
versus Single Photon Emission
Computed Tomography in the
Diagnosis of Hemodynamically
Significant Coronary Artery Disease.
(AFFECTS)
a
NCT02499679
Assessing Diagnostic Value of Non-
5000
Feb 2021
invasive FFRCT in Coronary Care
(ADVANCE)
NCT02208388
Prospective Evaluation of Myocardial
1000
Apr 2024
Perfusion Computed Tomography
Trial
Unpublished
NCT01810198a
Coronary Computed Tomographic
1631
Mar 2016
Angiography for Selective Cardiac
(completed)
Catheterization (CONSERVE)
NCT02805621
Machine Learning Based CT
352
Jan 2017
Angiography Derived FFR: A
(completed)
Multicenter, Registry
Table Key:
NCT: National Clinical Trial;
a: Denotes industry-sponsored or cosponsored trial.
Practice Guidelines and Position Statements: FFR
CT
National Institute for Health and Care Excellence (NICE)
In 2017, the NICE endorsed FFR using CCTA, with the following conclusions: “The committee
concluded that the evidence suggests that HeartFlow FFRCT is safe, has high diagnostic
accuracy, and that its use may avoid the need for invasive investigations.” (107)
Recommendations included:
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• “The case for adopting HeartFlow FFR for estimating fractional flow reserve from coronary
CT
CT angiography (CCTA) is supported by the evidence. The technology is non-invasive and safe,
and has a high level of diagnostic accuracy.”
• “HeartFlow FFR should be considered as an option for patients with stable, recent onset
CT
chest pain who are offered CCTA as part of the NICE pathway on chest pain. Using HeartFlow
FFRCT may avoid the need for invasive coronary angiography and revascularization. For correct
use, HeartFlow FFRCT requires access to 64-slice (or above) CCTA facilities.”
U.S. Preventive Services Task Force (USPSTF) Recommendations
No USPSTF recommendations for FFRCT have been identified.
Summary of Evidence: FFR
CT
For individuals with stable chest pain at intermediate risk of coronary artery disease (CAD; i.e.,
suspected or presumed stable ischemic heart disease) being considered for invasive coronary
angiography (ICA) who receive noninvasive fractional flow reserve (FFR) measurement
following positive coronary computed tomography angiography (CCTA), the evidence includes
both direct and indirect evidence: 2 meta-analyses on diagnostic performance; 1 prospective,
multicenter nonrandomized comparative study; 1 prospective cohort; 2 retrospective cohort
studies; and a study reporting changes in management associated with CCTA-based strategies
with selective addition of fractional flow reserve using coronary computed tomography
angiography (FFR
) and a randomized controlled trial (RCT) of CCTA alone compared with
CT
ICA.
Relevant outcomes are test accuracy and validity, morbid events, quality of life, resource
utilization, and treatment-related morbidity. The meta-analyses indicated that CCTA has high
sensitivity but moderately low specificity for hemodynamically significant obstructive disease.
Given the available evidence that CCTA alone has been used to select patients to avoid ICA,
the studies showing higher specificity of FFRCT and lower negative likelihood ratio of FFR
CT
compared with CCTA alone, may be used to build a chain of evidence that CCTA with a
selective FFRCT strategy would likely lead to changes in management that would be expected
to improve health outcomes by further limiting unnecessary ICA testing. Moreover, there is
direct evidence, provided by 2 prospective and 2 retrospective studies, that compares health
outcomes observed during 90-day to 1-year follow-up for strategies using CCTA particularly in
combination with selective FFRCT with strategies using ICA or other noninvasive imaging tests.
The available evidence provides support that use of CCTA with selective FFRCT is likely to
reduce the use of ICA in individuals with stable chest pain who are unlikely to benefit from
revascularization by demonstrating the absence of functionally significant obstructive CAD. In
addition, the benefits are likely to outweigh potential harms because rates of revascularization
for functionally significant obstructive CAD appear to be similar and treatment-related adverse
events do not appear to increase following CCTA with a selective FFRCT strategy. While
individual studies are noted to have specific methodologic limitations and some variation has
been noted in the magnitude of benefit across studies, in aggregate the evidence provides
reasonable support that the selective addition of FFRCT following CCTA results in a meaningful
improvement in the net health outcome. The evidence is sufficient to determine that the
technology results in meaningful improvements in the net health outcome.
Contract:
Each benefit plan, summary plan description or contract defines which services are covered,
which services are excluded, and which services are subject to dollar caps or other limitations,
conditions or exclusions. Members and their providers have the responsibility for consulting the
member's benefit plan, summary plan description or contract to determine if there are any
exclusions or other benefit limitations applicable to this service or supply. If there is a
discrepancy between a Medical Policy and a member's benefit plan, summary plan
description or contract, the benefit plan, summary plan description or contract will
govern.
Coding:
CPT code 71250, 71260, 71270 describe CT (computed tomography) of thorax without
contrast, with contrast or without contrast, followed by contrast administration. These codes are
not applicable for documenting computed tomography angiography (CTA).
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Using CPT code 71275 for CTA of the chest is not the appropriate code for heart or coronary
vessel testing. This code reflects the use for screening or diagnostic testing to rule out
pulmonary emboli or mediastinal masses.
The correct CPT codes are 75572, 75573, and 75574 CCTA of heart and/or coronary arteries.
There is no specific code to identify noninvasive fractional flow reserve using computed
tomography (FFR
).
CT
CODING:
Disclaimer for coding information on Medical Policies
Procedure and diagnosis codes on Medical Policy documents are included only as a general
reference tool for each policy. They may not be all-inclusive.
The presence or absence of procedure, service, supply, device or diagnosis codes in a Medical
Policy document has no relevance for determination of benefit coverage for members or
reimbursement for providers. Only the written coverage position in a medical policy should
be used for such determinations.
Benefit coverage determinations based on written Medical Policy coverage positions must
include review of the member’s benefit contract or Summary Plan Description (SPD) for defined
coverage vs. non-coverage, benefit exclusions, and benefit limitations such as dollar or duration
caps.
CPT/HCPCS/ICD-9/ICD-10 Codes
The following codes may be applicable to this Medical policy and may not be all
inclusive.
CPT Codes
75572, 75573, 75574, 0501T, 0502T, 0503T, 0504T
HCPCS Codes
None
ICD-9 Diagnosis Codes
Refer to the ICD-9-CM manual
ICD-9 Procedure Codes
Refer to the ICD-9-CM manual
ICD-10 Diagnosis Codes
Refer to the ICD-10-CM manual
ICD-10 Procedure Codes
Refer to the ICD-10-CM manual
Medicare Coverage:
The information contained in this section is for informational purposes only. HCSC makes no
representation as to the accuracy of this information. It is not to be used for claims adjudication
for HCSC Plans.
The Centers for Medicare and Medicaid Services (CMS) does have a national Medicare
coverage position for coronary computed tomography angiography; however, CMS does not
have a national Medicare coverage position for fractional flow reserve computed tomography.
A national coverage position for Medicare may have been changed/developed since this
medical policy document was written. See Medicare's National Coverage at
References:
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1. Mastouri R, Sawada SG, Mahenthiran J. Current noninvasive imaging techniques for
detection of coronary artery disease. Expert Rev Cardiovasc Ther. Jan 2010; 8(1):77-91. PMID
20030023
2. Chow BJ, Small G, Yam Y, et al.; CONFIRM Investigators. Incremental prognostic value of
cardiac computed tomography in coronary artery disease using CONFIRM: coronary computed
tomography angiography evaluation for clinical outcomes: an International Multicenter registry.
Circ Cardiovasc Imaging. Jul 5 2011; 4(5):463-72. PMID 21730027
3. Hadamitzky M, Achenbach S, Malhotra V, et al. Update on an International Registry for
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19190314
4. Gerber TC, Carr JJ, Arai AE, et al. Ionizing radiation in cardiac imaging: a science advisory
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Cardiology and Committee on Cardiovascular Imaging and Intervention of the Council on
Cardiovascular Radiology and Intervention. Circulation. Feb 24 2009; 119(7):1056-65. PMID
19188512
5. Hausleiter J, Meyer T, Hermann F, et al. Estimated radiation dose associated with cardiac CT
angiography. JAMA. Feb 4 2009; 301(5):500-7. PMID 19190314
6. Einstein AJ, Henzlova MJ, Rajagopalan S. Estimating risk of cancer associated with radiation
exposure from 64-slice computed tomography coronary angiography. JAMA. Jul 18 2007;
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