BCBS of Kansas City Medical Policy

Coronary Computed Tomography Angiography With Selective Noninvasive Fractional Flow Reserve 6.01.59

Coronary Computed Tomography

Angiography With Selective

Noninvasive Fractional Flow Reserve

Policy Number: 6.01.59

Last Review: 8/2017

Origination: 2/2017

Next Review: 8/2018

Policy

Blue Cross and Blue Shield of Kansas City (Blue KC) will provide coverage for

Coronary Computed Tomography Angiography With Selective Noninvasive

Fractional Flow Reserve when it is determined to be medically necessary because

the criteria shown below are met.

When Policy Topic is covered

The use of noninvasive fractional flow reserve following coronary computed

tomography angiography to guide decisions about the use of invasive coronary

angiography in patients with stable chest pain at intermediate risk of coronary

artery disease (ie, suspected or presumed stable ischemic heart disease) may be

considered medically necessary.

When Policy Topic is not covered

Considerations

CPT 75574 Computed tomographic angiography, heart, coronary arteries and

bypass grafts (when present), with contrast material, including 3D image

postprocessing (including evaluation of cardiac structure and morphology,

assessment of cardiac function, and evaluation of venous structures, if

performed).

As of 1/1/2018:

0501T Noninvasive estimated coronary fractional flow reserve (FFR) derived from

coronary computed tomography angiography data using computation fluid

dynamics physiologic simulation software analysis of functional data to assess the

severity of coronary artery disease; data preparation and transmission, analysis of

fluid dynamics and simulated maximal coronary hyperemia, generation of

estimated FFR model, with anatomical data review in comparison with estimated

FFR model to reconcile discordant data, interpretation and report (new code

effective 01/01/18)

Coronary Computed Tomography Angiography With Selective Noninvasive Fractional Flow Reserve 6.01.59

0502T data preparation and transmission (new code effective 01/01/18)

0503T analysis of fluid dynamics and simulated maximal coronary hyperemia, and

generation of estimated FFR model (new code effective 01/01/18)

0504T anatomical data review in comparison with estimated FFR model to

reconcile discordant data, interpretation and report(new code effective 01/01/18)

Description of Procedure or Service

Populations

Interventions

Comparators

Outcomes

Individuals:

Intervention of

Comparator of interest

Relevant outcomes

 With stable chest

interest are:

are:

include:

pain at

 Coronary

 Test accuracy

intermediate risk

computed

 Test validity

of coronary artery

tomography

 Morbid events

disease being

angiography with

angiography

 Quality of life

considered for

selective

 Invasive coronary

 Resource utilization

invasive coronary

noninvasive

angiography

 Treatment-related

angiography

fractional flow

 Other noninvasive

morbidity

reserve

functional tests

measurement

Summary

Invasive coronary angiography (ICA) is clinically useful in stable ischemic heart

disease (SIHD) when there is coronary artery obstruction that may benefit from

revascularization. However, many individuals currently undergoing ICA will not

benefit from revascularization. Therefore, if there are noninvasive alternatives to

guide decisions about the use of ICA to spare individuals from undergoing

unnecessary ICA, there is potential to improve health outcomes. Using noninvasive

measurement of fractional flow reserve as part of a noninvasive imaging strategy

prior to ICA may be beneficial to avoid the need for ICA.

For individuals with stable chest pain at intermediate risk of coronary artery

disease (CAD; ie, suspected or presumed SIHD) being considered for ICA who

receive coronary computed tomography angiography (CCTA) with selective

noninvasive fractional flow reserve (FFR-CT) measurement, the evidence includes

both direct and indirect evidence: 2 meta-analyses on diagnostic performance; 1

prospective, multicenter nonrandomized comparative study; 2 retrospective cohort

studies; and a study reporting changes in management associated with CCTA-

based strategies with selective addition of FFR-CT and a randomized controlled

trial (RCT) of CCTA alone compared with 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 FFR-CT 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 FFR-CT 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 1 prospective and 2 retrospective studies, that compares health

Coronary Computed Tomography Angiography With Selective Noninvasive Fractional Flow Reserve 6.01.59

outcomes observed during 90-day to 1-year follow-up for strategies using CCTA

particularly in combination with selective FFR-CT with strategies using ICA or other

noninvasive imaging tests. The available evidence provides support that use of

CCTA with selective FFR-CT 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 FFR-CT 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 FFR-CT 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.

Background

Stable Ischemic Heart Disease

Coronary artery disease (CAD) is a significant cause of morbidity and mortality and

various epidemiologic risk factors have been well studied. 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. However, invasive

coronary angiographies (ICAs) are frequently unnecessary in patients with

suspected stable ischemic heart disease (SIHD), as evidenced by low diagnostic

yields for significant obstructive CAD. For example, from a sample of over 132,000

ICAs, Patel et al (2010) found 48.8% of elective ICAs performed in patients with

stable angina did not detect obstructive CAD (left main stenosis ≥50% or ≥70% in

a major epicardial or branch >2.0 mm in diameter).¹ ICA is clinically useful when

patients with stable angina have failed optimal medical therapy and may benefit

from revascularization. A noninvasive imaging test, performed prior to ICA as a

gatekeeper, that can distinguish candidates who may benefit from early

revascularization (eg, 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.

Moreover, for the large majority of patients with SIHD, revascularization offers no

survival advantage over medical therapy; there are few who might benefit from

ICA if they have not first failed optimal medical therapy.²

Gatekeepers to ICA

Imposing an effective noninvasive gatekeeper strategy with 1 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

Coronary Computed Tomography Angiography With Selective Noninvasive Fractional Flow Reserve 6.01.59

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 coronary

computed tomography angiography (CCTA), magnetic resonance imaging, single-

photon emission computed tomography, positron emission tomography, and stress

echocardiography. More recently, adding noninvasive measurement of fractional

flow reserve (FFR) using CCTA has been suggested, combining functional and

anatomic information.

Fractional Flow Reserve

Invasively measured FFR evaluates the severity of ischemia caused by coronary

artery obstructions and can predict when revascularization may be beneficial.^3-5

FFR has not been used as a diagnostic test for ischemic heart disease, but as a

test to evaluate the degree of ischemia caused by a stenosis.

Invasive FFR is rarely used in the United States 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.⁶ 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 and observational studies have demonstrated that

FFR-guided revascularization can improve cardiovascular outcomes, reduce

revascularizations, and decrease costs. ⁷ For example, the Fractional Flow Reserve

versus Angiography for Multivessel Evaluation (FAME) trial randomized 1005

patients with multivessel disease and planned PCI.^5,8 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% vs 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.⁹

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”.¹⁰ 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).¹¹ U.S. guidelines (2012)

have stated that an FFR of 0.80 or less provides level Ia evidence for

Coronary Computed Tomography Angiography With Selective Noninvasive Fractional Flow Reserve 6.01.59

revascularization for “significant stenoses amenable to revascularization and

unacceptable angina despite guideline directed medical therapy.”¹² In addition, the

importance of FFR in decision making appears prominently in the 2017 appropriate

use criteria for coronary revascularization in patients with SIHD.¹³

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,14 and reproducibility is

high.¹⁵ 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.

Noninvasive FFR Measurement

FFR can be modeled noninvasively using images obtained during CCTA¹⁶—so-called

fractional flow reserve using coronary computed tomography angiography (FFR-

CT; HeartFlow software termed FFRCT; Siemens cFFR) using routinely collected

CCTA imaging data. The process involves constructing a digital model of coronary

anatomy and calculating FFR across the entire vascular tree using computational

fluid dynamics. FFR-CT can also be used for “virtual stenting” to simulate how

stent placement would be predicted to improve vessel flow.¹⁷

Only the HeartFlow FFRCT software has been cleared by the U.S. Food and Drug

Administration. 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. FFR-CT requires at least 64-slice CCTA and cannot be

calculated when images lack sufficient quality¹⁸ (11% to 13% in recent studies^19-

²²), eg, in obese individuals (eg, body mass index, >35 kg/m²).

Regulatory Status

In November 2014, FFRCT simulation software (HeartFlow) was cleared for

marketing by the U.S. Food and Drug Administration (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 postprocessing 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 FFRCT [fractional

flow reserve using coronary computed tomography 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

Coronary Computed Tomography Angiography With Selective Noninvasive Fractional Flow Reserve 6.01.59

evaluation of coronary artery disease. The results of this analysis [FFRCT] are

provided to support qualified clinicians to aid in 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.”

Rationale

This evidence review was originally created in December 2016 and has been

updated regularly with searches of the MEDLINE database. The most receive

literature review was performed through April 11, 2017, to identify literature

assessing 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; ie,

suspected or presumed stable ischemic heart disease [SIHD]) being considered for

ICA. HeartFlow also submitted a list of publications and materials for review.

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 fractional flow reserve using coronary

computed tomography angiography (FFR-CT) in patients with stable chest 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.

The following PICOTS were used to select literature to inform this review.

Patients

The population of interest includes patients with stable chest pain at intermediate

risk of CAD (ie, with suspected or presumed SIHD) who are being considered for

ICA. Patients may have undergone prior noninvasive testing and been treated for

presumed stable angina.

Interventions

The intervention of interest is CCTA with selective FFR-CT when CCTA shows

evidence of coronary artery stenosis.

Comparators

Coronary Computed Tomography Angiography With Selective Noninvasive Fractional Flow Reserve 6.01.59

The comparator of interest is CCTA may be performed alone without FFR-CT.

Individuals may proceed directly to ICA. Conventional noninvasive imaging tests

providing functional information, including myocardial perfusion imaging (MPI)

using single-photon emission computed tomography (SPECT), stress

echocardiography (SECHO), and cardiac positron emission tomography (PET), may

be used prior to ICA. Cardiovascular magnetic resonance imaging (MRI) is also an

option.

Outcomes

The final outcomes of interest include ICA rates, ICA without obstructive CAD,

major adverse cardiovascular events (MACE), and adverse events attributed to

testing and treatment.

The intermediate outcome of interest is the ability of the test to distinguish

clinically significant CAD for which revascularization may provide benefit.

Timing

Rates of ICA and treatment-related morbidity are typically short-term (eg, ≤3

months). In addition, rates of subsequent ICA, treatment-related morbidity, MACE,

quality of life, and resource utilization ascertained over a period of 1 to 3 years are

also of interest.

Setting

The setting is a general cardiology practice for patients undergoing nonemergent

chest pain evaluation.

Technical Performance

Data supporting technical performance derive from the test-retest reliability of

FFR-CT and invasively measured FFR (reference standard). Other technical

performance considerations were summarized in the Food and Drug Administration

(FDA) documentation.^18,23

Johnson et al (2015) reported on the repeatability of invasive FFR.²⁴ 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 0.84.²⁵ Gaur et al (2014) analyzed data

from 28 patients (58 vessels) with repeated FFR-CT and invasive FFR

measurements.²⁶ They reported coefficients of variation of 3.4% (95% CI, 1.5% to

4.6%) for FFR-CT 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 FFR-CT 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

Coronary Computed Tomography Angiography With Selective Noninvasive Fractional Flow Reserve 6.01.59

contraindicated) for vasodilatation, and a lack of nitrates can affect FFR-CT results.

In addition, the FDA de novo summary lists factors that can adversely impact FFR-

CT results, including: imaging data quality, incorrect brachial pressure, myocardial

dysfunction and hypertrophy, and abnormal physiology (eg, congenital heart

disease). Coronary calcium might also impact measurements.²⁷

Section Summary: Technical Performance

Reported results have indicated that the test-retest reliability is acceptable and

other known factors can impact variability of FFR-CT results.

Diagnostic Accuracy

Studies Included in FFR-CT Systematic Reviews: Per-Patient Diagnostic

Accuracy

Twenty-six studies have contributed patient-level results to a 2015 meta-analysis

that examined 5 non-FFR-CT imaging modalities (see Table 1).²⁸ Five studies

contributed results to 2 meta-analyses, Wu et al (2016)²⁹ and Danad et al

(2017),³⁰ evaluating the diagnostic accuracy of FFR-CT 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.^31,32 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.^19,22,33 The NXT Trial, the basis for device clearance by FDA,

was conducted at 11 sites in 8 countries (Canada, EU, Asia).²² Although not

examined in the 2 included meta-analyses, subgroup analyses suggested little

variation in results by sex and age.³⁴ 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

Danad et al (2017) included 23 studies published between January 2002 and

February 2015 evaluating the diagnostic performance of CCTA, FFR-CT, SPECT,

SECHO, MRI, or ICA compared with an invasive FFR reference standard.³⁰ The 3

included FFR-CT 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 FFR-CT

studies). Per-patient and per-vessel meta-analyses were performed. Study quality

was assessed using QUADAS-2³⁵; 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). FFR-CT had 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

Coronary Computed Tomography Angiography With Selective Noninvasive Fractional Flow Reserve 6.01.59

MRI (10.31; 95% CI, 3.14 to 33.9). The negative likelihood ratios were low (lower

is better) for both FFR-CT (0.16; 95% CI, 0.11 to 0.23) and MRI (0.12; 95% CI,

0.05 to 0.30); however, the confidence interval is more narrow for FFR-CT due to

larger sample for FFR-CT. CCTA had a slightly higher negative likelihood ratio

(0.22; 95% CI, 0.10 to 0.50). Per-vessel area under the summary receiver

operating characteristic curve results were similar except for CCTA where per-

patient results were considerably worse (eg, C statistic of 0.57 vs. 0.85).

Reviewers noted heterogeneity in many estimates (eg, CCTA sensitivity, I²=80%).

Finally, pooled results for some imaging tests included few studies.

Wu et al

Wu et al (2016) identified 7 studies (833 patients, 1377 vessels) comparing FFR-

CT with invasively measured FFR from searches of PubMed, Cochrane, EMBASE,

Medion, and meeting abstracts through January 2016.²⁹ Studies included patients

with established or suspected SIHD. In addition to the 3 FFR-CT studies pooled by

Danad et al, 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 1. All studies were rated at low risk of

bias and without applicability concerns using the QUADAS-2 tool.³⁵ Appropriate

bivariate meta-analyses (accounting for correlated sensitivity and specificity) were

used.

As expected given study overlap, FFR-CT performance characteristics were similar

to those reported by Danad et al, but with a slightly higher specificity (see Table

1). 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, FFR-CT

results were uninterpretable in 12.0%²² and 8.2%³⁶ of participants.

Takx et al

Takx et al (2015) identified studies reporting on the ability of perfusion computed

tomography (CT), MRI, SECHO, PET, and SPECT to detect hemodynamically

significant CAD as measured by ICA with invasive FFR.²⁸ Studies published through

May 2014 were eligible for inclusion; PubMed, EMBASE, and Web of Science were

searched. QUADAS-2 was used to assess study quality³⁵; 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 (ie, ability to exclude disease) noting that MPI (eg, 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 PROSPERO³⁷ (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 1) although the confidence interval for PET

was wide. Heterogeneity among studies included in the pooled patient-level results

was considered high for PET (I²=84%), moderate for CT (I²=70%) and SPECT

Coronary Computed Tomography Angiography With Selective Noninvasive Fractional Flow Reserve 6.01.59

(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 MRI,

CT, or PET has the potential to serve as a gatekeeper for invasive assessment of

hemodynamic significance by ICA and FFR.” Studies of FFR-CT were not included

in the analysis.

Table 1. Pooled Per-Patient Pooled Diagnostic Performance of Noninvasive

Tests for Invasive FFR

Sensitivity

Specificity

LR+ (95%

Test

Studies N

(95% CI)

CI)

LR- (95% CI)

Danad et al

(2017)³⁰

90% (75

94% (79 to

10.3

(3.14

0.12 (0.05 to

MRI

0.94

to 97)

99)

to 33.9)

0.30)

FFR-

90% (85

71% (65 to

3.3

(1.78

0.16 (0.11 to

609

0.94

to 93)

75)

to 6.25)

0.23)

90% (86

39% (34 to

1.5

(1.25

0.22 (0.10 to

CCTA

694

0.57

to 93)

44)

to 1.90)

0.50)

77% (61

75% (63 to

3.0

(1.94

0.34 (0.17 to

115

0.82

SECHO

to 88)

85)

to 4.65)

0.66)

70% (59

78% (68 to

3.4

(1.04

0.40 (0.19 to

SPECT

110

0.79

to 80)

87)

to 11.1)

0.83)

69% (65

67% (63 to

2.5

(1.25

0.46 (0.39 to

ICA

954

0.75

to 75)

71)

to 5.13)

0.55)

Wu et al

(2016)²⁹

FFR-

833

89% (85

76% (64 to

0.90

3.7

(2.41

0.14 (0.09 to

to 93)

84)

to 5.61)

0.21)

Takx et al (2015)²⁸

89% (86

87% (83 to

6.3

(4.88

0.14 (0.10 to

MRI

798

0.94

to 92)

90)

to 8.12)

0.18)

88% (82

80% (73 to

3.8

(1.94

0.12 (0.04 to

PCT

316

0.93

to 92)

86)

to 7.40)

0.33)

69% (56

84% (75 to

3.7

(1.89

0.42 (0.30 to

177

0.83

SECHO

to 79)

90)

to 7.15)

0.59)

74% (67

79% (74 to

3.1

(2.09

0.39 (0.27 to

SPECT

533

0.82

to 79)

83)

to 4.70)

0.55)

84% (75

87% (80 to

6.5

(2.83

0.14 (0.02 to

PET

224

0.93

to 91)

92)

to 15.1)

0.87)

CCTA: coronary computed tomography angiography; CI: confidence interval; FFR-CT: fractional

flow reserve using coronary computed tomography angiography; ICA: invasive coronary

angiography; LR: likelihood ratio; MRI: magnetic resonance imaging; PCT: perfusion computed

tomography; PET: positron emission tomography; SECHO: stress echocardiography; SPECT:

single-photon emission computed tomography.

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 Trial reported a

specificity of 54%.³⁸ Accordingly, pooled results from the Danad systematic review

must be interpreted carefully. In addition, there is some uncertainty in the

Coronary Computed Tomography Angiography With Selective Noninvasive Fractional Flow Reserve 6.01.59

generalizability of results obtained in these studies conducted under likely

controlled conditions (eg, data from the NXT Trial²² 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—ie,

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 FFR-CT for excluding physiologically significant coronary stenoses

tended to be lower (ie, 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. The steps

in the logic are illustrated in Figure 1.

Figure 1. Pathway for Clinical Use of FFR-CT to Support Clinical Utility

Optimal Medical

Therapy

Low Negative

Likelihood Ratio

identifies additional

individuals with low

disease probability

who may avoid

Invasive Coronary

Stable Chest Pain

Angiography

with Intermediate

Risk of Coronary

Artery Disease Being

Coronary Computed

Considered for

Tomography

Add FFR-CT

Invasive Coronary

Angiography

(CCTA)

(ie, Suspected Stable

Ischemic Heart

Disease)

Invasive Coronary

Obstructive

Angiography

Coronary Artery

(with invasive FFR if

Disease and

needed)

Revascularization

FFR-CT: fractional flow reserve using coronary computed tomography angiography.

Table 2 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). In contrast, beginning with a pretest probability of

0.50, a negative FFR-CT would yield a posttest probability of 0.14 (95% CI, 0.10

to 0.19) (Danad et al) and 0.12 (95% CI, 0.08 to 0.17) (Wu et al). Overall, the

Coronary Computed Tomography Angiography With Selective Noninvasive Fractional Flow Reserve 6.01.59

negative likelihood ratios and posttest probability estimates for FFR-CT are slightly

better than CCTA as well as SECHO and SPECT.

Table 2. Change in Disease Probability Following a Negative Test

Posttest Probability (95% CI) After

Negative Test

Study

Modality

Negative LR

Pretest

(95% CI)

Probability

0.25

0.50

0.75

Danad et al

(2016)

MRI

0.12

(0.05

0.04

(0.02

0.11 (0.05 to

0.26 (0.13 to

to 0.30)

to 0.09)

0.23)

0.47)

FFR-CT

0.16

(0.11

0.05

(0.04

0.14 (0.10 to

0.32 (0.25 to

to 0.23)

to 0.07)

0.19)

0.41)

CCTA

0.22

(0.10

0.07

(0.03

0.18 (0.09 to

0.40 (0.23 to

to 0.50)

to 0.14)

0.33)

0.60)

SECHO

0.34

(0.17

0.10

(0.05

0.25 (0.15 to

0.50 (0.34 to

to 0.66)

to 0.18)

0.40)

0.66)

SPECT

0.40

(0.19

0.12

(0.06

0.29 (0.16 to

0.55 (0.36 to

to 0.83)

to 0.22)

0.45)

0.71)

ICA

0.46

(0.39

0.13

(0.12

0.32 (0.28 to

0.58 (0.54 to

to 0.55)

to 0.15)

0.35)

0.62)

Wu et al

(2016)

FFR-CT

0.14

(0.09

0.04

(0.03

0.12 (0.08 to

0.30 (0.21 to

to 0.21)

to 0.07)

0.17)

0.39)

Takx et al

(2015)

MRI

0.14

(0.10

0.04

(0.03

0.12 (0.09 to

0.30 (0.23 to

to 0.18)

to 0.06)

0.15)

0.35)

Perfusio

0.12

(0.04

0.04

(0.01

0.11 (0.04 to

0.26 (0.11 to

n CT

to 0.33)

to 0.10)

0.25)

0.50)

SECHO

0.42

(0.30

0.12

(0.09

0.30 (0.23 to

0.56 (0.47 to

to 0.59)

to 0.16)

0.37)

0.64)

SPECT

0.39

(0.27

0.12

(0.08

0.28 (0.21 to

0.54 (0.45 to

to 0.55)

to 0.15)

0.35)

0.62)

PET

0.14

(0.02

0.04

(0.01

0.12 (0.02 to

0.30 (0.06 to

to 0.87)

to 0.22)

0.47)

0.72)

CCTA: coronary computed tomography angiography; CI: confidence interval; CT: computed

tomography; FFR-CT: fractional flow reserve using coronary computed tomography angiography;

ICA: invasive coronary angiography; LR: likelihood ratio; MRI: magnetic resonance imaging; PET:

positron emission tomography; SECHO: stress echocardiography; SPECT: single-photon emission

computed tomography.

We identified 1 study (Curzen et al, 2016) that examined 200 consecutive

individuals selected from the NXT trial population “to reproduce the methodology

of the invasive RIPCORD study” with elective management of stable chest pain.³⁹

All subjects received CCTA including FFR-CT “in at least 1 vessel with diameter ≥ 2

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 FFR-CT results) and selected a management plan from the following 4

options: “1) optimal medical therapy (OMT) alone; 2) PCI + OMT; 3) coronary

artery bypass graft + OMT; or 4) more information about ischemia required - they

Coronary Computed Tomography Angiography With Selective Noninvasive Fractional Flow Reserve 6.01.59

committed to option 1 by consensus.” Following the initial decision, results from

the FFR-CT 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 FFR-CT. 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 FFR-CT 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 FFR-CT as well as vessels identified as targets for

revascularization based on CCTA alone versus CCTA plus FFR-CT. 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 3) 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 FFR-CT results shifted

management for 26 of 87 (30%) to OMT (ie, no ischemic lesion on FFR-CT) and an

additional 16 (18%) individuals remained in the PCI category but FFR-CT identified

a different target vessel for PCI. These findings provide supportive information

that the improved diagnostic accuracy of FFR-CT 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 3. Summary of Overall Changes to Management in Patients Using

CCTA vs CCTA + FFR-CT

Management Category

CCTA Alone,

CCTA + FFR-CT, Strategy Change^a

Consensus Decision

n (%)

(95% CI)

More data required

38 (19.0%)



Optimal medical therapy

67 (33.5%)

113 (56.5%)

23% (18% to 29%)

Percutaneous coronary

87 (43.5%)

78 (39.0%)

-5% (-2% to -8%)

Coronary artery bypass graft

8 (4.0%)

9 (4.5%)

0.5% (0.1% to 3%)

CCTA: coronary computed tomography angiography; CI: confidence interval; FFR-CT: fractional

flow reserve using coronary computed tomography angiography.

^a p<0.001 for between-group change, CCTA alone vs CCTA + FFR-CT.

Direct Evidence

We identified 2 prospective comparative studies including 1 prospective

nonrandomized study that compared an FFR-CT strategy (CCTA with noninvasive

FFR measurement when requested or indicated) with ICA and 1 randomized

controlled trial that examined CCTA as a gatekeeper to ICA (see Tables 4 and 5).

In addition, we identified 2 retrospective cohort studies of patients referred for

CCTA, which included FFR-CT evaluation.

PLATFORM Study

The Prospective LongitudinAl Trial of FFRCT: Outcome and Resource Impacts

(PLATFORM) study compared diagnostic strategies with or without FFR-CT in

patients with suspected stable angina but without known CAD.^40,41 The study was

conducted at 11 EU sites. All testing was nonemergent. Patients were divided into

Coronary Computed Tomography Angiography With Selective Noninvasive Fractional Flow Reserve 6.01.59

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 FFR-CT

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). 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) 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 FFR-CT. 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). FFR-CT was requested in

134 patients and successfully obtained in 117 of 134 (87.3%) in the FFR-CT

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 FFR-CT 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 nonobstructive 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.⁴²

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 FFR-CT may provide clinically useful

information to physicians and patients. Study limitations include a nonrandomized

design; high rate of no obstructive disease with a 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

Coronary Computed Tomography Angiography With Selective Noninvasive Fractional Flow Reserve 6.01.59

effect. The propensity-matched analysis (in a matched subset) offers some

reassurance, but the sample size was likely too small to provide robust results.

CAD-Man Trial

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.⁴³ 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% vs.

31.3%; see Table 4). 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 vs 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

Coronary Computed Tomography Angiography With Selective Noninvasive Fractional Flow Reserve 6.01.59

standing chest pain. The single-center nature of the trial is an additional limitation;

a subsequent multicenter trial (DISCHARGE) is ongoing.

Table 4. Characteristics of Comparative Studies

Nonrandomized

Randomized

PLATFORM

CAD-Man

ICA

FFR-CT

ICA

CCTA

Characteristics

(n=187)

(n=193)

(n=162)

(n=167)

Age (SD), y

63.4

(10.9)

60.7

(10.2)

60.4

(11.4)

60.4

(11.3)

Female, n (%)

79 (42.2%)

74 (38.3%)

88 (52.7%)

78 (48.1%)

Race/ethnic minority, n (%)

2 (1.1%)

1 (0.5%)

Pretest probability obstructive

51.7%

49.4%

37.3%

31.3%

Angina (%)

Typical

52 (27.8%)

45 (23.3%)

Atypical

122 (65.2%)

142 (73.6%)

79 (48.8%)

65 (38.9%)

Noncardiac

12 (7.0%)

5 (2.6%)

80 (49.4%)

97 (58.1%)

Other chest discomfort

3 (1.8%)

5 (3.0%)

Prior noninvasive testing, n (%)

92 (49.2%)

101 (52.3%)

84 (50.3%)

92 (56.8%)

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%)

CAD: coronary artery disease; CCTA: coronary computed tomography angiography; FFR-CT:

fractional flow reserve using coronary computed tomography angiography; ICA: invasive coronary

angiography.

Table 5. Results of Comparative Studies

Nonrandomized

Randomized

PLATFORM

CAD-Man

ICA

FFR-CT

ICA

CCTA

Outcomes

(n=187)

(n=193)

(n=162)

(n=167)

Noninvasive FFR-CT

Requested, n (%)

134 (69.4%)

Successfully performed, n

117 (60.1%)

(%)

ICA no obstructive disease,

137

24 (12.4%)

137 (84.5%)

6 (3.6%)

n (%)

(73.3%)

Absolute difference (95%

60.8% (53.0% to 68.7%)

80.9% (74.6% to 87.2%)

CI), %

ICA, n (%)

187

76 (39.4%)

162 (100%)

24 (14.4%)

(100%)

Absolute difference (95%

60.6% (53.7% to 67.5%)

85.6% (80.3% to 90.9%)

CI), %

Revascularization, n (%)

PCI

49 (26.2%)

55 (28.5%)

CABG

18 (9.6%)

10 (5.2%)

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%)

MACE^b

6 (3.7%)

7 (4.2%)

CABG: coronary artery bypass grafting; CI: confidence interval; FFR-CT: fractional flow reserve

using coronary computed tomography angiography; ICA: invasive coronary angiography; MACE:

major adverse cardiovascular events; PCI: percutaneous coronary intervention.

^aDeath, myocardial infarction, unplanned urgent revascularization

^bCardiac death, myocardial infarction, stroke, unstable angina, any revascularization.

Nørgaard et al Retrospective Cohort

Coronary Computed Tomography Angiography With Selective Noninvasive Fractional Flow Reserve 6.01.59

Nørgaard et al (2017) reported on results from symptomatic patients referred for

CCTA at a single center in Denmark from May 2014 to April 2015.⁴⁴ 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-CT (185 [98%] obtained successfully). Of the 185 individuals who

successfully obtained FFR-CT, FFR-CT demonstrated values of 0.80 or less in 1 or

more vessels in 57 (31%) patients and 49 (86%) went on to ICA; whereas of the

128 with higher FFR-CT values, only 5 (4%) went on to ICA. Assuming ICA was

planned for all patients undergoing FFR-CT, these results are consistent with FFR-

CT being able to decrease the rate of 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 Retrospective Cohort

Lu et al (2017) retrospectively examined a subgroup referred to ICA⁴⁵ 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.⁴⁶ 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 nondiagnostic studies (n=50). Of the

remaining 271 patients, 90 scans were inadequate to obtain FFR-CT, leaving 181

(33%) of those 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 FFR-CT

of 0.80 or less, ICAs might have been avoided in 50 patients (ie, 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 FFR-CT 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 FFR-CT could have decreased the referral

Coronary Computed Tomography Angiography With Selective Noninvasive Fractional Flow Reserve 6.01.59

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 [C]CTA, we found that adding FFRCT may

improve the efficiency of referral to ICA, addressing a major concern of an

anatomic [C]CTA strategy. FFRCT has incremental value over anatomic [C]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,

FFR-CT 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 the some characteristics of the excluded group differed from

the analytic sample. Second, conclusions assume that an FFR-CT greater than

0.80 will always dissuade a physician from recommending ICA and even in the

presence of severe stenosis (eg, ≥70% in any vessel or ≥50% in the left main)—

or almost half (46%) of patients with an FFR-CT greater than 0.80. Finally,

estimates including patients with either nondiagnostic CCTA studies (n=50) or

studies inadequate for calculating FFR-CT (n=90) are more 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 FFR-CT than following usual care (18.3% vs.

12.0%) and ICA, with no obstructive disease more frequent in the FFR-CT arm

(12.5% vs. 6.0%).

Section Summary: Clinical Utility

The evidence on the diagnostic performance characteristics, particularly showing

higher specificity of FFR-CT and better negative likelihood ratio as compared to

CCTA alone, may be combined with indirect evidence that CCTA with a selective

FFR-CT 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 1 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 FFR-CT with strategies using ICA or other

noninvasive imaging tests. The available evidence provides support that use of

CCTA with selective FFR-CT 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 FFR-CT strategy. While individual studies are noted to have specific

methodologic limitations and some variation is noted in the magnitude of benefit

across studies, in aggregate the evidence provides reasonable support that the

Coronary Computed Tomography Angiography With Selective Noninvasive Fractional Flow Reserve 6.01.59

selective addition of FFR-CT following CCTA results in a meaningful improvement

in the net health outcome.

Summary of Evidence

For individuals with stable chest pain at intermediate risk of coronary artery

disease (CAD; ie, suspected or presumed stable ischemic heart disease [SIHD])

being considered for invasive coronary angiography (ICA) who receive coronary

computed tomography angiography (CCTA) with selective noninvasive fractional

flow reserve (FFR-CT) measurement, the evidence includes both direct and indirect

evidence: 2 meta-analyses on diagnostic performance; 1 prospective, multicenter

nonrandomized comparative study; 2 retrospective cohort studies; and a study

reporting changes in management associated with CCTA-based strategies with

selective addition of FFR-CT and a randomized controlled trial (RCT) of CCTA alone

compared with 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 FFR-CT 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 FFR-CT 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 1

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 FFR-CT with strategies using ICA or other noninvasive

imaging tests. The available evidence provides support that use of CCTA with

selective FFR-CT 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 FFR-CT

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 FFR-CT 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.

Supplemental Information

Practice Guidelines and Position Statements

National Institute for Health and Care Excellence

In 2017, the National Institute for Health and Care Excellence endorsed fractional

flow reserve using coronary computed tomography angiography (FFR-CT), with the

following conclusions: “The committee concluded that the evidence suggests that

Coronary Computed Tomography Angiography With Selective Noninvasive Fractional Flow Reserve 6.01.59

HeartFlow FFRCT is safe, has high diagnostic accuracy, and that its use may avoid

the need for invasive investigations.”⁴⁷

Recommendations included:



“The case for adopting HeartFlow FFR-CT for estimating fractional flow reserve

from coronary 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-CT should be considered as an option for patients with stable,

recent onset chest pain who are offered CCTA as part of the NICE pathway on

chest pain. Using HeartFlow FFR-CT may avoid the need for invasive coronary

angiography and revascularization. For correct use, HeartFlow FFR-CT requires

access to 64-slice (or above) CCTA facilities.”

U.S. Preventive Services Task Force Recommendations

Not applicable.

Medicare National Coverage

There is no national coverage determination (NCD). In the absence of an NCD,

coverage decisions are left to the discretion of local Medicare carriers.

Ongoing and Unpublished Clinical Trials

Some currently unpublished trials that might influence this review are listed in

Table 6.

Table 6. Summary of Key Trials

NCT No.

Trial Name

Planned

Completion

Enrollment

Date

Ongoing

NCT02173275 Computed TomogRaphic Evaluation of Atherosclerotic

618

Jul 2017

DEtermiNants of Myocardial IsChEmia

NCT02400229 Diagnostic Imaging Strategies for Patients With

3546

Sept 2019

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 reservE Computed

270

Oct 2020

Tomography Versus Single Photon Emission

Computed Tomography in the Diagnosis of

Hemodynamically Significant Coronary Artery

Disease. (AFFECTS)

NCT02499679^a Assessing Diagnostic Value of Non-invasive FFRCT in

5000

Feb 2021

Coronary Care (ADVANCE)

NCT02208388 Prospective Evaluation of MyocaRdial PerFUSion

1000

Apr 2024

ComputEd Tomography Trial

Unpublished

NCT01810198^a Coronary Computed Tomographic Angiography for

1631

Mar 2016

Selective Cardiac Catheterization (CONSERVE)

(completed)

NCT02805621 Machine leArning Based CT angiograpHy derIved

352

Jan 2017

FFR: a Multi-ceNtEr, Registry

(completed)

Coronary Computed Tomography Angiography With Selective Noninvasive Fractional Flow Reserve 6.01.59

NCT: national clinical trial.

^a Denotes industry-sponsored or cosponsored trial.

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Billing Coding/Physician Documentation Information

75574

Computed tomographic angiography, heart, coronary arteries and

bypass grafts (when present), with contrast material, including 3D

image postprocessing (including evaluation of cardiac structure and

morphology, assessment of cardiac function, and evaluation of venous

structures, if performed)

0501T Noninvasive estimated coronary fractional flow reserve (FFR) derived

from coronary computed tomography angiography data using

computation fluid dynamics physiologic simulation software analysis of

functional data to assess the severity of coronary artery disease; data

Coronary Computed Tomography Angiography With Selective Noninvasive Fractional Flow Reserve 6.01.59

preparation and transmission, analysis of fluid dynamics and simulated

maximal coronary hyperemia, generation of estimated FFR model, with

anatomical data review in comparison with estimated FFR model to

reconcile discordant data, interpretation and report (New code

1/1/2018)

0502T

Noninvasive estimated coronary fractional flow reserve (FFR) derived

from coronary computed tomography angiography data using

computation fluid dynamics physiologic simulation software analysis of

functional data to assess the severity of coronary artery disease; data

preparation and transmission (New code 1/1/2018)

0503T

Noninvasive estimated coronary fractional flow reserve (FFR) derived

from coronary computed tomography angiography data using

computation fluid dynamics physiologic simulation software analysis of

functional data to assess the severity of coronary artery disease;

analysis of fluid dynamics and simulated maximal coronary hyperemia,

and generation of estimated FFR model (New code 1/1/2018)

0504T

Noninvasive estimated coronary fractional flow reserve (FFR) derived

from coronary computed tomography angiography data using

computation fluid dynamics physiologic simulation software analysis of

functional data to assess the severity of coronary artery disease;

anatomical data review in comparison with estimated FFR model to

reconcile discordant data, interpretation and report (New code

1/1/2018)

ICD-10 Codes

I20.9

Angina pectoris, unspecified (includes ischemic chest pain)

I25.118-

Atherosclerotic heart disease of native coronary artery with angina

I25.119

pectoris other than unstable or with documented spasm

Additional Policy Key Words

N/A

Policy Implementation/Update Information

2/2017 New Policy. In patients with suspected stable ischemic heart disease is

considered investigational.

8/1/17 The policy statement was updated to medically necessary for individuals

with stable chest pain at intermediate risk of coronary artery disease

being considered for invasive coronary angiography. Changed title to

"Coronary Computed Tomography Angiography With Selective

Noninvasive Fractional Flow Reserve"

2/1/18 Added Category III codes.

State and Federal mandates and health plan contract language, including specific

provisions/exclusions, take precedence over Medical Policy and must be considered first in

determining eligibility for coverage. The medical policies contained herein are for informational

Coronary Computed Tomography Angiography With Selective Noninvasive Fractional Flow Reserve 6.01.59

purposes. The medical policies do not constitute medical advice or medical care. Treating health

care providers are independent contractors and are neither employees nor agents Blue KC and are

solely responsible for diagnosis, treatment and medical advice. No part of this publication may be

reproduced, stored in a retrieval system or transmitted, in any form or by any means, electronic,

photocopying, or otherwise, without permission from Blue KC.