FDA-approved FFRct technology may be considered reasonable and necessary in
the management of patients with:

a. Intermediate-risk* patients with acute or stable chest pain with no known
history coronary artery stenosis with finding of 40-90% in proximal or middle
coronary artery on CCTA1 **OR**

b. Intermediate risk* patients with acute chest pain and known non-obstructive
(<50%) CAD coronary artery stenosis with finding of of 40-90% stenosis in
proximal or middle coronary artery on CCTA1  **OR**

c. Stable non-obstructive coronary artery disease (<50% stenosis) with
persistent** symptoms requiring further test, and finding of 40-90% stenosis
on CCTA1

**AND**

Not in conjunction with stress testing* (unless CCTA was not sufficient
quality for FFRCT, and an alternative study needed)

*Intermediate and high-risk and stress test as as defined in the 2021 AHA/ACC/ASE/CHEST/SAEM/SCCT/SCMR Guideline for the Evaluation and Diagnosis of Chest Pain1

**Persistent symptoms are unacceptable ischemia-related symptoms despite
maximally tolerated medical therapy.

FFRct is not considered reasonable in the following clinical circumstances:

  1. Prior placement of prosthetic valves
  2. Prior placement of grafts in coronary bypass surgery
  3. Suspicion of acute coronary syndrome (where MI or unstable angina have not been ruled out)
  4. Intracoronary metallic stent
  5. Status post-heart transplantation
  6. Recent MI (30 days or less)
  7. Prior pacemaker or defibrillator lead placement
  8. Newly diagnosed systolic heart failure, with no prior left heart catherization
  9. Left main coronary artery disease with Intermediated Coronary Stenosis (lumen reduction less than or equal to 40%)
  10. Non-obstructing stenosis (<50% of all major epicardial vessels) on CTA or catherization in the past twelve months, in the absence of a new symptom complex.
  11. If turnaround times may impact prompt clinical care decisions

This service should be performed in patients with stable coronary symptoms. It
should not be performed until after the base study (CCTA) has been completed
and interpreted. If higher grade stenoses (i.e. greater than 90%) are present,
this study is not medically necessary, as the patient should proceed to
catheterization. Similarly, low-grade stenoses (less than 40%) do not require
additional confirmatory data. This should be performed as an alternative to
stress testing.

**Background**

The concept of invasive fractional flow reserve as a diagnostic tool was
introduced in the early 1990's. The FAME and FAME-II trials supported an FFR-
wire guided revascularization strategy as opposed to purely angiographically
guided revascularization.2 The National Cardiovascular Data Registry
demonstrated a low diagnostic yield from traditional exercise stress testing
when the patient progressed to invasive coronary angiography. Fractional flow
reserve is considered the gold standard for assessing the hemodynamic
significance of intermediate coronary stenosis by measuring the pressure
difference across a coronary artery stenosis.3 Intracoronary catheter pressure
measurement before and after the stenosis are compared, and FFR of 0.80
correlates with a 20% pressure drop after the stenosis. This measurement can
help determine if the vessel narrowing is limiting blood flow and assess the
need for revascularization or stenting. Clinical studies have demonstrated
that invasive FFR reduces unnecessary stenting procedures and associated
risk.2,4 The use of invasive FFR is supported by the Society of Cardiac
Angiography and Interventions (SCAI) and American College of Cardiology
(ACC).4,5

Noninvasive fractional flow reserve is an alternative modality to gain this
information without the need for invasive intracoronary instrumentation in
patients with known or suspected coronary artery disease (CAD). FFRct is a
fractional flow reserve derived from computed tomography that relies on
computer-assisted processing of coronary computed tomographic angiography
(CCTA) images to estimate coronary blood flow changes related to coronary
artery stenoses. Based on physical theories of fluid dynamic modeling, FFRct
is a post-processing software for analyzing previously acquired digital
imaging from CCTA. Limitations include that the technology is dependent on the
image quality of the CCTA, the images must be sent out for post-processing;
therefore, real time results are not feasible, and how to apply FFRct results
to clinical practice is still in development. Emerging technologies include
virtual FFR (vFFR), where the measurements are based on a 3-D image of
coronary vessels created by the software using x-ray angiographic imaging.
Angio-derived FFR is calculated at the time of coronary angiogram.

Persistent CAD symptoms are unacceptable ischemia-related symptoms that
persist despite optimal medical therapy. Optimal medical therapy is defined by
the ISCHEMIA trial protocol6 as unacceptable ischemia-related symptoms despite
maximally tolerated medical therapy. This includes at least two anti-anginal
drugs from different drug classes added to beta-blocker therapy and titrated
to maximally tolerated doses before medical therapy is considered to have
failed.6

The analysis of coronary artery disease by NON-INVASIVE CORONARY computed
tomographic analysis has been limited by low specificity. The addition of
computer derived flow analysis of the CTA data has added the potential for a
NON-INVASIVE test that yields both anatomic and functional data. This emerging
technology aims to reduce the need for invasive cardiac procedure, and
associated risks.

The DeFACTO study (Determination of Fractional Flow Reserve by Anatomic
Computed Tomographic Angiography) compared the first iteration of FFRct
technology against invasive angiography and FFR in patients with suspected or
known CAD, but did not achieve the pre-specified target accuracy.3 Another
study, DISCOVER-FLOW, demonstrated an accuracy of 84.6%.7 A second iteration
of the FFRct algorithm was tested against invasive angiography with FFR in 254
patients with suspected CAD in the NXT (Analysis of Coronary Blood Flow Using
CT Angiography- Next Steps) trial. This study reported a diagnostic accuracy,
sensitivity, specificity, positive predictive value, and negative predictive
value of 81%, 86%, 79%, 65% and 83% respectively.8 In this trial, 484 vessels
in 254 patients and found that FFRct significantly improved the per patient
specificity and PPV (32 to 84% and 40 to 65%, respectively) and the per vessel
specificity and PPV (60 to 86% and 33 to 67%, respectively) compared to CTA.
However, this does not translate into benefit compared to CTA alone for
identifying patients whose invasive FFR will warrant intervention, and 35% of
the abnormal results were false positives.9 A sub analysis of the NXT study
evaluated 206 participants and reported no cardiac death or myocardial
infarctions in participants with normal FFRct at a median follow-up of 4.7
years. The authors concluded that an FRRct value of 0.8 or less is a predictor
of long term outcomes driven by planned and unplanned revascularization and is
superior to clinically significant stenosis on coronary CCTA.10

The PROMISE study demonstrated that patients with an FFRct less than or equal
to 0.80 were significantly more likely to have coronary revascularization and
to meet the composite endpoint of major adverse cardiac events or
revascularization than those with FFRct greater than 0.80.9  The study also
showed that reserving invasive coronary angiography for patients with FFRct
less than or equal to 0.80 could reduce the rate of performing invasive
coronary angiography by 28%. The initial trial did include a CCTA strategy,
which did not improve outcomes after two years of follow-up. The study, a
retrospective, observational, cohort study, also highlighted the dependence of
FFRct on the quality of the CCTA images being post-processed, with one-third
of the images submitted for review of insufficient quality.11

The FFRct RIPCORD study involved 200 patients and compared the management of
patients by cardiologists with and without the addition of FFRct data to the
baseline CTA data. The additional FFRct data changed the management plan for
72 patients (36%) based on lesion severity assessment. With inclusion of
changes in the PCI target vessel, patient management was altered in 44% of
patients.12

In the PLATFORM study, 584 patients were allocated to noninvasive or invasive
coronary angiography cohorts. Each cohort was divided into standard of care
and FFRct guided care groups. The 90-day primary end point of invasive
catheterization without obstructive coronary artery disease occurred in
significantly fewer patients with FFRct guided care than with usual care in
both cohorts. This prospective, longitudinal comparative effectiveness study
demonstrated that in an appropriately selected population for CCTA, 88% of the
studies were of sufficient quality to perform FFRct on the derived
images.13-15 From the initial group of patients, 116 were identified to
undergo ICA. Fifty-two underwent CTA/FFRct resulting in the cancellation of
the ICA in 40 (77%). At one year, they reported no major cardiovascular events
in this group.16 While this is promising, there are significant limitations.
The group was not allocated randomly, and patients in the FFRct arm were
younger, had a lower incidence of diabetes, and lower pretest probability of
obstructive CAD. The small sample size was not powered to show a difference in
clinical events and major cardiac events; therefore, this data cannot be
extrapolated to a larger, more diverse population.

The ADVANCE registry (Assessing Diagnostic Value of Non-Invasive FFRct in
Coronary Care) is a large prospective registry that included 5,083 patients
with symptoms suggestive of angina from 38 centers in Europe, North America
and Japan. There was a change in management pathway in 66% of patients, after
FFRct data were available compared with CCTA alone.17 At one year, the authors
report that patients with FFRct 0.80 were less frequently referred for ICA
(from 62.9% to 252.9%, P < 0.001) and reported the prevalence of major events
was low and similar between the cohorts.18,19 This data is limited by the
observational nature of the study with the inability to adjust for confounding
factors such as additional studies being used to make the ultimate decision of
whether or not to proceed with ICA, the risk from multiple biases including
referral bias, attrition bias, and other bias, and variable experience with
FFRct among the study sites.

A recent Danish observational study that included 3674 patients with suspected
coronary artery disease who underwent CCTA with FFRct for stenosis between 30%
and 90% had supportive findings for use of this technology in care management.
Patients with FFRct greater than 0.8 had similar outcomes to patients without
obstructive disease on CCTA (i.e. less than 30%). By contrast, patients with
FFRct 0.8 had significantly more major adverse coronary events (9.6% vs.
1.4%).20

A 2017 systematic review by Cook et al. evaluated 908 vessels from 536
patients in five studies. They reported that the per-vessel diagnostic
accuracy of FFRct was 81.9% (95% CI: 79.4-84.4%). They further broke down the
diagnostic accuracy of FFRct by the FFRct values and reported values below
0.06, 0.06-0.07, 0.70-0.80, 0.80-0.90, and above 0.9 was 86.4%, 74.7%, 46.1%,
87.3% and 97.9%, respectively. This data showed a clustering of large numbers
of FFRct values in the >0.9 range, where the correlation between FFRct and FFR
was very high. However, when approaching the 0.8 level, the correlation
becomes less robust. Of significance, the FFRct correlation showed 82% overall
diagnostic accuracy through threshold was met for FFRct values lower than 0.63
or above 0.83; however, the correlation between the 0.7 to 0.8 group was
notably lower at 46.1%. More stringent 95% and 98% diagnostic accuracy
thresholds were met for FFRct values lower than 0.53 or above 0.93 and lower
than 0.47 or above 0.99, respectively.21

The 2019 PACIFIC trial is a prospective study comparing 208 patients with
suspected stable CAD who underwent coronary CTA with FFRct calculations,
SPECT, PET, and invasive FFR. 83% of vessels could be evaluated with FFRct,
which demonstrated a diagnostic accuracy, sensitivity, and specificity of 87%,
90%, and 86% on a per-vessel basis and 78%, 96%, and 63% on a per-patient
basis, respectively. FFRct outperformed coronary CTA and SPECT, and PET for
vessel-specific ischemia, while PET performed better for per-patient and
intention-to-diagnosis analysis.22

The 2019 ReASSESS trail is a single centered prospective study where 143
patients scheduled to undergo invasive coronary angiogram with stable angina
also underwent FFRct and SPECT. They found FFRct had similar overall
diagnostic accuracy, and FFRct had higher diagnostic sensitivity than SPECT
(91% (95% CI:81% to 97%) versus 41% (95% CI; 29% to 55%; p<0.001). The
specificity of FFRct compared to invasive FFR, was 55% (86% SPECT) with PPV a
58% and the overall accuracy of 70%. In analyzing diagnostic performance for
detection of coronary artery disease on an intention to treat basis positive
predictive value was 47% with accuracy of 63%.23

A 2020 meta-analysis of seventy-seven studies found that FFRct identifies
clinically significant stenosis in patients with suspected CAD with a high
sensitivity (mean 85%, 95% CI: 81-88%), but low to moderate specificity (mean
69%, 95% CI: 64 to 74%).24

Additional literature recommended by the ACC provided better insight into
current anatomic applications and the accuracy of the determinations. The
SYNTAX family of randomized controlled trials demonstrated that PCI or
stenting is a viable option in patients with three-vessel disease and applying
this technology to decision-making regarding CABG or PCI. Use of FFRct to
determine a functional SYNTAX Score (in the SYNTAX III study) reclassified 30%
of patients to a lower score.25-27 ACC also provided additional literature
supporting the accuracy of CCTA in obese patients.28,29

Accuracy with FFRct has been validated in several studies compared to invasive
FFR to be around 80% in patients with stable CAD. While non-invasive FFRct
shows promise as comparable or even superior performance to some existing
technologies, such as stress test or SPECT, it falls behind invasive FFR in
accuracy and PPV. The PPV ranges from 52-65% among the various studies.8,22,23
There is also a risk of false positive of up to 35%, so confirmation at the
time of invasive coronary angiogram confirmation of the lesion is often
performed before stent placement.9

Numerous pivotal trials repeatedly exclude patients with BMI >35 in inclusion
criteria. The ADVANCE registry indicated that high BMI was not a statistically
significant predictor of CCTA quality rejection. Many patients with a BMI >39
were successfully able to receive the FFRct service30. Additional literature
suggests that CCTA provide high diagnostic accuracy in both obese and non-
obese population.29 A sub-analysis from the PROMISE trial including 606
patients with BMI 40 showed a slightly higher (not statistically significant)
yield for positive noninvasive results (13.1% for BMI 35 compared to 12.1%
with BMI <35\. Significantly the ability to conduct and interpret the test was
not limited if the scanner could accommodate higher BMI's for the CCTA.31

A 2021 prospective study of forty-two patients (68 vessels) with severe aortic
stenosis underwent FFR and CTA with 88.2% of vessels having interpretable CTA
to allow FFR-CT analysis. There was a strong positive correlation between FBR
and FFR-CT (p<0.0001). The authors conclude that CTA and FFR-CT are safe and
feasible with diagnostic accuracy in patients with severe aortic stenosis.32

**Societal Guidance**

The use of invasive FFR is endorsed by multiple societies, including the
Society of Cardiac Angiography and Interventions (SCAI) and American College
of Cardiology (ACC)4,33 and European Society of Cardiology.34

The 2021 AHA/ACC/ASE/CHEST/SAEM/SCCT/SCMR Guideline for the Evaluation and
Diagnosis of Chest Pain: Executive Summary1 added recommendation that FFR can
be useful for diagnosis of vessel-specific ischemia and to guide decision-
making regarding the use of ICA for three categories of patients.1

  1. Intermediate-risk and previously unknown coronary stenosis of 40-90% in proximal or middle coronary artery
  2. Intermediate-risk with acute chest pain and known coronary stenosis of 40-90% in proximal or middle coronary artery
  3. Known nonobstructive coronary with stable chest pain and stenosis from 40-90% on CCTA.

The level of evidence was graded B-NR which represents moderate quality
evidence from one or more well-designed, non-randomized study and/or meta-
analysis of such studies, and a Class of Recommendation (COR) 2a which is
moderate strength of recommendation which means benefits are felt to outweigh
risk. In the clinical pathways they recommend FFRct or stress test. They
stated an advantage of FFRct is not needing to order an additional test but
should not be ordered in cases where CCTA imaging may be suboptimal or there
is extensive plaque present when stress test is preferred. Additionally, FFRct
should not be performed when a delay in the results could impact patient care.

These and other studies were discussed by the assembled subject matter experts
in a formal CAC discussion convened by Noridian on June 18, 2019. Based on a
review of the literature, there was a consensus that FFRct is a useful
modality in the guidance of and assessment of stable coronary artery disease.
At the time of the initial policy there was not sufficient evidence to allow
for obesity (BMI >39) and evidence supported vessel specific restrictions
within stenosis range of 40-70% range.

Since this LCD became active the 2021 AHA/ACC/ASE/CHEST/SAEM/ SCCT/SCMR
Guideline for the Evaluation and Diagnosis of Chest Pain: Executive Summary
was published with guidelines for use of FFRct with a moderate strength
recommendation to expand the role of FFRct in specific clinical settings as an
alternative to stress test.1 The LCD has been updated to reflect these
guidelines changes. The guidelines utilize FFRCT as a sequential test.
Therefore, the patient must meet the criteria specified within the algorithms
to qualify for CCTA. If CCTA is performed and reveals 40-90% stenosis in the
proximal or middle coronary artery than FFRct or stress test may be performed.
Based on these guidelines the intermediate stenosis range on CCTA has been
expanded to 40-90%, vessel specific limits revised, and expansion to stable
chest pain has been added to align with the clinical scenarios specified in
the guidelines. This does not reverse the previously established position that
the technology is not for use in the high-risk patients or when myocardial
infarction has not been excluded. It should not be performed until the base
study (CCTA) has been completed and interpreted and should not be relied upon
when a delay in the results could impact patient care.

 The 2021 Guidelines recommendations provide the option of FFRct or stress
test in the clinical settings which it has been determined to be an
alternative to stress test. Therefore, FFRct should be performed as an
alternative to stress testing. Based on this recommendation a new requirement
has been added that the FFRct will not be covered in conjunction with stress
testing unless CCTA was not sufficient quality for FFRCT, and an alternative
study is needed. While the FFRct offers the benefit of another test not
needing to be performed at a separate time, clinical judgement will be
necessary to limit to clinical circumstances that a high-quality FFRct study
will be expected. The severe obesity is removed as a limitation based on
publication of new literature to support its use in patients with BMI >39 if
the scanner used for CTTA can enable high quality images in setting of severe
obesity. The limitation on aortic stenosis was removed based on new literature
demonstrating accuracy in this population.