**Coverage Guidance, Limitations, and Reasonable and Necessary Criteria**

**Noninvasive Fractional Flow Reserve (FFR CT)**

Noninvasive fractional flow reserve deduced from computed tomography (FFRCT)
involves computer-assisted processing of coronary computed tomography
angiography (CCTA) images to estimate changes in blood pressure inside
coronary arteries that have partial blockages, with the goal of determining
how severely the blockages impede blood flow to the heart. FFRCT is a post-
processing software for the clinical quantitative and qualitative analysis of
previously acquired computed tomography (CT) Digital Imaging and
Communications in Medicine (DICOM) data for clinically stable symptomatic
patients with coronary artery disease (CAD). FFRCT analysis is intended to
support the functional evaluation of CAD. The results of this analysis are
provided to support qualified clinicians to aid in the evaluation and
assessment of coronary arteries.

United States (U.S.) Food and Drug Administration (FDA) approved non-invasive
calculated coronary fractional flow reserve
([FFRCT](https://www.accessdata.fda.gov/scripts/cdrh/cfdocs/cfpmn/denovo.cfm?ID=DEN130045))
technology derived from CCTA may be reasonable and necessary to guide
qualified-provider decisions about the use of invasive coronary angiography
(ICA) in clinically stable _symptomatic_ patients with CAD of unknown
functional significance, a technically adequate CCTA AND the following
criteria:

Intermediate risk* patients with acute or stable chest pain and no known
coronary artery disease, with coronary artery stenosis of 40-90% in proximal
or middle coronary artery on CCTA

**OR**

Intermediate risk with acute chest pain and known non-obstructive (<50%) CAD
with findings of coronary artery stenosis of 40-90% in a proximal or middle
coronary artery on CCTA

**OR**

Stable nonobstructive coronary artery disease (<50% stenosis) with persistent
symptoms requiring further test, and findings of 40-90% stenosis on CCTA

**AND**

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

FFRCT testing is not reasonable and therefore not covered for patients with
the following conditions:

  * Bare metal intracoronary stent
  * Prosthetic valves
  * Heart transplantation
  * Recent prior myocardial infarction (MI) within 30 days
  * Suspicion for acute coronary syndrome (where acute MI or unstable angina have not been ruled out)
  * Patients with prior pacemaker or internal defibrillator lead implantation
  * Post coronary artery bypass surgery
  * Newly diagnosed systolic heart failure with no prior left heart catheterization
  * Non-obstructive CAD (<50% stenosis in all major epicardial vessels) on prior CCTA or prior catheterization, performed in last 12 months in the absence of a new symptom complex
  * *If turnaround times may impact prompt clinical care decisions

*Intermediate and high-risk is as defined in the 2021 AHA/ACC/ASE/CHEST/SAEM/SCCT/SCMR Guideline for the Evaluation and Diagnosis of Chest Pain27

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.

Ischemic heart disease is a significant public health problem with an
estimated prevalence of greater than 1 in 3 adults in the U.S. with some form
of cardiovascular disease, including =40 million estimated to be = 60 years of
age.3 Stable ischemic heart disease (SIHD) is diagnosed by symptoms (e.g.,
chest pain or 'ischemic equivalents' such as shortness of breath (dyspnea),
neck/jaw or arm pain, palpitations, dizziness, syncope/near syncope) that are
reproducible primarily with exertion and are not progressing in severity. The
diagnostic approach for patients with symptoms that suggest SIHD, is to
determine whether such symptoms represent the initial clinical recognition of
chronic stable angina, a correlate of supply/demand mismatch precipitated by a
change in activity or concurrent illness (e.g., anemia or infection).4
Invasive coronary angiography (ICA) is frequently unnecessary in patients with
suspected SIHD, as evidenced by low diagnostic yields for significant
obstructive CAD. For example, from a sample of over 132,000 ICAs, Patel, et
al. found 48.8% of elective ICAs performed in patients with what was thought
to be stable angina did not detect obstructive CAD (left main stenosis =50% or
=70% in a major epicardial or branch >2.0 mm in diameter).5 Moreover, for the
large majority of patients with SIHD, revascularization offers no survival
advantage over medical therapy.1 Noninvasive CCTA is very sensitive in
detecting obstructive CAD, but is limited in its positive predictive value.6
CCTA also does not assess the functional significance of visualized lesions,
and often leads to further evaluation with either stress testing or invasive
angiography, or both.7

_Determination of Functionally Significant CAD Using Vessel Anatomy and FFR
CT_

Although it is recognized that individual coronary anatomy is highly variable,
the anatomic construct for CAD is based on the presence or absence of flow-
limiting obstructions in the coronary arteries categorized by the number of
vessels involved (1-, 2-, and 3-vessel, and/or left main CAD) as well as the
amount of myocardium at risk.1

Although imperfect, the commonly used classification of 1-, 2-, and 3-vessel
disease and left main disease remains widely used in clinical practice.1 The
coronary artery anatomy derived from CCTA can now be augmented with
information derived from the physiologic testing of stenosis with FFRCT
technology.8,9 The COURAGE investigators, along with outcome data from other
trials involving more than 5,000 patients, confirmed that PCI (percutaneous
coronary intervention) can be safely deferred with use of optimal medical
therapy (OMT) in patients with stable CAD, even in those with multi-vessel
involvement and inducible ischemia.10-13 The accepted standards for coronary
revascularization in patients with SIHD are outlined in collaborative, multi-
society guidelines that define appropriate use criteria for coronary
revascularization in patients with SIHD.1,4 These management recommendations
are determined by the number of vessels, vessel type, location of stenosis,
and intensity of medical therapy.1 When applied to the decision-making for
revascularization, FFRCT proves useful in providing information to
characterize vessel disease when PCI is a consideration, as opposed to when
optimal medical therapy is recommended.

_Selective FFR CT Guides Determination for Invasive Coronary Angiography _

There is evidence, provided by 2 prospective and 2 retrospective cohort
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 PLATFORM trial was a prospective, longitudinal, comparative-effectiveness
study designed to assess the impact of using FFRCT on stable patients with
suspected CAD and referred for ICA.14,15 The primary endpoint (rate of ICA
showing non-obstructive disease within 90 days) included a control cohort of
187 consecutive patients referred for ICA ("usual care") and 193 patients
referred instead to CCTA and FFRCT. Exclusion criteria included suspicion of
acute coronary syndrome, prior coronary artery bypass graft (CABG), prior PCI,
and contraindications for CCTA which included BMI > 35 kg/m2 (supplemental
data online). Using information obtained from the FFRCT analysis, clinicians
were able to cancel 61% of planned ICAs leading to an 83% reduction in the
primary endpoint of ICAs showing no obstructive disease. One-year outcomes
reported that FFRCT was safe to use with 0 adverse events for those patients
with canceled ICA. It is important to note that this study examined a strategy
of using FFRCT to guide management among patients eligible to undergo CCTA
testing. 88% of CCTAs performed were of sufficient quality to assess FFRCT
consistent with the fact that FFRCT may not be technically feasible in all
patients.14

The PROMISE FFRCT study further supports use of FFRCT for guiding referral to
ICA.16 This retrospective, observational, cohort study examined whether FFRCT
accurately predicts coronary revascularization and adverse events. Using FFRCT
to selectively refer patients to ICA improved catheterization lab efficiency
by showing a reduction in patients referred to ICA by 28% and an increase in
the rate of ICA leading to revascularization by 24%. A positive FFRCT value
was significantly better than CCTA at predicting whether a patient had an
adverse event or underwent revascularization. In a 'real world' patient
population and study design resulting in sites not receiving specific FFRCT
training and feedback (including standard administration of nitroglycerin and
appropriate image reconstruction), the image quality requirements for FFRCT
were much more significant. One-third (33%) of the CCTAs sent to the FFRCT
core laboratory were inadequate for FFRCT analysis. It is also notable that
the BMI of participants of the initial PROMISE CCTA study, the population from
which this FFRCT population was derived, reported to the mean BMI to be 30.5 
6.1kg/m2.7

The ADVANCE registry (Assessing Diagnostic Value of Non-invasive FFRCT in
Coronary Care) included 5,083 patients with symptoms suggestive of angina from
38 centers in Europe, North America, and Japan.17 FFRCT provided information
to physicians that resulted in a change in the management plans in two-thirds
of patients (66.9%), compared to the management plan after CCTA. The
prospective international multi-center study also demonstrated that for
patients with CAD by CCTA and a negative FFRCT (>0.80), medical management was
safe. There were 0 adverse events at 90 days for the 1592 patients in this
group. This contrasts with 19 adverse events (10 death, 4 MI, and 5
hospitalization and urgent revascularization) in patients with positive FFRCT
(=0.80) (MACE hazard ratio 19.75, p<0.001). The investigators concluded that
FFRCT can identify patients in need of invasive assessment. Among patients
whose post-FFRCT management plan was revascularization and who underwent ICA,
72.6% were re-vascularized. FFRCT effectively differentiated patients who
needed further invasive assessment from those who could be managed with
medical therapy. A total of 190 subjects did not have their CCTA examinations
submitted for FFRCT analysis at the site discretion: 111 because the invasive
treatment decision was made due to the severity of the stenosis; 61 owing to
minimal CAD; 9 because of multiple coronary stents; 2 because of CCTA exams
not acquired in a fashion acceptable for FFRCT analysis.17 BMI characteristics
were not reported, however, the U.S. population studied made up less than 23%
of the international registry that included patients from Canada, Europe, and
Japan and it is not clear from the data if the mean BMI across sites
significantly varied (supplemental data).

_2-Year FFR CT Data Demonstrate Positive Health Outcomes _

Norgaard, et al. (NXT Trial) reported 2-year outcomes from a single-center,
observational study that included 3,674 consecutive patients with stable chest
pain. Participants had a median age of 60  9 years and a BMI of 26  4 kg/m2
and were followed for a median of 24 months (range of 8-41 months) after
evaluated with CCTA and selective FFRCT.18 The results demonstrate the ability
of physicians to use the FFRCT service to differentiate patients in need of
PCI or CABG from those who could be managed with OMT alone. Patients with
intermediate stenosis (30-70%) by CCTA who had a negative FFRCT (>0.80) had
2-year outcomes equivalent to patients with no to minimal stenosis (0-30%) by
CCTA. The composite endpoint (all-cause death, MI, hospitalization for
unstable angina, and unplanned coronary revascularization) was 3.9% for the
intermediate stenosis/ FFRCT negative group versus 2.8% for no to minimal
stenosis by CCTA group (p=0.58). Additionally, patients with a positive FFRCT
(=0.80) who underwent invasive assessment had fewer MIs than those with a
positive FFRCT who were managed medically (1.3% versus 8.0%, p<0.001). This
study demonstrated the safety of using FFRCT information to select the best
treatment for patients.

_Positive Health Outcomes Demonstrated in Medicare Population_

Lastly, clinical evidence evaluating 254 Medicare-eligible subjects in a sub-
analysis for the NXT study found that FFRCT has a high diagnostic performance
compared to invasively measured FFR, identifying patients with hemodynamically
significant obstructions with high sensitivity (85%) and specificity (79%) in
subjects = 65 years old with stenosis in the intermediate range (30-70%).19
Over 90% of patients in the analysis had the intermediate range stenosis. The
data also established that myocardial ischemia is unlikely in patients with
FFRCT > 0.80 (negative predictive value (NPV) of 93%) again supporting the
role of CCTA with FFRCT as a reliable gatekeeper to ICA and revascularization.
Other notable characteristics of the study population include mean BMI of 26 
3 kg/m2, normal LVEF of 62%  7, and normal renal function. Patient with acute
coronary syndrome, previous coronary intervention or bypass surgery, or BMI >
35 kg/m2 were excluded. Additionally, 12% (44) CCTA subjects were excluded due
to CCTA image artifacts. Stringent protocols for CCTA acquisition and analysis
were also notable with laboratories following quality standards as defined in
the Society of Cardiovascular Computed Tomography (SCCT) guidelines.2 This
included oral and/or intravenous beta-blockers to achieve to target a heart
rate of < 60 beats/min and sublingual nitrates to ensure coronary
vasodilation.

Additional literature recommended by the America College of Cardiology (ACC)
provided better insight into current anatomic applications and accuracy of the
determinations. The SYNTAX family of randomized controlled trials demonstrated
that PCI or stenting is a viable option in patients with 3 vessel disease, and
in the application of 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.20,21,22 ACC also
provided additional literature supporting accuracy of CCTA in obese
patients.23,24

**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)28,29 and European Society of Cardiology.30

The 2021 AHA/ACC/ASE/CHEST/SAEM/SCCT/SCMR Guideline for the Evaluation and
Diagnosis of Chest Pain: Executive Summary27 added recommendation that FFR can
be useful for diagnosis of vessel-specific ischemia and to guide decision-
making regarding the use of ICA for 3 categories of patients.27

  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.

_Level of evidence - Good (I-IIb, with risks of bias)_

These and other studies were discussed by the assembled subject matter experts
in a formal Contractor Advisory Committee (CAC) discussion convened by
Noridian Healthcare Solutions 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.27 The LCD has been updated to reflect these
guidelines changes.

Based on these guidelines the intermediate stenosis range on CCTA has been
expanded to 40-90% and vessel specific limits revised. The 2021
recommendations include the use of the technology for intermediate-risk
patients with acute chest pain and no known coronary artery disease, with
coronary artery stenosis of 40-90% in proximal or middle coronary artery on
CCTA. This does not reverse the previously established position that the
technology is limited to individuals with stable coronary symptoms and not for
use in the high-risk patients or when myocardial infarction has not been
excluded. It should not be performed until after 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 Guideline 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. In
circumstances where the FFRCT was not high quality and a report could not be
generated then a stress test may be covered as the alternative test. 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. Additionally,
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
CCTA can enable high quality images in setting of severe obesity.