Circulation: Cardiovascular Interventions

CONTEMPORARY REVIEWS IN INTERVENTIONAL CARDIOLOGY

Novel Indices of Coronary Physiology

Do We Need Alternatives to Fractional Flow Reserve?
Giovanni Luigi De Maria, MD, PhD*; Hector M. Garcia-Garcia , MD, PhD*; Roberto Scarsini, MD; Alexandre Hideo-Kajita, MD;
Nieves Gonzalo López, MD, PhD; Antonio Maria Leone, MD, PhD; Giovanna Sarno, MD, PhD; Joost Daemen, MD, PhD;
Evan Shlofmitz, DO; Allen Jeremias, MD, MSc; Matteo Tebaldi, MD; Hiram Grando Bezerra, MD, PhD; Shengxian Tu, PhD;
Pedro A. Lemos, MD, PhD; Yuichi Ozaki, MD, PhD; Kazuhiro Dan, MD, PhD; Carlos Collet, MD, PhD; Adrian P. Banning, MD,
MBBS; Emanuele Barbato, MD, PhD; Nils P. Johnson, MD, MS; Ron Waksman, MD

ABSTRACT: Fractional flow reserve is the current invasive gold standard for assessing the ischemic potential of an
angiographically intermediate coronary stenosis. Procedural cost and time, the need for coronary vessel instrumentation,
and the need to administer adenosine to achieve maximal hyperemia remain integral components of invasive fractional flow
reserve. The number of new alternatives to fractional flow reserve has proliferated over the last ten years using techniques
ranging from alternative pressure wire metrics to anatomic simulation via angiography or intravascular imaging. This review
article provides a critical description of the currently available or under-development alternatives to fractional flow reserve
with a special focus on the available evidence, pros, and cons for each with a view towards their clinical application in the
near future for the functional assessment of coronary artery disease.

Key Words: angiography ◼ computed tomography ◼ coronary artery disease ◼ fractional flow reserve ◼ hyperemia ◼ intravascular imaging
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F
ractional flow reserve (FFR) has become the gold
standard invasive diagnostic test to guide revas-
cularization in patients with coronary artery dis-
ease (CAD).1
It quantifies the peak reduction in flow due to a ste-
nosis, conveniently expressed by the ratio of mean distal
coronary pressure (Pd) to mean aortic pressure (Pa) dur-
ing maximal hyperemia.
The amount of evidence supporting the role of FFR
in the catheterization laboratory is large and still grow-
ing, consistently backing up the results of the 3 landmark
trials DEFER (Deferral of Percutaneous Coronary Inter-
vention),2 FAME (Fractional Flow Reserve Versus Angi-
ography for Multivessel Evaluation),3 and FAME 2.4
Frequently commentators suggest that FFR uptake
in daily practice is limited by a variety of factors: invasive
instrumentation of the coronary artery that requires extra
time, cost, and risk and need for vasodilator medications for
hyperemia that carry effort, cost, and side effects. However,
an operator survey has shown that even after removing all
logistical barriers, operators only selected FFR in 21% of
cases and made angiographic-guided decisions in 71%.5
New physiological indices have been developed with a
view towards reducing the procedural and invasive aspects
of FFR assessment, as summarized in Figure 1. This review
article describes alternatives to FFR, providing insights as
to their development, clinical evidence, and trade-offs.
INVASIVE INDICES
Pressure Wire Based
All of the new wire-based indices share the same aim
of avoiding hyperemia to provide an alternative that is
cheaper, quicker, and with fewer side effects. As a group,

Correspondence to: Giovanni Luigi De Maria, MD, PhD, Heart Centre–John Radcliffe Hospital, Headley Way, OX3 9DU Oxford, United Kingdom, Email giovanniluigi.
demaria@ouh.nhs.uk or Hector M. Garcia-Garcia, MD, PhD, MedStar Washington Hospital Center, 110 Irving St NW, Washington DC, Email hector.m.garciagarcia@
medstar.net
*Drs De Maria and Garcia-Garcia contributed equally to this work.
The Data Supplement is available at https://www.ahajournals.org/doi/suppl/10.1161/CIRCINTERVENTIONS.119.008487.
For Sources of Funding and Disclosures, see page 12.
© 2020 American Heart Association, Inc.
Circulation: Cardiovascular Interventions is available at www.ahajournals.org/journal/circinterventions

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 De Maria et al Alternative Indices for Fractional Flow Reserve

2037 patients with intermediate coronary stenosis to

Nonstandard Abbreviations and Acronyms iFR- or FFR-guided revascularization.9
Of note, 20% of lesions typically present discordant
3D 3-dimensional values between iFR and FFR, and it is unclear what are
CAD coronary artery disease the clinical outcomes when different treatment decisions
CFD computational fluid-dynamic occur based on one or the other of the 2 metrics. Ongo-
cFFR contrast FFR ing debate remains regarding on what to do for lesions
DFR diastolic hyperemia-free ratio whose treatment strategies differ between iFR and FFR,
dPR diastolic pressure ratio with American guidelines emphasizing the larger avail-
FFR fractional flow reserve able evidence behind FFR10 whilst European guidelines
suggest equivalent value for both iFR and FFR.1
FFRCT computed tomography–derived FFR
iFR instantaneous wave-free ratio Pros and Cons
IVUS intravascular ultrasound The advantage of iFR is its elimination of hyperemic
NHPR nonhyperemic pressure-ratios medications, with the potential for reduction in time, side
OCT optical coherence tomography effects, and cost. Additionally, software from its vendor
Pa mean aortic pressure allows for an overlay of the iFR values onto the angio-
Pd mean distal coronary pressure gram during pullback, thereby facilitating physiological-
QFR quantitative flow ratio angiographic fusion (Figure 3).
Drawbacks to iFR include smaller gradients than FFR,
RFR resting full-cycle ratio
thereby making it more sensitive to noise, hydrostatic
vFFR vessel FFR
effects,11 and wire drift during pullback. Finally, iFR could
be more sensitive to variation of hemodynamic conditions
they have been called nonhyperemic pressure-ratios (systemic blood pressure and heart rate) that affect base-
(NHPR; Table I in the Data Supplement). line coronary flow.12 Induced maximal vasodilation satu-
All these indices use the ratio between distal coronary rates the intrinsic coronary autoregulation making FFR
pressure and aortic pressure, but they differ regarding less exposed to hemodynamic status fluctuations.
the phase of the cardiac cycle in which the measurement
Diastolic Pressure Ratio
takes place. In this way, they can be categorized into
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The diastolic pressure ratio (dPR) equals the resting ratio of

phase-specific versus whole-cycle indices (Figure 2).
Phase-Specific Indices
Instantaneous Wave-Free Ratio
The instantaneous wave-free ratio (iFR) is a wire-
based NHPR evaluating Pd/Pa during a specific phase
of diastole, referred to as the wave-free period6 (Fig-
ure 2A and 2B).
At this time, iFR is the only index alternative to FFR
to have been tested in randomized controlled trials. The
DEFINE-FLAIR study (Functional Lesion Assessment of
Intermediate Stenosis to Guide Revascularization) was a
prospective, multicentre, international trial in which 2492
patients with intermediate coronary stenosis were ran-
domized 1:1 to either iFR-guided or FFR-guided revas-
cularization.7 Patients with stable angina and nonculprit
arteries in patients with acute coronary syndromes were
evaluated. The primary end-point was the 1-year occur-
rence of major adverse cardiovascular events defined as
a composite of death, myocardial infarction, or unplanned
revascularization. The study demonstrated that iFR-
guided management was not inferior to FFR guidance.8
Similar results were reported in the iFR-SWEDE-
HEART trial (Instantaneous Wave-Free Ratio Versus
Fractional Flow Reserve in Patients With Stable Angina
Pectoris or Acute Coronary Syndrome) randomizing
mean diastolic pressure distal to the stenosis to the mean
diastolic aortic pressure. Several algorithms exist for calcu-
lating dPR with no significant advantage to any particular
technique. When using iFR as the reference standard, dPR
has been shown to have numerical equivalence.13
More recently, a new version of dPR has been derived
using a dedicated generic software developed at the
Erasmus University Medical Center (Rotterdam, the
Netherlands) has been validated.14 It differs from the pre-
vious version because the diastolic period is automati-
cally delineated based on the dP/dt curve of the aortic
pressure (Figure 2C and 2D). The dP/dt curve repre-
sents the increase and decrease of the pressure over
time during the heart cycle. The flat line of the dP/dt
tracing is being used as trigger for the software to detect
the diastolic wave-free period. dPR is currently provided
by Opsens Medical (Quebec, Canada) and has CE mark.
Pros and Cons
dPR shares the same trade-offs provided by iFR
(Figure 1).
Diastolic Hyperemia-Free Ratio
Diastolic hyperemia-free ratio (DFR) is a new resting
physiology index (Boston Scientific, Marlborough, MA).
DFR provides a resting index derived from the average
Pd/Pa during the period that occurs when the Pa is less

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 De Maria et al Alternative Indices for Fractional Flow Reserve
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Figure 1. Classification and comparisons across the indices for functional assessment of coronary stenosis alternative to
fractional flow reserve (FFR).
CCTA indicates coronary computed tomography angiography; cFFR, contrast FFR; DFR, diastolic hyperemia-free ratio; DPR, diastolic pressure
ratio; FFR, fractional flow reserve; FFRangio, fractional flow reserve angio; FFRCT, computed tomography–derived FFR; iFR, instantaneous wave-
free ratio; IVUSFFR, intravascular ultrasound fractional flow reserve; OCTFFR, optical coherence tomography fractional flow reserve; Pa, aortic
pressure; Pd, distal pressure; QFR, quantitative flow ratio; RCTs, randomized clinical trials; RFR, resting full-cycle ratio; and vFFR, vessel FFR.

than the mean Pa, and there is a down-sloping Pa. The
resultant value is based on a 5-beat average. No ECG sig-
nal is necessary for assessment (Figure 2E and 2F). The
proposed ischemic cutoff for DFR is ≤0.89 (Figure 1).
There is limited clinical data on this new resting index;
however, the data points towards a similarity between
DFR and the other nonhyperemic indices.13
Pros and Cons
DFR offers the same trade-offs as iFR.
Whole Cardiac Cycle Indices
Resting Pd/Pa Ratio
The resting Pd/Pa ratio is calculated over the entire car-
diac cycle (Figure 2G and 2H) and equals the ratio of
the mean (noninstantaneous) Pd and Pa over the entire
cardiac cycle. A multitude of studies has shown equiva-
lent diagnostic performance for Pd/Pa versus iFR when
using various standards (Table II in the Data Supple-
ment). A cutoff of 0.92 for resting Pd/Pa has most often
been identified in clinical studies (Figure 1).
Pros and Cons
Pd/Pa offers all the same trade-offs as other NHPRs.
Compared with other pressure wire-based indices, it has
a wider applicability since it can be measured with any
pressure wire monitoring system.
The main downsides are the lack of unique and validated
ischemic threshold, the lower reproducibility, and higher sus-
ceptibility to hemodynamic variability when compared with
FFR,15 the higher susceptibility to pressure-sensor drifts
and to pressure-curves artifacts when compared with iFR.16
Contrast FFR
Contrast FFR (cFFR) is the lowest mean (non-instanta-
neous) Pd/Pa value obtained after intracoronary injec-
tion of a standard dose of radiographic contrast medium.

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 De Maria et al Alternative Indices for Fractional Flow Reserve
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Figure 2. Pressure wire–based hemodynamic indices.

A, Instantaneous wave-free ratio (iFR) is measured as the ratio between the coronary pressure distal to the stenosis (mean distal coronary
pressure [Pd], green) and the aortic pressure (mean aortic pressure [Pa], red) assessed in the wave-free period identified at wave intensity
analysis (B). C, The diastolic pressure ratio (dPR) is defined as the diastolic Pd/Pa ratio under resting conditions. D, The diastolic period for
calculation of dPR is defined based on dP/dt curve of the aortic pressure. E and F, The diastolic hyperemia-free ratio (DFR) is calculated as the
Pd/Pa ratio in the diastolic period of the cardiac cycle. G and H, Baseline Pd/Pa, fractional flow reserve (FFR), and resting full-cycle ratio (RFR)
are calculated over the entire cardiac cycle. WIA indicates wave intensity analysis.

RINASCI (Rapid Injection of Contrast Medium vs of the Accuracy of the Contrast Medium Induced Pd/Pa
Nitroprusside or Adenosine in Intermediate Coronary Ste- Ratio in Predicting FFR), and CONTRAST (Can Contrast
noses), MEMENTO-FFR (The Multi-Center Evaluation Injection Better Approximate FFR Compared to Pure

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 De Maria et al Alternative Indices for Fractional Flow Reserve

Figure 3. Application of the instantaneous wave-free ratio (iFR) pullback coregistration.

A, Angiography and iFR pullback coregistration showing a physiologically positive result (iFR, 0.77) with the largest drop pressure located
in the stenosis of the mid–left anterior descending artery. B, Virtual stenting showing the estimated physiological result after treatment of
the lesion and the required stent length. C, Lesion was treated with a 3×28 mm stent with a good angiographic result. iFR pullback post
intervention confirmed an appropriate functional result with a normal iFR that correlates well with the estimated value.

Resting Physiology?) studies clearly reported the ability
of cFFR to predicting FFR values in intermediate coro-
nary stenosis.17–19
The results proposed that the cutoff of 0.83 for cFFR
was the best for prediction of FFR. Furthermore, at a cut-
off of 0.83, cFFR was more accurate than resting Pd/
Pa (cutoff of 0.92) and iFR (cutoff of 0.90) in predict-
ing FFR, with resting Pd/Pa and iFR providing equivalent
diagnostic accuracy (Table III in the Data Supplement).
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RFR was highly correlated to iFR (R2=0.99, P<0.001),
with a diagnostic accuracy of 97.4%, sensitivity of
98.2%, specificity of 96.9%, positive predictive value
of 94.5%, negative predictive value of 99.0%. Notably,
the RFR was detected outside the diastole in 12.2% of
all cardiac cycles and in 32.4% of cardiac cycles in the
right coronary artery.20
Pros and Cons
RFR offers the same trade-offs as all other NHPRs.

To maximize the accuracy of cFFR, a hybrid approach

has now been proposed deferring revascularization when
cFFR is above 0.88 and proceeding to stenting when
cFFR is ≤0.83 (Figure 4).
Pros and Cons
cFFR offers the benefit of wide application irrespec-
tively of the pressure wire monitoring system and
postprocessing analysis software. It is thus universally
available and virtually free of any side effects, except
for those related to the use of contrast media. How-
ever, since the hyperemia induced by contrast dye is
relatively short-acting and not steady, cFFR is not suit-
able for pullback analysis.
Resting Full-Cycle Ratio
The resting full-cycle ratio (RFR) seeks the lowest
instantaneous Pd/Pa ratio within the entire cardiac cycle
(Figure 2G and 2H). RFR can be measured online or
calculated offline from each individual waveform with a
fully automated software algorithm, either using equip-
ment from Abbott Vascular (Santa Clara, CA) or from
Coroventis Research AB (Uppsala, Sweden; Figure 5). A
minimum of five consecutive heart cycles is needed to
determine the RFR.
The RFR index was derived and validated for the first
time in the retrospective VALIDATE-RFR study20 with an
optimal RFR cutoff of 0.89 to predict a positive FFR.
Angiography Based
Angiography-based simulations have resurfaced to avoid
the need to instrument the coronary artery, as required by
NHPR, cFFR, and FFR.
Quantitative Flow Ratio
Quantitative flow ratio (QFR) is currently the angiogra-
phy-based index with the largest amount of evidence.
Because QFR seeks to simulate the FFR value, the same
thresholds apply.
The index is measured using the Angio XA 3-dimensional
(3D) software package (Medis Medical Imaging System bv,
the Netherlands) or the AngioPlus system (Pulse Medical
Imaging Technology, Shanghai, China) and is obtained by
application of flow equations to 3D reconstructions of the
coronary tree via combining 2 angiographic projections at
least 25° apart. Coronary flow is indirectly derived from
the measurement of Thrombolysis in Myocardial Infarction
frame count, although in a revised version of the technol-
ogy, Thrombolysis in Myocardial Infarction frame count is
not required anymore without affecting the diagnostic per-
formance of QFR. This analysis can be done either offline
as online.
After 3D reconstruction, an estimated contrast flow
velocity is derived using frame count, identifying the time
at which the contrast enters and leaves the vessel under

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 De Maria et al Alternative Indices for Fractional Flow Reserve

Figure 4. Contrast fractional flow reserve (cFFR).

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Left, Angiography showing an intermediate lesion in the left anterior descending artery. The baseline mean distal coronary pressure (Pd)/
mean aortic pressure (Pa) was 0.86. After injection of 6 mL of contrast medium, the cFFR was 0.71 suggesting the hemodynamic significance
of the lesion. FFR, measured during intravenous infusion of adenosine, confirmed the result of the cFFR (0.69). Right, Decision-making
hybrid algorithm for cFFR. When cFFR is <0.83 the lesion is considered flow-limiting, and percutaneous coronary intervention (PCI) is
indicated. Conversely, when cFFR is >0.88 PCI should be deferred. When the result of the cFFR is equivocal (0.84–0.88), a standard FFR is
recommended.

investigation. The estimated contrast flow velocity can be
assessed either at rest or under hyperemia during adenos-
ine infusion. Recent evidence has shown that there is no
difference in the ability to predict FFR when QFR is derived
using resting estimated contrast flow velocity or hyperemic
estimated contrast flow velocity. The software produces
details about pressure drop in each vessel segment, thus
mimicking a pressure wire pullback21 (Figure 6).
The FAVOR Pilot Study (Functional Diagnostic Accu-
racy of Quantitative Flow Ratio in Online Assessment
of Coronary Stenosis), the FAVOR II Europe-Japan, and
FAVOR II China studies were the first to show the supe-
riority of QFR over 3D quantitative coronary angiography
in predicting the FFR value.21–23 Importantly, when applied
by trained and experienced operators, the time to perform
online QFR has been shown to be significantly lower than
the time required to measure FFR (median time 5.0 min-
utes versus 7.0 minutes, respectively, P<0.001).
The potential clinical impact of QFR has been recently
confirmed by a meta-analysis showing a promising
diagnostic performance of QFR in predicting FFR: 84%
sensitivity, 88% specificity, a positive predictive value of
80%, and negative predictive value of 95%.24
Pros and Cons
QFR avoids the cost, time, and risk associated with
placing a pressure wire into a coronary artery, albeit
with a reduced accuracy versus invasive FFR. QFR, as
all the angiography-based indices, requires the opera-
tor to become acquainted with selection of best angi-
ographic views (in case of offline analysis) and with
appropriate identification of vessel lumen profile. More-
over, it is important to be aware of technique-specific
limitations, which make QFR not measurable in case
of aortic-ostial lesions, severe tortuosity, or overlapping
vessels on angiogram. Moreover, QFR has not been
validated for the assessment of bifurcations when
there is stenosis in both the side branch and the proxi-
mal main vessel.
The FAVOR III Europe-Japan and FAVOR III China
studies will compare for the first time QFR-guided

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 De Maria et al
Figure 5. Resting full-cycle ratio (RFR).
A, Angiography showing an intermediate lesion in the left circumflex coronary artery. B, The RFR was 0.83 suggesting the hemodynamic
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significance of the lesion. C, RFR is measured as the lowest mean distal coronary pressure (Pd)/mean aortic pressure (Pa) in the whole cardiac
cycle.
revascularization versus FFR guidance against clinical
outcome.25
Vessel FFR
Vessel FFR (vFFR) uses 3D quantitative coronary angi-
ography for functional assessment of coronary stenosis.
vFFR is calculated by software CAAS (Pie Medical Imag-
ing, Maastricht, the Netherlands) using 2 angiographic
views with at least 30° difference in rotation/angulation
to generate the 3D reconstruction of the coronary artery.
Within the CAAS software, the pressure drop across
stenosis is calculated by applying physical laws, including
viscous resistance and separation loss effects present in
coronary flow behavior. It requires the actual aortic pres-
sure to be measured and recorded during the coronary
angiography procedure. Maximum hyperemic blood flow
is empirically determined by applying the assumption that
the proximal coronary velocity is preserved along the ves-
sel of interest (Figure 6).25,26
The diagnostic accuracy of vFFR has been recently
validated in the FAST study (Fast Assessment of Stenosis
Severity), which has shown that vFFR has a high linear cor-
relation with pressure wire-based FFR (0.89; P<0.001),
with high diagnostic accuracy (area under the curve, 0.93
[95% CI, 0.88–0.97]) to detect FFR≤0.80, along with a
low interobserver variability.25
Circ Cardiovasc Interv. 2020;13:e008487. DOI: 10.1161/CIRCINTERVENTIONS.119.008487
Alternative Indices for Fractional Flow Reserve
Pros and Cons
vFFR potentially shares the same benefits and disad-
vantages with coronary angiography–based methods.
However, compared with QFR, the amount of support-
ing evidence is still limited and based on observational,
single-center experience.
This limitation will be partly addressed by FAST II study
designed to evaluate the diagnostic accuracy of vFFR in
identifying hemodynamic significant CAD using pressure
wire–based FFR as reference (https://www.clinicaltrials.
gov; Unique identifier: NCT03791320).
FFRangio
FFRangio is a resting, adenosine-free angiography-based
index developed by CathWorks, Ltd (Kfar-Saba, Israel).
FFRangio provides a functional angiogram starting from
a 3D reconstruction of the coronary tree, obtained from
at least 2 angiographic projections.27 A hemodynamic
evaluation is then applied to the 3D model, deriving an
FFRangio map by inferring resistance through the applica-
tion of a proprietary computational fluid-dynamic model.
A few studies are consistently reporting the correlation
between FFRangio and FFR (Table IV in the Data Supple-
ment); however, the multicenter FAST-FFR study is cur-
rently the main evidence supporting FFRangio. In 301 enrolled
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Figure 6. Case examples of quantitative flow ratio (QFR) and vessel fractional flow reserve (vFFR).
Case example QFR (A): coronary angiography showing intermediate stenosis in the left anterior descending artery (LAD). B, Example of QFR
evaluation suggesting the hemodynamic significance of the lesion in the LAD. Case example vFFR (C and D): Three-dimensional reconstruction
of coronary artery and computation of vFFR, using 2 angiographic projections with at least 30 degrees apart and invasively measured aortic
root pressure. CRA indicates cranial; LAO, left anterior oblique; and RAO, right anterior oblique.

subjects and 319 vessels, online measured FFRangio showed
a 92% accuracy in predicting pressure wire-based FFR.26
Pros and Cons
The same benefits and disadvantages described for
other angiography-based methods apply also to FFRangio.
However, compared with all other indices that allow
assessment of a specific coronary segment under inves-
tigation, FFRangio offers the advantage of a simultaneous
evaluation of the whole coronary tree.
Intravascular-Imaging Based Methods
Intravascular Ultrasound–Derived FFR
The intravascular ultrasound–derived FFR (IVUS-derived
FFR) is a pool of invasive (but no pressure wire needed)
methods combining the geometric advantages of gray-
scale IVUS images and angiography to derived functional
assessment of the target vessel.28–30
Three of 4 proposed methods rely on computer fluid
dynamics. They require, therefore, intense computer time

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 De Maria et al Alternative Indices for Fractional Flow Reserve

for the calculations of FFR, limiting their potential appli-
cation for online use. This is also the reason why most of
the reports only include a small sample size. The details
of each IVUS-derived FFR can be found in Table V in the
Data Supplement.
The IVUS-FFR 3D model study enrolled 24 patients
(34 lesions) with stable CAD. The area under the curve
was 0.93 for the comparison between FFR and IVUS-
FFR (40–43). In the 1-dimensional centerline IVUS-
FFR study, which included 20 patients (20 lesions), the
area under the curve was 0.97.28 The IVUS-FFR study,
included 48 stable angina patients (50 lesions) and
showed a correlation between IVUS-FFR and conven-
tional FFR with an area under the curve of 0.78.29 The
hybrid IVUS-angiography virtual functional assessment
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of coronary stenoses using intravascular ultrasound
imaging study reported, in a series of 5 left anterior
descending arteries, a similar correlation with FFR.30
Pros and Cons
Advantages of IVUS-derived FFR are no need for maxi-
mal hyperemia; anatomic and functional assessments
without wire exchange; whole vessel wall assessment,
not only luminography; grayscale IVUS qualitative and
quantitative variables in addition to flow. Additionally, it is
not affected by vessel tortuosity, and it can be assessed
in ostial lesions.
Currently, IVUS-FFR is a research tool, but clinical
prime time could be a realistic option when more clinical
data will be available.

Figure 7. Optical coherence tomography (OCT)–derived fractional flow reserve (FFR).

A, Coronary angiography shows a right coronary artery (RCA) lesion, minimal lumen area (MLA) by OCT is 2.76 mm2. FFR measured by
pressure wire at asterisk was 0.79. Four white triangles point to the positions of 4 side branches, which correspond with b1–b4 in B and in
C. B, The 4 white lines in the OCT longitudinal views show and the angulations of the cut-planes (b1–b4) perpendicular to the side branch
centerline. The cut-planes were automatically reconstructed, and the lumen of the side branches ostia in the cut-planes was automatically
delineated. C, The computed optical flow ratio (OFR) value was color-coded and superimposed on the 3-dimensional reconstructed artery. In
this case, the computed OFR was 0.80.

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 De Maria et al Alternative Indices for Fractional Flow Reserve

The disadvantages of IVUS- FFR are represented by
the need for vessel instrumentation.
Optical Coherence Tomography–Derived FFR
The optical coherence tomography (OCT)–based FFR
(OCT-FFR) can be computed in various ways applying
computational fluid dynamic (Figure 7).31
An index of OCT-based FFR, going under the acro-
nym of OFR (optical flow ratio; OctPlus, Pulse Medi-
cal Imaging Technology, Shanghai, China), has been
recently validated against pressure wire FFR.31 In optical
flow ratio, the lumen contour is automatically delineated
from the OCT image pullback, and a 3D reconstruction
of the coronary lumen is performed.The volumetric flow
rate is estimated using the reference lumen size and
a virtual hyperemic flow velocity of 0.35 m/s. Finally,
a novel algorithm that is adapted from the QFR algo-
rithm21 is used to compute FFR at each position along
the interrogated vessel.
Optical flow ratio showed high diagnostic accuracy
(90%) in predicting FFR≤0.80 in 125 vessels from
118 patients.31 Optical flow ratio computation required
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only 55±23 seconds with low intraobserver and
interobserver variability (0.00±0.02 and 0.00±0.03,
respectively).
Seike et al32 also showed that their OCT-derived
FFR method had good agreement with pressure wire-
based FFR (bias=0.01±0.06) and the correlation with
FFR (r=0.89) with a computational time of 10 minutes
per pullback.
Similar results were reported in a small cohort of
13 patients by Lee et al 33 (9) showing a 94% diag-
nostic concordance of OCT-FFR with pressure wire
based FFR and with a computational time of ≈29
minutes.
Pros and Cons
The invasive nature and cost associated with the method
are limiting factors for broader adoption. There are poten-
tial pitfalls for segmenting the side branches through
single main vessel pullback. Side branch ostium disease
and side branch angulation can impact on quantification
of the side branch size and, consequently, on the vessel-
tapering model.

Figure 8. Computed tomography–derived fractional flow reserve (FFRCT).

Application of the HeartFlow Planner. A, A 3-dimensional volume rendering of a left anterior descending artery with severe stenosis after the
bifurcation with the first diagonal branch. B shows a coronary CT angiography with a multiplanar reconstruction of the lesion. C, The FFRCT
analysis confirming the functional significance of the lesion with an FFRCT of 0.64. The application of the HeartFlow planner is shown in D; the
dashed white line corresponds to the segment in which the geometry was modified to recalculate FFRCT. After virtual stenting, the recalculated
FFRCT value is 0.94.

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 De Maria et al
However, OCT-derived FFR can combine the benefit
of functional assessment with high anatomic definition in
guiding and planning PCI (stent length selection/serial
lesions selection). The ability to assess final results both
from the anatomic (OCT) and physiological (OCT-FFR)
point of view is also very appealing.
NONINVASIVE INDICES
Computed Tomography–Derived FFR
Computed tomography–derived FRR (FFRCT) is based
on the application of computational flow dynamic to 3D
coronary geometries extracted from coronary computed
tomography angiography images. FFRCT is defined as
the computed mean coronary pressure distal to a lesion
divided by the mean blood pressure in the aorta under
conditions of simulated maximal hyperemia.
Over the past years, studies have pointed the poten-
tial of FFRCT to detect ischemia compared with pressure
wire–based FFR across the whole spectrum of CAD
(Table VI in the Data Supplement).
FFRCT-based clinical decision-making has been proved
to reduce unnecessary invasive coronary angiographies
with significant cost-saving implications.34 Moreover,
patients in whom revascularization was deferred on the
basis of an FFRCT >0.80 presented good midterm progno-
sis in terms of major adverse cardiovascular event rate.35
Downloaded from http://ahajournals.org by on April 17, 2020
FFRCT provides rapidly and simultaneously a three-vessel
functional evaluation facilitating management and decision-
making in patients with multivessel disease. In such regard,
the SYNTAX III Revolution trial (Synergy Between PCI With
Taxus and Cardiac Surgery) showed that coronary com-
puted tomography angiography with FFRCT was sufficient
to provide aid and support in selecting the best revascular-
ization modality (cardiac surgery s PCI), changing the treat-
ment recommendation in 7% of the cases and modifying
the revascularization plan in 12% of patients.36
Pros and Cons
FFRCT avoids invasive angiography and vessel instrumen-
tatiosn completely, albeit at the cost of reduced diagnos-
tic performance. In this sense, many of the same caveats
apply as detailed above for QFR: inability to obtain a
diagnostic study (present in 10%–15% of cases) and
discordance with invasive FFR. Perhaps the upstream
ability to plan revascularization procedures will offset
these drawbacks. A novel FFRCT-based tool, HeartFlow
Planner (Redwood City, California), uses interactive lumi-
nal remodeling of the area to be stented and recalculates
FFR after the virtual removal of coronary stenosis, mim-
icking invasive post-stenting FFR (Figure 8).
Being FFRCT planner a relative new diagnostic tool,
the main limitation preventing its extensive application is
the current lack of supporting studies and evidences.
Circ Cardiovasc Interv. 2020;13:e008487. DOI: 10.1161/CIRCINTERVENTIONS.119.008487
Alternative Indices for Fractional Flow Reserve
In this regard, the Precise PCI Plan P3 study (Precise
PCI Plan; https://www.clinicaltrials.gov; Unique identifier:
NCT03782688) will prospectively validate the Heart-
Flow Planner, whereas the results of the DECISION trial
are expected to evaluate the impact of clinical outcomes
of FFRCT-guided revascularization.
CONCLUSIONS AND FUTURE
PERSPECTIVES
There is no doubt that FFR has introduced a paradigm
shift in the way CAD is assessed. It provides a reliable
guidance in establishing when revascularization is indi-
cated for patients with angiographic intermediate coro-
nary stenosis.1
The alternative tools summarized in this review article
represent compromises in terms of a simpler test (avoid
hyperemia, avoid wire, or avoid invasive catheterization)
versus a reduction in diagnostic performance.
In the short and midterm, FFR remains the gold stan-
dard for detection of myocardial ischemia in guiding
revascularization in patients with CAD. Although there
is overall numerical and biologic equivalence across
the NHPR, all the current NHPRs have less validation
than FFR, having all been tested in noninferiority stud-
ies enrolling relatively low-risk cohorts of patients. More
importantly, at the present, NHPRs are not supported by
the same robust long-term data as for FFR. Moreover,
it is probably unrealistic to expect one NHPR index to
be preferred over the other because studies aiming to
assess a head-head comparison would be very difficult
(and probably not useful) to conduct or would not show
any meaningful difference because of the similar biologi-
cal background across the indices.
The growing amount of evidence may bring a future
in which the first line of functional assessment will be
entirely noninvasive, with invasive confirmation using
pressure wire free indices (QFR, vFFR, FFRangio) as
first-line approach mainly because of their quicker and
cheaper nature, with pressure wire based indices to be
adopted for borderline scenarios (bifurcations, left main
stem). In this context, it is possible also to speculate
about the role of intravascular-imaging–derived FFR that
would find application in those cases where the use of
IVUS or OCT is already anticipated as an integral proce-
dural step for PCI planning (selection of techniques for
lesion preparation and selection of stent size and length).
ARTICLE INFORMATION
Affiliations
Heart Centre, John Radcliffe Hospital, Oxford University Hospitals, NHS Foun-
dation Trust, Oxford, United Kingdom (G.L.D.M., R.S., A.P.B.). MedStar Wash-
ington Hospital Centre, Interventional Cardiology Department, Washington, DC
(Y.O., H.M.G.-G., A.H.-K., E.S., K.D., R.W.). Interventional Cardiology Department,
Hospital Clinico San Carlos, Madrid, Spain (N.G.L.). Fondazione Policlinico Uni-
versitario A. Gemelli IRCCS, Roma (A.M.L.). Interventional Cardiology Depart-
April 2020 11
 De Maria et al
ment, Uppsala University, Sweden (G.S.). Interventional Cardiologist at Erasmus
University Rotterdam, the Netherlands (J.D.). Cardiac Catheterization Laboratory,
St. Francis Hospital, Roslyn, NY (A.J.). Department of Cardiology, University of
Ferrara, Italy (M.T.). University Hospitals of Cleveland, OH (G.B.). Med-X Research
Institute, School of Biomedical Engineering, Shanghai Jiao Tong University, China
(S.T.). Instituto do Coracao (InCor), Universidade de São Paulo, Brazil (P.A.L.).
Hospital Israelita Albert Einstein, Brazil (P.A.L.). Cardiovascular Center Aalst, OLV
Clinic, Belgium (C.C.). Department of Advanced Biomedical Sciences, University
of Naples Federico II, Italy (E.B.). McGovern Medical School at UTHealth and
Memorial Hermann Hospital, Houston, TX (N.P.J.).
Sources of Funding
None.
Disclosures
Dr De Maria reports speaker fees from Miracor Medical SA. Dr Scarsini reports
personal fees from Abbott. Dr Gonzalo López reports personal fees from Abbott
and personal fees from Boston Scientific during the conduct of the study. Dr
Leone reports personal fees from Bracco Imaging, personal fees from Abbott
Vascular, personal fees from Medtronic, and personal fees from Abiomed out-
side the submitted work. Dr Daemen reports grants and personal fees from Acist
Medical, grants and personal fees from Medtronic, personal fees from ReCor
Medical, grants and personal fees from PulseCath, grants from Abbott Vascular,
and grants and personal fees from Boston Scientific outside the submitted work.
Dr Jeremias reports grants and personal fees from Philips/Volcano and grants
and personal fees from Abbott Vascular during the conduct of the study. Dr Te-
baldi reports personal fees from Abbott. Dr Tu reports grants from Medis medical
imaging technology and grants from Pulse medical imaging technology outside
the submitted work. Dr Collet reports personal fees from Heart Flow, grants and
personal fees from Philips, and grants and personal fees from Abbott Vascular
during the conduct of the study. Dr Barbato reports personal fees from Boston
Scientific, personal fees from Abbott Vascular, and personal fees from GE outside
the submitted work. Dr Johnson reports Institutional research grants from Philips
(DEFINE-FLOW [Distal Evaluation of Functional Performance With Intravascu-
lar Sensors to Assess the Narrowing Effect—Combined Pressure and Doppler
FLOW Velocity Measurements], https://www.clinicaltrials.gov; Unique identifier:
NCT02328820) and St Jude Medical (CONTRAST [Can Contrast Injection Bet-
Downloaded from http://ahajournals.org by on April 17, 2020
ter Approximate FFR Compared to Pure Resting Physiology?], https://www.
clinicaltrials.gov; Unique identifier: NCT02184117), and an institutional licens-
ing agreement from Boston Scientific (smart-minimum fractional flow reserve
algorithm), all outside the submitted work. Dr Waksman reports personal fees
from Amgen, grants and personal fees from AstraZeneca, grants and personal
fees from Biotronik, grants and personal fees from Boston Scientific, personal
fees from Cardioset, personal fees from Cardiovascular Systems, Inc, grants and
personal fees from Chiesi, other from MedAlliance, personal fees from Medtronic,
personal fees from Philips Volcano, and personal fees from Pi-Cardia Ltd outside
the submitted work. Dr Banning reports institutional funding for fellowship from
Boston Scientific and speaker fees from Boston Scientific, Miracor Medical SA,
Medtronic and Abbott. The other authors report no conflicts.
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