CORONARY INTERVENTIONS

EXPERT CONSENSUS
EuroIntervention 2023;19:464-481 published online ahead of print May 2023

Applied coronary physiology for planning and guidance of

percutaneous coronary interventions. A clinical consensus
statement from the European Association of Percutaneous
Cardiovascular Interventions (EAPCI) of the European Society
of Cardiology
Javier Escaned1*, MD, PhD; Colin Berry2, MB, ChB, PhD; Bernard De Bruyne3,4, MB, ChB, PhD;
Asad Shabbir1, MD; Carlos Collet3, MD, PhD; Joo Myung Lee5, MD, MPH, PhD;
Yolande Appelman6, MD, PhD; Emanuele Barbato3,7, MD, PhD; Simone Biscaglia8, MD;
Piotr P. Buszman9,10, MD, PhD; Gianluca Campo8, MD; Alaide Chieffo11, MD, PhD;
Róisín Colleran12,13, MB, BC; Damien Collison14, MB, BCh, MD; Justin Davies15, MBBS, PhD;
Daniele Giacoppo12,16,17, MD, PhD; Niels R. Holm18, MD, PhD; Allen Jeremias19, MD; Valeria Paradies20, MD;
Zsolt Piróth21, MD, PhD; Luís Raposo22, MD, PhD; Ariel Roguin23,24, MD, PhD; Tanja Rudolph25, MD;
Giovanna Sarno26, MD, PhD; Sayan Sen15, MBBS, PhD; Gabor G. Toth27, MD, PhD;
Eric Van Belle28,29, MD, PhD; Frederik M. Zimmermann30, MD; Dariusz Dudek31,32, MD;
Giulio Stefanini33,34, MD, PhD; Giuseppe Tarantini34,35, MD, PhD

The authors’ affiliations can be found in the Appendix paragraph.

This paper also includes supplementary data published online at: https://eurointervention.pcronline.com/doi/10.4244/EIJ-D-23-00194

KEYWORDS
Abstract
The clinical value of fractional flow reserve and non-hyperaemic pressure ratios are well established in
determining an indication for percutaneous coronary intervention (PCI) in patients with coronary artery
• fractional flow
disease (CAD). In addition, over the last 5 years we have witnessed a shift towards the use of physio-
reserve
logy to enhance procedural planning, assess post-PCI functional results, and guide PCI optimisation. In
• intravascular
this regard, clinical studies have reported compelling data supporting the use of longitudinal vessel analy-
ultrasound
sis, obtained with pressure guidewire pullbacks, to better understand how obstructive CAD contributes
• non-invasive
to myocardial ischaemia, to establish the likelihood of functionally successful PCI, to identify the pres-
imaging
ence and location of residual flow-limiting stenoses and to predict long-term outcomes. The introduction
of new functional coronary angiography tools, which merge angiographic information with fluid dynamic
equations to deliver information equivalent to intracoronary pressure measurements, are now available and
potentially also applicable to these endeavours. Furthermore, the ability of longitudinal vessel analysis to
predict the functional results of stenting has played an integral role in the evolving field of simulated PCI.
Nevertheless, it is important to have an awareness of the value and challenges of physiology-guided PCI
DOI: 10.4244/EIJ-D-23-00194

in specific clinical and anatomical contexts. The main aim of this European Association of Percutaneous
Cardiovascular Interventions clinical consensus statement is to offer up-to-date evidence and expert opin-
ion on the use of applied coronary physiology for procedural PCI planning, disease pattern recognition and
post-PCI optimisation.

*Corresponding author: Hospital Clínico San Carlos IdISCC, Complutense University of Madrid, Calle del Prof Martín Lagos,
28040, Madrid, Spain. E-mail: escaned@secardiologia.es

© Europa Digital & Publishing 2023. All rights reserved. SUBMITTED ON 03/03/2023 - REVISION RECEIVED ON 1st 05/04/2023 - ACCEPTED ON 23/04/2023

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EuroIntervention 2023;19:464-481
Abbreviations in different clinical scenarios is provided in Supplementary
ACS acute coronary syndrome Appendix 1.
CAD coronary artery disease
CCS chronic coronary syndrome From confirming the indication to planning and
CTCA computed tomography coronary angiography guiding PCI
FCA functional coronary angiography The limitations of coronary angiography in characterising the
FFR fractional flow reserve flow-limiting effect of coronary stenoses can be overcome by non-
FFRCT computed tomography-derived fractional flow reserve invasive and/or adjunctive invasive physiological assessments of
iFR instantaneous wave-free ratio coronary artery disease (CAD), the value of which are supported
IVUS intravascular ultrasound by evidence-based guideline recommendations5. When prior evi-
MACE major adverse cardiovascular event dence of myocardial ischaemia is not available, FFR or instanta-
MVD multivessel disease neous wave-free ratio (iFR) are recommended by the guidelines to
NHPR non-hyperaemic pressure ratio assess the haemodynamic relevance of intermediate-grade coro-
OCT optical coherence tomography nary stenoses. FFR can also be considered in patients with multi-
PCI percutaneous coronary intervention vessel disease (MVD) undergoing PCI5.
PPGindex pressure pullback gradient index Over the last decade, criticism concerning the use of angio-
QFR quantitative flow ratio graphy alone to guide revascularisation decisions has been
RFR resting full-cycle ratio extended to the decision of when an optimal functional result of
vFFR virtual fractional flow reserve the intervention has been achieved. Such criticism is supported by
suboptimal functional results identified in vessels despite a satis-
Introduction factory angiographic PCI result2,3. Prior and recent observations
Intracoronary physiological assessment is acknowledged as a valu- have shown that such functionally suboptimal PCI results carry
able strategy to identify the presence of flow-limiting epicardial prognostic relevance (Supplementary Table 1)4,6-25. Physiological
stenoses in patients with chronic coronary syndromes (CCS) and guidance could contribute to improved PCI results in at least
to determine an indication for percutaneous coronary interventions 3 ways: 1) improving preprocedural planning and simulation,
(PCI)1. Yet, its role in procedural planning and in assessing the 2) improving intraprocedural precision of PCI in addressing flow-
functional results of PCI is less clear. limiting disease, and 3) guiding procedural optimisation of subop-
In practice, it had been previously assumed that once the pres- timal PCI results (Central illustration).
ence of flow-limiting disease was confirmed with a single pressure Despite the limited number of available studies in this field, there
guidewire measurement, PCI guided by angiography should lead are now rational grounds to consider using physiological tools to
to effective restoration of vessel conductance. However, studies plan effective PCI strategies to ideally remove all flow-limiting sten-
with physiological post-PCI evaluation based on fractional flow oses, to verify that functionally successful PCI has been achieved,
reserve (FFR) and non-hyperaemic pressure ratios (NHPR) dem- and to contribute to procedural optimisation. Table 1 provides key
onstrate that this supposition is not correct and that relying on information on the physiological guidance of PCI.
angiographic guidance alone can be associated with suboptimal
functional results post-PCI in many cases2-4. Technological developments in applied coronary
This document addresses the use of coronary physiology to physiology in PCI
plan and guide PCI using physiological tools, providing evidence HYPERAEMIC AND NON-HYPERAEMIC PRESSURE INDICES
from the literature, expert opinion from operators, and revisiting FFR is the most widely used intracoronary tool to define flow-
available tools. The document provides an expert consensus on limiting epicardial stenoses, with randomised clinical trials and
how to use commercially available physiology tools for these observational studies supporting deferral26-28 or performance26,29 of
purposes. It has been reviewed and approved by the European revascularisation based on FFR values, predominately in patients
Society of Cardiology (ESC) Clinical Guidelines Committee to with CCS. Contrast-based FFR, which relies upon submaximal
ensure that no conflict exists with available guidelines. Many of myocardial hyperaemia induced by iodinated contrast administra-
the topics discussed herein pertain to the use of intracoronary tion, has been proposed as an adenosine-free alternative to FFR30.
pressure guidewires, which are the most widely used devices NHPR is increasingly utilised in clinical practice owing to a more
for physiological assessment in the cardiac catheterisation lab- favourable side-effect profile, reduced cost and procedure time,
oratory. Functional coronary angiography (FCA) tools, which and ease of use compared with pharmacological hyperaemia. This
merge angiographic information with fluid dynamic equations to facilitates multiple intraprocedural measurements either in differ-
deliver information equivalent to intracoronary pressure meas- ent vessels or at different stages of the PCI procedure. Guidance
urements and which constitute a valuable alternative to invasive by iFR, a widely utilised NHPR, was non-inferior to FFR guidance
tools in planning coronary revascularisation, are also discussed. of revascularisation for major adverse cardiac events (MACE) at
A detailed and updated revision of the use of NHPR and FFR 1-year31,32 and 5-year follow-ups33. Other diastolic NHPR correlate

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EuroIntervention

CENTRAL ILLUSTRATION Applications of physiology in planning and guiding PCI procedures.

Preprocedural PCI planning Improving the precision of PCI Postprocedural assessment

and simulation and optimisation
– Setting of indication for PCI – Avoidance of geographic – Longitudinal physiology analysis
– Identification of disease mismatch over PCI by to rule out flow-limiting disease
pattern: focal, tandem, diffuse identifying location of target – Focal patterns may be
flow-limiting disease amenable to post-PCI
– Simulation of functional results
with different PCI strategies – Intravascular imaging for optimisation
accurate planning and guidance
of stenting
Imaging/physiology coregistration Residual QFR
with angiography

iFR: instantaneous wave-free ratio; PCI: percutaneous coronary intervention; PPG: pullback pressure gradient; QFR: quantitative flow
ratio

closely with the iFR, with a similar ischaemic cut-off of ≤0.8934. In the extended scenario of planning and guiding PCI, the use
All NHPR have demonstrated significant association with the risk of pressure guidewires can be subject to specific caveats related
of 2-year vessel-oriented composite endpoints35. to physiological assessment in complex clinical and anatomical

Table 1. Objectives of physiological planning and guidance of PCI.

Pre-PCI physiology assessment
Objective Technique Benefit
Determining the indication for PCI Pressure wire or FCA to identify the –M
 anagement of significant stenoses may confer
presence of flow-limiting disease prognostic or symptom benefit
–D
 eferral of non-flow-limiting disease avoids
unnecessary PCI
Identifying patterns of flow-limiting Longitudinal physiological vessel – Assists in gauging effectiveness of PCI
disease analysis to identify focal, tandem, and –A ids with planning the length of stent and/or number
diffuse patterns of flow-limiting disease of stents
–R econsider PCI when a suboptimal result is
anticipated
Simulate impact of stenting in specific NHPR and imaging-based functional – Plan effectiveness of PCI before stent deployment
locations assessments to simulate relief of – Allows for several simulations prior to PCI
stenosis virtually
Facilitating precision stent deployment Correlating physiology and angiography –A voidance of geographical miss during stenting,
using either coregistration technologies missing flow-limiting lesions
or visual assessment, use of – Accurate sizing of balloons and stents
concomitant intracoronary imaging
Post-PCI physiology assessment
Objective Technique Benefit
Ensuring an optimal functional result of Physiological measurements in PCI –E
 arly identification of residual flow-limiting disease in
PCI target vessel after satisfactory the PCI target vessel after the intervention
angiographic result, jailed side-branch
interrogation
Identifying potential targets of functional Post-PCI longitudinal vessel analysis –E
 stablishing the cause of suboptimal functional PCI
optimisation of PCI results
–E
 stablishing the feasibility and mode of PCI
optimisation
Assessing the impact of PCI Repeat physiological measurements –R
 esidual disease not amenable to PCI may identify
optimisation after physiology-based optimisation need for directed medical therapy or surgical
revascularisation
FCA: functional coronary angiography; NHPR: non-hyperaemic pressure ratio; PCI: percutaneous coronary intervention

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EuroIntervention 2023;19:464-481
scenarios (Table 2). Additional information detailing potential pit- be derived from invasive coronary angiograms38-41; these are sup-
falls in physiological assessment and considerations regarding the ported by prospective validation studies. Quantitative flow ratio
use of guide catheters, guide catheter extensions and microcath- (QFR) is the only angiography-based physiological index that has
eters is provided in Supplementary Appendix 1. been prospectively validated and has already been demonstrated
to be associated with improved clinical outcomes when used to
FUNCTIONAL CORONARY ANGIOGRAPHY decide upon coronary revascularisation, compared with conven-
The success of FFR and NHPR as indices to estimate functional tional angiography42. A distinct advantage of all FCA modalities
stenosis severity has led to the development of new FCA tech- is that they provide longitudinal vessel analysis, allowing accu-
nologies. These can derive similar information from an invasive rate length measurements and localisation of flow-limiting disease
coronary angiogram or non-invasive computed tomography coro- to vessel anatomy. Detailed information on potential limitations
nary angiography (CTCA), with both approaches demonstrating of imaging-based functional coronary analysis is provided in
good correlation with wire-based FFR. Computed tomography- Supplementary Table 2.
derived FFR (FFRCT) is obtained by merging a three-dimensional
(3D) reconstruction of vessels from CTCA with computational LONGITUDINAL PHYSIOLOGICAL VESSEL ANALYSIS
fluid dynamics36, thereby providing a reliable estimate of invasive Customarily, indices of coronary physiology have been reported
FFR37. Similarly, several FFR-equivalent measurements can also as a single value in the distal segment of the interrogated coronary

Table 2. Challenges and pitfalls related to physiological assessment.

Patient factors
Challenges and pitfalls Comment Solution
Presence of significant ostial CAD Identified with ventricularisation or Reposition guide catheter to a more proximal position,
“damping” pressure waveform on ensure coaxiality, consider downsizing guide catheter,
engagement, not assessable with some use an additional guidewire or septal wire to control
FCA modalities catheter tip position
Haemodynamic crosstalk in presence of Sequential lesions along a vessel Consider simulated planning prior to undertaking PCI on
tandem lesions invariably physiologically influence the 1 or 2 stenoses based on longitudinal vessel analysis
other lesions in the vessel obtained with functional coronary angiography, NHPR,
or FFR
Procedural factors
Challenges and pitfalls Comment Solution
Pressure wire drift Offset of pressure reading during the Repeat procedure, use drift correction/re-normalise, or
procedure use image-based technique
Pseudostenosis caused by intracoronary Straightening of tortuous vessels by Consider FCA as an alternative to intracoronary pressure
wires intra-coronary wire may generate guidewires
introsusceptions with haemodynamic
relevance
Ventricularisation/damping of aortic Guiding catheter engaged abutting the Reposition guide catheter, ensure coaxiality, consider
pressure vascular lumen or in significant ostial downsizing guide catheter, equalisation of pressure
lesions guidewire is advised
Use of guide catheter with side holes False estimate of Pa at the tip of the Advise not to use catheter with side holes for
guiding catheter intracoronary assessment. If needed for clinical reasons,
ensure catheter disengagement and use of IV adenosine.
Use of guide catheter extensions May cause ventricularisation of Pa, if Perform pressure equalisation with extension within
introduced after pressure equalisation, guide catheter, withdraw guide extension at the time of
may modify Pa and affect measurements physiological assessment
Use of coronary microcatheters If used after pressure equalisation, may Perform pressure equalisation with microcatheter within
modify Pa and affect measurements guide catheter before measurements
Wire whipping Pressure wire signal degrading through Repositioning of the pressure wire often resolves this
contact with vascular lumen issue
Transient microvascular dysfunction Rotational atherectomy and PCI tools Consider FCA as an alternative to intracoronary
associated with the procedure generating microparticles may cause assessment if transient microvascular dysfunction is
transient microvascular dysfunction, assumed or suspected
affecting pressure indices
FFR measurement in region without Whilst the software reports the lowest Measure FFR in stable hyperaemia, and if needed adjust
stable hyperaemia physiological reading, these might not measurement points manually
be in stable hyperaemia and therefore
overestimate lesion severity
CAD: coronary artery disease; IV: intravenous; FCA: functional coronary angiography; FFR: fractional flow reserve; NHPR: non-hyperaemic pressure ratio;
Pa: aortic pressure; PCI: percutaneous coronary intervention

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artery, reflecting cumulative pressure losses along the entire length in Table 3 and Supplementary Table 3, respectively2,3,45,50-61. The
of the epicardial vessel. Longitudinal assessment, utilising a pres- current definitions of focal and diffuse disease are largely qualita-
sure wire pullback, adds an additional dimension to the physiolog- tive, and research to formally define these lesion characteristics is
ical analysis. Pullback manoeuvres can be performed manually43 awaited. The ability to discriminate between patterns of CAD car-
with either FFR or NHPR44,45. Accurate length measurements to ries immediate and relevant clinical implications; a focal pattern
the order of millimetres can be obtained by using either motor- is associated with an optimal physiological result after PCI, with
ised pullback46 or dedicated software that tracks the radiopaque consequent good prognosis and relief of angina. On the contrary,
wire tip during pullback47. Dedicated software is available to pro- a diffuse pattern of disease is associated with suboptimal post-PCI
vide stable FFR, iFR, and resting full-cycle ratio (RFR) pullback results and prognosis and more residual anginal symptoms62.
curves, free of fluctuations due to the Venturi effect, where a drop After PCI, longitudinal physiological vessel interrogation
in intracoronary pressure is seen as the sensor crosses the stenosis may identify residual focal pressure gradients inside or outside
(Supplementary Figure 1). the stent which might be amenable to additional stent post-dil-
Prior to PCI, longitudinal vessel assessment informs on the dis- atation or PCI2. Alternatively, a diffuse pattern of residual dis-
tribution of pressure losses along the epicardial vessel and can ease after PCI may discourage operators from further vessel
differentiate focal and/or diffuse patterns of flow-limiting disease instrumentation.
(Figure 1). Longitudinal vessel analysis allows for the identifica-
tion of focal and diffuse patterns of flow-limiting disease, either COREGISTRATION WITH ANGIOGRAPHY
subjectively by visual inspection of the pullback curve or objec- Merging longitudinal vessel physiology with the coronary angio-
tively by using the pressure pullback gradient index (PPGindex)45, gram allows for accurate localisation of flow-limiting athero-
which can be performed manually with high inter- and intraop- sclerotic disease and facilitates procedural planning47. The
erator reproducibility48. Differentiation of diffuse from focal dis- coregistered map provides signposts with a clear distribution of
ease is also feasible with an automated algorithm that analyses the regions of pressure loss, enabling optimal localisation of specific
instantaneous FFR gradient per time unit, the dFFR(t)/dt index49. target lesions that might benefit from PCI, and the implementation
Both the PPGindex and dFFR(t)/dt can be derived from QFR, and of length measurements (Supplementary Figure 2). This techno-
their prognostic relevance have been documented with post-PCI logy can be used in conjunction with iFR and is particularly useful
clinical outcomes49,50. The criteria used to define focal, tandem, when forming strategies for intervention on tandem lesions and
and diffuse patterns, as well as supporting studies, can be found interrogating areas of diffuse disease.

Focal disease pattern

Pre-PCI implications Post-PCI implications
– PCI particularly effective at removing – Suboptimal results within stent might
focal flow-limiting stenoses be treated with additional balloon
– Pre-PCI simulation robustly predicts dilatation
optimal post-PCI results – Residual disease outside the stented
– Intracoronary imaging may be segment, with focal pattern, likely
appropriate to guide stent dimensions amenable to PCI with good outcome
Angiography QFR Pullback and selection of adequate landing zone
Tandem disease pattern
Pre-PCI implications Post-PCI implications
– Separate stenosis assessment to – Physiology-guided optimisation is
identify flow-limiting ones. advised, particularly after single
– Pre-PCI simulation to predict functional stenosis treatment based on pre-PCI
results of different stenting strategies. analysis
– Intracoronary imaging to refine – Residual disease may be amenable to
decision-making on using separate or PCI
Angiography QFR Pullback
single stents.
Diffuse disease pattern
Pre-PCI implications Post-PCI implications
– PCI unlikely to be effective at removing – Post-PCI optimisation unlikely to deliver
diffuse disease acceptable physiological result
– Pre-PCI simulation less likely to predict – Consider accepting suboptimal result
post-PCI results and escalating medical therapy
– Consideration of further medical
Angiography QFR Pullback
therapy optimisation or surgical
intervention rather than PCI

Figure 1. Patterns of flow-limiting disease identified in longitudinal vessel analysis before and after PCI. PCI: percutaneous coronary
intervention; QFR: quantitative flow ratio

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Table 3. Criteria used to define focal, tandem and diffuse patterns of obstructive coronary disease.
Pre-PCI physiology assessments
Pattern FFR NHPR FCA
Focal FFR ≤0.80 at distal segment, abrupt iFR/RFR/DFR ≤0.89 at distal segment, QFR/vFFR/FFRCT ≤0.80 at distal
single point of pressure loss. with abrupt single point of ≥0.03 index segment, with single region of pressure
units over ≤15 mm segment. loss of >0.05 in <10 mm segment.
Tandem FFR ≤0.80 at distal segment, presence iFR/RFR/DFR ≤0.89, at distal segment, QFR/vFFR/FFRCT ≤0.80 at distal vessel
of ≥2 abrupt change of FFR values. with presence of ≥2 abrupt changes of with presence of ≥2 abrupt changes of
index values. pressure loss.
Diffuse* FFR ≤0.80 at distal segment with iFR/RFR/DFR ≤0.89 at distal segment, Progressive and linear loss in QFR/vFFR/
progressive and linear loss in FFR values with progressive and linear loss in FFRCT values over length of vessel during
over length of vessel. pressure over length of vessel during iFR longitudinal analysis.
pullback.
Post-PCI physiology assessments
Pattern FFR NHPR FCA
Focal FFR with abrupt pressure loss at the Abrupt drop of iFR/RFR/DFR values at Abrupt drop of QFR/vFFR values at the
stented site or elsewhere within the the stented site or elsewhere within the stented site or elsewhere within the
treated vessel. treated vessel. treated vessel.
Tandem Abrupt drop of FFR values at the level of Abrupt drop of iFR/RFR/DFR values at Abrupt drop of QFR/vFFR values at the
an untreated tandem stenosis. the level of an untreated tandem level of an untreated tandem stenosis.
stenosis.
Diffuse* Progressive and linear loss in FFR values Progressive and linear loss in iFR/RFR/ Progressive and linear loss in QFR/vFFR
over length of stented vessel during DFR values over length of stented vessel values over length of stented vessel.
pullback. during pullback.
*These criteria are clinical consensus statements and further validation is warranted. DFR: diastolic hyperaemia-free ratio; FCA: functional coronary
angiography; FFR: fractional flow reserve; FFRCT: computed tomography-derived FFR; iFR: instantaneous wave-free ratio; NHPR: non-hyperaemic
pressure ratio; PCI: percutaneous coronary intervention; QFR: quantitative flow ratio; RFR: resting full-cycle ratio; vFFR: virtual FFR

SIMULATION OF FUNCTIONAL PCI RESULTS post-PCI values after treatment of a given stenosis (residual QFR
Despite consistent evidence showing that suboptimal values of and vFFR), which has been shown to predict post-PCI FFR25,66,67.
physiological indices after PCI are associated with poorer out- Figure 3 shows a pullback curve analysis performed with iFR and
comes, there is a relative paucity of evidence regarding whether coregistration, including simulated stenting at a specific location.
they can be used to guide PCI optimisation and, ultimately, to
improve patient outcomes. Since the aim of PCI is the elimination CORONARY PRESSURE WIRES AND MEASURING TOOLS
of ischaemia-generating lesions, predicting the haemodynamic Continued improvement in pressure guidewire technology has
results of a given strategy before embarking on stenting appears to facilitated the accurate interrogation and measurement of com-
be a rational approach to avoid suboptimal results of the interven- plex coronary anatomies. Contemporary guidewire-based pressure
tion. The concept of in silico simulation of PCI to predict func- indices are fitted with sensors that use either electrical or fibre-
tional results of an intervention is appealing, as it allows for both optic signal transmission. Advances in manufacturing processes
procedural planning and modelling of post-PCI physiology prior have resulted in an improved accuracy and stability of the sen-
to undertaking the procedure. sor, thus, minimising the drift phenomenon with workhorse guide-
There are different approaches to simulate functional PCI results wire-like characteristics, resulting in optimised torque control and
from baseline longitudinal vessel analysis (Figure 2). A simple manoeuvrability. The latter is critical for the safe wiring of the
mathematical approach to estimate the impact of PCI based on target vessel prior to the measurement of pressure loss and PCI.
pullback curves can be followed: predicted NHPR (NHPRpred)=pre- Microcatheter-based pressure measurement technology requires
PCI NHPR (lowest value) + ∑intention-to-treat NHPR gradient(s). a 0.014” guidewire, according to anatomy or operator preference,
Pioneering studies with iFR pullback have demonstrated its abil- but requires a 0.020” shaft profile for the microcatheter, which
ity to predict post-PCI results63. Subsequently, this has also been may interfere with measurements, especially in small vessels or
confirmed for other NHPR such as the RFR and diastolic pres- severe stenoses, and can be difficult to navigate around tight angu-
sure ratio61. Subtraction of the flow-limiting effect of one or more lations. The currently available and pending devices for invasive
coronary stenoses can be readily performed with current software functional assessments are shown in Supplementary Table 4.
versions of iFR coregistration with angiography31. From the per-
spective of FCA, a dedicated virtual stenting tool has been devel- Physiological assessment of post-PCI results
oped for FFRCT64. The FFRCT Planner (HeartFlow) has been shown Post-PCI intracoronary pressure measurements can identify resid-
to be accurate and precise at predicting post-PCI FFR65. Analysis ual flow-limiting disease, differentiate residual focal lesions
with QFR and virtual FFR (vFFR) provides an estimate of from diffuse disease and provide prognostic information. Whilst

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Invasive summative calculation: FFR, NHPR

Manual calculation of
summative pressure-gain
pre-PCI to simulate
physiological effect of stent

Automated calculation of
pressure-gain pre-PCI to
simulate physiological
effect of stent

Angiography Pullback PCI simulation Precision PCI

Invasive functional coronary angiography: QFR

Angiography 3D-QCA Flow reconstruction Virtual PCI plan

Non-invasive functional coronary angiography: FFRCT

CTCA CT-derived FFR CFD PCI simulation Precision PCI

Figure 2. Approaches for simulating functional PCI results based on longitudinal vessel analysis. 3D-QCA: three-dimensional quantitative
coronary angiography; CFD: computational fluid dynamics; CTCA: computed tomography coronary angiography; FFR: fractional flow
reserve; FFRCT: computed tomography-derived FFR; iFR: instantaneous wave-free ratio; LAD: left anterior descending artery; NHPR:
non-hyperaemic pressure ratio; PCI: percutaneous coronary intervention; QFR: quantitative flow ratio; RCA: right coronary artery

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A B

Diagnostic angiography with iFR pullback Simulated PCI with physiological coregistration

Final angiographic and functional result

Figure 3. Simulation of functional PCI results using coregistration of physiology and the coronary angiogram. A) Angiography of the left
circumflex artery interrogated with longitudinal physiological assessment. B) The presence of flow-limiting disease in the vessel is
demonstrated by a distal iFR of 0.57. Longitudinal vessel analysis revealed a focal disease phenotype. iFR coregistration with angiography
allows accurate localisation of flow-limiting disease in the coronary anatomy. The PCI simulation suggests adequate functional results of the
intervention, with a predicted post-PCI iFR of 0.94. C) Final co-registered angiographic-physiology result shown, with final iFR of 0.90.
iFR: instantaneous wave-free ratio; PCI: percutaneous coronary intervention

a higher post-PCI FFR is associated with a lower incidence of manipulation. Intracoronary imaging may contribute to a better
adverse clinical outcomes, the cut-off point for an optimal PCI understanding of the cause of suboptimal functional results and
result is still debated68. A post-PCI FFR ≥0.90 has been associated to safer decision-making. Furthermore, it has to be kept in mind
with a significantly lower risk of repeat PCI and MACE in a sys- that cardiovascular risk may differ between patients despite having
tematic review of 7,470 patients69. The most robust recent data, achieved an optimal functional result; this is largely dictated by the
obtained in a patient-level meta-analysis of 5,869 vessels treated extension and characteristics of underlying atherosclerosis.
with modern drug-eluting stents, reported optimal post-PCI FFR While functionally suboptimal PCI results are associated with
cut-off values of 0.86 for target vessel failure and 0.80 for the adverse clinical outcomes and can be related to residual treatable
composite of cardiac death or target vessel myocardial infarction70. disease, they may more frequently be an epiphenomenon of diffuse
For NHPR, a post-PCI iFR ≥0.95 was associated with improved atherosclerosis that cannot be adequately addressed with revascu-
patient outcomes in the DEFINE PCI study3. An optimal cut-off larisation. This may explain why larger relative increases in FFR
for post-PCI distal coronary pressure/aortic pressure (Pd/Pa) ratio after stenting (typically achieved through treatment of focal, phys-
of >0.96 has also been proposed23. iologically severe lesions) are associated with lower rates of target
Contemporary reports indicate that post-PCI physiology results vessel failure, reduced incidence of angina and improved quality
might remain below the clinical revascularisation thresholds of of life14,21,72. As not all residual flow-limiting disease is amenable
≤0.80 for FFR and <0.90 for NHPR in approximately 24-36% of to treatment with PCI, achieving optimal post-PCI FFR or NHPR
cases2,3,71. Potential mechanisms of suboptimal post-PCI physiology target values can be challenging, or frequently impossible, in many
results are outlined in Figure 4. Additional interventions guided by patients73. Beyond the pattern of coronary artery disease, there are
post-PCI coronary physiology assessments can improve the final additional anatomical factors that may contribute to lower pres-
result2,10,71. Caution should be exerted to avoid overtreatment, for sure-based indices. Evolving evidence suggests that post-PCI FFR
example when the identified cause of suboptimal functional results values are consistently lower in left anterior descending (LAD)
entails treatment of long coronary segments or aggressive lesion versus non-LAD vessels and might require vessel-specific optimal

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Stent factors related to suboptimal Intracoronary imaging

post-PCI physiology results
– Stent underexpansion
– Stent malapposition
– Plaque protrusion
– Thrombus within stent
– Inadequate lesion coverage
– Incorrect stent sizing
– Edge dissection

Post-PCI

Target vessel factors

– Bystander diffuse disease
– Untreated focal lesion

Longitudinal vessel analysis

Figure 4. Mechanisms of suboptimal post-PCI physiological results. PCI: percutaneous coronary intervention; QFR: quantitative flow ratio

thresholds, adding a further level of complexity2,22. The lower procedural factors that are better addressed with intracoronary imag-
LAD values likely occur because of the interplay of several fac- ing techniques, such as intravascular ultrasound (IVUS) and optical
tors, including the higher prevalence of intramuscular coronary coherence tomography (OCT) − both of which provide detail on
tracts observed in the LAD (Supplementary Figure 3), the impact CAD patterns and guidance for PCI. A detailed description of these
of hydrostatic effects relating to coronary anatomy and the result- techniques and on their use in planning, guiding and optimising PCI
ant height of the pressure wire sensor above or below the aor- is available elsewhere76. The results of comprehensive vessel imag-
tic pressure transducer (typically causing a hydrostatic offset of ing post-PCI compared with FFR and its effect on long-term out-
around 3.6 mmHg)74, and higher coronary flow rates due to the comes have been reported77. In addition, there is growing interest in
larger myocardial mass subtended by the LAD (high flow across whether the presence of vulnerable atheroma in non-flow-limiting
long segments of mild residual diffuse atheroma can generate an lesions might be associated with a higher risk of future events78.
appreciable pressure gradient). Based on this, normal FFR values Merging information based on the presence and location of
for the LAD have recently been shown to be 0.92, compared to flow-limiting stenoses provided by physiology, with information
0.96 in non-LAD vessels75. Finally, in all anatomical locations, on plaque characteristics and distribution, and vessel dimensions
when NHPR are used, residual reactive hyperaemia induced by derived from imaging might aid in the selection of PCI devices and
intervention-related vessel manipulation may render false positive strategies in terms of lesion preparation, plaque-free landing zone
measurements if performed immediately after stent implantation for PCI, and the selection of stent diameter and length, all impor-
or contrast/saline injections. tant aspects which ultimately improve long-term procedural results.
Triregistration, with physiology and intracoronary imaging in con-
Complementary role of combined imaging and junction with angiography, is currently available for IVUS and
physiology in PCI planning and guidance iFR. Coregistration with angiography is also feasible with OCT.
Whilst the objective of PCI is the removal of flow-limiting dis- Intracoronary imaging-derived physiology, such as OCT-derived
ease, long-term results of interventions are strongly influenced by FFR, currently lacks validation and is not available for clinical use.

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EuroIntervention 2023;19:464-481
In addition, there is extensive evidence suggesting that PCI techniques, with post-PCI optimisation carried out when residual
optimisation with intravascular imaging improves long-term pro- focal or tandem pressure loss remains. Suggested algorithms for
cedural outcomes2,76,79-84. This benefit is independent of the mod- comprehensive lesion assessment using pre- and post-PCI physiol-
est increase in FFR values noted in image-based PCI optimisation ogy are shown in Figure 5 and Figure 6, respectively.
studies79,85,86. The synergistic use of intracoronary imaging and
post-PCI longitudinal vessel pullback can be used to investigate Applied coronary physiology in specific PCI
causes of focal pressure loss after PCI and assist with decisions scenarios
on how they could be rectified86. Imaging may also highlight the In addition to the general principles discussed above, the use of
existence of high-risk morphological features of coronary dis- physiology to plan and guide PCI in specific scenarios is deserv-
ease − both at baseline and post-PCI − with prognostic implica- ing of a separate discussion. Supplementary Appendix 2 outlines
tions, even when these are not ischaemia-generating87, such as in applied coronary physiology for the following contexts: multives-
instances of malapposition or significant edge dissection. sel coronary artery disease, vessels with tandem lesions or diffusely
diseased vessels, lesions in vessels providing collaterals to chroni-
Integrating available tools and knowledge into cally occluded arteries, patients with acute coronary syndromes,
algorithms for physiology-based planning and bifurcation lesions and jailed side branches, left main stem steno-
optimisation sis, coronary lesions in patients with aortic stenosis, native vessel or
The points discussed thus far can be tentatively integrated into surgical graft stenosis in patients with prior coronary artery bypass
algorithms for PCI planning and post-PCI evaluation. It is sug- graft, and in vessels with myocardial bridge − all in greater detail.
gested that a comprehensive virtual analysis of the target vessel
be performed prior to PCI, to support the indication for PCI and Future directions and outlook
to assist in procedural planning and strategising, with the sup- The use of physiology in procedural planning and simulation of
port of simulation if available. Following PCI, the result should PCI is an area of growing interest, though, as yet, supported only
be interrogated using a combination of physiology and/or imaging by a relatively small evidence base. Upcoming trials in the field

Distal vessel
FFR/NHPR/FCA

Revascularisation No Flow-limiting
may be deferred values?
Yes

Perform pullback and longitudinal vessel analysis

Establish functional disease pattern (focal, tandem, diffuse)
Simulate functional PCI and test alternative PCI plans

Optimal/acceptable PCI result predicted Suboptimal PCI result predicted

Perform PCI in agreement with plan

Consider medical therapy

Repeat post-PCI or CABG as indicated
functional assessment
(Figure 6)

Suboptimal result Good result

Consider imaging Accept functional
guidance PCI result

Figure 5. Proposed algorithm for pre-PCI physiology assessment and planning of PCI based on physiological interrogation. CABG: coronary
artery bypass graft; FCA: functional coronary angiography; FFR: fractional flow reserve; NHPR: non-hyperaemic pressure ratio;
PCI: percutaneous coronary intervention

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EuroIntervention 2023;19:464-481

Post-PCI physiology assessment

Suboptimal
Optimal functional results
functional
results Longitudinal vessel analysis

In-stent focal Proximal and distal Diffuse Medical

pressure loss focal pressure loss pressure loss therapy

Assessment with intracoronary imaging

Stent factors Vessel factors

– Stent underexpansion – Residual stenosis
– Edge dissection – Vessel dissection
– Intrastent thrombus – Intraluminal thrombus
– Plaque protrusion

Stent optimisation and PCI measures tailored to

image findings

Reassessment with physiology

– Accept results according to

End of Anomaly Anomaly not individual clinical situation
procedure corrected corrected – Consider further
optimisation

Figure 6. Proposed algorithm for postprocedural assessment and optimisation of functional PCI results based on physiological interrogation.
PCI: percutaneous coronary intervention

will provide valuable evidence on the use of invasive physiology significant value in objectively assessing the utility of pre-PCI
and FCA for this purpose. Whilst it is generally accepted that PCI simulation and planning using physiological indices.
is an appropriate therapy for patients with focal CAD, the optimal
treatment strategy for patients with haemodynamically significant Conclusions
lesions in the presence of diffuse disease is a subject of ongoing The raison d’être of PCI is to abolish flow-limiting stenoses and
investigation. ischaemia in order to improve patient symptoms and/or prognosis.
Prospective studies are also being conducted to assess the use of In conjunction with angiographic findings, physiology determined
coregistration technology on stent deployment and patient outcomes. by FFR, NHPR and FCA assists in weighing important decisions
The DEFINE GPS (Distal Evaluation of Functional Performance in procedural planning. Emerging studies hint at the application
With Intravascular Sensors to Assess the Narrowing Effect: of in silico PCI simulation prior to intervening on a patient. This
Guided Physiologic Stenting; ClinicalTrials.gov: NCT04451044) offers a novel perspective on planning the effectiveness of an inter-
and iLARDI (Usefulness of the Use of Co-registration Strategy vention and could enable the adoption of revascularisation strate-
With iFR in Long and/or Diffuse Coronary Lesions; ClincalTrials. gies associated with the highest physiological gain. Furthermore,
gov: NCT04283734) investigators aim to assess the impact of iFR identifying patients with little physiological gain after PCI, despite
coregistration (SyncVision; Philips) on guiding PCI and influenc- optimisation, is highly important, as they are at high risk of pre-
ing the number and lengths of implanted stents, and in DEFINE mature stent failure.
GPS, whether this might influence the rate of MACE. The PPG Physiology in the post-PCI setting facilitates procedural optimi-
Global Registry involves a prospective evaluation of the impact sation through descriptive longitudinal vessel analyses of stented
of the PPG index on clinical decision-making for PCI (or not) segments, offering clarity on the presence of residual flow-limiting
and related outcomes (ClinicalTrials.gov: NCT04789317). Future disease. These technologies, in combination with the ability to coreg-
studies should better define the role of microvascular dysfunction ister anatomy with physiology and intravascular imaging, which
in relation to PCI outcomes. Collectively, these studies will add allows for the identification of different disease phenotypes, have

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EuroIntervention 2023;19:464-481
revolutionised PCI in the modern era. Clinical trials assessing the Acknowledgements
effectiveness of these tools on clinical outcomes are eagerly awaited. We are indebted to Silvio Capuano for their technical support in
preparing the supplementary tables for this document.
Appendix. Authors’ affiliations
1. Hospital Clínico San Carlos IdISCC, Complutense University Conflict of interest statement
of Madrid, Madrid, Spain; 2. Institute of Cardiovascular & J. Escaned reports speaker or advisory board member fees from
Medical Sciences, BHF Glasgow Cardiovascular Research Centre, Abbott, Boston Scientific, Medis, and Philips. C. Berry is employed
University of Glasgow, Glasgow, UK; 3. Cardiovascular Center by the University of Glasgow, which holds consultancy and research
Aalst, OLV Clinic, Aalst, Belgium; 4. Department of Cardiology, agreements for his work with Abbott Vascular, AstraZeneca,
Lausanne University Center Hospital, Lausanne, Switzerland; Boehringer Ingelheim, Causeway Therapeutics, Coroventis,
5. Division of Cardiology, Department of Internal Medicine, Genentech, GSK, HeartFlow, Menarini, Neovasc, Novartis, Siemens
Heart Vascular Stroke Institute, Samsung Medical Center, Healthcare, and Valo Health. B. De Bruyne reports receiving con-
Sungkyunkwan University School of Medicine, Seoul, Republic of sultancy fees from Boston Scientific and Abbott Vascular; research
Korea; 6. Amsterdam UMC, Department of Cardiology, Amsterdam grants from Coroventis Research, Pie Medical Imaging, CathWorks,
Cardiovascular Sciences, Amsterdam, the Netherlands; 7. Division Boston Scientific, Siemens, HeartFlow, and Abbott Vascular; and
of Cardiology, Department of Advanced Biomedical Sciences, owning equity in Siemens, GE HealthCare, Philips, HeartFlow,
Federico II University of Naples, Naples, Italy; 8. Cardiology Edwards Lifesciences, Bayer, Sanofi, and Celyad. C. Collet reports
Unit, Azienda Ospedaliero Universitaria di Ferrara, Cona, Italy; receiving research grants from Biosensor, Coroventis Research,
9. Andrzej Frycz Modrzewski Kraków University, Kraków, Poland; Medis Medical Imaging, Pie Medical Imaging, CathWorks, Boston
10. American Heart of Poland, Ustroń, Poland; 11. Interventional Scientific, Siemens, HeartFlow, and Abbott Vascular; and consul-
Cardiology Unit, IRCCS San Raffaele Scientific Institute, tancy fees from HeartFlow, OpSens, Abbott Vascular, and Philips/
Milan, Italy; 12. Cardiovascular Research Institute Dublin and Volcano. J.M. Lee received institutional research grants from Abbott
Department of Cardiology, Mater Private Network, Dublin, Ireland; Vascular, Boston Scientific, Terumo Corporation, Philips/Volcano,
13. School of Medicine, RCSI University of Medicine and Health Medis Medical Imaging, and Zoll Medical. Y Appelman received
Sciences, Dublin, Ireland; 14. West of Scotland Regional Heart speaker fees from Abbott Vascular. Si. Biscaglia received unre-
& Lung Centre, Golden Jubilee National Hospital, Glasgow, stricted research grants and speaker's fees from SMT, Medis, Abbott,
UK; 15. Imperial College Healthcare NHS Trust, Hammersmith and Insight Lifetech. P.P. Buszman is employed by the American
Hospital, London, UK; 16. Department of Cardiology, Alto Vicentino Heart of Poland, which holds research agreements with Meril Life,
Hospital, Santorso, Italy; 17. ISAResearch, German Heart Centre and received speakers’ honoraria from Novartis. G. Campo received
Munich, Munich, Germany; 18. Department of Cardiology, Aarhus institutional research grants from Medis, GE HealthCare, Siemens
University Hospital, Aarhus N, Denmark; 19. St. Francis Hospital Healthcare, Abbott Vascular, Sahajanand Medical Technologies,
& Heart Center, Roslyn, NY, USA; 20. Department of Cardiology, and Insight Lifetech. D. Collison. has received consultancy and
Maasstad Hospital, Rotterdam, the Netherlands; 21. Gottsegen speaker fees from Abbott. A. Jeremias reports consultancy fees
National Cardiovascular Center, Budapest, Hungary; 22. Unidade from Philips/Volcano, Abbott Vascular, Boston Scientific, and
de Intervenção Cardiovascular, Serviço de Cardiologia, Hospital ACIST Medical Systems. Z. Piróth has received speakers’ fees from
de Santa Cruz, Centro Hospitalar de Lisboa Ocidental, Lisboa, Abbott, Boston Scientific, and Opsens. L. Raposo has received hon-
Portugal; 23. Hillel Yaffe Medical Center, Hadera, Israel; oraria and research grants from Philips/Volcano, St. Jude Medical
24. Faculty of Medicine, Technion, Haifa, Israel; 25. Heart and (now Abbott Vascular) and HeartFlow, as well as consultancy fees
Diabetes Center North Rhine-Westphalia, Bad Oeynhausen, from Boston Scientific. T. Rudolph received speaker honoraria
Germany; 26. Cardiology, Department of Medical Sciences and from Abbott Vascular, Philips, Neovasc, AstraZeneca, Bayer, Pfizer,
Uppsala Clinical Research Center, Uppsala University, Uppsala, Philips/Volcano, Zoll Medical, and RainMed. G. Sarno has received
Sweden; 27. Department of Cardiology, Medical University of a research grant from Boston Scientific (to the institution); and per-
Graz, Graz, Austria; 28. Department of Interventional Cardiology sonal fees from Abbott Vascular, Boston Scientific, and Pfizer/BMS.
for Coronary, Valves and Structural Heart Diseases, Institut Coeur D. Dudek reports participation in company-sponsored speaker’s
Poumon, Lille, France; 29. Department of Cardiology, Institut bureaus for Abbott, Boston Scientific, Bracco, Philips, and Siemens
Pasteur de Lille, Lille, France; 30. Department of Cardiology, Healthcare; and unrestricted grants from Abbott, Boston Scientific,
Catharina Hospital, Eindhoven, the Netherlands; 31. Interventional Bracco, Philips, and Siemens Healthcare. The other authors have no
Cardiology Unit, Maria Cecilia Hospital, GVM Care & Research, conflicts of interest to declare.
Cotignola, Italy; 32. Institute of Cardiology, Jagiellonian University
Medical College, Kraków, Poland; 33. Department of Biomedical References
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Supplementary data The supplementary data are published online at:

Supplementary Appendix 1. Guiding catheters, guide catheter https://eurointervention.pcronline.com/
extensions and microcatheters. doi/10.4244/EIJ-D-23-00194

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Supplementary data
Supplementary Appendix 1. Guiding catheters, guide catheter extensions and
microcatheters.
Operators should be aware that intracoronary pressure measurements can be influenced by
PCI hardware. The integrity of measured FFR and NHPR in PCI procedures depends on the
accuracy of the measured aortic (Pa) and intracoronary (Pd) pressures, and the persistence of
pressure calibration during the procedure. This is particularly important in instances when the
pressure guidewire is used as a workhorse wire during the entirety of the PCI procedure.
Damping of the catheter pressure waveform may affect mean Pa pressure measurements or
generate a mismatch with the Pd waveform, translating into diastolic pressure gradients.
Careful attention should be paid to the choice, sizing, and position of the guide catheter.
Guide catheter extensions or catheters with side holes may not provide sufficiently accurate
Pa measurements. Microcatheters inserted over the pressure guidewire might also affect
pressure equalisation. Intracoronary hyperaemic drugs should be avoided if the guide catheter
is disengaged, to prevent the loss of drug in the aorta. Drift is often caused by technical
and/or procedural issues related to the distal pressure sensor, the aortic pressure setup, or
both.

Supplementary Appendix 2. Applied coronary physiology in specific PCI scenarios.

Multivessel coronary artery disease
Invasive physiology in patients with MVD leads to a reclassification of revascularisation
strategy in approximately 30% of patients, and investigation of more vessels is associated
with higher reclassification rates (up to 66%) 88. In patients with MVD and truly intermediate
disease, physiological PCI planning decreases the number of lesions indicated for
intervention by approximately 20-30% 88, leading to fewer stents implanted and a lower
number of complex lesions treated 89,90. In the SYNTAX II study, the combined use of
physiology and other contemporary PCI techniques in patients with three-vessel disease was
associated with improved five-year outcomes with regard to MACE, MI, and stent
thrombosis, when compared with a matched patient population from the original SYNTAX
study 92. In the FAME III trial, FFR-guided PCI was not non-inferior to CABG concerning
the one-year incidence of death from any cause, myocardial infarction, stroke, or repeat
revascularisation 92. However, a differential effect according to the SYNTAX score was
apparent, suggesting that revascularisation decisions based on FFR in this setting may be
nuanced and that CAD complexity should also be taken into consideration. Nevertheless,
regarding patients with MVD in whom surgical revascularisation is planned, several studies
have demonstrated that high FFR values in the native coronary arteries prior to CABG are
associated with increased rates of arterial surgical conduit occlusion within the first year 93-96.

Functional coronary angiography might play an important role in planning and guiding MVD
due to its ability to evaluate all major vessels (avoiding intracoronary instrumentation
multiple times) and suitability for off-line analysis of diagnostic angiograms thus potentially
enabling post-hoc analysis and decision making, even in cases when invasive physiology was
not performed 57,58. Ongoing studies are exploring the value of FCA guidance to decide upon
revascularisation in patients with MVD 97. Functional evaluation of MVD based on CTCA
FFRCT has been tested in several studies 98,99. The SYNTAX III REVOLUTION study
reported the additive utility of FFRCT in assisting heart team decisions (18.3% adjustment in
procedural planning), allowing further characterisation and simplification of disease patterns
with fewer patients classified with MVD (13.5% absolute reduction in numbers of patients
with MVD with the assistance of FFRCT) 100.

Vessels with tandem lesions or diffusely diseased vessels

Physiologic assessment of vessels with tandem stenoses aims to identify the haemodynamic
contribution of each stenosis. As each stenosis in series limits hyperaemic flow across the
other 101, haemodynamic stenosis crosstalk may occur, generally causing underestimation of
individual stenosis severity 53,102. As such, interpretation of lesion-specific pressure gradients
is challenging in this setting and a definitive recommendation on how to quantify severity
based on each individual value cannot be made.

Assessment of tandem stenoses with FFR is typically performed using pressure wire
pullbacks with intravenous administration of adenosine. Based on the obtained curve,
treatment of the most haemodynamically significant lesion can be performed, followed by
reassessment of the vessel to ensure any residual disease is not haemodynamically significant
103
. NHPRs such as iFR are less prone to haemodynamic crosstalk between stenoses 63,
although experimental studies have shown that both NHPR and FFR are equally affected by
hemodynamic interdependence in cases in which the functional significance of serial
coronary stenoses is very severe 104. The haemodynamic contribution of separate stenosis can
be established from longitudinal NHPR pullback, and prediction of the haemodynamic result
of intervening on one or both stenoses can be based on mathematical calculation, or on
virtual stenting tools 55,105. The same approach can be followed using longitudinal vessel
analysis derived from FCA 106,107.

Patients with acute coronary syndromes

Most of the evidence addressing the safety of decision-making based on FFR stems from
trials and cohorts made up of patients primarily with CCS. The physiological implications of
acute coronary syndrome (ACS) may interfere with some basic assumptions made in the
theoretical framework of FFR, such as fixed stenosis geometry, stable microcirculatory
status, and an adequate hyperaemic response to adenosine. The enhanced adrenergic drive
associated with ACS might also interfere with NHPRs. These effects disappear quickly, and
their magnitude depends on the haemodynamic derangement of the patient.

The reproducibility of FFR and iFR measurements in ACS has been investigated previously
108–111
. More recent studies suggest that in patients with ST-segment elevation myocardial
infarction (STEMI), FFR and NHPR values in non-culprit vessels can shift in the transition
from the acute to subacute STEMI phases 108. Due to major dynamic changes in the coronary
microcirculation downstream of the infarct-related lesion, FFR or invasive physiologic
indices may not be used in the acute phase to guide PCI of the culprit lesion 112. Thus, FFR
might be considered to determine the significance of the lesion in the culprit artery after acute
and subacute phases 113. Prior studies have shown that the default use of FFR to guide
revascularisation of non-culprit lesions in STEMI patients reduces revascularisation rates 114-
116
, and carries prognostic information 117. However, FFR-guided complete revascularisation
in patients with STEMI was not superior to angiography guidance in terms of one-year
MACE in the large FLOWER MI trial 116. Fewer stents were used in the physiology guided
arm. A substudy of that trial demonstrated that the avoidance of revascularisation of non-
culprit lesions based on an FFR >0.80 is associated with an excess of events 118. However,
several limitations should be considered in the interpretation of the trial and sub-studies; the
study included a highly selected population, the functional evaluation was performed as a
staged procedure in the majority of patients limiting the potential FFR advantage in reducing
unnecessary procedures and the observed rate of adverse events was significantly lower than
expected. In addition, PCI was performed in 20% of lesions with FFR>0.80, FFR values were
missing in 25%, and it is unknown which lesions (treated or untreated) were responsible for
events during follow-up 119. The role of iFR-guided complete revascularisation in acute
STEMI patients with MVD is being evaluated in the Instantaneous wave-free ratio guided
Multivessel revascularizatiOn During percutaneous coronary intervEntion for acute
myocaRdial infarctioN (iMODERN) randomised trial (NCT03298659).

On occasion, the culprit lesion in patients with non-ST-segment elevation myocardial

infarction (NSTEMI) cannot be clearly identified. FFR-based deferral of revascularisation in
NSTEMI with an unclear culprit lesion is associated with worse outcomes 120. It should be
noted that ACS patients derive similar advantages from FFR-guidance (compared to angio-
guidance) as stable angina patients 121,122. Further details regarding the interpretation of
physiology with microcirculatory changes are available in the Supplementary Appendix 3
below.

Bifurcation lesions and jailed side branches

There is a paucity of studies evaluating bifurcation lesions with invasive physiology or FCA.
Angiographic guidance, the standard approach to guide PCI of bifurcation lesions 123,
frequently overestimates side branch (SB)-lesion severity 124. Physiologic assessment of
bifurcation anatomy may further assist PCI strategy and indicate the necessity of adopting a
non-provisional strategy in some instances. In the Nordic-Baltic Bifurcation Study III,
systematic kissing-balloon (KB) led to higher SB FFR values (0.92 versus 0.85 with no-KB;
P=0.011), but the difference was not clinically relevant, and attenuated over time (0.91 versus
0.87; P=0.19) 125.

Compared with an angiography-guided approach, an FFR-guided PCI strategy in bifurcation

PCI provided similar rates of functionally adequate revascularisation and hard cardiac events
with less stent implantation and was associated with numerically lower rates of TVF and
stent thrombosis 126. In the DKCRUSH-VI study, patients were randomly assigned to FFR or
angiography guided SB-PCI, which led to fewer stents being placed (25.9% in the FFR arm
versus 38.1% in the angiography arm, P=0.01), less main branch (MB) restenosis in the
physiology guided group (1.2% versus 9.2%, P=0.01), and no difference in MACE 126. Thus,
provided that coronary flow is normal, and signs of acute ischemia are absent after main-
branch stenting, current evidence suggests that a pressure-wire based provisional approach is
feasible, yielding reliable clinical outcomes.

Recent work has also supported the use of jailed pressure guidewires for continuous SB
monitoring 127, which seems safe and feasible, even with high-pressure MB inflations using
non-compliant balloons, however large prospective studies are lacking.

Left main stenosis

Safety of deferral of revascularisation in left main stem (LMS) stenosis when FFR or iFR
values are non-ischaemic has been reported 128-130. Of note, LMS stenosis <50% was
associated with positive FFR values (<0.80) in 23% of the cases, whilst the presence of a
significant LMS stenosis (>50%) was rarely (6% of the cases) associated with negative FFR
values (>0.80) 131.
Avoidance of technical pitfalls for wire-based interrogation in this location is particularly
important. Overall, the effect of downstream stenosis on FFR assessment of LMS disease has
been reported to be small, unless the downstream stenosis is proximal and very severe 132,133.
Longitudinal vessel analysis may provide a richer picture of the individual contribution of
LMS and downstream stenoses. Likewise, no studies on physiological optimisation of LMS
PCI are currently available. Information on the use of FCA in the LMS is scarce.

Coronary lesions in patients with aortic stenosis

The main challenge when assessing the functional relevance of coronary stenoses prior to
aortic valve replacement is that the boundary of haemodynamic and microvascular conditions
will shift owing to the intervention on the aortic valve 134,135. Thus, there is uncertainty
regarding whether intracoronary measurements made as part of diagnostic work-up of aortic
stenosis (AS) reliably predict stenosis relevance once such boundary conditions have been
modified by transcatheter aortic valve implantation (TAVI) or surgical aortic valve
replacement, or whether intracoronary indices are equally affected by changes in cardiac
physiology. One study has reported that both iFR and FFR 54correlate well with ischaemia
demonstrated with single-photon emission computerised tomography (SPECT) imaging 136.
Studies in patients with AS using FFR as a comparator for iFR are fraught by the fact that
discordance between both indices are compatible with a similar diagnostic efficiency against
non-invasive tests 137.

Although reduced adenosine-induced hyperaemia has been observed in patients with AS,
FFR-guided PCI was superior to angiographic-guided PCI in retrospective trials, and it has
been demonstrated that an FFR>0.85 effectively excludes the presence of ischaemia-
generating stenosis. Non-hyperaemic indices such as iFR do not rely on the effect of
adenosine, yet since basal coronary flow may be increased in AS, NHPR indices might
overestimate stenosis severity. The use of functional angiography has been explored in these
patients using FFR obtained at baseline or after TAVI as a comparator, reporting a good
diagnostic yield of QFR 138-140. One study suggests that severe AS (valve area <0.6 cm 2) is a
major determinant of the discrepancy between QFR and FFR values 138. Also, FFRCT values
have been shown to correlate well with invasive FFR values in patients with AS 141,142.

Lesions in vessels providing collaterals to chronically occluded arteries

As collateral donor vessels have an increased subtended myocardial bed, angiographically
mild or moderate stenoses may show disproportionally low FFR/iFR values 143. The impact
of a CTO on FFR measurements in the collateral donor vessel is highly variable, as it
depends on the magnitude of hyperaemic flow downstream to the occluded artery, which
might be decreased if myocardial scar or microvascular dysfunction are present. Reversal of
the above-described phenomenon and its impact on FFR values in the donor vessel must be
taken into account if CTO PCI is planned 144-148. In cases when myocardial viability is proven
downstream to a CTO, and PCI is not planned or possible, PCI of the donor vessel with
significant FFR/iFR, but only modest or moderate stenosis, might be beneficial. This scenario
deserves further investigation. Of note, assessment of stenosis severity utilising functional
angiography does not consider the increase in coronary flow linked to collateral blood
supply, thus it may potentially predict the functional stenosis relevance of the stenosis only
once CTO revascularisation has been performed.

Native vessel or surgical graft stenoses in patients with prior CABG

Assessing functional stenosis severity in patients with prior coronary artery bypass grafts
(CABG) is challenging due to complex hydraulic circuits generated by patent grafts, frequent
presence of CTO lesions with collateral supply, and tortuous mammary artery grafts. As
patients with patent surgical grafts have been excluded from most clinical trials pertaining to
the investigation of FFR or iFR to assist in decision making, with the exception of a few
retrospective studies 149, the safety of revascularisation deferral based on physiology has not
been adequately established in these patients also with the exception of few retrospective
studies 150. Relevant consideration in this regard is that the natural history of surgical graft
disease is different from that of native CAD 94,151. As a matter of principle, distal coronary
flow is the summed supply of the native vessel and the conduit. Currently, no studies are
available on the use of functional coronary angiography in patients with prior CABG and as
such, interpretation and clinical decisions must be judged according to the specificities of
each individual case. Functionally diffuse disease, demonstrated with physiological pullback,
might infer an increased risk of graft failure in patients undergoing CABG 50.

Vessels with myocardial bridge

The role of invasive functional testing in the evaluation of the impact of myocardial bridging
on coronary flow has not yet been standardised. Given the dynamic characteristics of
myocardial bridge stenosis, the traditional use of FFR requiring two mean pressures to be
obtained during maximal (adenosine-induced) hyperaemia is largely inadequate for the
assessment of their haemodynamic significance 152. In this regard it has been demonstrated
that the systolic pressure over-estimation in the distal segments of the vessel, with
ventricularisation of the pressure wave distal to the bridge, might artificially lead to a
negative FFR evaluation caused by a systolic distal pressure greater than systolic proximal
pressure 88,153,154. Hence, diastolic FFR in conjunction with dobutamine has been
demonstrated as the most appropriate approach for testing the haemodynamic significance of
a myocardial bridge, whereas standard mean FFR should be used with caution 155. Recently,
it has been suggested that iFR correlates more closely with respect to symptoms/non-invasive
tests than FFR, at rest and during dobutamine infusion, even if in this latter setting a specific
cut-off value has not yet been established 89. Furthermore, the use of the pullback scouting
analysis during iFR measurement might provide additional information on the length and the
location of a myocardial bridge. This may be due to the hydrostatic effect related to the vessel
distribution and also to a higher prevalence of intracoronary microvascular tracts.

Periprocedural systemic and microcirculatory changes

Transient haemodynamic changes at systemic and coronary level can influence
measurements made with intracoronary pressure indices. Hyperaemic indices may be
transiently blunted by microvascular embolisation of plaque components, adrenergic
activation, or profound ischaemia, potentially leading to false negative readings. NHPR
readings might be affected by adrenergic responses and reactive hyperaemia (for example
due to contrast injection and transient flow interruption during device inflation/implantation),
potentially causing false positive results.
SUPPLEMENTARY TABLE 1. Studies supporting the prognostic impact of functional PCI results.

First author Year Index Study aim No. of patients CAD type Comments

Bech et al. 1999 FFR Prognostic value of FFR post balloon 60 CCS Post-PCI FFR≥0.90 associated with lower rate of
angioplasty (PTCA), 2-year follow up composite MACE (death, MI, repeat PTCA,
recurrent ischemia) compared with FFR<0.90;
12% versus 41% respectively, P=0.0122

Pijls et al. 2002 FFR Correlation of post-PCI FFR with 750 CCS, ACS Residual low FFR post-PCI correlates with MACE
MACE, 6-month follow up outcome at 6-months. Composite MACE outcome
OR (adjusted for stent length) 7.35 (95%CI, 3.04-
17.73) for FFR<0.80, 1.25 (95%CI, 0.58-2.70) for
FFR>0.91

Klauss et al. 2005 FFR Prognostic implications of post-PCI 119 CCS Post-PCI FFR higher in patients without events
FFR on MACE, 6-month follow up versus with MACE; FFR>0.95 (±0.05) versus
FFR<0.88 (±0.08) respectively (P=0.001). Post-
PCI FFR<0.95 (OR 6.22, 95%CI 1.79-21.62)
predictor of MACE (calculated using logistical
regression model)

Nam et al. 2011 FFR Correlation of post-PCI FFR with 80 CCS, ACS No difference in death, MI or stent thrombosis at
MACE, 1-year follow up 1-year. Adverse MACE in low FFR group
(FFR≤0.90) driven by target vessel
revascularisation compared with high-FFR group
(FFR>0.90) 17.5% versus 2.5% (P<0.01)

Ito et al. 2014 FFR Impact of clinical outcomes with FFR 97 CCS No difference in death, MI or stent thrombosis
after IVUS assisted PCI, 1.5-year between post-PCI FFR≤0.90 and FFR>0.90
follow up groups. Increased rate of target vessel
revascularisation in low-FFR group compared
with high-FFR group; 15% versus 2% respectively
(P=0.04)

Agarwal et al. 2016 FFR Influence of post-PCI FFR on 574 CCS, ACS ROC analysis suggests optimal post-PCI cut-off
prognosis after PCI, with analyses for for death is ≤0.87, with patients with a post-PCI
different disease patterns, 2.5-year FFR>0.87 experiencing lower rates (13.5% versus
follow up 9%, P=0.03). Differences more profound in
patients with multi-vessel disease

Piroth et al. 2017 FFR Post-PCI FFR to predict clinical 639 CCS Higher rate of vessel orientated cardiac events in
outcome from patients in FAME 1 and patients with FFR<0.88 compared with FFR>0.92
FAME 2, 1-year follow up (with (HR 1.46, 95%CI 1.02-2.08), and target vessel
exploratory 2-year MACE outcomes) revascularisation (HR 1.59, 95%CI 1.03-2.46) at
2-years

Li et al. 2017 FFR Post-PCI FFR cut-off for prediction of 1476 CCS FFR≤0.88 correlates with TVF and cardiac death,
3-year TVF, 3-year follow up compared with FFR>0.88. By 1 year, 4% versus
8% in the FFR>0.88 compared with FFR≤0.88
respectively (P=0.001). Cardiac death in
FFR>0.88 0.2% versus FFR≤0.88 1.3% (P=0.017)

Kasula et al. 2016 FFR Prognostic utility of post-PCI FFR in 390 CCS, ACS In setting of ACS, post-PCI FFR associated with
setting of ACS, 2.4-year follow up increased MACE (calculated with Cox regression
model), optimal cut-off of FFR≤0.91 (ROC
analysis). Higher observed rate of MACE in low-
FFR group; 19% versus 30%, P=0.03

Lee et al. 2018 FFR Correlations between pre- and post- 621 CCS No differences in cardiac death between
PCI FFR and long-term prognostic FFR<0.84 and FFR≥0.84. Failure of resolution of
implications, 2-year follow up flow limiting disease associated with TVF
between groups at 2 years; (driven by
revascularisation) 11.5% versus 0% in low %FFR
increase compared with high %FFR increase
respectively (P=0.002)
Azzalini et al. 2019 FFR Effect of routine post-PCI FFR on 65 CCS, ACS FFR≥0.90 associated with significant reduction in
decision making and MACE, 1-year 1-year composite MACE (9.1% versus 31.6%,
follow up P=0.047). No significant difference observed in
individual hard endpoints of cardiac death, MI or
TVF

Fournier et al. 2019 FFR If an improvement in FFR (ΔFFR) 639 CCS No difference in death or myocardial infarction by
bears prognostic benefit, 2-year follow ΔFFR. Highest rate of TVR observed in patients
up with lowest tertile of ΔFFR (adjusted P=0.002)

Hwang et al. 2019 FFR Prognostic relevance of post-PCI FFR 835 CCS, ACS Different post-PCI FFR between LAD and non-
and identify an optimal cut-off value LAD vessels (P<0.001). Optimum LAD post-PCI
depending on target vessel (LAD or FFR cut-off to predict TVF is 0.82, and 0.88 in
non-LAD), 2-year follow up non-LAD. TVF higher in patients with lower post-
PCI FFR in LAD (10.9% versus 2.5%, P<0.001)
and non-LAD (8% versus 1.9%, P<0.004). No
difference in cardiac death or MI.

Jensen et al. 2007 Pd/Pa Predictive capacity of FFR, Pd/Pa and 98 CCS Distal residual abnormal Pd/Pa ratio post-PCI
pullback to determine risks of in-stent predictor of in-stent restenosis; OR 4.58 (95%CI
restenosis, 9-month follow up 1.11-18.84) P=0.034 (multivariate analysis).

Hakeem et al. 2019 Pd/Pa, Long-term prognostic value of post- 574 CCS, ACS Post-PCI Pd/Pa>0.96 associated with reduced
FFR PCI Pa/Pd and FFR, 2.5-year follow composite MACE, with additive benefit beyond
up post-PCI FFR alone (calculated using adjusted
Cox regression analysis)

Shin et al. 2019 Pd/Pa, Evaluate prognostic implications of 588 CCS, ACS 26.3% discordance between post-PCI Pd/Pa and
FFR post-PCI Pd/Pa compared with post- post-PCI FFR. Post-PCI Pd/Pa≤0.92 with
PCI FFR, 2-year follow up FFR>0.80 associated with 3.5% TVF and
FFR≤0.80 10.4%, P=0.045.

Biscaglia et al. 2019 QFR Whether post-PCI QFR correlates 602 CCS, ACS Lower QFR post-PCI correlates with adverse
with adverse events in patients patient outcomes. Post-PCI QFR≤0.89 associated
undergoing complete revascularisation with increased VOCE (cardiovascular death,
with PCI, 1.7-year follow up (median) vessel-related MI, TVR) with HR 2.91, 95%CI
1.63-5.19 (calculated using adjusted Cox
regression analysis).

Kogame et al. 2019 QFR Assess post-PCI QFR in 3-vessel 440 CCS, ACS Higher post-PCI QFR associated with more
disease on clinical outcomes favourable clinical outcomes in de novo 3-vessel
CAD, with optimal cutoff of 0.91 predicting 2-
year VOCE.

Lee et al. 2022 QFR Assessment of the clinical value of 274 CCS, ACS Estimated rQFR from pre-PCI diagnostic coronary
residual QFR (rQFR) in the prediction angiography and virtual PCI over-estimated
of residual ischaemia after virtual PCI functional benefit of PCI with good prediction of
suboptimal functional results and long-term
VOCE.

Zhang et al. 2022 QFR Retrospective analysis of PANDA III 2348 CCS, ACS Actual post-PCI and residual (simulated) post-PCI
cohort, correlation between pre-PCI QFR correlate. Optimal simulated residual
residual QFR and actual post-PCI QFR>0.92, with 2-year VOCE higher in
QFR, 2-year outcomes suboptimal residual QFR≤0.92, 2% versus 10.7%
respectively, HR 5.58 (95%CI 3.55-8.79), driven
by vessel-related cardiac death (HR 4.38, 95%CI
2-9.6, P<0.0002), MI (HR 4.30, 95%CI 1.75-10.6,
P<0.001) and TVF.

Patel et al. 2020 iFR Prospective assessment of post-PCI 500 CCS, ACS Post-PCI iFR correlates with composite MACE at
iFR and clinical outcomes quantified 1-year. Post-PCI iFR≥0.95 associated with
by MACE, 1-year outcomes improved symptoms of angina and MACE (1.8%
versus 5.7%, P=0.04)
SUPPLEMENTARY TABLE 2. Limitations related to image-based functional coronary analysis.

Invasive angiography derived

QFR • Reliant on adequate projections with good vessel opacification

• Not applicable in ostial and left main lesions, major bifurcations, myocardial bridges
• Single vessel analysis
• Nitrates required as angiographically derived
• Need for proprietary software
• Manual vessel contouring may be needed

vFFR • Similar limitations to QFR

• High quality diagnostic angiography required with orthogonal views
• Limited evidence to assess diagnostic accuracy or utility currently

caFFR • Similar limitations to QFR

• Relatively high-powered hardware required to compute simultaneous coronary arteries

FFRangio • Needs three angiographic projections

IVUSFFR • Requires vessel instrumentation

• Need to change to guide catheter to facilitate imaging
• Limited data on usage

OCTFFR • Similar to IVUSFFR

Non-invasive angiography derived

FFRCT • Analysis performed out of the hospital

• Relatively time consuming to obtain results
• Latest generation CT scanners required acquire images and avoid step artifact
• Patients often require beta-blockade to facilitate scan
• Awaiting prognostic validation
SUPPLEMENTARY TABLE 3. Supporting studies used to define focal, tandem and diffuse disease patterns.
Study title First author Year Ref Study type Technique No. of Focal disease Diffuse disease
no. patients

1 Measurement of Collet C 2019 45 Prospective, FFR, 79 Continuous metric, values approaching 1.0 represent focal
Hyperemic Pullback multicentre PPGindex haemodynamically focal CAD, whereas values close to 0
Pressure Gradients to et al. diffuse CAD.
Characterize Patterns of
Coronary
Atherosclerosis
2 Differential Collet C 2022 62 Sub-study of FFR, 103 Focal coronary artery disease (CAD) was defined as a
improvement in angina TARGET-FFR PPGindex pullback pressure gradient (PPG) value ≥0.66 and diffuse
and health-related et al. CAD as PPG <0.66. Increased residual angina post-PCI with
quality of life after PCI low PPG (diffuse disease).
in focal and diffuse
coronary artery disease

3 Post-stenting fractional Collison D 2021 2 Prospective, FFR 260 Change ≥0.05 FFR units. Anything else was considered
flow reserve vs coronary single centre, diffuse.
angiography for et al. randomised
optimization of
percutaneous coronary
intervention (TARGET-
FFR)

4 Single center experience van Beek K 2022 51 Retrospective FFR 59 1 or 2 abrupt changes with Anything else was considered
in the treatment of single centre ≥0.10 FFR units. diffuse.
hemodynamically et al.
significant diffuse
coronary artery disease
of the left anterior
descending

5 Automated algorithm Lee SH 2020 49 Prospective, dFFR(t)/d 234 Major FFR gradient Signal noise in the absence of
using pre-intervention et al. multicentre t dFFR(t)/dt ≥0.035/second. lesion dFFR(t)/dt
fractional flow reserve <0.015/second.
pullback curve to predict Minor FFR gradient dFFR(t)/dt
post-intervention 0.015-0.034/second.
physiological results
6 Blinded Physiological Jeremias A 2019 3 Prospective, iFR 494 Change ≥0.03 iFR units Change ≥0.03 iFR
Assessment of Residual et al. multicentre within 15mm. units >15mm.
Ischemia After
Successful
Angiographic
Percutaneous Coronary
Intervention (DEFINE
PCI)
7 Inter‐observer Warisawa T 2020 54 Retrospective iFR 545 Change ≥0.03 iFR units Change ≥0.03 iFR
differences in et al. multicentre within 15mm. units >15mm.
interpretation of
coronary pressure‐wire
pullback data by non‐
expert interventional
cardiologists

8 Utility of angiography– Matsuo A 2021 55 Prospective, iFR 70 Change ≥0.03 iFR units Change ≥0.03 iFR units with a
physiology co- et al. single centre within 20mm. length ≥20mm.
registration maps during
percutaneous coronary
intervention in clinical
practice

9 Impact of Scarsini R 2021 56 Retrospective iFR 194 Change ≥0.03 iFR units Progressive and constant iFR
physiologically diffuse et al. single centre within 15mm. change.
versus focal pattern of
coronary disease on
quantitative flow reserve QFR 194 Abrupt change in QFR of Progressive and constant QFR
diagnostic accuracy ≥0.05 units in length <10 change.
mm.
10 Clinical implication of Tang J 2021 57 Retrospective QFR 186 Abrupt change in QFR of Abrupt change in QFR of
QFR in patients with et al. Multicentre ≥0.03 units in length <20 ≥0.03 units in length ≥20 mm.
ST‐segment elevation mm.
myocardial infarction
after drug‐eluting stent
implantation

11 Angio-Based Fractional Biscaglia S 2021 58 Retrospective QFR 111 Abrupt change in QFR of Progressive and constant QFR
Flow Reserve, et al. Multicentre ≥0.05 units in length <10 change without significant
Functional Pattern of mm. focal change in QFR units.
Coronary Artery
Disease, and Prediction
of Percutaneous
Coronary Intervention
Result: a Proof-of-
Concept Study
12 Physiological 2021 59 Retrospective QFR 341
Distribution and Local Shin D The median value of QFR PPG index ≥0.78 used to define
Severity of Coronary Multicentre focal disease, and <0.78 to define diffuse disease. Major
et al. gradient determined to be dQFR/ds ≥0.025/mm.
Artery Disease and
Outcomes After
Percutaneous Coronary
Intervention
13 Anatomical Assessment Koszegi Z 2021 60 Retrospective RFR - Change in RFR of >0.05 Change in RFR of >0.05 units
vs. Pullback resting full- ?centre units in length <25 mm. in length >25 mm.
cycle ratio (RFR) et al.
Measurement for
Evaluation of Focal and
Diffuse coronary
Disease: Rationale and
Design of the “READY
Register”

14 Comparisons of Non- Omori H 2020 61 Prospective, iFR, 140 Change of index units Anything else was considered
hyperaemic pressure et al. multicentre, RFR, ≥0.03 within 15 mm diffuse.
Ratios randomized length.
dPR
SUPPLEMENTARY TABLE 4. Currently available and pending devices for invasive functional coronary
assessment.

Device name Manufacturer FDA approval Available Functional index

ComboWire Volcano 2004 Yes FFR, CFR, HSR,

HMR

Volcano Verrata Philips Volcano 2014 Yes FFR, iFR

COMET Boston Scientific 2015 Yes FFR, DFR

Volcano Verrata PLUS Philips Volcano 2016 Yes FFR, iFR

PressureWire X Abbott 2016 Yes FFR, RFR, IMR, CFR

COMET II Boston Scientific 2019 Yes FFR, DFR

Pressure Guidewire Zurich Medical 2019 Yes FFR

System Model 100

OmniWire Philips Volcano 2019 Yes FFR, iFR

Navvus® Rapid Acist Medical 2019 Yes FFR

Exchange FFR Systems
microcatheter

OptoWire 3 OpSens Medical 2020 Yes FFR, dPR

Wirecath® Cavis Technologies - Undergoing clinical FFR

trial, NCT04776577

TruePhysio pressure Insight Lifetech - Undergoing clinical FFR

microcatheter trial, NCT05437900,
NCT05417763

Previous versions of these devices have that are no longer available have not been included.
Supplementary Figure 1.
Correction of intracoronary pressure pullback curves with dedicated software addressing
fluctuations caused by the Venturi effect.
The pressure pullback curve obtained with intracoronary guidewires over a vessel with
stenoses typically show ups and downs caused by pressure – flow velocity relationships
(Venturi effect). Over the pullback, intraluminal pressure within the reference segment distal
to a stenosis (Pd) will decrease when reaching an intra-stenotic location with high flow
velocity (Ps). This translates into a dip of translesional pressure ratios like FFR, iFR and
others. The figure shows how software-based correction of the pullback curve omits such dip
in iFR values, facilitating interpretation of the longitudinal vessel analysis. See also an
example of software-based correction of RFR pullback curve below.
Supplementary Figure 2.

Longitudinal iFR mapping coregistered with coronary angiography.

Co-registration of iFR with angiography, showing flow limiting disease in the left main stem
and left anterior descending artery with a physiologically significant iFR of 0.81, and
predicted post-PCI iFR of 0.93 after successful treatment of selected segment.
Supplementary Figure 3.
Pre- and post-PCI functional test in the presence of myocardial bridge.

iFR analysis of a proximal LAD stenosis with a distal myocardial bridge. Longitudinal vessel
analysis allowed outlining the separate contribution of a coronary stenosis and a subtended
myocardial bridge to abnormal coronary haemodynamics. Post-PCI physiology confirmed the
residual flow-limiting effect of the myocardial bridge after stenting of the proximal
atherosclerotic lesion.