Optimising physiological-endpoints-of-percutaneous-coronary-intervention(1)

SUBMITTED ON 11/08/2020 - REVISION RECEIVED ON 1st
03/12/2020 / 2nd
07/01/2021 - ACCEPTED ON 11/02/2021
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online
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April
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DOI:
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© Europa Digital & Publishing 2021. All rights reserved.
*Corresponding author: National Heart and Lung Institute, Imperial College London, 2nd Floor, B Block,
Hammersmith Hospital, Du Cane Road, London, W12 0HS, United Kingdom. E-mail: r.al-lamee13@imperial.ac.uk
Optimising physiological endpoints of percutaneous coronary
intervention
Rasha K. Al-Lamee1,2
*, MA, MBBS, PhD; Christopher A. Rajkumar1,2
, BSc, MBBS;
Sashiananthan Ganesananthan1
, BSc; Allen Jeremias3
, MD, MSc
1. National Heart and Lung Institute, Imperial College London, London, United Kingdom; 2. Imperial College Healthcare
NHS Trust, London, United Kingdom; 3. Department of Cardiology, St. Francis Hospital, The Heart Center, Roslyn, NY, USA
Abstract
Invasive coronary physiology to select patients for coronary revascularisation has become established in
contemporary guidelines for the management of stable coronary artery disease. Compared to revascularisa-
tion based on angiography alone, the use of coronary physiology has been shown to improve clinical out-
comes and cost efficiency. However, recent data from randomised controlled trials have cast doubt upon
the value of ischaemia testing to select patients for revascularisation. Importantly, 20-40% of patients have
persistence or recurrence of angina after angiographically successful percutaneous coronary intervention
(PCI). This state-of-the-art review is focused on the transitioning role of invasive coronary physiology from
its use as a dichotomous test for ischaemia with fixed cut-points, towards its utility for real-time guidance
of PCI to optimise physiological results. We summarise the contemporary evidence base for ischaemia test-
ing in stable coronary artery disease, examine emerging indices which allow advanced physiological guid-
ance of PCI, and discuss the rationale and evidence base for post-PCI physiological assessments to assess
the success of revascularisation.
KEYWORDS
• clinical trials
• fractional flow
reserve
• stable angina
State of the Art
by

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Optimising physiological endpoints of PCI
Abbreviations
CAD coronary artery disease
FFR fractional flow reserve
iFR instantaneous wave-free ratio
IVUS intravascular ultrasound
MI myocardial infarction
OCT optical coherence tomography
OMT optimal medical therapy
PCI percutaneous coronary intervention
Physiological justification of PCI
INTRODUCTION
Contemporary guidelines suggest that the principal remit of percu-
taneous coronary intervention (PCI) in stable coronary artery dis-
ease (CAD) is to treat symptoms refractory to optimal medical
therapy (OMT)1
. Recent data from the largest trial studying the
impact of an early invasive strategy on hard outcomes in stable
CAD support these recommendations2
. Since we attribute symp-
toms not to the anatomic stenoses but to their association with
myocardial perfusion, it intuitively follows that, to treat angina
optimally, improvement of physiological, rather than anatomi-
cal characteristics of a diseased vessel should be the principal
goal. Ischaemia-guided revascularisation with invasive coronary
physiology has become a central component of modern-day evi-
dence-based treatment algorithms for the management of stable
CAD1
. By offering real-time assessment of the ischaemic signifi-
cance of epicardial stenoses, invasive coronary physiology identi-
fies patients who can benefit from revascularisation by bridging
the gap between anatomy, physiology and symptoms. However,
recent placebo-controlled data have challenged this paradigm and
it has become apparent that the link between ischaemia and symp-
toms may be more complex3
.
Physiological assessment allows vessel- and lesion-specific
assessment for ischaemia. Therefore, in optimising post-PCI
physiology, it may be possible to improve outcomes specific to
that vessel or lesion. However, it must be remembered that cardio-
vascular events also occur from angiographically and physiologi-
cally non-significant lesions, so, even with the best physiological
results, secondary prevention with optimum medical therapy
remains essential4
.
In this state-of-the-art review, we report the contemporary evi-
dence base for revascularisation based on invasive physiology, the
evolving role of physiology to guide PCI strategy, and the poten-
tial value of post-PCI physiological assessments. More broadly,
we discuss the current role of ischaemia testing in the diagnosis
and treatment of stable CAD and the implications for the future of
coronary physiology.
CORONARY PHYSIOLOGY INDICES AND CLINICAL OUTCOME
DATA
FRACTIONAL FLOW RESERVE
Summary characteristics and trial designs for landmark fractional
flow reserve (FFR) trials are presented in Table 1.
In an era where interventionalists believed that anatomy was the
gold standard and that treatment of moderate lesions was “preven-
tative”, the early FFR trials truly challenged dogma. The DEFER
(Deferral Versus Performance of PTCA in Patients Without
Documented Ischemia) trial demonstrated that, even in the pres-
ence of a significant single vessel anatomical stenosis, there were
patients in whom it was safer to opt for conservative treatment5
.
The trial showed that, when FFR was ≥0.75, optimum medical
therapy alone was equally safe to revascularisation with PCI and
optimum medical therapy5
. Importantly, it also showed that PCI
did not lead to eradication of hard clinical outcomes because the
reference group with FFR <0.75, in whom PCI was performed
albeit in the bare metal stent era, had the worst outcomes among
the three groups6
.
Once DEFER had shown that it was safe to leave non-phys-
iologically significant lesions alone, the next step was to inves-
tigate whether FFR could be used to guide whom to treat with
the larger FAME (Fractional Flow Reserve versus Angiography
for Multivessel Evaluation) trial. The investigators this time chose
a higher “clinical” FFR cut-point of 0.80 to ensure a safety mar-
gin for revascularisation at a time when the accepted belief was,
“If you see it, you must treat it”. They randomly assigned patients
with multivessel CAD to revascularisation based on angiography
Table 1. Summary characteristics for patient outcome FFR trials.
Trial Question Subjects
Study
population (n)
Primary
endpoint
FFR
cut-off
Mean FFR Conclusion
DEFER5
Safety of deferral of
PCI where FFR ≥0.75
SCD 325 24-month MACE <0.75
Defer: 0.87±0.07 (n=91)
Performance: 0.87±0.06 (n=90)
Registry: 0.56±0.16 (n=144)
Deferral of PCI safe
where FFR ≥0.75
FAME7
Efficacy of
FFR-guided PCI vs
PCI based on
angiography alone
Multivessel SCD/ACS
with non-culprit
stenosis
1,005 12-month MACE ≤0.80
Overall cohort: 0.71±0.18
Ischaemic lesions: 0.60±0.14
Non-ischaemic lesions: 0.88±0.05
FFR-guided PCI superior
to PCI based on
angiography alone
FAME 29
FFR-guided PCI+OMT
vs OMT alone where
FFR ≤0.80
Multivessel SCD 1,220
MACE
(trial halted at
7-month follow-up)
≤0.80
FFR-guided PCI+OMT: 0.68±0.10
OMT alone: 0.68±0.15
FFR-guided PCI+OMT
reduces urgent
revascularisation
compared to OMT alone
Values are mean±SD unless otherwise indicated. SCD: stable coronary disease

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alone or to revascularisation for any vessel with FFR ≤0.807
. At
12-month follow-up, there was a significantly lower incidence
of the primary composite endpoint of death, non-fatal myo-
cardial infarction (MI) and repeat revascularisation in the FFR
group, indicating superiority over angiography alone. Importantly,
there was no difference in symptom improvement by Canadian
Cardiovascular Society angina grade between the FFR- and angio-
graphy-guided groups7
.
The DEFER and FAME trials served to prove that, in stable
CAD, PCI for stenoses deemed to be “non-ischaemic” according
to FFR thresholds was less effective than conservative manage-
ment, and possibly even harmful5,7
. These landmark trials also
importantly questioned the role of anatomically guided treatment
and showed that reduction in number and length of stents was
clinically advantageous in terms of both clinical outcomes and
cost-effectiveness8
.
The FAME 2 (Fractional Flow Reserve guided PCI versus
Medical Therapy in Stable Coronary Disease) trial was designed
to answer whether a strategy of PCI in addition to medical therapy
was superior to medical therapy alone for patients with significant
ischaemia, defined as an FFR ≤0.80 in at least one vessel9
. This
unblinded trial was terminated early on ethical grounds because of
a marked reduction in the rate of urgent revascularisation in the
PCI+OMT group. The large majority of these unplanned revas-
cularisation events were not associated with electrocardiographic
(ECG) changes or biomarker elevation and, as a result, the end-
point was vulnerable to bias10
. There was no significant differ-
ence in the incidence of all-cause mortality, cardiac death and
MI, although there was a significant reduction in spontaneous MI
among patients undergoing PCI at longer-term follow-up11,12
.
INSTANTANEOUS WAVE-FREE RATIO
Despite evidence that the use of FFR was clinically and econom-
ically efficacious, global adoption of FFR remained limited13
.
Added time, cost, and lack of familiarity with the techniques may
have been barriers to its routine use14
. A resting index, the instan-
taneous wave-free ratio (iFR), that did not require the induction
of pharmacological hyperaemia, was developed to tackle some
of these issues. The diagnostic accuracy of iFR to identify FFR-
positive lesions was good and, when a third comparator was used
as a reference standard, no significant differences were observed
between FFR and iFR for their accuracy in identification of ischae-
mic stenoses15
. Randomised controlled trials that were essential for
the clinical validation of iFR are summarised in Table 2.
DEFINE-FLAIR (Functional Lesion Assessment of Intermediate
Stenosis to Guide Revascularisation)16
and iFR-SWEDEHEART
(Evaluation of iFR vs FFR in Stable Angina or Acute Coronary
Syndrome)17
were non-inferiority trials designed to test for equiva-
lence between iFR- and FFR-guided revascularisation. The trials
utilised identical cut-points for PCI (iFR ≤0.89 and FFR ≤0.80)
with a harmonised primary endpoint of 12-month incidence of all-
cause mortality, non-fatal MI and unplanned revascularisation.
With concordant results across the two trials, iFR-guided revas-
cularisation was found to be non-inferior to an FFR-guided strat-
egy. In a pooled patient-level analysis of the DEFINE-FLAIR and
iFR-SWEDEHEART trials, it was found that significantly more
patients were deferred in the iFR arm, with no impact on clinical
outcomes18
.
Treatment reclassification occurs in 22-48% of studied popula-
tions when an FFR measurement is used in addition to the coro-
nary angiogram to guide therapy in stable CAD19
. In a substudy
from iFR-SWEDEHEART, the use of iFR or FFR reclassified the
initial angiogram-based treatment decision in approximately 40%
of cases. The majority of these patients were reclassified from
a strategy of revascularisation with PCI to conservative therapy
with OMT20
. No significant differences were observed between
the reclassified iFR and FFR populations.
NOVEL NON-HYPERAEMIC PRESSURE RATIOS
Following the successful introduction and adoption of iFR in
clinical practice, a number of alternative non-hyperaemic pres-
sure ratios (NHPRs) have emerged in recent years. The common-
ality among these indices is a sub-cycle pressure measurement of
the ratio of distal coronary to proximal aortic pressure (Pd/Pa).
As these measurements are made independently of hyperaemia,
they share in the principal advantage of iFR, namely, the lack of
requirement of a vasodilator agent such as adenosine. The prin-
cipal point of difference between each NHPR lies in the period
of the cardiac cycle in which the Pd/Pa ratio is measured, the
so-called “sampling window”. The advantages and disadvantages
of NHPRs in comparison to hyperaemic indices are presented in
Table 3.
Several NHPRs have been shown to be closely related to iFR,
both numerically and in terms of the accuracy of their classifi-
cation when compared to a “gold standard” of FFR21
. However,
some indices, such as whole cycle Pd/Pa, may be more vulner-
able to pressure wire drift causing increased diagnostic reclassi-
fication compared to iFR and FFR22
. Despite evidence suggesting
Table 2. Summary characteristics of trials comparing FFR- versus iFR-guided revascularisation.
Trial
Study
population (n)
FFR mean iFR mean
Deferred by FFR
(% total assessed)
Deferred by iFR
(% total assessed)
FFR MACE
(%)
iFR MACE
(%)
p-value for
non-inferiority
DEFINE-FLAIR16
2,492
0.83±0.09
(n=1,250)
0.91±0.09
(n=1,242)
583 (46.6) 652 (52.5) 7 6.8 <0.001
iFR-SWEDEHEART17
2,037
0.82±0.10
(n=1,019)
0.91±0.10
(n=1,018)
438 (43.5) 476 (46.7) 6.1 6.7 0.007
Values are mean±SD unless otherwise indicated.

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diagnostic equivalence of NHPRs, there have been no prospective
randomised clinical outcome trials of any of these newer NHPRs.
Characteristics of the most commonly used NHPRs are presented
in Table 4.
DEFINING THRESHOLDS
Defining a cut-point for treatment is a necessity when design-
ing a clinical trial assessing the use of a measure of ischaemia.
Trial investigators must follow strict algorithms in order to reduce
the incidence of protocol deviation. Cut-points also aid statistical
analysis and interpretation of the results. However, any measure of
invasive physiology is continuous by its biological nature23
. There
can be no binary cut-point at which point the benefit of treatment
suddenly appears or disappears. By definition, there must be a gra-
dient of treatment response across the full spectrum of ischaemia.
This gradient will apply to both subjective “soft” (e.g., symptoms)
and objective “hard” (e.g., death) endpoints.
Initial FFR validation studies tested the index against non-inva-
sive tests including exercise electrocardiogram testing, myocardial
perfusion scintigraphy and dobutamine stress echocardiography.
They showed an optimal threshold of 0.75, whereby, if FFR was
positive, one or more of the other functional tests were also pos-
itive24
. This was termed the “ischaemic threshold”. The higher
“clinical threshold” of FFR ≤0.80 was introduced in the clinical
outcome trials to provide a “safety margin”. It was felt that rais-
ing the threshold would increase the negative predictive value of
this biological measurement compared to the previous cut-point
of FFR <0.757
.
Inadvertently, previous observations of decreased specificity in
the FFR range of 0.75 to 0.80 and shifting thresholds have now
led to the concept of a physiological “grey zone”. Within the “grey
zone”, consideration of other diagnostic modalities and risk versus
benefit analysis should be used to add clarity before a decision is
made to pursue intervention, especially since measurements clus-
tering around 0.77 to 0.83 demonstrate particular biological vari-
ability with respect to decision-making cut-points25
.
To define the cut-points for physiological measurements at rest
(iFR), validation against FFR was required; therefore, the perpet-
uation of dichotomy continued. In the early development of the
technique, iFR thresholds of 0.83 and 0.86 were reported to pro-
vide good agreement with an FFR of 0.8026,27
. Before the clini-
cal outcome data were available, hybrid algorithms were used for
iFR28
. For iFR <0.86, revascularisation was advised; for iFR >0.93,
deferral was recommended and, for iFR 0.86 to 0.93, hyperaemic
FFR measurements were required for adjudication, resulting in
avoidance of hyperaemia in 57% of patients and 95% agreement
with an FFR-only strategy28
. Higher iFR thresholds of ≤0.89 (with
diagnostic accuracy of 82.5%)29
were eventually adopted for use
in the landmark clinical trials16,17
.
Although decision making (to treat versus not to treat) is
regarded as binary, the process of dichotomisation of biologi-
cal measurements removes most of the information content and
assumes discontinuity in response once these interval boundaries
are crossed23
. Hence, despite clinical trials adopting these thresh-
olds, in clinical practice ischaemia should be regarded as a contin-
uum in the context of a patient rather than as a definitive cut-off.
Table 3. Advantages and disadvantages of hyperaemic and non-hyperaemic pressure ratios (NHPRs).
Pressure ratio Advantages Disadvantages
Hyperaemic • Established cut-points
• RCT clinical outcome data available
• Hyperaemic agent required
• Associated cost, time and side effects
•
Inter-patient variation in microcirculatory response to
adenosine
•
Haemodynamic “cross-talk” between serial stenoses
Non-hyperaemic • No requirement for hyperaemic agent
• RCT clinical outcome data for iFR
•
Individualised assessment of serial stenoses possible
•
Some indices require proprietary software
•
RCT data not yet available for majority of NHPRs
Table 4. Summary characteristics of non-hyperaemic pressure ratios.
Sampling window
Hyperaemia
required
Proposed
cut-point
Vendor
specific
RCT data
Phase specific
iFR Diastolic “wave-free” period No 0.89 Yes Yes
dPR Diastolic period when dP/dt signal is flat No 0.89 No No
DFR Diastolic period when Pa mean Pa with a negative slope No 0.89 Yes No
Whole cycle
Pd/Pa Whole cycle No 0.92 No No
RFR Whole cycle No 0.89 Yes No
DFR: diastolic hyperaemia-free ratio; dPR: diastolic pressure ratio; iFR: instantaneous wave-free ratio; RFR: resting full-cycle ratio

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CONSENSUS GUIDELINES
The importance of assessing the functional relevance of a coronary
artery stenosis is central to European Society of Cardiology (ESC)
guidance on decision making for myocardial revascularisation
in stable CAD. Invasive functional testing, with FFR or iFR, has
a class I, level of evidence “A” endorsement from the ESC to assess
the severity of an intermediate lesion where evidence of ischaemia
from non-invasive tests is not available1
. Furthermore, FFR guid-
ance of PCI is recommended with class IIa, level of evidence B for
patients with multivessel disease undergoing PCI. Importantly, the
ESC acknowledges a gap in the evidence base which prevents clear
recommendations for FFR for the assessment of non-infarct-related
artery (non-IRA) disease in the setting of ST-elevated MI (STEMI)
with bystander disease30
. Much like clinical trial design, nuanced
directives are difficult for consensus guideline documents; therefore,
dichotomous cut-offs are used but clinical judgement remains para-
mount. It is incumbent upon our guideline committees to continue
to refine and reassess these recommendations in the light of increas-
ing high-quality bias-resistant randomised controlled trial data.
Physiology to guide PCI
CHANGING DIRECTION FOR CORONARY PHYSIOLOGY
As the limitations of a dichotomised approach to the interpretation
of ischaemia tests become increasingly apparent, the application
of coronary physiology is moving away from simple justification
of PCI using binary cut-points towards real-time guidance of PCI
strategy. Advances in pressure wire software have allowed pres-
sure wire pullback and co-registration technology to provide oper-
ators with in-cath lab physiological mapping to inform stenting
strategy for the best haemodynamic result. This allows the iden-
tification of lesions with the largest pressure gradients and there-
fore the most favourable PCI targets. It also allows the operator to
differentiate between focal stenoses, amenable to PCI, and diffuse
disease which may result in an abnormal distal vessel physiology
assessment but may not represent a technically suitable PCI target.
LIMITATIONS OF FFR PULLBACK
Pressure wire pullback using FFR is limited by the phenomenon
of haemodynamic interdependence (“cross-talk”) between serial
stenoses or diffuse disease in the same vessel. This occurs because,
under conditions of stable hyperaemia, the maximal flow achieved
across one stenosis is limited by the haemodynamic characteris-
tics of a sequential stenosis, resulting in a tendency to underesti-
mate true stenosis severity for each of the lesions31,32
. The problem
this poses is that, once one stenosis is treated, hyperaemic flow,
and therefore the pressure drop, across the second stenosis will
increase. These haemodynamic characteristics make FFR less
favourable for pullback assessments, particularly in the presence
of tandem stenoses or diffusely diseased vessels.
iFR PULLBACK WITH CO-REGISTRATION
Under resting conditions, coronary flow is preserved across a wide
spectrum of stenosis severity until a vessel is subtotally occluded33
.
Consequently, the benefit of performing pressure wire pullback
assessments under resting conditions, without prerequisite hyper-
aemia, is that the assessment is less vulnerable to haemodynamic
interdependence between sequential stenoses within the same
vessel.
In this way, resting indices such as iFR, which are calculated on
a beat-to-beat basis, permit a physiological map to be created with
high spatial resolution during pressure wire pullback34
. Through
accurate quantification of the pressure gradient at each point
within a vessel, iFR pullback can guide intervention by highlight-
ing the stenoses which contribute the greatest pressure drop within
the vessel. Equally important is the use of this technology to pre-
vent unnecessary stenting of vessel segments which may angio-
graphically appear significant, but do not contribute meaningfully
to ischaemia in the vascular territory. iFR pullback, therefore,
allows the pattern of CAD to be characterised as focal, diffuse or
a mixed distribution.
The next derivation of this technology, iFR co-registration, is
now able to track the movement of the pressure wire through the
vessel in real time under continuous fluoroscopy. The data from
an iFR pullback manoeuvre can be co-registered to the coronary
angiogram, creating a physiological roadmap, whereby the pres-
sure drop at any given stenosis is depicted visually on the patient’s
angiogram (Figure 1A)32
. Furthermore, iFR co-registration enables
modelling of custom stenting strategies in order to predict the
post-PCI physiological result to a high degree of accuracy. This
allows operators to plan their preferred stenting strategy in order
to optimise the physiological gain per unit of stented segment
(Figure 1B).
Post-PCI physiology
FAILURES OF STANDARD APPROACH
Cardiologists have accepted that revascularisation decisions made
on the visual appearance of the coronary angiogram alone are
flawed. However, the success of coronary intervention is widely
adjudicated with nothing more than this limited assessment tech-
nique. More rigorous measures of procedural success have not
become well established and, as such, a contradiction exists
between the methods we deem appropriate for justification of
PCI and the methods by which we judge the success of our work.
Despite angiographic success, further interrogation of stented
lesions with optical coherence tomography (OCT), intravascu-
lar ultrasound (IVUS) and coronary physiology has shown that
patients may have suboptimal PCI results, with residual ischaemia
occurring in 18-25% of patients35,36
. Frequency of recurrent angina
with PCI guided by the angiogram alone can be as high as 50% at
short-term follow-up3
and around 30% at one year37
. With physio-
logy-guided revascularisation, one in five patients still reports
symptoms of angina, and major adverse cardiac events (defined
as death, non-fatal MI, and repeat revascularisation) remain rela-
tively frequent after revascularisation with PCI (13% at 1 year and
28% at 5 years)12
. While the link between invasive physiology and
symptoms requires further study, if we utilise physiology to justify

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revascularisation there may be a benefit to using the same tools to
judge the success of coronary intervention.
RATIONALE FOR POST-PCI PHYSIOLOGY ASSESSMENTS
Observational evidence exists linking post-PCI physiology with
clinical outcomes. A number of unblinded studies have now sug-
gested that post-PCI physiology is independently associated with
major adverse cardiovascular events, in particular target vessel
failure (Table 5).
Although various cut-off values have been suggested for post-PCI
physiology, a meta-analysis of 970 lesions from 10 studies found
that there was an independent and continuous relationship between
post-PCI FFR and major adverse cardiovascular events without
clear discontinuity in outcomes (Cox hazard ratio: 0.86, 95% con-
fidence interval [CI]: 0.80 to 0.93; p0.001)38
. Interestingly, only
post-PCI FFR retained prognostic value (adjusted Cox hazard ratio:
0.90, 95% CI: 0.82 to 0.99; p=0.032) compared to pre-PCI FFR
(adjusted Cox hazard ratio: 0.97, 95% CI: 0.92 to 1.02; p=0.28)
after adjustment for pre- and post-PCI measurements. Hence, in
corroboration with the concept of continuous ischaemic risk, fur-
ther intervention in an effort to reduce ischaemia when post-PCI
FFR values are suboptimal should be attempted. Individual studies
are shown in Table 536,39-41
.
It is pertinent to consider, however, that the post-PCI cut-off
values in the individual studies are derived from observational
data and post hoc analysis. It is therefore likely that there is
a continuous post-PCI ischaemia spectrum with no dichotomous
cut-point for an optimum post-PCI result. However, in order to
test the use of post-PCI physiology formally, pre-specified opti-
mum thresholds will be needed for clinical trials, just as was
necessary with pre-PCI physiology trials. In the available post-
PCI physiology studies, thresholds have been variously defined
with margins above the currently accepted ischaemic threshold
(FFR ≤0.80, iFR ≤0.89). A key limitation of the available evi-
dence base is that blinded evaluation of post-PCI physiology
among operators and patients was not always mandated. Hence,
certain endpoints, such as urgent revascularisation, may be influ-
enced by knowledge of post-PCI physiological results because
they are vulnerable to bias.
Most studies have not evaluated further intervention to optimise
physiological measurements, as these procedures were deemed
angiographically successful. Therefore, the mechanisms for sub-
optimal post-PCI physiology remain unknown. Before incorpo-
rating the logical construct of post-PCI physiology into guideline
recommendations, randomised controlled trials are needed to
define the utility of post-PCI physiology and the additive benefit
of subsequent intervention on clinical endpoints.
MECHANISMS FOR POST-PCI ISCHAEMIA
Determining the mechanism of post-PCI ischaemia is fundamental
to an operator’s ability to target further intervention and optimise the
result. Equally important is the possibility that discovering the mech-
anism of post-PCI ischaemia may confirm that additional treatment
would be futile in achieving further incremental gains in the haemo-
dynamic properties of the vessel, such as in the setting of diffuse dis-
ease. This may save the patient unnecessary additional intervention.
An excellent final angiographic result may frequently co-exist
with residual post-PCI ischaemia. Clues regarding the mechanism
of a poor physiological result may not be forthcoming from the
angiogram alone. As a lumenogram, the coronary angiogram often
hides diffuse disease within an artery: the “normal” reference dia-
meter of the vessel may therefore be underestimated and, without
intravascular imaging, this will not be appreciated. Secondly, fol-
lowing PCI, an increase in flow to the distal vessel may result in
an angiographically moderate tandem stenosis taking on greater
physiological significance.
Imperfections with PCI itself must also be recognised as
important causes of post-intervention ischaemia. At worst, a geo-
graphic miss of the culprit lesion may have occurred (Figure 2).
Experienced operators remain vulnerable to this if ancillary tools
such as pullback and co-registration are not used to guide PCI by
Figure 1. iFR co-registration images. The yellow dots overlying each
angiogram correspond to the location of a 0.01 iFR pressure drop.
A) A focal stenosis in the right coronary artery. The operator has
specified the planned stented segment, which results in a predicted
physiological gain of 0.31 iFR units, resulting in an estimated
post-PCI iFR of 0.92 for the vessel. B) A diffusely diseased left
anterior descending artery. The cursor may be moved to any given
location in the vessel to determine the estimated iFR at that position.

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localising the regions of maximal pressure loss. More commonly,
undersized or underexpanded stents may impair the physiological
result and may be confirmed with intravascular imaging. Finally,
proximal or distal stent edge dissections may meaningfully impede
flow to the distal vessel and should always be considered in the
setting of post-PCI ischaemia.
The DEFINE PCI (Physiologic Assessment of Coronary Stenosis
Following PCI) study examined the frequency and mechanism of
residual post-PCI ischaemia using blinded post-PCI iFR-pullback
assessments35
. After angiographically successful PCI, 24.0% of
patients in the study were found to have residual ischaemia, as
defined by post-PCI iFR 0.90. When this was stratified by the
pattern of disease on iFR pullback, 81.6% had one or more focal
areas of pressure loss and only 18.4% of patients had diffuse
disease. Where residual focal stenoses existed, these were geo-
graphically distributed within (38.4%), proximal (31.5%) and dis-
tal (30.1%) to the stented segment. These residual focal pressure
gradients were poorly correlated to core lab quantitative coronary
Table 5. Recent studies linking post-PCI physiology and clinical outcomes.
Study Intervention group Physiology outcomes Comments
Agarwal 201636
574 patients with mean FFR
0.65±0.14, treated with DES
(79%)
Post-PCI FFR ≤0.86 had the best predictive accuracy for
MACE and ≤0.85 for TVR. Patients with post-PCI FFR 0.86
had lower MACE compared to FFR ≤0.86 group (17% vs
23%; p=0.02).
Final FFR ≤0.86 had incremental prognostic value over
clinical and angiographic variables for prediction of MACE.
Li 201739
1,476 patients with baseline
FFR 0.8 treated with DES
At one year, 40 (4.0%) TVFs occurred in the post-PCI FFR
0.88 and 48 (8.0%) in the post-PCI FFR ≤0.88 group
(p=0.001), driven mainly by TVR (3.8% vs 8.8%; p=0.005)
and cardiac death (0.2% vs 1.3%; p=0.017).
The difference in TVF between the 2 groups was maintained
up to 3-year follow-up (p=0.002). Disease in the LAD, stent
diameter, and stent length were independent predictors of
impaired post-PCI FFR.
Piroth 201740
639 patients from FAME 1 and
FAME 2 who had post-PCI FFR
measured
Two-year overall vessel-oriented composite endpoint was
significantly higher for lower tertile (0.88) compared to
upper tertile (0.92) post-PCI FFR (9.2% vs 3.8%,
respectively; p=0.037) and target vessel revascularisation
(7.0% vs 2.4%, respectively; p=0.037).
Post-PCI FFR of 0.92 was found to have the highest
diagnostic accuracy for the vessel-orientated composite
endpoint; however, the positive likelihood ratio was low
(1.4).
Hakeem 201941
574 patients with post-PCI FFR
and Pd/Pa measurements
A post-PCI FFR of ≤0.86 had the best predictive accuracy for
MACE (17% vs 23%; p=0.02). For post-PCI Pd/Pa,
a threshold ≤0.96 was the best predictor of MACE (15% vs
24%; p=0.0006).
Patients with Pd/Pa ≤0.96 and FFR ≤0.86 had the highest
event rate (25%), whereas those with Pd/Pa 0.96 and FFR
0.86 had the lowest event rate (15%).
Patel 202042
467 patients treated in the
DEFINE-PCI study with
post-PCI iFR measurements
At 1-year follow-up, post-PCI iFR ≥0.95 was associated with
a significant reduction in the composite endpoint of cardiac
death, spontaneous MI and clinically driven TVR, compared
with patients with post-PCI iFR0.95 (1.8% vs 5.7%,
respectively, p=0.04).
Highly symptomatic patients at baseline derived
significantly greater angina relief at 12 months if a post-PCI
iFR ≥0.95 was achieved compared to patients with residual
ischaemia. Non-randomised data; however, patients and
physicians were blinded to post-PCI physiology.
DES: drug-eluting stents; iFR: instantaneous wave-free ratio; TVF: target vessel failure; TVR: target vessel revascularisation
Figure 2. An example of a geographic miss during PCI to the proximal left anterior descending (LAD) artery and left main stem (LMS).
A) A moderate stenosis noted in the distal left main stem. A’) The distal iFR in the LAD is 0.83. The operator performs PCI to the LMS,
extending into the proximal LAD. B) Post-PCI iFR co-registration shows localised focal pressure loss at the entry of the stent, but also
a second, larger pressure loss distal to the stented segment. B’) The distal iFR remains the same (0.83) as pre-PCI due to geographic miss.

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angiography (QCA) analysis of minimum lumen diameter or per-
cent residual stenosis, demonstrating the inability of coronary
angiography to determine physiological lesion severity. DEFINE
PCI therefore served to prove that post-PCI residual ischaemia
is common, even after contemporary, angiographically success-
ful PCI. Secondly, it found that residual focal lesions, potentially
amenable to further treatment, were most commonly the cause.
The one-year outcomes of DEFINE-PCI showed that achiev-
ing a post-PCI iFR ≥0.95 was associated with a significant reduc-
tion in a composite endpoint of cardiac death, spontaneous MI, or
clinically driven target vessel revascularisation42
, albeit with the
limitations of an observational study design.
TECHNICAL CONSIDERATIONS
PITFALLS IN PHYSIOLOGICAL ASSESSMENTS
Adherence to meticulous technique is the cornerstone of accurate
physiological assessments, in the pre- or post-PCI setting. Pitfalls
in the optimal assessment technique are frequently encountered,
but are often easily resolved. In Table 6 and Figure 3, we highlight
the most common errors for any physiological assessment, their
physiological consequences, and techniques to resolve the problem.
TECHNICAL CONSIDERATIONS SPECIFIC TO POST-PCI
PHYSIOLOGICAL ASSESSMENTS
Coronary vasospasm is common following PCI as the vessel reacts
to stenting. It follows that administration of intracoronary nitrates
before repeating physiological assessment is particularly pertinent
after PCI, regardless of the physiological assessment technique.
In the post-PCI setting, advancement of the pressure wire may be
technically challenging, particularly through more complex stented
segments. Passing the pressure wire alongside the workhorse wire
can be an effective strategy. Consideration should also be given to
the possible risk of advancing a pressure wire through concealed
ruptures or dissections which may not be apparent angiographically
if there is significant post-PCI haziness. For this reason, a potential
advantage may be offered by the use of a miniaturised dual lumen
catheter for wire exchange distal to the stented segment, although
damping of the proximal aortic pressure tracing through the guid-
ing catheter affects the accuracy of this technique. Dedicated
microcatheter-based pressure sensors have been developed, but sys-
tematically overestimate lesion severity due to a pressure effect of
the catheter across the vessel segment under assessment43
. To avoid
these sources of inaccuracy, a small outer diameter over-the-wire
microcatheter may be used to exchange the workhorse wire for
a pressure wire, with use of a trapping balloon technique inside the
guiding catheter to remove the microcatheter. This more complex
solution is helpful to ensure accurate haemodynamic measurements.
Previous discussion has centred upon the validity of NHPRs
in the post-PCI setting. A theoretical concern was raised regard-
ing the period of hyperaemia that follows balloon inflation dur-
ing PCI. NHPRs are susceptible to residual hyperaemia, which
will reduce the NHPR result if resting conditions are not restored
before measurement. However, based on current evidence, hyper-
aemia following transitory coronary occlusion only persists for
approximately one minute on average44
. Hence, in the time it takes
Table 6. Common pitfalls in physiological assessment technique and methods of resolution.
Pitfall in assessment technique Description Physiological consequence Remedy
Omission of therapeutic heparin dose Subtherapeutic anticoagulation prior to
instrumentation of coronary artery
Thrombus formation in catheter or on
pressure wire
Ensure therapeutic dose unfractionated
heparin administration for every pressure wire
assessment
Omission of intracoronary nitrates Spasm of coronary artery during
instrumentation
↓Pd=↓FFR
Stenosis severity overestimated
Intracoronary bolus glyceryl trinitrate titrated
to blood pressure prior to normalisation
Failure to perform normalisation Poor calibration of Pa and Pd trace Fixed error in Pd/Pa ratio Normalise every assessment and ensure Pd/
Pa=1.00 before passing wire distally
Failure to remove needle introducer Presence of the needle introducer in the
haemostatic valve precludes accurate Pa
assessment
Needle introducer ↓Pa=↑FFR
Stenosis severity underestimated
Always remove needle introducer prior to
normalisation and again prior to measurement
of FFR
Damped Pa trace (Figure 3A) Guiding catheter “wedged” trace occurs
when the guiding catheter position abuts the
arterial wall
↓Pa=↑FFR
Ensure coaxial catheter position, use smaller
guiding catheter
Ostial stenosis Ventricularisation of Pa trace due to catheter
damping in presence of ostial stenosis
↓Pa=↑FFR
Retract catheter into aorta. Perform
normalisation with pressure sensor in aorta
Use of side hole catheter Pa pressure inaccurately measured due to
the presence of side holes in the aortic root
↑Pa=↓FFR
Do not use side hole catheter for physiological
assessments
Whipping artefact (Figure 3B) During systole the pressure wire contacts the
arterial wall creating Pd artefact
↑Pd=↑FFR
Easily recognised, retract or advance several
millimetres to new position and retest
Wire signal drift Development of piezoelectric pressure sensor
electronic signal offset during assessment
Inaccurate FFR measurement in
either direction.
Stenosis severity underestimated or
overestimated
Always perform a “drift check”. Where Pd/Pa
falls outside 1.00±0.02, re-normalise and
repeat assessment
Incorrect FFR assessment point Consoles typically report the lowest Pd/Pa
measured, but FFR should be measured at
stable hyperaemia
↓FFR
Manually adjust the FFR assessment point to
the period of stable hyperaemia

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to carry out physiological assessments post PCI, resting conditions
are typically restored.
On a more practical note, the purpose of carrying out post-PCI
physiological assessment is twofold – to diagnose a suboptimal
haemodynamic result and, secondly, to elicit its cause. We pro-
pose that for the first objective available data would suggest that
either FFR or an NHPR could be used. However, where post-PCI
ischaemia is found, an NHPR is more robust for performance
of pullback and co-registration which will provide focus on the
underlying mechanism of ischaemia. The use of a hyperaemic
pressure ratio for pullback assessments in the post-PCI setting is
likely to be vulnerable to the same limitations as in the pre-PCI
setting, namely haemodynamic cross-communication between dis-
eased segments of the same vessel32
.
METHODS OF OPTIMISATION
For post-PCI physiology to be useful, operators must be equipped
with a strategy to intervene on the results of a suboptimal post-
PCI physiology result. This strategy will vary on a case-by-case
basis but, when performed effectively, post-intervention optimisa-
tion can reclassify vessels from “ischaemic” to “non-ischaemic”
physiological criteria. In the largest study to date, Agarwal et al36
examined post-PCI FFR in 574 patients (664 lesions); 21% of
these lesions had a post-PCI FFR ≤0.81, again highlighting the
frequency of post-PCI ischaemia. Repeat interventions were car-
ried out in the majority of this group, including post-dilation of the
implanted stent (42%), another stent implantation (33%) and fur-
ther stenting with further balloon post-dilation (18%). As a result
of these interventions, the mean post-PCI FFR in this group
increased from 0.78±0.07 to 0.87±0.05.
As previously discussed, the optimal method for any further
post-PCI intervention will depend upon the mechanism of the
suboptimal result. The importance of intravascular imaging with
IVUS or OCT to determine this mechanism cannot be overstated.
Reliance on angiographic views alone to assess the success of
revascularisation is particularly limited in the setting of post-PCI
haziness which may preclude visualisation of concealed ruptures or
dissections. Operators must therefore be confident with the inter-
pretation of post-PCI intravascular imaging in order to determine
an effective optimisation strategy. Stent underexpansion, malap-
position and entry and exit site dissections may only be identified
with this approach. Randomised data are now available to support
a reduction in target vessel failure when PCI is guided by intravas-
cular imaging as opposed to angiography alone45,46
. Trials specific
to post-PCI imaging optimisation have not been conducted; how-
ever, it is a reasonable assumption that the benefits would extend
to this setting. Ultimately, synergistic data from intravascular
imaging and adjunctive tools such as physiology co-registration
will afford the operator the best opportunity to target any post-
PCI intervention to where it is most needed (Central illustration).
Unresolved questions regarding myocardial
ischaemia
Recent randomised controlled trials have cast doubt on the prac-
tice of ischaemia testing as a method of selecting patients able
to benefit from revascularisation. It is important to consider these
broader data to contextualise the evolving roles of invasive coro-
nary physiology.
Scientifically it seems logical that the degree of ischaemia may
be associated with clinical outcomes. Early observational studies
showed that, in order to obtain a survival benefit from revas-
cularisation over and above medical therapy, greater than 10%
of the myocardium needed to be ischaemic47
. However, this was
based on retrospective data assessing the difference in outcomes
Figure 3. Pitfalls in the assessment of coronary physiology. A) Example of damped Pa trace with a characteristic waveform. B) Example of
whipping artefact. C) Example of an incorrect cursor position to measure FFR. The console may default measurement to the lowest Pd/Pa
value. However, this position does not correspond to stable hyperaemia and will overestimate stenosis severity. D) The cursor has now been
adjusted to ensure that FFR is measured at a period of stable hyperaemia.

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according to the degree of ischaemia with patients allocated to
two groups depending on whether or not PCI was performed.
Patients were not randomised, and the data were therefore poten-
tially confounded. It is quite possible that the drivers for con-
servative management were unmeasured and highly influential.
Nevertheless, these limited data informed clinical guidelines and
set the precedent for widespread practice of ischaemia-guided
revascularisation1,48
.
Subsequent randomised data emerged from a nuclear substudy
of the COURAGE (Clinical Outcomes Utilising Revascularisation
and Aggressive Drug Evaluation) trial49,50
. While a substudy of
patients who underwent serial myocardial perfusion scintigraphy
demonstrated that adding PCI to OMT resulted in greater reduc-
tion in ischaemia compared with OMT alone50
, there was no evi-
dence that PCI reduced the primary endpoint of death or MI in
patients with moderate to severe ischaemia49
.
The ISCHEMIA (International Study of Comparative Health
Effectiveness with Medical and Invasive Approaches) trial was
designed to answer definitively the question of whether an early
invasive strategy offered additive clinical benefit versus conserva-
tive management in patients with moderate to severe ischaemia
for hard clinical endpoints2
. Overall, there was no significant dif-
ference between an initial invasive approach with cardiac cath-
eterisation and revascularisation in comparison to a conservative
approach for a five-component composite endpoint of death, MI,
hospitalisation for heart failure or unstable angina and resuscitated
cardiac arrest (HR 0.93, p=0.34). In the group randomised to an
early invasive approach, there was a significant reduction in spon-
taneous MI when compared to the control arm, a benefit that was
offset by a significant increase in the risk of periprocedural MI
which resulted in no difference between the groups in overall MI
or cardiovascular death. This highlights the potential trade-off in
risk between early (periprocedural) and late (spontaneous) MI that
may be observed with an invasive approach. A similar reduction in
spontaneous MI was also observed in the extended follow-up of the
FAME 2 trial12
. While the implications of a spontaneous MI may
be of greater clinical relevance than a periprocedural MI, these dif-
ferences have not translated into a difference in the overall rates of
cardiovascular death in those trials. Longer-term follow-up will be
required to understand the clinical implications of these results fully.
These data should allow us to be confident that treatment of
myocardial ischaemia with OMT is safe and effective. PCI has
been prognostically neutral in the patient populations studied. The
principal driver for revascularisation in stable coronary disease is,
therefore, not the presence of residual ischaemia but the persis-
tence of angina, despite OMT.
A simple linear relationship between the severity of ischae-
mia and symptomatic angina again seems scientifically logical.
However, clinical practice would suggest that this reasonable
assumption is misplaced. The physiology-stratified sub-analysis
of the ORBITA (Objective Randomised Blinded Investigation
with optimal medical Therapy of Angioplasty in stable angina)
trial showed that the greater the degree of ischaemia measured by
FFR and the iFR at baseline, the greater the extent of myocardial
perfusion improvement seen on stress echocardiography follow-
ing revascularisation51
. However, while these tests of ischaemia
were very well correlated, the correlation of baseline ischaemia
with exercise time and the symptom and quality-of-life endpoints
of ORBITA were less clear51
. Further research in broader patient
populations is required to understand more fully the relationship
between ischaemia and symptom severity. The clearest message
of ORBITA was the importance of blinding, with placebo control,
when symptoms are the endpoint under investigation. Unblinded
assessments of symptoms in trials of revascularisation should be
disregarded, as knowledge of treatment allocation profoundly
affects physician and patient reporting10
.
PCI complete
Satisfactory angiographic appearance
Abnormal physiology
Normal physiology
Diffuse disease only
Consider defining mechanism
Consider further intervention
Further PCI Post-dilation
Treatment complete
Treatment complete
NHPR pullback ±
co-registration
Re-assess post-
PCI physiology
Intravascular imaging
IVUS / OCT
Assessment of post-PCI physiological
result (FFR or NHPR)
Central illustration. Proposed potential algorithm for post-PCI physiological assessment and treatment.

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Taken together, it is incumbent upon all in our community
to reflect upon these trial results and to consider carefully the
indication for PCI on an individual patient basis. It also seems
timely now to reconsider the value of ischaemia testing. If the
presence of ischaemia does not predict poor clinical outcomes
and these outcomes are not mitigated by resolution of ischaemia,
what is the value of these tests? Their role may be predominantly
in the diagnosis of symptoms that are the result of cardiac dis-
ease and the guidance of where to treat rather than in selecting
those patients who stand to benefit the most. Most importantly,
in the absence of symptoms, they may have a limited role in the
prediction of risk.
Future directions and recommendations
A number of upcoming trials will investigate the association
between post-PCI physiology and clinical outcomes. DEFINE-GPS
(Distal Evaluation of Functional performance with Intravascular
sensors to assess the Narrowing Effect: Guided Physiologic Stenting
[NCT04451044]) is a randomised controlled trial that aims to ran-
domise ~3,000 participants to PCI guided by iFR co-registration or
angiography alone52
. The primary endpoint will be major adverse
cardiac events or rehospitalisation for unstable angina at two years.
The DEFINE-GPS trial will improve our understanding of the util-
ity of NHPR co-registration techniques in guiding PCI and subse-
quent intervention as coronary stenting is increasingly applied to
more complex patients.
The double-blind ORBITA-2 trial (NCT03742050) is currently
randomising patients with single and multivessel CAD to PCI ver-
sus placebo for the treatment of stable angina. Post-PCI physio-
logical assessments will be performed allowing, for the first time,
the association between post-PCI physiological results and subse-
quent angina relief to be tested in a cohort of patients blinded to
treatment allocation.
ORBITA-STAR (NCT04280575) is an “n-of-1” study assess-
ing whether placebo-controlled verification of angina symptoms
during induced ischaemia can more accurately predict a positive
response to PCI. This may offer the potential to maximise the
therapeutic efficacy of PCI by identifying the patients most able to
benefit symptomatically from treatment.
The role of artificial intelligence is increasing in prominence
in a number of settings in cardiology; coronary physiology is no
exception to this trend. It has been shown that around 30% of coro-
nary physiology data is excluded after core laboratory assessment
due to signal drift or abnormal waveforms53
. Artificial intelligence
has been identified as an approach to real-time identification of
abnormal waveforms to alert the interventionist and avoid diag-
nostic errors in measurements. Arterial waveform analysis using
neural networks has been shown to identify rapidly and accurately
(98.7% to 99.4% accurate) the presence of damping, demonstrat-
ing how machine learning can aid in ensuring the quality and
safety of routine clinical practice54
. Future research will determine
whether neural networks can be trained to guide the optimum site
of revascularisation based on physiology and pullback data.
We also envisage that novel techniques for physiological assess-
ment that eliminate additional pharmacology or even coronary
wire use may supersede current practice and further enhance both
operator and patient experiences. Quantitative flow reserve (QFR),
initially described in the FAVOR (Functional Diagnostic Accuracy
of Quantitative Flow Ratio in Online Assessment of Coronary
Stenosis) pilot study, uses a three-dimensional angiographic recon-
struction of the stenosed vessel and the contrast flow frame count
to make an assessment of FFR. Studies have shown promising
results regarding the ability of QFR to identify the presence of
functionally significant stenosis55
, and a possible prognostic value
of post-PCI QFR56,57
. This, along with FFR-CT58
, may offer newer
technologies that encompass anatomic and physiological assess-
ment of CAD with reduced procedural risk.
When considering prognostic endpoints, it must be remem-
bered that many adverse cardiac events originate from angio-
graphically and physiologically non-significant lesions. The
PROSPECT (Providing Regional Observations to Study
Predictors of Events in the Coronary Tree) study showed that,
after acute coronary syndrome (ACS), the majority of non-cul-
prit lesions responsible for major adverse cardiac events dur-
ing follow-up were angiographically mild, non-flow-limiting
lesions at baseline, but with high-risk features such as thin-cap
fibroatheromas or large plaque volumes4
. More recently, the
LRP (lipid-rich plaque) and PROSPECT ABSORB (Providing
Regional Observations to Study Predictors of Events in the
Coronary Tree II combined with a randomised, controlled, inter-
vention trial) studies have demonstrated the utility of intravas-
cular imaging including near-infrared spectroscopy (NIRS) for
the identification of vulnerable lipid-rich plaques, which may
be physiologically non-flow-limiting, but pose high risk of rup-
ture and associated MACE59,60
. Whether preventative treatment
of these lipid-rich plaques can translate into improved clini-
cal outcomes remains to be determined and requires further
dedicated trials. Nevertheless, together these data suggest that
physiological optimisation of PCI can only achieve so much:
development of clinical tools to identify the vulnerable plaque
will be pivotal for meaningful steps to be made towards the aim
of cardiac risk reduction through revascularisation. These tools,
in combination with truly optimum medical therapy, will allow
prognostic endpoints to be optimised in stable CAD.
Conclusion
More than 30 years ago, the concept of FFR was developed in
order to help coronary interventionalists decide whom to treat with
revascularisation. It was an attractive technique which offered
immediate numerical results and unambiguous interpretation with
a clear-cut threshold for treatment.
More recently, based on randomised data including many thou-
sands of patients, our understanding of myocardial ischaemia
and coronary physiology and their association with prognostic
and symptomatic endpoints in stable coronary artery disease has
begun to evolve. The simplistic relationships between myocardial

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ischaemia, coronary revascularisation and long-term outcomes are
much more complex than previously thought.
Coronary physiology is now evolving to support new roles in
the catheterisation laboratory, and its use to optimise physiological
results of PCI should be encouraged. Nevertheless, randomised,
blinded data examining these new roles should be considered
essential to their long-term success as tools to optimise clinical
outcomes for patients.
Acknowledgements
C. Rajkumar is supported by a Clinical Research Training Fellow-
ship from the Medical Research Council (MR/S021108/1). The
authors acknowledge the support of the Imperial College London
British Heart Foundation Centre of Research Excellence.
Conflict of interest statement
R. Al-Lamee has received speaker’s honoraria from Philips Volcano
and Menarini Pharmaceuticals. A. Jeremias has received institu-
tional funding (unrestricted education grant) from, and serves as
a consultant for, Philips Volcano and Abbott Vascular, and is a con-
sultant for Boston Scientific and ACIST Medical Systems. The
other authors have no conflicts of interest to declare.
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