Instantaneous wave-free ratio and fractional flow reserve in clinical practice
Instantaneous wave-free ratio and fractional flow reserve in clinical practice
R. Pisters 0 1 2
M. Ilhan 0 1 2
L. F. Veenstra 0 1 2
B. C. G. Gho 0 1 2
M. Stein 0 1 2
J. C. A. Hoorntje 0 1 2
S. Rasoul 0 1 2
0 Department of Cardiology, Rijnstate , Arnhem , The Netherlands
1 Department of Cardiology, Maastricht University Medical Centre , Maastricht , The Netherlands
2 Department of Cardiology, Zuyderland Medical Centre , Heerlen , The Netherlands
Objectives To compare fractional flow reserve (FFR) and instantaneous wave-free ratio (iFR) measurements in an all-comer patient population with moderate coronary artery stenoses. Background Visual assessment of the severity of coronary artery stenoses is often discordant in moderate lesions. FFR allows reliable functional severity assessment in these cases but requires adenosine-induced hyperaemia with associated additional time, costs and side effects. The iFR is a hyperaemia-independent index. Methods and results Between November 2015 and February 2017, 356 consecutive patients were included in whom 515 coronary stenoses were measured using both iFR and FFR. Mean iFR and FFR were 0.90 ± 0.09 and 0.86 ± 0.08, respectively. iFR correlated well with FFR [r = 0.75; p < 0.001]. Receiver operating characteristic analysis identified an area under the curve of 0.92. An iFR-only strategy with a treatment cut-off 0.89 revealed a diagnostic classification agreement with the FFR-only strategy in 420 lesions (82%) with a sensitivity of 87%, a specificity of 80%, a positive predictive value of 56% and a negative predictive value of 96%. Conclusions Real-time iFR measurements have good negative predictive value compared to FFR, but moderate diagnostic accuracy (82%). It exposes fewer patients to adenosine, reduces procedure time and costs. Further prospective trials are needed to evaluate specific clinical settings, cut-off values and endpoints.
Coronary stenosis; Fractional flow reserve; iFR
● What is known?
Functional flow reserve (FFR) outperforms visual
assessment in moderate coronary artery stenosis but remains
● What is new?
Although instantaneous wave-free ratio (iFR) has an
excellent diagnostic performance FFR discordant
● What is next?
Evaluation of iFR-FFR mismatches.
Visual and functional assessments of the severity of
coronary artery stenoses are often discordant in moderate lesions
]. Fractional flow reserve (FFR) allows a reliable
functional severity assessment in these cases and has become
the gold standard. However, it does require
adenosine-induced maximal hyperaemia [
] with associated additional
side effects, time and costs.
The instantaneous wave-free ratio (iFR) is a new,
adenosine-independent index of coronary artery stenosis severity.
Whereas the used pressure ratio (that is, distal transstenotic
to proximal aortic pressure) does not differ between iFR
and FFR, its recording timing does. As opposed to the
several full cardiac cycles averaged in FFR, the iFR is recorded
during the most stable and minimised coronary resistance:
a specific diastolic wave-free period in several cardiac
]. iFR shows a good classification agreement with
] and promising results from a hybrid iFR-FFR
]. Two recent large randomised clinical trials
demonstrated non-inferiority of an iFR compared to FFR
guided revascularisation strategy regarding major adverse
cardiovascular events [
]. However, real-life data on
concomitant iFR-FFR measurements are scarce but could be
useful to improve our understanding of discrepancies,
cutoff values and consequently coronary revascularisation
]. We therefore aimed to prospectively compare
real-time FFR and iFR measurements in patients with
moderate coronary stenosis.
A prospective registry at Zuyderland Medical Centre of
all-comers between November 2015 and February 2017 in
which intermediate coronary stenoses (i. e. 50–90%
diameter stenosis by visual assessment) were measured using
both iFR and FFR.
Coronary angiogram was acquired via either a radial
(preferred) or femoral approach with administration of, 50 U/kg
unfractionated heparin. When a radial approach was used
an intra-arterial vasodilator cocktail (nitroglycerin 100 mcg
and verapamil 2.5 mg) was administered. A 0.014-inch
pressure sensor-tipped wire (PrimeWire Prestige, Volcano
Corporation, San Diego, USA) was positioned at the tip of
a guiding catheter. After pressure equalisation at the tip
of the catheter, the wire was advanced into the target
vessel as distally as reasonably possible for pressure
recordings. First, iFR was automatically calculated online using
the Volcano CORE System version 3.3.0 (Volcano
Corporation). Subsequently, FFR was measured during
adenosine-induced hyperaemia either via central intravenous
administration [at 140 μg/kg/min] or an intracoronary bolus
100–150 μg. At the end of each measurement, the pressure
sensor was retracted to the catheter tip to preclude pressure
drift. Use of intracoronary nitroglycerin injection was left
at the discretion of the cardiologist. Clinical decisions were
based exclusively on the currently recommended FFR
treatment cut-off value of 0.8 because at that time the results
from the DEFINE-FLAIR [
] and iFR-SWEDEHEART [
trials were unknown.
The gold standard consisted of an FFR-only approach using
a cut-off value of 0.8 to defer or treat when the
measurement was higher or lower, respectively. For the iFR-only
strategy, we used a cut-off value of 0.89 based on limited
available data [
]. Finally, we tested the proposed hybrid
iFR-FFR approach [
] incorporating an ‘iFR grey zone’
to revascularise (iFR <0.86), defer percutaneous coronary
intervention (>0.93) or to require a subsequent FFR
measurement to decide (iFR 0.86–0.93).
We used SPSS statistical software version 22.0 (SPSS Inc.,
Chicago, Illinois) to perform data analysis. Continuous
variables are reported as mean (SD) or median (25th–75th
percentiles) and categorical variables as number of observed
patients (percentage). We used Fisher’s exact test when
we compared categorical variables between groups and the
Student’s t test when we compared normally distributed
continuous variables between two groups. If the
continuous variable did not follow a normal distribution, we used
the Mann-Whitney U test when we drew a comparison
between two groups. Correlation between FFR and mean iFR
was assessed with Spearman’s rank correlation coefficient
(rs). Conventional summary statistics for diagnostic tests,
compared with a patient’s true disease status as indicated
by FFR 0.80, were calculated from a 2 × 2 contingency
table, comparing either the iFR-only strategy or the hybrid
iFR–FFR strategy with standard FFR. The area under the
receiver operating characteristic (ROC) curve was assessed
through nonparametric ROC analysis. Subsequently, the
optimal mean iFR threshold was verified using the minimally
important change (MIC) threshold as the cut-off level,
corresponding to a 45-degree tangent line intersection.
The investigation conforms with the principles outlined in
the Declaration of Helsinki.
Between November 2015 and February 2017, a total of
356 consecutive, predominantly (69%) male patients, aged
67 ± 10 years were enrolled, in whom 515 intermediate
coronary stenoses were measured using both iFR and FFR.
All clinical decisions were based on the FFR measurement
using central intravenous adenosine administration in 45%
and an intracoronary bolus in the remainder of patients. FFR
and iFR measurements were technically simple and feasible
in all patients, without procedure-related complications.
Baseline characteristics are summarised in Tab. 1. Mean
iFR and FFR were 0.90 ± 0.09 and 0.86 ± 0.08, respectively.
iFR correlated well with FFR [r = 0.75; p < 0.001] (Fig. 1).
ROC analysis identified an area under the curve of 0.92
suggesting a high accuracy of iFR as a diagnostic test for
FFR (Fig. 2). The estimation of MIC thresholds revealed an
iFR of 0.86 (95% confidence interval: 0.90–0.95) as the best
cut-off for prediction of an FFR of 0.8 in our population.
The iFR-only strategy using a cut-off of 0.89 showed
a diagnostic agreement with the FFR in 420 (82%) lesions
(Fig. 3a) with a sensitivity of 87%, a specificity of 80%,
a positive predictive value of 56% and a negative
predictive value of 96%. Using the hybrid iFR-FFR approach the
functional severity of 484 (94%) lesions were accurately
assessed (Fig. 3b) with the need of adenosine exposure limited
to 178 (35%) lesions.
Of the three false negative results using the hybrid
approach two were in males measuring stenoses in the more
distal and diffusely diseased left (n = 2) and right (n = 1)
coronary artery (vasospasm during measurement).
Due to diagnostic reclassification using a hybrid
iFRFFR approach over an iFR only approach (Tab. 2)
percutaneous coronary intervention was deferred in 372 (72%)
stenoses. We observed no statistically significant
differences in baseline characteristics between FFR concordant
and discordant iFR measurements (data not shown).
This is the largest, prospective registry of real-time
concomitant iFR-FFR measurements to date. These data
demonstrate that single iFR measurements are feasible,
safe and correlate well with FFR measurements, with
a particularly high negative predictive value.
Our objective was to provide additional evidence for the
clinical, real-time use of iFR measurements in functional
assessment of intermediate coronary artery stenoses. These
data are in line with recent observations that iFR has the
potential to become such a diagnostic tool [
5–7, 12, 13
iFR measurements were technically feasible, readily
available and a single iFR measurement sufficed. The iFR-only
strategy was based on the ‘non-clinically’ derived cut-off
of 0.89 and resulted in similar diagnostic agreement with
FFR, lower specificity and positive predictive value but
higher sensitivity and negative predictive value compared
with prior studies [
]. However, following the result of
] and iFR-SWEDEHEART [
appropriateness of FFR as the gold standard is questionable.
Perhaps the clinical trial iMODERN (iFR Guided Multi-vessel
revascularizatiOn During percutaneous coronary
intervEntion for acute myocaRdial iNfarction; NCT03298659) can
provide insight into this matter.
Adopting the previously suggested hybrid approach with an
iFR cut-off value for revascularisation (0.86) and deferral
(0.93) resulted in an expected substantial improvement in
diagnostic agreement. However, when relying upon a
hybrid strategy as the solution the outset should be to minimise
irreversible actions, in other words, inappropriate
revascularisation and its sequelae such as antiplatelet therapy.
The diagnostic agreement between FFR and iFR depends
on the used cut-off values. Whereas some might argue there
is room for debate regarding the optimal FFR cut-off [
], this is particularly true for iFR cut-off values. Although
an iFR-guided revascularisation strategy was noninferior
to FFR-guided revascularisation in the trials reported by
Davies et al. and Götberg et al. [
], outcomes in
paFig. 1 Correlation of
instantaneous wave-free ratio and
fractional flow reserve
Instantaneous wave-free ratio receiver operating characteristic
tients with iFR-guided deferral of revascularisation were
not reported. If indeed the clinical outcomes were similar,
interventional cardiologists would have more confidence in
deferring revascularisation if the iFR is higher than 0.89,
and these findings would help to encourage transition to
a sole iFR-guided strategy.
Both the iFR-only strategy (0.89) and the ‘iFR grey zone’
(0.86–0.93) are established based on a model, not on
clinically derived values [
]. Within our cohort the
MICderived optimal iFR cut-off value was slightly lower
compared with the applied, in other words the accepted,
cutoff, opposed to a previous study showing identical values
. A recent study by Kobayashi et al. showed that the
diagnostic accuracy of iFR depends on the location of the
lesion in the coronary tree [
]. In particular, the diagnostic
accuracy of iFR was significantly lower than that of FFR
for lesions located in the left main or proximal left anterior
descending coronary artery; this is probably related to the
larger amount of myocardium supplied [
]. This difference
may have clinical relevance. Altogether it appears that the
hybrid functional assessment of coronary artery stenoses
could benefit from more clinical data on optimal cut-off
Discordant measurements consisted mainly of
false-positive results which is in contrast with prior studies [
FFR fractional flow reserve, iFR instantaneous wave-free ratio, neg negative. pos positive
Further analysis did not reveal a significant difference in
patient or haemodynamic characteristics and this
observation might be best explained by microvascular dysfunction.
We corroborate prior evidence of significantly higher iFR
and FFR values in the right coronary and circumflex artery
with their branches [data not shown] [
]. Given the vast
majority of discordant iFR and FFR measurements
consisted of false positive results, these two observations could
be linked. How the latter can be explained, physiologically
or otherwise, remains as interesting as speculative and
requires dedicated further research such as the recently
initiated study FiGARO (FFR versus iFR Assessment of
Hemodynamic Lesion Significance; NCT03033810).
Additionally, a previous study with direct comparisons
between iFR and FFR found also a mismatch in about 20%
of cases and they found iFR appeared to correlate better
with flow measurements (coronary flow reserve) than FFR
iFR measurements eliminate the necessity for adenosine
exposure and thereby the associated side effects, additional
time and costs as proven by the studies
iFR-SWEDEHEART (Evaluation of iFR vs. FFR in Stable Angina or
Acute Coronary Syndrome) and DEFINE-FLAIR
(Functional Lesion Assessment of Intermediate Stenosis to Guide
]. Our data are in line with the
evidence. This alone could stimulate more systematic use of
functional stenosis assessment. Which is important as it not
only answers the question whether or not to revascularise,
but also impacts the preferred method of revascularisation
. However, the added value of iFR measurements could
extend to at least two other important clinical settings.
Maybe this is not the case for diffusely diseased coronary
arteries or tandem lesions (although FFR is very well suited
for single ‘spot’ or non-complex lesions). In such cases
a pullback is required to determine the culprit section.
Considering that the hyperaemic flow, but not the resting flow,
of tandem lesions are interdependent, iFR measurements
provide both a more practical and better physiological
roadmap of the entire coronary artery [
Second, the book on culprit lesion versus complete
revascularisation in the setting of ST-elevation myocardial
infarction or non-ST-elevation myocardial infarction is still
not closed [
]. As such, iFR measurements could
potentially provide an adenosine-free practical alternative for
which the results of the WAVE trial (Instantaneous
WaveFree Ratio and Fractional Flow Reserve for the Assessment
of Non Culprit Lesions in Patients with ST-segment
Elevation Myocardial Infarction; NCT02869906) trial are much
anticipated. Although iFR may be non-inferior to FFR, as
mentioned above, there are some concerns about iFR: first,
experimental studies supporting the hypothesis behind iFR
are lacking; second, the existence of the wave-free period,
upon which iFR is based, has been questioned [
third, outcome studies that compare with FFR have been
primarily performed in low-risk patients.
Finally, despite clear non-inferiority (but not
independent superiority) of an iFR compared to an FFR guided
revascularisation strategy on key clinical endpoints [
future research to improve current intracoronary diagnostic
measurements is necessary to improve our understanding
of discrepancies, cut-off values and consequently coronary
revascularisation and clinical outcome in high-risk patients
First, as certain technical aspects (e. g. arterial access, route
of adenosine administration and subsequent catheter
position check) were left at the discretion of the operator this
potentially introduced bias, in particular the use of
intracoronary nitrates considering its effect beyond the
vasotonic constriction of the stenosis. Second, despite the many
relevant patient and haemodynamic characteristics that we
collected, some important aspects with regard to analysing
FFR discordance and concordance could have been omitted.
Therefore, based on these data, the possibility of a
significant interaction cannot be eliminated. Third, even though
these data are from a large all-comer prospective registry, it
is not a randomised clinical trial. In other words, all stenoses
were assessed by both iFR and FFR and the FFR
measurement was leading in the decision to revascularise or defer
percutaneous coronary intervention.
Real-time iFR measurements are easily performed, have
a good negative predictive value compared with FFR but
the diagnostic accuracy is moderate with 82%.
Measurements with iFR have the potential to expose fewer
patients to adenosine, reduce procedure time and costs.
Further prospective and randomised trials are needed to
evaluate specific clinical settings.
Conflict of interest R. Pisters, M. Ilhan, L.F. Veenstra, B.C.G. Gho,
M. Stein, J.C.A. Hoorntje and S. Rasoul declare that they have no
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