Functional ComprEhensive AssessmenT by Intravascular UltrasoUnd Reconstruction in Patients With Suspected IschEmic Coronary Artery Disease (FEATURE)
Conditions: Ischemic Heart Disease
Sponsor: Ruijin Hospital

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Study Protocol
Official Title
Functional ComprEhensive AssessmenT by
Intravascular UltrasoUnd Reconstruction in
Patients With Suspected IschEmic Coronary
Artery Disease (FEATURE)
NCT Number
NCT05694065
Study ID
20221110025331724
Principal
Investigator
Fenghua Ding
Responsible
Party
Ruijin Hospital, Shanghai Jiao Tong University
School of Medicine

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1. Study Background
Intravascular ultrasound (IVUS), an invasive coronary imaging technique, provides
accurate visualization of lumen dimensions and subintimal plaque morphology. This
facilitates guiding percutaneous coronary intervention (PCI), intra-procedural stent
sizing optimization and post-procedural stent apposition assessment in patients with
ischemic heart disease[1].
Although
IVUS-derived
minimal
lumen
area
(MLA)
could
predict
functionally
significant stenosis, defined by fractional flow reserve (FFR)≤0.80 - the gold standard
for functional evaluation of coronary stenosisI[2-3], its diagnostic performance varies:
MLA cutoff values (2.0 - 4.0 mm2) showed moderate accuracy (60-80%) for non-left
main lesions[4-7] with variation observed across coronary vessel segments[8]; A recent
study reported that MLA<2.79 mm2 achieved 77.4% accuracy (AUC=0.86) with
sensitivity of 76.2% and specificity of 78.5% in large vessels (diameter >2.5mm by
visual estimation)[9]. Despite providing valuable anatomical insights, IVUS remains
suboptimal for physiological ischemia assessment. However, a recent landmark trial
demonstrated comparable major adverse cardiac events rates between IVUS-guided
PCI and FFR-guided PCI, while the latter significantly reduced stent utilization[10].
The complementary nature of these two modalities presents a compelling rationale for
their
integrated
use.
Notably,
the
recent
development
of
an
artificial
intelligence-enhanced computational ultrasonic flow ratio (UFR), enables derivation of
functional information directly from IVUS datasets. This innovation establishes a
unified morpho-functional assessment system, effectively obviating dependence on
pressure-wire instruments and pharmacologically-induced hyperemia[11]. Preliminary
data showed 92% diagnostic concordance between UFR and FFR (AUC=0.97)[12],
though evidence remains limited to retrospective, single-vessel analyses.
This prospective, single-center observational study will consecutively enroll patients
with suspected ischemic heart disease to evaluate the diagnostic performance of
catheterization laboratory-derived UFR in identifying hemodynamically significant
coronary stenosis (defined as FFR ≤0.80).

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2. Study Objective
Investigating
the
diagnostic
accuracy
of
online
UFR
assessment
to
identify
hemodynamically significant coronary stenosis in patients with suspected ischemic
heart disease using angiography-derived FFR as a reference standard.
2.1 Primary Endpoint
Diagnostic
accuracy
of
online
UFR
as
compared
with
FFR
to
identify
hemodynamically significant coronary stenosis (FFR ≤0.80).
2.2 Second Endpoint
Sensitivity and specificity of online UFR as compared with IVUS-derived MLA, when
using FFR as a golden standard.
2.3 Prespecified Subgroup Analysis
Lesion location, multivessel disease and imaging catheters.
3. Study Design
3.1 Study Description
This is a prospective, single-center, observational clinical study. Patients with
suspected ischemic heart disease admitted for coronary angiography will be
consecutively enrolled.
3.2 Study Subject
3.2.1 Inclusion Criteria
1. Subject must be ≥18 years
2. Patients suspected with ischemic heart disease
3. ≥1 diseased vessel with angiographic percent diameter stenosis between 40% and
80% in a vessel ≥2.5mm by visual estimation
4. Target vessels are limited to major epicardial coronary arteries (left anterior
descending artery [LAD], left circumflex artery [LCX], right coronary artery [RCA])
3.2.2 Exclusion Criteria
1. Patients with previous coronary artery bypass grafting (CABG)
2. Myocardial infarction within 72h of coronary angiography

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3. Allergy to the contrast agent or adenosine
4. Left main coronary artery stenosis ≥50%
5. Target vessel with in-stent restenosis
6. Target vessel with severe tortuosity or angulation
7. 100% occlusion of target vessel
8. Target vessel spasm or injury
9. Target vessel with severe myocardial bridge
10. Target vessel with severe thrombosis
11.IVUS pullback fails to cover the complete target lesion
12. Presence of false lumen at target vessel based on IVUS
13. A serum creatinine level >150 umol/l, or a glomerular filtration rate < 45 ml/kg/1.73 m^2
14. Heart failure
15. Ineligible for diagnostic intervention (IVUS or FFR examination)
3.3 Sample Size Calculation
Study population
and sample
size
calculation are based
on the diagnostic
performance of previous studies, where an accuracy of 92% was found for UFR.
Investigators
conservatively
estimate
the
diagnostic
accuracy
of
online
UFR
assessment as 90% for consecutively enrolled patient population, and with a test
target value set as 78% at a two-side significance level of 0.05, statistical power as
90%. Considering incomplete FFR/UFR data of 10% at most, a total of 112 patients
need to be enrolled.
4. Data Acquisition
FFR is measured using a pressure wire (St. Jude Medical, Saint Paul, MN, USA) or a
pressure microcatheter (TruePhysio, Insight Lifetech, Shenzhen, China) at least 2 cm
distal to the most distal part of the target lesion. FFR is calculated as the ratio
between the average distal pressure and the average aortic pressure recorded during
stable maximal hyperemia induced by injection of adenosine via an antecubital vein at
140~180 μg/ (kg·min).

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IVUS images are obtained after intracoronary injection of nitroglycerin using either
OptiCross 40 MHz or OptiCross HD 60 MHz Imaging Catheter with an automated
pullback at a speed of 1 mm/s and a frame rate of 30 frames/s on the commercially
available systems (OptiCross, iLab(TM) Polaris, Boston Scientific, Boston, USA).
IVUS catheters should be consistent with the FFR pressure guide wire measurement.
After IVUS image acquisition, the image pullbacks will be transferred to computation
of UFR online using commercially available software (IvusPlus, version V1; Pulse
Medical, Shanghai, China) by a certified analyst who is blinded to the FFR data. The
algorithm of UFR computation includes the reconstruction of the geometric model and
computation of the pressure drop along the imaged segment. Firstly, the arterial
lumen and external elastic membrane contours are automatically delineated and
reconstructed in 3D by AI. Secondly, the ostia of side branches perpendicular to the
side branch centerline are automatically reconstructed to enable cross-sectional area
measurement of the side branches. Subsequently, the reference vessel diameter
(RVD), the hypothetical healthy lumen with absence of any stenosis, is derived based
on the bifurcation fractal law. Finally, the pressure drops along each cross-section of
the pullback are calculated using validated computational FFR algorithm based on
fluid dynamics equations, and the UFR pullback will be obtained.
5. Statistical Analysis
Continuous variables are reported as mean±standard deviation (SD) for normally
distributed data or median (interquartile range [IQR]) for non-normally distributions.
Categorical variables are expressed as counts (percentages). The median value of
FFR and UFR are compared by Wilcoxon signed-rank test. Correlation between FFR
and UFR is assessed by the Spearman or Pearson correlation analysis, as
appropriate. Bland-Altman analysis quantifies measurements bias and 95% limits of
agreement between FFR and UFR. The diagnostic discrimination abilities of UFR and
MLA are compared by the area under the receiver operating characteristic (ROC)
curves using the DeLong method. Cutoff value of ≤0.80 is used for FFR and UFR to
define the physiological significance of a coronary stenosis. All statistical analyses are
performed using R v4.5.0, (R Foundation for Statistical Computing, Vienna, Austria.)

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and MedCalc v23.2.1 (MedCalc Software, Ostend, Belgium), with two-sided P<0.05
considered statistically significant.

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6. References
[1]
DE LA TORRE HERNANDEZ J M, BAZ ALONSO J A, GOMEZ HOSPITAL J A, et al.
Clinical impact of intravascular ultrasound guidance in drug-eluting stent implantation for
unprotected left main coronary disease: pooled analysis at the patient-level of 4 registries [J].
JACC Cardiovasc Interv, 2014, 7(3): 244-54.
[2]
DE BRUYNE B, FEARON W F, PIJLS N H, et al. Fractional flow reserve-guided PCI for
stable coronary artery disease [J]. N Engl J Med, 2014, 371(13): 1208-17.
[3]
NEUMANN F J, SOUSA-UVA M, AHLSSON A, et al. 2018 ESC/EACTS Guidelines on
myocardial revascularization [J]. Eur Heart J, 2019, 40(2): 87-165.
[4]
BEN-DOR I, TORGUSON R, GAGLIA M A, JR., et al. Correlation between fractional flow
reserve and intravascular ultrasound lumen area in intermediate coronary artery stenosis [J].
EuroIntervention, 2011, 7(2): 225-33.
[5]
JANG J S, SHIN H C, BAE J S, et al. Diagnostic Performance of Intravascular
Ultrasound-Derived Minimal Lumen Area to Predict Functionally Significant Non-Left Main
Coronary Artery Disease: a Meta-Analysis [J]. Korean Circ J, 2016, 46(5): 622-31.
[6]
CHU M, DAI N, YANG J, et al. A systematic review of imaging anatomy in predicting
functional significance of coronary stenoses determined by fractional flow reserve [J]. Int J
Cardiovasc Imaging, 2017, 33(7): 975-90.
[7]
WAKSMAN R, LEGUTKO J, SINGH J, et al. FIRST: Fractional Flow Reserve and
Intravascular Ultrasound Relationship Study [J]. J Am Coll Cardiol, 2013, 61(9): 917-23.
[8]
KOO B K, YANG H M, DOH J H, et al. Optimal intravascular ultrasound criteria and their
accuracy for defining the functional significance of intermediate coronary stenoses of different
locations [J]. JACC Cardiovasc Interv, 2011, 4(7): 803-11.
[9]
KANG S J, KWEON J, YANG D H, et al. Mathematically Derived Criteria for Detecting
Functionally
Significant
Stenoses
Using
Coronary
Computed
Tomographic
Angiography-Based
Myocardial
Segmentation
and
Intravascular
Ultrasound-Measured
Minimal Lumen Area [J]. Am J Cardiol, 2016, 118(2): 170-6.
[10] KOO B K, HU X, KANG J, et al. Fractional Flow Reserve or Intravascular Ultrasonography
to Guide PCI [J]. N Engl J Med, 2022, 387(9): 779-89.
[11] RD S. Invasive fractional flow reserve: Which technology is best? [J]. Catheter
Cardiovasc Interv, 2020, 95(6): 1102-3.
[12] YU W, TANIGAKI T, DING D, et al. Accuracy of Intravascular Ultrasound-Based
Fractional Flow Reserve in Identifying Hemodynamic Significance of Coronary Stenosis [J].
Circ Cardiovasc Interv, 2021, 14(2): e009840.