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TRANSCRIPT
The association between physiological stenosis severity and angina-limited
exercise time in stable coronary artery disease
Christopher M Cooka MBBS BSc, Yousif Ahmada BMBS, James P Howarda MB BChir., Matthew J
Shun-Shina BM BCh., Amarjit Sethia MBBS Ph.D., Gerald J Cleshamb,c MB BChir., Ph.D., Kare H Tangb
MBBS., Sukhjinder S Nijjera MB ChB., Ph.D, Paul A Kellyb MB ChB, MD, John R Daviesb,c MBBS,
Pd.D., Iqbal S Malika MBBChir MA PhD., Raffi Kaprieliana MBBS, M.D., Ghada Mikhaila MBBS, M.D.,
Ricardo Petracoa M.D., Takayuki Warisawaa M.D., Firas Al-Janabib,c MBBS, Grigoris V Karamasisb,c
M.D., Shah Mohdnazrib,c M.D., Reto Gammab M.D., Guus A. de Waarda M.D., Rasha Al-Lameea
MBBS Ph.D., Thomas R Keebleb,c MBBS, M.D., Jamil Mayeta MB ChB, M.D., MBA, Sayan Sena
MBBS, Ph.D., Darrel P Francisa MB BChir., MA, M.D. and Justin E Daviesa M.D., Ph.D.
a Imperial College London, London, UK; b Essex Cardiothoracic Centre, Basildon, UK; c Anglia
Ruskin School of Medicine, Chelmsford, Essex, UK.
Funding: This study was funded in part by the National Institute for Health Research (NIHR) and
Imperial College Healthcare NHS Trust Biomedical Research Centre. CC (MR/M018369/1), SS
(G1000357) and SSN (G1100443) are Medical Research Council fellows. JH is a Wellcome Trust
fellow (212183/Z/18/Z). RP (FS/11/46/28861), MSS (FS/14/27/30752), JED (FS/05/006), and DPF
(FS 04/079) are British Heart Foundation fellows.
Conflicts of interest statement: JED and JM hold patents pertaining to the iFR technology. JED and
AS are consultants for Philips Volcano. RA-L, SS, RP, CC, and SSN have received speaker’s
honoraria from Philips Volcano. JED and TK have received research grants from Philips Volcano. All
other authors declare no competing interests.
Address for correspondence:
Dr Justin E Davies
The Hammersmith Hospital
1
London W12 0NN
Telephone: +44 207 594 1093
Fax: +44 208 082 5109
E-mail: [email protected]
Word count: 1219
Table and Figures count: 3
Reference count: 12
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Key points
Question: Are measurements of physiological stenosis severity associated with angina-limited
exercise time in patients with stable angina and coronary stenosis?
Findings: In this observational study, anatomical stenosis characteristics were not significantly
associated with angina-limited exercise time (p>0.05 for all). Conversely, Fractional Flow Reserve
(R2=0.27, p=0.01), instantaneous wave-Free Ratio (R2=0.46, p<0.001), Hyperemic Stenosis
Resistance (R2=0.39, p<0.01) and Coronary Flow Reserve (R2=0.16, p<0.05) were all associated with
angina-limited exercise time.
Meaning: In a selected group of severe, single-vessel stable angina patients, FFR, iFR, HSR and
CFR were all modestly correlated with angina-limited exercise time, to varying degrees.
Notwithstanding the limited sample size, no clear relationship was demonstrated between anatomical
stenosis severity and angina-limited exercise time.
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Abstract
Importance: Physiological stenosis assessment is recommended to guide percutaneous coronary
intervention (PCI) in patients with stable angina.
Objective: To determine the association between all commonly-used indices of physiological stenosis
severity and angina-limited exercise time in patients with stable angina.
Design: Observational study design. Data (without follow-up) was collected over one-year.
Setting: Multicenter study from two cardiac hospitals.
Participants: Selected patients with stable angina and physiologically severe single-vessel coronary
artery disease presenting for clinically-driven elective PCI.
Exposures: Fractional Flow Reserve (FFR), instantaneous wave-Free Ratio (iFR), hyperemic
stenosis resistance (HSR) and coronary flow reserve (CFR) were measured invasively. Immediately
after, patients maximally exercised on a catheter-table-mounted supine ergometer until they
developed rate-limiting angina (ETangina). Subsequent PCI was performed in the majority of patients,
followed by repeat maximal supine exercise testing.
Main Outcome(s) and Measure(s): Relationships between FFR, iFR, HSR, CFR and ETangina were
assessed using linear regression and Pearson correlation coefficients. Additionally, the relationships
between the post-PCI increment in exercise time (ET) and baseline FFR, iFR, HSR, CFR were
assessed.
Results: Twenty-three patients (21 male; age, 60.6 ± 8.1 years) completed the pre-PCI component of
the study protocol. Mean stenosis diameter was 74.6%±10.4. Median FFR, iFR, HSR and CFR were
0.54 (0.44-0.72), 0.53 (0.38-0.83), 1.67 (0.84-3.16) and 1.35 (1.11-1.63), respectively. Mean ETangina
was 144±77 seconds. Anatomical stenosis characteristics were not significantly associated with
ETangina (p>0.05 for all). Conversely, FFR (R2=0.27, p=0.01), iFR (R2=0.46, p<0.001), HSR (R2=0.39,
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p<0.01) and CFR (R2=0.16, p<0.05) were all associated with ETangina. Twenty-one patients (19 male;
age, 60.1 ± 8.2 years) competed the full study protocol comprising of PCI, post-PCI physiological
assessment and post-PCI maximal exercise. Post-PCI, median FFR rose to 0.91 (0.85-0.96), iFR to
0.98 (0.94-0.99), CFR to 2.73 (2.50-3.12) and HSR fell to 0.16 (0.06-0.37, p<0.0001 for all). Post-PCI
ET was most significantly associated with baseline iFR (R2=0.26, p=0.02).
Conclusions and Relevance: In a selected group of severe, single-vessel stable angina patients,
FFR, iFR, HSR and CFR were all modestly correlated with angina-limited exercise time, to varying
degrees. Notwithstanding the limited sample size, no clear relationship was demonstrated between
anatomical stenosis severity and angina-limited exercise time.
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Introduction
Physiology-guided revascularization is recommended by treatment guidelines1; primarily due to
reductions in clinical events demonstrated in randomized clinical trials. However, in clinical practice,
the majority of percutaneous coronary intervention (PCI) for stable angina is performed for
symptomatic and not prognostic benefit. Despite this, the association between physiological stenosis
severity and angina-limited exercise capacity is poorly understood.
Recently we reported a study that utilized supine exercise during invasive coronary catheterization to
determine the impact of PCI on exercise hemodynamics in patients with stable angina2. In the present
study we perform a separate analysis to determine the association between angina-limited exercise
time and fractional flow reserve (FFR), instantaneous wave-Free Ratio (iFR), hyperemic stenosis ratio
(HSR) and coronary flow reserve (CFR). Additionally, we test whether any of these indices were
associated with the change in maximal exercise time assessed immediately following PCI.
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Methods
Study population
Selected patients with stable angina and physiologically severe single-vessel coronary artery disease
presenting for clinically-driven elective PCI were recruited from two cardiac centers. All subjects gave
written informed consent in accordance with the protocol approved by the regional ethics committee
(16/LO/1928).
Catheterisation and exercise protocol
The catheterization and exercise protocol have previously been described2 and are detailed in
Methods Appendix 1 and eFigure 1. In brief, all patients performed an incremental exercise protocol
whilst simultaneous coronary pressure-flow measurements were made in the target vessel using a
Combowire. Patients exercised until the development of angina (defined as chest pain or rate-limiting
shortness of breath). The time from the start of exercise to the onset of angina (ETangina) was recorded,
with each patient blinded to their pre-PCI exercise time.
Stenting was then performed according to standard clinical practice. Following stenting, for the
majority of patients, the Combowire was reintroduced to the same intracoronary position as previous.
All aforementioned stages of the pre-PCI study protocol were then repeated, including the incremental
exercise protocol.
Data analysis
FFR, iFR, HSR and CFR were calculated offline (eTable 1).
Statistical analysis
Linear regression analysis and Pearson correlation coefficients were used to investigate the
association between ETangina and patient characteristics, anatomic stenosis characteristics and FFR,
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iFR, HSR and CFR. Tests for non-linearity were performed to validate this approach and exclude the
need for modelling using restricted cubic splines. Log transformation of HSR values was performed to
permit linear regression analysis. Applicable tests were 2 tailed and p < 0.05 was considered
statistically significant. All analyses were performed using R version 3.2.1 (R Foundation, Vienna,
Austria).
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Results
Study population
Baseline characteristics of the pre-PCI study population are summarized in eTable 2. Twenty-three
patients (21 male; age, 60.6 ± 8.1 years) completed the pre-PCI component of the study protocol.
Twenty-one of these patients (19 male; age, 60.1 ± 8.2 years) competed the full study protocol,
inclusive of post-PCI physiological assessment and post-PCI maximal exercise. Stenosis and
procedural characteristics are summarized in Table 1. Vessel-specific data are summarized in eTable
3.
Symptoms and exercise capacity
Mean exercise time before PCI was 144 ± 77 seconds (4.3 ± 1.2 metabolic equivalents). Following
PCI, exercise time increased to 219 ± 69 seconds (+ 75 seconds, 95% CI 31-120 seconds, p<0.001
for the difference in exercise time).
Associations with angina-limited exercise time
Univariate linear regression results between angina-limited exercise time (ETangina), patient
characteristics, anatomical and physiological stenosis characteristics are displayed in eTable 4.
Patient characteristics were not significantly associated with ETangina (p>0.05 for all). Similarly,
anatomical stenosis characteristics did not correlate with ETangina (eFigure 2).
Conversely, correlations between angina-limited exercise capacity and pre-PCI coronary physiology
index value were R2=0.27 (R=0.52 [0.14-0.77], p=0.01) for FFR, R2=0.46 (R=0.68 [0.37-0.85],
p<0.001) for iFR, R2=0.39 (R=-0.62 [-0.82--0.28], p<0.01) for HSR and R2=0.16 (R=0.40 [0.02-0.70],
p<0.05) for CFR (Figure 1).
Associations with the observed change in exercise time following PCI
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Correlations between the change in exercise time following PCI (ET) and pre-PCI coronary
physiology index value were R2=0.18 (R=-0.42 [-0.72- -0.01], p=0.06) for FFR, R2=0.26 (R=-0.51 [-
0.77- -0.11], p=0.02) for iFR, R2=0.15 (R=0.39 [-0.05- -0.70], p=0.08) for HSR and R2=0.01 (R=-0.09 [-
0.50-0.36], p=0.70) for CFR (Figure 2).
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Discussion
The main findings of this study were as follows. First, in selected patients with stable angina and
physiologically severe single-vessel CAD, neither patient nor anatomical stenosis characteristics were
associated with angina-limited exercise time. Second, conversely, FFR, iFR, HSR and CFR were all
associated with angina-limited exercise time. Third, iFR was closest related to the improvement in
exercise capacity observed following PCI.
Physiological stenosis severity and angina-limited exercise time
Because the extraction of oxygen is already near maximal in the resting state, the increase in
myocardial oxygen demand during exercise must principally be met by the augmentation of coronary
blood flow3. By respectively quantifying the trans-stenotic pressure ratio during maximal hyperemia4 or
the wave-free period of diastole at rest5, both FFR and iFR provide pressure-based estimates of
coronary flow (and thus mechanistic rationale for their association with angina-limed exercise time).
Additionally, the numerically closest association between iFR and ETangina may result from the ability of
iFR to quantify microcirculatory vasodilator capacity6 and its close relationship to hyperemic coronary
flow velocity7,8.
Physiological stenosis severity and the change in exercise capacity following PCI
Within the present study, and in contrast to the physiology-stratified analysis of ORBITA9, pre-PCI
FFR and iFR were associated with the improvement in exercise time following PCI. A number of
reasons may explain this difference. Unlike in ORBITA, all patients in the present study were aware
they had undergone successful PCI, and therefore may have had the greatest willingness to exert
themselves maximally. Secondly, the number of anti-anginal medications per patient in the present
study were significantly fewer (1.4 ± 0.7 per patient) than in ORBITA (2.9 ± 1.1 per patient).
Clinical implications
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Compared to anatomy alone, coronary physiology provides superior ischemia detection 10, improved
clinical patient outcomes when used to guide myocardial revascularization 11 and, as demonstrated in
the present study, proof-of-concept that physiological measurements of stenosis severity are related
to angina-limited exercise time in selected patients with stable angina and severe coronary stenosis.
Limitations
We recruited predominantly male patients with physiologically severe, focal, single vessel coronary
artery disease. Accordingly, the generalizability of our findings to wider populations is limited.
Furthermore, the small sample size of this invasive study cohort limits more detailed exploration of the
(unadjusted for) patient characteristics that may confound the relationship between a coronary lesion
and angina-limited exercise time.
Although the reproducibility of physiological indices has been previously reported12, intracoronary flow
measurements are technically demanding to perform. This may negatively bias the relationship
between angina-limited exercise capacity and HSR/CFR as compared to FFR/iFR. However, only
high-quality Doppler flow data were included for analysis.
Lastly, this study did not blind patients to the presence of PCI. Although patients were blinded to their
pre-PCI exercise time, the observed improvement in exercise time post-PCI must be considered to be
inclusive of a combination of the physical and placebo effects of PCI as well as statistical effects such
as regression to the mean. Future invasive exercise studies should aim to incorporate a sham-PCI
control arm to provide greater insight.
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Conclusions
In a selected group of physiologically severe, single-vessel stable angina patients; FFR, iFR, CFR and
HSR were all associated with angina-limited exercise time to varying degrees. Conversely,
notwithstanding the limited sample size, no clear relationship was demonstrated between anatomical
stenosis severity and angina-limited exercise time.
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References
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revascularization. Eur Heart J. doi:10.1093/eurheartj/ehy394
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Hemodynamics in Patients With Stable Coronary Disease. J Am Coll Cardiol. 2018;72(9):970-
983. doi:10.1016/j.jacc.2018.06.033
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2008;88(3):1009-1086. doi:10.1152/physrev.00045.2006
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angioplasty. Circulation. 1993;87(4):1354-1367. doi:10.1161/01.CIR.87.4.1354
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8. Petraco R, Hoef TP van de, Nijjer S, et al. Baseline Instantaneous Wave-Free Ratio as a
Pressure-Only Estimation of Underlying Coronary Flow Reserve Results of the JUSTIFY-CFR
Study (Joined Coronary Pressure and Flow Analysis to Determine Diagnostic Characteristics of
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Basal and Hyperemic Indices of Functional Lesion Severity–Coronary Flow Reserve). Circ
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9. Al-Lamee R, Howard JP, Shun-Shin MJ, et al. Fractional Flow Reserve and Instantaneous
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Figure legends
Figure 1: The relationship between angina-limited exercise time and pre-PCI FFR, iFR, HSR
and CFR value
Scatter plots of the relationship between angina-limited exercise time and pre-PCI FFR (red), iFR
(blue), HSR (green) and CFR (grey) value.
Figure 2: The relationship between the change in exercise time following PCI and pre-PCI FFR,
iFR, HSR and CFR value
Scatter plots of the relationship between the change in exercise time following PCI and pre-PCI FFR
(red), iFR (blue), HSR (green) and CFR (grey) value.
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Table 1: Overall anatomical and physiological stenosis characteristics
Target vessel (LAD/Cx/RCA) 14/5/4
Stenosis location (proximal/mid/distal) 13/8/2
Diameter stenosis by QCA 74.6% (10.4)
Stenosis length (mm) 10.7 (3.9)
FFR 0.54 (0.44 - 0.72)
iFR 0.53 (0.38 - 0.83)
CFR 1.35 (1.11 - 1.63)
HSR 1.67 (0.84 - 3.16)
Stent length (mm) 23 (8.3)
Stent diameter (mm) 3.4 (0.5)
Stent post-dilatation 83% (19/23)
FFR post-PCI 0.91 (0.85 - 0.96) *
iFR post-PCI 0.98 (0.94 - 0.99) *
CFR post-PCI 2.73 (2.50 - 3.12) *
HSR post-PCI 0.16 (0.06 - 0.37) *
FFR 0.34 (0.21 - 0.42) *
iFR 0.25 (0.09 - 0.54) *
CFR 1.28 (0.74 - 1.50) *
HSR -1.37 (-2.38 - -2.08) *
Values are n, mean ± SD, median (IQR) or n (%). LAD indicates left anterior descending; Cx,
circumflex; RCA, right coronary artery; QCA, quantitative coronary angiography; mm, millimetre; FFR,
fractional flow reserve; iFR, instantaneous wave-free ratio; CFR, coronary flow reserve; HSR,
hyperemic stenosis resistance; PCI, percutaneous coronary intervention. *Significant difference pre
versus post-PCI, p<0.0001.
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Figure 1
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Figure 2
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