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

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London W12 0NN

Telephone: +44 207 594 1093

Fax: +44 208 082 5109

E-mail: drjustindavies@googlemail.com

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.

350/350

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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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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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