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Randomized Controlled Trial
. 2025 Jan 21;151(3):202-214.
doi: 10.1161/CIRCULATIONAHA.124.072281. Epub 2024 Oct 27.

Fractional Flow Reserve and Instantaneous Wave-Free Ratio as Predictors of the Placebo-Controlled Response to Percutaneous Coronary Intervention in Stable Coronary Artery Disease

Michael J Foley  1   2 , Christopher A Rajkumar  1   2 , Fiyyaz Ahmed-Jushuf  1   2 , Florentina Simader  1   2 , Shayna Chotai  1   2 , Henry Seligman  1   2 , Krzysztof Macierzanka  1 , John R Davies  3   4 , Thomas R Keeble  3   4 , Peter O'Kane  5 , Peter Haworth  6 , Helen Routledge  7 , Tushar Kotecha  8 , Gerald Clesham  3 , Rupert Williams  9 , Jehangir Din  5 , Sukhjinder S Nijjer  1   2 , Nick Curzen  10 , Manas Sinha  11 , Ricardo Petraco  1   2   12 , James Spratt  9 , Sayan Sen  1   2 , Graham D Cole  1   2 , Frank E Harrell Jr  13 , James P Howard  1   2 , Darrel P Francis  1   2 , Matthew J Shun-Shin  1   2 , Rasha Al-Lamee  1   2 ; ORBITA-2 Investigators
Collaborators, Affiliations
Randomized Controlled Trial

Fractional Flow Reserve and Instantaneous Wave-Free Ratio as Predictors of the Placebo-Controlled Response to Percutaneous Coronary Intervention in Stable Coronary Artery Disease

Michael J Foley et al. Circulation. .

Abstract

Background: ORBITA-2 (the Placebo-Controlled Trial of Percutaneous Coronary Intervention for the Relief of Stable Angina) provided evidence for the role of percutaneous coronary intervention (PCI) for angina relief in stable coronary artery disease. Fractional flow reserve (FFR) and instantaneous wave-free ratio (iFR) are often used to guide PCI; however, their ability to predict placebo-controlled angina improvement is unknown.

Methods: Participants with angina, ischemia, and stable coronary artery disease were enrolled, and anti-anginal medications were stopped. Participants reported angina episodes daily for 2 weeks using the ORBITA smartphone symptom application (ORBITA-app). At the research angiogram, FFR and iFR were measured. After sedation and auditory isolation, participants were randomized to PCI or placebo before entering a 12-week blinded follow-up phase with daily angina reporting. The ability of FFR and iFR, analyzed as continuous variables, to predict the placebo-controlled effect of PCI was tested using Bayesian proportional odds modeling.

Results: Invasive physiology data were available for 279 patients (140 PCI and 139 placebo). The median (interquartile range) age was 65 years (59.0-70.5), and 223 (79.9%) were male. Median FFR was 0.60 (0.46-0.73), and median iFR was 0.76 (0.50-0.86). The lower the FFR or iFR, the greater the placebo-controlled improvement with PCI across all end points. There was strong evidence that a patient with an FFR at the lower quartile would have a greater placebo-controlled improvement in angina symptom score with PCI than a patient at the upper quartile (FFR, 0.46 versus 0.73: odds ratio, 2.01; 95% credible interval, 1.79-2.26; probability of interaction, >99.9%). Similarly, there was strong evidence that a patient with an iFR at the lower quartile would have greater placebo-controlled improvement in angina symptom score with PCI than a patient with an iFR at the upper quartile (iFR, 0.50 versus 0.86: odds ratio, 2.13; 95% credible interval, 1.87-2.45; probability of interaction, >99.9%). The relationship between benefit and physiology was seen in both Rose angina and Rose nonangina.

Conclusions: Physiological stenosis severity, as measured by FFR and iFR, predicts placebo-controlled angina relief from PCI. Invasive coronary physiology can be used to target PCI to those patients who are most likely to experience benefit.

Registration: URL: https://www.clinicaltrials.gov; Unique identifier: NCT03742050.

Keywords: angina, stable; cardiovascular physiology; clinical trials, randomized; coronary artery disease; ischemia, myocardial.

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Conflict of interest statement

Dr Foley has received speaker fees from Menarini and has received consulting and speaker fees from Shockwave Medical, Inc, and Philips. Dr Rajkumar has received speaker fees from Menarini, has received consulting fees from Philips, and has received shares in Mycardium AI. Dr Simader has received a sponsorship from Servier Pharmaceuticals. Dr Khokhar has received speaker fees and travel support from Boston Scientific and Abbott. Dr Davies has received grants from Medtronic and Abbott; has received sponsorship from Vascular Perspectives, Boston Scientific, Medtronic, and Abbott; and has received speaker fees from AstraZeneca, Pfizer, Bristol Myers Squibb, and Novartis. Dr Keeble has served on advisory boards for Abbott Vascular and SMT; and has received institutional research funding from Terumo, Medtronic, Boston Scientific, Abbott Vascular, Philips Volcano, and Cardionovum. Dr O’Kane has received speaker fees from Abbott Vascular, Biosensors, Boston Scientific, Heartflow, Medtronic, Philips, Shockwave, and Terumo. Dr Kotecha has received honoraria from Bayer and Janssen. Dr Nijjer has received speaker fees from Philips Volcano, Pfizer, Bayer, AstraZeneca, Boehringer Ingelheim, and Amarin. Dr Spratt has received speaker fees from Boston Scientific Corporation and Shockwave Medical, Inc. Dr Sen has received speaker and consulting fees from Philips, Medtronic, Recor, and AstraZeneca. Dr Curzen has received grants from Beckman Coulter, Inc, Boston Scientific Corporation, Haemonetics Corporation, and HeartFlow Inc; and has received speaker fees from Heartflow. Dr Howard has received shares in Mycardium AI; and has received a grant from the British Heart Foundation. Dr Cole has received shares in Mycardium AI. Dr Al-Lamee has served on advisory boards for Janssen Pharmaceuticals, Abbott, and Philips; and has received speaker fees from Abbott, Philips, Medtronic, Servier, Omniprex, and Menarini. The other authors report no conflicts.

Figures

Figure 1.
Figure 1.
The placebo-controlled effect of PCI on angina symptom score dichotomized by median FFR and iFR. The angina symptom score ranges from 0 to 79, with lower scores indicating a better angina health status. It is calculated using the number of daily angina episodes, the number of units of anti-anginal medication prescribed that day, and high-level category override events (severe angina leading to unblinding, myocardial infarction, and death). FFR indicates fractional flow reserve; iFR, instantaneous wave-free ratio; and PCI, percutaneous coronary intervention.
Figure 2.
Figure 2.
Daily angina episodes stratified by FFR and iFR. Vertical lines on the x axis represent the distribution of individual FFR and iFR values. Rose is a symptom characteristics questionnaire from which patients can be designated as having Rose angina or Rose nonangina. FFR indicates fractional flow reserve; iFR, instantaneous wave-free ratio; PCI, percutaneous coronary intervention; and Pr(Interaction), probability of interaction.
Figure 3.
Figure 3.
The placebo-controlled effect of PCI on daily angina episodes dichotomized by median FFR and iFR. FFR indicates fractional flow reserve; iFR, instantaneous wave-free ratio; and PCI, percutaneous coronary intervention.
Figure 4.
Figure 4.
Physiology-stratified placebo-controlled PCI treatment effect. The placebo-controlled effect of PCI on SAQ angina frequency, CCS class, treadmill exercise time, and dobutamine stress echocardiography score stratified by FFR and iFR. Vertical lines on the x axis represent the distribution of individual FFR and iFR values. CCS indicates Canadian Cardiovascular Society; FFR, fractional flow reserve; iFR, instantaneous wave-free ratio; PCI, percutaneous coronary intervention; Pr(Interaction), probability of interaction; and SAQ, Seattle Angina Questionnaire.
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