Clinical trial NCT03729739: Functional Assessment by Virtual Online Reconstruction. The FAVOR III Europe Trial
Official title: Comparison of Quantitative Flow Ratio (QFR) and Conventional Pressure-wire Based Functional Evaluation for Guiding Coronary Intervention. A Randomized Clinical Non-inferiority Trial
Study type: INTERVENTIONAL
Overall status: ACTIVE_NOT_RECRUITING
Phase: NA
Conditions: Coronary Artery Disease
Keywords: Fractional Flow Reserve (FFR)
Quantitative Flow Ratio (QFR)
Stable coronary artery disease
Angina pectoris
Angiography derived fractional flow reserve
Lead sponsor: Aarhus University Hospital Skejby
Sponsor class: OTHER
Collaborators: name: Medis Medical Imaging Systems
First posted: 2018-11-05
Enrollment: 2001
Sex: ALL
Minimum age (years): 18
Standard ages: ADULT
OLDER_ADULT
Accepts healthy volunteers: no
Allocation: RANDOMIZED
Intervention model: PARALLEL
Intervention model description: Randomized clinical non-inferiority trial
Primary purpose: DIAGNOSTIC

Brief summary: Quantitative Flow Ratio (QFR) is a novel method for evaluating the functional significance of coronary stenosis. QFR is estimated based on two angiographic projections. Studies have shown a good correlation with the present wire-based standard approach Fractional Flow Reserve (FFR) for assessment of intermediate coronary stenosis. The purpose of the FAVOR III Europe Japan study is to investigate if a QFR-based diagnostic strategy will results in non-inferior clinical outcome after 12 months compared to a standard pressure-wire guided strategy in evaluation of patients with chest pain (stable angina pectoris) and intermediate coronary stenosis.

Detailed description: Patients at high risk of having one or more coronary stenosis are evaluated routinely by invasive coronary angiography (CAG). Lesions are often quantified by visual assessment of the angiogram, but physiological assessment of the functional significance by fractional flow reserve has been shown to improve clinical outcome, to reduce number of stents implanted, and has obtained the highest recommendation in European guidelines. FFR is assessed during CAG by advancing a wire with a pressure transducer towards the stenosis and measure the ratio in pressure between the two sides of the stenosis during medical induced maximum blood flow (hyperaemia).

The solid evidence for FFR evaluation of coronary stenosis and the relative simplicity in performing the measurements have supported adoption of an FFR based strategy but the need for interrogating the stenosis by a pressure wire, the small risks associated hereto, the cost of the wire, and the drug inducing hyperaemia has limited more widespread adoption.

Quantitative Flow Ratio is a novel method for evaluating the functional significance of coronary stenosis by calculation of the pressure drop in the vessel based on computation of two angiographic projections.

Two multi-center studies, the FAVOR II Europe-Japan and China studies evaluated the feasibility and diagnostic performance of in-procedure QFR, showing very good agreement between QFR and FFR.

The purpose of the FAVOR III Europe Japan study is to investigate if a QFR-based diagnostic strategy yields non-inferior 12-month clinical outcome compared to a standard pressure-wire guided strategy in evaluation of patients with stable angina pectoris and intermediate coronary stenosis.

Primary hypothesis: A QFR based diagnostic strategy results in non-inferior clinical outcome, assessed by a composite endpoint of all cause death, non-fatal myocardial infarction (MI) and unplanned revascularization after one year, compared to a strategy of pressure wire-based FFR for assessment of physiological significance of intermediate coronary artery stenosis.

Methods: Investigator initiated, 1:1 randomized, prospective, clinical outcome, non-inferiority, multi-center trial performed at up to 40 international sites with inclusion of 2000 patients.

Patients with stable angina pectoris or need for evaluation of non-culprit lesions after acute MI are enrolled. At least two angiographic projections are acquired during resting conditions. If the angiographic criteria are met, the patient is randomized to either a QFR- or an FFR-based diagnostic strategy.

Revascularization is performed according to best standard by percutaneous coronary intervention (PCI) or coronary artery bypass grafting (CABG).

Patient follow-up is continued until 24 months.

Eligibility criteria: Inclusion Criteria:

* Age of 18 years and above
* Both genders
* Indication for invasive coronary angiography
* Patients with stable angina pectoris, or assessment of secondary lesions in stabilized non-STEMI patients or assessment of secondary lesions in patients with prior STEMI and staged evaluation of secondary lesions.
* Able to provide written informed consent

Angiographic inclusion criteria

* Diameter stenosis of 40-90% diameter stenosis
* Vessel diameter of at least 2.5 mm and supplying viable myocardium
* Patients with restenosis in a native coronary artery can be included

Exclusion Criteria:

* Severely impaired renal function: Glomerular filtration rate (GFR) \< 20 mL/min/1.73m²
* Life expectancy less than one year
* Cardiogenic shock or unstable haemodynamic state (Killip class III and IV)
* ST-elevation myocardial infarction (STEMI) within 24 hours
* Bypass graft to any target vessel
* Atrial fibrillation at the time of the procedure
* Chronic total occlusions of any vessel with possible or established indication for treatment
* Pregnancy or intention to become pregnant during the course of the trial
* Breast feeding
* Planned need for concomitant valvular or aortic surgery
* Left ventricular ejection fraction (LVEF) \< 30%
* Previous inclusion in the FAVOR III trial
* Enrolled in another clinical study, and for this reason not treated according to present European Society of Cardiology guidelines, or the protocol treatment conflicts with the protocol treatment of FAVOR III
* Inability to tolerate contrast media
* Inability to tolerate Adenosine

Angiographic exclusion criteria

* Ostial right coronary artery \> 50% diameter stenosis
* Left main coronary artery \> 50% diameter stenosis
* Lesions properties indicative of myocardial bridging
* Bifurcation lesions with major (\>1 mm) step down in reference size across the bifurcation
* Severe tortuosity of any target vessel
* Severe overlap in the stenosed segment
* Poor image quality precluding identification of vessel contours

Primary outcomes:
measure: Patient oriented composite endpoint (PoCE)
timeFrame: 12 months
Secondary outcomes:
measure: Target vessel failure
timeFrame: 1 month
measure: Target vessel failure
timeFrame: 12 months
measure: Target vessel failure
timeFrame: 24 months
measure: All-cause mortality
timeFrame: 1 month
measure: All-cause mortality
timeFrame: 12 months
measure: All-cause mortality
timeFrame: 24 months
measure: Cardiac death
timeFrame: 1 month
measure: Cardiac death
timeFrame: 12 months
measure: Cardiac death
timeFrame: 24 months
measure: Myocardial infarction
timeFrame: 1 month
measure: Myocardial infarction
timeFrame: 12 months
measure: Myocardial infarction
timeFrame: 24 months
measure: Target vessel myocardial infarction
timeFrame: 1 month
measure: Target vessel myocardial infarction
timeFrame: 12 months
measure: Target vessel myocardial infarction
timeFrame: 24 months
measure: Any unplanned revascularization
timeFrame: 1 month
measure: Any unplanned revascularization
timeFrame: 12 months
measure: Any unplanned revascularization
timeFrame: 24 months
measure: Any ischemia driven de novo revascularization
timeFrame: 1 month
measure: Any ischemia driven de novo revascularization
timeFrame: 12 months
measure: Any ischemia driven de novo revascularization
timeFrame: 24 months
measure: Ischemia driven target vessel revascularization
timeFrame: 1 month
measure: Ischemia driven target vessel revascularization
timeFrame: 12 months
measure: Ischemia driven target vessel revascularization
timeFrame: 24 months
measure: Ischemia driven treated target lesion revascularization
timeFrame: 1 month
measure: Ischemia driven treated target lesion revascularization
timeFrame: 12 months
measure: Ischemia driven treated target lesion revascularization
timeFrame: 24 months
measure: Ischemia driven, measured segment revascularization
timeFrame: 1 month
measure: Ischemia driven, measured segment revascularization
timeFrame: 12 months
measure: Ischemia driven, measured segment revascularization
timeFrame: 24 months
measure: Ischemia driven measured segment de novo revascularization
timeFrame: 1 month
measure: Ischemia driven measured segment de novo revascularization
timeFrame: 12 months
measure: Ischemia driven measured segment de novo revascularization
timeFrame: 24 months
measure: Feasibility of QFR
timeFrame: 1 hour
measure: Feasibility of FFR
timeFrame: 1 hour
measure: Number of lesion interrogated
timeFrame: 1 hour
measure: Procedure time
timeFrame: 1 hour
measure: Contrast volume
timeFrame: 1 hour
measure: Fluoroscopy time
timeFrame: 1 hour
measure: Number of stents implanted
timeFrame: 1 hour
Other outcomes:
Locations:
city: Aalborg
country: Denmark
facility: Aalborg University Hospital
city: Aarhus N
country: Denmark
facility: Aarhus University Hospital
city: Hellerup
country: Denmark
facility: Gentofte Hospital
city: Saint-Laurent-du-Var
country: France
facility: Institut Arnault Tzanck
state: Nice
city: Aix-en-Provence
country: France
facility: GCS ES Axium - Parc Rambot
city: Lille
country: France
facility: CHU de Lille, Lille University Hospital
city: Massy
country: France
facility: Institut Cardiovasculaire Paris Sud (ICPS), Hopital Jacques Cartier
city: Pessac
country: France
facility: Hopital Haut-Leveque, Pessac
city: Quincy
country: France
facility: Hôpital Privé Claude Galien
city: Toulouse
country: France
facility: Clinique Pasteur, Toulouse
city: Berlin
country: Germany
facility: Charite-Universitatsmedizin Berlin
city: Essen
country: Germany
facility: Elisabeth Krankenhaus
city: Leipzig
country: Germany
facility: University Clinic Leipzig
city: Bologna
country: Italy
facility: Ospedale Maggiore, AUSL Bologna
city: Ferrara
country: Italy
facility: Azienda Ospedaliero-Universitaria di Ferrara, University of Ferrara
city: Naples
country: Italy
facility: Azienda Ospedaliero Universitaria Federico II di Napoli
city: Orbassano
country: Italy
facility: San Luigi Gonzaga University Hospital, Turin
city: Reggio Emilia
country: Italy
facility: Arcispedale S. Maria Nuova di Reggio Emilia
city: Rimini
country: Italy
facility: Ospedale degli Infermi di Rimini
city: Torino
country: Italy
facility: Ospedale di Rivoli, Torino
city: Verona
country: Italy
facility: Azienda Ospedaliera Universitaria integrata Verona
city: Riga
country: Latvia
facility: Riga Stradini University Hospital
city: Kaunas
country: Lithuania
facility: Hospital of Lithuanian University of Health Sciences Kauno Klinikos
city: Amsterdam
country: Netherlands
facility: VU University Medical Center
city: Amsterdam
country: Netherlands
facility: Academic Medical Center (AMC)
city: The Hague
country: Netherlands
facility: HagaZiekenhuis
city: Warsaw
country: Poland
facility: Medical University of Warsaw
city: El Palmar
country: Spain
facility: Hospital Clinico Universitario Virgen de la Arrixaca
state: Murcia
city: Coruña
country: Spain
facility: Hospital Clinico de Coruña
city: Lugo
country: Spain
facility: Hospital Lucus Agusti LUGO
city: Madrid
country: Spain
facility: Hospital Clinico San Carlos
city: Valladolid
country: Spain
facility: Hospital Clinico Universitario de Valladolid
city: Vigo
country: Spain
facility: Hospital Álvaro Cunqueiro
city: Göteborg
country: Sweden
facility: Sahlgrenska University Hospital
city: Zürich
country: Switzerland
facility: Barbera Stähli
state: Zûrich
Study officials:
affiliation: Aarhus University Hospital, Denmark
name: Evald H. Christiansen, Prof.
role: PRINCIPAL_INVESTIGATOR
References:
citation: Tu S, Westra J, Yang J, von Birgelen C, Ferrara A, Pellicano M, Nef H, Tebaldi M, Murasato Y, Lansky A, Barbato E, van der Heijden LC, Reiber JHC, Holm NR, Wijns W; FAVOR Pilot Trial Study Group. Diagnostic Accuracy of Fast Computational Approaches to Derive Fractional Flow Reserve From Diagnostic Coronary Angiography: The International Multicenter FAVOR Pilot Study. JACC Cardiovasc Interv. 2016 Oct 10;9(19):2024-2035. doi: 10.1016/j.jcin.2016.07.013.
citation: Westra J, Andersen BK, Campo G, Matsuo H, Koltowski L, Eftekhari A, Liu T, Di Serafino L, Di Girolamo D, Escaned J, Nef H, Naber C, Barbierato M, Tu S, Neghabat O, Madsen M, Tebaldi M, Tanigaki T, Kochman J, Somi S, Esposito G, Mercone G, Mejia-Renteria H, Ronco F, Botker HE, Wijns W, Christiansen EH, Holm NR. Diagnostic Performance of In-Procedure Angiography-Derived Quantitative Flow Reserve Compared to Pressure-Derived Fractional Flow Reserve: The FAVOR II Europe-Japan Study. J Am Heart Assoc. 2018 Jul 6;7(14):e009603. doi: 10.1161/JAHA.118.009603.
citation: Westra J, Tu S, Winther S, Nissen L, Vestergaard MB, Andersen BK, Holck EN, Fox Maule C, Johansen JK, Andreasen LN, Simonsen JK, Zhang Y, Kristensen SD, Maeng M, Kaltoft A, Terkelsen CJ, Krusell LR, Jakobsen L, Reiber JHC, Lassen JF, Bottcher M, Botker HE, Christiansen EH, Holm NR. Evaluation of Coronary Artery Stenosis by Quantitative Flow Ratio During Invasive Coronary Angiography: The WIFI II Study (Wire-Free Functional Imaging II). Circ Cardiovasc Imaging. 2018 Mar;11(3):e007107. doi: 10.1161/CIRCIMAGING.117.007107.
citation: Xu B, Tu S, Qiao S, Qu X, Chen Y, Yang J, Guo L, Sun Z, Li Z, Tian F, Fang W, Chen J, Li W, Guan C, Holm NR, Wijns W, Hu S. Diagnostic Accuracy of Angiography-Based Quantitative Flow Ratio Measurements for Online Assessment of Coronary Stenosis. J Am Coll Cardiol. 2017 Dec 26;70(25):3077-3087. doi: 10.1016/j.jacc.2017.10.035. Epub 2017 Oct 31.