Since its foundation in 1989, Medis has been deeply involved in X-ray imaging, particularly 2D and 3D QCA (Quantitative Coronary Angiography), with solutions used worldwide, particularly in Japan. Given the increasing clinical interest in coronary physiology globally, the Medis’ Applied Research team in Leiden, the Netherlands, began exploring a new solution in 2013. Their goal was to assess coronary physiology using only X-ray angiographic images, eliminating the need for an FFR (Fractional Flow Reserve) pressure wire. The idea was to obtain a measure similar to FFR by combining a 3D reconstruction of a coronary segment with an estimation of coronary flow velocity through that segment.
Our first publication in 2014 was based on this 3D calculation of the 2D QCA anatomy from 2 views, at least 25 degrees apart (QAngio XA 3D solution) and the so-called TIMI frame count. The CFD approach (computational fluid dynamics), used at that time, was based on solving the Navier-Stokes equations, under hyperemic conditions. The correlation between this FFRQCA, as it was called initially, and the FFR was promising with an r=0.81, and this work was subsequently published in the JACC Interventions journal in 2014, receiving a very encouraging Editorial Comment by Dr Alexandra Lansky from Yale University [1,2]. Shengxian Tu, employed by Medis in Leiden, the Netherlands, from 2008 until June 2014, was the first author of several of these early publications. Afterwards, Dr Tu returned to Shanghai Jiao Tong University.
Since CFD is computationally intensive, Medis aimed to simplify the solution. By 2016, we developed a mathematical model that did not require hyperemia, which involves adenosine administration (as is required by the FFR pressure wire) often not well-tolerated by patients. We realized this model in 2016 by developing a simplified mathematical model that is based on the segmental differences between the lumen of the coronary artery from 3D QCA and the best estimation of the normal size of the artery, still using the TIMI frame count for the estimation of the coronary flow velocity. The non-hyperemic approach, based on the basal flow, was validated in the multi-center FAVOR Pilot study, led by Dr Niels Holm, and showed comparable results to the hyperemic solution [3]. These results, published in JACC Interventions in 2016, led us to name our solution “QFR®”.
This breakthrough opened up an avenue for further research and development at Medis to create extensive clinical evidence and make the QFR solution more robust and automated for practical use during interventional procedures: in daily practice (“on-line” use), and not only in a core-lab environment outside of the Cath lab (“off-line” use).
Various multi-center clinical trials, organized by Aarhus University Medical Center in Denmark with PI Dr. Niels Holm, demonstrated the clinical feasibility of QFR in the Cath lab, such as the FAVOR II EU study, which demonstrated in 329 patients from multiple European centers, that online intramural computation of QFR in the Cath lab is clinically feasible and is superior to angiographic assessment for evaluation of intermediary coronary artery stenosis using FFR as a reference standard [4]. The FAVOR III EU Outcome trial, involving 2000 patients from over 30 centers, hypothesized that QFR is non-inferior to FFR. The 1-year follow-up (FU) results will be presented at the upcoming TCT congress 2024, in October, in Washington, USA. FAVOR II Japan trial led to PMDA approval in August 2023, and reimbursement by the Japanese government as per January 1, 2024. To date, the QFR can rely on the most extensive clinical evidence of any angio-based solution on the market, with over 250 peer-reviewed scientific publications by Key Opinion Leaders (KOLs) and users.
Significant findings from trials like FAVOR III China, HAWKEYE, and FIRE highlight the effectiveness of QFR. For instance, the FAVOR III China study demonstrated that a QFR-guided strategy for lesion selection improved 1-year clinical outcomes compared to standard angiography guidance: 5.8% in the QFR-guided group versus 8,8% in the angiography-guided group [5]. A 2-year FU has also been published with similar results: 2-year MACE occurred in 8.5% in the QFR-guided group vs 12.5% in the angiography-guided group [6].
From a clinical application point of view, a number of very important developments should be mentioned. Dr Simone Biscaglia and Prof Gianluca Campo from Ferrara University Medical Center in Italy, demonstrated in the HAWKEYE trial that a Post-PCI QFR ≤ 0.89 was associated with a 3-fold increase in risk for Vessel Oriented Composite Endpoint (VOCE) [7]. Based also on other papers, this has led to the general rule that a post-PCI FFR should be higher than 0.89-0.91. From the AQVA trial the same authors demonstrated the superiority of QFR-based virtual PCI over angiography-based PCI with regards to post-PCI optimal physiological results [8].
FIRE trial demonstrated in patients older than 75 years with myocardial infarction and multi-vessel disease, that those who underwent physiology-guided complete revascularization had a lower risk of Major Adverse Cardiac Events (MACE) [9]. Also, from the QFiRe study, the authors concluded that this sub-analysis of the FIRE trial, provides evidence supporting the safety and efficacy of QFR-guided interventions, as well as non-inferiority to pressure wire-based FFR, for the treatment of nonculprit vessels in MI patients [10].
A next application in angio-based FFR was the development of the index of microcirculatory disease (IMR) using QFR, led by Dr. Roberto Scarcini and Dr. Giovanni de Maria from Oxford University, United Kingdom, who released the first publication based on the QFR software with IMR [11]. This field is of enormous importance as roughly 60% of the patients with chest pain have no epicardial disease [12]. The work of Dr. Scarcini and D. De Maria, and subsequent studies by Dr. Hernan Mejia-Renteria and Dr. Javier Escaned from Clinico San Carlos in Madrid in 2021 showed that estimating IMR without a wire and adenosine is feasible and reliable, and that microcirculatory dysfunction causing high IMR can be ruled-out with high-confidence in vessels with low angio-IMR [13].
Finally, Prof Patrick W Serruys from the CORRIB Core lab in Galway, Ireland continues to apply the QFR in clinical research, such as the MultiTalent trial and the Pioneer IV trial [14, 15].
The Medis approach for the angio-based FFR has always been to make QFR solution robust, reproducible and simple to use in the cardiac catheterization laboratories, both for clinical use as well as clinical research. Over the years, Medis has released various QFR versions, each improving automation and simplifying training and certification.
Today, Medis’ QFR V3.0 requires only 3 simple steps in a highly automated approach using Deep Learning, which has proven to be robust. This release is browser-based (not to be confused with cloud-based) version, significantly decreases the footprint in the cardiac Cath labs, and features a redesigned user-interface, making it very simple for Cath lab professionals to use it in their daily clinical practice. Integration into the Cath lab infrastructure allows interventional cardiologists to use QFR during procedures with results displayed on the Large Display Monitor (LDM). Given the high degree of automation, only a short cloud-based training session is required.
Though other angio-based solutions are sometimes called “QFR” in daily speech, Medis holds the worldwide rights to the QFR® trademark, except in China.
References:
[1] Tu S, Barbato E, Köszegi Z.et al. Fractional flow reserve calculation from 3-dimensional quantitative coronary angiography and TIMI frame count: a fast computer model to quantify the functional significance of moderately obstructed coronary arteries. JACC Cardiovasc Interv. 2014 Jul;7(7):768-77. doi: 10.1016/j.jcin.2014.03.004. PMID: 25060020.
[2] Lansky, A, Pietras, C. Fractional Flow Reserve From 3-Dimensional Quantitative Coronary Angiography: Fresh Light Through an Old Window∗. J Am Coll Cardiol Intv. 2014 Jul, 7 (7) 778–780.https://doi.org/10.1016/j.jcin.2014.05.002
[3] Tu, S, Westra, J, Yang, J. et al. Diagnostic Accuracy of Fast Computational Approaches to Derive Fractional Flow Reserve From Diagnostic Coronary Angiography: The International Multicenter FAVOR Pilot Study. J Am Coll Cardiol Intv. 2016 Oct, 9 (19) 2024–2035.https://doi.org/10.1016/j.jcin.2016.07.013
[4] Westra J, Andersen BK, Camp G et al. 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; 7: e009603. Doi:10.1161/JAHA.118.009603
[5] Xu Bo, Tu S, Song L, Jin Z. et al. Angiographic quantitative flow ratio-guided coronary intervention (FAVOR III China): a multicentre, randomised, sham-controlled trial
Lancet, Nov 4, 2021; doi.org/10.1016/S0140-6736(21)002248-0
[6] Song L, Xu B, Tu S. Et al.
Angiographic Quantitative Flow Ratio-guided coronary intervention: two-year outcomes of the FAVOR III China Trial.
J Am Coll Cardiol 2022; 80: 2089-2101; doi.org/10.1016/j.jacc.2022.09.007
[7] Biscaglia S, Tebaldi M, Brugaletta S. et al. Prognostic value of QFR measured immediately after successful stent implantation: The International Multicenter Prospective HAWKEYE Study.
J Am Coll Cardiol Intv 2019; 12: 2079-2088. Doi.org/10.1016/j.jcin.2019.06.003
[8] Biscaglia S, Verardi FM, Tebaldi M. et al.
QFR-based virtual PCI or conventional angiography to guide PCI; the AQVA trial
JACC Intv 2023; 16: 783-794; doi.org/10.1016/j.jcin.2022.10.054
[9] Biscaglia S, Guiducci V, Escaned J. et al.
Complete or culprit-only PCI in older patients with myocardial infarction.
New Eng J Med 2023; doi.org/10.1056/NEJMoa2300468
[10] Erriquez A, Campo G, Guiducci V. et al.
QFR for the revascularization of nonculprit vessels in MI patients. Insights from the FIRE trial.
JACC Intv 2024; doi.org/10.1016/j.jcin.2024.04.022
[11] Scarsini R, Shanmuganathan M, Kotronias RA. et al.
Angiography-derived index of microcirculatory resistance (IMRangio) as a novel pressure-wire-free tool to assess coronary microvascular dysfunction in acute coronary syndromes and stable coronary artery disease.
Int J Cardiovasc Imaging 2021; 37: 1801-1813; doi.org/10.1007/s10554-021-02254-8
[12] Sara J. et al., Prevalence of Coronary Microvascular Dysfunction Among Patients With Chest Pain and Nonobstructive Coronary Artery Disease. JACC: Cardiovascular Interventions
Volume 8, Issue 1 September 2015, Pages 1445-1453. https://doi.org/10.1016/j.jcin.2015.06.017
[13] Mejia-Renteria H, Lee JM, Choi K-H. et al.
Coronary microcirculation assessment using functional angiography: development of a wire-free method applicable to conventional coronary angiograms.
Catheter Cardiovasc Interv 2021; 98(6):1027-1037; doi.org: 10.1002/ccd.29863
[14] Hara H, Serruys PW, O’Leary N. et al.
Angiography-derived physiology guidance vs usual care in an All-comers PCI population treated with the healing-targeted supreme stent and Ticagrelor monotherapy: PIONEER IV trial design.
Am Heart J 2022; 246: 32-43; doi.org/10.1016/j.ahj.2021.12.018
[15] Kageyama S, O’Leary N, Revaiah PC. et al.
Quantitative flow ratio for the prediction of coronary events after percutaneous coronary intervention.
Eurointervention 2024; 20: 104-106; doi.org/10.4244/EIJ-D-23-00561; A research Correspondence.
