FAVOR III China: quantitative flow ratio-guided coronary intervention in practice 

Pressure wire-based physiological assessment with fractional flow reserve (FFR) and the instantaneous wave-free ratio (iFR) more accurately identifies flow-limiting lesions than angiographic assessment alone. As such, they are recommended by international guidelines to aid decisions on revascularization.^1,2 Incorporation of FFR data during lesion assessment alters revascularization decisions in the cardiac catheterization laboratory.³ Importantly, it may lead to improved prognosis in chronic⁴ and acute coronary syndromes.⁵

However, the adoption of invasive physiological measurements remains limited in clinical practice. This is partially driven by the need for coronary instrumentation, increased procedural time and cost. As such, there is increasing interest in non-invasive physiological measurements as an adjunct to angiography. In general, these techniques are calculated by computational modelling and flow dynamics based on the laws of Bernoulli and/or Poiseuille.⁶ Data can be acquired from either CT⁷ or invasive coronary angiography.⁸ Studies so far have shown reliable correlation between non-invasive indices and invasive FFR.⁶ In the FAST II study, Masdjedi et al.⁸ demonstrated a 81% sensitivity and 95% specificity of quantitative coronary angiography-based vessel FFR in identifying an invasive FFR ≤ 0.80. Akin to many other non-invasive indices, the upload and analysis of angiographic data using a central core-lab have thus far limited its real-time utility in clinical practice. Morris et al.⁶ provided a summary of recent angiography-based physiological assessment techniques, along with their potential pitfalls.

Within this context, Xu et al.⁹ provide new data from the FAVOR III China trial, which sought to determine whether the peri-procedural use of quantitative flow ratio (QFR) to guide lesion selection for percutaneous coronary intervention (PCI) might improve clinical outcomes, compared with angiography-guidance alone. This investigator-initiated, multicentre, blinded, randomized, sham-controlled trial enrolled 3847 patients from 26 centres in China between 25/12/2018 and 19/01/2020. Patients aged ≥18 years with chronic coronary syndromes or myocardial infarction ≥72 h before screening, who had ≥1 lesion with diameter stenosis 50–90% in a coronary artery ≥2.5 mm reference diameter were eligible. The main exclusion criteria were moderate or severe chronic kidney disease (defined as creatinine >150 μmol/L or estimated glomerular filtration rate <45 mL/kg/173 m²), severe vessel tortuosity, vessel overlap, or suboptimal angiographic images for QFR determination. n = 22 patients elected to not undergo PCI, or were withdrawn by the treating physicians.

The final cohort of n = 3825 was randomized 1:1 to either the QFR-guided (n = 1913) or the angiography-guided (n = 1912) group. The baseline characteristics were well-balanced between groups, with a mean age of 62.7 years, 70.6% men, and 33.9% with diabetes mellitus. The proportion of vessels with QFR ≤ 0.80 was similar between groups, as was the post-PCI minimum luminal diameters of treated vessels in both groups. Post-procedural optimal medical therapy was also comparable, with no significant difference in the prescription of statins, beta-blockers, or angiotensin–aldosterone system blockers.

A 10-min blinding window was built into the protocol workflow for both groups, to allow sufficient time for data transfer and analysis in the QFR-guided arm. The primary endpoint was the 1-year rate of major adverse cardiac events, defined as the composite of death from any cause, myocardial infarction, or ischaemia-driven revascularization.

In the QFR-guided group, QFR was derived during the procedure for all coronary arteries >2.5 mm reference diameter with visually assessed diameter stenosis of 50–90%. The assessment was based on at least two angiographic projections >25° apart. Electronic image transmission to the AngioPlus system reportedly took 2–3 min, with a further analysis time of typically <5 min. This total was well within the 10-min blinding window period. 3D reconstruction algorithms reconstructed the target vessel and generated a ‘pullback’ curve, with QFR values available at each position of the target vessel. PCI was performed if the QFR ≤ 0.80, or deferred if higher. Of note, PCI was also performed if the visually assessed stenosis was >90%. Conversely, if no lesions were >90% and all QFR values were >0.80, the patient was treated with medical therapy alone. Ultimately, PCI was undertaken in 90.5% of patients in the QFR-guided group.

In the angiography-guided group, PCI was performed based on visual assessment alone, according to local practice. Importantly, invasive physiological assessment (i.e. FFR) was not allowed in either group.

Accordingly, a greater proportion of lesions with QFR ≤ 0.80 was treated in the QFR-guided group than in the angiography-guided group [1990 (96.7%) of 2058 lesions vs. 1843 (91.1%) of 2023 lesions]. The proportion of patients achieving complete functional revascularization (no residual ischaemia according to post-PCI QFR assessment) was also higher in the QFR-guided group [1669 (88.1%) of 1894 vs. 1552 (82.2%) of 1887 patients].

At 1-year follow-up, the primary endpoint MACE occurred in 110 (5.8%) of the QFR-guided group, vs. in 167 (8.8%) of the angiography-guided group; HR 0.65 (95%CI 0.51–0.83; P = 0.0004). This was driven by lower rates of myocardial infarction [65 (3.4%) of 1913 in the QFR group vs. 109 (5.7%) of 1912 in the angiography group] and ischaemia-driven revascularization [38 (2.0%) vs. 59 (3.1%)] in the QFR-guided group. There was no difference in mortality.

The blinding procedure in this study is worth acknowledging. Music playing headphones were applied to all patients for the 10-min blinding window. Patients and all post-catheterization physicians and researchers were masked to randomization group allocation. Clinicians involved in the PCI procedure did not take part in clinical follow-up. Blinding questionnaires were also administered to patients at 6- and 12-months.

When considering this study in clinical practice, we should recognize the mixed clinical presentations amongst participants. 63.5% presented with acute coronary syndromes, which limits comparison with the FAME II study⁴. Furthermore, up to 10% of patients were asymptomatic ischaemia presentations. Regardless, these results draw some parallels with the FAMOUS-NSTEMI cohort.⁵

This is the first large, multicentre study demonstrating the utility of peri-procedural non-invasive physiology assessment in guiding revascularization. For single vessel disease, FFR assessment may still be more time efficient. However, the strength of QFR lies is its capacity for simultaneous multi-vessel assessment without the need for multi-coronary instrumentation.

The main limitations of QFR are inherent to all non-invasive indices. Even if 100% correlation with FFR was achieved, we would still need to contend with the challenges of decision making in the ‘grey-zone’ FFR of 0.75–0.80. Angiography-derived indices are also limited in cases with suboptimal image quality, or severe overlap and tortuosity of the interrogated vessels.

In conclusion, this study represents a step forward for non-invasive physiological assessments and their applicability in real-time. Future work should focus on longer-term follow-up and head-to-head comparisons of non-invasive vs. invasive physiology-guided revascularization.

Funding

C.B. receives research funding from the British Heart Foundation grant (RE/18/6134217), Chief Scientist Office, EPSRC (EP/R511705/1, EP/S030875/1), European Union (754946-2), Medical Research Council (MR/S018905/1), and UKRI (MC/PC/20014).

Data Availability

Data sharing not applicable to this article as no datasets were generated or analysed for this editorial.

References

Authors

Biography: Professor Colin Berry holds a Chair in Cardiology and Imaging in the University of Glasgow. He is Director of Research in the Golden Jubilee National Hospital and a Consultant Cardiologist in this hospital and in the Queen Elizabeth University Hospital in Glasgow. Professor Berry is currently an Executive Editor of the European Heart Journal, Senior Consultant Editor of EuroIntervention, and Editorial Board member of the Cardiovascular Research journal. He is President-Elect of the British Society of Cardiovascular Magnetic Resonance, Research Lead and Board Member of the British Cardiovascular Intervention Society, and Past-Chair of the British Society of Cardiovascular Research and the Clinical Trials Committee of the Society of Cardiovascular Magnetic Resonance. Professor Berry undertook undergraduate medical studies at the University of Glasgow (1987–1993) and completed an intercalated science degree (Maîtrise, Physiology) at the University of Paris (1989–1990). He was awarded a PhD at the University of Glasgow (2002) in Cardiovascular Science and his studies were supported by a Medical Research Council Clinical Training Fellowship. He then undertook post-doctoral studies (2007–2009) in advanced cardiovascular imaging in Andrew Arai’s group at the National Heart, Lung and Blood Institute, US National Institutes of Health, Bethesda, MD. This appointment was supported by a Lord Kelvin Adam Smith Fellowship from the University of Glasgow. In 2014, Professor Berry was awarded the Marshall Research Excellence Prize from the British Society of Cardiovascular Research. His research has won multiple awards at national and international conferences.

Biography: Dr Ang undertook undergraduate medical studies at the University of Edinburgh, graduating with an MBChB in 2013. He is a Cardiology Specialist Registrar from the West of Scotland Deanery with a subspecialty interest in interventional cardiology. He is currently a Clinical Research Fellow at the Institute of Cardiovascular and Medical Sciences at the University of Glasgow. He is undertaking a PhD under the supervision of Professor Colin Berry and Professor Alex McConnachie. The International study of Coronary Microvascular Angina (iCorMicA) is a randomized, double-blind, parallel group trial, and registry examining the benefit of invasive microvascular function testing on the management of patients with angina. Dr Ang has accrued research experience since his undergraduate years and won a number of awards for his work, including the national Fitzgerald Peel prize in 2014. He has also served as sub-investigator for a number of trials including CISCO-19, EURO-ICE, and the COR-family of studies at the Golden Jubilee National Hospital.

Author notes