Introduction
Fractional flow reserve (FFR) is the gold standard for the functional assessment of the severity of coronary artery stenosis.1 FFR-guided percutaneous coronary intervention (PCI) has been shown to be superior to angiography guided.2–4 A number of guidelines have recommended revascularisation guided by FFR.1 5 However, FFR measurement requires the administration of vasodilators to induce maximum hyperaemia, which has drawbacks such as prolonged procedure time, drug side effects and patient discomfort. As a result, its clinical utilisation rate is low (6%–8%).6 In recent years, non-hyperaemic pressure ratios (NHPRs) that do not require the induction of maximum hyperaemia, such as instantaneous wave-free ratio (iFR) and diastolic pressure ratio, have shown unique advantages in the functional assessment of coronary arteries. Previous studies have shown that iFR-guided revascularisation strategies are not inferior to FFR-guided revascularisation in terms of 1-year clinical outcomes.4 7 Resting full-cycle ratio (RFR) is a novel NHPR, used to identify the lowest value of the ratio of distal coronary artery pressure (Pd) to aortic pressure (Pa) over five consecutive complete heart cycles. RFR is comparable to iFR in terms of diagnostic efficacy.8 In fact, measuring only the diastolic phase in resting functional algorithms may miss the systolic phase. Therefore, compared with iFR which only measures the diastolic phase, measuring the entire cardiac cycle with RFR may have a greater clinical significance. Multiple international studies have demonstrated a high level of consistency between RFR and FFR.9–12 However, there is currently limited research on the relationship between RFR and FFR in Chinese patients with non-ST-segment elevation acute coronary syndrome (NSTE-ACS). This study aims to investigate the correlation and consistency between RFR and FFR in the functional assessment of coronary arteries in Chinese patients with NSTE-ACS.
Methods
Study subjects
A total of 239 Chinese patients (308 diseased vessels) with NSTE-ACS who underwent coronary artery angiography and invasive coronary artery functional assessment at Cangzhou Central Hospital of Hebei Medical University from September 2021 to June 2023 were included. Inclusion criteria were as follows: (1) age ≥18 years; (2) diagnosed with NSTE-ACS; (3) coronary angiography (CAG) indicating stenosis severity between 30% and 90% and (4) consent to undergo invasive coronary functional assessment. Exclusion criteria were as follows: (1) the presence of severe bronchial asthma or inability to tolerate vasodilators such as adenosine; (2) second-degree or higher-degree atrioventricular block; (3) cardiogenic shock and (4) lack of simultaneous measurement of RFR and FFR or data drift. 12 patients (15 lesion vessels) who were not evaluated for RFR and 1 patient (1 lesion vessel) with data drift in FFR were excluded. Finally, a total of 226 patients (292 vessels) were included in this study.
Functional assessment of coronary artery
All functional assessments were performed after CAG. After CAG, two experienced interventional cardiologists at the centre determined whether the invasive functional assessment was necessary based on the CAG results and the patient’s clinical condition. Before the functional assessment, 200 µg of nitroglycerin was routinely administered intracoronary to prevent coronary artery spasm, and a PressureWireTMx0.014 pressure guidewire (Abbott Vascular, Santa Clara, California, USA) was delivered to the distal part of the lesion. First, the RFR and resting Pd/Pa values were measured in a non-hyperaemic state, and then ATP disodium injection was administered through the median elbow vein at a rate of 167 µg/kg/min to achieve the maximal hyperaemia state and the FFR values were measured. In the expert consensus related to FFR in China, the intravenous dose is recommended as 140–180 µg/(kg×min), with a configuration of 1 mg/mL. The infusion rate calculation formula is infusion rate (mL/hour)=weight (kg)×8.4 (or ×10.8). For the convenience of clinical operation, the infusion rate can be directly calculated by multiplying 10 by the kg of body weight, which is simple in calculation and the dose is approximately equal to 167 µg/(kg×min). When the FFR value is at the critical value, there is no need to increase the dose for secondary measurement.13
Statistical analysis
Kolmogorov-Smirnov normality test was performed for continuous variables, and variables conforming to normal distribution were expressed as mean±SD while the variables not normally distributed were expressed as median and IQR; categorical variables were expressed as frequency (percentage). The correlation between RFR and FFR, resting Pd/Pa and FFR were analysed by using Person correlation, and the consistency between RFR and FFR, resting Pd/Pa and FFR were assessed by Bland-Altman test. The diagnostic values of RFR and resting Pd/Pa for predicting FFR≤0.80 were evaluated according to the receiver operating characteristic (ROC) curves. Bilateral p<0.05 was considered statistically significant. All data were assessed statistically by SPSS V.25.0.
Patient and public involvement
Patients and/or the public were not involved in the design, or conduct, or reporting or dissemination plans of this research.
Results
Baseline clinical characteristics and angiographic features
The study included 226 patients with a median age of 62.6 (56.0–69.0) years. Among them, 41.6% were female, 5.8% had NSTE myocardial infarction (NSTEMI), and 58.8%, 24.8% and 12.8% had hypertension, diabetes and a history of smoking, respectively. The median body mass index was 25.4 (23.5–27.4 kg/m2). The median values of FFR, RFR and resting Pd/Pa were 0.83 (0.76–0.90), 0.91 (0.88–0.95) and 0.94 (0.92–0.98), respectively. Among the 292 diseased vessels, 89.0% of lesions had a stenosis severity of ≥70%, 62.3% of lesions were located in the left anterior descending (LAD), and 32.5% of lesions underwent interventional therapy (table 1).
Baseline and physiological characteristics
Correlation and consistency analysis of RFR, resting Pd/Pa and FFR
The distribution of RFR, resting Pd/Pa and FFR values is shown in figure 1. The correlation coefficients of RFR with FFR and resting Pd/Pa with FFR were 0.787 and 0.765, which showed a significant correlation (p<0.001) (figure 2). Bland-Altman analysis showed mean (SD) differences of RFR and FFR, resting Pd/Pa and FFR were 0.088 (0.116) (95% limits of agreement: −0.03 to 0.20) and 0.117 (0.124) (95% limits of agreement: −0.01 to 0.24), respectively. Bland-Altman analysis demonstrated no significant differences between RFR and FFR, as well as between resting Pd/Pa and FFR, indicating good consistency between RFR, resting Pd/Pa and FFR (figure 3).
Histograms of the distribution of RFR, resting Pd/Pa and FFR values. (A) RFR; (B) resting Pd/Pa; (C) FFR. FFR, fractional flow reserve; Pa, aortic pressure; Pd, distal coronary pressure; RFR, resting full-cycle ratio.
Correlation between RFR, resting Pd/Pa and FFR. (A) RFR versus FFR (r=0.787, p<0.001); (B) resting Pd/Pa versus FFR (r=0.765, p<0.001). FFR, fractional flow reserve; Pa, aortic pressure; Pd, distal coronary pressure; RFR, resting full-cycle ratio.
Bland-Altman plots of differences against the means are displayed for RFR and resting Pd/Pa. (A) RFR; (B) resting Pd/Pa. The Bland-Altman plots demonstrate a good agreement between RFR, resting Pd/Pa and FFR. FFR, fractional flow reserve; Pa, aortic pressure; Pd, distal coronary pressure; RFR, resting full-cycle ratio.
Diagnostic performance of RFR and resting Pd/Pa for predicting FFR≤0.80
Using FFR≤0.80 as the gold standard for determining coronary artery functional ischaemia, the areas under the ROC curves for predicting FFR≤0.80 were 0.883 (95% CI 0.840 to 0.917, p<0.001) for RFR and 0.858 (95% CI 0.813 to 0.896, p<0.001) for resting Pd/Pa. The optimal cut-off values were 0.91 for RFR and 0.93 for resting Pd/Pa, respectively. There was no statistically significant difference in the areas under the ROC curves between RFR and resting Pd/Pa (p=0.106) (figure 4). The accuracy, sensitivity, specificity, positive predictive value, negative predictive value, positive likelihood ratio and negative likelihood ratio of RFR≤0.91 for predicting FFR≤0.80 were 79.1%, 84.0%, 76.6%, 65.1%, 90.2%, 3.58 and 0.21, respectively. The accuracy, sensitivity, specificity, positive predictive value, negative predictive value, positive likelihood ratio and negative likelihood ratio of resting Pd/Pa≤0.93 for predicting FFR≤0.80 were 78.4%, 74.0%, 80.7%, 66.7%, 85.6%, 3.84 and 0.32, respectively.
Receiver operating characteristic (ROC) curves. The areas under the ROC curves for predicting FFR≤0.80 were 0.883 (p<0.001) for RFR and 0.858 (p<0.001) for resting Pd/Pa, with optimal cut-off values of 0.91 and 0.93, respectively. FFR, fractional flow reserve; Pa, aortic pressure; Pd, distal coronary pressure; RFR, resting full-cycle ratio.
Discussion
Ischaemic heart disease is one of the leading causes of cardiovascular disease morbidity and mortality worldwide.14 Current guidelines recommend functional assessment of coronary artery stenosis to guide more precise revascularisation strategies.1 5 FFR, defined as the ratio of the mean Pd to the Pa during maximal hyperaemia, is the gold standard for functional assessment of coronary artery stenosis.1 There is substantial evidence supporting the use of FFR-guided revascularisation strategies.15–17 However, FFR measurement requires the use of vasodilators, which can be invasive and have potential adverse effects and contraindications such as chest pain and discomfort. This limits the clinical utility of FFR, particularly in patients with asthma, arrhythmias and hypotension. NHPRs provide an alternative by allowing functional assessment without the need for vasodilators, thus avoiding related adverse effects and expanding the applicability of functional assessment to more patients. iFR, based on precise timing during diastole (‘wave-free’ period), is a representative NHPR. Studies have shown that an iFR-guided revascularisation strategy is non-inferior to FFR-guided revascularisation at 1-year clinical outcomes.18 19 RFR, a new NHPR, evaluates the minimum value of the ratio between the average pressure Pd stenosis and the average Pa during five consecutive complete cardiac cycles in a resting state. RFR has been shown to have a high correlation and consistency with iFR in diagnosing coronary artery functional stenosis.9 Compared with previous methods of coronary artery functional assessment, RFR not only avoids the use of vasodilators but also incorporates the measurement of systolic pressure, providing more accurate data by assessing coronary artery function throughout the cardiac cycle.
Several clinical studies have validated the correlation and consistency between RFR and FFR. A study from Germany, which included 617 patients with a total of 712 coronary artery lesions, demonstrated significant correlations between RFR and FFR, as well as between resting ratio of Pd/Pa and FFR, with correlation coefficients of 0.766 (p<0.01) and 0.792 (p<0.01), respectively, they also found a high diagnostic agreement between RFR and FFR at 78%, and the area under the ROC curve for RFR predicting FFR≤0.80 was 0.86.12 Goto et al11 compared RFR and FFR in a Japanese population, found a good correlation (r=0.774, p<0.001) and consistency between RFR and FFR.20 However, there are limited studies in Chinese patients. A recent study, which included 235 Chinese patients (277 diseased vessels), showed a good correlation between RFR and FFR (r=0.727, p<0.001) and a diagnostic agreement of 79.8%, the area under the ROC curve for RFR predicting FFR≤0.80 was 0.85.21 The results of our study showed a strong correlation between RFR and FFR (r=0.787, p<0.001), a diagnostic agreement of 80.8%, and the area under the ROC curve for RFR predicting FFR≤0.80 was 0.883, which is consistent with the results of previous studies.
In our study, we found that 89.0% of patients had diameter stenosis ≥70% while only 34.2% of lesions showed positive FFR, a notable contrast to the Fractional Flow Reserve Versus Angiography for Multivessel Evaluation (FAME) trial. Several factors could account for this variance. First, the estimation of lesion severity in our study relied on visual assessment, which may introduce variability across different medical centres, potentially leading to either overestimation or underestimation. Second, the functional significance of lesions is influenced not only by the degree of stenosis but also by factors such as the extent of myocardial blood supply affected by the diseased vessels, as well as the length and location of the lesions. Third, our findings regarding the proportion of lesions with positive FFR and those undergoing revascularisation were comparable to those reported in the multicentre real-world REsting Full-Cycle Ratio Comparation versus Fractional Flow Reserve study (32.5% vs 32.7%) and notably lower than the FAME trial (61%).22 We also recognised that a mere 32.5% of patients underwent PCI, potentially due to the enrolment of relatively stable ACS patients, specifically 94.2% with unstable angina (UA). This discrepancy may underscore the inherent differences between real-world studies and randomised controlled clinical trials.
It is worth noting that in this study, the optimal cut-off value of RFR for predicting FFR≤0.80 was 0.91, which is higher than the observed optimal cut-off value of RFR (0.89) in the VALIDATE RFR study and the study by Lee et al.8 23 Previous study has shown that lesion characteristics and the state of hyperaemia may affect the cut-off value, and differences in myocardial perfusion areas provided by the left main artery, the LAD artery and the non-LAD arteries (non-LAD) may contribute to the inconsistency between RFR and FFR.20 In this study, the majority of the diseased vessels were located in the LAD (62.3%), and there may be differences in myocardial perfusion areas due to the involvement of different vessel types, lesion locations and myocardial territories supplied. Furthermore, the vasodilator used in this study was ATP instead of adenosine, which is commonly used in other studies. This difference may affect myocardial perfusion and coronary artery capacity, thereby influencing the consistency between RFR and FFR. Finally, a previous study found that the consistency between RFR and FFR in patients with ACS was significantly lower than that in stable coronary artery disease patients (65.5% vs 85.7%, p=0.012), which may be related to the lower coronary artery flow reserve in patients with ACS.24 These factors contribute to the differences in the optimal cut-off values observed in different studies.
In this study, RFR showed close correlation, excellent consistency and similar diagnostic performance with FFR. These results suggest that RFR can be used as an invasive tool to guide revascularisation strategy. Although the diagnostic agreement between RFR and FFR reached 80.8%, there is still a 19.2% inconsistency in the diseased vessels. Therefore, further validations through larger-scale clinical studies are needed to determine the optimal cut-off value and clinical value of RFR.
Limitations
This study has several limitations. First, it is a study with a relatively small sample size (226 patients and 292 diseased vessels). Second, the majority of the diseased vessels in this study were located in the LAD (62.3%), and compared with the non-LAD, the LAD provides a larger myocardial perfusion area, which may contribute to the inconsistency between RFR and FFR. Moreover, our study encompassed only 13 (5.8%) patients diagnosed with NSTEMI. Reflecting on real-world scenarios, clinicians found it notably easier to pinpoint culprit lesions and target vessels by employing CAG alongside clinical indicators in NSTEMI patients. Such indicators comprised typical ischaemic symptoms, marked ECG alterations and more pronounced coronary artery stenosis in contrast to patients with UA. Consequently, this could diminish the need for functional assessment in NSTEMI patients. Due to the presence of bias between patients with NSTEMI who underwent invasive physiology and those who did not, the study findings cannot be generalised to the broader NSTEMI population. Lastly, the vasodilators used in this study were ATP instead of adenosine, which is commonly used in other studies. This difference may affect myocardial perfusion and coronary capacity, thereby influencing the agreement between RFR and FFR.
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