Diagnostic Performance of QFR for the Evaluation of IntermediateCoronary Artery Stenosis Confirmed by Fractional Flow Reserve

INTRODUCTION

Accurate evaluation of coronary artery disease, especially intermediate coronaryartery stenosis, is crucial for the evaluation of myocardial ischemia and nexttreatment. The gold standard for diagnosis and confirmation of functionalsignificance of a stenosis is the fractional flow reserve (FFR). Previous studieshave demonstrated that FFR-guided coronary revascularization increases the ratio ofevent-free survival when compared with a coronary stenosis-guidedstrategy^[1,2]. Despite these advantages, the clinical applicationof FFR has been variable and slow^[3]. FFR requires not only the hyperemic state, but also additionalcost, time, and efforts.

Quantitative flow ratio (QFR) is a novel method enabling efficient computation of FFRfrom three-dimensional quantitative coronary angiography (3D QCA) and thrombolysisin myocardial infarction (TIMI) frame counting^[4]. Compared with FFR, QFR does not require any invasivephysiological measurements, pharmacological hyperemia induction, and additionalcost. The recently FAVOR (Functional Diagnostic Accuracy of Quantitative Flow Ratioin Online Assessment of Coronary Stenosis) II China study showed solid results forQFR computation in identifying the presence of functionally significant stenosis ineligible patients^[5]. Severalstudies have been published in the literature addressing the correlation between theassessment of functionally significant stenosis obtained by QFR versus FFR andaddressing the diagnostic accuracy of QFR for intermediate coronary arterystenosis^[5,6]. The purpose of our study was to perform asystematic review and quantitative meta-analysis of the literature to determine thecorrelation between the diagnosis of functionally significant stenosis obtained byQFR versus FFR, and to determine the diagnostic accuracy of QFR for intermediatecoronary artery stenosis.

METHODS

This protocol is reported following the Preferred Reporting Items for SystematicReview and Meta-Analysis Protocols (PRISMA) guidelines^[7]. We searched PubMed, Embase, and Web of Sciencepublished before March 15, 2018. The keywords used for search were "QFR orQuantitative flow ratio". Results were limited to trials published in English. Wemanually searched reference lists of relevant studies and reviews, editorials, andletters to identify further articles. We used Endnote (Thompson ISI ResearchSoft,Philadelphia, USA) to manage relevant articles and remove duplicated articles.

RESULTS

Study Selection and Characteristics

The flowchart of our search and selection process was presented in Figure 1. Our combined search strategyidentified possible relevant studies. Nine studies were retrieved for a moredetailed evaluation. Finally, 9 studies consisting of 1175 vessels in 1047patients met our inclusion criteria^[4-6),(9-15]. Characteristics of includedstudies were shown in Table 1. Clinicalheterogeneity was mostly due to different inclusion criteria.Mejia-Renteria^[9] andEmori^[13] includedpatients with myocardial infarction. Emori^[13] included two different populations: patients withprevious myocardial infarction (MI) and patients without previous MI.Spitaleri^[12] includedpatients with ST- elevation myocardial infarction (STEMI) and multivesseldisease. Four studies were performed in Japan, two in China, one each in Spain,Italy, and Netherlands. The mean (SD) age was 63.2 years, and 68.1% of thepatients were male. The quality assessment of included studies according toQUADAS-2 was presented in Supplementary Figure1. In general, there was low risk of bias and low concern regardingapplicability of all included studies.

Fig. 1

Flowchart for the identification of studies.

Table 1

Characteristics of included studies.

Study	Design	Country	Mean age (years)	Males (%)	Patients' characteristics	Cutoff
Emori et al.[15]	Multicenter	Japan	-	-	Intermediate stenosis with FFR	0.8
Xu et al.[5]	Prospective, multicenter	China	61	73.7	Intermediate stenosis with FFR	0.8
Yazaki et al.[6]	Retrospective, single-center	Japan	72.5	29.6	Intermediate stenosis with FFR	0.8
Emori et al.[13] MI*	Retrospective, single-center	Japan	69	83	Patients with previous MI undergoing CAG andFFR	0.8
Emori et al.[13] non-MI*	Retrospective, single-center	Japan	70	54	Intermediate stenosis with FFR	0.8
Tu et al.[4]	Prospective, multicenter	China	65.8	61	Intermediate stenosis with FFR	0.8
Kameyama et al.[11]	Multicenter	Japan	-	-	ACS patients with CAG and FFR	0.8
van Rosendael et al.[10]	Prospective, single-center	Netherlands	64	71	Intermediate stenosis with FFR	0.8
Mejia-Renteria et al.[9]	Multicenter	Spain	-	-	Patients with CAG and FFR	0.8
Spitaleri et al.[12]	Prospective, multicenter	Italy	62	28	STEMI patients with MVD and FFR	0.8
Spitaleri et al.[12]	Prospective, multicenter	Denmark	61	67	Intermediate stenosis with FFR	0.8

*Emori 2018 contained two groups: patients with previous myocardialinfarction (MI) and patients with no previous MI.

ACS=acute coronary syndrome; CAG=coronary angiography; FFR=fractionalflow reserve; MVD=multivessel disease; STEMI=ST-elevation myocardialinfarction

Diagnostic Accuracy of QFR

The results of the included study were presented in Table 2. The accuracy ranged from 80% in Kameyama^[11] and 94% in Spitaleri, etal.^[12]. Sensitivityranged between 74% in Tu, et al.^[4] and 100% in van Rosendael, et al.^[10] and the specificity rangedfrom 79% in Emori, et al.^[15]to 97% in Spitaleri, et al.^[12]. The correlation between QFR and FFR ranged from r = 0.69to r = 0.94.

Table 2

Results of included studies in these meta-analyses.

Study	Included vessels (n)	Sensitivity (%)	Specificity (%)	Accuracy (%)	Correlation (r)
Emori et al.[15]	73	82	79	81	0.69
Xu et al.[5]	328	94.6	91.7	92.7	0.86
Yazaki et al.[6]	151	88.7	89.1	88.7	0.84
Emori et al.[13] MI	75	92	82	87	0.88
Emori et al.[13] non-MI	75	95	88	92	0.94
Tu et al.[4]	84	74	91	86	0.77
Kameyama et al.[11]	25	80	80	80	0.63
van Rosendael et al.[10]	15	100	79	80	0.78
Mejia-Renteria et al.[9]	300	88	86	87	-
Spitaleri et al.[12]	49	88	97	94	0.90

MI=myocardial infarction

In pooled data weighted by the number of vessels, QFR had a combined sensitivityand the specificity of QFR for diagnosis of functional significance of astenosis according to FFR were 0.89 (95% CI: 0.86-0.92) and 0.88 (95% CI:0.86-0.91), respectively, using a random effects model (Figure 2). No heterogeneity was found for both sensitivity(I²=38.3%, P=0.10) and specificity(I²=24.1%, P=0.22). The pooled estimate ofpositive likelihood ratio (LR+) and negative likelihood ratio (LR-) was 6.86(95% CI: 5.22-9.02) and 0.14 (95% CI: 0.10-0.21) (Figure 3). For QFR, Spearman's correlation coefficients were 0.619(P=0.102), indicating that the diagnostic threshold effectdid not exist in QFR data. The area under the ROC curve was 0.94 (Figure 4) and the diagnostic OR was 53.05(95% CI: 29.75-94.58) (Supplementary Figure2).

Fig. 2

Forest plot of the sensitivity and specificity of included study,summary sensitivity and specificity and I2 statistic forheterogeneity.

Fig. 3

Forest plot of LR+ and LR- of included study, summary sensitivity andspecificity, and I2 statistic for heterogeneity.

Fig. 4

Summary receiver operating characteristic (sROC) curve for QFR.

DISCUSSION

In the present study, we performed a systematic review of the diagnostic performanceof QFR for functional significance of intermediate coronary artery stenosis comparedwith invasive FFR. Data from 1175 vessels in 1047 patients showed the situation inwhich QFR is helpful for surgeons to determine whether stents should be implanted atno additional cost, time, and effort. Our study is the first systemic review andmeta-analysis that evaluates the diagnostic accuracy of QFR for the assessment offunctionally significant stenosis confirmed by FFR.

FFR-guided percutaneous coronary intervention (PCI) is associated with a betteroutcome compared with revascularization based on angiographic stenosis severityalone in patients with intermediate coronary artery stenosis^[2,16,17]. FFR has thehighest recommendation (class I, level A) in the European Society of Cardiologyguideline on myocardial revascularization^[18]. Although FFR has better outcomes in patients withintermediate coronary artery stenosis, the clinical application has been limited dueto the invasive procedure with a pressure wire, the cost of pressure wire, and theside effects associated with induction of hyperemia. QFR, an angiographic index ofcoronary stenosis severity based on 3D QCA and thrombolysis in myocardial infarction(TIMI) frame counting, estimates FFR without invasive procedure^[4]. FAVOR Pilot Study and FAVOR IIChina study have shown good agreement of QFR with invasive FFR^[4,5]. However, the simple size was too small. Our meta-analysisincluded^[9] studies ofwhich the majority were performed in China and Japan from 2016 to 2018, with a totalof 1175 vessels in 1047patients, and demonstrated that the diagnostic accuracy ofQFR for functionally significant stenosis confirmed by FFR was high, with a summarysensitivity and specificity of 0.89 (95% CI: 0.86-0.92) and 0.88 (95% CI:0.86-0.91), respectively.

Our studies included different study populations (stable coronary artery disease,suspected coronary artery disease, STEMI, previous MI). However, our meta-regressionshowed that different study populations did not affect our diagnostic accuracy. QFRwas more often used in patients with stable coronary artery disease. A recent studyhas found that QFR may be a safe and reliable tool to guide revascularization inpatients with STEMI and multivessel disease. Furthermore, Spitaleri found thatfunctional complete revascularization evaluated by QFR showed a good 5-yearoutcome^[12].

However, the diagnostic accuracy of QFR for assessing the functional severity ofcoronary stenosis might be affected in coronary arteries related to previousMI^[13]. Microcirculatoryresistance may affect this phenomenon. Mejia-Renteria, et al. found that thediagnostic accuracy of QFR was lower in patients with high microcirculatoryresistance, which is supported by our subgroup analysis. Due to its specificalgorithm based on QCA and TIMI frame counting, coronary collateral circulation mayreduce its accuracy. Therefore, corrective measures need to be developed to improvethe diagnostic accuracy in patients with previous MI or high microcirculatoryresistance. Furthermore, coronary calcification or thrombus may lead to angiographichaziness which undoubtedly reduces the diagnostic accuracy of QFR. A hybrid QFR-FFRapproach may be a way to overcome these limitations. Yazaki, et al.^[6] found that FFR should be performedin stenosis with QFR 0.75-0.85. This hybrid approach may allow clinicians to get thebest of both worlds by ensuring diagnostic accuracy while reducing cost and sideeffects.

It should be noted that our conclusion should be seen in the context of itslimitation. First, the simple size is relatively small. Second, although there wasno apparent heterogeneity in statistics, the heterogeneity in clinical andmethodology was inevitable.

CONCLUSION

QFR is a simple, useful, and noninvasive modality for the diagnosis of functionalsignificance of intermediate coronary artery stenosis.