Diagnostic Performance of QFR for the Evaluation of IntermediateCoronary Artery Stenosis Confirmed by Fractional Flow Reserve
Abstract
Introduction
Quantitative flow ratio (QFR) is a novel method enabling efficientcomputation of FFR from three-dimensional quantitative coronary angiography(3D QCA) and thrombolysis in myocardial infarction (TIMI) frame counting. Wedecided to perform a systematic review and quantitative meta-analysis of theliterature to determine the correlation between the diagnosis offunctionally significant stenosis obtained by QFR versus FFR and todetermine the diagnostic accuracy of QFR for intermediate coronary arterystenosis.
Methods
We searched PubMed, Embase, and Web of Science for studies concerning thediagnostic performance of QFR. Our meta-analysis was performed using theDerSimonian and Laird random effects model to determine sensitivity,specificity, positive likelihood ratio (LR+), negative likelihood ratio(LR-), and diagnostic odds ratio (DOR). The sROC was used to determinediagnostic test accuracy.
Results
Nine studies consisting of 1175 vessels in 1047 patients were included in ourstudy. The pooled sensitivity, specificity, LR+, LR-, and DOR for QFR were0.89 (95% CI: 0.86-0.92), 0.88 (95% CI: 0.86-0.91), 6.86 (95% CI,:5.22-9.02), 0.14 (95% CI: 0.10-0.21), and 53.05 (95% CI: 29.75-94.58),respectively. The area under the summary receiver operating characteristic(sROC) curve for QFR was 0.94.
Conclusion
QFR is a simple, useful, and noninvasive modality for diagnosis of functionalsignificance of intermediate coronary artery stenosis.
Abbreviations,acronyms & symbols | ||||
---|---|---|---|---|
3D | = Three-dimensional | LR+ | = Positive likelihoodratio | |
3D QCA | = Three-dimensionalquantitative coronary angiography | LR | = Negative likelihoodratio | |
AUC | = Area under thecurve | OR | = Odds ratio | |
CI | = Confidence interval | MI | = Myocardialinfarction | |
DOR | = Diagnostic oddsratio | PCI | = Percutaneous coronaryintervention | |
EAPCI | = European Association ofPercutaneous Cardiovascular Interventions | PRISMA | = Preferred ReportingItems for Systematic Review and Meta-Analysis Protocols | |
ESC | = European Society ofCardiology | QFR | = Quantitative flowratio | |
FFR | = Fractional flowreserve | QUADAS-2 | = Quality Assessment ofDiagnostic Accuracy Studies 2 | |
FP | = False positive | sROC | = Summary receiveroperating characteristic | |
FAVOR | = Functional DiagnosticAccuracy of Quantitative Flow Ratio in Online Assessment of CoronaryStenosis study | STEMI | = ST-elevation myocardialinfarction | |
FN | = False negative | TIMI | = Thrombolysis inmyocardial infarction | |
LR | = Likelihood ratio | TN | = True negative | |
TP | = True positive |
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.
Study Eligibility
The inclusion criteria for studies in the analysis were as follows: 1) The designwas a diagnostic accuracy study; 2) The study assess the diagnostic performanceof QFR compared with invasive FFR as the standard procedure; 3) Data from truepositive (TP), false positive (FP), true negative (TN), false negative (FN),sensitivity and specificity can be retrieved or calculated. When relevant datawere missing, authors were contacted by e-mail, before excluding the study dueto inaccessibility of data.
Data Collection and Quality Assessment
Relevant data were initially extracted by two independent reviewers (Zh Xing andJy Pei). Disagreements were resolved by consensus or by a third investigator (XQHu). We abstracted the following data from the selected articles: first author,publication date, study design, patient demographics; FFR threshold used todescribe ischemia; and the data of TP, FP, TN, and FN. When different flowmodels of QFR were performed, contrast-flow QFR was preferred. Contrast-flow QFRwas more accurate for predicting FFR ≤0.80 as compared with fixed-flowQFR[4]. Includedstudies were analyzed by the Quality Assessment of Diagnostic Accuracy Studies 2(QUADAS-2)[8].
Data Analysis
The inter-reviewer agreement regarding the quality assessment of included studieswas assessed by the Cohen kappa test. Our meta-analysis was performed using theDerSimonian and Laird random effects model to determine sensitivity,specificity, positive likelihood ratio (LR+), negative likelihood ratio (LR),and diagnostic odds ratio (DOR). The sROC was used to determine diagnostic testaccuracy. An area under the curve (AUC) between 0.75 and 0.92 represented a highdegree of diagnostic accuracy, and an AUC between 0.93 and 0.96 was consideredmore accurate. In order to assess heterogeneity among the studies,the[2] statistic wasused. For[2], a value >50%was considered of severe heterogeneity. The Spearman correlation coefficient wascalculated to evaluate diagnostic threshold variation among the includedstudies.
We also performed a meta-regression analysis to identify predefined potentialsources of heterogeneity. All statistical analyses were completed usingMeta-DiSc (version 1.4).
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.
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.
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.
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 |
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).
Meta-regression Analysis and Subgroup Analysis
Meta-regression was performed using the potential sources of heterogeneity amongstudies (age, country, sex, different inclusion criteria). We found no factoreffecting the diagnostic accuracy.
Emori, et al.[13] andMejia-Renteria, et al.[9]included patients with previous MI that might affect the diagnostic accuracy.Exclusion of these two trials slightly improved the specificity (0.90,0.87-0.92), but did not affect sensitivity.
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.
ZX | Designed the study and provided methodologicalexpertise; final approval of the version to be published |
JP | Drafted the manuscript; final approval of the versionto be published |
JH | Drafted the manuscript; final approval of the versionto be published |
XH | Drafted the tables and figures; final approval of theversion to be published |
SG | Designed the study and provided methodologicalexpertise; final approval of the version to be published |
Footnotes
References
- 1. Fractional flow reserve versus angiography for guidance of PCI inpatients with multivessel coronary artery disease (FAME): 5-year follow-upof a randomised controlled trialLancet
07 11 20153861000618531860[PubMed][Google Scholar] - 2. Fractional flow reserve-guided PCI versus medical therapy instable coronary diseaseN Engl J Med
13 9 2012367119911001Epub 2012 Aug 27. Erratum in: N Engl J Med. 2012 Nov;367(18):1768.Mobius-Winckler, Sven [corrected to Möbius-Winkler, Sven].[PubMed][Google Scholar] - 3. Contemporary patterns of fractional flow reserve andintravascular ultrasound use among patients undergoing percutaneous coronaryintervention in the United States: insights from the National CardiovascularData RegistryJ Am Coll Cardiol
04 12 2012602223372339[PubMed][Google Scholar] - 4. Diagnostic Accuracy of Fast Computational Approaches to DeriveFractional Flow Reserve From Diagnostic Coronary Angiography: TheInternational Multicenter FAVOR Pilot StudyJACC Cardiovasc Interv
10 10 201691920242035[PubMed][Google Scholar] - 5. Diagnostic Accuracy of Angiography-Based Quantitative Flow RatioMeasurements for Online Assessment of Coronary StenosisJ Am Coll Cardiol
26 12 2017702530773087[PubMed][Google Scholar] - 6. Applicability of 3-Dimensional Quantitative CoronaryAngiography-Derived Computed Fractional Flow Reserve for IntermediateCoronary StenosisCirc J
23 6 2017817988992[PubMed][Google Scholar] - 7. The PRISMA statement for reporting systematic reviews andmeta-analyses of studies that evaluate healthcare interventions: explanationand elaborationBMJ
21 7 2009339b2700b2700[PubMed][Google Scholar] - 8. The development of QUADAS: a tool for the quality assessment ofstudies of diagnostic accuracy included in systematicreviewsBMC Med Res Methodol
10 11 200332525[PubMed][Google Scholar] - 9. TCT-70 Influence of microcirculatory resistance on the assessmentof coronary stenosis severity with Quantitative Flow Ratio (QFR): Results ofan international multicentre studyJ Am Coll Cardiol20177018
Suppl B B30B31[PubMed][Google Scholar] - 10. Accuracy and reproducibility of fast fractional flow reservecomputation from invasive coronary angiographyInt J Cardiovasc Imaging
9 201733913051312[PubMed][Google Scholar] - 11. TCT-542 Usefulness of QFR measurement for non-culprit lesion ofACS patientsJ Am Coll Cardiol20166818
Suppl B B219B219[PubMed][Google Scholar] - 12. Quantitative Flow Ratio Identifies Nonculprit Coronary LesionsRequiring Revascularization in Patients With ST-Segment-Elevation MyocardialInfarction and Multivessel DiseaseCirc Cardiovasc Interv
2 2018112e006023 [PubMed][Google Scholar] - 13. Diagnostic Accuracy of Quantitative Flow Ratio for AssessingMyocardial Ischemia in Prior Myocardial InfarctionCirc J
23 2 2018823807814[PubMed][Google Scholar] - 14. TCT-522 The Independence of Coronary Microvascular Dysfunctionfrom Epicardial Disease Severity: Three-Vessel Invasive Coronary PhysiologicStudyJ Am Coll Cardiol201618Suppl BB210B211[PubMed][Google Scholar]
- 15. TCT-529 The correlation between Quantitative Flow Ratio (QFR) andFractional Flow Reserve (FFR)J Am Coll Cardiol20166818 Suppl BB213B214[PubMed][Google Scholar]
- 16. Angiographic versus functional severity of coronary arterystenoses in the FAME study fractional flow reserve versus angiography inmultivessel evaluationJ Am Coll Cardiol
22 6 2010552528162821[PubMed][Google Scholar] - 17. Percutaneous coronary intervention of functionally nonsignificantstenosis: 5-year follow-up of the DEFER StudyJ Am Coll Cardiol
29 5 2007492121052111[PubMed][Google Scholar] - 18. Authors/Task Force members2014 ESC/EACTS Guidelines on myocardial revascularization: TheTask Force on Myocardial Revascularization of the European Society ofCardiology (ESC) and the European Association for Cardio-Thoracic Surgery(EACTS)Developed with the special contribution of the European Associationof Percutaneous Cardiovascular Interventions (EAPCI)Eur Heart J
01 10 2014353725412619[PubMed][Google Scholar]