Author + information
- Received October 9, 2016
- Revision received December 1, 2016
- Accepted December 15, 2016
- Published online March 29, 2017.
- Doyeon Hwang, MDa,
- Ki-Hyun Jeon, MDb,
- Joo Myung Lee, MD, MPH, PhDc,
- Jonghanne Park, MD, PhDa,
- Chee Hae Kim, MDa,
- Yaliang Tong, MDd,
- Jinlong Zhang, MDa,
- Ji-In Bang, MDe,
- Minseok Suh, MDe,
- Jin Chul Paeng, MD, PhDe,
- Sang-Hoon Na, MD, PhDf,g,
- Gi Jeong Cheon, MD, PhDe,
- Christopher M. Cook, MBBSh,
- Justin E. Davies, MBBS, PhDh and
- Bon-Kwon Koo, MD, PhDa,g,∗ ()
- aDepartment of Internal Medicine and Cardiovascular Center, Seoul National University Hospital, Seoul, Korea
- bDepartment of Internal Medicine, Sejong General Hospital, Bucheon, Korea
- cDivision of Cardiology, Department of Internal Medicine, Heart Vascular Stroke Institute, Samsung Medical Center, Seoul, Korea
- dChina-Japan Union Hospital of Jilin University, China
- eDepartment of Nuclear Medicine, Seoul National University Hospital, Seoul, Korea
- fDepartment of Internal Medicine and Emergency Medical Center, Seoul National University Hospital, Seoul, Korea
- gInstitute of Aging, Seoul National University, Seoul, Korea
- hInternational Centre for Circulatory Health, National Heart and Lung Institute, Imperial College London and Imperial College Healthcare National Health Service Trust, London, United Kingdom
- ↵∗Address for correspondence:
Dr. Bon-Kwon Koo, Department of Internal Medicine and Cardiovascular Center, Seoul National University Hospital, 101 Daehang-ro, Chongno-gu, Seoul, 03080, Korea.
Objectives The authors sought to compare the diagnostic performance of fractional flow reserve (FFR), instantaneous wave-free ratio (iFR), and resting distal coronary artery pressure/aortic pressure (Pd/Pa) using 13N-ammonia positron emission tomography (PET).
Background The diagnostic performance of invasive physiological indices was reported to be different according to the reference to define the presence of myocardial ischemia.
Methods A total of 115 consecutive patients with left anterior descending artery stenosis who underwent both 13N-ammonia PET and invasive physiological measurement were included. Optimal cutoff values and diagnostic performance of FFR, iFR, and resting Pd/Pa were assessed using PET-derived coronary flow reserve (CFR) and relative flow reserve (RFR) as references. To compare discrimination and reclassification ability, each index was compared with integrated discrimination improvement (IDI) and category-free net reclassification index (NRI).
Results All invasive physiological indices correlated with CFR and RFR (all p values <0.001). The overall diagnostic accuracies of FFR, iFR, and resting Pd/Pa were not different for CFR <2.0 (FFR 69.6%, iFR 73.9%, and resting Pd/Pa 70.4%) and RFR <0.75 (FFR 73.9%, iFR 71.3%, and resting Pd/Pa 74.8%). Discrimination and reclassification abilities of invasive physiological indices were comparable for CFR. For RFR, FFR showed better discrimination and reclassification ability than resting indices (IDI = 0.170 and category-free NRI = 0.971 for iFR; IDI = 0.183 and category-free NRI = 1.058 for resting Pd/Pa; all p values <0.001).
Conclusions The diagnostic performance of invasive physiological indices showed no differences in the prediction of myocardial ischemia defined by CFR. Using RFR as a reference, FFR showed a better discrimination and reclassification ability than resting indices.
- 13N-ammonia positron emission tomography
- coronary artery disease
- fractional flow reserve
- instantaneous wave-free ratio
- myocardial ischemia
Previous studies demonstrated that percutaneous coronary intervention for coronary artery disease is only beneficial in patients with myocardial ischemia (1,2). Among invasive physiological indices, fractional flow reserve (FFR) has been a standard invasive method to detect lesion-specific myocardial ischemia and has been commonly used in daily clinical practice (3–6). In recent years, resting indices such as instantaneous wave-free ratio (iFR) and resting distal coronary artery pressure/aortic pressure (Pd/Pa) were introduced as a simple invasive index to define myocardial ischemia. Three large clinical studies investigated the diagnostic performance of resting index against FFR and reported various ranges of diagnostic accuracy, from 60% to 90% (7–9). However, the diagnostic performance of FFR and iFR was comparable when an independent reference test was used to define the presence of myocardial ischemia (10,11).
Noninvasive myocardial perfusion imaging plays an important role in determining a therapeutic plan for patients with coronary artery disease. Positron emission tomography (PET) has been considered the most accurate noninvasive myocardial perfusion imaging to define myocardial ischemia (12). In addition to absolute myocardial blood flow (MBF), perfusion PET scans can provide coronary flow reserve (CFR) and relative flow reserve (RFR) (13,14). PET-derived CFR and RFR have been regarded as some of the gold standard methods to define myocardial ischemia (13–18). We performed this study to compare the diagnostic performance of FFR, iFR, and resting Pd/Pa using PET-derived CFR and RFR as reference standards.
The study population was selected from the IRIS FFR (Study of the Natural History of FFR Guided Percutaneous Coronary Intervention; NCT01366404) registry. The IRIS FFR registry is a Korean multicenter registry enrolling consecutive patients who underwent FFR measurement for any major epicardial coronary artery. The exclusion criteria were stenosis with Thrombolysis In Myocardial Infarction flow grade of <3, graft vessel, depressed left ventricular systolic function (ejection fraction <30%), and stenosis that was technically not suitable for FFR evaluation. From June 2011 to September 2015, 144 consecutive patients with available 13N-ammonia PET within 3 months of FFR measurement in the left anterior descending coronary artery were included in this study. Fifteen patients with poor image quality and 14 patients with unavailable iFR measurement were excluded. All patients were enrolled from Seoul National University Hospital. The study protocol was approved by the institutional review board and was conducted in accordance with the Declaration of Helsinki. All patients provided written informed consent before enrollment.
13N-ammonia PET protocol
The 13N-ammonia PET images were acquired during resting and stress state by continuous intravenous infusion of adenosine (140 μg/kg/min). Adenosine was administered 3 min before the stress scan, and low-dose computed tomographic scans were used to correct scatter and attenuation (19). All patients were informed to refrain from any caffeine- or xanthine-containing products for 24 h before scanning, and vasodilating medications including nitrate, beta-blocker, and calcium channel blocker were also stopped for 24 h before PET acquisition. The 370 MBq of 13N-ammonia was administrated in resting and stress states into a peripheral vein, and then a list mode dynamic scan was performed with a Siemens Biograph-40 PET/CT scanner (Siemens Medical Solutions, Erlangen, Germany). For image analysis and quantification of resting and stress absolute MBF in milliliters per minute per gram of tissue image acquisition, Carimas TM software, version 2.8 (Turku PET Centre, Finland) was used (20).
Quantification of absolute MBF and physiological indices from 13N-ammonia PET
A 2-compartment model was applied to quantify absolute MBF (ml/min/g). The absolute MBF and physiological indices of a target segment were calculated from PET scans as described previously (21). The 6 basal segments in PET images were not quantified due to low counts in membranous interventricular septum and to artifacts. CFR was calculated as the ratio of stress MBF to resting MBF in target segments (13). RFR was calculated as the ratio of stress MBF in target myocardial segments to that of reference myocardial segments (14,15,21). Parametric stress MBF polar maps were used to delineate defect areas in target myocardial segments and to obtain MBF values in those areas (18). The averaged stress MBF in 3 segments with the highest MBF was used as reference hyperemic MBF (Online Figure 1). In order to compare the diagnostic performance of invasive physiological indices, CFR <2.0 and RFR <0.75 were used as reference standards to define the presence of myocardial ischemia (13–15,22).
Invasive coronary angiography and measurement of physiological indices
Coronary angiography was performed by standard techniques. Angiographic views were obtained following the administration of intracoronary nitrate (100 or 200 μg). All angiograms were analyzed at a core laboratory (Seoul National University Hospital) in a blinded fashion. Quantitative coronary angiography was performed in optimal projections with validated software (CAAS II, Pie Medical System, Maastricht, the Netherlands). The minimal lumen diameter, reference vessel size, and lesion length were measured, and % diameter stenosis was calculated.
All coronary physiological measurements were obtained after diagnostic angiography as previously described (3). Briefly, a 5-F to 7-F guide catheter without side holes was used to engage the coronary artery. The pressure–temperature sensor guidewire (St. Jude Medical, St. Paul, Minnesota) was zeroed and equalized to aortic pressure, and then the pressure sensor was positioned at the distal segment of a target vessel. Intracoronary nitrate (100 or 200 μg) was administered before each physiological measurement. Resting Pd/Pa was calculated as the ratio of mean distal coronary artery pressure to mean aortic pressure in the resting state. Continuous infusion of adenosine (140 μg/kg/min) was used to induce hyperemia. Hyperemic distal coronary artery pressure and aortic pressure were obtained during sustained hyperemia, and FFR was calculated by mean distal coronary artery pressure/aortic pressure during hyperemia. After measurements, the pressure wire was pulled back to the guide catheter and the presence of pressure drift was checked. All FFR readings were collected and validated at the core laboratory (Seoul National University Hospital) in a blinded fashion. iFR was calculated as the mean pressure distal to the stenosis divided by the mean aortic pressure during the diastolic wave-free period. The baseline tracing data of more than 5 heart beats were extracted and then anonymized and coded as an ASCII text file. Those data were sent to the iFR core laboratory (Imperial College, London, United Kingdom) where iFR was calculated using fully automated algorithms acting over the wave-free period over a minimum of 5 beats (9).
Categorical variables were presented as numbers and relative frequencies. Continuous variables were presented as mean ± SD or median with interquartile range according to their distributions, which were checked by the Kolmogorov-Smirnov test. Spearman correlation coefficients were calculated to estimate the correlations between invasive physiological indices and PET-derived parameters due to the non-normal distributions of FFR, iFR, and resting Pd/Pa. The Pearson correlation coefficient was used to estimate the correlations between PET-derived CFR and RFR. The differences of correlation coefficients were tested by the Fisher r-to-z transformation.
The optimal cutoff values of invasive physiological indices for defining myocardial ischemia were calculated on the basis of maximizing the sum of sensitivity and specificity of each index. Comparison of the area under curve (AUC) from receiver-operating characteristic curve analysis was performed with the DeLong method (23). Diagnostic performance of invasive physiological indices was presented with sensitivity, specificity, positive predictive value, negative predictive value, and diagnostic accuracy. Diagnostic accuracies of FFR, iFR, and resting Pd/Pa were compared using the McNemar test. To compare discrimination and reclassification ability, each index was compared by absolute and relative integrated discrimination improvement (IDI) index, as well as category-free net reclassification index (NRI) (24).
All probability values were 2-sided, and a p value <0.05 was considered statistically significant. The statistical package SPSS version 22.0 (SPSS, Chicago, Illinois) and SAS software, version 9.3 (SAS Institute, Cary, North Carolina) were used for statistical analyses.
Baseline characteristics and coronary physiology data
Table 1 shows baseline patient and lesion characteristics. The mean age was 63.6 ± 9.0 years, and 103 patients (89.6%) were male. The mean diameter stenosis was 46.7 ± 16.0%, and 58.5% of the lesions had an intermediate degree of stenosis. The median (interquartile range) values FFR, iFR, and resting Pd/Pa values were 0.81 (0.73 to 0.85), 0.92 (0.87 to 0.94), and 0.93 (0.90 to 0.95), respectively. The distributions of invasive physiological indices and angiographic lesion severity are shown in Figure 1. The mean values of CFR and RFR by PET were 2.13 ± 0.58 and 0.77 ± 0.09, respectively (Table 1).
Correlations between invasive physiological indices and PET-derived CFR and RFR
The invasive physiological indices showed positive correlations with both PET-derived CFR and RFR (Figure 2). The degree of correlation among the FFR, iFR, and resting Pd/Pa was not different for both CFR and RFR (Online Table 1). The trend was the same with the relationship between stress MBF and invasive physiological indices (Online Figure 2, Online Table 1).
Optimal cutoff values and diagnostic accuracies of invasive physiological indices
The optimal cutoff values of FFR, iFR, and resting Pd/Pa for defining myocardial ischemia were calculated using CFR (<2.0) and RFR (<0.75) as reference standards. The optimal cutoff values of FFR, iFR, and resting Pd/Pa were 0.79, 0.92, and 0.93 using CFR as a reference standard. The optimal cutoff values of FFR, iFR, and resting Pd/Pa for RFR <0.75 were the same as CFR <2.0.
Figure 3 shows diagnostic performance of FFR, iFR, and resting Pd/Pa using ischemic cutoff values calculated from this study. With CFR as a reference, the sensitivity, specificity, positive predictive value, negative predictive value, and diagnostic accuracy of FFR were 64.7%, 73.4%, 66.0%, 72.3%, and 69.6%, respectively. Those of iFR were 72.5%, 75.0%, 69.8%, 77.4%, and 73.9%, and those of resting Pd/Pa were 64.7%, 75.0%, 67.3%, 72.7%, and 70.4%, respectively (Figure 3A). With RFR as a reference, the diagnostic accuracies of FFR, iFR, and resting Pd/Pa were 73.9%, 71.3%, and 74.8%, respectively (Figure 3B). There was no difference in diagnostic accuracies among 3 physiological indices for both CFR (p = 0.359 for FFR vs. iFR, p = 1.000 for FFR vs. resting Pd/Pa) and RFR (p = 0.648 for FFR vs. iFR, p = 1.000 for FFR vs. resting Pd/Pa).
The diagnostic performance of invasive physiological indices was not changed significantly when the previously well-defined cutoff values (cutoff value 0.80 for FFR, 0.90 for iFR and 0.92 for resting Pd/Pa) were used (Online Figure 3).
Discrimination and reclassification abilities of invasive physiological indices
There was no difference in AUC among the 3 invasive indices to predict CFR <2.0 (0.716 for FFR, 0.762 for iFR, and 0.761 for resting Pd/Pa) (Figure 4A). The AUC for RFR <0.75 was 0.826 (95% confidence interval [CI]: 0.749 to 0.903), 0.771 (95% CI: 0.684 to 0.858), and 0.774 (95% CI: 0.684 to 0.864) for FFR, iFR, and resting Pd/Pa, respectively. The AUC of FFR was higher than that of iFR (p = 0.047 for comparison) (Figure 4B).
Compared with iFR and resting Pd/Pa, FFR showed comparable discrimination and reclassification ability for determining myocardial ischemia defined by CFR< 2.0 (IDI = −0.029 and NRI = −0.357 with iFR; IDI = −0.036 and NRI = −0.317 with resting Pd/Pa) (Table 2). As for RFR <0.75, FFR showed improvement of discrimination and reclassification ability for determining myocardial ischemia compared with resting indices (IDI = 0.170 and NRI = 0.971 with iFR; IDI = 0.183 and NRI = 1.058 with resting Pd/Pa) (Table 3).
In this study, we compared the diagnostic performance of FFR, iFR and resting Pd/Pa for the prediction of myocardial ischemia defined by PET-derived CFR and RFR. The main findings of this study were as follows. First, all invasive physiological indices and PET-derived CFR and RFR showed significant correlations. Second, optimal cutoff values of FFR, iFR, and resting Pd/Pa for defining myocardial ischemia defined by PET parameters were 0.79, 0.92, and 0.93, respectively. Third, there were no significant differences in diagnostic accuracies among FFR, iFR, and resting Pd/Pa against CFR and RFR. Fourth, discrimination and reclassification ability of FFR to define low RFR was better than those of resting indices. These findings imply that the diagnostic abilities of these physiological indices can be different according to the reference used for the comparison.
Physiological indices to define myocardial ischemia
The presence of myocardial ischemia is the key prognostic indicator in patients with coronary artery disease (1,2). Because coronary angiography has several limitations to define myocardial ischemia, the use of invasive physiological studies has become more popular (13,16,17). The benefit of FFR has been validated through several clinical studies, and FFR is considered the gold standard for defining lesion-specific myocardial ischemia in daily practice (3–5,17). Recently, resting indices, such as iFR and resting Pd/Pa, that do not require hyperemia have been proposed as a simple alternative for FFR. Previous studies reported various ranges (60% to 90%) of diagnostic accuracies of iFR and resting Pd/Pa compared with FFR (7–9). However, the diagnostic performance can be different according to the reference index used to define myocardial ischemia. Sen et al. (10) reported comparable diagnostic agreement of FFR and iFR when hyperemic stenosis resistance was used as a reference to define myocardial ischemia. Petraco et al. (11) used coronary flow velocity reserve as a reference and showed a better diagnostic discrimination of iFR than that of FFR (iFR AUC 0.82; FFR AUC 0.72; p < 0.001). In our study, PET-derived CFR and RFR were used as references to compare the diagnostic performance between FFR and resting indices. PET has been considered the gold standard to measure myocardial blood flow, and PET-derived CFR and RFR have been thoroughly investigated as noninvasive methods to define myocardial ischemia and prognostic indicators in patients with coronary artery disease (13–15,22).
Rationale of validating invasive physiological indices using PET-derived CFR and RFR
CFR is the ratio of stress MBF and resting MBF, and represents how much MBF can be supplied in stress conditions compared with that of a resting condition (13,16). RFR is the ratio of stress MBF in diseased segments and that in normal segments and means the degree of hyperemic flow decrease due to the coronary artery stenosis; this is a noninvasive version of FFR (14,15). Although the concept of CFR and RFR are different, the prognostic values of both parameters have been thoroughly investigated. CFR is the oldest and extensively investigated physiological index, and the prognostic implication of CFR was consistently observed regardless of the methods of measurement, such as invasive flow measurement, stress echocardiography, and PET (25–28). The clinical relevance of RFR can be inferred from the well-validated FFR studies (3–5,15,26).
Each physiological index can represent different aspects of myocardial ischemia and has its own strength and weakness (29). As for RFR, it is a more epicardial stenosis–specific index and cannot reflect the microvascular dysfunction of diseased myocardial territory, because it is also influenced by microvascular disease state of normal reference myocardial territory. By contrast, CFR reflects not only the severity of epicardial stenosis, but also the microvascular disease status (29,30). These differences lead to the 37.4% discordance between CFR and RFR in this study, and this was similar to the previous results (Online Figure 4) (29).
Comparison between invasive physiological indices and PET-derived parameters
FFR, iFR, and resting Pd/Pa showed significant correlations with PET-derived parameters, but showed different patterns to the CFR and RFR. With CFR, FFR demonstrated a numerically lower correlation coefficient than iFR and resting Pd/Pa. This result is similar to a previous study by Petraco et al. (11) that reported a better correlation of iFR with coronary flow velocity reserve than FFR (iFR r = 0.68; FFR r = 0.50; p for comparison <0.001). In contrast to the CFR, the correlation coefficient of FFR with RFR was numerically higher than those of resting indices. The degree of correlation between FFR and RFR from our study was comparable to a previous study reported by Stuijfzand et al. (14) (FFR vs. RFR r = 0.54; p < 0.01). Considering RFR is a hyperemic index and the concept of RFR is more similar to FFR than that of iFR and resting Pd/Pa, the better correlation between FFR and RFR seems to be natural. These different patterns of correlations with PET-derived parameters between resting and hyperemic physiological indices suggest that the diagnostic performance of invasive physiological indices can be different according to the reference standard used for comparison.
Diagnostic performance of invasive physiological indices
In this study, we compared the diagnostic performance of resting and hyperemic indices using 2 different concepts of myocardial ischemia, PET-derived CFR and RFR. Like previous studies, our study results showed the different diagnostic performance of resting and hyperemic indices according to the reference (10,11). Although the overall diagnostic accuracy was not different regardless of cutoff values of invasive physiological indices (6,7), the discrimination and reclassification ability of FFR was better than those of resting indices when RFR was used as a reference. Even though it was not statistically significant, the resting indices showed numerically higher correlation and better diagnostic agreement with CFR, compared with those of FFR. These results are in line with the previous study of Petraco et al. (11), which used Doppler-measured coronary flow velocity reserve as a reference standard. Because CFR reflects both macrovascular and microvascular disease status and RFR is more epicardial stenosis–specific, this study implies that resting and hyperemic indices may represent different aspects of myocardial ischemia. Therefore, these differences need to be appreciated with caution when the different invasive physiological index is used in clinical practice.
Although it is beyond the scope of this study, the demonstration of prognostic implication is the most important aspect in the evaluation of clinical relevance of any diagnostic test. The benefit of a FFR-guided revascularization strategy has been well-demonstrated by several clinical studies (3–5). Ongoing clinical studies that compare the clinical outcomes of FFR-guided and iFR-guided strategies (DEFINE-FLAIR [NCT02053038], iFR SWEDEHEART [NCT02166736]) will provide additional information on the prognostic implication of iFR.
First, reference standards used in this study are also the surrogate for myocardial ischemia. With the lack of a clinically available true gold standard, this limitation can be applied to all clinical studies. Second, PET segmentation by vascular territory can be influenced by individual variations in coronary anatomy. Although the quantification of myocardial blood flow by PET is known to have low intra- and interobserver variability, myocardial segmentation of the target vascular territory in PET images could be different by different observers. Third, our study used 13N-ammonia as a PET tracer, and the absolute MBF measured by different tracers could be different. However, the flow ratio such as CFR or RFR was reported to be relatively constant among different tracers (31). Fourth, there is a possibility of insufficient statistical power due to the relatively small sample size of this study to detect significant difference among physiological indices. Further study with a larger sample size is warranted to clarify this issue.
The diagnostic performance of invasive physiological indices showed no difference in the prediction of myocardial ischemia defined by CFR. Using RFR as a reference standard, FFR showed higher discrimination and reclassification ability than iFR or resting Pd/Pa. The user needs to understand this difference when applying an invasive physiological index in clinical practice.
WHAT IS KNOWN? The presence of myocardial ischemia is the key prognostic indicator in patients with coronary artery disease, and the use of invasive physiological studies has become more popular. However, the diagnostic performance of invasive physiological indices was reported to be different according to the reference to define the presence of myocardial ischemia.
WHAT IS NEW? This study compared the diagnostic performance of FFR, iFR and resting Pd/Pa using CFR and RFR from 13N-ammonia PET. The study results showed that FFR, iFR, and resting Pd/Pa had similar diagnostic performance when CRF was used as a reference, and better discrimination and reclassification ability of FFR when RFR was used as a reference. Because each physiological index can represent different aspects of myocardial ischemia and has its own strength and weakness, the user needs to understand these differences when applying an invasive physiological index in clinical practice.
WHAT IS NEXT? Although we compared the diagnostic performance of invasive physiological indices using PET, the demonstration of prognostic implication is the most important aspect in the evaluation of clinical relevance of any diagnostic test. Therefore, further study is needed to demonstrate the prognostic value of resting indices such as iFR and resting Pd/Pa.
For supplemental figures and table, please see the online version of this paper.
Dr. Cook has received speakers fees from Volcano Philips. Dr. Davies is a consultant for and receives research funding from Volcano Philips; and holds intellectual property rights pertaining to pressure wire technology. Dr. Koo has received an institutional research grant from St. Jude Medical. All other authors have reported that they have no relationships relevant to the contents of this paper to disclose. The first 2 authors contributed equally to this work.
- Abbreviations and Acronyms
- area under curve
- coronary flow reserve
- confidence interval
- fractional flow reserve
- integrated discrimination improvement
- instantaneous wave-free ratio
- myocardial blood flow
- net reclassification index
- distal coronary artery pressure/aortic pressure
- positron emission tomography
- relative flow reserve
- Received October 9, 2016.
- Revision received December 1, 2016.
- Accepted December 15, 2016.
- 2017 American College of Cardiology Foundation
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