In stable coronary artery disease (CAD), one of the key questions in clinical practice is whether and when a patient needs invasive study and revascularization such as percutaneous coronary intervention (PCI) or coronary artery bypass grafting surgery (CABG). Currently, there are two major therapeutic strategies for stable CAD; the invasive strategy including early coronary angiography (CAG) and subsequent revascularization if indicated, and the non-invasive strategy including optimal medical therapy (OMT). In both the strategies, there have been major advances in the last few decades including the use of drug-eluting stent for PCI and addition of statins in OMT. However, the basic principle of selecting treatment option in stable CAD has not been changed; to reduce futile invasive CAG and revascularization using non-invasive studies for selecting high-risk patients.

Myocardial perfusion imaging (MPI) using single-photon emission computed tomography (SPECT) or positron emission tomography (PET) has been used in stable CAD for selecting high-risk patients who require revascularization. In a milestone study by Hachamovitch et al., it was reported that revascularization is more beneficial than OMT in patients who showed moderate to large amounts of inducible ischemia on SPECT.1 However, there have been some conflicting results. For example, in the nuclear substudy of the COURAGE trial, it was reported that the extent of ischemia on MPI was not predictive of adverse events and did not affect treatment effectiveness.2 Despite these conflicting results, there have been hundreds of reports on the prognostic role of MPI in CAD, which were summarized in several review articles.3,4 Additionally, there have been other studies that demonstrated effectiveness of MPI in selecting treatment options. In an observation study that followed up 13,969 patients for more than 7 years, early revascularization was beneficial in patients who exhibited significant ischemia without extensive scar on SPECT, whereas OMT was superior to revascularization in patients with minimal ischemia.5 In another study that used MPI PET, coronary flow reserve (CFR) measured on PET was an independent factor from CAG in modifying the effectiveness of early CABG or PCI.6

In the current issue of Journal of Nuclear Cardiology, Boiten et al. reported treatment effectiveness according to MPI SPECT findings.7 They followed up 702 patients who exhibited ischemia on SPECT for a median of 12 years, and observed that early revascularization was more beneficial than OMT in this group. Additionally, prognosis was associated with the extent of ischemia on SPECT. Although the study has some limitations of retrospective design, enrollment of only patients with ischemia, and treatment based on relatively old methods like bare metal stent or old drug regimens, it demonstrated again the effectiveness of MPI in selecting high-risk patients who require revascularization. MPI-based decision of invasive treatment is still a valid strategy.

Another option of non-invasive imaging method in CAD is coronary computed tomography angiography (CCTA). Because CCTA targets for anatomical stenosis that is also the diagnostic target in CAG, it has high diagnostic performance for CAG-confirmed CAD.8,9 Thus, CCTA can be effectively used for determining the need for CAG; in the SCOT-HEART trial in which 4146 patients were randomly assigned to standard care group or standard care plus CCTA group, CCTA led to more appropriate use of CAG and alterations in subsequent medication.10 In terms of prognosis, a meta-analysis reported that annual event rates for obstructive and normal CCTA were 8.8% and 0.17%, respectively.11 However, it is still not clear whether CCTA can be used for selecting treatment option. In the PROMISE trial that compared CCTA and functional studies as initial testing strategy, a strategy of initial CCTA did not improve clinical outcome, although it reduced futile CAG compared with a strategy of initial functional study (3.4% and 4.3%, respectively).12 Currently, it appears that the most effective role of CCTA is gatekeeping to invasive CAG.

In recent years, intervention cardiologists consider functional significance of a stenotic lesion as an important factor for decision making of revascularization. When a patient undergoes CAG, functional significance of a stenotic lesion can be evaluated using a pressure wire. Fractional flow reserve (FFR) is calculated as the pressure ratio of proximal and distal parts of a lesion. In the famous FAME study, FFR-guided PCI was performed in 509 patients and CAG-guided PCI, in 496 patients.13 In this study, FFR-guide group exhibited lower rates of cardiac events and lower cost than CAG-guide group. In the subsequent report of the FAME study that included 1220 patients, patients who had functionally insignificant (FFR > 0.80) lesions were treated with OMT.14 Their cardiac event rate was not different from that of patients who had significant lesions (FFR ≤ 0.80) and treated with PCI. In contrast, those who had significant lesions and treated with OMT exhibited higher rate of cardiac event like urgent revascularization. In the DEFER trial, FFR-guided deferral of PCI exhibited excellent outcome compared with early performance of PCI, even in a 15-year follow-up study.15 Based on the successful results of FFR-guided treatment decision, FFR is deemed to be a standard index to determine revascularization by intervention cardiologists.

Thus, non-invasive imaging has been pursuing diagnosis of significant ischemic lesions of low FFR in recent studies. If FFR can be correctly predicted on a non-invasive imaging method, it could be used to determine the need of CAG and revascularization. In CCTA, a method has been developed to calculate FFR based on hydraulic assumptions.16 The PLATFORM study enrolled patients who had intermediate likelihood of CAD and randomly assigned them into usual non-invasive test, standard CAG, and CCTA-based FFR measurement group as the initial testing.17 When combined criteria of CAG and invasive FFR were used as the gold standard, futile CAG was reduced in CCTA-based FFR measurement group (12%), compared with standard CAG group (73%). In the EVINCI trial, hybrid imaging of CCTA/MPI was used to diagnose significant CAD that was defined by combined criteria of CAG and invasive FFR. The hybrid imaging exhibited negative and positive predictive values of 88% and 87%, respectively.18

However, CFR can be measured directly using dynamic MPI. It was reported that relative CFR (RFR) on PET exhibits excellent correlations with invasive FFR.19,20 In a recent study, Lee et al. also reported that RFR on ammonia PET has a significant correlation with FFR, and the diagnostic performance of RFR for diagnosing significant stenosis (FFR ≤ 0.80) was 0.897 of area under curve.21 Currently, heart-dedicated SPECT scanners that have cadmium-zinc-telluride detector and fixed-angle geometry are available, and it has been attempted to perform dynamic scans and to measure flow reserve using these scanners.22,23 The efficacy of MPI SPECT-based flow reserve measurement needs to be evaluated in further studies. Additionally, it should be proved in further researches whether MPI-based flow reserve measurement is a prognostic factor and whether it can be used for selecting treatment options.

Currently, one of the biggest requests for non-invasive imaging study in stable CAD is to select patients who needs invasive CAG (Fig. 1). Once a patient is referred to CAG, functional significance as well as presence of stenotic lesions can be determined on CAG using FFR measurement. Both CCTA and MPI can be used effectively for this purpose because they can detect anatomically or functionally significant stenotic lesions. Another request for non-invasive imaging is a prognostic role that can predict or complement FFR. It has been shown that revascularization is superior to OMT alone when MPI is extensively abnormal, as reported by Boiten et al. in the current issue.1,5,7 Additionally, RFR measured on MPI has a significant correlation with FFR measurement. Thus, it should be investigated in further researches whether and how MPI can predict FFR effectively, and whether MPI has an independent diagnostic power for selecting patients who need invasive CAG. Based on the results of these future studies, the effectiveness of MPI for stable CAD in the era of FFR would be determined.

Fig. 1
figure 1

A flow chart for risk assessment and treatment selection in stable coronary artery disease. Non-invasive imaging can be used for screening low-significant CAD that can be medically treated and selecting highly significant CAD that needs to be referred for CAG. Currently, functional significance of a lesion can also be determined on CAG by using FFR. CAD coronary artery disease, CAG coronary angiography, CCTA coronary computed tomography angiography, CFR coronary flow reserve, FFR fractional flow reserve, MPI myocardial perfusion imaging, RFR relative flow reserve

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