Prior studies have shown clinical and economic benefits from assessing and utilizing invasive fractional flow reserve (FFR_cath) measurements to guide percutaneous coronary intervention (PCI). In the randomized controlled fractional flow reserve versus angiography for multivessel evaluation (FAME) study including 1,005 patients, it was demonstrated that deferring PCI in vessels not associated with myocardial ischemia based on FFR_cath resulted in improved clinical outcomes and lower costs [1, 2]. Furthermore, the FAME II study involving 888 patients demonstrated that PCI in vessels associated with myocardial ischemia based on FFR_cath significantly reduced urgent revascularization when compared to medical therapy alone [3]. In all studies published to date, invasive FFR has been assessed during angiography (FFR_cath). While FFR_cath is widely recommended and offers clinical and economic benefits, it is not yet widely used due to inconvenience and costs [4].

A new technology based on standard coronary computed tomographic angiography (cCTA) allows FFR to be estimated non-invasively (FFR_CT) before sending a patient to angiography. Three prospective, multicenter, validation studies have been performed (DISCOVER-FLOW—diagnosis of ischemia-causing stenosis obtained via non-invasive fractional flow reserve [5]; DeFACTO—determination of fractional flow reserve by anatomic computed tomographic angiography [6]; and HeartFlowNXT—HeartFlow analysis of coronary blood flow using CT angiography: NeXT steps [7] to determine the diagnostic accuracy of FFR_CT using FFR_cath as the reference standard. Good concordance between FFR_CT and FFR_cath was found with high diagnostic accuracy of FFR_CT for the detection or exclusion of hemodynamically significant stenosis using FFR ≤0.80 as the reference standard.

An analysis of potential costs and consequences of utilizing FFR_CT to guide clinical decision-making in the United States has suggested the possibility of meaningful cost savings and clinical benefits [8]. In the present paper, we report a similar analysis, using data from the most recently published trial, HeartFlowNXT [7], as well as Japanese procedure and device cost information. The primary objective of this analysis is to determine the potential magnitude of cost savings and clinical benefit which could be expected in Japan through utilization of FFR_CT.

We used data from 254 patients enrolled in the HeartFlowNXT trial [7]. All patients had known or suspected stable coronary artery disease (CAD) and were scheduled for coronary angiography (CAG). Each patient in the trial was evaluated with cCTA, FFR_CT, clinically-indicated CAG and FFR_cath. Calculation of FFR_CT from standard acquired cCTA images and evaluation of FFR_cath were performed independently at core laboratories [7]. The study results demonstrated that FFR_CT provided high per-patient diagnostic accuracy (81 %) for the detection of hemodynamically significant CAD with a sensitivity of 86 % (95 % CI 77–92 %) and specificity of 79 % (95 CI 72–84 %) using FFR_cath as the reference standard. FFR_CT also provided excellent discrimination of patients with and without lesion-specific ischemia with an area under the receiver-operating characteristics curve of 0.90 (95 % CI 0.87–0.94 %) [7]. Using patient-specific data from this study, we modeled four hypothetical diagnostic/treatment pathways for patients with known or suspected CAD who are scheduled for coronary angiography (Fig. 1):

For each pathway, we estimated the costs in Japan in accord with the Japanese Ministry of Health, Labour and Welfare (MHLW) medical insurance medical expense database [9]. We considered cost data from the detailed economic analysis in the 2 years follow-up report of the FAME study [1] and applied the conversion rate of 93.42 Yen/Dollar. The peri-procedural costs utilized in this study are shown in Table 1. While the actual cost of FFR_CT analysis has not yet been determined, for the purposes of this analysis, we sought the cost of FFR_CT which produced equivalence between the costs of Pathway 2 and Pathway 4. This was calculated to be $2,000, which is comparable to the FFR_cath disposable costs + CAG procedure fee as reimbursed by the MHLW medical insurance. The analysis of each pathway involved totaling the costs for each test and procedure described for all patients in that pathway and dividing by the total number of patients (254) giving the average cost per patient.

We estimated future event rates for appropriately and inappropriately treated patients using the FFR cutoff value of <0.80 drawing on data from the deferral versus performance of PTCA in patients without documented ischemia (DEFER) [10], FAME [11, 12] and providing regional observations to study predictors of events in the coronary tree (PROSPECT) [13] studies. We considered a coronary lesion to be significant by visual assessment of the CAG or cCTA if lumen stenosis was ≥50 % and defined functional significance of a lesion as either an FFR_cath or FFR_CT of ≤0.80. Accordingly, we used the following assumptions to estimate the combined 1 year death/MI rate for: (a) PCI in patients with FFR_cath ≤0.80: 3 %; (b) PCI in patients with FFR_cath >0.80: 3 %; (c) medical therapy in patients with FFR_cath >0.80: 1 %; (d) medical therapy in patients with FFR_cath ≤0.80: 5 %; (e) invasive measurement of FFR_cath: 0.4 % [7, 14].

A total of 254 patients from the international, multicenter HeartFlowNXT trial had complete information and were included in the analysis. Fifty-seven patients (22 %) in the study were from Japanese clinical sites. Patient characteristics are shown in Table 2. One-third of the patients (80/254) had ischemia-causing stenoses with FFR ≤0.80 and 21 % of the 484 vessels in which invasive FFR was measured had FFR_cath ≤0.80.

Three prospective, multicenter clinical trials, comprising 609 patients and 1,050 vessels have evaluated the diagnostic accuracy of FFR_CT using FFR_cath as the reference standard [5‐7]. Each study has shown FFR_CT to have high diagnostic accuracy for the diagnosis of lesion-specific ischemia using FFR_cath as the reference standard with significant improvement in the ability to discriminate patients with and without ischemia when compared to cCTA [5‐7] and CAG [7]. The use of invasive FFR_cath to identify lesion-specific ischemia and guide coronary intervention is now well-established and has been shown to not only improve patient outcome but also reduce costs [1]. It has been suggested that non-invasive FFR_CT may be poised to assume the role of gatekeeper to the interventional catheterization laboratory, especially for intermediate stenosis [15], and a previously modeled analysis based on US data has suggested that the use of FFR_CT may improve patient outcomes while reducing healthcare costs [8].

In this study we based our analysis on the most recently published experience with FFR_CT which incorporates the latest refinements in software technology with automated image processing and improved physiologic modeling of coronary flow parameters [7]. The results show that the diagnostic performance of non-invasive FFR_CT compares favorably to invasive FFR_cath and can discriminate ischemia-causing stenoses from non-functional stenoses. According to European Society of Cardiology [16] and American Heart Association [17] practice guidelines, FFR_cath is the gold standard for assessing the hemodynamic significance of coronary lesions and for interventional clinical decision-making; however, FFR_cath is not practical in many cases for reasons of safety and time. FFR_CT has potential value in selecting patients for CAG and interventional treatment with the potential of achieving significant reduction in costs and improving outcomes compared to visual angiography-guided treatment. As indicated by the model in this study, the utilization of FFR_CT in Japan may result in fewer diagnostic catheterizations, fewer inappropriate PCI treatments, improved patient outcomes, and a 30 % reduction in average cost per patient relative to standard care (Pathway 1) if fully implemented.

In addition to advancing patient care, utilizing FFR_CT technology in Japan may provide significant cost savings for the overall Japanese Healthcare System by safely deferring unnecessary CAG and identifying patients who would benefit from PCI. In 2011 it is estimated that 504,476 coronary angiographies and 181,991 non-emergent PCIs were performed in Japan [18]. If our analysis can be extrapolated to the larger population, the utilization of FFR_CT might decrease coronary angiographies by as much as ~60 % and PCI procedures by ~40 %. Based on the results in this study, we estimate that widespread implementation of FFR_CT in Japan has the potential to result in considerable cost savings to the Japanese Healthcare System while improving the clinical outcome for patients.

This study has several important limitations. First, this study is a simulation of possible costs and outcomes rather than documentation of costs incurred and outcomes experienced utilizing FFR_CT in actual clinical practice. While direct assessment of cost-efficacy is not yet available for FFR_CT or other non-invasive testing modalities in stable CAD, the source data for this study represents the largest clinical experience of any non-invasive testing modality using FFR_cath as the reference standard. FFR_CT has close direct correlation to measured FFR, which has well-documented outcome and cost data in more than 1,005 patients [11], but independent confirmation with actual outcome data utilizing FFR_CT for clinical decision making is needed. The extent to which patients analyzed in this report may not precisely reflect the spectrum of patients undergoing CAG in Japan may limit the ability to extrapolate directly to expected outcomes in Japan. A prospective longitudinal study evaluating clinical outcomes, resource utilization and quality of life of FFR_CT-guided evaluation and treatment of patients with suspected CAD is currently underway (PLATFORM trial, clinical trials.gov NCT01943903). Second, this study did not include patients with acute coronary ischemia, patients with prior PCI or CABG, and patients who are not suitable candidates for cCTA. Thus, the usefulness of FFR_CT in this broader population of patients with CAD is unknown. Third, costs related to clinical adverse events during follow-up were not considered; however, the FFR_CT guided pathway had the lowest event rate during follow-up. Fourth, FFR_CT is not yet widely available and market pricing for this test has not yet been determined. This analysis uses an FFR_CT price of $2,000, the price at which the costs of Pathways 2 and 4 were equivalent. The resulting average total cost of treating a patient in Pathway 4 (cCTA-FFR_CT-CAG) is $7,222. If the price of FFR_CT is modeled as $1,500, the average cost of treating a patient in this pathway decreases to $6,848, a 34 % savings compared to standard care (Pathway 1). If the price of FFR_CT is modeled as $2,500, the average cost for a patient in this pathway is $7,596, a 27 % reduction compared to standard care (Pathway 1). Finally, this analysis does not consider the possibility of only partial or limited adoption of the FFR_CT decision pathway, which inherently would limit the potential cost savings of this approach. For example, the decision to send a patient to CAG is made by comprehensive evaluation of the patient’s symptoms and physical findings, risk profile, and results of other non-invasive tests for myocardial ischemia and may cause the physician to override the results of the FFR_CT. Similarly, physicians in Pathway 2 may choose to—not measure FFR in the cath lab or may override the results of FFR_cath thus reducing the potential economic and outcome benefit. Thus, actual savings achieved may be limited by physicians’ adherence to the clinical decision making pathway. Further evaluations including prospective outcome studies are underway to better understand and quantify the potential clinical and economic improvements identified in this simulation.

Analysis of data from the HeartFlowNXT trial and using Japanese costs of goods and services suggest that utilization of non-invasive FFR_CT for clinical decision making could improve clinical outcomes and decrease costs by more accurately identifying patients for CAG and PCI.