Fractional Flow Reserve Derived from Coronary Computed Tomography Angiography Safely Defers Invasive Coronary Angiography in Patients with Stable Coronary Artery Disease

Objectives: In the United States, the real-world feasibility and outcome of using fractional flow reserve from coronary computed tomography angiography (FFRCT) is unknown. We sought to determine whether a strategy that combined coronary computed tomography angiography (CTA) and FFRCT could safely reduce the need for invasive coronary angiography (ICA), as compared to coronary CTA alone. Methods: The study included 387 consecutive patients with suspected CAD referred for coronary CTA with selective FFRCT and 44 control patients who underwent CTA alone. Lesions with 30–90% diameter stenoses were considered of indeterminate hemodynamic significance and underwent FFRCT. Nadir FFRCT ≤ 0.80 was positive. The rate of patients having ICA, revascularization and major adverse cardiac events were recorded. Results: Using coronary CTA and selective FFRCT, 121 patients (32%) had at least one vessel with ≥50% diameter stenosis; 67/121 (55%) patients had at least one vessel with FFRCT ≤ 0.80; 55/121 (45%) underwent ICA; and 34 were revascularized. The proportion of ICA patients undergoing revascularization was 62% (34 of 55). The number of patients with vessels with 30–50% diameter of stenosis was 90 (23%); 28/90 (31%) patients had at least one vessel with FFRCT ≤ 0.80; 8/90 (9%) underwent ICA; and five were revascularized. In our institutional practice, compared to coronary CTA alone, coronary CTA with selective FFRCT reduced the rates of ICA (45% vs. 80%) for those with obstructive CAD. Using coronary CTA with selective FFRCT, no major adverse cardiac events occurred over a mean follow-up of 440 days. Conclusion: FFRCT safely deferred ICA in patients with CAD of indeterminate hemodynamic significance. A high proportion of those who underwent ICA were revascularized.


Introduction
Accurately identifying coronary artery disease (CAD) in patients with symptoms of chest pain is critical in clinical medicine. For nearly four decades, functional-stress testing has served as the standard cardiovascular diagnostic practice for those with stable symptoms suspected to represent CAD, although it has been reported to have low diagnostic yield at the time of invasive coronary angiography (ICA) [1]. A contemporary analysis from the National Cardiovascular Data Registry (NCDR) of more than 385,000 patients from >1100 United States hospitals noted that less than half of patients undergoing exercise-treadmill testing, stress echocardiography, single-photon emission computed tomography (SPECT) imaging, and stress-cardiac magnetic resonance imaging prior to their ICA were found to have obstructive CAD [2,3]. Noninvasive testing made a similar prediction of obstructive CAD compared to clinical factors [2]. In addition, a recent study of over 15,000 patients found that among patients referred for ICA, those with a positive stress test were less likely to have obstructive CAD and receive revascularization compared to those with either a negative stress test or no testing at all [4].
The ideal noninvasive test would identify patients with CAD and lesion-specific ischemia and strengthen the correlation between symptoms and anatomic findings. Coronary computed tomographic angiography (CTA) has emerged as the gold standard noninvasive test for detecting CAD [5][6][7][8]. However, the identification of CAD alone is insufficient, as the relationship between coronary stenosis and ischemia is complex and frequently discordant [9][10][11][12]. In a study of over 1300 coronary artery lesions, 65% of all stenoses with 50-70% diameter reduction and 20% of all stenoses with 71-90% diameter reduction were not hemodynamically significant (FFR ≤ 0.80) [11]. Furthermore, 33% of lesions graded between 31-50% had fractional flow reserve (FFR) values ≤0.80 [12]. FFR is commonly employed to adjudicate lesion-specific ischemia in indeterminate angiographic lesions and to guide revascularization, with its use supported by the guidelines of the European Society of Cardiology and the American Heart/American College of Cardiology [13,14]. Over the past few years, there has been strong interest in computing FFR noninvasively using coronary CTA. The application of computational fluid dynamics (CFD) to resting coronary CTA datasets allows FFR to be calculated noninvasively (FFR CT ) [15]. The emergence of FFR CT provides a noninvasive test that yields both anatomic and functional data. FFR CT has been validated through a number of accuracy studies and a large clinical utility trial [16][17][18][19][20][21].
There is a paucity of data on the real-world feasibility and outcome of a diagnostic strategy using FFR CT in patients suspected of CAD in the United States. Thus, we sought to determine whether the use of a coronary CTA plus FFR CT guided strategy, as compared to coronary CTA alone, reduces rates of ICA without associated major adverse cardiac events (MACE).

Methods
Consecutive patients with suspected CAD referred for coronary CTA and FFR CT between May 2015 and June 2017 without known CAD at Loyola University, Chicago (Chicago, IL USA) were included in the analysis. Forty-four patients who underwent CTA alone prior to our institutional implementation of FFR CT were included as controls. Patient demographics and clinical data were collected from the electronic medical records of all patients. The decision to proceed with ICA was at the discretion of the care providers, using information from both the coronary CTA and FFR CT when available. Ineligible patients were defined as those with prior coronary artery bypass graft surgery (CABG), prior percutaneous coronary intervention (PCI), active arrhythmias or acute kidney injury. The study was approved by the Institutional Review Board.

Coronary Computed Tomography Angiography Acquisition and Analysis
Coronary CTA was performed with electrocardiographic-gated prospective or retrospective gating on ≥64 detector row scanners (Siemens Sensation Cardiac 64, Siemens Medical Solutions, Malvern, Pennsylvania, PA, USA; Discovery HD 750, GE Healthcare, Milwaukee, Wisconsin, WI, USA; Revolution CT 256-row, GE Healthcare, Milwaukee, Wisconsin, WI, USA) in accordance with the Society of Cardiovascular Computed Tomography (SCCT) guidelines [22]. Oral, and, when needed, intravenous, beta-blocker was administered to achieve a target heart rate (HR) of 60 bpm. Sublingual nitroglycerin 0.4-0.8 mg was given approximately 5 min prior to contrast administration. CTA datasets were interpreted using a commercially available dedicated workstation (Aquarius 3D Workstation, TeraRecon, San Mateo, CA, USA). Lesions with 30-90% diameter of stenosis were considered of indeterminate hemodynamic significance. Subtotal and total occlusions were classified as ≥90% and 100%, respectively. A coronary lesion with ≥50% diameter of stenosis was considered obstructive on coronary CTA alone. Coronary vessel branches for the left anterior descending, left circumflex, and right coronary arteries were categorized according to the SCCT guidelines [23].

Computation of Fractional Flow Reserve from Coronary Computed Tomography Angiography
FFR CT analysis was performed by HeartFlow Inc. (Redwood City, California, CA, USA) as previously described [15]. After semi-automated segmentation of the epicardial coronary arteries and determination of left ventricular mass, calculations of FFR CT were performed by CFD modeling [15]. Three-dimensional (3D) blood-flow modeling of the coronary arteries was performed, with blood modeled as a Newtonian fluid using incompressible Navier-Stokes equations, and solved subject to appropriate initial and boundary conditions using a finite element method on a parallel supercomputer. As coronary blood flow and pressure were unknown a priori, a technique to couple lumped parameter models of the microcirculation to the outflow boundaries of the 3D model was used [15]. Coronary blood flow was simulated under conditions modeling intravenous adenosine-mediated coronary hyperemia. A positive FFR CT was defined as the nadir value ≤0.80 in a vessel of diameter >1.8 mm.
Ongoing clinical studies are evaluating which parameter (nadir value vs. value distal to a lesion) is more appropriate to guide decision-making and yield superior prognostic information [24][25][26][27].

Diagnostic Invasive Coronary Angiography
ICA was performed by board-certified interventional cardiologists following clinical indications and imaging standards set forth by the American College of Cardiology/American Heart Association Task Force on Practice Guidelines and the Society for Cardiac Angiography and Interventions [28]. Decision-making to proceed with ICA was at the discretion of the care providers, using information from both the coronary CTA and FFR CT .

Study End Points and Follow-Up
Rates of patients having ICA; revascularization with PCI or CABG; and MACE, defined by cardiovascular death, myocardial infarction or unplanned hospitalizations leading to urgent revascularization, were recorded. Revascularization was considered to be urgent when a patient was admitted to hospital with persistent or increasing symptoms (with or without electrocardiographic changes or elevated biomarker levels) and the revascularization procedure was performed during the same hospitalization.

Statistical Analysis
Baseline characteristics of the selected subjects were calculated and presented as frequencies and percentages for categorical variables and mean ± standard deviation (SD) for continuous variables (Table 1). A comparison of the observed ICA rates to what would be expected based on coronary CTA alone, and the differences in these when FFR CT is available, was performed by analyzing 2 × 2 contingency tables of ICA (Yes/No) and maximum stenosis >/≤ 50% (ICA expected, based on coronary CTA alone) stratified by FFR CT availability/unavailability. Rates within strata were tested using the Fisher's exact test; differences between FFR CT strata were tested using the Cochran-Mantel-Haenszel χ 2 test. Also calculated were 95% exact confidence intervals (CI) for ICA rates (Table S1). All analyses were performed using SAS Proprietary software (version 9.2, SAS Institute, Cary, North Carolina, NC, USA). Data are expressed as mean ± SD or number (%) of patients. CTA, computed tomography angiography; FFR CT , fractional flow reserve from coronary computed tomography angiography; BMI, body mass index; ACE-I, angiotensin-converting enzyme inhibitors; ARB, angiotensin receptor blockers.

Results
A total of 387 stable patients were managed using a coronary CTA/FFR CT diagnostic strategy, whilst 44 underwent coronary CTA alone and served as control patients. The baseline clinical characteristics of patients are shown in Table 1. For those that underwent coronary CTA and selective FFR CT, the mean age was 58.9 ± 13.1 years with a female predominance (51%). Comorbidities included hypertension in 60%, diabetes in 17%, and hyperlipidemia in 64%. Mean BMI was 29.7 kg/m 2 . Approximately half of the patients were referred with atypical chest pain and 149 (39%) patients underwent functional stress testing less than six months prior to CTA acquisition. Using the Diamond-Forrester score, 90.1% of patients were at an intermediate clinic risk.
For those that underwent coronary CTA/FFR CT, 71.2% of patients received metoprolol before the scan, with an average oral dose of 106 ± 57 mg reaching an HR during the scan of 59 ± 7 bpm (Table 2). Sublingual nitroglycerin was administered in all but one patient. The use of beta-blockers and sublingual nitroglycerin was not reported in nine and ten patients, respectively. Mean radiation doses for prospective and retrospective acquisitions were 4.8 mSv and 10.9 mSv, respectively.
Out of the 387 patients, 204 had CAD of indeterminate hemodynamic significance by coronary CTA and were submitted for possible FFR CT . FFR CT results were available in 187 of 204 (92%) patients. Coronary CTA image quality was not acceptable for FFR CT analysis in 17 of 204 (8%) patients due to motion artifact, calcification and misregistration. 10.9 ± 6.0 Values are mean ± standard deviation, range, or n (%). CTA, computed tomography angiography.
For those that underwent coronary CTA alone (control patients), ten patients (23%) had at least one vessel with ≥50% diameter of stenosis; 8/10 (80%) underwent ICA, and three were revascularized (3 PCI, 0 CABG). One patient in the control group experienced unstable angina leading to urgent revascularization three years after their CTA. Based upon what would have been expected in our institutional practice, compared to coronary CTA alone, coronary CTA and selective FFR CT reduced the rates of ICA (45% vs. 80%) for those with obstructive CAD. The proportion of ICA patients undergoing revascularization was 38% (3/8).
Only 1% of patients who had stenosis <50% and were FFR CT -negative underwent ICA. Three of the 40 patients (8%) who had stenosis ≥50% and were FFR CT -negative underwent ICA. Of the patients with stenosis ≥50% with positive nadir FFR CT 61% underwent ICA (Table 3).

Discussion
In our evaluation of intermediate clinical follow-up of FFRCT in clinical practice, we identified a number of important findings: (1) FFRCT was feasible with a conclusive result in >90% of patients; (2) A diagnostic strategy of coronary CTA plus FFRCT was associated with less ICA in patients with CAD, compared to coronary CTA alone; (3) Among those who deferred ICA, there was no MACE after more than a one-year follow-up; (4) A high proportion of those who underwent ICA were revascularized, resulting in higher diagnostic ICA yield and more efficient utilization of catheterization lab resources.
Over the past decade, the field of coronary CTA has seen tremendous progress. Anatomic assessment using coronary CTA is excellent for the detection and exclusion of CAD [5][6][7][8]. Recent studies, such as the SCOT-HEART trial, established that, in patients with suspected angina due to CAD, coronary CTA halved fatal and non-fatal myocardial infarction [29,30]. A contemporary systematic review and meta-analysis of over 20,000 patients determined that, compared with functional-stress testing, coronary CTA was associated with reduced incidence of myocardial infarction, but with an increased incidence of ICA [31]. Coronary CTA alone tends to overestimate the severity of disease, and the relationship between stenosis and ischemia is poor [9][10][11][12]. In the

Discussion
In our evaluation of intermediate clinical follow-up of FFR CT in clinical practice, we identified a number of important findings: (1) FFR CT was feasible with a conclusive result in >90% of patients; (2) A diagnostic strategy of coronary CTA plus FFR CT was associated with less ICA in patients with CAD, compared to coronary CTA alone; (3) Among those who deferred ICA, there was no MACE after more than a one-year follow-up; (4) A high proportion of those who underwent ICA were revascularized, resulting in higher diagnostic ICA yield and more efficient utilization of catheterization lab resources.
Over the past decade, the field of coronary CTA has seen tremendous progress. Anatomic assessment using coronary CTA is excellent for the detection and exclusion of CAD [5][6][7][8].
Recent studies, such as the SCOT-HEART trial, established that, in patients with suspected angina due to CAD, coronary CTA halved fatal and non-fatal myocardial infarction [29,30]. A contemporary systematic review and meta-analysis of over 20,000 patients determined that, compared with functional-stress testing, coronary CTA was associated with reduced incidence of myocardial infarction, but with an increased incidence of ICA [31]. Coronary CTA alone tends to overestimate the severity of disease, and the relationship between stenosis and ischemia is poor [9][10][11][12]. In the majority of patients with stable ischemic heart disease, a revascularization strategy based only on anatomic evidence of CAD does not appear to confer clinical benefit [32][33][34]. On the other hand, revascularization of functionally significant CAD as assessed by FFR improves clinical outcomes in a highly cost-effective manner [35][36][37][38]. These findings led invasive FFR to become the gold standard test for determining the functional significance of indeterminate lesions and in guiding revascularization, supported by American and European guidelines [13,14]. Recently, there has been great interest in deriving FFR noninvasively, augmenting the anatomic data from coronary CTA with the functional relevance of disease in a lesion-specific manner. FFR CT has been validated in a number of accuracy studies, with the most recent NXT trial reporting per-vessel sensitivities and specificities of 84% and 86%, respectively [16][17][18]20]. Based on the evidence, our diagnostic pathway utilizing coronary CTA and FFR CT when needed is promoted by objective third-party bodies, such as the National Institute for Health and Care Excellence (NICE), whose stable chest pain guidelines recommend coronary CTA in lieu of functional testing as the first-line test for the evaluation of patients with chest pain and FFR CT, as it may avoid the need for ICA [39,40].
FFR CT was feasible with a conclusive result in >90% of patients. This finding is in line with prior studies performed outside the United States [41][42][43]. Clinical interpretation of FFR CT in conjunction with anatomic assessment of CAD by coronary CTA is dependent on appropriate coronary luminal modeling. Inadequate signal or contrast relative to noise and coronary motion or misalignment artifacts may compromise the accuracy of plaque, lumen, CT interpretation and FFR CT analysis. Misalignment artifact has consistently been shown to mostly affect the accuracy of FFR CT [44]. Guideline-directed coronary CTA acquisition methods, including adequate beta-blockade for heart rate control and nitroglycerin, are designed to optimize image quality. Adherence to these methods, in conjunction with feedback on the acceptability of data sets for FFR CT analysis, may improve acceptance rates for FFR CT and coronary CTA image quality, even at experienced centers.
In the invasive arm of the prospective PLATFORM (Prospective LongitudinAl Trial of FFR CT : Outcome and Resource Impacts) clinical utility trial, a diagnostic strategy guided by FFR CT resulted in the elimination of 61% of previously planned ICA with no adverse events over a one-year follow-up [20]. In doing so, coronary CTA and FFR CT helped enrich the population undergoing ICA, with an 83% reduction in the incidence of non-obstructive disease noted on ICA. Our findings are in line with PLATFORM, and, in our study, FFR CT reduced the frequency of ICA.
Half (45 of 90) of patients with nadir FFR CT positivity did not proceed with ICA. The mean distal FFR CT value for all FFR CT -positive vessels in these 45 patients was 0.75. FFR values between 0.75-0.80 have been described as the "gray zone", with clinically relevant ischemia ambiguous in this range [45]. Among those with 30-50% diameter of stenosis, a minority of nadir FFR CT -positive vessels underwent ICA and revascularization. A recent study found that high-risk plaque, increasing lipid necrotic core and non-calcified plaque burden on coronary CTA predict ischemia in non-obstructive lesions [46]. Thus, for those with 30-50% diameter of stenosis, it may be reasonable to reserve FFR CT for those lesions with adverse plaque characteristics or significant atherosclerotic burden. Further studies are needed to help define the role of FFR CT in stenoses <50%. Additionally, in our practice, the focus when interpreting FFR CT has shifted to FFR CT values that are distal to a treatable focal stenosis. Simply relying on distal-tip values rather than values distal to lesions may not be the most clinically significant [24,25]. Decisions to proceed with ICA should involve additional information, such as anatomy, the location of stenosis, vessel size, suitability for performing revascularization, patient symptoms and clinical judgment.
Norgaard et al. recently demonstrated that deferring ICA in patients with FFR CT > 0.80 had a favorable short-term prognosis (median follow-up period of 12 months) [41]. Importantly, in our study, there were no adverse events in a slightly longer follow-up interval of 15 months. This underscores the favorable clinical outcome in individuals with FFR CT > 0.80 and in select patients with distal-tip FFR CT ≤ 0.80, which may further aid clinicians in their decision-making.
Although diagnostic ICA utilization was reduced using the coronary CTA/FFR CT strategy, among those with obstructive CAD, the proportion of ICA patients who underwent revascularization was 62% (34 of 55). Multiple other studies in various clinical settings, including Emergency Departments, the Veterans Affairs health system, and in various countries, have reported lower diagnostic yield and revascularization rates with a standard of care practice not incorporating FFR CT in the diagnostic pathway [47][48][49][50][51][52]. We observed a higher diagnostic yield of cardiac catheterization through improved patient selection combining anatomic with functional data in one platform using FFR CT. This strategy enriched the catheterization-laboratory experience for our patients by sending those individuals to the laboratory who would benefit most from revascularization.
Our study has several limitations. Being an observational study, patients were not randomized and there was inherent subjectivity of patients referred for CTA, FFR CT evaluation, ICA and revascularization. FFR CT was adjudicated positive if the value was below 0.80 anywhere along the length of the vessel. As clinical data were collected from the hospital electronic medical record, there could have been a small number of patients who had follow-up at another health system which were not accounted for. Prior to our institutional implementation of FFR CT , we performed very few coronary CTAs. Thus, our control group is small. Finally, the generalizability of the study is limited as the data is from a single center with access to FFR CT .

Conclusions
FFR CT is feasible and has utility within the United States healthcare system. Deferral of ICA based on coronary CTA and FFR CT is safe and improves catheterization-laboratory efficiency.