Added value of computed tomography fractional flow reserve in the diagnosis of coronary artery disease

www.nature.com/scientificreports OPEN Added value of computed tomography fractional flow reserve in the diagnosis of coronary artery disease J. Peper1,2*, J. Schaap3, J. C. Kelder1, B. J. W. M. Rensing1, D. E. Grobbee4, T. Leiner2 & M. J. Swaans1 Multiple non-invasive tests are performed to diagnose coronary artery disease (CAD), but all are limited to either anatomical or functional assessments. Computed tomography derived Fractional Flow Reserve (CT-FFR) based on patient-specific lumped parameter models is a new test combining both characteristics simulating invasive FFR. This study aims to evaluate the added value of CT-FFR over other non-invasive tests to diagnose CAD. Patients with clinical suspicion of angina pectoris between 2010 and 2011 were included in this cross-sectional study. All underwent stress electrocardiography (X-ECG), SPECT, CT coronary angiography (CCTA) and CT-FFR. Invasive coronary angiography (ICA) and FFR were used as reference standard. Five models mimicking the clinical workflow were fitted and the area under receiver operating characteristic (AUROC) curve was used for comparison. 44% of the patients included in the analysis had a FFR of ≤ 0.80. The basic model including pre-test-likelihood and X-ECG had an AUROC of 0.79. The SPECT-strategy had an AUROC of 0.90 (p = 0.008), CCTA-strategy of 0.88 (p < 0.001), 0.93 when adding CT-FFR (p = 0.40) compared to 0.94 when combining CCTA and SPECT. This study shows adding on-site CT-FFR based on patient-specific lumped parameter models leads to an increased AUROC compared to the basic model. It improves the diagnostic work-up beyond SPECT or CCTA and is non-inferior to the combined strategy of SPECT and CCTA in the diagnosis of hemodynamically relevant CAD. The generally accepted reference standard to physiologically assess stenosis-specific ischemia is wire-based fractional flow reserve (FFR)1–3. FFR is used for the diagnosis of coronary artery disease (CAD) requiring revascularization. It is defined as the ratio of maximum blood pressure distal to a stenotic lesion relative to normal maximum pressure in the same vessel4 It is therefore a useful addition to the anatomical assessment based on invasive coronary angiography (ICA) for the diagnosis of hemodynamically relevant C AD5. As part of a standard protocol to diagnose relevant CAD, multiple non-invasive tests are performed prior to invasive testing in patients with complaints of stable chest pain and a low or intermediate probability of C AD1,2. The current non-invasive tests are either limited to anatomical or functional assessments of the degree of coronary artery stenosis and therefore have a low specificity. One of the recommended non-invasive diagnostic tests that uses functional information only is Single Photon Emission Computed Tomography (SPECT). A recent patient-based meta-analysis reported a sensitivity of 0.70 and a specificity 0.786. Another often-used non-invasive diagnostic test, coronary computed tomography angiography (CCTA) is only based on anatomical information and the ability of assessing the functional severity is lacking. The sensitivity of CCTA is high (87–99%) while the specificity is moderate (61–83%)7–9 since CCTA tends to overestimate the lesions severity especially in the presence of calcified plaque. Multiple studies found that visual assessment alone is not sufficient to identify hemodynamically relevant C AD10,11. Recently, a new non-invasive strategy, virtual computed tomography based FFR, that combines both anatomical and functional testing has been developed. The CT-FFR is calculated using parametric lumped models 1 Department of Cardiology, St. Antonius Hospital, Koekoekslaan 1, 3435 CM Nieuwegein, The Netherlands. 2Department of Radiology, University Medical Center Utrecht, Heidelberglaan 100, 3584 CX Utrecht, The Netherlands. 3Department of Cardiology, Amphia Hospital, Molengracht 21, 4818 CK Breda, The Netherlands. 4Julius Center for Health Sciences and Primary Care, University Medical Center Utrecht, Heidelberglaan 100, 3584 CX Utrecht, The Netherlands. *email: Scientific Reports | (2021) 11:6748 | https://doi.org/10.1038/s41598-021-86245-8 1 Vol.:(0123456789) www.nature.com/scientificreports/ for computational fluid dynamic simulations of the blood flow to estimate invasive F FR12. Different algorithms have already been evaluated in multicenter studies demonstrating an improved diagnostic accuracy compared to CCTA alone13–16. Diagnostic test results of 0.85 for sensitivity and 0.78 for specificity were reported8. Based on these studies, it is reasonable to assume that CT-FFR might add diagnostic value after a positive or inconclusive CCTA, especially since it does not require additional testing, radiation or contrast medium. Furthermore, it might be an alternative to SPECT and therefore avoid additional use of gamma radiation, additional scan time and no stress testing is needed. To date, the diagnostic performance of CT-FFR has only been described as single test and not in the context of the entire clinical work-up of patients with angina pectoris. Therefore, the aim of this study is to evaluate the added value of CT-FFR beyond the exercise ECG, SPECT or CCTA in patients with intermediate to high pre-test probability of CAD. Methods Design and study population. This single center study population and the diagnostic work-flow have been previously described by Schaap et al.17. Briefly, the study population includes patients having a clinical suspicion of stable angina pectoris and an intermediate to high pre-test likelihood of CAD. Patients were included between 2010 and 201117,18. Exclusion criteria for participating in this study were a history of revascularization for CAD (PCI or CABG) or emergency patients (unstable cardiac condition) since the CT-FFR software is not yet validated in these patients. Patients not in sinus rhythm or with severe heart failure, valvular disease, (possible) pregnancy and contraindications to receive iodinated contrast agent were also excluded for participation in this study. The study conforms to the principles of the Declaration of Helsinki and the regional ethical review board (Medical research Ethics Committees United [MEC-U]) approved the study protocol. Written informed consent was obtained from all patients. Diagnostic workflow. All patients underwent an exercise electrocardiogram (X-ECG), stress/rest SPECT, CCS, CCTA and CT-FFR17. Imaging acquisition was performed on a hybrid SPECT-CT system, consisting of a gamma camera in combination with a 64-slice CT scanner (CardioMD and Brilliance 64, Philips Medical Systems, Best, the Netherlands). Prior to stress SPECT, X-ECG was performed. Pharmacological stress testing (adenosine at a standard rate of 0.14 mg per kg per minute over 6 min) was used in the cases that patients were unable to perform bicycle stress testing or failed to reach 85% of the predicted maximum heart rate. Rest SPECT was acquired in the (...truncated)