Fractional Flow Reserve Measurement by Computed Tomography: An Alternative to the Stress Test

Login or register to view PDF.
Abstract

Recent advances in computed tomographic technology have contributed towards improving coronary computed tomography angiography (CCTA) in determining the severity of coronary artery disease anatomically. Although the viability of CCTA has most often been confined to anatomical assessment, recent development has enabled evaluation of the haemodynamic significance of coronary artery disease. In light of this, CCTA-derived fractional flow reserve (FFRCT), a novel imaging modality, now permits the physiological assessment of coronary artery disease. To date, several studies have documented the diagnostic performance of FFRCT, and more trials are being performed that will further substantiate this technique. The present paper provides an overview and discussion of the available evidence for FFRCT in the clinical setting as well as potential future directions of FFRCT.

Disclosure
JKM has served as a consultant or on the medical advisory boards for GE Healthcare, HeartFlow Inc, and Arineta Ltd; and has received research support from GE Healthcare. JHL, BóH, DH, AR and FL have no conflicts of interest to declare.
Correspondence
James K Min, Weill Cornell Medical College, New York–Presbyterian Hospital, Dalio Institute of Cardiovascular Imaging, 413 E. 69th Street, Suite 108, New York, New York 10021, USA. E: jkm2001@med.cornell.edu
Received date
18 December 2015
Accepted date
31 May 2016
DOI
https://doi.org/10.15420/icr.2016:1:2
Acknowledgement
This study was supported by the National Institutes of Health (Bethesda, Maryland) under award numbers R01 HL111141 and R01 HL118019. This study was also funded, in part, by a generous donation from the Dalio Institute of Cardiovascular Imaging (New York, NY) and the Michael Wolk Foundation (New York, NY).

Coronary computed tomography angiography (CCTA) is a noninvasive tool capable of directly visualising the coronary anatomy with high sensitivity and negative predictive value (NPV) for coronary artery disease (CAD) compared to invasive coronary angiography (ICA).1,2 Recent innovations in computed tomography (CT) technology have led to the rapid development of CCTA and its selection as an anatomic alternative to stress imaging.3 Despite this, CCTA alone cannot independently determine the haemodynamic significance of coronary stenosis, as compared with stress imaging, due to the low specificity for identifying coronary stenoses that induce ischaemia.4 This emphasises the unpredictable relationship between stenosis severity and ischaemia, which may provoke the need for unnecessary invasive coronary angiography (ICA) in patients who do not have ischaemia.5 For instance, patients undergoing CCTA with an intermediate lesion requiring ischaemia evaluation may have layers of additional testing, such as stress echocardiography, myocardial perfusion imaging by single-photon emission computed tomography, positron emission tomography or cardiac magnetic resonance image.6

Fractional flow reserve (FFR), defined as the ratio of maximum flow in a stenotic artery to maximum blood flow if the same artery were normal, is an invasive technique to determine lesion-specific ischaemia and can assist in guiding coronary revascularisation.7,8 Notably, in the Fractional Flow Reserve Versus Angiography for Multivessel Evaluation (FAME) trial, the use of FFR to guide coronary intervention compared with ICA guidance resulted in a 33 % reduction in major adverse cardiac events.9

Recent advances in computational fluid dynamics enable the calculation of CCTA-derived FFR (FFRCT) from three-dimensional imaging anatomic models. Foremost, FFRCT reflects a novel imaging modality with the ability to determine the haemodynamic significance of CAD without additional radiation exposure or contrast injection beyond the initial CCTA (Figure 1). This review provides an overview of current evidence describing the appropriate use of FFRCT in the clinical setting, along with a discussion of the potential future directions of FFRCT.

Clinical Usefulness of FFR

FFR has been utilised to assess physiological function at the time of ICA in the cardiac catheterisation laboratory. The former procedure provides a reliable physiological index for determining whether coronary stenosis may cause ischaemia by measuring flow with a coronary guidewire before and after a visualised stenosis during maximal hyperaemia.10 A common definition of FFR is the maximal blood flow to the myocardium in the presence of a stenosis in the supplying coronary artery divided by the theoretical normal maximal flow in the same distribution.7 In current guidelines, a FFR value ≤0.80 is widely considered the threshold for revascularisation.

Numerous studies have confirmed the clinical benefit of utilising FFR in clinical practice.9,11–15 Revascularisation in the coronary arteries with a measured FFR of ≤0.80 was associated with improved prognosis, including a reduction in death rates, non-fatal myocardial infarction and urgent revascularisation when compared with ICA guided revascularisation alone or optimal medical therapy alone.16,17 Further still, Pijls et al. demonstrated in the DEFER trial that 5-year outcomes, and even 15-year outcomes, following deferral of percutaneous coronary intervention in the vessel of an intermediate coronary stenosis based on FFRs of ≥0.75 demonstrated excellent prognoses.11,18 In light of previous findings, current guidelines advocate a FFR-guided revascularisation strategy as a Class IA recommendation for identifying haemodynamically-relevant coronary lesions in stable patients, especially when non-invasive testing evidence of ischaemia is not available.19

Figure 1: Example Case of Coronary Computed Tomography Angiography (CCTA): a 69-year-old Caucasian Man with Exertional Angina who Underwent CCTA

Open in new tab
Open ppt

Diagnostic and Clinical Performance of FFRCT

To date, three prospective multicentre trials, namely the Diagnosis of Ischemia-Causing Stenoses Obtained via Non-invasive Fractional Flow Reserve (DISCOVER-FLOW),20 Determination of Fractional Flow Reserve by Anatomic Computed Tomographic Angiography (DeFACTO)21 and analysis of Coronary Blood Flow Using CT Angiography: Next Steps (NXT)22 studies, have evaluated the diagnostic performance of FFRCT compared with invasive FFR as a reference standard. These studies are summarised in Table 1.

The DISCOVER-FLOW study was the first multicentre trial that assessed the diagnostic performance of FFRCT against ICA and invasive FFR. It included 103 patients with 159 measured coronary vessels from four sites in the United States, Europe and Asia.20 Anatomical obstruction was defined as a CCTA with stenosis ≥50 %, and either FFR ≤0.80 or FFRCT ≤0.80 was defined as ischaemia. In this study, both FFRCT and FFR correlated well on a per-vessel analysis according to Spearman’s rank correlation, reporting a coefficient of 0.72 (P<0.001). Further, utilising FFRCT on a per-vessel analysis revealed a diagnostic accuracy of 84.3 %, sensitivity of 87.9 %, specificity of 82.2 %, positive predictive value (PPV) of 73.9 %, and NPV of 92.2 %. The results did not differ materially on a per-patient analysis. Conversely, the accuracy, specificity and PPV were 58.5 %, 39.6 % and 46.5 %, respectively, based on a per-vessel analysis of CCTA; while a per-patient analysis demonstrated an accuracy of 61.2 %, specificity of 24.5 % and PPV of 58.0 %, respectively, according to CCTA. The area under the receiver operating characteristic curve (AUC) was 0.90 for FFRCT, which was superior to CCTA, which had an AUC of 0.75 (P=0.001), indicating a significant improvement in the discrimination of ischaemia.

The DeFACTO trial included 252 patients across 17 centres in five countries with the measurement of 407 coronary vessels. It was conducted to determine the accuracy of FFRCT in comparison with invasive FFR as a gold standard for the diagnosis of haemodynamicallysignificant coronary stenosis.21 On a per-patient analysis, FFRCT was superior in detecting ischaemia when compared with CCTA according to diagnostic accuracy (73 % versus 64 %), sensitivity (90 % versus 84 %), specificity (54 % versus 42 %), PPV (67 % versus 61 %) and NPV (84 % versus 72 %), respectively. In a patient-based analysis restricted to those presenting with intermediate stenosis (i.e. 30–70 % stenosis), sensitivity was significantly higher for FFRCT than for CCTA (82 % versus 37 %), without a change in specificity. In addition, FFRCT displayed superior discrimination for ischaemia based on a per-patient as well as per-vessel analysis when compared with CCTA, with improved AUCs (0.81 versus 0.68 and 0.81 versus 0.75, respectively; P<0.001 for all). Though DeFACTO was unable to meet its pre-specified primary outcome, which was a per-patient diagnostic accuracy lower bound 95 % confidence interval no worse than 70 %, the utilisation of non-invasive FFRCT plus CT among stable patients demonstrated improved diagnostic accuracy as well as discrimination in comparison with CT alone for the diagnosis of haemodynamically-significant CAD.23

Most recently, the prospective multicentre NXT trial evaluated the diagnostic performance of FFRCT in 254 patients, with 484 vessels being studied.22 On a per-patient analysis, diagnostic accuracy, specificity and PPV were markedly higher for FFRCT (81 %, 79 % and 65 %, respectively) versus CCTA (53 %, 34 % and 40 %, respectively) (P<0.001, for all). Similarly, on a per-vessel analysis the accuracy, specificity and PPV were 86 %, 86 % and 61 %, respectively, for FFRCT compared with CCTA (65 %, 60 % and 33 %, respectively) (P<0.001, for all), without disparity in sensitivity (84 % versus 83 %). In the same study, a subgroup analysis among patients with intermediate stenosis severity (i.e. 30–70 % stenosis) demonstrated that FFRCT was superior to CCTA on a per-patient level, with better accuracy (80 % versus 51 %), specificity (79 % versus 32 %) and PPV (63 % versus 37 %) (P<0.001, for all) observed. Moreover, the AUCs for FFRCT on a per-patient and per-vessel basis were 0.90 and 0.93 versus 0.81 and 0.79 for CCTA, respectively (P<0.001 for all), indicating superior discrimination for ischaemia on the background of FFRCT. In summary, findings from the NXT multicentre trial support the contention that adding FFRCT to CCTA might provide a more comprehensive anatomical and physiological assessment of CAD.

Table 1: Summary of Diagnostic Accuracy Studies of Coronary Computed Tomography Angiography-derived Fractional Flow Reserve (FFRCT)

Open in new tab
Open ppt

In previous studies, CT datasets were transferred so software applications could be run, and consequently hours of processing were required before the results were returned to the physician. To this end, recent studies have explored on-site prototype algorithms to compute FFR from CCTA, which in turn may enable a more efficient patient flow and reduce analysing time to within 1 hour.24–26 Among these studies, De Geer et al. demonstrated that the sensitivity, specificity, NPV, PPV and accuracy of FFRCT for detecting significant stenosis (FFR≤0.80) were 0.83, 0.76, 0.93, 0.56 and 0.78, respectively, on a perlesion basis, and displayed a Spearman rank correlation coefficient of ρ=0.77 (P<0.001).26 Although still in its infancy, these investigators have strongly emphasised that this software permits on-site assessment of FFRCT within clinically-practical time frames, and may therefore have the necessary potential to be performed in a clinical setting.

Recently, the Prospective Longitudinal Trial of FFRCT: Outcome and Resource Impacts (PLATFORM) trial compared a FFRCT-guided diagnostic strategy (n=297) with usual care (n=287) in 584 patients with new-onset chest pain and intermediate risk of CAD.27 Usual care was stratified by planned ICA or planned non-invasive testing prior to enrollment. In the planned ICA stratum (FFRCT-guided, n=193; usual care, n=187), ICA was cancelled in 61 % after receiving coronary CTA/ FFRCT results, because the rate of non-obstructive CAD by ICA was 12.4 % (n=24) in the coronary CTA/FFRCT arm versus 73.3 % (n=137) in the usual care arm (P<0.001), with similar cumulative radiation exposure and 90 days clinical event rates. This result was similar after applying propensity score matching for 148 patients in each group (e.g. 12 % for CTA/FFRCT versus 72 % for usual care, P<0.001). In the planned non-invasive testing stratum (FFRCT-guided, n=104; usual care, n=100), the rate of non-obstructive CAD by ICA was comparable in both arms (12.5 % versus 6.0 %, P=0.95). Overall, there was no significant difference in revascularisation in subjects allocated to CTA/FFRCT compared to usual care in either the planned non-invasive or planned invasive testing arms (P=0.29 and 0.58, respectively). The PLATFORM trial suggests that FFRCT may be a useful and safe gatekeeper to ICA, particularly for reducing the likelihood of normal ICA when used as an alternative diagnostic tool to guide care in patients with planned invasive catheterisation.

Principal Components for Determining FFRCT

The scientific principles for determining FFRCT have been described in detail elsewhere.28 In brief, FFRCT utilises a computational fluid dynamics approach to determine the FFR of three vessels from typically-obtained CCTA images without additional imaging, changes of image acquisition protocols, additional medication or radiation exposure.28 The computational fluid dynamics method enables the quantification of fluid pressure and velocity based upon laws of mass conservation and momentum balance, while also solving the equations of human blood flow when applied to CCTA.

Details regarding the steps involved in the calculation of FFRCT have been outlined previously,23 and are briefly described as follows: 1) the acquisition of CCTA and creation of patient-specific anatomical models; 2) the quantification of total and vessel-specific coronary flow; 3) the calculation of baseline microvascular resistance; 4) the computation of hyperaemic changes in coronary artery resistance; and 5) the application of computational fluid dynamics to calculate coronary flow, pressure and velocity during the stages of rest and hyperaemia. While it can take approximately 8 hours to calculate the results of FFRCT, the majority of FFRCT measurements can generally be calculated within a few hours, and it is anticipated that more advanced techniques in the field of FFRCT will eventually induce a substantial reduction in calculation time.

Further Study of FFRCT

At present, studies related to FFRCT have mostly focused on its diagnostic performance for the determination of ischaemia, and comparisons of FFRCT with other stress imaging tests have not yet been implemented. To this end, several prospective multicentre clinical trials are currently on-going for the purpose of exploring the utility of FFRCT against other more established myocardial perfusion imaging procedures (Table 2). The upcoming Computed Tomographic Evaluation of Atherosclerotic Determinants of Myocardial Ischemia (CREDENCE) trial aims to evaluate the direct comparison of coronary CTA plus FFRCT with MPI by SPECT or PET (NCT02173275). Moreover, two other multicenter trials, the Dual Energy CT for Ischemia Determination Compared to “Gold Standard” Non-Invasive and Invasive Techniques (DECIDE-Gold)29 and the comparison between stress cardiac computed tomography PERfusion versus Fractional flow rEserve measured by Computed Tomography angiography In the evaluation of suspected cOroNary artery disease (PERFECTION),30 aim to assess the diagnostic power of FFRCT as compared with single/dual-energy CT perfusion stress imaging testing. The results of these trials will undoubtedly spark further interest in the clinical utility of FFRCT.

Table 2: On-going Prospective Multicentre Trials for Coronary Computed Tomography Angiography-derived Fractional Flow Reserve (FFRCT)

Open in new tab
Open ppt

Current Limitations of FFRCT

Despite the recent approval of FFRCT by the US Food and Drug Administration for routine use in patients without known CAD in the clinical setting, there remain several considerations relative to FFRCT that should be emphasised. Foremost, impaired image quality is capable of affecting the susceptibility of FFRCT. This infers that significant motion, beam-hardening from calcified lesions and artefacts from irregular breathing can affect image quality. Moreover, irregular and/or high heart rate, as well as a high body mass index, can further impair the quality of CT images. Further, several important factors are required to determine the accuracy of FFRCT, including the mathematical models related to coronary flow, lumen size, vessel resistance and potential variation in the hyperaemic response.6 To date, the extant literature has mostly focused on data from patients with an intermediate risk of CAD in contrast to those with a high pretest probability for whom performing ICA is typically mandatory in light of the time-consuming process of FFRCT. To this end, although the computation of FFRCT often takes several hours, forthcoming innovative iterations improve this limitation.23 At present, whether the impact of FFRCT is influenced by symptom typicality remains to be elucidated, and underlines the importance of future studies to examine the connection between FFRCT and symptom typicality. Although previous studies have demonstrated positive results in terms of diagnostic performance, we may add that FFRCT might not reliably reproduce the data obtained when using invasive FFR. To this end, the most recent NXT trial using the latest version of computational fluid dynamics demonstrated a PPV of only 65 % based on per-patient analysis. As such, additional studies are warranted to reliably determine the clinical performance of FFRCT for detecting significant lesion ischaemia. In addition, the performance of FFRCT is not yet indicated in patients with a prior history of coronary artery bypass surgery or percutaneous coronary intervention with suspected in-stent restenosis. Forthcoming studies will advance our understanding through utilising further FFRCT development, including automated segmentation methods, machinelearning techniques and the refinement of the boundary conditions that underlie the FFRCT technology, thereby hopefully addressing the limitations of this method.23

Future Directions for FFRCT

Several potential studies should be considered in future research that utilises FFRCT. Beyond improved diagnostic accuracy, FFRCT may enable improved guidance for clinical decision making. Importantly, further studies will assist in determining the role of FFRCT as a gatekeeper to cardiac catheterisation as well as its impact on cost and outcomes, thus building upon the near-term data brought to light by the PLATFORM trial.27 To this end, future studies such as the Assessing Diagnostic Value of Non-invasive FFRCT in Coronary carE (ADVANCE) study will investigate the clinical and economic impact of FFRCT as well as the potential reclassification of subjects with abnormal FFRCT for adverse cardiovascular outcomes.23 Determining the appropriate risk factors and CT characteristics for performing FFRCT remains a pressing issue for future research to address. Further, studies aimed at evaluating the cost-effectiveness of FFRCT should be considered. Hlatky et al. investigated the initial treatment costs from 96 patients in the DISCOVER-FLOW trial.31 In this study, the use of FFRCT for guiding the referral of patients for ICA and percutaneous coronary intervention reduced costs by 30 % ($7,674 per patient) when compared with the most commonly used ICA/visual strategy ($10,702 per patient), highlighting the potential value of FFRCT in a clinical setting.

The performance of ‘virtual stenting’ is an emerging topic in the field of FFRCT. In this regard, the computational modelling required for FFRCT allows for the modification of coronary flow models. Moreover, Kim and colleagues documented a positive correlation between invasive FFR and FFRCT before and after stenting, while displaying a 96 % overall accuracy.32 In that study, the investigators demonstrated the feasibility of virtual coronary stenting of CT-derived computational models, suggesting this technology may prove useful for predicting functional outcomes after coronary revascularisation.

Conclusion

FFRCT is a novel non-invasive technique for determining the haemodynamic significance of coronary artery stenosis. Prospective advances in FFRCT technology will assist in overcoming some of the current considerations associated with FFRCT. On-going prospective studies designed to compare the diagnostic power of FFRCT with other stress imaging tests will also offer clinicians an evidence-based alternative for detecting significant CAD, allowing for appropriate utilisation of FFRCT in the clinic.

References
  1. Miller JM, Rochitte CE, Dewey M, et al. Diagnostic performance of coronary angiography by 64-row CT. N Engl J Med 2008;359:2324–36.
    Crossref | PubMed
  2. Meijboom WB, Meijs MF, Schuijf JD, et al. Diagnostic accuracy of 64-slice computed tomography coronary angiography: a prospective, multicenter, multivendor study. J Am Coll Cardiol 2008;52:2135–44.
    Crossref | PubMed
  3. Marwick TH, Cho I, Ó Hartaigh B, et al. Finding the gatekeeper to the cardiac catheterization laboratory: Coronary CT angiography or stress testing? J Am Coll Cardiol 2015;65: 2747–56.
    Crossref | PubMed
  4. Meijboom WB, Van Mieghem CA, van Pelt N, et al. Comprehensive assessment of coronary artery stenoses: computed tomography coronary angiography versus conventional coronary angiography and correlation with fractional flow reserve in patients with stable angina. J Am Coll Cardiol 2008;52:636–43.
    Crossref | PubMed
  5. Hachamovitch R, Di Carli MF. Methods and limitations of assessing new noninvasive tests: part I: Anatomy-based validation of noninvasive testing. Circulation 2008;117: 2684–90.
    Crossref | PubMed
  6. Choi AD, Joly JM, Chen MY, et al. Physiologic evaluation of ischemia using cardiac CT: current status of CT myocardial perfusion and CT fractional flow reserve. J Cardiovasc Comput Tomogr 2014;8:272–81.
    Crossref | PubMed
  7. Pijls NH, De Bruyne B, Peels K, et al. Measurement of fractional flow reserve to assess the functional severity of coronary-artery stenoses. N Engl J Med 1996;334:1703–8;
    Crossref | PubMed
  8. de Bruyne B, Bartunek J, Sys SU, et al. Simultaneous coronary pressure and flow velocity measurements in humans. Feasibility, reproducibility, and hemodynamic dependence of coronary flow velocity reserve, hyperemic flow versus pressure slope index, and fractional flow reserve. Circulation 1996;94:1842–9;
    Crossref | PubMed
  9. Tonino PA, De Bruyne B, Pijls NH, et al. FAME Study Investigators. Fractional flow reserve versus angiography for guiding percutaneous coronary intervention. N Engl J Med 2009;360:213–24.
    Crossref | PubMed
  10. Pijls NH, De Bruyne B. Coronary pressure measurement and fractional flow reserve. Heart 1998;80:539–42. PMC1728867
    Crossref | PubMed
  11. Pijls NH, van Schaardenburgh P, Manoharan G, et al. Percutaneous coronary intervention of functionally nonsignificant stenosis: 5-year follow-up of the DEFER Study. J Am Coll Cardiol 2007;49:2105–11;
    Crossref | PubMed
  12. Fearon WF, Bornschein B, Tonino PA, et al. Fractional Flow Reserve Versus Angiography for Multivessel Evaluation (FAME) Study Investigators. Economic evaluation of fractional flow reserve-guided percutaneous coronary intervention in patients with multivessel disease. Circulation 2010;122: 2545–50.
    Crossref | PubMed
  13. Li J, Elrashidi MY, Flammer AJ, et al. Long-term outcomes of fractional flow reserve-guided angiography-guided percutaneous coronary intervention in contemporary practice. Eur Heart J 2013;34:1375–83.
    Crossref | PubMed
  14. Park SJ, Ahn JM, Park GM, et al. Trends in the outcomes of percutaneous coronary intervention with the routine incorporation of fractional flow reserve in real practice. Eur Heart J 2013;34:3353–61.
    Crossref | PubMed
  15. Van Belle E, Rioufol G, Pouillot C, et al. Investigators of the Registre Français de la FFR-R3F. Outcome impact of coronary revascularization strategy reclassification with fractional flow reserve at time of diagnostic angiography: insights from a large French multicenter fractional flow reserve registry. Circulation 2014;129:173–85.
    Crossref | PubMed
  16. De Bruyne B, Pijls NH, Kalesan B, et al. FAME 2 Trial Investigators. Fractional flow reserve-guided PCI versus medical therapy in stable coronary disease. N Engl J Med 2012;367:991–1001.
    Crossref | PubMed
  17. De Bruyne B, Fearon WF, Pijls NH, et al. FAME 2 Trial Investigators. Fractional flow reserve-guided PCI for stable coronary artery disease. N Engl J Med 2014;371:1208–17.
    Crossref | PubMed
  18. Zimmermann FM, Ferrara A, Johnson NP, et al. Deferral vs. performance of percutaneous coronary intervention of functionally non-significant coronary stenosis: 15-year follow-up of the DEFER trial. Eur Heart J 2015;36:3182–8.
    Crossref | PubMed
  19. Windecker S, Kolh P, Alfonso F, et al. Authors/Task Force Members. 2014 ESC/EACTS Guidelines on myocardial revascularization: The Task Force on Myocardial Revascularization of the European Society of Cardiology (ESC) and the European Association for Cardio-Thoracic Surgery (EACTS) Developed with the special contribution of the European Association of Percutaneous Cardiovascular Interventions (EAPCI). Eur Heart J 2014;35:2541–619.
    Crossref | PubMed
  20. Koo BK, Erglis A, Doh JH, et al. Diagnosis of ischemiacausing coronary stenoses by noninvasive fractional flow reserve computed from coronary computed tomographic angiograms. Results from the prospective multicenter DISCOVER-FLOW (Diagnosis of Ischemia-Causing Stenoses Obtained Via Noninvasive Fractional Flow Reserve) study. J Am Coll Cardiol 2011;58:1989–97.
    Crossref | PubMed
  21. Min JK, Leipsic J, Pencina MJ, et al. Diagnostic accuracy of fractional flow reserve from anatomic CT angiography. JAMA 2012;308:1237–45;
    Crossref | PubMed
  22. Nørgaard BL, Leipsic J, Gaur S, et al. NXT Trial Study Group. Diagnostic performance of noninvasive fractional flow reserve derived from coronary computed tomography angiography in suspected coronary artery disease: the NXT trial (Analysis of Coronary Blood Flow Using CT Angiography: Next Steps). J Am Coll Cardiol 2014;63:1145–55.
    Crossref | PubMed
  23. Min JK, Taylor CA, Achenbach S, et al. Noninvasive Fractional Flow Reserve Derived From Coronary CT Angiography: Clinical Data and Scientific Principles. JACC Cardiovasc Imaging 2015;8:1209–22.
    Crossref | PubMed
  24. Renker M, Schoepf UJ, Wang R, et al. Comparison of diagnostic value of a novel noninvasive coronary computed tomography angiography method versus standard coronary angiography for assessing fractional flow reserve. Am J Cardiol 2014;114:1303–8.
    Crossref | PubMed
  25. Coenen A, Lubbers MM, Kurata A, et al. Fractional flow reserve computed from noninvasive CT angiography data: diagnostic performance of an on-site clinician-operated computational fluid dynamics algorithm. Radiology 2015;274:674–83.
    Crossref | PubMed
  26. De Geer J, Sandstedt M, Bjorkholm A, et al. Software-based on-site estimation of fractional flow reserve using standard coronary CT angiography data. Acta Radiol 2015. pii: 0284185115622075; epub ahead of press
    Crossref | PubMed
  27. Douglas PS, Pontone G, Hlatky MA, et al. PLATFORM Investigators. Clinical outcomes of fractional flow reserve by computed tomographic angiography-guided diagnostic strategies vs. usual care in patients with suspected coronary artery disease: the prospective longitudinal trial of FFRct: outcome and resource impacts study. Eur Heart J 2015;36:3359–67.
    Crossref | PubMed
  28. Taylor CA, Fonte TA, Min JK. Computational fluid dynamics applied to cardiac computed tomography for noninvasive quantification of fractional flow reserve: scientific basis. J Am Coll Cardiol 2013;61:2233–41.
    Crossref | PubMed
  29. Truong QA, Knaapen P, Pontone G, et al. Rationale and design of the dual-energy computed tomography for ischemia determination compared to “gold standard” non-invasive and invasive techniques (DECIDE-Gold): A multicenter international efficacy diagnostic study of rest-stress dual-energy computed tomography angiography with perfusion. Journal of nuclear cardiology : official publication of the American Society of Nuclear Cardiology 2015;22:1031–40.
    Crossref | PubMed
  30. Pontone G, Andreini D, Guaricci AI, et al. Rationale and design of the PERFECTION (comparison between stress cardiac computed tomography PERfusion versus Fractional flow rEserve measured by Computed Tomography angiography In the evaluation of suspected cOroNary artery disease) prospective study. Journal of Cardiovascular Computed Tomography 2016.
  31. Hlatky MA, Saxena A, Koo BK, et al. Projected costs and consequences of computed tomography-determined fractional flow reserve. Clin Cardiol 2013;36:743–8.
    Crossref | PubMed
  32. Kim KH, Doh JH, Koo BK, et al. A novel noninvasive technology for treatment planning using virtual coronary stenting and computed tomography-derived computed fractional flow reserve. JACC Cardiovasc Interv 2014; 7:72–8.
    Crossref | PubMed