A growing body of evidence supports the use of functional computed tomography (CT) imaging, including myocardial stress CT perfusion and CT-derived fractional flow reserve (FFRCT), for guiding clinical management in appropriately selected patients with suspected ischemic heart disease. Briefly, CT perfusion is a myocardial perfusion imaging technique that measures the amount of iodine contrast present within the myocardium, allowing one to create an attenuation map of the left ventricle analogous to a single-photon emission CT (SPECT) perfusion map.¹ FFRCT, in contrast, is a computational fluid dynamics modeling technique that can be applied to a CT coronary angiography (CTCA) dataset for estimating lesion-specific functional information of a coronary stenosis without requiring any protocol modifications.² Both CT perfusion and FFRCT are complementary to CTCA and offer greater specificity and positive predictive value for detecting hemodynamically significant coronary artery disease (CAD) compared with anatomic imaging alone. The two strategies are particularly valuable in guiding clinical management for patients with moderate stenosis (50-70%) detected on CTCA and in special circumstances when the accuracy of CTCA is compromised, such as in patients with coronary stents and heavily calcified arteries. Data from the FAME (Fractional Flow Reserve Versus Angiography for Multivessel Evaluation)³ and FAME 2 (Fractional Flow Reserve Guided Percutaneous Coronary Intervention Plus Optimal Medical Treatment Verses OMT)⁴ trials have demonstrated that invasive fractional flow reserve ischemic-guided revascularization reduce major adverse cardiac events (MACE), whereas angiographic strategies alone are ineffective for guiding revascularization. Functional CT imaging in combination with CTCA offers an opportunity for comprehensive noninvasive evaluation of coronary anatomy and function within a single imaging session, leveraging both the strong negative predictive value of CTCA in low-to-intermediate-risk patients and the higher specificity and positive predictive value of CT perfusion and FFRCT in intermediate-to-high-risk patients.

In appropriately selected patients, CT perfusion and FFRCT are ready for clinical use in light of their demonstrated added value across four key domains: 1) improvement in accuracy for hemodynamically significant CAD, 2) safety and improvement in patient outcomes, 3) reduction in healthcare costs, and 4) streamlined diagnostic workflow (Figure 1).

Figure 1: Value added With CT perfusion and FFRCT in Appropriately Selected Patients

Improvement in Accuracy for Hemodynamically Significant CAD

Compared with CTCA alone, functional CT strategies offer additional incremental accuracy for detecting hemodynamically significant CAD among patients with intermediate stenosis. This is largely driven by the incremental improvement in specificity and positive predictive value afforded by stress CT perfusion and FFRCT.

Stress CT perfusion has consistently demonstrated high diagnostic accuracy over CTCA alone when compared with other functional imaging techniques and invasive fractional flow reserve. For example, in a multicenter study of 110 subjects comparing the accuracy of CT perfusion against SPECT, Cury et al.⁵ demonstrated that regadenoson CT perfusion was non-inferior to SPECT for detecting reversible ischemia with an agreement rate of 0.87. When comparing stress CT perfusion to invasive fractional flow reserve as a reference standard, Ko et al.⁶ demonstrated that the combination of ≥50% stenosis on CTCA and a perfusion defect on stress CT perfusion was 68% sensitive and 98% specific for fractional flow reserve ≤0.8, whereas <50% stenosis on CTCA and normal perfusion on stress CT perfusion were 100% specific for exclusion of ischemia by fractional flow reserve. In CORE320,¹ a multicenter trial of 381 subjects, the combination of a perfusion defect on CT perfusion and ≥50% stenosis on CTCA was compared against the combination of a perfusion defect on SPECT and ≥50% stenosis on invasive coronary angiography. Results from CORE320 (Combined Non-invasive Coronary Angiography and Myocardial Perfusion Imaging Using 320 Detector Computed Tomography) trial demonstrated improved accuracy for flow-limiting disease with combined stress CT perfusion and CTCA compared with CTCA alone, driven by an increase in specificity and positive predictive value. In a meta-analysis on the diagnostic performance of stress CT perfusion by Pelgrim et al., which included 22 articles and a pooled sample size over 1,500 subjects, the combination of CT perfusion and CTCA yielded a pooled vessel-based sensitivity of 85% (67-93%) and specificity of 93% (89-96%) when using stenosis >50% on invasive coronary angiography as the reference standard.

Stress CT perfusion may be particularly valuable in patients with a high burden of coronary calcification. Prior studies have demonstrated limited diagnostic power of CTCA for detecting obstructive CAD among patients with severe coronary calcification due to partial volume averaging (blooming) artifacts. For example, in the CORE-64 (Diagnostic Accuracy of Multi-Detector Spiral Computed Tomography Angiography Using 64 Detectors) multicenter study evaluating diagnostic accuracy of CTCA, Arbab-Zadeh et al. demonstrated a lower area under the receiver-operating-characteristics curve for patients with calcium scores ≥600 (0.81 vs. 0.93) when compared with quantitative coronary angiography.⁷ Further, the negative predictive value for patients with calcium scores ≥100 decreased from 0.93 to 0.75. In a sub-study of CORE320, Sharma et al.⁸ further noted that combined stress CT perfusion and CTCA yielded a higher diagnostic accuracy than CTCA for patients with coronary artery calcium scores >400, suggesting added value of stress CT perfusion in patients with severe coronary calcification.

FFRCT has also demonstrated high diagnostic performance when compared against invasive fractional flow reserve as a reference standard. In the DISCOVER-FLOW (The Diagnosis of Ischemia-Causing Stenoses Obtained Via Noninvasive Fractional Flow Reserve)² trial, FFRCT yielded 82% specificity and 74% positive predictive value, with incremental improvement in accuracy over CTCA alone (84 vs. 59%). In the follow-up NXT (Analysis of Coronary Blood Flow Using CT Angiography: Next Steps)⁹ validation study comparing FFRCT against invasive fractional flow reserve in 251 patients with CTCA stenosis 30-90%, FFRCT yielded 81% accuracy and 79% specificity. More importantly, FFRCT correctly reclassified 68% of false positive patients as true negatives, highlighting the potential role of FFRCT as a gatekeeper to invasive coronary angiography. In a recent meta-analysis by Danad et al.,¹⁰ FFRCT showed high sensitivity (85-93%) and moderate specificity (65-75%) when compared with invasive fractional flow reserve, and the authors concluded that FFRCT in combination with CTCA could significantly improve diagnostic specificity of CTCA given the coupling of anatomic and functional measures.

Safety and Improvement in Patient Outcomes

Functional CT imaging strategies appear safe and may improve patient outcomes in appropriately selected patients. In PLATFORM (Prospective Longitudinal Trial of FFRCT: Outcome and Resource Impacts),^11,12 a recent multicenter, controlled, prospective comparative effectiveness trial, 584 patients with stable chest pain across 11 centers underwent testing with a combination of FFRCT and CTCA. The study was designed to evaluate the effectiveness of usual care compared against testing with a combination of FFRCT and CTCA. Among 117 patients whose invasive coronary angiogram was cancelled based on findings from FFRCT, there were no adverse clinical events between 90 days and 1 year. In addition, only 4 patients required invasive coronary angiography during the follow-up interval, of which 3 showed no obstructive disease. These data highlight the safety and durability of an FFRCT-based approach for evaluating CAD. Further, patients in the FFRCT/CTCA arm reported superior improvement in quality of life, both overall and angina-specific, throughout the surveillance period.¹²

In a recent study by Nørgaard et al.,¹³ the safety and clinical utility of FFRCT for decision-making in patients with stable CAD was evaluated to understand how FFRCT could be translated into clinical practice and what impact it would have on clinical decision-making. Among patients with FFRCT >0.80 who were deferred from invasive coronary angiography, no MACE events occurred during a median follow-up of 12 months. These results suggest a favorable 1-year prognosis for patients without detectable ischemia on FFRCT and further demonstrate the feasibility of FFRCT in real-world symptomatic patients with intermediate-range stenosis.

Although safety and outcomes data for CT perfusion are lacking, there is robust evidence substantiating the safety and prognostic value of related myocardial perfusion imaging strategies, including SPECT. Lee et al.¹⁴ investigated the prognostic value of stress myocardial perfusion imaging using SPECT for prediction of cardiovascular death and nonfatal myocardial infarction within 1 year. Among 3,466 patients studied and followed, the addition of myocardial perfusion imaging to clinical factors yielded a 15% improvement in the net reclassification index of MACE risk beyond that afforded by clinical factors alone.

Functional CT imaging may also lower exposure to ionizing radiation in the diagnostic work-up of patients for CAD. With the advent of modern scanner technology such as dual-source high-pitch helical scanning, high-quality CTCA can be performed with less than 1 mSv radiation exposure, approximating the radiation exposure of a diagnostic mammogram.¹⁵ CT scanners with 264- and 320-multidetector rows can acquire a full CTCA dataset within 1-2 cardiac cycles with approximately 4 mSv radiation exposure.¹⁶ FFRCT is derived from the original CTCA dataset and thus does not demand additional radiation exposure. Although performance of stress CT perfusion does require additional CT scanning, the reported effective dose for these protocols ranges from 4.5 to 9 mSv, which is less than the typical radiation dose for nuclear medicine myocardial perfusion imaging (Table 1).¹⁶

Table 1: Ionizing Radiation Exposure From Common Noninvasive Cardiac Imaging Exams

Modality	Representative Effective Radiation Dose (mSv)
Chest x-ray (posteroanterior and lateral)	0.1
CTCA (64-multidetector system, retrospective gating)	12
CTCA (64-multidetector system, reduced kVp [100])	6
CTCA (64-multidetector system, prospective triggering)	3
CTCA (264- or 320-multidetector system)	4
CTCA (dual-source high-pitch helical scanning)	1
Sestamibi (1-day) stress/rest myocardial perfusion imaging	12
Tetrofosmin (1-day) stress/rest myocardial perfusion imaging	10
Thallium stress/redistribution myocardial perfusion imaging	29
Positron Emission Tomography Rubidium-82 stress/rest myocardial perfusion imaging	10
Diagnostic invasive coronary angiogram	7

Reduction in Healthcare Costs

By functioning as a gatekeeper to invasive coronary angiography, functional CT imaging has the potential to prevent unnecessary catheterizations and lower healthcare costs. Recent data from PLATFORM highlight the incremental cost-effectiveness provided by an FFRCT-guided approach.^11,12 The addition of FFRCT to CTCA increased diagnostic certainty as reflected by a cancellation of 61% of invasive coronary angiograms in patients who were initially planned to undergo the invasive procedure.¹¹ Incorporation of FFRCT also yielded a markedly lower normal catheterization rate among patients referred for invasive coronary angiography (31.6 vs 73.3%). Further, a FFRCT-guided strategy was associated with significant cost savings at 1 year: among patients who had an invasive test planned, there was a greater than $4,000 mean reduction in costs for those in the FFRCT arm compared with usual care. The estimated total savings to the healthcare system was 26% at 1 year.¹¹

To validate the generalizability of these data in clinical practice, a multicenter sub-study of the NXT trial (RIPCORD [Does Routine Pressure Wire Assessment Influence Management Strategy at Coronary Angiography for Diagnosis of Chest Pain?])¹⁷ evaluated the interpretation of CTCA from multiple cardiologists who also reported their initial plan to prescribe optimal medical therapy, percutaneous coronary intervention, or coronary artery bypass graft surgery. The cardiologists were then provided results of FFRCT, and their proposed management strategies were reassessed. Results indicated a significant increase in the prescription of optimal medical therapy alone with a reduction in unnecessary invasive coronary angiograms.

As for stress CT perfusion, a meta-analysis of 37 studies by Takx et al.¹⁸ comparing multiple noninvasive myocardial perfusion imaging strategies with invasive fractional flow reserve as a reference standard, the authors concluded that stress CT perfusion can accurately rule out hemodynamically significant CAD and perfusion defects as a gatekeeper for invasive coronary angiography. When compared against other myocardial perfusion imaging strategies, stress CT perfusion performed similarly to stress cardiac magnetic resonance imaging (MRI) but superiorly to SPECT and echocardiography as demonstrated by the pooled negative likelihood ratios (negative likelihood ratio 0.12 for CT perfusion vs. 0.39 for SPECT vs. 0.42 for echocardiography).

Streamlined Diagnostic Work-up

When combined with CTCA, both stress CT perfusion and FFRCT offer a comprehensive evaluation of coronary anatomy and hemodynamic evaluation of stenosis within a single imaging session. Such a "one-stop shop" work-up of CAD can be leveraged to expedite a final diagnosis and reduce the number of diagnostic tests necessary to arrive at a final diagnosis. More importantly, such a work-up can be the gateway to appropriate revascularization. These functional CT imaging strategies are complementary to CTCA. With the excellent anatomic definition provided by CTCA, one can identify a culprit coronary artery, assess plaque morphology for high-risk features,¹⁹ determine the extent of subclinical atherosclerosis for initiation and intensification of medical therapy, and exclude CAD in low-to-intermediate-risk patients with high negative predictive value.²⁰ In contrast, functional CT imaging with CT perfusion and FFRCT allow one to identify the impact of plaque on blood flow, optimize clinical management, and avoid unnecessary invasive testing or guide for appropriate revascularizations. CT technology is widely available at most hospitals, and patient throughput is generally faster when compared with MRI and positron emission tomography. Such accessibility and efficiency are favorable factors for both patients and hospital systems. In fact, recent data by Feger et al.²¹ demonstrate improved patient satisfaction with stress CT perfusion compared with MRI, SPECT, and invasive coronary angiography. Stress CT perfusion was rated more comfortable than SPECT, and more patients preferred CT as a future diagnostic test.

Limitations and Future Considerations

Because the clinical benefit of revascularization is largely limited to ischemia-causing lesions, functional CT imaging with stress CT perfusion and FFRCT will likely play an important role in guiding optimal management among patients with intermediate coronary lesions. Although there is potential for these strategies to become competitive with one another, growing evidence suggests they may have complementary roles. Some patients may experience greater benefit from a stress CT perfusion approach, and others may benefit more from FFRCT. For example, CT perfusion may be better suited in patients with heavy coronary calcium and coronary stents because these variables currently limit the accuracy of FFRCT. Likewise, FFRCT may be better suited for patients with multi-vessel disease in whom identifying lesion-specific ischemia for revascularization planning is in question. A recent study by Coenen et al.²² further suggests that a combination of both CT perfusion and FFRCT may offer diagnostic performance that is superior to either technique alone, as demonstrated by an improvement of the area under the curve from 0.78 to 0.85 (p < .05).

The benefits of CT perfusion and FFRCT are well established, but there are limitations to both techniques. FFRCT is currently a proprietary technology, which demands off-site analysis, and its accuracy depends upon a high-quality CTCA exam with minimal motion. CT perfusion requires protocol and workflow modifications that may be difficult at some centers and incrementally increases radiation dose beyond that of CTCA. Nevertheless, both strategies are ready for clinical use in appropriately selected patients and are likely to have a significant impact on patient care in years to come.

References

1. Rochitte CE, George RT, Chen MY, et al. Computed tomography angiography and perfusion to assess coronary artery stenosis causing perfusion defects by single photon emission computed tomography: the CORE320 study. Eur Heart J 2014;35:1120-30.
2. Koo BK, Erglis A, Doh JH, et al. Diagnosis of ischemia-causing 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.
3. Tonino PA, De Bruyne B, Pijls NH, et al. Fractional flow reserve versus angiography for guiding percutaneous coronary intervention. N Engl J Med 2009;360:213-24.
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7. Arbab-Zadeh A, Miller JM, Rochitte CE, et al. Diagnostic accuracy of computed tomography coronary angiography according to pre-test probability of coronary artery disease and severity of coronary arterial calcification. The CORE-64 (Coronary Artery Evaluation Using 64-Row Multidetector Computed Tomography Angiography) International Multicenter Study. J Am Coll Cardiol 2012;59:379-87.
8. Sharma RK, Arbab-Zadeh A, Kishi S, et al. Incremental diagnostic accuracy of computed tomography myocardial perfusion imaging over coronary angiography stratified by pre-test probability of coronary artery disease and severity of coronary artery calcification: The CORE320 study. Int J Cardiol 2015;201:570-7.
9. Nørgaard BL, Leipsic J, Gaur S, et al. 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.
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12. Hlatky MA, De Bruyne B, Pontone G, et al. Quality-of-Life and Economic Outcomes of Assessing Fractional Flow Reserve With Computed Tomography Angiography: PLATFORM. J Am Coll Cardiol. 2015;66:2315-23.
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14. Lee DS, Husain M, Wang X, Austin PC, Iwanochko RM. Cardiovascular outcomes after pharmacologic stress myocardial perfusion imaging. Am Heart J 2016;174:138-46.
15. Achenbach S, Marwan M, Ropers D, et al. Coronary computed tomography angiography with a consistent dose below 1 mSv using prospectively electrocardiogram-triggered high-pitch spiral acquisition. Eur Heart J 2010;31:340-6.
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17. Curzen N, Rana O, Nicholas Z, et al. Does routine pressure wire assessment influence management strategy at coronary angiography for diagnosis of chest pain?: the RIPCORD study. Circ Cardiovasc Interv 2014;7:248-55.
18. Takx RA, Blomberg BA, El Aidi H, et al. Diagnostic accuracy of stress myocardial perfusion imaging compared to invasive coronary angiography with fractional flow reserve meta-analysis. Circ Cardiovasc Imaging 2015;8:e002666.
19. Puchner SB, Liu T, Mayrhofer T, et al. High-risk plaque detected on coronary CT angiography predicts acute coronary syndromes independent of significant stenosis in acute chest pain: results from the ROMICAT-II trial. J Am Coll Cardiol 2014;64:684-92.
20. Samad Z, Hakeem A, Mahmood SS, et al. A meta-analysis and systematic review of computed tomography angiography as a diagnostic triage tool for patients with chest pain presenting to the emergency department. J Nucl Cardiol 2012;19:364-76.
21. Feger S, Rief M, Zimmermann E, et al. Patient satisfaction with coronary CT angiography, myocardial CT perfusion, myocardial perfusion MRI, SPECT myocardial perfusion imaging and conventional coronary angiography. Eur Radiol. 2015;25:2115-24.
22. Coenen A, Rossi A, Lubbers MM, et al. Integrating CT Myocardial Perfusion and CT-FFR in the Work-Up of Coronary Artery Disease. JACC Cardiovasc Imaging 2017 Jan 12 [Epub ahead of print].

Keywords: Atherosclerosis, Chest Pain, Angiography, Constriction, Pathologic, Coronary Angiography, Coronary Artery Bypass, Coronary Artery Disease, Coronary Stenosis, Diagnostic Tests, Routine, Diagnostic Imaging, Echocardiography, Heart Ventricles, Magnetic Resonance Imaging, Myocardial Infarction, Myocardial Perfusion Imaging, Myocardium, Percutaneous Coronary Intervention, Positron-Emission Tomography, Rubidium, Stents, Thallium, Tomography, Emission-Computed, Single-Photon, Tomography, X-Ray Computed

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