Non-Invasive Fractional Flow Reserve (FFR) for Ischemic Heart Disease

Title XVIII of the Social Security Act, §1862 (a)(1)(A) allows coverage and payment for only those services that are considered to be reasonable and necessary for the diagnosis or treatment of illness or injury or to improve the functioning of a malformed body member.

Title XVIII of the Social Security Act, §1862 (a)(1)(D) Items and services related to research and experimentation.

Title XVIII of the Social Security Act, §1862 (a)(7) states Medicare will not cover any services or procedures associated with routine physical checkups.

Title XVIII of the Social Security Act, §1833 (e) prohibits Medicare payment for any claim which lacks the necessary information to process the claim.

42 CFR §410.32 indicates that diagnostic tests may only be ordered by the treating physician (or other treating practitioner acting within the scope of his or her license and Medicare requirements).

CMS Internet-Only Manual, Pub 100-03, Medicare National Coverage Determinations Manual, Chapter 1, Part 4,

• 220.

The Protecting Access to Medicare Act (PAMA) of 2014, Section 218(b), established a new program to increase the rate of appropriate advanced diagnostic imaging services provided to Medicare beneficiaries.

42 CFR §414.92 codifies the Appropriate use Criteria Program policies.

FDA-approved FFRct technology may be considered reasonable and necessary in the management of patients with:

1. Intermediate-risk* patients with acute or stable chest pain and with no known history coronary artery stenosis with finding of 40-90% in proximal or middle coronary artery on CCTA¹OR
2. Intermediate-risk* patients with acute chest pain and known non-obstructive (<50%) CAD coronary artery stenosis with finding of 40-90% stenosis in proximal or middle coronary artery on CCT¹ OR
3. Stable nonobstructive coronary artery disease (<50% stenosis) with persistent** symptoms requiring further test, and finding of 40-90% stenosis on CCTA¹

AND

Not in conjunction with stress testing* (unless CCTA was not sufficient quality for FFRCT, and an alternative study is needed)

• Intermediate and high-risk and stress test as defined in the 2021 AHA/ACC/ASE/CHEST/SAEM/SCCT/SCMR Guideline for the Evaluation and Diagnosis of Chest Pain¹

** Persistent symptoms are unacceptable ischemia-related symptoms despite maximally tolerated medical therapy.

FFRct is not considered reasonable in the following clinical circumstances:

1. Prior placement of prosthetic valves
2. Prior placement of grafts in coronary bypass surgery
3. Suspicion of acute coronary syndrome (where MI or unstable angina have not been ruled out)
4. Intracoronary metallic stent
5. Status post-heart transplantation
6. Recent MI (30 days or less)
7. Prior pacemaker or defibrillator lead placement
8. Newly diagnosed systolic heart failure, with no prior left heart catheterization
9. Left main coronary artery disease with Intermediated Coronary Stenosis (lumen reduction less than or equal to 40%)
10. Non-obstructing stenosis (<50% of all major epicardial vessels) on CTA or catheterization in the past twelve months, in the absence of a new symptom complex.
11. If turnaround times may impact prompt clinical care decisions

This service should be performed in patients with stable coronary symptoms. It should not be performed until after the base study (CCTA) has been completed and interpreted. If higher grade stenoses (i.e. greater than 90%) are present, this study is not medically necessary, as the patient should proceed to catheterization. Similarly, low-grade stenoses (less than 40%) do not require additional confirmatory data. This should be performed as an alternative to stress testing. 

Background

The concept of invasive fractional flow reserve as a diagnostic tool was introduced in the early 1990’s. The FAME and FAME-II trials supported an FFR-wire guided revascularization strategy as opposed to purely angiographically guided revascularization.² The National Cardiovascular Data Registry demonstrated a low diagnostic yield from traditional exercise stress testing when the patient progressed to invasive coronary angiography. Fractional flow reserve is considered the gold standard for assessing the hemodynamic significance of intermediate coronary stenosis by measuring the pressure difference across a coronary artery stenosis.³ Intracoronary catheter pressure measurement before and after the stenosis are compared, and FFR of 0.80 correlates with a 20% pressure drop after the stenosis. This measurement can help determine if the vessel narrowing is limiting blood flow and access the need for revascularization or stenting. Clinical studies have demonstrated that invasive FFR reduces unnecessary stenting procedures and associated risk.^2,4 The use of invasive FFR is supported by the Society of Cardiac Angiography and Interventions (SCAI) and American College of cardiology (ACC). ^4,5

Noninvasive fractional flow reserve is an alternative modality to gain this information without the need for invasive intracoronary instrumentation in patients with known or suspected coronary artery disease (CAD). FFRct is a fractional flow reserve derived from computed tomography that relies on computer-assisted processing of coronary computed tomographic angiography (CCTA) images to estimate coronary blood flow changes related to coronary artery stenoses. Based on physical theories of fluid dynamic modeling, FFRct is a post-processing software for analyzing previously acquired digital imaging from CCTA. Limitations include that the technology is dependent on the image quality of the CCTA, the images must be sent out for post-processing; therefore, real time results are not feasible, and how to apply FFRct results to clinical practice is still in development. Emerging technologies includes virtual FFR (vFFR), where the measurements are based on a 3-D image of coronary vessels created by the software using x-ray angiographic imaging. Angio-derived FFR the FFR is calculated at the time of coronary angiogram.

Persistent CAD symptoms are unacceptable ischemia-related symptoms that persist despite optimal medical therapy. Optimal medical therapy is defined by the ISCHEMIA trial protocol⁶ as unacceptable ischemia-related symptoms despite maximally tolerated medical therapy. This includes at least two anti-anginal drugs from different drug classes added to beta-blocker therapy and titrated to maximally tolerated doses before medical therapy is considered to have failed.⁶

The analysis of coronary artery disease by non-invasive coronary computed tomographic analysis has been limited by low specificity. The addition of computer derived flow analysis of the CTA data has added the potential for a non-invasive test that yields both anatomic and functional data. This emerging technology aims to reduce the need for invasive cardiac procedures, and associated risks. 

The DeFACTO study (Determination of Fractional Flow Reserve by Anatomic Computed Tomographic Angiography) compared the first iteration of FFRct technology against invasive angiography and FFR in patients with suspected or known CAD but did not achieve the pre-specified target accuracy.³ Another study, DISCOVER-FLOW, demonstrated an accuracy of 84.6%.⁷ A second iteration of the FFRct algorithm was tested against invasive angiography with FFR in 251 patients with suspected CAD in the NXT (Analysis of Coronary Blood Flow Using CT Angiography- Next Steps) trial. This study reported a diagnostic accuracy, sensitivity, specificity, positive predictive value and negative predictive value of 81%, 86%, 79%, 65% and 83% respectively.⁸ In this trial, 484 vessels in 254 patients and found that FFRct significantly improved the per patient specificity and PPV (32 to 84% and 40 to 65%, respectively) and the per vessel specificity and PPV (60 to 86% and 33 to 67%, respectively) compared with CTA. However, this does not translate into benefit compared to CTA alone for identifying patients whose invasive FFR will warrant intervention, and 35% of the abnormal results were false positives.⁹ A sub analysis of the NXT study evaluated 206 participants and reported no cardiac death or myocardial infarctions in participants with normal FFRct at a median follow-up of 4.7 years. The authors concluded that an FRRct value of 0.8 or less is a predictor of long-term outcomes driven by planned and unplanned revascularization and is superior to clinically significant stenosis on coronary CCTA.¹⁰

The PROMISE study demonstrated that patients with an FFRct less than or equal to 0.80 were significantly more likely to have coronary revascularization and to meet the composite endpoint of major adverse cardiac events or revascularization than those with FFRct greater than 0.80.⁹ The study also showed that reserving invasive coronary angiography for patients with FFRct less than or equal to 0.80 could reduce the rate of performing invasive coronary angiography by 28%. The initial trial did include a CCTA strategy which did not improve outcomes after two years of follow-up. The study, a retrospective, observational, cohort study, also highlighted the dependence of FFRct on the quality of the CCTA images being post-processed, with one-third of the images submitted for review of insufficient quality.¹¹

The FFRct RIPCORD study involved 200 patients and compared the management of patients by cardiologists with and without the addition of FFRct data to the baseline CTA data. The additional FFRct data changed the management planform 72 patients (36%) based on lesion severity assessment. With the inclusion of changes in the PCI target vessel, patient management was altered in 44% of patients.¹²

In the PLATFORM study, 584 patients were allocated to noninvasive or invasive coronary angiography cohorts. Each cohort was divided into the standard of care and FFRct guided care groups. The 90-day primary end point of invasive catheterization without obstructive coronary artery disease occurred in significantly fewer patients with FFRct guided care than usual care in both cohorts. This prospective, longitudinal comparative effectiveness study demonstrated that in an appropriately selected population for CCTA, 88% of the studies were of sufficient quality to perform FFRct on the derived images.^13-15 From the initial group of patients, 116 were identified to undergo ICA. Fifty-two underwent CTA/FFRct resulting in the cancellation of the ICA in 40 (77%). At one year, they reported no major cardiovascular events in this group.¹⁶ While this is promising, there are significant limitations. The group was not allocated randomly, and patients in the FFRct arm were younger, had a lower incidence of diabetes, and lower pretest probability of obstructive CAD. The small sample size was not powered to show a difference in clinical events and major cardiac events; therefore, this data cannot be extrapolated to a larger, more diverse population. 

The ADVANCE registry (Assessing Diagnostic Value of Non-Invasive FFRct in Coronary Care) is a large prospective registry that included 5,083 patients with symptoms suggestive of angina from 38 centers in Europe, North America and Japan. There was a change in the management pathway in 66% of patients, after FFRct data were available compared with CCTA alone.¹⁷ At one year, the authors report that patients with FFRct =0.80 were less frequently referred for ICA (from 62.9% to 252.9%, P < 0.001) and reported the prevalence of major events was low and similar between the cohorts. ^18,19 This data is limited by the observational nature of the study with the inability to adjust for confounding factors such as additional studies being used to make the ultimate decision of whether or not to proceed with ICA, the risk from multiple biases including referral bias, attrition bias, and other bias, and variable experience with FFRct among the study sites. 

A recent Danish observational study that included 3674 patients with suspected coronary artery disease who underwent CCTA with FFRct for stenosis between 30% and 90% had supportive findings for using this technology in care management. Patients with FFRct greater than 0.8 had similar outcomes to patients without obstructive disease on CCTA (i.e. less than 30%). By contrast, patients with FFRct <  0.8 had significantly more major adverse coronary events (9.6% vs. 1.4%).²⁰

A 2017 systematic review by Cook et al. evaluated 908 vessels from 536 patients in five studies. They reported that the per-vessel diagnostic accuracy of FFRct was 81.9% (95% CI: 79.4-84.4%). They further broke down the diagnostic accuracy of FFRct by the FFRct values and reported values below 0.06, 0.06-0.07, 0.70-.80, 0.80-0.90, and above 0.9 was 86.4%, 74.7%, 46.1%, 87.3% and 97.9%, respectively. This data showed a clustering of large numbers of FFRct values in the >0.9 range, where the correlation between FFRct and FFR was very high. However, when approaching the 0.8 level, the correlation becomes less robust. Of significance, the FFRct correlation showed 82% overall diagnostic accuracy through threshold was met for FFRct values lower than 0.63 or above 0.83; however, the correlation between the 0.7 to 0.8 group was notably lower at 46.1%. More stringent 95% and 98% diagnostic accuracy thresholds were met for FFR-CT values lower than 0.53 or above 0.93 and lower than 0.47 or above 0.99, respectively.²¹

The 2019 PACIFIC trial is a prospective study comparing 208 patients with suspected stable CAD who underwent coronary CTA with FFRct calculations, SPECT, PET, and invasive FFR. 83% of vessels could be evaluated with FFRct, which demonstrated a diagnostic accuracy, sensitivity, and specificity of 87%, 90%, and 86% on a per-vessel basis and 78%, 96%, and 63% on a per-patient basis, respectively. FFRct outperformed coronary CTA and SPECT, and PET for vessel-specific ischemia, while PET performed better for per-patient and intention-to-diagnosis analysis.²²

The 2019 ReASSESS trail is a single centered prospective study where 143 patients scheduled to undergo invasive coronary angiogram with stable angina also underwent FFRct and SPECT. They found FFRct had similar overall diagnostic accuracy, and FFRct had higher diagnostic sensitivity than SPECT (91% (95% CI:81% to 97%) versus 41% (95% CI; 29% to 55%; p<0.001). The specificity of FFRct compared to invasive FFR, was 55% (86% SPECT) with PPV a 58% and the overall accuracy of 70%. In analyzing diagnostic performance for detection of coronary artery disease on an intention to treat basis positive predictive value was 47% with accuracy of 63%.²³

A 2020 meta-analysis of seventy-seven studies found that FFRct identifies clinically significant stenosis in patients with suspected CAD with a high sensitivity (mean 85%, 95% CI: 81-88%), but low to moderate specificity (mean 69%, 95% CI: 64 to 74%). ²⁴

Additional literature recommended by the ACC provided better insight into current anatomic applications and the accuracy of the determinations. The SYNTAX family of randomized controlled trials demonstrated that PCI or stenting is a viable option in patients with three -vessel disease and applying this technology to decision-making regarding CABG or PCI. Use of FFRct to determine a functional SYNTAX Score (in the SYNTAX III study) reclassified 30% of patients to a lower score. ^25-27 ACC also provided additional literature supporting the accuracy of CCTA in obese patients. ^{28, 29}

Accuracy with FFRct has been validated in several studies compared to invasive FFR to be around 80% in patients with stable CAD. While non-invasive FFRCT shows promise as comparable or even superior performance to some existing technologies, such as stress test or SPECT, it falls behind invasive FFR in accuracy and PPV. The PPV ranges from 52-65% among the various studies.^{8, 22, 23} There is also a risk of false positive of up to 35%, so confirmation at the time of invasive coronary angiogram confirmation of the lesion is often performed prior to before stent placement.⁹ 

Numerous pivotal trials repeatedly exclude patients with BMI >35 in inclusion criteria. The ADVANCE registry indicated that high BMI was not a statistically significant predictor of CCTA quality rejection. Many patients with a BMI >39 were successfully able to receive the FFRct service.³⁰ Additional literature suggests that CCTA provide high diagnostic accuracy in both obese and non-obese population.²⁹ A sub-analysis from the PROMISE trial including 606 patients with BMI = 40 showed a slightly higher (not statistically significant) yield for positive noninvasive results (13.1% for BMI = 35 compared to 12.1% with BMI <35. Significantly the ability to conduct and interpret the test was not limited if the scanner could accommodate higher BMI’s for the CCTA.³¹

A 2021 prospective study of forty-two patients (68 vessels) with severe aortic stenosis underwent FFR and CTA with 88.2% of vessels having interpretable CTA to allow FFR-CT analysis. There was a strong positive correlation between FBR and FFR-CT (p<0.0001). The authors conclude that CTA and FFR-CT are safe and feasible with diagnostic accuracy in patients with severe aortic stenosis.³²

Societal Guidance

The use of invasive FFR is endorsed by multiple societies, including the Society of Cardiac Angiography and Interventions (SCAI) and American College of Cardiology (ACC)^4,33 and European Society of Cardiology.³⁴ 

The 2021 AHA/ACC/ASE/CHEST/SAEM/SCCT/SCMR Guideline for the Evaluation and Diagnosis of Chest Pain: Executive Summary¹ added recommendation that FFR can be useful for diagnosis of vessel-specific ischemia and to guide decision-making regarding the use of ICA for three categories of patients¹.

a. Intermediate-risk and previously unknown coronary stenosis of 40-90% in proximal or middle coronary artery
b. Intermediate-risk with acute chest pain and known coronary stenosis of 40-90% in proximal or middle coronary artery
c. Known nonobstructive coronary with stable chest pain and stenosis from 40-90% on CCTA.

The level of evidence was graded B-NR which represents moderate quality evidence from one or more well-designed, non-randomized study and/or meta-analysis of such studies, and a Class of Recommendation (COR) 2a which is moderate strength of recommendation which means benefits are felt to outweigh risk. In the clinical pathways they recommend FFRct or stress test. They stated an advantage of FFRct is not needing to order an additional test but should not be ordered in cases where CCTA imaging may be suboptimal or there is extensive plaque present when stress test is preferred. Additionally, FFRct should not be performed when a delay in the results could impact patient care.

These and other studies were discussed by the assembled subject matters experts in a formal CAC discussion convened by Noridian on June 18, 2019. Based on a review of the literature there was a consensus that FFRct is a useful modality in the guidance of and assessment of stable coronary artery disease. At the time of the initial policy there was not sufficient evidence to allow for obesity (BMI >39) and evidence supported vessel specific restrictions within stenosis range of 40-70% range.

Since this LCD became active the 2021 AHA/ACC/ASE/CHEST/SAEM/ SCCT/SCMR Guideline for the Evaluation and Diagnosis of Chest Pain: Executive Summary was published with guidelines for use of FFRct with a moderate strength recommendation to expand the role of FFRct in specific clinical settings as an alternative to stress test.¹ The LCD has been updated to reflect these guidelines changes. The guidelines utilize FFRCT as a sequential test. Therefore, the patient must meet the criteria specified within the algorithms to qualify for CCTA. If CCTA is performed and reveals 40-90% stenosis in the proximal or middle coronary artery than FFRct or stress test may be performed. Based on these guidelines the intermediate stenosis range on CCTA has been expanded to 40-90%,vessel specific limits revised, and expansion to stable chest pain has been added to align with the clinical scenarios specified in the guidelines. This does not reverse the previously established position that the technology is not for use in the high-risk patients or when myocardial infarction has not been excluded. It should not be performed until the base study (CCTA) has been completed and interpreted and should not be relied upon when a delay in the results could impact patient care.

The 2021 Guidelines recommendations provide the option of FFRct or stress test in the clinical settings which it has been determined to be an alternative to stress test. Therefore, FFRct should be performed as an alternative to stress testing. Based on this recommendation a new requirement has been added that the FFRct will not be covered in conjunction with stress testing unless CCTA was not sufficient quality for FFRCT, and an alternative study is needed. While the FFRct offers the benefit of another test not needing to be performed at a separate time, clinical judgement will be necessary to limit to clinical circumstances that a high-quality FFRct study will be expected. The severe obesity is removed as a limitation based on publication of new literature to support its use in patients with BMI >39 if the scanner used for CTTA can enable high quality images in setting of severe obesity. The limitation on aortic stenosis was removed based on new literature demonstrating accuracy in this population.

N/A

U.S. Food and Drug Administration (FDA), Center for Devices and Radiologic Health. Coronary Vascular Physiologic Simulation Software: Heartflow FFRct. DeNovo Number: DEN 130045. Rockville, MD: FDA November 6, 2013.

Abbara S, Blanke P, Maroules CD, et al. SCCT guidelines for the performance and acquisition of coronary computed tomographic angiography J Cardio Computed Tomog. 2016(10): 435-449.

Washington State Health Care Authority, Health Technology Clinical Committee. Coronary Computed Tomographic Angiography. Final Findings and Coverage Decision. Olympia, WA: Washington State Health Care Authority; May 8, 2009.

Noridian Healthcare Solutions- Carrier Advisory Committee- June 18, 2019.

Additional literature was reviewed includes:^35-46

1. Gulati M, Levy PD, Mukherjee D, et al. 2021 AHA/ACC/ASE/CHEST/SAEM/SCCT/SCMR Guideline for the Evaluation and Diagnosis of Chest Pain: Executive Summary: A Report of the American College of Cardiology/American Heart Association Joint Committee on Clinical Practice Guidelines. 2021:CIR. 0000000000001030.
2. De Bruyne B, Pijls NH, Kalesan B, et al. Fractional flow reserve–guided PCI versus medical therapy in stable coronary disease. J New England Journal of Medicine. 2012;367(11):991-1001.
3. Min JK, Leipsic J, Pencina MJ, et al. Diagnostic accuracy of fractional flow reserve from anatomic CT angiography. J Jama. 2012;308(12):1237-1245.
4. Patel MR, Calhoon JH, Dehmer GJ, et al. ACC/AATS/AHA/ASE/ASNC/SCAI/SCCT/STS 2017 Appropriate Use Criteria for Coronary Revascularization in Patients With Stable Ischemic Heart Disease : A Report of the American College of Cardiology Appropriate Use Criteria Task Force, American Association for Thoracic Surgery, American Heart Association, American Society of Echocardiography, American Society of Nuclear Cardiology, Society for Cardiovascular Angiography and Interventions, Society of Cardiovascular Computed Tomography, and Society of Thoracic Surgeons. J Nucl Cardiol. 2017;24(5):1759-1792.
5. ECRI. Product Brief: FFRct Software (HeartFlow, Inc.) for Evaluating Coronary Artery Disease. 2019; Product Brief - Guidance. Available at: https://www.ecri.org/components/ProductBriefs/Pages/24990.aspx. Accessed 03/19/2020, 2020.
6. Maron DJ, Hochman JS, O'Brien SM, et al. International Study of Comparative Health Effectiveness with Medical and Invasive Approaches (ISCHEMIA) trial: Rationale and design. Am Heart J. 2018;201:124-135.
7. Nakanishi R, Matsumoto S, Alani A, et al. Diagnostic performance of transluminal attenuation gradient and fractional flow reserve by coronary computed tomographic angiography (FFR(CT)) compared to invasive FFR: a sub-group analysis from the DISCOVER-FLOW and DeFACTO studies. Int J Cardiovasc Imaging. 2015;31(6):1251-1259.
8. Norgaard 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). Journal Of The American College Of Cardiology. 2014;63(12):1145-1155.
9. Hecht HS, Narula J, Fearon WF. Fractional Flow Reserve and Coronary Computed Tomographic Angiography: A Review and Critical Analysis. Circ Res. 2016;119(2):300-316.
10. Ihdayhid AR, Norgaard BL, Gaur S, et al. Prognostic Value and Risk Continuum of Noninvasive Fractional Flow Reserve Derived from Coronary CT Angiography. Radiology. 2019;292(2):343-351.
11. Lu MT, Ferencik M, Roberts RS, et al. Noninvasive FFR Derived From Coronary CT Angiography: Management and Outcomes in the PROMISE Trial. JACC Cardiovasc Imaging. 2017;10(11):1350-1358.
12. Curzen NP, Nolan J, Zaman AG, Norgaard BL, Rajani R. Does the Routine Availability of CT-Derived FFR Influence Management of Patients With Stable Chest Pain Compared to CT Angiography Alone?: The FFRCT RIPCORD Study. JACC Cardiovasc Imaging. 2016;9(10):1188-1194.
13. Douglas PS, De Bruyne B, Pontone G, et al. 1-Year Outcomes of FFRCT-Guided Care in Patients With Suspected Coronary Disease: The PLATFORM Study. J Am Coll Cardiol. 2016;68(5):435-445.
14. Douglas PS, Pontone G, Hlatky MA, et al. 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. J European heart journal. 2015;36(47):3359-3367.
15. Douglas PS, Hoffmann U, Patel MR, et al. Outcomes of anatomical versus functional testing for coronary artery disease. J New England Journal of Medicine. 2015;372(14):1291-1300.
16. Colleran R, Douglas PS, Hadamitzky M, et al. An FFRCT diagnostic strategy versus usual care in patients with suspected coronary artery disease planned for invasive coronary angiography at German sites: one-year results of a subgroup analysis of the PLATFORM (Prospective Longitudinal Trial of FFRCT: Outcome and Resource Impacts) study. Open Heart. 2017;4(1):e000526.
17. Fairbairn TA, Nieman K, Akasaka T, et al. Real-world clinical utility and impact on clinical decision-making of coronary computed tomography angiography-derived fractional flow reserve: lessons from the ADVANCE Registry. European heart journal. 2018;39(41):3701-3711.
18. Nous F, Budde RP, Fairbairn TA, et al. Temporal Changes in FFRCT-Guided Management of Coronary Artery Disease–Lessons from the ADVANCE Registry. J Journal of Cardiovascular Computed Tomography. 2020.
19. Patel M, Norgaard B, Fairbairn T, et al. . 1-Year Impact on Medical Practice and Clinical Outcomes of FFRCT: The ADVANCE Registry. JACC Cardiovasc Imaging. 2019.

20. Norgaard BL, Terkelsen CJ, Mathiassen ON, et al. Coronary CT Angiographic and Flow Reserve-Guided Management of Patients With Stable Ischemic Heart Disease. J Am Coll Cardiol. 2018;72(18):2123-2134.
21. Cook CM, Petraco R, Shun-Shin MJ, et al. Diagnostic Accuracy of Computed Tomography-Derived Fractional Flow Reserve : A Systematic Review. JAMA Cardiol. 2017;2(7):803-810.
22. Driessen RS, Danad I, Stuijfzand WJ, et al. Comparison of Coronary Computed Tomography Angiography, Fractional Flow Reserve, and Perfusion Imaging for Ischemia Diagnosis. J Am Coll Cardiol. 2019;73(2):161-173.
23. Sand NPR, Veien KT, Nielsen SS, et al. Prospective Comparison of FFR Derived From Coronary CT Angiography With SPECT Perfusion Imaging in Stable Coronary Artery Disease: The ReASSESS Study. JACC Cardiovasc Imaging. 2018;11(11):1640-1650.
24. Pontone G, Guaricci AI, Palmer SC, et al. Diagnostic performance of non-invasive imaging for stable coronary artery disease: A meta-analysis. Int J Cardiol. 2020;300:276-281.
25. Collet C, Miyazaki Y, Ryan N, et al. Fractional Flow Reserve Derived From Computed Tomographic Angiography in Patients With Multivessel CAD. Journal of the American College of Cardiology. 2018;71(24):2756-2769.
26. Nam CW, Mangiacapra F, Entjes R, et al. Functional SYNTAX score for risk assessment in multivessel coronary artery disease. Journal of the American College of Cardiology. 2011;58(12):1211-1218.
27. Escaned J, Collet C, Ryan N, et al. Clinical outcomes of state-of-the-art percutaneous coronary revascularization in patients with de novo three vessel disease: 1-year results of the SYNTAX II study. European heart journal. 2017;38(42):3124-3134.
28. Zimmerman SL, Kral, B.G., and Fishman, E.K. Diagnostic quality of dual source coronary CT examinations performed without heart rate control: importance of obesity and heart rate on image quality. J Comput Assist Tomogr 2014;38(6):949-955.
29. Mangold S, Tesche C, Wichmann J, et al. Diagnostic accuracy of coronary CT angiography using 3(rd)1-generation dual-source CT and automated tube voltage selection: Clinical application in a non-obese and obese patient population. Eur Radiolo. 2017;27(6):2298-2308.
30. Pontone G, Weir-McCall JR, Baggiano A, et al. Determinants of Rejection Rate for Coronary CT Angiography Fractional Flow Reserve Analysis. Radiology. 2019;292(3):597-605.
31. Litwin SE, Coles A, Pagidipati N, Hoffmann U, Douglas PS. Effects of obesity on noninvasive test results in patients with suspected cardiac ischemia: Insights from the PROMISE trial. J Cardiovasc Comput Tomogr 2019;13:211-218.
32. Michail M, et al. CAST-FFR study, Feasibility and Validity of Computed Tomography - Derived Fractional Flow Reserve in Patients with Severe Aortic Stenosis: Circulation. Cardiovascular Interventions. 2021;14(1).
33. Lotfi A, Davies JE, Fearon WF, Grines CL, Kern MJ, Klein LW. Focused update of expert consensus statement: Use of invasive assessments of coronary physiology and structure: A position statement of the society of cardiac angiography and interventions. Catheter Cardiovasc Interv. 2018;92(2):336-347.
34. Knuuti J. 2019 ESC guidelines for the diagnosis and management of chronic coronary syndromes. European Heart Journal. 2020;41:407-477.
35. Levine GN, et al. ACCF/AHA/SCAI Guideline for Percutaneous Coronary Intervention: a report of the American College of Cardiology Foundation/American Heart Association Task Force on Practice Guidelines and the Society for Cardiovascular Angiography and Interventions. . Circulation 2011;124(23):e574-651.
36. 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(3):213-224.
37. Sud M, Han L, Koh M, et al. Association Between Adherence to Fractional Flow Reserve Treatment Thresholds and Major Adverse Cardiac Events in Patients With Coronary Artery Disease. JAMA. 2020;324(23):2406-2414.
38. McNabney CG, Sellers SL, Wilson RJ, et al. Prognosis of CT-derived fractional flow reserve in the prediction of clinical outcomes. Radiology: Cardiothoracic Imaging

2019;1(2):e190021.

39. Members TF, Montalescot G, Sechtem U, et al. 2013 ESC guidelines on the management of stable coronary artery disease: the Task Force on the management of stable coronary artery disease of the European Society of Cardiology. 2013;34(38):2949-3003.
40. Neumann FJ, Sousa-Uva M, Ahlsson A, et al. ESC/EACTS Guidelines on myocardial revascularization. Kardiol Pol. 2018;76(12):1585-1664.
41. Patel MR, Peterson ED, Dai D, et al. Low diagnostic yield of elective coronary angiography. 2010;362(10):886-895.
42. Völz S, Dworeck C, Redfors B, et al. Survival of patients with angina pectoris undergoing percutaneous coronary intervention with intracoronary pressure wire guidance. Journal of the American College of Cardiology. 2020;75(22):2785-2799.
43. 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. Journal of the American College of Cardiology. 2015;66(21):2315-2323.
44. Parikh RV, Liu G, Plomondon ME, et al. Utilization and outcomes of measuring fractional flow reserve in patients with stable ischemic heart disease. Journal of the American College of Cardiology. 2020;75(4):409-419.
45. Sonck J, Miyazaki Y, Collet C, et al. Feasibility of planning coronary artery bypass grafting based only on coronary computed tomography angiography and CT-derived fractional flow reserve: a pilot survey of the surgeons involved in the randomized SYNTAX III Revolution trial. J Interactive cardiovascular thoracic surgery. 2019;29(2):209-216.
46. Budde R, Nous F, Roest S, et al. Non-Invasive Functional Coronary Artery Evaluation by CT-Derived Fractional Flow Reserve (FFRct) in Heart Transplant Patients. J Heart Lung Transplant. 2020;39(4S):S62.