The Game Changer
Accepted Manuscript
The Game Changer?
Harvey S. Hecht, MD
PII:S0735-1097(14)00170-3
DOI:10.1016/j.jacc.2013.12.014
Reference:JAC 19726
To appear in:Journal of the American College of Cardiology
Received Date:13 December 2013
Accepted Date:17 December 2013
Please cite this article as: Hecht HS, The Game Changer?, Journal of the American College of Cardiology (2014), doi: 10.1016/j.jacc.2013.12.014.
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The Game Changer? Running Title: FFR CT
Harvey S. Hecht, MD
Author’s Affiliation: Icahn School of Medicine at Mount Sinai
Relationships to Industry:
Harvey Hecht – Philips Medical Systems Consultant
Address for correspondence
Harvey S. Hecht, MD, FACC, FSCCT
Mount Sinai Medical Center
One Gustave L. Levy Place – Box 1030
New York, NY 10029-6574
Tel: 212 241-4790
Fax: 646 537-8560
e-mail: harvey.hecht@https://www.sodocs.net/doc/d216082693.html,
Key Words : computational fluid dynamics, coronary CT angiography, fractional flow reserve, invasive coronary angiography
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Aside from its inability to accurately triage patients with obstructive disease to the interventional laboratory (1), the noninvasive evaluation of coronary artery disease has from its inception been plagued by a poorly appreciated, fundamental paradox that renders its application to individual patients problematic. All the technologies employed to measure the significance of an
angiographic coronary stenosis have been validated by using the coronary stenosis itself as the gold standard, and have then used the technology to judge the gold standard from which it was derived (2). For instance, the sensitivity and specificity of myocardial perfusion imaging was defined by its ability to identify a >50% diameter stenosis on coronary angiography. Thus, a normal scan in the setting of an 80% stenosis is by definition a false negative test. Yet, current
clinical practice concludes that the 80% stenosis being evaluated was incapable of producing ischemia. Which is it, a false negative MPI or a misleading 80% stenosis? Is an abnormal scan in the setting of apparently normal coronary arteries a false positive or evidence of microvascular ischemia? We simply cannot have it both ways! This critique applies as well to
electrocardiographic stress testing, stress echocardiography, positron emitting tomography, magnetic resonance imaging, coronary computed tomographic angiography (CTA) and CTA perfusion, all of which were validated by using angiographic stenosis as the gold standard. The argument of whether or not function trumps anatomy is irrelevant if all are fundamentally flawed.
Critics of this logic would point to the very large databases demonstrating the prognostic value of each of these technologies as confirmation of their utility and validity. This argument reflects the viewpoint of “lumpers” who regard patients as representatives of a large database, rather than “splitters” who appropriately treat them as unique individuals. For example, the benign prognosis of a normal stress echocardiogram or myocardial perfusion test in large
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databases is assumed to apply to all patients who have had a normal study, irrationally equating those with normal coronary arteries to those with left main or triple vessel disease.
What then is to be used as the gold standard to evaluate individual patients? Two invasive technologies have been utilized, intravascular ultrasound and fractional flow reserve (FFR). Intravascular ultrasound is subject to the same criticism as the noninvasive technologies: it was validated by myocardial perfusion imaging and stress echocardiography, which, as noted above, were validated by angiographic coronary stenosis. FFR, on the other hand, has become the accepted gold standard (3,4). While initially validated by myocardial perfusion imaging and stress echocardiography, it has emerged from the bonds of the paradox to be the first technology
to use clinical outcomes, most notably in the DEFER and FAME studies (5-7), as its gold standard. Decisions based upon specific FFR values significantly affected patient morbidity and mortality, resulting in the incorporation of FFR guided intervention for intermediate stenoses in the interventional guidelines with a CLASS IIa, level of evidence A recommendation (3).
However, it is even more invasive than coronary angiography and is clearly not suitable for routine patient evaluation.
FFR CT (HeartFlow, Redwood City, CA, USA) is the first noninvasive test to be validated from its inception by an outcome based gold standard, i.e., invasive FFR, rather than one ultimately based on coronary stenosis measurement. The application of computational fluid dynamics allows for derivation of FFR, based upon projected adenosine induced vasodilation at any point in the vascular tree, from a CTA of at least moderate quality acquired at rest, without adenosine infusion (8). The brief history of FFR CT trials is summarized in Table 1.
The initial report (Discover) was nothing short of spectacular, with remarkable improvements in specificity, PPV and accuracy with the addition of FFR CT to CT alone using invasive FFR as
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the gold standard, but was a single center study with only 103 patients (9). The first multicenter study (DEFACTO) was eagerly awaited, but proved to be a disappointment; the addition of FFR CT did not yield significant increases in any parameter (10). Consequently, for the multicenter study (NXT) presented in this issue by N?rgaard, et al (11), the investigators went to great lengths to correct the perceived shortcomings of DEFACTO. Improved automated image processing methods were implemented for better lumen boundary identification, physiologic models of microcirculatory resistance that yielded better diagnostic performance of the prior studies were utilized, and strict adherence to the best practices for image acquisition, particularly rate control and nitroglycerine administration, was mandated. The results reflect the remedies: in
484 vessels in 251 patients, the addition of FFR CT to CT dramatically and significantly improved the per patient specificity, positive predictive value and accuracy for invasive FFR <0.80 (Table 1), and the area under the receiver operating characteristic curve increased from 0.81 to 0.90 (p=0.0008). Similar results were obtained for per vessel analysis, 30%-70% stenoses
and for patients with coronary artery calcium Agatston scores >400. Thus, FFR CT appears poised to assume the role of gatekeeper to the interventional laboratory for patients with CTA defined intermediate stenoses, a role initially envisioned for, but not fulfilled by, CTA alone. There are numerous issues to be considered:
1. Are there sufficient data to warrant implementation of this new technology? There have been a total of only 606 patients reported in the literature using FFR CT, and only the current study of 251 patients employed the latest physiologic modeling and improved automated image processing. As the authors acknowledge, additional appropriately
designed prospective trials are needed. Is it appropriate to demand randomized controlled trials (RCT’s), similar to FAME and DEFER, to prove that FFR CT improves outcomes,
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or is a strong correlation with invasive FFR sufficient? Ironically, there has never been an RCT demonstrating that any form of noninvasive testing improves outcomes, yet the
absence of RCT’s has been a constant criticism of coronary CTA and coronary artery calcium scanning. 2. Demonstration of superior cost effectiveness compared to other noninvasive testing, as well as superior accuracy, will be a prerequisite. Such analyses (12) may already have been or will be presented to payors, and will also be instrumental in determining the level of reimbursement.
3. Will an FFR CT <0.8 be sufficient to proceed with intervention or will confirmation by
invasive FFR be necessary? The positive predictive value of 65% is simply not high enough to preclude the need for confirmation by invasive FFR. Further improvements in the Heartflow technology or new algorithms from other vendors may render confirmation unnecessary. The negative predictive value of CTA alone (92%) is high enough to defer catheterization, and is not augmented by FFR CT. 4. If future studies lend convincing additional support for FFR CT as the preferred modality, there is likely to be a devastating impact on all the noninvasive functional technologies, with expensive, high technology myocardial perfusion imaging bearing the brunt. So long as invasive FFR reigns supreme, the correlations with FFR CT remain excellent, and CTA technology continues to improve as radiation exposure decreases, why would other tests be utilized except in those cases not suitable for CTA (renal dysfunction, very
excessive calcification)? In turn, the resulting decreased income from noninvasive testing will accelerate the rapidly ongoing hospital acquisition of private practices with all the implications thereof.
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6 5. Succession of invasive FFR to the throne of functional evaluation is based upon several reports in a limited number of patients. If further studies cast doubt on its supremacy, CT FFR will suffer accordingly. 6. Logistical issues, i.e., offsite data analysis by Heartflow and the attendant turnaround time, are unlikely to be problematic for stable patients.
7. There will always be skeptics who will not accept the derivation of vasodilator parameters without applying vasodilation itself. However, the data, although counterintuitively derived, will speak for themselves. Time will tell whether or not FFR CT will emerge as the gold standard of noninvasive functional testing. The initial experience, however, is quite promising, and wide acceptance would indeed be a major “game changer”.
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References 1. Patel MR, Peterson ED, Dai D, et al. Low diagnostic yield of elective coronary angiography.
N Eng J Med 2010;362:886-95. 2. Hecht HS. Is coronary computed tomographic angiography the ‘‘gold standard’’ for coronary artery disease? J Cardiovasc Comput Tomogr 2009:3;334-9 3. Levine GN, Bates ER, Blankenship JC, Bailey SR, Bittl JA, Cercek B, Chambers CE, Ellis SG, Guyton RA, Hollenberg SM, Khot UN, Lange RA, Mauri L, Mehran R, Moussa ID,
Mukherjee D, Nallamothu BK, Ting HH. 2011 ACCF/AHA/ SCAI guideline for percutaneous coronary intervention: a report of the American College of Cardiology Foundation/American
Heart Association Task Force on Practice Guide- lines and the Society for Cardiovascular Angiography and Interventions. J Am Coll Cardiol 2011;58:e44–122. 4. Montalescot G, Sechtem U, Achenbach S, 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. Eur Heart J 2013;34:2949-3003.
5. 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.
6. Tonino PA, Fearon WF, De Bruyne B, et al. Angiographic versus functional severity of coronary artery stenoses in the FAME study fractional flow reserve versus angiography in multivessel evaluation. J Am Coll Cardiol 2010;55:2816-
7. De Bruyne B, Pijls NH, Kalesan B, et al. Fractional flow reserve-guided PCI versus medical therapy in stable coronary disease. N Engl J Med 2012;367:991-1001.
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8. 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. 9. Koo BK, Erglis A, Doh JH, et al. Diagnosis of ischemia-causing coronary stenoses by non- invasive 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.
10. Min JK, Leipsic J, Pencina MJ, et al. Diagnostic accuracy of fractional flow reserve from
anatomic CT angiography. JAMA 2012;308:1237-45. 11. N?rgaard BL, Leipsic J, Gaur S, et al. Diagnostic performance of non-invasive fractional flow reserve derived from coronary CT angiography in suspected coronary artery disease: The NXT trial. J Am Coll Cardiol. In Press.
12. Hlatky MA, Saxena A, Koo BK, et al. Projected costs and consequences of computed tomography-determined fractional flow reserve. Clin Cardiol. 2013 Oct 1. doi:
10.1002/clc.22205. [Epub ahead of print]
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E D 9 Table 1. Summary of FFR CT trials for detection of invasive FFR <0.80
Discover (9) DEFACTO (10) NXT (11) Year 2011 2012 2013
N 103 252 251
Design Single Center Multicenter Multicenter CT FFR CT CT FFR CT CT FFR CT Sensitivity 94% 93% 84% 90% 94% 86% Specificity 25% 82% 42% 54% 34% 79% PPV 58% 85% 61% 67% 40% 65% NPV 80% 91% 72% 84% 92% 93% Accuracy 61% 81% 64% 73% 53% 81%