Anatomic and Functional Assessment With CTA: Are Diagnostic Catheterizations a Way of the Past?
In recent years, the evolution of coronary computed tomography angiography (CTA) has heralded its transition from a limited role in the exclusion of obstructive disease in selected low-risk patients to the forefront of cardiovascular imaging with diverse applications. These applications now extend beyond conventional assessments of anatomic severity of coronary artery disease (CAD) to include evaluation of coronary plaque and the physiological consequences of coronary atherosclerosis. In this brief review, we discuss the role of coronary CTA in both the anatomic and functional assessment of CAD and explore whether diagnostic coronary catheterization is a way of the past.
Anatomic Assessment of CAD
The documented high rate of normal diagnostic invasive angiograms has highlighted the fact that current diagnostic strategies used to guide referrals to the catheterization laboratory are suboptimal. Indeed, in a national registry of over 600 centres including approximately 400,000 patients, almost two thirds of patients had normal or nonobstructive disease on invasive angiography, when a stenosis of >70% was considered significant.1 The ability of coronary CTA to provide anatomic information regarding the presence or absence of stenosis, disease burden, and plaque composition without subjecting patients to an invasive procedure has led to the proposal that its use may provide a superior strategy for the initial evaluation of symptomatic patients with suspected CAD, particularly those with a low-intermediate pre-test likelihood of CAD.
Stenosis and Disease Burden
Since 64-slice coronary CTA first became commercially available in 2005, multiple studies have documented its high accuracy in the detection and exclusion of coronary disease that would be considered obstructive on invasive coronary angiography. The sensitivity for the detection of significant CAD is superior to any other noninvasive modality in both a per-patient and per-vessel basis, highlighting its utility in identifying significant CAD. Of note, coronary CTA is very unlikely to "miss" patients with highest risk CAD, such as those with left main or proximal left anterior descending artery stenosis. The associated very high negative predictive value is a powerful attribute of coronary CTA.2 In addition to ruling out obstructive stenosis, the absence of coronary disease on CTA is associated with an excellent prognosis with very low rates of adverse cardiac events extending over the following 5 years, often referred to as a "warranty period." In initial large prognostic studies, the absence of disease on coronary CTA over a mean of 3 years was associated with a mean annualised all-cause mortality rate of 0.28%.3 It is estimated that the rate of myocardial infarction or cardiac death remains less than 1% per year for at least 8 years, providing an opportunity to offer reassurance to patients while potentially avoiding unnecessary downstream hospital visits and investigations.4,5
Beyond the identification or exclusion of stenosis, coronary CTA allows the detection of nonobstructive atherosclerosis that is not identified by ischemia testing. Detection of nonobstructive CAD provides an opportunity to improve outcomes in individuals with mild disease that would not be detected by stress testing and may not be detected even by invasive angiography. This feature allows treatments to be directed to and intensified in patients with coronary atherosclerosis, including therapies such as statins, aspirin, and recommendations for lifestyle changes. Indeed, the presence of nonobstructive disease on coronary CTA is associated with an increased risk of mortality when compared with those with no CAD (hazard ratio 1.60; 95% confidence interval, 1.18-2.16; p = 0.002),3 and the use of statin therapy has been associated with a reduction in mortality in this population.6
The anatomic extent of disease on coronary CTA has also been demonstrated to have prognostic implications. In the initial report of the CONFIRM (Coronary CT Angiography Evaluation For Clinical Outcomes International Multicenter) registryan international, multicentre registry of over 24,000 patients from which numerous manuscripts regarding CTA and prognosis have been generatedthere was a progressive increase in mortality with nonobstructive, single vessel, two vessel, and three vessel/left main disease (Figure 1).3 The strong prognostic value of coronary CTA in risk stratification has indeed been shown consistently in a large number of studies covering a broad spectrum of presentations of patients with suspected CAD.
In addition to detecting both obstructive and nonobstructive disease and providing an indication of plaque burden on both a per-vessel and per-patient level, coronary CTA provides the opportunity for detailed characterization of plaque morphology. The detection of CT-defined high-risk plaque features such as positive remodeling and low attenuation plaque (the latter a CT-surrogate for lipid core), can aid prediction of future acute coronary events.7 In an early study by Motoyama et al., patients with evidence of high-risk plaque as defined on CT were ten times more likely to experience a future event, and the risk of future acute coronary syndromes was amplified by having more than one high-risk plaque feature.8
In a more recent study, the same authors reported that plaque progression in terms of volume and the development of high-risk plaque features from non-high-risk plaque led to an increased risk of acute coronary syndromes.7 Patients who did not demonstrate any plaque progression on follow-up CTA, even if high-risk plaque features were evident on the baseline CTA, had a low incidence of adverse coronary events. This suggests that serial changes in disease features and composition may help to refine patient risk. Recent development of sophisticated semi-automated software capable of detailed objective plaque characterisation may facilitate the application of serial coronary CTA in this role (Figure 2).9 The potential routine use of automated quantification of various plaque components may lead to a future role of coronary CTA in monitoring interval change in plaque burden and plaque characteristics in response to novel therapies. Regarding quantification of plaque features and plaque burden, adverse plaque features detected by coronary CTA also provide incremental information over stenosis assessment in predicting abnormal fractional flow reserve in the catheterization laboratory10,11 and in predicting myocardial ischemia by positron emission tomography.12 Beyond positive remodelling and low attenuation plaque, spotty calcification and the "napkin-ring sign" have been described as high-risk plaque features. Potentially, the presence of plaques with high-risk characteristics could add to stenosis assessment in guiding referral for invasive coronary angiography.
Figure 2: Automated Quantitative Plaque Analysis (Autoplaque [Cedars-Sinai Medical Center, Los Angeles, CA])
Functional Assessment of CAD
Despite its high diagnostic accuracy in determining the presence of obstructive disease, a limitation of coronary CTA is a reduced accuracy in the grading of intermediate stenoses, especially in the presence of dense calcification. Further, large randomized trials have shown that revascularization based on anatomic stenosis alone does not improve outcomes.13,14 By current guidelines, invasive intervention in patients with stable CAD should be guided by the demonstration of myocardial ischemia.15 The development of novel methods to assess ischemia by CTA, offering the opportunity to combine detailed anatomical and physiological assessments in a single noninvasive test, may substantially increase the impact of coronary CTA.
CT perfusion can assess myocardial perfusion by measuring CT contrast enhancement before and after pharmacological stress. The CORE 320 (Coronary Artery Evaluation Using 320-Row Multidetector CT Angiography) study investigated the diagnostic accuracy of coronary CTA with CT perfusion in predicting hemodynamically significant coronary stenosis, using invasive coronary angiography and single photon emission computed tomography as gold standard. The results demonstrated the high accuracy of this approach, with an improved prediction of hemodynamically significant CAD when CT perfusion was added to CTA alone.16 This may be of particular value in improving the diagnostic accuracy of CTA for detection of flow-limiting disease in patients in whom stenosis assessment by CTA is compromised, such as those with high coronary calcium scores or coronary stents.17 CT perfusion has limitations with respect to practical implementation, including the need to determine at the time of testing whether stress perfusion is needed, the extra time required to prepare for and perform the stress imaging, and additional contrast and radiation.18
Noninvasive Fractional Flow Reserve
The emergence of CT-derived fractional flow reserve (FFRCT) has provided another novel opportunity to combine physiological assessment with anatomic data from coronary CTA. The principal approach developed to date for this assessment applies computational fluid dynamics to model and predict fractional flow reserve from conventionally acquired CTA. This method is applied to standardly acquired coronary CTA without need for additional radiation, medication, or image acquisition.19 Three prospective multicenter trials (DISCOVER-FLOW [Diagnosis of Ischemia-Causing Stenoses Obtained Via Noninvasive Fractional Flow Reserve], DEFACTO [Determination of Fractional Flow Reserve by Anatomic Computed Tomographic Angiography], and NXT [Analysis of Coronary Blood Flow Using CT Angiography: Next Steps]) have explored the diagnostic accuracy of FFRCT in detecting myocardial ischemia and reported sensitivities of between 88 and 90% and specificities between 54 and 90% on a per-patient basis.20-22 The addition of FFRCT has been shown to improve the specificity of CTA in identifying hemodynamically significant stenoses, suggesting that the incorporation of FFRCT may improve the power of CTA as a gatekeeper to the catheterization laboratory.22,23 Indeed, although PROMISE (Prospective Multicenter Imaging Study for Evaluation of Chest Pain) showed that the use of CTA led to a lower incidence of nonobstructive disease on invasive angiography when compared with an initial functional testing strategy, the percentage of patients undergoing invasive angiography in the CTA arm with nonobstructive disease was still high (28%), even when 50% luminal narrowing was used to define obstructive stenosis. Further, because the majority of lesions with 50-70% stenosis by invasive coronary angiography are not associated with abnormal FFR, this would imply that CTA alone may lead to an even higher proportion of patients being referred for invasive angiography after CTA without hemodynamically significant disease. The integration of FFRCT measurements, however, may help direct patients more likely to require revascularization to the catheterization laboratory. However, FFRCT interpretation is subject to a "grey zone," and the diagnostic accuracy has been reported to be much lower in mid-range values, particularly when FFRCT is between 0.70 and 0.80, highlighting the importance of taking all clinical findings into account when interpreting individual FFRCT results.24 The recent FFRCT RIPCORD (Does Routine Pressure Wire Assessment Influence Management Strategy at Coronary Angiography for Diagnosis of Chest Pain?) study, simulating the effects of FFRCT in clinical practice based on a group of patients from the NXT trial, suggested that the incorporation of FFRCT measurements into routine patient care could have led to a change in subsequent management in almost half of patients (44%).25 Concerns regarding increasing unnecessary invasive coronary angiography after CTA are likely to have played a role in the long delay of many insurance carriers in approving CTA in clinical practice. Of note, large carriers in the United States have recently approved the use of coronary CTA, provided measurement of FFRCT is available in the laboratory performing testing. Unlike CT perfusion, FFRCT has not yet been demonstrated to be effective in vessels with coronary stents or in bypassed coronary vessels. Dense coronary calcification, which results difficulty in assessing stenosis, may be problematic. If there is an inability to see a coronary lumen, FFRCT cannot be performed. A further limitation is the relatively high cost of the procedure.
Applications of Coronary CTA in Stable Ischaemic Heart Disease
In the stable symptomatic population, the role of coronary CT angiography is growing as an initial test of choice in symptomatic patients with suspected CAD. The recent The National Institute for Health and Care Excellence guidelines, published in the United Kingdom, have recommended offering coronary CT angiography as a first-line test in patients with suspected stable angina. This recommendation has placed coronary CTA at the forefront of diagnostic imaging in this selected group of patients, ahead of any functional imaging strategy. Providing strong evidence in support of this recommendation were the results of the recent SCOT-HEART (Scottish Computed Tomography of the HEART) study, which demonstrated that the adoption of coronary CTA in addition to standard care led to improved clarity of the diagnosis of angina secondary to coronary heart disease, changes in therapy, and more appropriate referrals for invasive angiography. A landmark analysis of the trial demonstrated that there was a halving of fatal and non-fatal myocardial infarction in the CTA arm.26,27 This may be the first large randomized trial to show that a noninvasive imaging modality results in improved patient outcomes with respect to cardiac events.
Coronary CTA as a Gatekeeper to the Catheterization Laboratory
The above considerations suggest that coronary CTA is well-positioned to become a gatekeeper to the catheterization laboratory; however, its application in this regard is not always simple. The influence of coronary CTA on subsequent management is illustrated in case examples in Figure 3. When the findings are completely normal, treatment and subsequent testing is clear. The very high negative predictive valuethe definitive ability to rule out CAD and the associated long "warranty period"allows for reassurance to the patient, reducing the need for subsequent testing, and appropriately selecting patients who may not need aggressive preventive medications. The identification of nonobstructive CAD can prompt the use of aggressive evidence-based therapies, which is likely to ultimately improve long-term outcomes. When proximal high-grade stenosis is found, referral for invasive coronary angiography would be indicated (Figures 4-5).28 When lesions causing borderline stenosis (categorized as 50-69%) or non-critical stenosis (categorized as 70-89%) or in which dense calcification reduces accuracy of stenosis assessment are identified, further testing such as stress imaging is often needed to appropriately select the patients most likely to have flow-limiting disease for invasive angiography. The use of CT perfusion or FFRCT may allow the assessment of this functional significance of most of these lesions from the single CTA examination.
Figure 3: FFRCT for Evaluation of Lesion-Specific Ischemia
As coronary CTA continues to evolve, evidence is mounting that this imaging modality has the potential to markedly reduce the need for diagnostic invasive coronary angiography, reserving this invasive test for those patients likely to require revascularisation. From anatomic information gained from CTA, we are provided the ability to safely obviate the need for further diagnostic testing in those without disease, direct and intensify preventive therapies in those with established atherosclerosis, and ultimately implement appropriate treatment decisions to reduce cardiovascular outcomes. The addition of functional information from CTA itself has the potential to further expand the role of this test as these methods continue to evolve, potentially allowing coronary CTA to act as an effective gatekeeper to the catheterization laboratory.
- Patel MR, Peterson ED, Dai D, et al. Low diagnostic yield of elective coronary angiography. N Engl J Med 2010;362:886-95.
- Douglas PS, Hoffmann U, Patel MR, et al. Outcomes of anatomical versus functional testing for coronary artery disease. N Engl J Med 2015;372:1291-300.
- Min JK, Dunning A, Lin FY, et al. Age- and sex-related differences in all-cause mortality risk based on coronary computed tomography angiography findings results from the International Multicenter CONFIRM (Coronary CT Angiography Evaluation for Clinical Outcomes: An International Multicenter Registry) of 23,854 patients without known coronary artery disease. J Am Coll Cardiol 2011;58:849-60.
- Andreini D, Pontone G, Mushtaq S, et al. A long-term prognostic value of coronary CT angiography in suspected coronary artery disease. JACC Cardiovasc Imaging 2012;5:690-701.
- Dougoud S, Fuchs TA, Stehli J, et al. Prognostic value of coronary CT angiography on long-term follow-up of 6.9 years. Int J Cardiovasc Imaging 2014;30:969-76.
- Chow BJ, Small G, Yam Y, et al. Prognostic and therapeutic implications of statin and aspirin therapy in individuals with nonobstructive coronary artery disease: results from the CONFIRM (COronary CT Angiography EvaluatioN For Clinical Outcomes: An InteRnational Multicenter registry) registry. Arterioscler Thromb Vasc Biol 2015;35:981-9.
- Motoyama S, Ito H, Sarai M, et al. Plaque Characterization by Coronary Computed Tomography Angiography and the Likelihood of Acute Coronary Events in Mid-Term Follow-Up. J Am Coll Cardiol 2015;66:337-46.
- Motoyama S, Sarai M, Harigaya H, et al. Computed tomographic angiography characteristics of atherosclerotic plaques subsequently resulting in acute coronary syndrome. J Am Coll Cardiol 2009;54:49-57.
- Dey D, Schepis T, Marwan M, Slomka PJ, Berman DS, Achenbach S. Automated three-dimensional quantification of noncalcified coronary plaque from coronary CT angiography: comparison with intravascular US. Radiology 2010;257:516-22.
- Park HB, Heo R, ó Hartaigh B, et al. Atherosclerotic plaque characteristics by CT angiography identify coronary lesions that cause ischemia: a direct comparison to fractional flow reserve. JACC Cardiovasc Imaging 2015;8:1-10.
- Nakazato R, Shalev A, Doh JH, et al. Aggregate plaque volume by coronary computed tomography angiography is superior and incremental to luminal narrowing for diagnosis of ischemic lesions of intermediate stenosis severity. J Am Coll Cardiol 2013;62:460-7.
- Diaz-Zamudio M, Dey D, Schuhbaeck A, et al. Automated Quantitative Plaque Burden from Coronary CT Angiography Noninvasively Predicts Hemodynamic Significance by using Fractional Flow Reserve in Intermediate Coronary Lesions. Radiology 2015;276:408-15.
- Boden WE, O'Rourke RA, Teo KK, et al. Optimal medical therapy with or without PCI for stable coronary disease. N Engl J Med 2007;356:1503-16.
- BARI 2D Study Group, Frye RL, August P, et al. A randomized trial of therapies for type 2 diabetes and coronary artery disease. N Engl J Med 2009;360:2503-15.
- 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.
- 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.
- Rief M, Zimmermann E, Stenzel F, et al. Computed tomography angiography and myocardial computed tomography perfusion in patients with coronary stents: prospective intraindividual comparison with conventional coronary angiography. J Am Coll Cardiol 2013;62:1476-85.
- 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.
- 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.
- 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.
- Nakazato R, Park HB, Berman DS, et al. Noninvasive fractional flow reserve derived from computed tomography angiography for coronary lesions of intermediate stenosis severity: results from the DeFACTO study. Circ Cardiovasc Imaging 2013;6:881-9.
- 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.
- Min JK, Leipsic J, Pencina MJ, et al. Diagnostic accuracy of fractional flow reserve from anatomic CT angiography. JAMA 2012;308:1237-45.
- Cook CM, Petraco R, Shun-Shin MJ, et al. Diagnostic Accuracy of Computed Tomography-Derived Fractional Flow Reserve : A Systematic Review. JAMA Cardiol 2017;2:803-10.
- Curzen NP, Nolan J, Zaman AG, Nørgaard 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;9:1188-94.
- SCOT-HEART investigators. CT coronary angiography in patients with suspected angina due to coronary heart disease (SCOT-HEART): an open-label, parallel-group, multicentre trial. Lancet 2015;385:2383-91.
- Williams MC, Hunter A, Shah ASV, et al. Use of Coronary Computed Tomographic Angiography to Guide Management of Patients With Coronary Disease. J Am Coll Cardiol 2016;67:1759-68.
- Berman DS, Rozanski A, Slomka P, et al. "Value Based Imaging for Coronary Artery Disease: Implications for Nuclear Cardiology and Cardiac CT." In Budoff, M, ed. Cardiac CT Imaging Diagnosis of Cardiovascular Disease. Switzerland: Springer International Publishing; 2016:349-80.
Clinical Topics: Acute Coronary Syndromes, Dyslipidemia, Invasive Cardiovascular Angiography and Intervention, Noninvasive Imaging, Stable Ischemic Heart Disease, Atherosclerotic Disease (CAD/PAD), Lipid Metabolism, Nonstatins, Novel Agents, Statins, Interventions and ACS, Interventions and Coronary Artery Disease, Interventions and Imaging, Angiography, Computed Tomography, Nuclear Imaging, Chronic Angina
Keywords: Acute Coronary Syndrome, Angina, Stable, Arteries, Aspirin, Atherosclerosis, Calcium, Catheterization, Coronary Angiography, Constriction, Pathologic, Coronary Artery Disease, Coronary Stenosis, Follow-Up Studies, Coronary Vessels, Hydroxymethylglutaryl-CoA Reductase Inhibitors, Incidence, Hydrodynamics, Life Style, Myocardial Infarction, Myocardial Ischemia, Patient Care, Lipids, Plaque, Atherosclerotic, Positron-Emission Tomography, Prognosis, Prospective Studies, Referral and Consultation, Registries, Stents, Tomography, Emission-Computed, Single-Photon, Tomography, X-Ray Computed, Diagnostic Imaging, Cardiac Imaging Techniques
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