Today, I review, link to and excerpt from SCCT 2021 Expert Consensus Document on Coronary Computed Tomographic Angiography: A Report of the Society of Cardiovascular Computed Tomography [PubMed Abstract] [Full-Text HTML] [Full-Text PDF]. J Cardiovasc Comput Tomogr. 2021 May-Jun;15(3):192-217. doi: 10.1016/j.jcct.2020.11.001. Epub 2020 Nov 20.
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- 1. Introduction: scope of the document
- 2. Evidence base
- 3. Guidelines and pre-test probability
- 4. Clinical indications for coronary CTA
- 5. Decision making
- 6. Summary
- Footnotes
- References
1. Introduction: scope of the document
Cardiac computed tomography (CT) has changed rapidly since the last major guideline from SCCT.1 While there have been significant advances in technology, the most gratifying part has been the development of a robust evidence base for the use of cardiac CT in diagnoses of heart disease, prognostication and modulating therapy (both medical and interventional). Such a systematic development of knowledge base has not been the usual practice for any other imaging modality before widespread clinical acceptance in the past. It is no surprise that major guideline bodies have started to endorse incorporation of cardiac CT more definitively than before, and some, like the NICE guidelines in the UK,2 have even given it first line status. While CTA has been shown to be very good for prognosticating risk, excluding significant coronary artery disease (CAD) in stable patients with chest pain and has high sensitivity for the identification of significant coronary stenoses, it is somewhat less robust in specificity and positive predictive accuracy, leading to the development of value added CT angiography (CTA) strategies like fractional flow reserve derived from CT (CT-FFR) and CT perfusion (CTP); these have arrived into the clinical arena since the last guidelines and, more importantly, have produced a large volume of scientific data showing significant clinical utility. Finally, some questions that often arise in regular clinical practice lack robust trial based evidence and a considered expert opinion might help the clinician make appropriate decisions in everyday practice. It is thus clear that an updated scholarly compendium of recent data is needed to bridge the knowledge gap since the last iteration of the SCCT guideline documents. This SCCT consensus statement summarizes current evidence, updates previous recommendations, addresses key questions regarding the use of CTA in multiple different cardiac scenarios and brings together the collective corpus of literature in the form of definitive recommendations. CTA in acute coronary syndromes will be presented in a separate document. The Expert Consensus recommendations are summarized in Table 1 and Fig. 1.
Table 1.
SCCT coronary CTA expert consensus recommendations.
Evaluation of Stable Coronary Artery Disease: Coronary CTA in Native Vessels
It is appropriate to perform CTA as the first line test for evaluating patients with no known CAD who present with stable typical or atypical chest pain, or other symptoms which are thought to represent a possible anginal equivalent (e.g., dyspnea on exertion, jaw pain).
It is appropriate to perform CTA as a first line test for evaluating patients with known CAD who present with stable typical or atypical chest pain, or other symptoms which are thought to represent a possible anginal equivalent (e.g., dyspnea on exertion, jaw pain).
It is appropriate to perform coronary CTA following a non-conclusive functional test, in order to obtain more precision regarding diagnosis and prognosis, if such information will influence subsequent patient management.
It is recommended to perform CTA as the first line test when considering evaluation for revascularization strategies using the ISCHEMIA Trial.
It may be appropriate to perform CTA in selected asymptomatic high risk individuals, especially in those who have a higher likelihood of having a large amount of non-calcified plaque
It is rarely appropriate to perform coronary CTA in very low risk symptomatic patients, e.g., <40 years of age with non-cardiac symptoms (chest wall pain, pleuritic chest pain).
It is rarely appropriate to perform CTA in low- and intermediate risk asymptomatic patients.
Evaluation of Stable Coronary Artery Disease: Coronary CTA Post Revascularization
It is appropriate to perform coronary CTA in symptomatic patients with intracoronary stent diameter ≥3.0 mm. Measures to improve accuracy of stent imaging should be utilized, to include strict heart rate control (goal <60 bpm), iterative reconstruction, sharp kernel reconstruction, and mono-energetic reconstructions (when available). Protocols to optimize stent imaging should be developed and followed.
It may be appropriate to perform coronary CTA in symptomatic patients with stents <3.0 mm, especially those known to have thin stent struts (<100 mm) in proximal, non-bifurcation locations.
It is appropriate to perform CTA for evaluation of patients with prior CABG, particularly if graft patency is the primary objective.
It is appropriate to perform CTA to visualize grafts and other structures prior to re-do cardiac surgery.
Evaluation of Stable Coronary Artery Disease: Coronary CTA with FFR or CTP
It may be appropriate to perform CT derived FFR and CT myocardial perfusion Imaging to evaluate the functional significance of intermediate stenoses on CTA (30e90% diameter stenosis) particularly in the setting of multivessel disease to help guide ICA referral and revascularization treatment planning. LM stenosis≥50% and severe triple vessel disease should undergo invasive coronary angiography.
Adding FFRCT and stress-CTP to CTA increases specificity, positive predictive value, and diagnostic accuracy over regular CTA.
FFRCT and stress-CTP may be largely comparable in diagnostic utility. CTP is a potentially valuable alternative particularly when CT-FFR is technically difficult (e.g., suboptimal CTA quality, prior revascularization).
Evaluation of Stable Coronary Artery Disease: Coronary CTA in Other Conditions
It is appropriate to perform CTA for coronary artery evaluation prior to noncoronary cardiac surgery as an equivalent alternative to invasive angiography in selected patients, e.g., low-intermediate probability of CAD, younger patients with primarily non-degenerative valvular conditions.
CTA may be considered an appropriate alternative to other noninvasive tests for evaluation of selected patients prior to noncardiac surgery.
It is appropriate to perform CTA to exclude coronary artery disease in patients with suspected non-ischemic cardiomyopathy.
It may be appropriate to perform late enhancement CT imaging to detect infiltrative heart disease or scar in selected patients who have non-ischemic or ischemic cardiomyopathy and who cannot undergo cardiac MRI. Such imaging may be performed if it has the potential to impact the diagnosis and/or treatment (e.g. planning for ablation therapy).
It may be appropriate to perform CTA as an alternative to invasive coronary angiography for the screening of patients for coronary allograft vasculopathy in selected clinical practice settings.
It is appropriate to perform CTA for the evaluation of coronary anomalies.
It is appropriate to EKG gate aortic dissection and aneurysm CTA, as well as pulmonary embolus studies in men >45 years and women >55 years, and analyze and report the coronary arteries.
CTA with a limited delayed image (60e90 sec) is an appropriate alternative to TEE when the primary aim is to exclude LA/LAA thrombus and in patients where the risks associated with TEE outweigh the benefits. In all situations CTA and TEE should be discussed with the patient in the setting of shared decision making.
It may be appropriate to perform late enhancement CT imaging for the evaluation of myocardial viability in selected patients who cannot undergo cardiac MRI. Such imaging may be performed if it has the potential to impact the diagnosis and/or treatment (e.g. planning for revascularization).
Reporting on CTA: Coronary and Non Coronary Information
The CAD-RADs reporting is recommended.
It is appropriate to report prior myocardial infarction when its features are evident on CTA.
It is appropriate to report remote myocardial infarction when fatty metaplasia or calcification within an area of infarction are present.
Fig. 1.
Central Illustration Role of CTA in chronic CAD. Also please see Table 1.
2. Evidence base
2.1. Diagnostic accuracy
2.1.1. Introduction
Since the recognition that coronary artery stenoses can produce chest pain, the imperative has been to identify through noninvasive testing both the patients whose chest pain is ischemic in etiology, and, with a view towards revascularization, the arteries and specific stenoses that are responsible for the ischemia. To fulfill this need, testing has evolved from simple exercise treadmill test (ETT) to (a) Measures estimating myocardial blood flow changes: myocardial perfusion imaging by single photon emission computed tomography (SPECT), positron emission tomography (PET), magnetic resonance imaging (MRI), (b) Measures detecting the functional consequence of reduced myocardial blood flow: stress echocardiography (SE), (c) Anatomic Imaging: CTA, and finally (d). Combination of anatomic coronary imaging coupled with physiology or perfusion: CTA derived fractional flow reserve (FFRCT) and CTP. How these modalities compare with each other has important implications for diagnostic strategies.
The gold standard for determining ischemia has also evolved from percent diameter stenosis (DS) on invasive coronary angiography (ICA) to more physiologic measures, such as invasive fractional flow reserve (FFR) that better reflect coronary blood flow and inducible ischemia. Using DS as a reference standard often provides an inaccurate assessment of ischemia. For instance, when compared to invasive FFR ≤0.80, the sensitivity of ICA is 69%, and the specificity is 67%.3 Although invasive FFR was initially validated by functional noninvasive testing (SPECT and SE), this method has become a universally accepted gold standard by virtue of its strong association with outcomes.4–6 Nonetheless, %DS continues to be used much more often than invasive FFR before percutaneous coronary intervention (PCI), – In the ALKK Registry in Germany, FFR was performed in only 3.3% of 40,160 patients undergoing ad hoc PCI from 2010 to 2013.7 There has been an increase in invasive FFR use in the US, from 8.1% in 2010 to 30.8% in 2014, in a registry of 397,737 patients undergoing nonacute PCI.8 Consequently, the noninvasive imaging modalities will be compared to both %DS and FFR. The best level of evidence is provided by meta-analyses, which will serve as the basis for comparisons, with the exception of 2 recent single center studies not included in meta-analyses. The meta-analyses included patients with and without confirmed CAD and did not draw distinctions between them.
2.1.2. Diagnostic performance of functional imaging and CTA compared to >50% diameter stenosis by ICA
The National Cardiovascular Data Registry9 suggested that functional testing is suboptimal for detecting significant coronary stenoses. Of the 661,063 patients undergoing elective catheterization, 64% had testing before the invasive coronary angiogram (ICA); of those, only 51.9% were abnormal. The percentages of patients with <50% DS on subsequent ICA ranged from 55 to 56% after an abnormal exercise treadmill test (ETT), stress echocardiography (SE), single photon emission computed tomography (SPECT) and magnetic resonance imaging (MRI); for resting CTA, the percentage was 30%. In the oldest report, Fleischmann et al. evaluated 5874 patients in 41 studies from 1990 to 1997, and reported sensitivity and specificity of 85% and 77% for SE and 87% and 64% for SPECT, with 52% and 71% for exercise ECG.10 DeJong et al. (Table 2A), in a meta-analysis of 5088 patients in 51 studies from 2000 to 2011 evaluated MRI, SE and SPECT with >50%DS by ICA as reference.11 MRI was the most sensitive and specific (91% and 80%), with SE (87% and 72%) and SPECT (83% and 77%) roughly similar. Jaarsma et al. (Table 2B), reported on SPECT, MRI and positron emission tomography (PET) in 141 per-patient studies and 70 per-vessel studies.12 Per-patient diagnostic odds ratio (DOR) was highest for PET (36.47) followed by MRI (26.42) and SPECT (16.31). In per-vessel analysis, PET and MRI were equal (24.74 and 24.11), while SPECT was lowest (11.75). In a meta-analysis limited to 26 studies in which CTA was compared to either ETT or SPECT in the same group of patients, Nielsen et al.13 (Table 2C) reported CTA sensitivities of 95–99%, specificities of 68–93% and DOR of 128–728. Corresponding ranges for ETT were 65–70%, 24–60% and 0.7–4 and for SPECT were 67–73%, 48–52% and 2–4. It is important to understand that available meta-analyses are also challenged by the small numbers of patients in some of the individual reports, potential referral bias, and often include a mixture of newer and older technology (e.g., planar and SPECT imaging). Finally, in a paper published too recently for meta-analysis inclusion, 391 symptomatic patients, 52% with intermediate and 46% with high risk pre-test probability, who were scheduled for ICA, underwent both CTA and SPECT with >50%DS by ICA as reference.14 Sensitivity, specificity, positive and negative predictive values were 0.92, 0.75, 0.84 and 0.87 for CTA and 0.62, 0.68, 0.74 and 0.55 for SPECT. AUC was significantly higher for CTA (0.91 versus 0.69, p < 0.001.
Table 2.
Meta-analyses of the diagnostic performance of functional imaging and CCTA with ICA >50%DS as reference standarda.
A. MRI, SE and SPECT Sensitivity Specificity PLR NLR DOR MRI (n = 2970) Overall 91% 80% 4.43 0.12 37.69 Suspected 90% 86% 6.61 0.12 54.70 CAD>50% 89% 79% 4.25 0.13 31.84 CAD>70% 91% 82% 4.97 0.11 46 SE (n = 795) Overall 87% 72% 3.08 0.18 16.94 Suspected 88% 89% 8.35 0.13 62.76 CAD>50% 86% 74% 3.28 0.19 17.59 CAD>70% 90% 65% 2.58 0.15 17.04 SPECT (n = 1323) Overall 83% 77% 3.56 0.22 15.84 Suspected 83% 79% 3.88 0.21 18.15 CAD>50% 81% 81% 4.15 0.24 17.24 CAD>70% 85% 66% 2.53 0.22 11.42
B. SPECT, MRI and PET No. of studies Sensitivity Specificity DOR Patient SPECT 105 88% 61% 15.31 MRI 27 89% 76% 26.42 PET 11 84% 81% 36.47 Territory SPECT 46 69% 79% 11.75 MRI 17 84% 83% 24.11 PET 7 77% 88% 24.74
C. CCTA, XECG and SPECT No. studies Sensitivity Specificity PPV NPV DOR CCTA vs ETT 7 CTA 98% 87% 85 97.5 221 ETT 67% 46% 41 72 2 CCTA vs ETT (ICA in all) 5 CCTA 99% 88% 89% 99% 728 ETT 68% 39% 50% 51% 1.2 CCTA vs ETT (inconclusive excluded) 4 CCTA 98% 68% 75% 97% 128 ETT 70% 60% 49.5% 78% 4 CCTA vs ETT (intention to diagnose) 3 CCTA 95% 93% 93% 96% 192 ETT 65% 24% 32% 55% 0.7 CCTA vs SPECT 5 CCTA 99% 71% 91% 95.5% 172 SPECT 73% 48% 80% 33% 2 CCTA vs SPECT (ICA in all) 2 CCTA 99% 74% 91% 96% 228 SPECT 67% 52% 78% 38% Abbreviations: AUC = area under receiver operator characteristic curve, CAD = coronary artery disease.
DOR = diagnostic odds ratio, CTA = coronary computed tomographic angiography, MRI = stress magnetic resonance imaging, NLR = negative likelihood ratio, NPV = negative predictive value, PET = positron emission tomography, PLR = positive likelihood ratio, PPV = positive predictive value, SE = stress echocardiography, SPECT = single photon emission computed tomography myocardial perfusion imaging, XECG = exercise electrocardiogram.
a Reprinted with permission of Oxford Academic from Hecht et al. Eur Heart J 2019:40;1440–1453
2.1.3. Diagnostic performance of functional imaging and CTA compared to FFR
There have been several recent meta-analyses of the correlation between noninvasive testing and Invasive FFR ≤0.80. Takx et al.15 (Table 3A) compared multiple myocardial perfusion imaging modalities to FFR in 2048 patients and 4721 vessels in 37 studies. They reported the highest areas under the receiver operator characteristic curve (AUC) per patient for CTP (0.93), PET (0.93) and MRI (0.94) compared to SPECT (0.82) and SE (0.83). Similarly, the highest per vessel sensitivities were for MRI (89%), CTP (88%) and PET (84%) compared to SE (69%) and SPECT (74%). Specificities were similar for all modalities, ranging from 79% for SPECT to 87% for PET, with 80% for CTP and 84% for SE and MRI.
Table 3.
Meta-analyses of the diagnostic performance of functional imaging and CCTA with FFR ≤0.80 as reference standarda.
A. CTP, SPECT, SE, MRI, PET Index test N Sensitivity Specificity PLR NLR AUC Patients CTP 316 88% 80% 3.79 0.12 0.93 SPECT 533 74% 79% 3.13 0.39 0.82 SE 177 69% 84% 3.68 0.42 0.83 MRI 798 89% 84% 6.29 0.14 0.94 PET 224 84% 87% 6.53 0.14 0.93 Vessels CTP 1074 78% 86% 5.74 0.22 0.91 SPECT 924 81% 84% 3.76 0.47 0.83 SE NA – – – – – MRI 1830 83% 89% 8.27 0.16 0.95 PET 870 83% 89% 7.43 0.15 0.95
B. CCTA, SE, FFRCT, ICA, MRI, and SPECT Index test N Sensitivity Specificity PLR NLR DOR AUC Patients CCTA 694 90% 39% 1.54 0.22 6.91 0.57 FFRCT 609 90% 78% 3.34 0.16 21.94 0.94 SPECT 110 70% 78% 3.40 0.40 9.06 0.79 SE 115 77% 75% 3.00 0.34 9.51 0.82 MRI 70 90% 94% 10.31 0.12 92.15 0.94 ICA 954 69% 67% 2.52 0.46 5.46 0.79 Vessels CCTA 2085 91% 51% 2.09 0.17 13.15 0.85 FFRCT 1050 83% 78% 4.02 0.22 19.15 0.92 SPECT 470 57% 75% 2.34 0.55 4.72 0.74 SE NA – – – – – – MRI 371 91% 85% 6.16 0.11 73.53 0.97 ICA 3196 71% 66% 2.26 0.45 5.34 0.76 C. CMR, FFRCT, CTP, DSE, PET and SPECT Index test N Sensitivity Specificity PLR NLR DOR AUC Patient MRI 1054 88% 84% 5.62 0.14 40.69 0.91 FFRct 662 90% 75% 3.60 0.14 25.87 0.90 CTP 532 88% 87% 6.97 0.14 49.88 0.94 DSE 359 69% 77% 2.96 0.40 7.40 0.78 PET 609 90% 84% 6.00 0.12 56.59 0.92 SPECT 1142 78% 79% 3.76 0.28 13.52 0.85 Vessel MRI 3260 87% 89% 8.15 0.14 57.93 0.94 FFRCT 2782 86% 83% 5.10 0.17 29.37 0.89 CTP 1444 89% 89% 7.82 0.13 61.98 0.94 DSE 94 62% 87% 4.66 0.44 10.51 0.86 PET 2017 86% 88% 7.15 0.17 42.39 0.92 SPECT 1288 72% 79% 3.45 0.36 9.71 0.83
D. CCTA, CTP and FFRCT Index test N Sensitivity Specificity PLR NLR DOR PPV NPV Per patient CCTA 1039 92% 43% 1.64 0.19 9.17 57% 87% CTP 187 94% 77 3.85 0.09 63.42 83% 92% FFRCT 662 90% 72% 3.70 0.16 24.34 70% 90% Per vessel CCTA 1239 89% 65% 2.66 0.17 19.78 48% 94% CTP 264 83% 76% 3.68 0.22 20.10 61% 91% FFRCT 714 83% 77% 3.76 0.23 18.21 63% 91% Abbreviations: CTA = coronary computed tomographic angiography CTP = CT perfusion DOR = diagnostic odds ratio FFR = fractional flow reserve FFRCT = fractional flow reserve by computed tomography ICA = invasive coronary angiography MRI = stress magnetic resonance imaging NA = not available NLR = negative likelihood ratio NPV = negative predictive value PET = positron emission tomography PLR = positive likelihood ratio PPV = positive predictive value SE = stress echocardiography SPECT = single photon emission computed tomography myocardial perfusion imaging.
a Reprinted with permission of Oxford Academic from Hecht et al. Eur Heart J 2019:40;1440–1453.A second meta-analysis, analyzing 3798 patients and 5323 vessels in 23 studies, by Danad et al.,3 (Table 3B), excluded studies in which <75% of vessels were evaluated by FFR, included CTA >50% diameter stenosis and ICA >50%DS and excluded PET, for which there were not sufficient numbers after excluding studies with <75% of vessels having invasive FFR. Sensitivity was highest for CTA and MRI in both per patient (90%) and per vessel (91%) analyses. SPECT sensitivity was the lowest of the functional tests for both patients (70%) and vessels (57%) while SE was also suboptimal (77%). ICA sensitivity was dramatically lower (69%) than for CTA even though both depict coronary anatomy. Specificity was highest for MRI for both per patient (94%) and per vessel analysis (85%), followed by the other 2 functional modalities of SPECT and SE in the 75–78% range. CTA specificity was remarkably lower (39%) than both the functional tests and ICA (66%). The likelihood ratios and AUC reflect these differences; MRI was superior for both positive and negative likelihood ratios and AUC. CTA negative likelihood was excellent as well but had the lowest per patient and per vessel positive likelihood ratio and AUC. Comparison of the anatomical modalities indicates that %DS is overestimated by CTA and under-estimated by ICA, explaining the higher sensitivity and lower specificity for CTA.A third meta-analysis of all the functional imaging modalities with considerably more patients, by Dai et al.16 (Table 3C) of 74 studies, included CTFFR and CTP and excluded solely anatomic CTA. As before, CTP, CTFFR CMR and PET had superior per patient sensitivity (88–90%), specificity (84–87%) and DOR (41–57). The 2 most frequently performed functional imaging modalities of SE and SPECT were the least accurate: 69% and 78% sensitivity, 77% and 79% specificity, and 7.40 and 13.40 DOR.Finally, in the PACIFIC trial, a single center study of 208 patients who underwent CTA, SPECT, PET and ICA with FFR, CTA was 90% sensitive, 60% specific and 74% accurate, compared to 87%, 84% and 85% for PET and 57%, 94% and 77% for SPECT.17CT has 2 additional advantages in diagnosis and management of chronic stable CAD. It can prognosticate very well18–22, and has the unique ability to identify adverse coronary plaque characteristics that portend adverse risk23–33 and might even influence the occurrence of ischemia (34). Some of the newer value added technologies like CT-FFR and CTP (35,36) have now been shown to improve the accuracy of CAD diagnosis over and above CTA alone.Addition of physiologic studies to anatomic information in the same CT scan improve test performance.35,36 The meta-analysis by Gonzalez et al., of 1535 patients in 18 studies, compared CTA, CTP and CT-FFR.35 Per patient sensitivities were similar (90–94%), but specificities (43%, 77% and 72%) and DOR (9.17, 63.42 and 24.34) were lowest for CTA without a functional imaging component. Per-vessel results were much less disparate, with sensitivities of 89%, 83% and 83%, specificities of 65%, 76% and 77%, and virtually identical DOR of 19.78, 20.10 and 18.21. A more recent meta-analysis (5330 patients) comparing CTA, CTP and CT-FFR also showed improved efficacy for diagnosing hemodynamically significant CAD compared with CTA alone with higher vessel level, pooled specificity with CTP (0.86; 95% confidence interval [CI]: 0.76 to 0.93), and CT-FFRCT (0.78; 95% CI: 0.72 to 0.83) than that of CTA (0.61; 95% CI: 0.54 to 0.68); addition of either FFRCT, or CTP to CTA improved specificities (0.80–0.92) and superior diagnostic accuracy for CTP, FFRCT, and combined CTA and CTP, compared with CTA. On-site FFR performed as well as off-site FFR and dynamic CTP was more sensitive (0.85 vs. 0.72), but less specific (0.81 vs. 0.90) than static CTP.36With few exceptions, these meta-analyses represent a compilation of prospective and retrospective single center studies with their implicit biases and general lack of direct inter-modality comparisons in the same group of patients. Nonetheless, they offer the most comprehensive evaluation by virtue of their large numbers, and the similarities of the findings irrespective of the inclusion criteria for the meta-analyses.2.1.4. General conclusions
With ICA >50%DS as the reference, CTA, MRI and PET are the most sensitive and specific modalities; SPECT and SE are less sensitive and specific.
With invasive FFR ≤0.80 as the reference, CTA, MRI and PET are the most sensitive and MRI and PET are the most specific. CTA is the least specific but CT-FFR and CTP increase the specificity to the level of MRI and PET without loss of sensitivity. SPECT and SE are the least sensitive.
These accuracy data should inform the suspected ischemia decision making process, which will also be strongly affected by the availability and expertise of the imaging centers, as well as by outcome and cost studies, some of which are already available after short term analysis.
While proceeding to testing was predicated upon estimating pre test probability, the current practice patterns pose some challenges – patients are at lower risk than before and the percentage of positive tests is declining. Models for predicting pre test probability, derived from older data perform sub optimally37,38 and therefore require an update.39 There is now a strong movement towards dispensing wth this completely as formulated in the NICE guidelines.
Adding non CT modalities for myocardial perfusion (which have better specificity) to CTA (which has excellent sensitivity) is an attractive strategy to minimize the disadvantages of each technique but this has not worked out very well in practice; hybrid cardiac imaging improves diagnostic specificity but with only modest improvement in overall diagnostic performance.
2.2. Prognostic value and comparison with functional testing
The prognostic value of CTA has now been established in both large registry studies and more recent randomized controlled trials. This increasing depth of evidence highlights that CTA provides prognostic information for patents with all levels of cardiovascular risk. In addition, both normal and abnormal CTA results provide important information that can alter downstream investigations and management and influence subsequent outcomes. Our knowledge of the utility of CTA has moved beyond confirmation of diagnostic accuracy, with comparative effectiveness studies now underpinning the prognostic benefit of CTA in large randomized populations. The identification of both obstructive and non-obstructive coronary artery disease by CTA provides important information in patients with both stable chest pain and acute symptoms.
Registry studies have established the excellent prognostic value of a normal CTA, both for short-term outcomes and longer term mortality.40–44 Previous analysis of stress myocardial perfusion imaging (MPI) identified that a normal study is associated with a low risk of subsequent major adverse cardiovascular events, equating to less than a 1% annual risk for patients without comorbidities.45 Similarly, a meta-analysis of patients 122,721 patients in 165 studies identified that a normal CTA (without plaque) in patients with suspected or known coronary artery disease (CAD) was associated with a low risk of subsequent events, which is below an annual event rate of 1%.46 This low event rate was maintained after correction for the underlying population event risk and the proportion of patients with CAD.46 After correction, the event rate for a normal CTA was similar to that of a normal SPECT, ETT, CMR, PET or stress echocardiogram.46 Indeed, a normal CTA is associated with an excellent prognosis extending beyond 5 years.40–44 There is now data showing that a normal CTA strongly predicts event free survival even over a 10 year follow up.47
The identification of both obstructive and non-obstructive CAD is associated with worse prognosis in patients undergoing CTA. The COronary CT Angiography EvaluatioN For Clinical Outcomes: An InteRnational Multicenter (CONFIRM) registry found that both the presence and severity of CAD was important in predicting subsequent events.48,49 The presence of obstructive disease and number of vessels involved were predictive of mortality at 2 years in 23,854 patients without known CAD undergoing CTA.48 Other registry and cohort studies have identified a similar impact on subsequent outcomes based on the presence and severity of obstructive CAD.40,42,50,51 A meta-analysis of 25,258 patients with suspected or known CAD in 21 studies identified a similar long term (>2.5 years) prognostic value for CTA and stress MPI in the prediction of death and non-fatal myocardial infarction.52 Registry studies have also shown that CTA provides incremental prognostic information over cardiovascular risk factors48,49,51,53,54 and, in some sub-groups, over coronary artery calcium score (CACS).51,55,56 The PROMISE (PRO-spective Multicentre Imaging Study for Evaluation of chest pain) trial assessed stable symptomatic outpatients referred for non-invasive investigation for suspected CAD.57 The 10,003 participants were randomized to anatomical testing with CTA or functional testing with exercise electrocardiography, stress echocardiography or SPECT.57 After 25 months of follow-up there was no difference between the two groups in the primary outcome of mortality, myocardial infarction, hospitalization for unstable angina and major complications of procedures or diagnostic testing.57 However, subsequent assessment of this study identified that the discriminatory ability to predict subsequent events was higher for CTA than functional testing (c-index 0.72; 95% CI 0.68 to 0.76 versus 0.64; 0.59 to 0.69; p = 0.04), mostly due to the ability of CTA to detect prognostically important non-obstructive disease.18 A methodical description of the extent of CAD on CTA allows finer evaluation of the prognostic value of different levels of CAD. Application of the CAD-RADs classification to the CONFIRM database19 showed a graded decrease in event free survival with more severe disease (5-year event-free survival of 95% with CAD-RADS 0–69.3% for CAD-RADS 5). An analysis of the PROMISE study20 showed that increasing severity (CAD-RADs score) continued to have additional prognostic value over and above CAC and ASCVD scores.
In addition to the presence and severity of coronary artery stenosis, CTA can provide additional information on plaque burden and adverse coronary artery plaque characteristics. Semi-quantitative assessment of plaque burden such as the CT-Leaman score21 or segment involvement score can provide additional stratification of patients with non-obstructive coronary artery disease that is an independent predictor of subsequent prognosis. In the Partners registry, among 3242 patients evaluated with CTA, patients with non-obstructive plaque involving at least 4 segments had the same risk of hard cardiovascular events as those who had obstructive CAD22 Moreover, treatment of such individuals with extensive plaque was associated with a reduction in cardiovascular events22 which is supported by other data showing that plaques can be stabilized with various therapies. Quantitative assessment of plaque characteristics is also associated with subsequent outcomes in multiple studies.23–25 In a study looking at serial CTAs, the percent atheroma volume (PAV) at baseline was the strongest predictor of progression of non-obstructive disease to obstructive lesions.25 The non calcified component of plaque is important: while not different from patients with low vs. high clinical risk (based on number of risk factors), high volume of noncalcified plaque is one of the strongest parameters for predicting ACS in patients with extensive CAD.24 Not surprisingly, an increased total, non-calcified or low-density plaque volume is associated with a significant increase in cardiac mortality in >5 years follow-up, independent of the segment involvement score.23 Similar data are seen in high risk groups like asymptomatic diabetic subjects.26 A composite inclusion of plaque volume, location and composition, might be advantageous for prognostication.27
Adverse coronary artery plaque characteristics (also known as high risk plaques or vulnerable plaques) include the presence of positive remodeling, spotty calcification, low attenuation plaque and the ‘napkin ring’ sign.28,29 and these predict adverse outcomes including acute coronary events.30–32 Motoyama et al. identified that the presence of positive remodeling or low attenuation plaque was an independent predictor of subsequent acute coronary syndromes in patients undergoing CTA.28 In the PROMISE study the presence of positive remodeling, low attenuation plaque or the napkin-ring sign was associated with an increased rate of major cardiovascular events, independent of cardiovascular risk score and the presence of significant stenosis.31 In the Scottish COmputed Tomography of the HEART (SCOT-HEART) trial the presence of positive remodeling and or low attenuation plaque was associated with an increased rate of myocardial infarction or coronary heart disease death.32 However, at 5 years the presence of adverse plaque was not an independent predictor of events compared to coronary artery calcium score. This suggests that adverse plaque features are a predictor of increased risk in the short-term but that plaque burden is a more important predictor of longer-term prognosis.32 Future quantitative assessment of adverse coronary artery plaque characteristics may provide more precise risk assessment.
Thus, a normal CTA is associated with a prognosis similar to, or better than a normal functional imaging assessment. The presence, extent, and severity of coronary artery disease on CTA is strongly associated with prognosis in patients with stable and acute chest pain. Additional characteristics including plaque volume and adverse coronary artery plaque characteristics can provide information on prognosis, over and above the assessment of stenosis severity.
2.3. Randomized controlled trials of coronary computed tomography angiography in patients with stable chest pain
There have been five randomized controlled trials of coronary computed tomography angiography (CTA) in patients with stable chest pain (Table 4) that have been performed in Europe and North America with important differences in study populations and design. Most trials have undertaken head-to-head comparisons with functional testing (predominantly exercise electrocardiography, myocardial perfusion imaging or stress echocardiography). These trials assessed the effect of CTA on diagnosis, risk stratification, clinical management (invasive coronary angiography and coronary revascularization), symptoms and clinical outcomes.
2.3.1. Diagnosis
CTA is a diagnostic test and its accuracy has been established for the diagnosis of coronary artery disease (see section 2.1). It is important to distinguish between its diagnostic accuracy for atherosclerosis, obstructive coronary artery disease and angina pectoris due to coronary artery disease. Clearly, the latter also relies on the patient history and the clinical context. The SCOT-HEART,33,58 Cardiac CT for the Assessment of Pain and Plaque (CAPP),59 the Computed Tomography versus Exercise Testing in Suspected Coronary Artery Disease (CRESCENT 1),60 and CRESCENT II62 and Min et al.61 trials directly assessed the influence of CTA on the diagnosis of stable chest pain that was suspected to be due to coronary artery disease. All studies found that CTA was superior to functional testing or standard of care, with the SCOT-HEART trial reporting a 2-fold increase in diagnostic certainty compared to standard of care. Whilst the frequency of the diagnosis of coronary artery disease rose in all trials, the diagnosis of angina pectoris due to coronary heart disease tended to fall in the SCOT-HEART trial perhaps reflecting the absence of obstructive disease in those who were initially presumed to have angina.
2.3.2. Clinical management
The effect of CTA on subsequent clinical management is highly dependent on the population studied. In the SCOT-HEART,63 CAPP59 and CRESCENT60 trials, the study population consisted of patients specifically referred for the evaluation of chest pain suspected to be due to coronary artery disease, with a high prevalence of obstructive coronary artery disease. In these trials, rates of invasive coronary angiography were either reduced or unchanged. However, documentation of obstructive coronary artery disease was more frequent at the time of invasive coronary angiography, which led to a modest increase in coronary revascularizations in the short term trials. In the 5 year follow up of the SCOT-HEART trial, the apparent early increases in coronary angiography and coronary revascularization were offset by later reductions in both invasive angiography and coronary revascularization; by 5 years there was no difference in these procedures. Indeed, beyond the first year, CTA was associated with less invasive coronary angiography (hazard ratio, 0.70; 95% CI, 0.52 to 0.95; p = 0.022) and coronary revascularization (hazard ratio, 0.59; 95% CI, 0.38 to 0.90; p = 0.015).58 This suggests that the right patients are identified early and treated more promptly, thereby preventing progression of disease and avoiding later reinvestigation and revascularization.
2.3.2. Clinical management
The effect of CTA on subsequent clinical management is highly dependent on the population studied. In the SCOT-HEART,63 CAPP59 and CRESCENT60 trials, the study population consisted of patients specifically referred for the evaluation of chest pain suspected to be due to coronary artery disease, with a high prevalence of obstructive coronary artery disease. In these trials, rates of invasive coronary angiography were either reduced or unchanged. However, documentation of obstructive coronary artery disease was more frequent at the time of invasive coronary angiography, which led to a modest increase in coronary revascularizations in the short term trials. In the 5 year follow up of the SCOT-HEART trial, the apparent early increases in coronary angiography and coronary revascularization were offset by later reductions in both invasive angiography and coronary revascularization; by 5 years there was no difference in these procedures. Indeed, beyond the first year, CTA was associated with less invasive coronary angiography (hazard ratio, 0.70; 95% CI, 0.52 to 0.95; p = 0.022) and coronary revascularization (hazard ratio, 0.59; 95% CI, 0.38 to 0.90; p = 0.015).58 This suggests that the right patients are identified early and treated more promptly, thereby preventing progression of disease and avoiding later reinvestigation and revascularization.
2.3.4. Clinical outcomes
The SCOT-HEART and PROMISE trials were sufficiently large to assess the impact of CTA on hard clinical outcomes.57,58,65 The PROMISE trial had a large composite clinical outcome that included all-cause mortality as well as coronary events (myocardial infarction and unstable angina). Although there was no difference in this primary outcome, CTA appeared to be associated with a lower rate of death or myocardial infarction at 12 months. Meta-analysis has reported reduced rates of myocardial infarction with CTA (hazards ratio, 0.69 [95% confidence intervals, 0.49 to 0.98]) but no effect on overall mortality.66 Similar reductions in myocardial infarction have also been reported in a large (n = 86,705) observational Danish registry (hazards ratio, 0.71 [95% confidence intervals, 0.61 to 0.82]).67 The 5-year outcome data from the SCOT-HEART trial have now confirmed these earlier promising results: hazard ratios were 0.59 (p = 0.004) for CTA compared to standard of care for the primary endpoint of death from CAD or nonfatal myocardial infarction and 0.60 for nonfatal myocardial infarction alone, without overall differences in ICA or revascularization.58,68
2.4. Cost effectiveness of CTA
We define in this guideline use of the term cost effectiveness to include the cost consequences of CTA use as well as comparisons of costs associated with CTA-guided strategies of care.69 There have been numerous decision analytic models which have explored the cost effectiveness of CTA as compared to functional testing strategies of care in the evaluation of acute, low risk and stable chest pain syndromes. For this guideline, we will highlight evidence available from high quality clinical trials and large multicenter registries.70
Following CTA-detection of obstructive CAD, there have been concerns regarding an increasing rate of downstream invasive coronary angiography (ICA). Early reports noted higher rates of post-CTA use of ICA but more recent data support a more selective referral of patients to ICA following index CTA testing. In a report from the CONFIRM registry (n = 15,207 symptomatic patients), follow-up rates of ICA were low over 3 years of follow-up for patients with normal (2.5%) and mild CAD (8.3%), defined as a stenosis 1–49%.71 By comparison, for patients with obstructive CAD, use of ICA occurred promptly within 3 months of follow-up and occurred in 44%, 53%, and 69%, respectively of patients with 1-, 2-, and 3-vessel CAD. Overall, in the PROMISE trial, a relatively low rate of ICA use was reported for patients randomized to CTA (12%) as compared to the functional testing (8%) arms of the trial.57 Evidence is not available to judge the appropriateness of ICA use, as post-CTA use of stress testing or additional documentation of ischemia prior to ICA referral is not available. A synthesis of this evidence supports a relatively low rate of referral to ICA, notably for those patients without any obstructive CAD.
Many of the recent randomized clinical trials also include economic sub-studies that have been synthesized in a recent review (Table 5).60,72–77 Importantly, for these analyses, comparisons of cost differences are valid given the documentation of similar rates of 2–3 year rates of major adverse events.57,33 From the PROMISE trial, near term costs at ≤90 days and cumulative costs through 3-years of follow-up were aggregated. Within the near-term, there were no differences in cost between patients randomized to CTA as compared to functional testing, with a mean difference in cost of $254.72 Within 90 days, there was a notable but not significantly higher use of ICA and revascularization. When aggregated through 3 years of follow-up, the differences in cost by randomization to CTA as compared to functional testing did not yield significant differences.
Through 3 years of follow-up, the difference in costs by randomized test strategy in PROMISE was non-significant (Δ = $627); with similar findings for stress nuclear, echocardiography, and ECG testing. These longer-term cost findings identify the importance of follow-up testing patterns to reflect the cost-consequences of a given index procedure.69 Results from the SCOT-HEART trial revealed slightly higher costs associated with randomization to CTA, with cost differences of $462. Importantly, the induced costs did not result from additional outpatient or inpatient services or medication use.76 Several reports have noted higher use of anti-platelet and statin therapy following CTA but that has not translated into significantly higher costs associated with medications.67,72,76 Importantly, medication use appears to be targeted to higher risk patients, more often with evidence of obstructive CAD or to those with evidence of atherosclerosis.
Additional cost analyses are available from the CRESCENT trial whereby referral to exercise electrocardiography was associated with a higher rate of additional diagnostic testing; nearly half of patients in the stress testing arm had induced diagnostic testing procedures as compared to only 1 in 4 in the CTA arm of the CRESCENT trial (p < 0.0001).60 This higher rate of diagnostic testing following exercise electrocardiography was associated with a 16% higher cost of care. Additional cost savings were achieved in the CTA arm of the CRESCENT trial as nearly 42% of this arm had a 0 CAC score and did not undergo follow-up CTA, per the selective testing protocol whereby only those with detectable CAC proceeded to CTA. The randomized trial evidence supports the conclusion that costs associated with a CTA strategy are similar to those following stress testing, with only minimal differences through 2–3 years of follow-up.
Additional relevant data are provided by the cost effectiveness analysis employed in the UK’s NICE guidance document on stable chest pain78 which identified the lowest cost per correct diagnosis of obstructive CAD.79 The rate of detection of obstructive CAD was higher for CCTA than for all other diagnostic testing approaches.9,80 In a recent review, a synthesis of available randomized trial data revealed that concordance between CTA and ICA detected obstructive CAD was demonstrably higher than that of stress testing (71% of 1047 patients undergoing ICA versus 53% of 819 patients undergoing ICA).70 As such, in the NICE cost effectiveness analysis, CTA had the lowest cost per correct diagnosis and was projected to save the National Health Service approximately £16 million each year by excluding CAD with a high negative predictive value.78 Moreover, an index testing approach with CTA allows for a selective use of higher cost stress testing in a smaller proportion of patients with stable chest pain.
2.5. Plaque characterization
Pathologic studies have demonstrated that the acute coronary events, including sudden death, myocardial infarction and unstable angina, in a majority of cases result from acute coronary thrombosis secondary to rupture of plaques. These plaques demonstrate large plaque and necrotic core burden, positive remodeling and thin inflamed fibrous caps, and these characteristics have been referred to as high risk plaque (HRP) features. It has been proposed that noninvasive identification of atherosclerotic lesions with HRP features in stable patients should help predict the likelihood of adverse outcomes. It is therefore important to identify HRP for prevention of major adverse coronary events (MACE). Such thinking could be of clinical value because relief of luminal stenosis alone does not prevent the likelihood of acute events.
Intracoronary imaging modalities, including intravascular ultrasound (IVUS) and optical coherence tomography (OCT), have confirmed the histopathological observations and allowed assessment of HRP features in vivo. Whereas IVUS has demonstrated the presence of large plaque burden, echolucent necrotic core, and positive remodeling, OCT has successfully measured the fibrous cap thickness in vivo. Noninvasive imaging with CTA offers the most convenient basis of identification of the HRP characteristics and can be used to predict plaques that could cause acute events.28,30,31,81,82 Two CTA characteristics have demonstrated the best association with clinical outcomes up to 10 years of follow-up, and include the presence of low-attenuation plaques (LAP) with <30 HU density and positive remodeling (PR) of ≥110%. The plaques with these two CTA characteristics were called 2-feature-positive plaques (2-FPP); 22.5% of 2-FPP resulted in an acute event over a 2-year follow-up. On the other hand, 2-feature-negative plaques (2-FNP) were associated with benign outcomes with less than 0.5% resulting in acute events (Fig. 2). Multiple other adverse plaque characteristics have been suggested, such as the presence of circumferential necrotic cores (napkin-ring sign) and spotty calcification.
(A1) Presence of positive remodeling (yellow arrows) and low attenuation plaques (LAP, red arrow) are the most important determinants of plaque vulnerability. (A2) Stable plaques lack both these features. Major adverse cardiac events by the presence of 1 or both features in a follow up of — patients for 2 years (A3), and 300 patients for up to 10 years. (A4) Patients with HRP had 45 and 10 folds higher likelihood of adverse outcomes, respectively. Presence of significant stenosis over and above HRP features (A5) and interval progression in plaque magnitude (A6) increased the likelihood of adverse events further. Greater number of adverse plaque characteristics were associated with greater of adverse outcomes (A7) and the HRP characteristics were associated with abnormal fractional flow reserve regardless of luminal stenosis (A8).
(B) Potential indicators of inflammation by CTA as a complementary feature for identification of plaque vulnerability. It can be detected either by simultaneous PET imaging with F-18 FDG (that targets macrophage infiltration) (A1 & A2), or by fat attenuation index of perivascular fat (that represents lower prevalence of adipocytes consequent to greater cytokines in neointima) (A3 & A4). Modified from Motoyama et al. JACC 2007, Motoyama et al. JACC 2009, Lee et al. JACC 2019 Ahmadi et al. JACC-Imaging 2018, Rogers et al. JACC-Imaging 2010, Antoniades et al. Lancet 2018.
