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Since the introduction of coronary CT angiography (CCTA) there has been an enormous growth in the quantity of evidence to support the role of CCTA in the diagnosis of patients with suspected coronary artery disease (CAD). But what is the level of diagnostic accuracy of CCTA today? Have we attained sufficient reliable evidence to fully appreciate the role of CCTA in cardiologic practice?
Hierarchical model of diagnostic efficacy
The technical details and potential clinical applications of CCTA have been reported in two recent reviews in ‘Education in Heart’.1 ,2 In this current state-of-the-art exposition of CCTA for patients with suspected CAD it appears useful to arrange the available evidence according to a hierarchical model of efficacy of diagnostic imaging first described by Fryback and Thornburg in 1991.3 Efficacy is defined as: “the probability of benefit to individuals in a defined population from medical technology (CCTA) applied for a given medical problem under ideal conditions”.3
The model consists of six levels of efficacy: level 1—technical efficacy; level 2—diagnostic accuracy efficacy; level 3—diagnostic thinking accuracy; level 4—therapeutic efficacy; level 5—patient outcome efficacy; level 6—societal efficacy. The goal of the model not only involves the traditional view of the assessment of diagnostic imaging to generate optimal quality images and hence optimal diagnosis, but rather is a comprehensive assessment of patient and societal benefits of CCTA.3
This review is an update of the current position of CCTA in the diagnosis of patients with suspected CAD.
The spatial resolution of 64-slice (or more) CCTA in the laboratory setting is 0.3–0.4 mm³ (isotropic spatial resolution allowing undistorted reconstruction of images in any plane), but in the clinical setting this is 0.5–0.6 mm³. The spatial resolution of CCTA is still limited compared to the 0.1–0.2 mm of invasive coronary angiography (ICA). The temporal resolution (time required for the acquisition of data necessary for the generation of one slice) of CCTA depends mainly on the gantry rotation time which with current scanners ranges between 280–420 ms per rotation, resulting in a temporal resolution of maximally 75 ms (ie, a quarter of the rotation time in the case of a dual source CT scanner) to 210 ms (ie, half the rotation time in a single source scanner). Although this is acceptable for CCTA imaging, it falls short of the 4–8 ms of ICA. Low heart rates <60–65 beats/min (bpm) are required to generate nearly motion-free coronary images. The scan time (time required for data acquisition of the entire coronary tree) ranges between 6–8 s for 64-slice CT scanners, but is dramatically reduced with the use of 256- to 320-slice CT scanners that allow coverage of the entire heart in one single rotation with data acquisition during one heart beat. These fast scanners have reduced the susceptibility of CT to the occurrence of arrhythmias.
The radiation dose of earlier types of CCTA scanners was worrisome (with effective dose of 15–20 mSv); however, newly introduced technical CT improvements together with radiation dose reduction protocols, including prospective ECG triggered (‘step-and-shoot’) scanning, and low tube potential (100 kVp instead of 120 kVp) in patients <90 kg, have now reduced the effective dose to 3.5±2.1 mSv, with preservation of diagnostic image quality and no increase in downstream testing due to poor image quality.4–6 In a preliminary report, a prospectively ECG triggered high pitch helical acquisition protocol enabling coverage of the heart in one heart beat, combined with low tube voltage (80 kVp) and currents (50 mAs) and iterative reconstruction, further reduced the radiation dose to <1 mSv.7 These results require confirmation by other large sized studies in various patient populations.
Diagnostic accuracy efficiency
Numerous single centre and multicentre studies attest to the high diagnostic accuracy of CCTA (figure 1) and highlight the ability of CCTA to exclude the presence of obstructive CAD (≥50% diameter stenosis) in patients with suspected CAD (figure 2). A recent pooled analysis of 3674 patients, examined between December 2006 and March 2009, showed the diagnostic performance of 64-slice (or more) CCTA with high patient sensitivity and specificity of 98% and 82%, respectively,8 (table 1) with ICA as standard of reference. The per-segment calculated sensitivity was lower, but the specificity was higher (91% and 94%, respectively). The per vessel analysis outcomes were in between those of patient and segment analysis (table 1).
Von Ballmoos et al12 reported the diagnostic accuracy of CCTA which was achieved with low dose radiation by using a ‘step-and shoot’ protocol. The sensitivities and specificities of per patient, per vessel or per segment analysis remained high with an average estimated effective radiation dose of 2.7 mSv (95% CI 2.2 to 3.2 mSv) (table 3). However, this was achieved with non-diagnostic image quality that occurred in 2.4% of the coronary segments.
A serious limitation of all these studies was the retrospective nature of the study design and they all suffered from the inevitable referral bias because these patients were referred for ICA.
An additional significant problem, seriously limiting the clinical value of a positive CT outcome, is that CCTA can identify coronary obstructions (≥50% diameter stenosis) but it cannot reliably predict the presence of myocardial ischaemia (table 4).13–16 The limited positive predictive value of CCTA to detect myocardial ischaemia is usually caused by overestimation of calcified lesions due to blooming artefacts or motion artefacts (figure 3).
The prognostic accuracy of CCTA in combination with the diagnostic accuracy efficacy is important for diagnostic and therapeutic patient management. A recently published systematic review evaluating 9592 patients with a median follow-up of 1.7 years revealed that a normal CCTA was associated with an excellent prognosis and that an increasing burden of non-obstructive or obstructive CAD was associated with an increasing rate of major adverse cardiovascular events (table 5).17 The prognostic accuracy was reported from a prospective multicentre study, CONFIRM (Coronary CT Angiography Evaluation for Clinical Outcomes: An International Multicenter Registry), including 23 854 symptomatic patients who underwent ≥64-slice CCTA and were followed for 2.3±1.1 years during which period 404 all cause deaths occurred.18 The risk adjusted per patient analysis revealed that patients with non-obstructive CAD (<50% stenosis) or obstructive CAD (≥50% stenosis) had a risk adjusted hazard ratio of 1.6 (95% CI 1.2 to 2.2) and 2.6 (95% CI 1.9 to 3.5), respectively, with normal CCTA as the reference. Similar outcomes were observed if patients were classified into normal, non-obstructive CAD, or one-, two-, or three-vessel disease, with higher mortality with increasing disease burden. Absence of CAD was associated with a favourable prognosis with an annualised all cause death rate of 0.28%.
These prognostic studies have some limitations. The total all cause mortality, although important, is not a CAD specific end point (like cardiac death or myocardial infarction), and the revascularisation rate is biased by the index CCTA because treating physicians were not blinded and anatomic CT abnormalities may easily have led to referral for ICA and subsequent revascularisation. In addition there was no adjustment for other confounding co-variables such as medication or left ventricular ejection fraction.
Diagnostic thinking efficacy
A relevant question for the clinician is: in which patient population does CCTA achieve the greatest diagnostic benefit or where is virtually no benefit to be expected? According to Bayesian theory, patients with intermediate pre-test probability of CAD will gain most benefit from CCTA.19 The accuracy of a negative CCTA scan to rule out CAD is high in patients with intermediate pre-test probability of CAD and this obviates the need for further downstream diagnostic testing (figure 4). Unfortunately, a positive CCTA is associated with a relatively insufficient increase in post-test probability of CAD, in particular in the per-vessel and per-segment analysis (table 1). This results in a high number of false positive outcomes and an unnecessary number of referrals to ICA.
CCTA is not useful in patients with a high pre-test probability of CAD, as a negative CCTA is associated with a relatively high number of false negative outcomes requiring further downstream testing to avoid ‘missing’ patients with significant CAD. A positive CT scan provides only a limited increase of the post-test probability of CAD and direct referral to ICA is preferred. In addition, the CCTA diagnostic accuracy in patients with a high pre-test probability is lower due to the higher prevalence of coronary calcifications or diffuse CAD, which render precise assessment of obstructions more difficult.
Patients with a low pre-test probability of CAD may not benefit from CCTA either. A negative scan does not significantly decrease the post-test probability in these patients as this is already low, and a positive scan is associated with a considerable number of false positive outcomes leading to over-diagnosis and unnecessary referral to ICA.
A relevant question in regard to therapeutic efficacy would be: does CCTA change patient management? This depends on the diagnostic and prognostic accuracy of CCTA to determine further need of testing.
In patients with intermediate pre-test probability, CCTA results in reclassification to either low post-test (in the case of negative CCTA which is associated with an excellent prognosis) or high post-test (in the case of positive CCTA which is associated with a high adverse event rate) probability groups that would be associated with a clinically relevant change of diagnostic and therapeutic management. Patients with low post-test probability do not require further testing and may be safely discharged. In contrast, patients with high post-test probability may be directly referred for ICA with or without fractional flow reserve (FFR). Obviously this is related to the achieved post-test probability level and the associated diagnostic certainty of a negative CT scan to exclude CAD or a positive CT scan to rule in CAD. The level of diagnostic certainty is arbitrary and depends on whether additional testing is deemed necessary that may improve patient management and prognosis. In general one may assume that a post-test probability of <5% or >90% indicates sufficient diagnostic certainty and no further testing is helpful. Further testing is indicated if the post-test probability is between 5–90%.
In a recent study of 249 patients with intermediate pre-test probability a negative CCTA virtually ruled out the presence of CAD20 (figure 5). These patients have an excellent prognosis and can be safely discharged.17 ,18 In contrast, patients with a positive CCTA achieved a high probability of CAD and these patients required referral to ICA and, in the case of multivessel CAD, invasive FFR to consider revascularisation to relieve symptoms and improve prognosis (figure 5).
The post-test probability is related to the estimated pre-test probability and the sensitivity and specificity of the test.21
The diagnostic performance of single photon emission CT (SPECT), MRI, and CCTA in patients with intermediate pre-test probability is shown in figure 6. Sensitivities and specificities were obtained from a recent extensive review.22 The positive predictive value of CCTA was highest, but most important was the very high negative predictive value of CCTA that outperformed the two other non-invasive tests. This supports the use of CCTA as a first line diagnostic test to act as gatekeeper of ICA, because a negative CCTA scan virtually rules out the presence of significant CAD.
It seems reasonable to expect that the outcome of non-invasive diagnostic imaging tests would exert a significant impact on referral to ICA or a change in medical treatment. Yet, this was disappointing. The SPARC (Study of Myocardial Perfusion and Coronary Anatomy Imaging Roles in Coronary Artery Disease) study that evaluated the impact of SPECT, positron emission tomography (PET), and CCTA on the management of patients with suspected CAD demonstrated that there was only a modest impact. CCTA was associated with a relatively higher referral to ICA than SPECT and PET.23
Patient outcome efficacy and societal efficacy
Currently, there are no (comparative) effectiveness studies available that evaluate the benefits and harms of CCTA, in terms of improved clinical outcomes or cost effectiveness at the societal level, to assess the role of CCTA as an alternative to other non-invasive diagnostic imaging strategies in patients with suspected CAD.
The importance of comparative effectiveness studies is well recognised and is now considered a prerequisite to judge the definitive role of CCTA in the diagnosis and management of symptomatic coronary patients.24
We have to await the finalisation of the ongoing PROMISE (Prospective Multicenter Imaging for Evaluation of Chest Pain) study, which is randomising symptomatic patients suspected of having CAD to either a usual stress testing (functional) strategy or a CCTA strategy (anatomy) with clinical outcomes and costs as end points.
CTTA for patients presenting with acute chest pain at the emergency department
Given the excellent negative predictive value of CTTA to exclude CAD and coronary stenosis, CCTA was introduced as a quick imaging procedure in the emergency department to aid the evaluation of patients with acute chest pain with the premise that a negative CTTA would mean immediate discharge. A few randomised studies have been published that evaluated the merits of CCTA in the emergency department. The first controlled trial randomised 197 patients who were recruited in a single centre.25 This study revealed that CCTA was useful and safe to definitely establish or exclude CAD as the cause of chest pain. This was followed by three multicentre randomised trials evaluating the safety, length of hospital stay, and costs of CCTA compared to usual care.26–28 They studied low risk patients with chest pain who had no ischaemic ECG changes and no initial biomarker elevation. The number of evaluated patients—the primary end point of the study—and the outcomes are presented in table 6. The mean age of the patients ranged from 49–54 years, and 46–53% were males. All three primary end points were favourable for the use of CCTA. The number of patients with myocardial infarction was minimal and there were no deaths in this low risk group of patients. Overall the three studies indicated that CCTA was safe, reduced the length of hospital stay, reduced costs but was associated with slightly higher (non-significant) rates of invasive coronary angiography and coronary revascularisation.
The European guidelines recommend that CCTA should be considered as an alternative to ICA to exclude acute coronary syndrome when there is a low to intermediate likelihood of CAD and when troponin and ECG changes are inconclusive, with class 2A and level B indication.29
New CT developments: CT functional imaging
The physiological significance of a coronary obstruction is dependent on both the vessel wall morphology (anatomy) and coronary blood flow. The combined information of the presence of a coronary obstruction (local or diffuse) and coronary blood flow limitation is crucial for optimal decision-making for patients with chest pain.
One of the main shortcomings of CCTA is that it cannot adequately predict the functional significance of a coronary obstruction (≥50% diameter stenosis) (table 4).13–16 This has prompted the search for a single CT examination combining CT functional imaging with CT coronary anatomical imaging. Several CT functional imaging approaches are now being investigated including CT-FFR, CT myocardial perfusion, and CT intracoronary attenuation gradient assessment.
CT-FFR is a promising technique that has been recently introduced into clinical practice. The technique uses computational fluid dynamics with simulated hyperaemia that enables prediction of blood flow and pressure fields in coronary arteries. This then allows calculation of the FFR of a coronary stenosis from data derived from a usual single CCTA. A multicentre prospective study demonstrated that CT-FFR correlated reasonably well with the standard of reference invasive FFR.30 The current drawbacks of CT-FFR are the extreme need for computational ability and analysis time and the need for high quality CT images. Other studies are needed to confirm the robustness and reliability of the technique.
CT myocardial perfusion can be evaluated by assessing the myocardial contrast enhancement at rest or during pharmacological stress to analyse the impact of a coronary obstruction on myocardial blood flow.31 The method is technically demanding but dynamic CT perfusion is able to provide absolute measurement of the myocardial blood flow, thereby allowing functional assessment of individual coronary artery territories (figure 3). The initial results are promising, but serious problems that need to be resolved are the additional (unacceptable) high radiation dose and the limited collection of sufficient contrast enhanced samples during the passage of contrast through the myocardium that may cause inexact determination of the myocardial blood flow.
CT measurement of the gradient of intraluminal attenuation along the proximal to distal course of a coronary artery provides information about the coronary blood flow. The difference between the attenuation proximal and distal of an obstruction allows the degree of a coronary stenosis to be predicted, and preliminary results suggest that this method can moderately predict stenosis severity.32 ,33 However, the gradient is only measured at rest and it is unknown how the technique would perform under conditions of stress induced hyperaemia.
The addition of non-invasive CT functional imaging to CT coronary anatomical imaging is clinically significant as it augments the diagnostic performance and prognostic power which is expected to translate into improved patient management and improved prognosis.
CCTA: areas of uncertainty
CCTA not only provides information about the coronary arteries but also about the heart, great thoracic vessels, portions of the lungs, mediastinum, chest wall, spine, and upper abdomen. This will inevitably result in the detection of incidental findings that may require adequate interpretation and subsequent management, which may cause unforeseen complex medico-legal consequences. A multidisciplinary cardiologic and radiologic approach is recommended to face these problems.
The lifetime attributable risk of cancer associated with ionising radiation from CCTA scanning may lead to adverse events that should be taken into account when comparing the effectiveness of CCTA with other non-radiation diagnostic modalities.
The assessment of the severity of a coronary obstruction is expected to be more precise using CT imaging compared to two dimensional ICA imaging, particularly with complex, asymmetrical, irregular lesions. However, there is concern about the grading of the severity of CT coronary obstructions by visual assessment. Quantitative CCTA, using automated border lumen detection algorithms, showed that these measurements were more precise than visual assessment. But compared to intravascular ultrasound there was still overestimation (minimum lumen area and diameter stenosis) and underestimation (minimal lumen area and area stenosis).34 ,35 It remains to be seen whether quantitative CCTA better predicts the haemodynamic consequences of coronary obstructions than visual assessment.
Another area of debate is whether usual functional testing should be the first line diagnostic test (now endorsed by European guidelines), or whether CCTA, with its established higher diagnostic accuracy to exclude the presence of significant stenosis, could be an effective alternative anatomic test. More scientific clinical evidence is needed to settle this important issue.
CCTA has matured into a robust non-invasive imaging technique due to the ever increasing enhancement in temporal and spatial resolution in recent years. Yet, it should not be regarded as a replacement for ICA that is still the anatomic ‘standard of reference’ in the assessment of coronary revascularisation.
The high negative predictive value of CCTA effectively identifies patients without significant CAD. This supports the use of CCTA as a viable alternative to established functional tests to act as an effective gatekeeper for ICA (figure 7).
The high sensitivity of CCTA indicates that CCTA can identify the majority of patients with significant CAD, but at the cost of a rather high false positive rate due to overestimation of the severity of stenoses. This is further complicated by the fact that CCTA cannot reliably predict which identified obstruction is haemodynamically significant. The current paradigm dictates that therapeutic interventions should only be applied to stenoses that are coronary flow limiting. Further non-invasive functional testing is recommended in CT anatomic non-high risk patients (single or double vessel disease), which in the case of ischaemia may be referred for revascularisation. CT anatomic high risk patients may be directly referred to ICA with FFR to guide functional lesion revascularisation.
Preliminary studies have shown that the combination of CT anatomy and CT function in one examination is feasible, but establishment of the reliable robustness of the combined technique needs further clinical testing.
Further directions of CCTA should focus on the continued improvement of spatial and temporal resolution, the development of approaches that minimise calcification effects and reduce radiation exposure with preservation of diagnostic image quality, and advancement of CT techniques that increase the reliability of the application of a single protocol for CT anatomic and CT functional CAD assessment.
Formal guidelines for the use of CCTA do not exist. Before accepting CCTA as an inferior, similar or superior imaging technique compared to existing functional tests, we need evidence from comparative effectiveness research with patient outcome and costs as end points.
Coronary CT angiography for patients with suspected coronary artery disease: key points
64-slice (or more) coronary CT angiography (CCTA) generates nearly motion-free high quality images, but still requires low heart rates (<65 bpm).
The introduction of 256- or 320-slice CT scanners has not improved the spatial resolution, but the scan time is reduced to one heart beat.
Concern remains about lifetime attributable risk of cancer by ionising radiation which with updated CT technology can be reduced to an effective dose of <5 mSv.
CCTA is least useful in patients with low or high pre-test probability of coronary artery disease (CAD).
CCTA is highly effective in reducing the number of unnecessary invasive coronary angiograms in patients with intermediate pre-test probability of CAD.
CCTA cannot adequately predict that a CT identified obstruction is coronary flow limiting. This requires further downstream functional testing.
The combination of CT anatomic imaging and CT functional imaging is feasible, but further studies should provide evidence for clinical utility.
A normal CCTA is associated with an excellent prognosis while increasing CT CAD burden is associated with increasing adverse event rates.
There is no solid evidence that CCTA either improves health outcome or decreases costs.
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- ↵Randomised trial demonstrating reduction of CT radiation dose using dose reduction acquisition protocols, while preserving CT image quality.
- ↵Most recent systematic review of diagnostic performance of 64-slice or more CCTA in patients with suspected CAD.
- ↵Multicentre study that investigated the diagnostic accuracy of CCTA in patients with relatively low pre-test likelihood of CAD.
- ↵Multicentre study that investigated the diagnostic performance of CCTA in patients with intermediate pre-test likelihood of CAD, while many patients had known CAD.
- ↵Multicentre, multivendor study that investigated the diagnostic accuracy of 64-slice CCTA in patients with intermediate to high pre-test likelihood of CAD. All three multicentre studies confirmed the high negative predictive value of CCTA.
- ↵Meta-analysis of the prognostic value of CCTA reporting excellent prognosis of a normal CCTA.
- ↵Large international prospective multicentre study reporting all cause deaths in symptomatic patients with a follow-up of 2–3 years. The all cause deaths were higher in patients with increasing CT plaque burden. A normal CCTA was associated with an excellent prognosis.
- ↵Interesting study demonstrating the influence of the pre-test probability of CAD on the clinical usefulness of CCTA.
- ↵Single centre study reporting that the clinical utility of CCTA in patients with suspected CAD was superior to conventional non-invasive exercise testing.
- ↵Randomised, prospective, multicentre study reporting the diagnostic accuracy of CT-FFR correlated reasonably well with invasive FFR, but the primary end point, the per-patient diagnostic accuracy of CT-FFR plus CCTA, was not achieved.
Competing interests In compliance with EBAC/EACCME guidelines, all authors participating in Education in Heart have disclosed potential conflicts of interest that might cause a bias in the article. The authors have no competing interests.
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