doi: 10.1161/CIRCIMAGING.108.823807
Controversies in Imaging |
Noninvasive Diagnostic and Prognostic Assessment of Individuals With Suspected Coronary Artery Disease
Coronary Computed Tomographic Angiography Perspective
From the Departments of Medicine and Radiology (J.K.M.), Weill Medical College of Cornell University and the New York Presbyterian Hospital, New York, NY; and Department of Medicine (L.J.S.), Emory University School of Medicine.
Correspondence to James K. Min, MD, Department of Medicine, Division of Cardiology, Weill Cornell Medical College and the New York Presbyterian Hospital, New York, NY 10021. E-mail jkm2001{at}med.cornell.edu
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Introduction |
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 Top Introduction Usefulness of a Noninvasive...Diagnostic Accuracy of CCTAPrognostic Value of CCTAClinical Effectiveness of CCTAFuture Directions of CCTAProposed Clinical Strategy of...References |
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Despite significant advances in medical and interventional therapies, coronary artery disease (CAD) remains the most common cause of mortality and morbidity worldwide. In the United States alone, CAD is responsible for approximately one third of all deaths in individuals <75 years of age.1 Each year, upwards of 800 000 individuals within the United States will present with a symptomatic myocardial infarction (MI), and an additional 200 000 will occur as "silent," or clinically unrecognized infarctions.2
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Traditionally, evaluation of individuals at risk for CAD events has used the noninvasive cardiac imaging modalities, primarily by evaluation of myocardial perfusion with single-photon emission computed tomography (MPS CT), positron-emission tomography, echocardiography, and MRI or by identification of regional wall motion abnormalities with stress echocardiography.3,4 These functional methods of assessment, aimed primarily at indirect identification of flow-limiting coronary artery stenoses, have proven robust in the diagnosis and risk stratification of individuals with and without CAD.
Recently, coronary computed tomographic angiography (CCTA) has emerged as a promising method for anatomic detection of atherosclerotic plaque within coronary arteries.5–7 Developments in CT—driven primarily by improvements in temporal and spatial resolution and volume coverage—now permit routine evaluation of the coronary arteries and cardiovascular structures with exquisite clarity. Given the recent introduction of 64-detector row CCTA in 2005, numerous questions remain as to when it should be used in clinical practice and if so, before, after, in conjunction with or in lieu of functional stress testing.
The purpose of the following review is to provide an overview of the diagnostic performance and prognostic value of CCTA in symptomatic individuals with suspected CAD. Furthermore, we offer a framework by which the strengths of CCTA may be used for successful use in daily clinical practice.
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Usefulness of a Noninvasive Imaging Test |
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TopIntroductionUsefulness of a Noninvasive...Diagnostic Accuracy of CCTAPrognostic Value of CCTAClinical Effectiveness of CCTAFuture Directions of CCTAProposed Clinical Strategy of...References |
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Traditionally, effectiveness of noninvasive imaging tests has been evaluated with respect to diagnostic test performance and risk stratification. Diagnostic test performance characteristics—which are most commonly reported by measures of sensitivity, specificity, and negative and positive predictive values—are influenced by disease prevalence; that is, pretest likelihood of CAD significantly influences posttest diagnostic accuracy. Risk stratification of events on the basis of test results is not only dependent on the prevalence of disease in the population studied but also on a complex interplay between test result, physician behavior, and patient compliance. Thus, for effectiveness of a test to be properly evaluated, great care must be taken to evaluate it in the population for which it is proposed to be used. Simply stated, a diagnostic test must be able to not only discriminate those with disease versus those without disease, but also must be able to calibrate the future risk of those identified with that disease.
For the past 3 decades, cardiac imagers using functional perfusion testing have examined diagnostic and prognostic characteristics beyond simple angiographic definitions of CAD to focus on prognostically valuable flow-limiting CAD resulting in myocardial ischemia as a benchmark for clinical management.3,4 In this model, flow limitations can be derived from both severe as well as intermediate angiographic coronary artery lesions, and endothelial dysfunction of resistive coronary vessels.8
For anatomic tests—such as CCTA—to find equal or enhanced success in comparison to functional perfusion testing for assessment of symptomatic individuals with suspected CAD, several criteria are required to be met. Within measures of diagnostic accuracy, CCTA must not only be examined with respect to its ability to diagnose or exclude obstructive coronary artery stenosis but also for its potential to successfully appraise differing aspects of CAD plaque burden which may be clinically valuable. In this manner, the diagnostic accuracy model of CCTA may be expanded beyond that of obstructive versus nonobstructive stenosis to incorporate other measures of CAD—such as severity, extent, distribution, composition, and remodeling. Whether these measures of CAD are consistently evaluable by CCTA will determine whether CCTA can be successfully used for its ability to diagnose and exclude any (rather than obstructive) CAD or to identify certain CAD plaque patterns, which may confer higher risk. Furthermore, given the widespread success of MPS in the evaluation of individuals with suspected CAD, in order for CCTA to be widely advocated for adoption into daily clinical practice, studies will be required that assess its comparative efficacy to MPS—that is, demonstration of either enhanced or equivalent clinical effectiveness with equivalent or reduced overall costs. Finally, given its ability to offer information relating myocardial structure and function as well as noncardiac structures, CCTA should also be evaluated in the context of incremental information beyond angiography to gauge its full potential for use in the evaluation of symptomatic individuals with suspected CAD.
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Diagnostic Accuracy of CCTA |
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TopIntroductionUsefulness of a Noninvasive...Diagnostic Accuracy of CCTAPrognostic Value of CCTAClinical Effectiveness of CCTAFuture Directions of CCTAProposed Clinical Strategy of...References |
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Diagnostic Accuracy of CCTA to Detect and Exclude Obstructive Coronary Artery Stenosis
Despite the relatively recent introduction of 64-detector row CCTA, numerous reports, including several meta-analyses and systematic reviews, have been published on its diagnostic accuracy for the identification of obstructive coronary artery stenosis.9–13 For example, one recent meta-analysis of 12 studies using CT scanners of 64-detector rows or more demonstrated high diagnostic test performance of CCTA for the identification of
50% coronary artery stenosis: sensitivity, 97% (95 CI, 95% to 98%); specificity, 90% (95% CI, 86% to 93%); positive predictive value, 93% (95% CI, 91% to 96%); and negative predictive value, 96% (95% CI, 92% to 98%).14 The single-center studies included within this meta-analysis were largely limited by referral biases similar to those that have clouded measures of MPS diagnostic test performance, as the decision to perform invasive coronary angiography (ICA) was, in large part, because of the results of the CCTA. Furthermore, prior studies relating the diagnostic accuracy of CCTA have been largely performed in patient populations with relatively high pretest likelihood of significant CAD who were already being referred for ICA. Diagnostic test performance of CCTA may differ in the low-intermediate risk patients for which it has been proposed to be most useful.
Recently, 2 prospective multicenter studies (ACCURACY and CoRE64) have evaluated the diagnostic test performance of CCTA in populations with differing disease prevalence in whom the CCTA did not influence the decision to perform ICA. The Assessment by CCTA of Individuals Undergoing ICA, or ACCURACY trial, was a US-based multicenter study involving 16 centers and enrolling 230 participants who were being referred for elective coronary angiography.15 In this study, 72 (24.8%) and 32 (13.9%) subjects were found to have 50% or 70% stenosis (Figure 1). The diagnostic sensitivity, specificity, and positive and negative predictive values to detect a 50% or 70% stenosis on a per-patient basis were 95%, 83%, 64%, and 99%, respectively, and 94%, 83%, 48%, and 99%, respectively. Similarly, at the per-vessel level, the negative predictive value to exclude 50% or 70% stenosis was 99%.
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In the ACCURACY study, no differences in diagnostic sensitivity and specificity were observed for obese compared with nonobese subjects, or for individuals with heart rates
65 versus >65 bpm. Notably, the ACCURACY trial is the only study to date to report diagnostic test performance of CCTA in a symptomatic population with a low-intermediate prevalence of CAD, which has been the population in which it is proposed to be most useful. In this cohort, the area under the receiver operator characteristics curve for identification of patients with 50% or 70% stenosis was 96% and 95%, respectively.
In contrast, the CoRE64 study was a multicenter prospective international study of 9 centers enrolling 291 patients >40 years of age with suspected or known CAD.16 In this study, which excluded patients with coronary artery calcium (CAC) scores 600, analysis of nonstented coronary artery segments >1.5 mm, the prevalence of obstructive coronary artery stenosis at the 50% threshold was 56%. The diagnostic performance of CCTA revealed a sensitivity of 85%, specificity of 90%, positive predictive value of 91%, and negative predictive value of 83%.
Although the diagnostic test performance of CCTA from the CoRE64 study and the ACCURACY study appear, at first glance, at odds with each other, they simply underscore the effect of disease prevalence on diagnostic test performance characteristics. As disease prevalence rises, fewer positive tests will be false positives and resultantly, positive predictive value will rise. Similarly, as disease prevalence rises, more negative tests will represent false negatives and thus, negative predictive value will fall. From the ACCURACY data, it is suggested that to achieve negative predictive values to exclude obstructive coronary artery stenosis with >90% certainty that disease prevalence should be <60%.
These studies established the high accuracy of CCTA for detection and exclusion of obstructive coronary artery stenosis at the 50% and 70% thresholds. Indeed, measures of sensitivity of CCTA compare favorably with other noninvasive imaging cardiac tests; furthermore, the negative predictive value of CCTA in intermediate disease prevalence populations is superior to all other modalities.
Diagnostic Accuracy of CCTA to Detect and Exclude "Ischemic" Coronary Artery Stenosis
Several landmark studies using nuclear perfusion methods have documented the inverse relationship between hyperemic myocardial blood flow and degree of coronary artery stenosis. Given the high degree of correlation of CCTA-identified stenosis to quantitative coronary angiography, several recent studies have evaluated the association of CCTA-identified obstructive coronary artery lesions to MPS-identified ischemia. In a combination of 3 studies encompassing 231 patients, agreement between CCTA and MPS was examined in the present of a negative (ie, no obstructive stenosis present) CCTA and a positive (ie, obstructive stenosis present) CCTA.17 In the cases of a negative CCTA, myocardial perfusion was noted to be normal in 85% of cases and abnormal in 15% of cases. In contrast, for individuals with CCTA-identified obstructive CAD, myocardial perfusion was abnormal in only 52% of cases and normal in 48% of cases.
Given the lack of corroboration of CCTA stenosis by ICA in the aforementioned studies, Gaemperli et al18 recently examined 78 patients undergoing 64-slice CCTA and MPS, confirmed by ICA. In this cohort (mean age, 65 years; 35% female), a binary end point of obstructive versus nonobstructive coronary artery stenosis was used. Obstructive CAD was identified in 137 segments (13%) of 91 arteries (29%) in 46 patients (59%). Although the ability of CCTA-identified obstructive CAD to correlate to any perfusion defect (94%) or any reversible perfusion defect (95%) at the patient level was high, the specificity (64% and 53%, respectively) was relatively modest. Expectedly, the negative predictive value was uniformly high and the positive predictive value was moderate for the detection of any perfusion defect (94% and 63%, respectively) or of any reversible perfusion defect (94% and 58%, respectively). The relatively modest predictive value of a CCTA-identified lesion to identify individuals with ischemia was not because of CCTA inaccuracy, as the area under the receiver operative characteristics curve for CCTA (0.88; 95% CI, 0.80 to 0.96) to identify ischemia was similar to QCA (area under the curve, 0.87; 95% CI, 0.79 to 0.94). The probabilistic odds for detection of ischemia by CCTA % diameter stenosis was identical to that predicted by QCA % diameter stenosis.
From these data, many have argued that MPS and CCTA may provide discrete and potentially complementary information related to CAD—that is, detection of myocardial ischemia and detection of coronary atherosclerosis.
Beyond Obstructive Versus Nonobstructive Stenosis for Identification of Individuals With Ischemia
Nevertheless, proponents of current generation CCTA have argued that the preoccupation with "obstructive versus nonobstructive" CAD may oversimplify the paradigm of identification of individuals at risk. Beyond simple "lumenography," CCTA proponents point to other coronary plaque characteristics—such as overall plaque burden, distribution, composition, and remodeling—which may help enhance identification of not only those individuals with myocardial ischemia but also those individuals at risk for incident MI and/or sudden cardiac death.
Evidence to support these contentions is based on prior invasive angiographic studies. De Bruyne et al19 recently examined the fractional flow reserve in 106 coronary arteries in 62 individuals without CAD but no evident obstructive stenosis, comparing it to 37 arteries in 10 patients without any evidence of CAD (both nonobstructive and obstructive). In contrast to individuals without CAD, individuals with CAD but no evident obstructive stenosis exhibited significantly greater degrees in pressure during maximal coronary hyperemia (10±8 versus 3±3; P<0.001) with accompanying decreases in fractional flow reserve (FFR) (0.89±0.08 versus 0.97±0.02; P<0.05). Among atherosclerotic arteries without evident obstructive coronary stenosis, approximately half demonstrated reductions in FFR compared with normal coronary arteries. This landmark study elicited the importance of identification of diffuse, yet nonobstructive, atherosclerosis as a potential cause of ischemia in individuals for whom no obstructive coronary stenosis is identified.
In this regard, several investigators have now examined CCTA plaque characteristics beyond "obstructive versus nonobstructive" stenosis—for factors such as plaque location, distribution, composition and overall burden—as potentially useful metrics for prediction of individuals in whom coronary artery plaque is identified and myocardial ischemia risk may be heightened. In a recent study by Lin et al,20 163 patients undergoing MPS and 64-detector row CCTA were studied. In addition to classification of patients as having or not having obstructive CAD, coronary artery plaque was also graded by a segments-at-risk score as well as a plaque composition score. The segments-at-risk score, which preferentially weights plaque located proximally, comprises a measure of overall coronary plaque burden accounting for extent of myocardium subtended by stenotic plaque. Plaque composition scores denote increasing burden of coronary plaque (as measured by numbers of coronary segments) by noncalcified, calcified or mixed plaque types. Finally, Lin et al also examined coronary artery plaque burden using a modified Duke CAD index, based on the angiographically derived Duke coronary artery jeopardy score, which accounts for plaque severity, extent and location in the left main or proximal left anterior descending (LAD) artery.
In this analysis, CCTA measures of obstructive versus nonobstructive plaque did not identify individuals with mildly abnormal (summed stress score >4) or moderate-severely abnormal (summed stress score >8) MPS. In contrast, however, measures of overall coronary plaque burden considering plaque proximity within the coronary artery tree identified individuals with mildly abnormal MPS (odds ratio [OR], 2.78; 95% CI, 1.01 to 7.68; P=0.05) as well as moderate-severely abnormal MPS (OR, 2.65; 95% CI, 0.91 to 7.77; P=0.07). Furthermore, increasing numbers of segments exhibiting mixed plaque similarly identified individuals with moderate-severely abnormal (OR, 3.95; 95% CI, 1.39 to 11.2; P=0.01) MPS. These findings indicate a simple dichotomous classification of obstructive versus nonobstructive plaque is insufficient to identify individuals at risk for ischemia, and that measures of overall plaque burden, location, and composition may enhance detection of individuals with coronary artery stenoses that cause myocardial ischemia.
In an expansion of these findings, 165 individuals with suspected CAD who underwent exercise treadmill testing and CCTA were examined.21 In this analysis, obstructive CAD was significantly associated with ST-segment depression (OR, 3.38; 95% CI, 1.32 to 8.64; P=0.002) and higher risk Duke treadmill scores (OR, 4.67; 95% CI, 1.97 to 11.03). Furthermore, CCTA plaque severity, distribution and location, as measured by the Duke CAD index, identified individuals with increasing severity of exercise-induced ST-segment depression as well as decreasing Duke treadmill score. Similar to the relationship to MPS, increasing numbers of coronary segments exhibiting mixed plaque type by CCTA successfully identified individuals at higher risk of ST-segment depression (OR, 1.48 per segment; 95% CI, 1.18 to 1.85) as well as higher risk Duke treadmill scores (OR, 1.30 per segment; 95% CI, 1.05 to 1.61). Notably, increasing gradations of CAD by CCTA from none to nonobstructive to obstructive coronary artery stenosis predicted progressively shorter overall Bruce treadmill protocol exercise times, suggesting that the presence of nonobstructive CAD by CCTA may identify at-risk individuals with subclinical impaired exercise tolerance. Together, these findings suggest that a more comprehensive assessment of coronary artery plaque may result in enhanced prediction of individuals with concurrent CCTA-evident CAD and poorer overall functional capacity and ischemia as measured by ST-segment depression.
Beyond Obstructive Versus Nonobstructive Stenosis for Identification of Individuals at Risk for Myocardial Events
Although identification of flow-limiting stenoses for myocardial ischemia by functional perfusion testing remains robust in its prognostic ability to risk stratify individuals at incident risk of major adverse cardiac events (MACE), CAD-related deaths and, in particular, sudden cardiac death rates remain consistently high, accounting for upwards of 60% of all deaths related to cardiac causes.2 Notwithstanding the benefit derived from identification of obstructive CAD, it remains a well-known fact that most MIs occur in individuals with lower-grade nonobstructive stenoses. The recent introduction of CCTA now permits visualization of not only severity, but extent, distribution, composition and remodeling of coronary artery plaque, thereby permitting overall enhanced assessment of coronary artery plaque burden. This ability to define plaque burden holds the potential to expand greatly our paradigm of risk prediction.
To properly frame this expanded model of risk, it is useful to examine prior studies which have evaluated individuals presenting with sudden cardiac death and/or MI by intravascular ultrasound (IVUS). In a recent study of 85 patients presenting with unstable angina or acute coronary syndrome versus 46 patients with stable coronary syndromes, IVUS analysis of culprit lesions demonstrated patients with ACS to exhibit higher overall plaque areas (13.9±5.5 versus 11.1±4.8 mm2; P=0.005), higher external elastic membrane areas (16.1±6.2 versus 13.0±4.8 mm2; P=0.004), and higher degrees of positive remodeling (1.06±0.2 versus 0.94±0.2; P=0.008).22 In this analysis, positive remodeling was identified in more than half of individuals with unstable coronary syndromes, whereas negative remodeling was identified in more than half of individuals with stable coronary syndromes. Furthermore, in individuals with unstable coronary syndromes, echolucent plaques were more common than in individuals with stable chest pain syndromes (19% versus 4%; P=0.02). In contrast, no differences were noted for echodense, mixed, or calcified plaques.
In a subsequent IVUS study of 171 patients (61 patients with acute MI, 70 patients with unstable angina, and 47 patients with stable angina pectoris), Ehara et al23 examined the frequency and number of calcium deposits within a 90 degree arc. In individuals presenting with acute MI, number of calcium deposits within a 90 degree arc per patient were significantly higher than in those presenting with stable angina pectoris. However, individuals presenting with stable angina pectoris were significantly more likely to exhibit longer lengths of calcified plaque (P<0.0001). When plaque was graded as having no calcification, spotty calcification, intermediate calcification or extensive calcification, individuals presenting with acute MI or unstable angina pectoris were more likely to exhibit spotty calcifications or no calcification when compared with extensive calcifications in individuals with stable angina pectoris (P<0.0001).
A further IVUS study of 73 patients presenting with acute MI examining coronary arterial remodeling in relation to plaque composition revealed positive remodeling in 55% of the patients and negative remodeling in only 25% of the patients (55% versus 25%).24 Although patients with positive remodeling were noted to have higher frequencies of calcified plaque, the most frequent "culprit plaques" were noncalcified plaques with small amounts of spotty calcium.
These IVUS studies teach several lessons. Plaques associated with acute coronary syndromes tend to be located within artery segments that exhibit high rates and degrees of positive remodeling and are associated with primarily noncalcified echolucent plaques, typified by spotty calcifications. Conversely, patients presenting with stable angina pectoris possess culprit plaques that tend toward arterial segments with negative remodeling and greater extent and lengths of calcified plaque.
Can CCTA Offer a Noninvasive Method for Plaque Characterization?
In light of these prior IVUS findings, many studies have focused on the ability of CCTA to measure plaque characteristics in a manner similar to IVUS. These studies have focused on noninvasive characterization of any atherosclerotic plaque, plaque location, plaque composition, and plaque remodeling in a diverse range of individuals.
Any Plaque
Using multidetector row CCTA, Leber et al25 evaluated 58 vessels in 37 patients who underwent CCTA and IVUS, examining the diagnostic accuracy of CCTA to identify any (rather than obstructive) plaque as well as plaque composition. CCTA demonstrated high specificity for the detection of any plaque, successfully excluding plaque in 484 of 525 (92%) vessel segments. Plaques that were undetected by CCTA generally demonstrated lower plaque thickness (0.9±0.3 versus 1.5±0.3 mm; P<0.05), were located in smaller vessels (3.6±1.1 versus 4.5±1.2 mm; P<0.05), and comprised a lesser percentage of plaque cross-sectional area (22±5% versus 42±16%; P<0.05).
Plaque Locations
On the basis of the findings from the ACCURACY trial, Lin et al26 recently reported the diagnostic accuracy of CCTA to localize disease to an arterial distribution using QCA as the reference standard. High sensitivity and specificity for detection of obstructive coronary artery stenoses were noted for the LAD artery (89% and 80%, respectively), left circumflex artery (71% versus 91%, respectively), and right coronary artery (89% versus 92%, respectively) compared with ICA. These characteristics appear superior to the sensitivity and specificity of MPS for localization of obstructive CAD.
Plaque Composition
Leber et al27 also studied the ability of CCTA to identify different plaque compositions. In a recent study of 19 patients undergoing 64-detector row CCTA, IVUS was performed on 36 vessels. Each vessel, divided into 3-mm sections, was assessed for correct detection of plaque composition and volume. Calcified and "mixed" plaques were correctly identified compared with IVUS in 41 of 43 (95%) cases for both, whereas noncalcified plaques were correctly identified in 54 of 65 (83%) of cases. Overall plaque volume per vessel by CCTA compared favorably with IVUS-measured plaque (r2=0.69; P<0.01), with a general underestimation of mixed and noncalcified plaque volumes (P=0.03) and a trend toward overestimation of calcified plaques. For plaques with "lipid" cores and for plaques with spotty calcifications, CCTA identified 7 of 10 (70%) and 27 of 30 (90%) of lesions correctly.
Plaque Remodeling
Furthermore, the ability of CCTA to assess coronary artery remodeling has been recently examined. In a study by Achenbach et al,28 coronary artery plaques from 44 patients undergoing CCTA and ICA were examined for a negative or positive remodeling in comparison to IVUS measurements. Both vessel area (r2=0.77) and remodeling indices (r2=0.82) by CCTA correlated well as compared with IVUS. Positive remodeling by CCTA, confirmed by IVUS, was more common in nonstenotic arteries as compared with stenotic arteries (P<0.001).
Clinical Relevance of CCTA-Identified Plaque Characteristics
To identify the clinical relevance of the aforementioned CCTA-identified plaque characteristics, Motoyama et al recently evaluated the role of plaque compositions and coronary artery remodeling in 38 patients presenting with ACS and 33 patients with stable angina pectoris. Using either 16- or 64-detector row CCTA, positive remodeling (87% versus 12%; P<0.0001), noncalcified plaques (79% versus 9%; P<0.0001), and spotty calcifications (63% versus 21%; P=0.0005) were noted to be significantly more frequent in ACS lesions when compared with stenotic lesions in stable angina patients.29 In contrast, extensive calcification was noted more often in individuals with stable angina when compared with ACS (55% versus 22%; P=0.004). Indeed, when examining a combined CCTA end point of plaque that included positive remodeling, noncalcified plaque or spotty calcifications, the sensitivity for detection and the negative predictive value for exclusion of the ACS culprit lesions was 100%. These findings were confirmed by Hoffman et al30 in both acute coronary syndrome and unstable angina patients.
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Prognostic Value of CCTA |
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TopIntroductionUsefulness of a Noninvasive...Diagnostic Accuracy of CCTAPrognostic Value of CCTAClinical Effectiveness of CCTAFuture Directions of CCTAProposed Clinical Strategy of...References |
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Because the introduction of ICA >50 years ago, cardiologists have used information from the angiogram as an adjunct to clinical risk stratification. Califf et al31 developed a Duke coronary artery jeopardy score which accounted for 13 categories of stratified risk in accordance to severity, extent, and location of CAD. Given these invasive angiographic findings, much interest has been focused on assessing the prognostic value of CCTA.
Prognostic Value of CCTA for All-Cause Mortality
We recently performed a survival analysis of 1127 low-intermediate risk symptomatic patients with suspected CAD undergoing 16-detector row CCTA as their primary imaging modality.32 In patients with no evident plaque in any coronary artery, in the left main artery or in the proximal LAD artery, the negative predictive value for death by all causes in a 15 month follow-up were 99.7%, 97.8%, and 98.4%, respectively. Indeed, among the 333 patients with no evident coronary artery plaque by CCTA, death rates were significantly lower (0.3% versus 4.8%; hazard ratio [HR], 0.12; 95% CI, 0.02 to 0.89; P=0.04) than in the remaining population studied. Using a modified Duke coronary artery jeopardy score, CCTA effectively stratified grades of risk for all-cause death by increasing coronary artery plaque severity, location, distribution and extent, with the highest mortality observed in patients with moderate or severe CCTA-identified plaque of the left main artery (Figure 2).
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Prognostic Value of CCTA for MACE
CCTA has also been evaluated for its ability to stratify risk for incident MACE. In a recent 16-month study of 100 patients with suspected or known CAD, 16- and 64-detector row CCTA measures of nonobstructive (HR, 1.3; 95% CI, 1.1 to 1.6; P=0.0009) and obstructive (HR, 1.8; 95% CI, 1.5 to 2.2; P<0.0001) plaque, especially of the left main or LAD artery (HR, 35; 95% CI, 4.3 to 288; P<0.0009) successfully identified individuals at higher risk of death, nonfatal MI, unstable angina requiring hospitalization and/or target vessel revascularization.33 The pooled data from 5 studies assessing prognosis of CCTA demonstrate a substantial difference in annualized cardiovascular death or MI rates in individuals with obstructive (79/543; 14%) versus nonobstructive (8/1371; 0.6%) plaque.
Prognostic Value of Nonobstructive Plaque by CCTA
In an analysis of 810 patients without nonobstructive CAD by CCTA, nonobstructive low-density plaques (Hounsfield unit of mild or moderate stenosis severity were identified.34 In a 35-month follow-up for MACE, the presence of low density plaques (presumably more lipid-laden) in individuals conferred a significantly higher risk of MACE (HR, 4.60; 95% CI, 1.08 to 5.92) compared with individuals without low density plaques. These findings lend credence to the thought that additional plaque characteristics above and beyond obstructive coronary artery stenosis are important for identifying individuals at risk for myocardial events.
Warranty Period of Normal CCTA
Thus, it appears that normal coronary arteries by CCTA accurately identify individuals with low risk of incident death and/or myocardial events. Given the recent introduction of 64-detector row CCT, it remains uncertain as to the "warranty period" of a normal CCTA by CT scanners of 64-detector rows. Notably, however, the negative predictive value of CCTA to successfully exclude obstructive coronary artery stenosis has been very high for not only 64- but also older generation CCTA (16- and 4-detector row and electron beam CT angiography). In a recent analysis by Ostrum et al, 2538 patients without known CAD undergoing CCTA by an electron beam CT scanner were categorized as having no evident coronary artery plaque, nonobstructive CAD and obstructive CAD. In a mean follow-up of 78 months, 86 deaths occurred.35 In comparison to individuals without CAD, individuals exhibiting nonobstructive 3-vessel CAD (HR, 1.77; 95% CI, 1.34 to 2.34; P=0.0001), obstructive CAD in 1 vessel (HR, 1.87; 95% CI, 1.4 to 2.51; P=0.0001), 2 vessels (HR, 2.37; 95% CI, 1.91 to 2.93; P=0.0001) or 3 (HR, 2.61; 95% CI, 2.00 to 3.37; P=0.0001) vessels experienced higher rates of death by all causes, indicating the prognostic significance of increasing gradations of obstructive as well as nonobstructive CAD by CCTA.
In patients with no evident CAD by CCTA, overall survival was 98.3% at 6.5 years, in contrast to 80% survival in individuals with 3-vessel obstructive CAD. This long-term follow-up is possible only from data gathered from electron beam CCTA—which possess poorer diagnostic performance and resolution—and it is reasonable to assume that the "warranty period" of a normal 64-detector row CCTA will be as 6.5 years.
Robustness of CCTA Prognostic Value
Given that CCTA-identified plaque characteristics appear prognostically valuable, questions remain as to the robustness of the risk predictive value. Shaw et al36 recently compared a propensity matched cohort of 693 patients undergoing CCTA with 3067 patients undergoing MPS for 2-year survival. Similar rates of death (3.2%) were noted for both CCTA and MPS patients. Notably, in these cohorts, annual death rates of individuals undergoing CCTA classified by the Duke prognostic CAD index were directly proportional to death rates of individuals undergoing MPS classified by percentage of ischemic myocardium. CCTA annual mortality rates ranged from 0.2 to 11.0%, whereas MPS annual mortality rates ranged from 0 to 12.5%. Although low- and high-risk patients exhibited similar ranges of mortality risk whether undergoing CCTA or MPS, a more gradual increase in risk of mortality was noted for CCTA patients who were identified with less extensive CAD (Figure 3). These results reflect the prognostic importance of detection of mild—and likely nonischemia producing—CAD stenoses as predictors of adverse prognosis of symptomatic patients.
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Incremental Usefulness of CT in Addition to MPS
Before widespread adoption of CCTA, measures of atherosclerotic plaque were and continue to be characterized by CAC scoring. In a study of 1195 patients without known CAD who underwent MPS and CAC scoring, rates of myocardial ischemia were low in individuals with CAC scores <100 (<2%).37 Conversely, among ischemic MPS patients, a CAC >400 was associated with high rates of myocardial ischemia (39.8%). Indeed, 56% of patients with a normal MPS had a CAC score >100, thereby permitting the diagnosis of atherosclerosis in patients with normal perfusion.
These data were confirmed by Schenker et al38 using combined rest-stress rubidium 82 positron-emission tomography perfusion imaging in 695 patients also undergoing CAC scoring. The prevalence of abnormal positron-emission tomography scans was significantly higher in individuals with CAC >400 versus <400 (48.5% versus 21.7%; P<0.001). Importantly, a CAC score >1000 (versus <1000) was significantly associated with annualized MACE event rates, even among patients with normal perfusion scans (12.3% versus 2.6%). The relationship of CAC score to incident MACE in patients with positron-emission tomography–derived ischemia was significantly higher in patients with higher CAC score >1000 compared with patients with no CAC (22.1% versus 8.2%). Thus, the anatomic identification of calcified plaque by noncontrast CT provides incremental and additive value to functional perfusion imaging for the detection of individuals at risk for death or MI. Future studies assessing the incremental value of CCTA plaque characteristics to perfusion abnormalities should be performed.
CCTA has also been evaluated as an adjunct to both normal as well as mild-moderately abnormal MPS imaging. Recently van Werkhoven et al39 evaluated the anatomic CCTA correlates of 180 individuals with chest pain with normal MPS examinations. In this cohort, CCTA identified nonobstructive and obstructive CAD in 38% and 19% of individuals, respectively. Notably, 4% of individuals with normal MPS were identified to have high-risk CAD (left main and 3-vessel obstructive coronary artery stenosis). These data are in keeping with our recent findings of 119 consecutive individuals with normal MPI who also underwent CCTA.40 Within this population, 24% of individuals were identified to have obstructive CAD by CCTA. Although the most common CAD pattern observed in individuals with obstructive CAD by CCTA was single vessel CAD (61%), proximal involvement (46%) and high risk left main or 3-vessel CAD (11%) were not infrequently observed. Furthermore, in this cohort, patients with obstructive CAD by CCTA were almost 3 times more likely to have exhibited significant ST-segment depression than patients with patent coronary arteries (36% versus 13%; P=0.007). These results suggest that CCTA may be useful for identification of individuals with high risk CAD features in whom an MPS is normal.
Danciu et al41 evaluated use of CCTA as a gatekeeper to ICA in individuals with intermediate risk after MPS. In this analysis of 421 patients, intermediate risk was defined as either stress-induced moderate perfusion defect involving 10% to 20% of the myocardium with left ventricular dilatation or <10% perfusion defect at rest or stress in the presence of either a Duke treadmill score <11 or newly diagnosed left ventricular ejection fraction <35%. After MPS-CCTA, only 78 of 421 (18.5%) were sent directly for ICA, whereas 343 (81.5%) were managed medically. Among the medically managed group during a follow-up of 15 months, no myocardial events or death occurred and only 6 patients required late ICA of whom only 1 underwent revascularization. These early results suggest that use of CCTA after intermediate risk MPS may be useful for identification of individuals in whom unnecessary ICA can be successfully avoided.
Prognostic Value of Noncoronary Findings by CCTA
Although CCTA has been evaluated for its diagnostic accuracy for assessment of cardiac structure and function—including ventricular and atrial volume measures, valvular regurgitation and stenosis, and aortic atherosclerosis—prognostic valuations of these measures have not yet been comprehensively performed. Indeed, only recently have age- and gender-specific normative reference value for the heart and great vessels by CCTA been developed, thereby permitting study of these parameters.42
Nevertheless, prior studies using CT of the chest highlight the potential additive prognostic value of noncoronary findings. In a recent 4.5- to 6-year follow-up of 361 patients with stable angina pectoris undergoing multidetector CT, presence of aortic calcifications conferred significantly higher risk for cardiovascular events (HR, 4.65; 95% CI, 1.19 to 18.26; P=0.028).43 Similarly, in an analysis of 1155 subjects free of known CAD, CT measures of intrathoracic and pericardial fat were significantly correlated with higher triglycerides (P<0.0001), hypertension (P<0.0001), impaired fasting glucose (P<0.001), diabetes mellitus (P<0.009), and metabolic syndrome (P<0.00001).44 These and other findings may add predictive value of CCTA beyond coronary artery information regarding comprehensive risk assessment of incident MACE.
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Clinical Effectiveness of CCTA |
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Until recently, measures of diagnostic accuracy and prognostic value have been accepted as sufficient measures of test effectiveness. Recently, however, some have suggested that a noninvasive imaging test should not only exhibit high diagnostic accuracy and effectively risk stratify individuals at risk of death or MACE but should also prompt either therapy and/or behavior which improves clinical outcomes. This new criteria has been put forth as a "value-based" method, which expands historical thinking behind noninvasive testing to include derivation of clinical benefit.45 Furthermore, the enthusiasm for adoption of CCTA as a novel imaging modality must be tempered within a medical environment that is increasingly taxed by excessive costs. Therefore, CCTA must be evaluated in the context of not only its own clinical effectiveness and costs, but also compared with other previously used modalities which have been demonstrated robust in diagnosis, prognosis, and identification of individuals for whom differential therapies may offer the most clinical benefit.46
When considering an evaluation of procedural costs, one must initially differentiate procedural reimbursement from production costs. It is certainly true that reimbursement for CCTA is less than that of MPS; with CCTA costs constrained by related, thoracic CT codes. As well, reimbursement for MPS has unfolded over the last decade to include an array of add-ons such as evaluation for not only perfusion but also ejection fraction and wall motion interpretation. It is likely that these differences between reimbursements will harmonize across diagnostic procedures over time with an ever-increasing focus on induced costs. This latter statement is important for payers and radiology benefit managers that focus on shifting testing toward the lowest cost procedure (ie, often the exercise ECG or echocardiogram); policies that do not consider the frequent downstream procedures that occur within the patient’s diagnostic work-up.
In this regard, we recently evaluated the downstream clinical and cost outcomes in individuals undergoing CCTA by way of Medicare category III transaction codes.47 Within a database encompassing >10 million insured lives, we identified 142 535 adult individuals undergoing CCTA or MPS during a 3-month period. Intermediate-risk patients undergoing CCTA (n=1938) were compared with matched MPS (n=7752) patients for 9 month CAD-related health expenditures and clinical outcomes. At the 9-month follow-up, no differences were noted for CCTA or MPS individuals for rates of hospitalizations (4.2% versus 4.1%; P=NS), CAD-related outpatient visits (17.4% versus 13.3%; P=NS), MI (0.4% versus 0.6%; P=NS), and new-onset angina (3.0% versus 3.5%; P=NS). Despite no differences in clinical outcomes, adjusted CAD-related costs were 33% lower for individuals undergoing CCTA by an average of $467 (95% CI, $99 to $984; P<0.001). In a similar analysis of individuals with known CAD undergoing CCTA (n=375) or MPS (n=1500), rates of posttest MI (2.4% versus 1.7%; P=NS) and new-onset angina (7.7% versus 6.7%) were similar among both groups. Despite the lack of differences, MPS resulted in a $2540 cost savings in a 9-month follow-up period.48 As the baseline costs of CCTA and MPS are different, these economic analyses were performed without consideration of the baseline cost of the test.
We performed a similar analysis in low risk matched individuals without known CAD undergoing CCTA (n=1647) or MPS (n=6588).49 Individuals undergoing initial evaluation by CCTA were more likely to undergo downstream layered testing with MPS (OR, 6.65; 95% CI, 5.05 to 8.75; P<0.001), whereas individuals undergoing MPS were more likely to undergoing downstream ICA (OR, 6.25; 95% CI, 4.35 to 9.09; P<0.001). By this strategy, individuals undergoing CCTA were less likely to undergo coronary artery revascularization (HR, 0.76; 95% CI, 0.75 to 0.77; P<0.001). Despite this, no significant differences were observed for individuals undergoing CCTA or MPS for rates of MI (0.4% for both; P=NS) or CAD hospitalization (0.7% versus 1.1%. respectively; P=NS) and new-onset angina was slightly lower in the CCTA individuals (4.3% versus 6.4%; P<0.001).
Together, these findings suggest that for low- and intermediate-risk individuals without known CAD, use of CCTA as a strategy for evaluation is clinically as effective as MPS while reducing healthcare costs. Conversely, in individuals with known CAD, use of MPS as a strategy for evaluation may be more cost efficient.
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Future Directions of CCTA |
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Assessment of Myocardial Perfusion by CCTA
Recently, a landmark publication assessed the feasibility of adenosine-mediated stress CCTA to identify myocardial segments with decreased flow.50 Using a canine model of LAD stenosis and identification of myocardial perfusion defects using a regional myocardial signal density ratio (myocardial signal density/left ventricular blood pool density), George et al performed whole-heart acquisition CCTA. These investigators successfully demonstrated decreased flow reserve in stenosed versus remote (nonstenosed) areas within the left ventricular myocardium (1.9±0.6 versus 7.3±4.7 mL/g per min; P<0.05).
Further expanding this animal model to humans, these investigators used adenosine-mediate stress 256-detector row CCTA to assess ischemia in the subendocardial versus subepicardial regions.51 Nineteen patients with abnormal MPS underwent adenosine 256-CCTA perfusion imaging and were evaluated for a transmural perfusion ratio, which was derived by division of the endocardial attenuation density by the epicardial attenuation density within each myocardial segment. Ischemia, as defined by a transmural perfusion ratio <0.8 was compared with the presence or absence of obstructive CAD by CCTA as well as by perfusion deficits by MPS. Mean transmural perfusion ratio was significantly lower in abnormal versus normal myocardial segments (0.71±0.05 versus 1.01±0.06; P<0.01). Furthermore, average number of abnormal myocardial segments increased from patients with no stenoses to 1-vessel obstructive CAD to multivessel obstructive CAD (1.6 versus 2.5 versus 6.3; P<0.05). The transmural perfusion ratio as measured by adenosine-mediated stress CCTA successfully identified obstructive CAD stenosis by CCTA in a manner similar to abnormal perfusion abnormalities by MPS.
Another method for quantification of regional myocardial blood flow has examined partial heart cine imaging. Using this technique, the inferior portion of the heart was imaged repeatedly in 14 patients undergoing CCTA.52 Myocardial blood flow was estimated from the slope of the signal density rise within the myocardium. In this study, myocardial blood flow in territories with stenosis were significantly lower than in those without stenosis (1.19 versus 2.06 mL/g per min; P<0.01). In individuals with moderate-severely abnormal MPS, myocardial blood flow (MBF) was significantly lower than in those without (1.32 versus 1.95 mL/g per min; P<0.01). These proof-of-principle studies highlight the vast potential of CCTA to perform simultaneous plaque and perfusion imaging (Figure 4).
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Proposed Clinical Strategy of Use for CCTA and MPS |
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From the evidence to date, CCTA appears to be diagnostically accurate, prognostically robust and cost efficient for individuals without known CAD. Despite these favorable characteristics, the precise role of CCTA in the clinical evaluation of symptomatic patients remains undefined. Although proponents of CCTA argue that it should serve as an alternative, or even "gatekeeper" to MPS or ICA, critics of CCTA point to the discordance between CCTA findings and MPS measures of ischemia. These debates will be difficult to answer without comparative efficacy trials. Nevertheless, clinicians can rely on the scientific evidence to date, which may guide the clinical application of this emerging technology:
- The negative predictive value of CCTA in individuals with intermediate prevalence of obstructive CAD approaches 100%.
- The negative predictive value of CCTA is associated with a long-term warranty period.
- There is high concordance between "negative" CCTAs and normal MPS.
- CCTA plaque measures of overall burden, severity, distribution, location, composition, and remodeling are useful for enhancing identification of individuals with ischemia or who are at risk for myocardial events.
- Among individuals with apparently normal MPS, CCTA may be useful for further differentiation (and possibly risk stratification) of those individuals with increasing degrees of coronary atherosclerosis.
- In individuals without known CAD, use of a CCTA strategy appears to be cost-savings.
Given these findings, we propose that CCTA may be successfully used in symptomatic individuals without known CAD as a first-line test (Figure 5). The absence of CAD by CCTA virtually excludes it with 100% certainty and the incident risk for individuals with normal coronary arteries by CCTA is very low. In individuals with severe high-risk CAD (eg, left main obstructive CAD or 3-vessel CAD) identified by CCTA, direct referral for ICA appears most prudent. In the remaining individuals with moderate CAD by CCTA, further refinement of the physiological significance of these lesions by functional perfusion testing may be warranted. Future studies assessing CCTA plaque characterization, myocardial perfusion and noncoronary structures will be useful to determine whether CCTA may be safely and effectively used as a stand alone test for evaluation of symptomatic individuals with suspected CAD. These studies will require large sample sizes to address issues of clinical effectiveness, safety and cost.
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Acknowledgments |
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Disclosures
James K. Min serves on the speaker’s bureau and medical advisory board for GE Healthcare.
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Footnotes |
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The opinions expressed in this article are not necessarily those of the editors or of the American Heart Association. This article is Part II of a 2-part article. Part I appears on page 257.
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