Combined CT angiography and CT myocardial perfusion enables similar prediction of 2-year major adverse cardiovascular event–free survival, including the need for myocardial revascularization procedures, similar to that achieved with standard invasive coronary angiography and single photon emission CT perfusion imaging.
Abstract
Purpose
To compare the prognostic importance (time to major adverse cardiovascular event [MACE]) of combined computed tomography (CT) angiography and CT myocardial stress perfusion imaging with that of combined invasive coronary angiography (ICA) and stress single photon emission CT myocardial perfusion imaging.
Materials and Methods
This study was approved by all institutional review boards, and written informed consent was obtained. Between November 2009 and July 2011, 381 participants clinically referred for ICA and aged 45–85 years were enrolled in the Combined Noninvasive Coronary Angiography and Myocardial Perfusion Imaging Using 320-Detector Row Computed Tomography (CORE320) prospective multicenter diagnostic study. All images were analyzed in blinded independent core laboratories, and a panel of physicians adjudicated all adverse events. MACE was defined as revascularization (>30 days after index ICA), myocardial infarction, or cardiac death; hospitalization for chest pain or congestive heart failure; or arrhythmia. Late MACE was defined similarly, except for patients who underwent revascularization within the first 182 days after ICA, who were excluded. Comparisons of 2-year survival (time to MACE) used standard Kaplan-Meier curves and restricted mean survival times bootstrapped with 2000 replicates.
Results
An MACE (49 revascularizations, five myocardial infarctions, one cardiac death, nine hospitalizations for chest pain or congestive heart failure, and one arrhythmia) occurred in 51 of 379 patients (13.5%). The 2-year MACE-free rates for combined CT angiography and CT perfusion findings were 94% negative for coronary artery disease (CAD) versus 82% positive for CAD and were similar to combined ICA and single photon emission CT findings (93% negative for CAD vs 77% positive for CAD, P < .001 for both). Event-free rates for CT angiography and CT perfusion versus ICA and single photon emission CT for either positive or negative results were not significantly different for MACE or late MACE (P > .05 for all). The area under the receiver operating characteristic curve (AUC) for combined CT angiography and CT perfusion (AUC = 68; 95% confidence interval [CI]: 62, 75) was similar (P = .36) to that for combined ICA and single photon emission CT (AUC = 71; 95% CI: 65, 79) in the identification of MACE at 2-year follow-up.
Conclusion
Combined CT angiography and CT perfusion enables similar prediction of 2-year MACE, late MACE, and event-free survival similar to that enabled by ICA and single photon emission CT.
© RSNA, 2017
Introduction
Coronary artery disease (CAD) is the leading cause of morbidity and mortality worldwide (1). The care of patients with CAD has evolved rapidly over the past decade. The Courage study showed that not all patients with coronary artery stenosis benefit from coronary revascularization (2). In fact, in the majority of patients suspected of having CAD, those who received only medical therapy fared just as well as those who underwent coronary revascularization. In addition, the Fractional Flow Reserve Versus Angiography for Multivessel Evaluation (or FAME)study, which incorporated the use of fractional flow reserve along with invasive coronary angiography (ICA) to guide coronary revascularization, showed improved patient outcomes in the fractional flow reserve guided treatment arm (3). The FAME2 study also showed that revascularization of a hemodynamically significant stenosis and optimal medical therapy were superior to optimal medical therapy alone (4). Moreover, in patients without hemodynamically significant stenosis in the FAME2 study, optimal medical therapy alone resulted in very good patient outcomes, regardless of the angiographic appearance of the stenosis (4). These studies suggest that understanding of the hemodynamic significance of atherosclerotic lesions via additional assessment of myocardial perfusion should play a greater role in directing therapy to optimize patient outcomes.
Cardiac imaging, measurement of serum biomarkers, and standard 12-lead electrocardiography are the most important noninvasive tools in the diagnosis and management of CAD. Direct validation of angiographic measurements of coronary stenosis and atherosclerotic plaque burden with computed tomography (CT) on a vessel-by-vessel and segment-by-segment basis has been established by using histopathology, intravascular ultrasonography, or both (5–9). However, in addition to diagnostic accuracy, the effectiveness of noninvasive strategies to diagnose and monitor CAD should demonstrate similar or superior ability to predict future adverse events as compared with the most commonly used clinical technologies in medical practice. Invasive coronary angiography (ICA) yields important information on the prognosis of patients with CAD (10,11). Prior studies have shown higher risk of mortality in patients who have multivessel CAD as compared with those who have single-artery disease (10,11). Similarly, data from noninvasive CT coronary angiography have established increased mortality in patients with three-vessel and left main CAD compared with patients with one- or two-vessel disease (12,13). Conversely, absence of CAD at CT angiography is associated with a low annualized risk of cardiac mortality (<0.02% per year) (14). In this regard, previous studies from four different patient populations suggest that the anatomic information from CT angiography has prognostic importance similar to that of ICA (10–13).
However, a critical step in the care of patients with CAD is to establish the prognosis of functionally important lesions, which will be used to determine the most appropriate treatment (3,4). Thus, the principal aim of this study was to compare the prognostic importance (time to major adverse cardiovascular event [MACE]) of combined CT angiography and CT myocardial stress perfusion imaging with that of combined ICA and stress single photon emission CT myocardial perfusion imaging.
Materials and Methods
Study Overview and Population
The Combined Noninvasive Coronary Angiography and Myocardial Perfusion Imaging Using 320-Detector Row Computed Tomography (CORE320) prospective multicenter international study enrolled patients from November 2009 to July 2011 at 16 sites (13 academic centers, three private hospitals) in eight countries; the study design, methods, and diagnostic results have been reported previously (15–18). The study sponsor, Toshiba Medical Systems (Otawara, Japan), was not involved in any stage of the study design, data acquisition, data analysis, or manuscript preparation. The study investigators had full control of the data. In addition, this research was supported in part by the Intramural Research Program of the National Heart, Lung, and Blood Institute of the National Institutes of Health. The study was approved by a central institutional review board, as well as by local institutional review boards, and all patients provided written informed consent. The study design included complete medical history, coronary CT angiography, adenosine stress CT perfusion, single photon emission CT myocardial perfusion, and ICA. All noninvasive imaging was performed before ICA. Images were interpreted in central core laboratories by readers who were blinded to clinical history and to each other’s findings. All image acquisition and interpretation methods have been described in detail previously (15–17,19).
End Points and Follow-up
The primary end point was MACE at 2 years. MACE was defined as a composite of cardiac death, myocardial infarction, hospitalization for chest pain or congestive heart failure, late revascularization (>30 days after index ICA), or arrhythmia. Late MACE was defined similarly, except for the exclusion of revascularizations occurring within the first 182 days after ICA.
Follow-up assessments were performed 30 days and 6, 12, and 24 months after ICA. Data were obtained at office visits, via telephone interviews, or with a standardized questionnaire sent by mail. The questionnaire assessed death, myocardial infarction, hospitalization, new or unstable angina, congestive heart failure, percutaneous intervention, coronary artery bypass surgery, and current medications. All events were adjudicated by a committee of cardiologists (M.Y.C., C.E.R., A.A., R.T.G., J.M.M., A.E.A., J.A.B., J.A.C.L.) and a radiologist (M.D.), all of whom were board certified with 10 or more years of experience in medicine. Non-English medical records were translated to English for adjudication.
Statistical Analyses
Descriptive statistics were compared with the Wilcoxon rank-sum test or χ2 test, as appropriate. Unadjusted comparisons of the distribution of 2-year survival used standard Kaplan-Meier curves and restricted mean survival times (RMSTs) (20); standard errors were estimated with the bootstrap method with 2000 replicates and resampling at the patient level. Bootstrapping at the patient level accommodates within-patient correlation due to the fact that each patient underwent imaging with both modalities. The RMST is calculated as the area under the Kaplan-Meier curve, and it can be interpreted as the expected time of event-free survival within 2 years after ICA. To determine whether CT angiography and ICA can yield additional information when adjusted for standard risk factors, a series of Cox proportional hazard models were used to compute hazard ratios for a base model and then for each imaging modality alone and together. The base model included age, coronary artery calcium score, history of myocardial infarction, prior congestive heart failure, and coronary artery bypass within 30 days of enrollment. Each variable in the base model was tested for linear time dependency. Similar comparisons were also made for subgroups with and those without previous CAD, as well as the number of obstructive coronary arteries (zero to three vessels). Area under the receiver operating characteristic curve (AUC) was used as a measure of diagnostic power. The reference standard was defined as occurrence of a MACE by 2 years after ICA. Two events that were captured during follow-up but occurred after 2 years were excluded from the Kaplan-Meier curves and their comparisons but were included in the Cox proportional hazards models.
Combined CT angiography and CT perfusion and combined ICA and single photon emission CT were defined as positive for disease if at least one vessel had stenosis of 50% or more with a corresponding perfusion defect (sum stress score) (17) of two or more at CT perfusion or one or more at single photon emission CT. In the AUC analyses, CT angiography, CT perfusion, ICA, and single photon emission CT were modeled as continuous variables, with the corresponding Leaman score also included in the model. In Cox proportional hazard models, CAD severity at CT angiography and ICA was defined as an ordinal variable (0, no disease; 1, <50% stenosis; 2, single-vessel disease; 3, two-vessel disease; 4, two-vessel disease including proximal left anterior descending artery; 5, three-vessel disease; 6, left main disease). CT perfusion sum stress score and single photon emission CT sum stress score were modeled as continuous variables.
Results
The CORE320 prospective multicenter study enrolled 381 patients who had been clinically referred for ICA and were aged 45–85 years. Overall, 379 participants (99.5%) underwent all imaging tests, including coronary CT angiography, adenosine stress CT perfusion, single photon emission CT, and ICA and had complete 2-year follow-up data. Baseline characteristics are provided in Table 1. Within the 2-year follow-up period, a MACE (49 late revascularizations [>30 days after index coronary catheterization], five myocardial infarctions, one cardiac death, nine hospitalizations for chest pain or congestive heart failure, and one arrhythmia) occurred in 51 (13.5%) of 379 patients. Similarly, within the 2-year follow-up period, late MACE (24 late revascularizations [>182 days after index coronary catheterization], five myocardial infarctions, one cardiac death, nine hospitalizations for chest pain or congestive heart failure, and one arrhythmia) occurred in 32 (8.4%) of 379 patients. Follow-up data were not available in two patients.
Table 1.
Baseline Characteristics of Patients with and without Cardiovascular Events
Note.—Unless otherwise indicated, data are numbers of patients, and data in parentheses are percentages. ARB = angiotensin-receptor blockers, ACE = angiotensin-converting enzyme, NYHA = New York Heart Association.
Combined Anatomic and Physiologic Predictors of MACE-Free Survival
MACE.—The absence of a hemodynamically obstructive coronary artery stenosis at combined CT angiography and CT perfusion and at combined ICA and single photon emission CT was associated with very high 2-year MACE-free survival of 94% and 93%, respectively, with a difference of 1.8% (Table 2; Fig 1, A). Similarly, the RMST was very high, with absence of stenosis being associated with average MACE-free survival of 1.932 years for combined CT angiography and CT perfusion and 1.896 years for combined ICA and single photon emission CT (Table 2). Conversely, the presence of hemodynamically obstructive coronary artery stenosis (≥50% stenosis with corresponding perfusion defect) was associated with significantly (P < .001 for combined CT angiography and CT perfusion, P < .001 for combined ICA and single photon emission CT) poorer survival rates of 82% and 77%, respectively, with a difference of 4.8% (Table 2; Fig 1, A). RMSTs for these groups were 1.751 years and 1.700 years, respectively (Table 2). Significant differences in RMST were noted between patients with and those without hemodynamically obstructive coronary artery stenosis at combined CT angiography and CT perfusion and at combined ICA and single photon emission CT. Although no significant difference was found between combined CT angiography and CT perfusion and combined ICA and single photon emission CT in their ability to enable prediction of MACE-free survival or RMST in patients without hemodynamically obstructive coronary artery stenoses (P = .42 for event-free survival, P = .27 for RMST; Table 2), in patients with obstructive lesions, differences in event-free survival significantly favored combined ICA and single photon emission CT (P = .047) (Table 2; Fig 1, A).
Table 2.
Comparison of the Diagnostic and Prognostic Capabilities of Combined CT Angiography/CT Perfusion and ICA/Single Photon Emission CT for 2-year Event-Free Survival
Note.—Data in parentheses are 95% confidence intervals (CIs). NA = not applicable.
Figure 1:
Kaplan-Meier survival curves used to predict MACE (composite end point of late revascularization [>30 days], myocardial infarction, cardiac death, arrhythmia, and hospitalization for chest pain or congestive heart failure) and late MACE (composite end point of late revascularization [>182 days], myocardial infarction, cardiac death, arrhythmia, and hospitalization for chest pain or congestive heart failure) at 2 years after index cardiac catheterization. A, MACE survival curves for patients with and those without hemodynamically obstructive CAD at combined CT angiography and CT perfusion (CTA /CTP) and combined ICA and single photon emission CT (ICA /SPECT ). Significant differences in event-free survival were noted between patients with and those without hemodynamically obstructive coronary artery stenosis at both combined CT angiography and CT perfusion and combined ICA and single photon emission CT (P < .001). However, although no significant difference was found in the ability of combined CT angiography and CT perfusion to help us predict event-free survival in patients without hemodynamically obstructive coronary artery stenoses when compared with combined ICA and single photon emission CT (P = .42), in patients with obstructive lesions, differences significantly favored the combination of ICA and single photon emission CT (P = .047). B, Late MACE survival curves in patients with and in those without hemodynamically obstructive CAD at CT angiography and CT perfusion and at ICA and single photon emission CT. Significant differences in event-free survival were noted between patients with and those without hemodynamically obstructive coronary artery stenosis at combined CT angiography and CT perfusion and at combined ICA and single photon emission CT (P < .01). However, although no significant difference was found in the ability of combined CT angiography and CT perfusion to enable us predict event-free survival in patients without hemodynamically obstructive coronary artery stenoses when compared with combined ICA and single photon emission CT (P = .62), for those with obstructive lesions differences were of borderline significance and favored the combination of ICA and single photon emission CT (P = .098).
Having a greater number of hemodynamically obstructive coronary arteries at combined CT angiography and CT perfusion and at combined ICA and single photon emission CT was associated with poorer survival. In patients who had no vessels with hemodynamically obstructive CAD, the 2-year MACE-free survival rates were 94% and 93%, respectively, at CT angiography and ICA, whereas MACE-free survival rates were 67% and 63% (Fig 2, A and B), respectively, at CT angiography and ICA in patients with three-vessel disease. At combined CT angiography and CT perfusion and at combined ICA and single photon emission CT, a significant difference in survival was observed between patients without hemodynamically obstructive stenosis (94% vs 82% [P < .001]) and those with three vessels containing hemodynamically obstructive coronary stenosis (93% vs 77% [P = .007]). Hemodynamically significant one-vessel CAD and two-vessel CAD had intermediate MACE-free survival rates for CT angiography and CT perfusion and for ICA and single photon emission CT (Fig 2).
Figure 2:
Kaplan-Meier survival curves used to predict MACE (composite end point of late revascularization [>30 days], myocardial infarction, cardiac death, arrhythmia, and hospitalization for chest pain or congestive heart failure) and late MACE (composite end point of late revascularization [>182 days], myocardial infarction, cardiac death, arrhythmia, and hospitalization for chest pain or congestive heart failure) at 2 years after index cardiac catheterization. A, Survival curves for combined CT angiography and CT perfusion in patients without hemodynamically obstructive CAD and in those with one, two, or three vessels with hemodynamically obstructive CAD. B, Survival curves for combined ICA and single photon emission CT myocardial perfusion in patients without hemodynamically obstructive CAD and in those with one, two, or three vessels with hemodynamically obstructive CAD. C, Survival curves for combined CT angiography and myocardial perfusion in patients without hemodynamically obstructive CAD and in those with one, two, or three vessels with hemodynamically obstructive CAD. D, Survival curves for combined ICA and single photon emission CT myocardial perfusion in patients without hemodynamically obstructive CAD and in those with one, two, or three vessels with hemodynamically obstructive CAD.
The AUC for CT angiography alone in the prediction of MACE at 2-year follow-up was 65 (95% CI: 60, 70). When CT perfusion was added to the CT angiography model, AUC improved to 68 (95% CI: 62, 75); however, there was not a significant difference between the AUC of CT angiography and that of combined CT angiography and CT perfusion (P = .31). Similarly, a significant difference was not found in AUC between ICA alone (AUC = 73 [95% CI: 68, 77]) and ICA and single photon emission CT (AUC = 71 [95% CI: 65, 79]) in the prediction of MACE (P = .63). The AUCs for combined CT angiography and CT perfusion (AUC = 68; 95% CI: 62, 75) and for combined ICA and single photon emission CT (AUC = 71, 95% CI: 65, 79) in the prediction of MACE were similar (Table 2; Fig 3, A). A significant difference was not found between the AUC of combined CT angiography and CT perfusion and the AUC of combined ICA and single photon emission CT in the prediction of MACE (P = .36, Table 2).
Figure 3:
Receiver operating characteristic curves for combined CT angiography and myocardial perfusion imaging (CTA+CTP) and combined ICA and single photon emission computed tomography (ICA+SPECT ) used to predict, A, MACE (composite end point of late revascularization [>30 days], myocardial infarction, cardiac death, arrhythmia, or hospitalization for chest pain or congestive heart failure) at 2-year follow-up or, B, late MACE (composite end point of late revascularization [>182 days], myocardial infarction, cardiac death, arrhythmia, or hospitalization for chest pain or congestive heart failure) at 2-year follow-up.
Combined CT angiography and CT perfusion did not enable us to identify eight cases in which the patient had a subsequent MACE. In six (75%) cases, findings were interpreted as positive for disease at CT angiography and as negative for disease at CT perfusion. In one (13%) case, findings were deemed negative at both CT angiography and CT perfusion (Table 3). Similarly, combined ICA and single photon emission CT did not enable us to identify nine cases with MACE: four (44%) in which findings were positive at ICA and negative at single photon emission CT and four (44%) in which findings were negative at ICA and negative at single photon emission CT (Table 3).
Table 3.
Imaging Characteristics in Cases in Which Combined CT Angiography and CT Perfusion and Combined ICA and Single Photon Emission CT Failed to Identify a Patient with Subsequent MACE or Late MACE
Note.—Data are numbers of patients. Data in parentheses are percentages.
Late MACE.—The absence of hemodynamically obstructive coronary artery stenosis at combined CT angiography and CT perfusion and at combined ICA and single photon emission CT was associated with very high 2-year event-free survival of 97% and 96%, respectively, with a difference of 0.9% (Table 2; Fig 1, B). The presence of hemodynamically obstructive coronary artery stenosis (≥50% stenosis with corresponding perfusion defect) was associated with poorer (P < .01 for CT angiography and CT perfusion, P < .01 for ICA and single photon emission CT) 20-year MACE-free survival rates of 89% for CT angiography and CT perfusion and 85% for ICA and single photon emission CT, with a difference of 3.3% (Table 2). RMSTs for the groups were 1.967 and 1.955 years for absence of stenosis at CT angiography and CT perfusion and at ICA and single photon emission CT, respectively. Presence of stenosis yielded significantly lower RMSTs of 1.887 and 1.859 at CT angiography and CT perfusion and at ICA and single photon emission CT, respectively (P < .01 for both, Table 2). Significant differences in event-free survival and RMST were noted between patients with and those without hemodynamically obstructive coronary artery stenosis at combined CT angiography and CT perfusion and at combined ICA and single photon emission CT. However, although no significant difference was found in the ability of combined CT angiography and CT perfusion to enable prediction of MACE-free survival in patients without hemodynamically obstructive coronary artery stenoses when compared with that of combined ICA and single photon emission CT (P = .62 for event-free survival, P = .50 for RMST; Table 2), in patients with obstructive lesions, differences were of borderline significance and favored combined ICA and single photon emission CT in terms of event-free survival (P = .098) but not RMST (P = .13) (Table 2; Fig 1, B).
A greater number of hemodynamically obstructive coronary arteries was associated with poorer survival at combined CT angiography and CT perfusion and at combined ICA and single photon emission CT. In patients who had no vessels with hemodynamically obstructive CAD, MACE-free survival rates were 97% and 96%, respectively, at combined CT angiography and CT perfusion and at combined ICA and single photon emission CT, whereas in patients with three-vessel disease, event-free survival rates were 87% and 73%, respectively (Fig 2, C and D). Hemodynamically significant one- and two-vessel CAD had intermediate rates of late MACE for CT angiography and CT perfusion and for ICA and single photon emission CT (Fig 2).
The AUC for CT angiography alone to predict late MACE was 68 (95% CI: 63, 72). When CT perfusion was added to the CT angiography model, the AUC improved to 69 (95% CI: 63, 79); however, there was not a significant difference between the AUC of CT angiography and that of combined CT angiography and CT perfusion (P = .39). Similarly, a significant difference was not found in AUC between ICA alone (AUC = 72; 95% CI: 67, 77) and combined ICA and single photon emission CT (AUC = 71; 95% CI: 64, 80) in the prediction of late MACE (P = .90). The AUC for combined CT angiography and CT perfusion (AUC = 69; 95% CI: 63, 79) and that for combined ICA and single photon emission CT (AUC = 71; 95% CI: 64, 80) to predict late MACE were similar (Table 2; Fig 3, B). No difference between combined CT angiography and CT perfusion and combined ICA and single photon emission CT was found in the ability of AUC to enable prediction of late MACE (P = .75, Table 2).
Relative Contributions of Anatomic and Physiologic Predictors of MACE
A significant hazard ratio (HR) was found for CT angiography severity (HR,1.252; 95% CI: 1.028, 1.526) and ICA severity (HR, 1.395; 95% CI: 1.152, 1.688) after controlling for age, calcium score, prior myocardial infarction, prior heart failure, and early surgical revascularization (Table E1 [online]). When both CT angiography and ICA severity were included in the same model, ICA severity remained significant (HR, 1.354; 95% CI: 1.069, 1.716). CT angiography and ICA remained significant predictors when CT perfusion and single photon emission CT were added to the base model (HR, 1.231; 95% CI: 1.010, 1.499) and to ICA (HR, 1.365; 95% CI: 1.119, 1.665) (Table E1 [online]). Moreover, the HR for ICA remained significant after adjustment for CT angiography, CT perfusion, and single photon emission CT when added to the base model (HR, 1.304; 95% CI: 1.020, 1.669); however, CT angiography did not maintain significance when ICA, CT perfusion, and single photon emission CT were added to the base model (HR, 1.059; 95% CI: 0.830, 1.349) (Table E1 [online]).
Discussion
We report an overall composite event rate of 13.5% at 2-year follow-up in this prospective multicenter study of 379 symptomatic patients referred for conventional coronary angiography and who underwent CT angiography, stress CT perfusion, and single photon emission CT before ICA. Previous studies have reported on the prognostic value of CT angiography alone or ICA alone in the prediction of MACE; however, those studies were limited since they did not have prognostic data for both CT angiography and ICA from the same patient at virtually the same time (mean, 9.2 days ± 11.4 between tests in our study) (11–14). When we looked at anatomic predictors alone, a significant difference was noted in survival between those with and those without obstructive CAD at both CT angiography and ICA. Moreover, in patients without obstructive CAD, there was not a significant difference in survival between invasive versus noninvasive assessment. Similarly, in the combined anatomic and physiologic predictive approaches, a significant difference was noted in survival between those with and those without hemodynamically obstructive CAD at combined CT angiography and CT perfusion and at combined ICA and single photon emission CT; however, there was no significant difference in the identification of patients with or without hemodynamically obstructive CAD when we used either the invasive method or the noninvasive method. The number of vessels identified with obstructive CAD is associated with poorer survival by both anatomic predictors alone, as well as by combined anatomic and physiologic predictors. Thus, the presence of myocardial ischemia in association with anatomic obstruction entails worse prognosis in patients with symptomatic CAD.
Our ensemble of findings clearly shows that a purely noninvasive anatomic and physiologic assessment is adequate in the assessment of patients suspected of having CAD. Differences between CAD and ICA that cannot be excluded by the data are given as CIs in Table 2. The median procedure time for combined CT angiography and CT perfusion was 34 minutes, whereas historic data show 30 minutes are needed for diagnostic invasive angiography and 120 or more minutes are needed for single photon emission CT depending on the acquisition protocol. The angiographic prognostic power of CT angiography is preserved when compared with that of ICA, and the addition of myocardial perfusion enhances the ability to distinguish patients with a high MACE-free survival rate from those who will experience major cardiac complications in the subsequent 2 years. Ischemic burden, evaluated indirectly as the number of vessels containing coronary stenoses or measured directly as the extent of a myocardial perfusion defect downstream from a coronary atherosclerotic plaque, relates to the probability that the patient will experience untoward cardiovascular events (21). In the United States and abroad, single photon emission CT remains the most commonly used modality to assess the extent and severity of myocardial ischemia with proven prognostic value. Thus, combined single photon emission CT and ICA is the most used combination of technologies selected to depict the presence of obstructive CAD in current clinical practice.
Linde et al (22) have previously reported that CT perfusion yielded incremental prognostic power over the Diamond and Forrester score in the prediction of MACE in patients with low risk of unstable angina pectoris. In our study, we report the effect of the addition of myocardial perfusion to angiography in the prediction of MACE or late MACE was minimal for combined CT angiography and CT perfusion and for ICA and single photon emission CT in both AUC and proportional hazard analyses. In the combined CT angiography and CT perfusion analysis, the AUC improved from 65 (95% CI: 60, 70) to 68 (95% CI: 62, 75) when CT perfusion was added to the model; however, the improvement in AUC was not significant. Similarly, a significant difference in AUC was not found between ICA alone (AUC = 73; 95% CI: 68, 77) and combined ICA and single photon emission CT (AUC = 71; 95% CI: 65, 79) in the prediction of MACE. However, when modeled alone, CT angiography, CT perfusion, single photon emission CT, and ICA were all significant predictors of MACE and late MACE with proportional hazard models. Invasive fractional flow reserve studies primarily are used to determine the functional importance of coronary stenoses at conventional invasive angiography (23). This technique was validated against single photon emission CT but remains limited in availability and clinical use worldwide because it requires crossing the suspected coronary stenosis with a wire to measure distal pressure during infusion of adenosine-induced hyperemia. Thus, the approach entails cardiac catheterization and decision making at a time when the patient is sedated and already undergoing an invasive procedure; thus, he or she is largely unable to objectively participate in the decision to forgo or proceed with revascularization. Our results suggest that the combined CT angiography and CT perfusion approach is a noninvasive method with which to assess the presence and hemodynamic significance of coronary stenoses. This approach has prognostic power similar to that of single photon emission CT and ICA in the prediction of clinical events.
Theoretically, CT fractional flow reserve and related methods can be used to determine the functional significance of coronary stenosis at rest (24,25). Such approaches, while promising, are sophisticated and expensive and have not yet been shown to enable prediction of future morbidity and mortality. The presence of coronary calcification in association with atherosclerosis significantly limits the ability of CT methods that use direct visualization of the epicardial coronary lumen to help us assess severity. Coronary calcium level can also affect the accuracy with which CT fractional flow reserve can be used to determine the vessel boundaries; thus, it can influence the functional evaluation of coronary stenosis. CT perfusion is not affected by the presence or absence of coronary calcium. However, as emerging technologies, both new CT techniques have the potential to significantly improve the diagnostic approach in patients suspected of having CAD.
Our study had limitations. In the interpretation of our results, we included revascularization events because we aimed to determine which patients will develop symptoms and require revascularization over a relatively short period (2 years) after an index clinical event for which a patient suspected of having CAD was referred to the ICA. We excluded events that occurred within 30 days after the index event because those relate directly to clinical decision making at the time of the index event that led to ICA. We did not require invasive fractional flow reserve because all these patients underwent single photon emission CT before ICA and because the single photon emission CT results were available to the clinical team. Furthermore, fractional flow reserve is not routinely performed currently, and it was conducted even less frequently during the time of patient recruitment. However, one strength of this study was the use of distinct core laboratories for all angiographic and myocardial perfusion measurements that were performed with blinding to all other clinical and phenotypic characterizations. Moreover, all comparative analyses were performed by an independent biostatistical core group.
In conclusion, the combination of CT angiography and CT myocardial perfusion yields similar prediction of 2-year MACE-free survival, including the need for myocardial revascularization procedures in comparison with standard ICA and single photon emission CT perfusion imaging.
Advances in Knowledge
■ The 2-year major adverse cardiovascular event (MACE)-free rates for combined CT angiography and CT perfusion findings were 94% negative for coronary artery disease (CAD) versus 82% positive for CAD (P < .001) and were similar to those for combined ICA and single photon emission CT (93% negative for CAD vs 77% positive for CAD) (P < .001).
■ MACE-free rates for CT angiography and CT perfusion versus those for ICA and single photon emission CT for either positive or negative results were not significantly different from those for MACE or late MACE (P > .05 for all).
■ The overall area under the receiver operating characteristic curve (AUC) of combined CT angiography and CT perfusion (AUC = 68; 95% confidence interval [CI]: 62, 75]) and of combined ICA and single photon emission CT (AUC = 71; 95% CI: 65, 79]) in the identification of MACE at 2-year follow-up were similar (P = .36).
■ A significant difference in survival was observed between patients without hemodynamically obstructive stenosis and those with three vessels containing hemodynamically obstructive coronary stenoses for combined CT angiography and CT perfusion (P < .001) and combined ICA and single photon emission CT (P = .007).
Implications for Patient Care
■ When looking at anatomic predictors alone, a significant difference in survival was noted between those with and those without obstructive CAD at both invasive assessment and noninvasive assessment.
■ Understanding the hemodynamic significance of atherosclerotic lesions via additional assessment of myocardial perfusion should play a greater role in directing therapy to optimize patient outcomes.
■ A purely noninvasive anatomic and physiologic assessment via CT angiography and myocardial perfusion is adequate to identify patients with a MACE at 2-year follow-up in symptomatic patients suspected of having CAD.
SUPPLEMENTAL TABLE
Received July 16, 2016; revision requested September 12; revision received November 7; accepted November 29; final version accepted December 15.
Supported by Toshiba Medical Systems and the Intramural Research Program of the National Heart, Lung, and Blood Institute of the National Institutes of Health (ZIA-HL006138).
Disclosures of Conflicts of Interest: M.Y.C. Activities related to the present article: disclosed no relevant relationships. Activities not related to the present article: institution has a research agreement with Toshiba Medical Systems. Other relationships: disclosed no relevant relationships. C.E.R. disclosed no relevant relationships. A.A. Activities related to the present article: received a grant from Toshiba Medical Systems. Activities not related to the present article: disclosed no relevant relationships. Other relationships: disclosed no relevant relationships. M.D. Activities related to the present article: received a grant from Toshiba Medical Systems. Activities not related to the present article: is a consultant for Guerbet; institution received grants from GE Healthcare, Bracco, Guerbet, and Toshiba Medical Systems; has served as a speaker for Toshiba Medical Systems, Bayer-Schering, and Guerbet; was compensated for travel expenses by Toshiba Medical Systems and Guerbet; is course director for Cardiac CT Hands-on Courses at Charité in Berlin, Germany; institution has research agreements with Siemens Medical Solutions, Philips Medical Systems, and Toshiba Medical Systems; receives royalties from Springer. Other relationships: disclosed no relevant relationships. R.T.G. Activities related to the present article: received a grant from Toshiba Medical Systems. Activities not related to the present article: is employed by MedImmune; is a consultant for ICON Medical Imaging; holds U.S. patents 7,853,309, 8,160,338, and 8,615,116. Other relationships: disclosed no relevant relationships. J.M.M. Activities related to the present article: received a grant from Toshiba Medical Systems. Activities not related to the present article: disclosed no relevant relationships. Other relationships: disclosed no relevant relationships. H.N. Activities related to the present article: received a grant from Toshiba Medical Systems. Activities not related to the present article: disclosed no relevant relationships. Other relationships: disclosed no relevant relationships. K.Y. disclosed no relevant relationships. K.K. Activities related to the present article: received a grant from Toshiba Medical Systems. Activities not related to the present article: received grants from Siemens and Philips. Other relationships: disclosed no relevant relationships. H.S. Activities related to the present article: received a grant from Toshiba Medical Systems. Activities not related to the present article: received grants from Siemens, Philips, Bayer, Guerbet, Daiichi Sankyo, Fuji Film Holdings, and Nihon Medi-Physics. Other relationships: disclosed no relevant relationships. R.L. disclosed no relevant relationships. A.L.V. disclosed no relevant relationships. R.J.C. Activities related to the present article: received a grant from Toshiba Medical Systems. Activities not related to the present article: disclosed no relevant relationships. Other relationships: disclosed no relevant relationships. V.C.M. disclosed no relevant relationships. C.N. disclosed no relevant relationships. K.F.K. Activities related to the present article: received a grant from Toshiba Medical Systems. Activities not related to the present article: disclosed no relevant relationships. Other relationships: works on the advisory board of Vital Images. M.J. disclosed no relevant relationships. S.K. disclosed no relevant relationships. A.J.S. Activities related to the present article: disclosed no relevant relationships. Activities not related to the present article: received a speakers fee from Toshiba Medical Systems. Other relationships: disclosed no relevant relationships. M.L. disclosed no relevant relationships. S.Y.T. disclosed no relevant relationships. J.H. Activities related to the present article: received a grant and support for travel to attend research meetings from Toshiba Medical Systems. Activities not related to the present article: served as a speaker for Toshiba Medical Systems. Other relationships: disclosed no relevant relationships. N.P. Activities related to the present article: received a grant from Toshiba Medical Systems. Activities not related to the present article: disclosed no relevant relationships. Other relationships: disclosed no relevant relationships. F.J.R. Activities related to the present article: received a grant and support from travel from Toshiba Medical Systems. Activities not related to the present article: served as a speaker for Toshiba Medical Systems in 2006 and 2007. Other relationships: disclosed no relevant relationships. J.A.B. disclosed no relevant relationships. A.E.A. disclosed no relevant relationships. M.B.M. Activities related to the present article: received a grant from Toshiba Medical Systems. Activities not related to the present article: disclosed no relevant relationships. Other relationships: disclosed no relevant relationships. C.H.C. Activities related to the present article: received a grant from Toshiba Medical Systems. Activities not related to the present article: disclosed no relevant relationships. Other relationships: disclosed no relevant relationships. M.E.C. Activities related to the present article: received a grant from Toshiba Medical Systems. Activities not related to the present article: disclosed no relevant relationships. Other relationships: disclosed no relevant relationships. M.F.D.C. disclosed no relevant relationships. J.A.C.L. Activities related to the present article: received a grant from Toshiba Medical Systems. Activities not related to the present article: received a grant from Toshiba Medical Systems. Other relationships: disclosed no relevant relationships.
Abbreviations:
- AUC
- area under the receiver operating characteristic curve
- CAD
- coronary artery disease
- CI
- confidence interval
- CORE320
- Combined Noninvasive Coronary Angiography and Myocardial Perfusion Imaging Using 320-Detector Row Computed Tomography
- HR
- hazard ratio
- ICA
- invasive coronary angiography
- MACE
- major adverse cardiovascular event
- RMST
- restricted mean survival time
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