Abstract
Background
The prognostic value of coronary computed tomographic angiography (CCTA) for evaluating coronary artery disease in asymptomatic older adults is controversial. We investigated the prognostic value of CCTA in community‐dwelling elderly Koreans.
Methods and Results
Participants (n=470; mean age: 75.1±7.3 years) who underwent CCTA were enrolled from KLoSHA (Korean Longitudinal Study on Health and Aging), a community‐based prospective cohort. Using CCTA, coronary artery disease was classified as normal, nonobstructive, or obstructive according to the presence of 0%, <50%, or ≥50% stenosis, respectively. Coronary artery calcium scores were investigated together with Framingham risk score, atherosclerotic cardiovascular disease score, and individual risk factors. Major adverse cardiac events (MACE) were defined as a composite of cardiac event–related death or nonfatal myocardial infarction. During a median follow‐up of 8.2 years (interquartile range: 7.7–10.1 years), MACE occurred in 24 participants (5.1%). Compared with the normal group, participants in the obstructive group showed higher incidence of MACE (hazard ratio: 5.65; 95% CI, 1.22–26.16; P=0.027), whereas there were no significant differences in MACE between the normal and nonobstructive groups. The 8‐year event‐free survival rates were 98.1±1.1%, 94.9±1.6%, and 81.7±4.8% in the normal, nonobstructive, and obstructive groups, respectively. Compared with the Framingham risk score and coronary artery calcium score model, CCTA improved risk prediction by C‐index (from 0.698 to 0.749) and category‐free net reclassification index (0.478; P=0.022).
Conclusions
CCTA showed better long‐term prognostic value for MACE than coronary artery calcium score in this asymptomatic older population.
Keywords: Asian, elderly, major adverse cardiac outcome, prognosis, subclinical atherosclerosis
Subject Categories: Computerized Tomography (CT)
Clinical Perspective
What Is New?
In this long‐term prospective cohort study with 470 asymptomatic older adults (median follow‐up: 8.2 years; mean age: 75.1±7.3 years), coronary computed tomographic angiography showed better prognostic value for cardiac events than coronary artery calcium scores and conventional risk factors.
What Are the Clinical Implications?
Information obtained from coronary computed tomographic angiography likely gives more reliable clinical guidance to prevent or delay future cardiac events in asymptomatic older adults than traditional methods.
Additional studies are needed to evaluate whether treatment changes according to coronary computed tomographic angiography findings affect cardiac outcomes.
Introduction
Coronary artery disease (CAD) is a major cause of death worldwide.1 It often occurs without typical symptoms in older populations, and this hampers its timely detection. Higher CAD‐related mortality rates are frequently observed in these groups.2 Screening for CAD in older populations by using an appropriate method is likely to bring substantial benefits for health care.
As a screening tool for CAD, the coronary artery calcium score (CACS) has shown powerful predictive value beyond conventional cardiac risk factors in asymptomatic people, including older adults.3, 4 Given this background, coronary computed tomographic angiography (CCTA) has received much attention as an advanced screening tool for CAD because it can provide comprehensive information on coronary arteries based on reliable visualization.5 In addition, CCTA showed improved predictive value over conventional cardiac risk factors, even among patients who were not recommended to be tested by CCTA according to the current guidelines.6
Over the past decade, many researchers have investigated the prognostic value of CCTA over CACS or cardiovascular risk scores.7, 8, 9, 10, 11 In a large multicenter registry study, CCTA failed to show additional gain versus CACS in the predictability of hard outcomes among generally asymptomatic people during 2‐year follow‐up.9 In contrast, more recent studies demonstrated that CCTA had additional predictive value over CACS in asymptomatic patients with high‐risk features, such as high CACS and the presence of diabetes mellitus (DM) and multiple risk factors.7, 8, 11, 12
Aging is a strong risk factor for CAD13; however, few studies have examined the prognostic value of CCTA among asymptomatic elderly populations in particular. A recent study showed that CCTA had better prognostic value than did cardiac risk factors or CACS for predicting major adverse cardiac events (MACE) in asymptomatic older adults.14 However, the 26‐month follow‐up was too short to confirm CCTA's prognostic value robustly. A debate remains regarding the use of CCTA as a screening tool, particularly in asymptomatic people. In this study, we aimed to investigate the prognostic value of CCTA compared with CACS and conventional risk factors in asymptomatic elderly Korean people over a long period.
Methods
The data that support the findings of this study are available from the corresponding author on reasonable request.
Study Design
KLoSHA (Korean Longitudinal Study on Health and Aging) is a community‐based prospective cohort study on health, aging, and common geriatric diseases among Korean older adults.15 At baseline, 1000 participants aged ≥65 years were recruited via an age‐ and sex‐stratified random sampling of residents of Seongnam‐City, South Korea. All baseline evaluations were performed by trained researchers at the Seoul National University Bundang Hospital (SNUBH) in 2005–2006.
Study Population
Among the participants of this cohort, CCTA was performed on 541 patients who agreed to the procedure and had no contraindications medically for injection with a contrast dye. To select asymptomatic participants without a known history of CAD, we excluded 71 participants with the exclusion criteria (Data S1). Finally, 470 asymptomatic participants aged ≥65 years were enrolled in the study, which was approved by the institutional review board of SNUBH (B‐1507/306‐306), and all participants signed an informed consent form.
Anthropometric and Biochemical Parameters
Medical histories were obtained from the personal interview or medical records. The 10‐year Framingham risk score (FRS) and the 10‐year atherosclerotic cardiovascular disease (ASCVD) risk score were calculated.16, 17 Changes in the levels of antiplatelet agents and statins were evaluated during the follow‐up periods and adjusted in multivariate analyses (Data S1).
Image Acquisition and Analysis
CCTA was performed using a 64‐slice multidetector‐row computed tomography scanner (Brilliance 64; Philips Medical Systems). A standard scanning protocol was used, as described previously.18 Detailed methods for image acquisition are described in Data S1.
Two experienced radiologists who were blinded to the clinical information analyzed all scanned images independently and provided a consensus interpretation of each final CCTA diagnosis. CACS was acquired simultaneously during CCTA examination. We adopted 4 CACS categories (0–100, 101–400, 401–1000, and >1000) with prognostic values that were validated in an elderly population in a previous study.4 The diameter of stenosis of each coronary artery segment was defined as the proportion that was enhanced by the contrast dye, which was semiautomatically traced at the site of maximal stenosis and compared with the mean value of proximal and distal reference sites, as shown in our previous study.19 Plaques were categorized as calcified, mixed, or noncalcified according to the extent of calcification (Data S1).
We applied several methods to categorize coronary artery findings in CCTA. First, the severity of CAD was categorized according to the highest value of stenosis of the diameter among segments (normal, 0% stenosis; nonobstructive CAD, 1–49% stenosis; obstructive CAD, ≥50% stenosis).9 Within the category of obstructive CAD, we further divided CCTA findings as 1‐, 2‐, or 3‐vessel disease/left main (Data S1).
We used 3 coronary artery plaque scoring systems—a segment involvement score (SIS), a segment stenosis score (SSS), and a modified Duke CAD index—to categorize the CCTA findings in detail, as described in previous studies.9 In addition to per‐score–based analyses, we applied categories for each scoring system as follows, according to its distribution: 0, 1 to 4, or ≥5 for SIS and SSS and 1, 2, or ≥3 for modified Duke score.
Clinical Outcomes
We gathered clinical outcome data by reviewing medical records at the end of the follow‐up period, in June 2018. As the primary end point, a MACE was defined as a composite outcome of cardiac death and nonfatal myocardial infarction (Data S1). Coronary revascularizations were performed at the cardiologists’ discretion. Revascularizations for reasons other than myocardial infarction were regarded as censored because this could affect future outcomes significantly.
Statistical Analyses
One‐way ANOVA was used to compare continuous variables, and the χ2 test was used to compare categorical variables. To construct event‐free survival curves, we used Kaplan–Meier analysis and log‐rank tests. Univariable or multivariable Cox proportional hazards regression analyses were used to calculate the hazards for the association of the various measures of CCTA findings with MACE outcomes. Cardiovascular risk factors (FRS and ASCVD risk scores), CACS, and medication changes (statins and antiplatelet agents) were adjusted for in the multivariable Cox proportional hazards regression analysis. However, because the FRS and ASCVD risk score have not been validated in adults aged >74 and >79 years, respectively, we also applied individual risk factors (age, sex, systolic blood pressure, antihypertensive drug usage, current smoking status, DM, HDL [high‐density lipoprotein] cholesterol level, and total cholesterol level) that were used in a previous study of an elderly population.20
To test the discriminative ability for the prognosis of various measures of CCTA findings in addition to cardiovascular risk factors and CACS, we calculated C statistics, the categorical net reclassification index (cNRI), and the category‐free net reclassification index (cfNRI) (Data S1). In each analysis, P<0.05 was considered statistically significant. Statistical analyses were performed using Stata software (v13; StataCorphttps://www.stata.com) and R v3.4.2 (R Foundation for Statistical Computinghttps://www.r-project.org).
Results
Baseline Characteristics
The baseline characteristics of the study participants are shown in Table 1. Among the 470 participants, the mean age was 75.1±7.3 years, and 242 (51.5%) were male. The mean 10‐year FRS and 10‐year ASCVD risk score were 33.4±20.4% and 32.3±20.5%, respectively. During the total follow‐up period, antiplatelet agents and statins were used by 28.1% and 12.8% of participants, respectively (Table S1). Individuals in the obstructive CAD group had a higher FRS and ASCVD risk score compared with those in the normal and nonobstructive groups.
Table 1.
Baseline Characteristics of Asymptomatic Older Adults According to CAD Severity as Measured by CCTA
| Total (n=470) | Normal (n=170) | Nonobstructive CAD (n=224) | Obstructive CAD (n=76) | P Value | |
|---|---|---|---|---|---|
| Age, y | 75.1±7.3 | 72.7±5.4 | 75.7±7.4 | 78.8±8.8 | <0.001 |
| Men | 242 (51.5) | 65 (38.2) | 129 (57.6) | 48 (63.2) | <0.001 |
| Body mass index, kg/m2 | 24.2±3.2 | 24.2±3.1 | 24.2±3.2 | 24.4±3.5 | 0.912 |
| Systolic blood pressure, mm Hg | 133.3±17.7 | 130.7±18.5 | 134.3±17.1 | 135.8±17.6 | 0.055 |
| Diastolic blood pressure, mm Hg | 83.7±10.7 | 82.4±11.6 | 84.3±9.6 | 84.5±11.3 | 0.168 |
| Fasting blood glucose, mg/dL | 112.3±27.0 | 108.6±24.4 | 112.8±26.0 | 118.7±33.6 | 0.023 |
| HbA1c, % | 6.1±0.9 | 6.0±0.8 | 6.1±0.9 | 6.2±1.0 | 0.057 |
| Total cholesterol, mg/dL | 203.6±37.3 | 204.7±38.5 | 204.9±37.5 | 197.1±34.2 | 0.262 |
| Triglyceride, mg/dL | 141.3±92.6 | 141.5±100.8 | 146.2±94.5 | 126.3±62.2 | 0.270 |
| HDL‐C, mg/dL | 45.7±12.6 | 47.5±13.0 | 44.9±11.5 | 43.8±12.7 | 0.045 |
| LDL‐C, mg/dL | 129.6±34.5 | 128.9±35.8 | 130.7±34.9 | 128.1±30.8 | 0.796 |
| Serum creatinine, mg/dL | 1.09±0.20 | 1.05±0.22 | 1.11±0.19 | 1.11±0.19 | 0.016 |
| MDRD eGFR, mL/min/1.73 m2 | 59.6±10.7 | 60.2±11.5 | 59.1±9.8 | 59.6±11.7 | 0.622 |
| DM | 133 (28.3) | 36 (21.2) | 64 (28.6) | 33 (43.4) | 0.002 |
| Antidiabetic medication | 82 (17.4) | 20 (11.8) | 42 (18.8) | 20 (26.3) | 0.016 |
| Hypertension | 317 (67.4) | 105 (61.8) | 152 (68.2) | 60 (78.9) | 0.028 |
| Antihypertensive medication | 187 (39.8) | 51 (30) | 98 (43.8) | 38 (50) | 0.003 |
| Dyslipidemia (ATP III)a | 354 (75.3) | 111 (65.3) | 179 (79.9) | 64 (84.2) | 0.001 |
| Antiplatelet agent usage | 87 (18.5) | 23 (13.5) | 43 (19.2) | 21 (27.6) | 0.029 |
| Lipid‐lowering medication | 37 (7.9) | 13 (7.6) | 14 (6.3) | 10 (13.2) | 0.153 |
| Current or past smoker | 199 (42.3) | 57 (33.5) | 103 (46.0) | 39 (51.3) | 0.010 |
| Family history of CAD | 38 (8.1) | 13 (7.6) | 18 (8.0) | 7 (9.2) | 0.917 |
| 10‐year FRS, % | 33.4±20.4 | 25.3±16.6 | 36.1±20.6 | 43.6±21.0 | <0.001 |
| 10‐year ASCVD risk, % | 32.3±20.5 | 23.7±15.0 | 34.4±20.4 | 45.6±23.0 | <0.001 |
| CACS, median (IQR) | 17.6 (0.0–126.5) | 0.0 (0.0–0.0) | 60.2 (18.7–136.3) | 477.4 (92.5–903.1) | <0.001 |
Continuous values are mean±SD, and categorical values are numbers and percentages (%), except as noted. ASCVD indicates atherosclerotic cardiovascular disease; ATP III, Adult Treatment Panel III; CACS, coronary artery calcium score; CAD, coronary artery disease; CCTA, coronary computed tomography angiography; DM, diabetes mellitus; eGFR, estimated glomerular filtration rate; FRS, Framingham risk score; HDL‐C, high‐density lipoprotein cholesterol; IQR, interquartile range; LDL, low‐density lipoprotein cholesterol; MDRD, Modification of Diet in Renal Disease.
Dyslipidemia (ATP III) refers to dyslipidemia defined using individualized LDL‐C levels according to the ATP III guideline.
CCTA Findings in All Participants
Detailed information regarding CCTA findings among the study population is provided in Table 2. Nonobstructive CAD was observed in 47.7% of participants, and 16.2% had obstructive CAD as assessed by CCTA. Among the latter group, 4.5% of participants had obstructive lesions in 3‐vessel disease/left main, and 63.8% had any kind of plaque: calcified plaques in 38.5%, mixed plaques in 32.4%, and noncalcified plaques in 9.1% of participants (one person can have multiple plaque sites). In the CACS evaluation, 28.9% of participants had a CACS >100 and 12.1% had a CACS >400. The proportion of participants with a CACS >400 was significantly higher in the obstructive CAD group compared with the normal group (Table S2).
Table 2.
Results of CCTA Findings in Asymptomatic Older Adults
| CCTA Finding | Participants, n (%) |
|---|---|
| Severity of CAD | |
| Normal | 170 (36.2) |
| Nonobstructive CAD | 224 (47.7) |
| Obstructive CAD | 76 (16.2) |
| Number of diseased vessels | |
| 1‐VD | 45 (9.6) |
| 2‐VD | 10 (2.1) |
| 3‐VD/LM | 21 (4.5) |
| Segment involvement score | |
| 0 | 289 (61.5) |
| 1–4 | 151 (32.1) |
| ≥5 | 30 (6.4) |
| Segment stenosis score | |
| 0 | 289 (61.5) |
| 1 to 4 | 131 (27.9) |
| ≥5 | 50 (10.6) |
| Modified Duke score | |
| 1 | 338 (71.9) |
| 2 | 75 (16.0) |
| ≥3 | 57 (12.1) |
| Plaquesa | |
| None | 170 (36.2) |
| Noncalcified | 43 (9.1) |
| Mixed | 152 (32.4) |
| Calcified | 181 (38.5) |
| CACS categories | |
| 0–100 | 334 (71.1) |
| 101–400 | 79 (16.8) |
| 401–1000 | 38 (8.1) |
| >1000 | 19 (4.0) |
CACS indicates coronary artery calcium score; CAD, coronary artery disease; CCTA, coronary computed tomography angiography; LM, left main; VD, vessel disease.
Multiple plaque sites are possible in participants.
Clinical Outcomes and Survival
During the 8.2‐year median follow‐up period (interquartile range: 7.7–10.1 years), MACE occurred in 24 participants (5.1%). Cardiac death and nonfatal myocardial infarction rates increased significantly according to the severity of CAD findings (Table 3). Noncardiac death occurred in 88 participants (18.7%). The detailed causes of death are shown in Table S3. The Kaplan–Meier curve based on the severity of CAD showed that the 8‐year event‐free survival rates were 98.1±1.1%, 94.9±1.6%, and 81.7±4.8% in the normal, nonobstructive, and obstructive groups, respectively, with a significant difference observed between the normal/nonobstructive and the obstructive groups (P<0.001; Figure A). Among the individuals with obstructive CAD, the event‐free survival rates decreased in proportion to the number of diseased vessels (Figure B).
Table 3.
Cardiac Outcomes According to the Severity of CAD on CCTA During Median Follow‐up of 8.2 Years (IQR: 7.7–10.1 Years)
| Total (n=470) | Normal (n=170) | Nonobstructive CAD (n=224) | Obstructive CAD (n=76) | P Value | |
|---|---|---|---|---|---|
| Death | 104 (22.1) | 26 (15.3) | 52 (23.2) | 26 (34.2) | 0.004 |
| Cardiac | 16 (3.4) | 3 (1.8) | 5 (2.2) | 8 (10.5) | 0.001 |
| Noncardiac | 88 (18.7) | 23 (13.5) | 47 (21.0) | 18 (23.7) | 0.082 |
| Nonfatal MI | 8 (1.7) | 0 (0.0) | 4 (1.8) | 4 (5.3) | 0.011 |
| MACE (cardiac death or nonfatal MI) | 24 (5.1) | 3 (1.8) | 9 (4.0) | 12 (15.8) | <0.001 |
Values are number (percentage). CAD indicates coronary artery disease; CCTA, coronary computed tomography angiography; IQR, interquartile range; MACE, major adverse cardiac event; MI, myocardial infarction.
Figure 1.
Kaplan–Meier curves for cardiac event‐free survival based on coronary computed tomographic angiography (CCTA) findings among asymptomatic older adults. Event‐free survival curves according to (A) the severity of coronary artery disease (CAD), (B) the number of diseased vessels, (C) segment involvement score (SIS), (D) segment stenosis score (SSS), and (E) modified Duke score. LM, left main; VD, vessel disease.
When using coronary artery plaque score systems such as SIS, SSS, and modified Duke score, participants in higher score categories showed progressively poorer prognosis than did those in a lower score category (log‐rank P<0.001 for all; Figure E).
Cox Regression Models of Cardiovascular Risk Factors, CACS, and CCTA Findings
In unadjusted Cox regression analyses, CACS, FRS, ASCVD risk score, and individual risk factors were significantly associated with MACE (Table S4). In turn, after adjustment for the FRS, ASCVD risk score, or individual risk factors, a high CACS still showed a significant association with MACE. Next, to evaluate the prognostic value of various measures from CCTA findings, we performed multivariate analyses adjusted according to CACS and the FRS, ASCVD risk score, or individual risk factors (Table 4). In the multivariate analyses, obstructive CAD findings were significantly associated with MACE in the model adjusted for FRS and CACS, in the model adjusted for ASCVD risk score and CACS, and in the model adjusted for individual risk factors and CACS (hazard ratio: 5.65 [95% CI, 1.22–26.16; P=0.027], 5.68 [95% CI, 1.24–25.98; P=0.025], and 5.15 [95% CI, 1.08–24.64; P=0.040], respectively). Conversely, nonobstructive CAD lesions were not associated with MACE in all 3 models. Among the participants in the obstructive CAD group, the number of involved vessels was independently associated with MACE in all 3 adjusted models, whereas hazard ratios increased with the increasing number of diseased vessels. Individual higher categories of SIS, SSS, and modified Duke scores were also associated with MACE proportionately (Table 4).
Table 4.
Cox Regression Analyses of CCTA Findings for MACE, Adjusted by CACS and Conventional Cardiovascular Risk Factors
| Univariable | Multivariable | |||||||
|---|---|---|---|---|---|---|---|---|
| FRSa +CACSb | ASCVDa+CACSb | IRFa+CACSb | ||||||
| HR (95% CI) | P Value | HR (95% CI) | P Value | HR (95% CI) | P Value | HR (95% CI) | P Value | |
| Severity of CADc | ||||||||
| Nonobstructive | 2.39 (0.65–8.83) | 0.191 | 1.53 (0.37–6.30) | 0.555 | 1.47 (0.36–6.07) | 0.596 | 1.36 (0.32–5.74) | 0.675 |
| Obstructive | 11.21 (3.16–39.76) | <0.001 | 5.65 (1.22–26.16) | 0.027 | 5.68 (1.24–25.98) | 0.025 | 5.15 (1.08–24.64) | 0.040 |
| Number of diseased vesselsc | ||||||||
| Nonobstructive | 2.39 (0.65–8.83) | 0.191 | 1.55 (0.38–6.35) | 0.543 | 1.51 (0.37–6.22) | 0.569 | 1.37 (0.33–5.77) | 0.665 |
| 1‐ or 2‐VD | 8.83 (2.28–34.17) | 0.001 | 5.05 (1.06–23.98) | 0.042 | 5.34 (1.15–24.82) | 0.033 | 4.68 (0.96–22.93) | 0.057 |
| 3‐VD/LM | 18.03 (4.30–75.53) | 0.001 | 12.18 (1.77–83.57) | 0.011 | 10.59 (1.47–76.19) | 0.019 | 9.17 (1.20–70.32) | 0.033 |
| SIS (category)c | ||||||||
| 1–4 | 6.37 (2.31–17.52) | <0.001 | 4.32 (1.37–13.64) | 0.013 | 4.50 (1.46–13.87) | 0.009 | 4.38 (1.37–14.07) | 0.013 |
| ≥5 | 9.96 (2.67–37.10) | 0.001 | 5.72 (1.00–32.65) | 0.050 | 6.49 (1.15–36.65) | 0.034 | 5.68 (0.93–34.61) | 0.059 |
| SSS (category)c | ||||||||
| 1–4 | 5.36 (1.86–15.43) | 0.002 | 4.12 (1.29–13.21) | 0.017 | 4.27 (1.36–13.39) | 0.013 | 4.23 (1.30–13.74) | 0.016 |
| ≥5 | 11.34 (3.71–34.69) | <0.001 | 7.86 (1.52–40.54) | 0.014 | 8.57 (1.68–43.74) | 0.010 | 7.97 (1.43–44.46) | 0.018 |
| Modified Duke score (category)c | ||||||||
| 2 | 6.65 (2.48–17.86) | <0.001 | 5.10 (1.62–16.06) | 0.005 | 5.22 (1.72–15.82) | 0.003 | 5.38 (1.67–17.30) | 0.005 |
| ≥3 | 8.45 (3.06–23.33) | <0.001 | 6.01 (1.61–22.45) | 0.008 | 6.07 (1.62–22.69) | 0.007 | 6.06 (1.50–24.50) | 0.011 |
ASCVD indicates atherosclerotic cardiovascular disease risk score; CACS, coronary artery calcium score; CAD, coronary artery disease; CCTA, coronary computed tomography angiography; FRS, Framingham risk score; HR, hazard ratio; IRF, individual risk factors; LM, left main; MACE, major adverse cardiac events; SIS, segment involvement score; SSS, segment stenosis score; VD, vessel disease.
All multivariable analyses were adjusted for conventional risk factors, CACS, and medication change (antiplatelet agents, statins) during the follow‐up period. As conventional risk factors, FRS, ASCVD risk score, and IRFs were used individually. The FRS and ASCVD risk score were adjusted as continuous variables. For IRFs, variables included in the FRS and ASCVD risk score (age, sex, systolic blood pressure, antihypertensive medication use, current smoking, diabetes mellitus, HDL [high‐density lipoprotein] cholesterol level, and total cholesterol level) were used.
CACS was adjusted as a categorical variable: 0 to 100, 101 to 400, 401–1000, >1000.
Reference categories are 0% stenosis for the severity of CAD, 0‐VD for the number of diseased vessels, 0 for SIS (category) and SSS (category), and 1 for the modified Duke score (category), respectively.
In addition, we performed Cox regression analyses of plaque characteristics among CCTA findings (Table S5). When adjusting for conventional risk factors and medication changes (statins and antiplatelet agents), noncalcified plaques showed a significant association with MACE (hazard ratio: 2.46; 95% CI, 1.02–5.96; P=0.046); however, these associations disappeared when additionally adjusting for CACS or the severity of CAD.
Prognostic Value of CCTA Findings
To evaluate the additional prognostic value of CCTA findings over CACS and other conventional cardiovascular risk factors, we used C statistics, cNRI, and cfNRI (Table 5). The C index was 0.698 in the model including the FRS and CACS, 0.733 in the model including ASCVD risk score and CACS, and 0.738 in the model including individual risk factors and CACS. When the severity of CAD among the CCTA findings was added to all 3 models, C indexes increased to 0.749 in the model including the FRS and CACS, 0.774 in the model including ASCVD risk score and CACS, and 0.785 in the model including individual risk factors and CACS. The respective cfNRI values were also significant for these models: 0.478 (95% CI, 0.070–0.886; P=0.022), 0.752 (95% CI, 0.347–1.156; P<0.001), and 0.495 (95% CI, 0.089–0.901; P=0.017). Moreover, the respective cNRI values were significant for these 3 models: 0.259 (95% CI, 0.032–0.486; P=0.026), 0.319 (95% CI, 0.124–0.514; P=0.001), and 0.303 (95% CI, 0.067–0.538; P=0.012). Event cNRI and nonevent cNRI were both positive in all 3 models (Table 5 and Table S6). Additional predictability was also obtained in the models that were further adjusted for the number of diseased vessels, SIS, SSS, or modified Duke score (Table 5). Analyses using other CACS categories are shown in Table S7 (CACS categories: 0–10, 11–100, 101–400, and >400) and Table S8 (CACS categories: 0, 1–100, 101–400, and >400). Similar results were found with these different CACS categories.
Table 5.
Additive Prognostic Value of CCTA Over Conventional Risk Factors and CACS Using C‐Index, cfNRI, and cNRI
| C Index (95% CI) | cfNRI (95% CI) | P Valuea | cNRI (95% CI) | P Valueb | Event cNRI | Nonevent cNRI | |
|---|---|---|---|---|---|---|---|
| FRS | |||||||
| FRS | 0.665 (0.554–0.775) | … | … | … | … | … | … |
| FRS+CACSc | 0.698 (0.576–0.819) | 0.620 (0.217–1.023) | 0.003 | 0.385 (0.089–0.682) | 0.011 | 0.125 | 0.260 |
| FRS+CACS+severity of CADe | 0.749 (0.633–0.865) | 0.478 (0.070–0.886) | 0.022 | 0.259 (0.032–0.486) | 0.026 | 0.167 | 0.092 |
| FRS+CACS+number of diseased vesselse | 0.753 (0.636–0.870) | 0.552 (0.149–0.956) | 0.007 | 0.320 (0.085–0.556) | 0.008 | 0.208 | 0.112 |
| FRS+CACS+SIS (category)e | 0.748 (0.634–0.861) | 0.631 (0.234–1.028) | 0.002 | 0.253 (0.033–0.473) | 0.024 | 0.125 | 0.128 |
| FRS+CACS+SSS (category)e | 0.748 (0.634–0.862) | 0.636 (0.239–1.032) | 0.002 | 0.262 (0.042–0.482) | 0.020 | 0.125 | 0.137 |
| FRS+CACS+modified Duke score (category)e | 0.758 (0.648–0.867) | 0.723 (0.321–1.125) | <0.001 | 0.272 (0.035–0.508) | 0.025 | 0.083 | 0.188 |
| ASCVD | |||||||
| ASCVD | 0.699 (0.593–0.805) | … | … | … | … | … | … |
| ASCVD+CACSd | 0.733 (0.621–0.844) | 0.629 (0.226–1.032) | 0.002 | 0.295 (0.037–0.552) | 0.025 | 0.167 | 0.128 |
| ASCVD+CACS+severity of CADe | 0.774 (0.672–0.875) | 0.752 (0.347–1.156) | <0.001 | 0.319 (0.124–0.514) | 0.001 | 0.167 | 0.152 |
| ASCVD+CACS+number of diseased vesselse | 0.778 (0.676–0.881) | 0.554 (0.147–0.961) | 0.008 | 0.278 (0.062–0.494) | 0.012 | 0.125 | 0.152 |
| ASCVD+CACS+SIS (category)e | 0.782 (0.692–0.873) | 0.636 (0.239–1.032) | 0.002 | 0.269 (0.004–0.533) | 0.046 | 0.208 | 0.061 |
| ASCVD+CACS+SSS (category)e | 0.787 (0.697–0.878) | 0.766 (0.393–1.140) | <0.001 | 0.236 (−0.045 to 0.518) | 0.100 | 0.167 | 0.070 |
| ASCVD+CACS+modified Duke score (category)e | 0.795 (0.708–0.882) | 0.727 (0.325–1.129) | <0.001 | 0.199 (−0.078 to 0.475) | 0.159 | 0.042 | 0.157 |
| IRFs from FRS and ASCVD | |||||||
| IRFs | 0.696 (0.585–0.806) | … | … | … | … | … | … |
| IRFs+CACSf | 0.738 (0.631–0.846) | 0.611 (0.208–1.014) | 0.003 | 0.303 (0.039–0.566) | 0.025 | 0.208 | 0.094 |
| IRFs+CACS+severity of CADe | 0.785 (0.685–0.886) | 0.495 (0.089–0.901) | 0.017 | 0.303 (0.067–0.538) | 0.012 | 0.208 | 0.094 |
| IRFs+CACS+number of diseased vesselse | 0.786 (0.681–0.890) | 0.590 (0.183–0.997) | 0.005 | 0.274 (0.020–0.528) | 0.034 | 0.167 | 0.108 |
| IRFs+CACS+SIS (category)e | 0.779 (0.685–0.873) | 0.631 (0.234–1.028) | 0.002 | 0.228 (0.010–0.446) | 0.040 | 0.125 | 0.103 |
| IRFs+CACS+SSS (category)e | 0.785 (0.692–0.878) | 0.465 (0.057–0.872) | 0.026 | 0.235 (0.016–0.453) | 0.035 | 0.125 | 0.110 |
| IRFs+CACS+modified Duke score (category)e | 0.796 (0.707–0.885) | 0.678 (0.275–1.080) | 0.001 | 0.352 (0.114–0.589) | 0.004 | 0.208 | 0.143 |
ASCVD indicates atherosclerotic cardiovascular disease risk score; CACS, coronary artery calcium score; CAD, coronary artery disease; CCTA, coronary computed tomography angiography; cNRI, categorical net reclassification index; cfNRI, category‐free net reclassification index; FRS, Framingham risk score; IRFs, individual risk factors; SIS, segment involvement score; SSS, segment stenosis score.
P values for cfNRI.
P values for cNRI.
FRS was used as a reference.
ASCVD was used as a reference.
The CACS‐added model was used as a reference.
IRFs were used as a reference.
Prognostic Value of CCTA According to Sex and Age Subgroups
Among 242 male and 228 female participants, MACE occurred in 15 men and 9 women. Because no MACE occurred in the CACS 101–400 group of women and in the normal CAD group of men, we adopted slightly modified categories of CACS and CCTA findings (Table S9). As in the total population, CCTA findings in male participants were significantly associated with MACE, and their cfNRI values confirmed the incremental predictive values of CCTA over CACS. In female participants, Cox regression analyses showed insufficient association between CCTA findings and MACE after adjusting for CACS. In addition, for the subgroup analyses with age groups, there were 366 participants aged <80 years and 104 participants aged ≥80 years, and MACE occurred in 14 and 10 participants, respectively. In the subgroup aged <80 years, Cox regression analyses and cfNRI showed an additive predictive value over CACS (Table S10). In contrast, in the subgroup aged ≥80 years, both analyses failed to show additional predictive value.
Discussion
In this population‐based prospective cohort study with a median follow‐up of 8.2 years, information about significant stenosis and presence of atheromatous plaques in coronary arteries obtained from CCTA had long‐term prognostic value for the prediction of MACE in an asymptomatic elderly population and was better than that obtained considering CACS and other conventional cardiovascular risk factors. Although the older adults in this population were asymptomatic, the incidence of obstructive CAD defined as >50% stenosis by CCTA was not negligible (16.2%). Moreover, these participants exhibited a poor 8‐year event‐free survival rate compared with the individuals in the normal and nonobstructive CAD groups, who showed very good 8‐year event‐free survival rates. These findings confirmed the good negative predictiveness for CCTA reported in previous studies.7, 9, 14, 21
To predict cardiac events among asymptomatic people, previous studies used a variety of screening tools such as the FRS, biomarkers, and CACS.3, 22, 23 Among them, CACS proved to have better predictive value than did the FRS in asymptomatic people.3 Moreover, in older adult populations, it is known that conventional risk factors cannot predict cardiovascular events satisfactorily,24, 25 and CACS was shown to have good predictability among asymptomatic older populations.4, 20, 26 However, a CACS simply indicates the burden of calcium deposits in the coronary vessels and is not able to indicate stenosis or reflect plaque burden. In contrast, CCTA has the advantage of providing comprehensive information on the health status of coronary arteries via direct visualization. Of note, among participants with very low CACS in a previous study, the number of participants with noncalcified plaque or stenotic lesions detected by CCTA was not negligible, consistent with our findings.27 Nonetheless, contrary to our expectations, CCTA failed to show an additional predictiveness over CACS among general asymptomatic individuals in a large multicenter registry study.9 In addition, in a randomized controlled study of asymptomatic patients with DM over 4 years, no differences in outcomes were found between those who underwent CCTA as a screening tool and those who did not.10 However, recent studies have demonstrated an additive predictive value of CCTA over the CACS in asymptomatic patients with high‐risk features, such as a high CACS, presence of DM, and multiple risk factors.7, 8, 11, 28 In addition, a recent randomized controlled study showed that the use of CCTA information improved cardiovascular outcomes compared with standard care alone in patients with stable chest pain, and this finding was also shown in the elderly subgroup.29
A recent study that analyzed asymptomatic older adults in CONFIRM (Coronary CT Angiography Evaluation for Clinical Outcomes: An International Multicenter Registry), revealed the prognostic value of detailed information from CCTA over that of the CACS and FRS.14 However, the median follow‐up of that study was only 26 months. Another recent study conducted using CONFIRM revealed longer diagnostic utility of CCTA in an elderly population (mean follow‐up of 5.6 years), but considerable numbers of symptomatic patients (chest pain, 56.7%; dyspnea, 42.4%) were included.30 Both studies had limitations that their primary outcomes were all‐cause mortality, not cardiac death, which can be important in older adults because substantial numbers died from noncardiac causes in this population. In addition, therapeutic information after CCTA was not considered in these studies. Our present study addresses to these limitations.
To the best of our knowledge, this study is the first to assess the long‐term (>8 years) prognostic value of CCTA among an asymptomatic group recruited from a community‐based elderly cohort. Our results provided new information. The incidence of obstructive CAD was not trivial (16.2%), although the participants were asymptomatic. Among those in the low CACS groups, the proportions of participants with obstructive CAD identified from CCTA were not negligible in this study (4.6% in the group with a CACS of 0–10; 7.8% in the group with a CACS of 11–100; Table S2), which suggests that CCTA might be a better screening tool for cardiovascular disease than CACS alone in older populations.
In the sex comparison, there were no significant associations between CCTA findings and MACE in the female group. However, there were increasing tendencies of hazard ratios between abnormal CCTA findings and MACE with positive cfNRI values. This result might have been caused by the relatively few MACE in female participants. In addition, CCTA showed insufficient additive prognostic value over CACS in the subgroup aged ≥80 years in our study. This result might also have arisen from the small number of participants in this subgroup. Future studies with more female participants or people aged ≥80 years are needed to confirm this finding.
In a previous study of asymptomatic older adults conducted using the CONFIRM registry, the prevalence of any CAD in the highest tertile of the aged population was similar to that in our study (67.9% versus 63.6%), despite the participants in our study being older and having worse metabolic profiles (Table S11).14 However, several studies have reported that East Asian people have lower CACSs than those of European ancestry, and this difference is more prominent in the older adult population.31, 32 Our study comprised participants with Korean ethnicity, whereas CONFIRM was conducted mainly with North American and European participants; consequently, there might be ethnic differences in the development of CAD, including CACS.33
It is well known that aging itself contributes to the development of cardiovascular disease.13 In turn, CAD is a major cause of death in older adults, who are frequently asymptomatic. From this point of view, our finding is clinically important because CCTA can be a good screening tool for CAD in elderly populations. There has been concern about radiation exposure from CCTA. However, modern multidetector‐row computed tomography technologies have reduced radiation dosages.34 In addition, the incidence of secondary cancers after radiation exposure at old age is not high, and radiation‐related secondary cancers usually occur >2 decades after exposure.35, 36
This study had several limitations. First, it included only a single Asian ethnic group. Second, the FRS and ASCVD risk score used in this study have not been validated in adults aged >74 and >79 years, respectively. Therefore, we used individual risk factors to avoid this problem. Third, in KLoSHA, participants who underwent CCTA were younger compared with those who did not, and there were greater proportions of men and DM, with higher fasting glucose and HbA1c levels (CCTA group) (Table S12). This might attenuate the generalization of our findings. Last, participants with obstructive CAD were advised to consult doctors for optimal medical therapies, and this might have modified or attenuated our results.
Conclusions
In this community‐based cohort from an asymptomatic elderly Korean population, CCTA proved to have better long‐term prognostic value than did CACS with conventional cardiovascular risk factors. In addition, the highly negative predictability of CCTA was shown in normal groups over >8‐year follow‐up. Additional studies are needed to evaluate whether changes in treatment according to CCTA findings affect cardiovascular outcomes and the type of treatment that would be suitable for an asymptomatic elderly population with abnormal CCTA findings.
Sources of Funding
This research was supported by Seoul National University Bundang Hospital (11‐2008‐029, 04‐2013‐002, 02‐2016‐053).
Disclosures
None.
Supporting information
Data S1. Supplemental Methods and Results.
Table S1. Changes in Medications (Antiplatelet Agents and Statins) During the Follow‐Up Period
Table S2. Population Distribution of Each Coronary Artery Calcium Score Category According to Coronary Artery Disease Severity by Coronary Computed Tomography Angiography
Table S3. Causes of Death
Table S4. Cox Regression Analyses With Coronary Artery Calcium Score, Framingham Risk Score, Atherosclerotic Cardiovascular Disease Risk Score, and Individual Risk Factors for Major Adverse Cardiac Events
Table S5. Cox Regression Analyses of Plaque Features for Major Adverse Cardiac Events
Table S6. Predicted Risk of Major Adverse Cardiac Events Using Multivariate Risk Prediction Model With and Without Coronary Computed Tomography Angiography (Severity of Coronary Artery Disease)
Table S7. Cox Regression Analyses and Category‐Free Net Reclassification Index of Coronary Computed Tomography Angiography Findings, Adjusted by Other Coronary Artery Calcium Score Category (0–10, 11–100, 101–400, >400)
Table S8. Cox Regression Analyses and Category‐Free Net Reclassification Index of Coronary Computed Tomography Angiography Findings, Adjusted by Other Coronary Artery Calcium Score Category (0, 1–100, 101–400, >400)
Table S9. Subgroup Analysis of Cox Regression and Category‐Free Net Reclassification Index, According to Sex
Table S10. Subgroup Analysis of Cox Regression and Category‐Free Net Reclassification Index, According to Age
Table S11. Comparison of CONFIRM (Coronary CT Angiography Evaluation for Clinical Outcomes: An International Multicenter Registry) and KLoSHA (Korean Longitudinal Study on Health and Aging)
Table S12. Baseline Characteristics of Participants With and Without Coronary Computed Tomography Angiography
Acknowledgments
This study used data from KLoSHA (Korean Longitudinal Study on Health and Aging). The authors appreciate the help from the participants and staff of the KLoSHA.
(J Am Heart Assoc. 2019;8:DOI: e013523 DOI: 10.1161/JAHA.119.013523.)
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Associated Data
This section collects any data citations, data availability statements, or supplementary materials included in this article.
Supplementary Materials
Data S1. Supplemental Methods and Results.
Table S1. Changes in Medications (Antiplatelet Agents and Statins) During the Follow‐Up Period
Table S2. Population Distribution of Each Coronary Artery Calcium Score Category According to Coronary Artery Disease Severity by Coronary Computed Tomography Angiography
Table S3. Causes of Death
Table S4. Cox Regression Analyses With Coronary Artery Calcium Score, Framingham Risk Score, Atherosclerotic Cardiovascular Disease Risk Score, and Individual Risk Factors for Major Adverse Cardiac Events
Table S5. Cox Regression Analyses of Plaque Features for Major Adverse Cardiac Events
Table S6. Predicted Risk of Major Adverse Cardiac Events Using Multivariate Risk Prediction Model With and Without Coronary Computed Tomography Angiography (Severity of Coronary Artery Disease)
Table S7. Cox Regression Analyses and Category‐Free Net Reclassification Index of Coronary Computed Tomography Angiography Findings, Adjusted by Other Coronary Artery Calcium Score Category (0–10, 11–100, 101–400, >400)
Table S8. Cox Regression Analyses and Category‐Free Net Reclassification Index of Coronary Computed Tomography Angiography Findings, Adjusted by Other Coronary Artery Calcium Score Category (0, 1–100, 101–400, >400)
Table S9. Subgroup Analysis of Cox Regression and Category‐Free Net Reclassification Index, According to Sex
Table S10. Subgroup Analysis of Cox Regression and Category‐Free Net Reclassification Index, According to Age
Table S11. Comparison of CONFIRM (Coronary CT Angiography Evaluation for Clinical Outcomes: An International Multicenter Registry) and KLoSHA (Korean Longitudinal Study on Health and Aging)
Table S12. Baseline Characteristics of Participants With and Without Coronary Computed Tomography Angiography