Objective To evaluate the prevalence and characteristics of coronary atherosclerosis in asymptomatic subjects classified as low risk by National Cholesterol Education Program (NCEP) guideline using coronary CT angiography (CCTA).
Design An observational study.
Setting A single tertiary referral centre.
Patients 2133 (49.2%) subjects, who were classified as low risk by the NCEP guideline, of 4339 consecutive middle-aged asymptomatic subjects who underwent CCTA with 64-slice scanners as part of a general health evaluation.
Main outcome measures The incidence of atherosclerosis plaques, significant stenosis.
Results In the subjects at low risk, 11.4% (243 of 2133) of subjects had atherosclerosis plaques, 1.3% (28 of 2133) of subjects had significant stenosis, and 0.8% (18 of 2133) of subjects had significant stenosis caused by non-calcified plaque (NCP). Especially, 75.0% (21 of 28) of subjects with significant stenosis and 94.4% (17 of 18) of subjects with significant stenosis caused by NCP were young adults. Mid-term follow-up (29.3±14.9 months) revealed four subjects with cardiac events: three subjects with unstable angina requiring hospital stay and one subject with percutaneous coronary intervention.
Conclusions Although an asymptomatic population classified as low risk by the NCEP guideline has been regarded as a minimal risk group, the prevalence of atherosclerosis plaques and significant stenosis were not negligible. However, considering very low event rate for those patients, CCTA should not be performed in low-risk asymptomatic subjects, although CCTA might have the potential for identification of high-risk groups in the selected subjects regarded as a minimal-risk group by NCEP guideline.
- CORONARY ARTERY DISEASE
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A large proportion of patients with sudden cardiac death or non-fatal myocardial infarction do not experience prior symptoms of chest pain or exertional dyspnoea, emphasising the importance of early detection and treatment of underlying subclinical coronary atherosclerosis.1 The National Cholesterol Education Program (NCEP) Adult Treatment Panel III has been one of the most frequently used cardiovascular prevention algorithms based on traditional risk factors for coronary artery disease (CAD).2
The NCEP guideline allows risk stratification of asymptomatic individuals into low-risk, intermediate-risk, or high-risk categories in determining the next appropriate intervention, based on the Framingham Risk Score (FRS) of 10-year risk for coronary heart disease (CHD) events. It is evident that asymptomatic individuals are frequently judged to be at low risk by the NCEP guideline.3–5 However, it is also known that the NCEP guideline tends to underestimate event risk for those at low risk.3–5
Recently, evidence supporting the use of non-invasive imaging tests to screen for CAD is gradually accumulating. It has been well known that coronary artery calcium score (CACS), a marker of subclinical atherosclerosis, provides incremental prognostic information in addition to the assessment of traditional risk factors.6 ,7 However, CACS does not represent the whole spectrum of atherosclerosis and has a limitation to diagnose obstructive CAD.8
With the advent of multidetector-row CT (MDCT) technology, coronary CT angiography (CCTA) has the potential to provide comprehensive information regarding the location, severity and characteristics of atherosclerotic plaque.9 ,10 However, to the best of our knowledge, there is a paucity of data regarding the prevalence and characteristics of coronary atherosclerosis in asymptomatic individuals classified as low risk by the NCEP guideline using CCTA.
In this study, we aimed to evaluate the prevalence and characteristics of coronary atherosclerosis in asymptomatic individuals classified as low risk by the NCEP guideline using CCTA.
The institutional review board approved the study protocol and did not require informed consent from study patients.
We retrospectively enrolled 4587 consecutive subjects who had undergone CCTA evaluation with 64-slice MDCT scanners for general routine health evaluation in Seoul National University Bundang Hospital from January 2006 and December 2007.
All subjects were asked whether they had chest pain or equivalent symptoms according to a Rose angina questionnaire.11 As a result, we excluded 248 subjects who had chest pain or discomfort before enrolment without a diagnostic workup to rule out history of CHD, invasive coronary angiography or percutaneous coronary intervention (PCI) (n=101), age under 20 or over 80 years old (n=4), insufficient medical records (n=140), or poor image quality (n=3). Therefore, a total of 4339 self-referred middle-aged asymptomatic subjects were finally enrolled.
All subjects were categorised into three different groups according to the NCEP-ACP III guideline2: low-risk (0–1 risk factor), intermediate-risk (more than two risk factors and 10-year risk <=20%), or high-risk group (CHD risk equivalents or 10-year risk >20%). Subjects who were classified as low-risk group were included in the subsequent analysis.
Risk factor assessment and stratification
Medical history of hypertension, stroke, diabetes mellitus (DM), family history of premature CHD (CHD in male first-degree relative age <55 years; CHD in female first-degree relative age <65 years), current medication profile, and cigarette smoking, were systematically acquired. Hypertension was defined as blood pressure >=140/90 mm Hg, or taking any antihyperensive medications. DM was defined as a fasting plasma glucose >=126 mg/dl or self-reported history of diabetes and/or receiving antidiabetic treatment. Total cholesterol, triglyceride, high-density lipoprotein cholesterol, low-density lipoprotein (LDL) cholesterol, fasting plasma glucose, glycated haemoglobin, blood urea nitrogen and serum creatinine levels were measured after at least a 12 h fasting period on the same day of the study. Serum C-reactive protein was measured by latex agglutination with an autoanalyser (Toshiba-200 FR, Tokyo, Japan).
Data acquisition and image analysis
CCTA were performed using 64-slice MDCT scanners (Brilliance 64, Philips Medical Systems, Best, The Netherlands). Prior to CCTA, all patients with a baseline heart rate >70 beats/min received intravenous esmolol 10–30 mg (Jeil Pharm, Seoul, Korea). With the exception of patients with contraindications to nitroglycerine, nitroglycerine 0.6 mg was immediately administered sublingually before contrast injection.12 During CCTA acquisition, a bolus of 80 ml iomeprol (Iomeron 400, Bracco, Milan, Italy) was injected intravenously (4 ml/s) followed by a 50 ml saline ‘chaser.’ Detail of data acquisition has previously been described elsewhere.10
Coronary MDCT scans were analysed independently by two experienced radiologists (SIC 7 years; EJC 5 years), who were unaware of the clinical information using a three-dimensional workstation (Brilliance, Philips Medical Systems). The presence of coronary atherosclerotic plaque was evaluated according to the modified American Heart Association classification.13 The image analysis methods have previously been described in detail.9 ,10 Luminal narrowing of greater than 50% was defined as significant stenosis. The plaques occupied by calcified tissue more than 50% of the plaque area (density >130 HU in native scans) were classified as calcified plaques, those with less than 50% calcium were classified as mixed plaques, and those without any calcium were termed as non-calcified plaques (NCP).14
CACS were measured with the scoring system previously described by Agaston et al.15 ,16 Participants, on the basis of the CACS, were categorised in the following manner: CACS=zero, no; 0<CACS<100.0, mild; 100<CACS<400, moderate; and CACS>400, severe calcification.
Mid-term clinical outcome and secondary diagnostic tests
Follow-up data were obtained from medical records or telephone contact with trained personnel. Subjects were asked for the occurrence of new chest pain, subsequent diagnostic test (ie, single-photon emission CT or coronary angiography (CAG) within 90 days after index CCTA), and subsequent revascularisation therapy (PCI or coronary artery bypass graft surgery) on the basis of index CCTA or cardiac events. Cardiac events were defined as: cardiac death, non-fatal myocardial infarction, unstable angina requiring hospital stay, or revascularisation therapy. Clinical follow-up (29.3±14.9 months (range 3–55 months)) was available in 97.4% of cases. Unstable angina requiring hospital stay was defined according to the European Society of Cardiology guidelines as acute chest pain with or without the presence of ECG abnormalities, and negative cardiac enzyme levels.17
Continuous variables are expressed in means±SD, whereas categorical values are expressed in absolute values and percentages. Differences between continuous variables were analysed by the unpaired Student t test, and those between categorical variables by the χ2 test or Fisher exact test, as appropriate. The subjects with age ≤55 years for male and age ≤65 years for female were regarded as young adults. Multiple logistic regression analysis (forward conditional) was employed to identify independent predictors of the prevalence of plaques, significant stenosis and significant stenosis caused by NCP on CCTA. A p value of <0.05 was considered statistically significant. Microsoft Excel (Microsoft, Redmond, Washington) was used for organisation of data, and SPSS V.17.0 package (SPSS, Chicago, Illinois, USA) was used for statistical analysis.
Clinical characteristics of asymptomatic population classified as low risk by NCEP guideline
From the 4339 asymptomatic individuals, 2133 (49.2%), 1583 (36.5%) and 622 (14.3%) subjects were classified by the NCEP guideline as low-risk, intermediate-risk and high-risk groups, respectively. The clinical characteristics of the low-risk group are summarised in table 1. The age of the subjects in low-risk group was 48.7±8.1 years (mean±SD), and 92.1% (1965 of 2133) of them were young adults. In the subjects in the low-risk group, CACS was 8.1±108.1 (mean±SD): almost all (2109 of 2133, 98.9%) individuals had CACS ≤100; and 0.1% (2 of 2133) of subjects had CACS >400.
Prevalence and characteristics of coronary atherosclerosis in asymptomatic subjects classified as low risk by NCEP
CCTA revealed atherosclerotic plaques in 347 segments in 243 of 2133 (11.4%) subjects (1.4±0.9 segments/subject; range 1–8). The number of segments of calcified plaques, mixed plaques and NCPs were 110 (31.7%), 106 (30.5%) and 131 (37.8%), respectively. Twenty-eight (1.3%) subjects had significant stenosis on CCTA, and 18 (64.3%) of them had significant stenosis caused by NCP (table 2). Most of them had single-vessel disease (23/28, 82.1%), and most of the significant lesions were located in the left anterior descending coronary artery (18/23, 78.3%). The majority of the subjects with significant stenosis (21 of 28, 75.0%) and with significant stenosis caused by NCP (17 of 18, 94.4%) were young adults.
The prevalence of significant stenosis in the subjects with CACS ≤100.0 was 0.8% (18 of 2,133), accounting for 64.3% (18 of 28) of those with significant stenosis. The prevalence of significant stenosis caused by NCP in the subjects with CACS ≤100.0 was 0.7% (15 of 2133), accounting for 83.3% (15 of 18) of those with significant stenosis caused by NCP.
Predictors of coronary atherosclerosis in asymptomatic subjects classified as low risk by NCEP
Table 3 illustrates univariate and multivariate logistic regression analysis for the association between traditional risk factors and presence of plaque, significant stenosis, significant stenosis caused by NCP in asymptomatic subjects classified as low risk by the NECP guideline. In multivariate analysis, age, male gender, hypertension and LDL-cholesterol were independent predictors for presence of the presence of atherosclerosis plaque. Age, male gender and LDL-cholesterol were independent predictors for significant stenosis. Male gender and LDL-cholesterol were independent predictors for significant stenosis caused by NCP (table 3).
Mid-term outcome and secondary test of asymptomatic population according to CTA results
Of 2133 asymptomatic subjects classified the by NCEP guideline as low risk, four (0.2%) subjects had cardiac events: no cardiac death, three subjects with unstable angina requiring hospital stay and one subject with PCI. All four subjects had plaques, and three of them had stenosis caused by NCP.
The main findings of the present study are the following: (1) a significant percentage (11.4%) of the asymptomatic subjects classified as low risk by the NCEP guideline had atherosclerosis plaques, 1.3% had significant stenosis and 0.8% had significant stenosis caused by NCP; (2) among the subjects in the low-risk group, 75.0% of subjects with significant stenosis and 94.4% of subjects with significant stenosis caused by NCP were young adults; (3) 64.3% of subjects with significant stenosis and 83.3% of subjects with significant stenosis caused by NCP had lower CACS (ie, less than 100).
From our study, the prevalence of subclinical atherosclerosis in the subjects classified as low risk by the NCEP guideline was not negligible. Especially, the prevalence of atherosclerosis plaques and significant stenosis was more prominent in young adults. These results corroborate with the previous studies demonstrating that the NCEP guideline has limited predictive power for the development of cardiovascular events for asymptomatic subjects classified as low risk, especially in young adults.3–5
CACS is known to provide incremental prognostic information over traditional risk stratification, such as the NCEP guideline, and has recently been proposed as an index parameter of routine screening.10 ,18 The Screening for Heart Attack Prevention and Education guidelines recommend screening of all asymptomatic men 45–75 years of age and asymptomatic women 55–75 years of age. However, the use of CACS for asymptomatic subjects with low risk remains controversial.19 Some prognostic studies addressing CACS in relation to the NCEP guideline observed that CACS had no additive value in subjects classified as low risk by the NCEP guideline.20 On the other hand, Lakoski et al suggested that perhaps CACS may identify higher risk in certain subsets of asymptomatic subjects at low risk by the NCEP guideline.3–5 However, this study focused only on women younger than 70 years of age. Note that CACS intrinsically has limitation for the detection of obstructive CAD and NCPs.8 ,21 ,22 In our study, we found that CCTA could detect a substantial percentage of subjects with significant stenosis (64.3%), especially subjects with significant stenosis caused by NCP (83.4%), which might be misclassified by CACS.
To our knowledge, our study is the first to report on the experience with CCTA in a large number of asymptomatic subjects classified as low risk by NCEP. Our study showed that age, gender, hypertension and LDL-C are associated with the presence of plaque, significant stenosis or significant stenosis caused by NCP. Interestingly, although smoking has been reported to have an association with subclinical atherosclerosis in young age as our study population, no association was found in our study. This result might be due to the fact that we only considered current smoking status as a predictive factor, rather than taking total pack-year, smoking duration, or smoking dose, into account.
Currently, CCTA is not justified as a screening tool for CAD in asymptomatic populations.23 Cost effectiveness with regard to radiation hazard, use of contrast media and downstream testing is still questionable. However, we suggest that selective use of CCTA might be helpful for those individuals classified as low risk by NCEP, although they are only few percentages of individuals. Furthermore, with the advent of MDCT technology, the radiation dose for CCTA could be minimised to the level of less than 1 mSv in the era of wide-detector MDCT.24
Assessing cardiovascular risk can be used to the target-preventive treatment of asymptomatic subjects at high risk for developing CAD. Therefore, we suggest that CCTA could help identify asymptomatic subjects with subclinical coronary atherosclerosis who might benefit from intensified risk factor modification to prevent or retard the onset of clinical disease. CCTA is not justified as a screening tool for CAD in asymptomatic populations due to concern regarding radiation exposure. However, with the advent of MDCT technology, the radiation dose for CCTA has been minimised to less than 1 mSv. As such, the practical use of CCTA can be extended beyond symptomatic patients to asymptomatic adults.25
Our study has limitations. First, all subjects in our study were self-referred, suggesting that selection bias might intervene. Second, the study population was drawn from the same ethnic background and geographical region.
In conclusion, although an asymptomatic population classified as low risk by the NCEP guideline has been regarded as a minimal risk group, prevalence of atherosclerosis plaques and significant stenosis were not negligible. However, considering very low event rate for those patients, CCTA should not be performed in low-risk asymptomatic subjects, although CCTA might have the potential for identification of high-risk groups in the selected subjects regarded as a minimal risk group by NCEP guideline.
Contributors SIC had full access to all the data in the study, and takes responsibility for the integrity of the data and the accuracy of the data analysis. Study concept and design: KJK and SIC. Analysis and interpretation of data: KJK, SIC, MSL, JAK, EJC and CHJ. Drafting of the manuscript: KJK and SIC. Critical revision of the manuscript for important intellectual content: KJK, SIC, MSL, JAK, EJC and CHJ. Study supervision: SIC.
Funding This work was supported by Mid-career Researcher Program through National Research Foundation of Korea funded by the MEST (No. 2012-0005395) and by a National Research Foundation of Korea (NRF) grant funded by the Korea Government (MEST) (No. 2011-0023624).
Competing interests None.
Ethics approval Seoul National University Bundang Hospital, Korea.
Provenance and peer review Not commissioned; externally peer reviewed.