Retrospective analysis was performed with data from three different CCTA registries that have been launched to assess clinical utility of CCTA involving three cardiac centers in Korea (Seoul National University Hospital, Seoul; Seoul National University Bundang Hospital, Seongnam; and Boramae Medical Center, Seoul). Between November 2004 and November 2010, all study patients underwent CCTA because they were suspected of having CAD. Patients who had at least one of following criteria were excluded: 1) previous myocardial infarction (MI) and/or coronary revascularization, 2) inadequate image quality, and 3) insufficient clinical information for the study analysis. After exclusion, a total of 1,857 patients remained. Among them, 454 (24.4%), 171 (9.2%), and 1,232 (66.3%) had no (0% stenosis), non-obstructive (1%-49% stenosis) and obstructive (≥ 50% stenosis) CAD, respectively. In this study, a total of 625 with no or nonobstructive CAD by CCTA was analyzed. Information on baseline clinical characteristics, including cardiovascular risk factors and type of symptoms, was obtained by reviewing patients' medical records. Hypertension was defined as documented history of high blood pressure or use of anti-hypertensive medications. Diabetes mellitus was defined by diagnosis of Diabetes mellitus made previously by a physician or use oral hypoglycemic agents or insulin. Dyslipidemia was defined as known but untreated dyslipidemia or current treatment with lipid lowering agents (4). The pretest probability of CAD was determined by age, sex and the nature of chest pain during initial presentation (7). The pretest probabilities were classified as low (<10%), intermediate (10%-90%) and high (>90%). Chest pain was classified as typical, atypical and non-cardiac. Typical chest pain was defined as chest pain that was 1) substernal, 2) provoked by exertion or emotional stress, and 3) relieved by rest and/or nitroglycerin. Chest pain was classified as atypical if two of these features were present, and non-cardiac if one or none of these features were present (8). Renal function was estimated by estimated creatinine clearance (eCCr), which was calculated using the Cockcroft-Gault equation: eCCr (mL/min/1.73 m²)=(140-age)×weight (kg)/serum creatinine (mg/dL)/72×(0.85 for females)×1.73 m²/body surface area (BSA), and BSA calculated as follows: BSA = weight (kg)^0.425 ×height (cm)0.725×0.007184 (9).

All CCTAs were obtained using 16-slice (18.4%) or 64-slice (81.6%) CT scanners (Somatom Definition; Siemens Medical Solutions, Forchheim, Germany and Brilliance 64; Philips, Best, the Netherlands). Details of CT scan protocol have been described in previous studies (1011). Before CCTA, all patients with an average heart rate of >65 beats/min received oral metoprolol 50-100 mg in the absence of contraindications, and were given sublingual nitroglycerin 0.2-0.6 mg immediately before scanning. During image acquisition, 60-80 mL of contrast was injected, followed by a saline flush. Helical scan data was obtained using the retrospective ECG-gating protocol. Image acquisition was prescribed to include the coronary arteries, left ventricle and proximal ascending aorta. All CCTA results were transferred to an external three dimensional workstation, and analyzed independently by two experienced radiologists. Coronary atherosclerotic lesions were classified by severity of luminal stenosis, graded as no CAD (0% luminal stenosis) and non-obstructive CAD (1%-49% stenosis) and obstructive CAD (≥50% stenosis). Patient-based analysis was performed.

The primary clinical endpoint was time to composite events consisting of cardiac death, non-fatal MI, unstable angina and late (≥90 days after CCTA) revascularization. Secondary clinical endpoint was time to composite of hard cardiac events consisting of cardiac death and non-fatal MI. Patients with stable clinical features undergoing an early elective revascularization within 90 days after CCTA were excluded from survival analysis (1213). Patient follow-up data were gathered by two observers blinded to the results of CCTA using hospital records or standardized telephone interviews for patients with a follow-up loss of more than recent six months. If a patient could not be reached even by a phone, information on death was obtained from the Korean Ministry of Public Administration and Security. Cause of death was identified. Cardiac death was defined as death in the setting of MI, ventricular arrhythmia, decompensated heart failure or cardiogenic shock. Sudden unexplained death was also considered as cardiac death. Noncardiac death was death not related to cardiac disease. MI was defined based on the following criteria: typical chest pain, elevated cardiac enzyme levels, and typical changes in electrocardiogram (ECG) (14). Unstable angina was defined as acute chest pain regardless of the presence of ECG abnormalities, and negative cardiac enzyme levels (14). The first event was considered as the event of the patient. When two or more events were recorded at the same day, the most serious event was considered as the event of the patient in the following order: cardiac death, non-fatal MI, unstable angina and revascularization.

Categorical variables are presented as frequencies with percentages and continuous variables are presented as mean±standard deviation. Categorical variables are evaluated using the chi-square test and continuous variables are evaluated using a Student's t-test. Cox proportional hazards analysis was used to assess predictors of clinical events. Age, sex, body mass index (BMI), smoking status, diabetes mellitus and hypertension considered as confounders should be adjusted. The event rates according to the eCCr, categorized as ≥90 mL/min/1.73 m², 60-89 mL/min/1.73 m² and <60 mL/min/1.73 m², was estimated by the chi-square test of linear by linear association. To assess the cut-off value of eCCr as a predictor of events, receiver operating characteristic (ROC) curve analysis was used. Cumulative event free survival was assessed using the Kaplan-Meier method and compared using the log-rank test. A two tailed P value of <0.05 was considered statistically significant. All data were analyzed using SPSS for Windows 18.0 (IBM Co., Armonk, NY, USA).

The study protocol was approved by the institutional review board (IRB) of each hospital (IRB No. at Boramae Medical Center: 06-2011-222). Informed consent was exempted by the IRB due to anonymous information collection and retrospective study design.

Baseline clinical characteristics of study subjects are shown in Table 1. Their mean age was 62.5±10.3 yr (range, 25 to 85 yr) and 52.5% of the patients were male. About a half of patients had hypertension (53.1%) and diabetes mellitus (47.5%). Most of patients (84.6%) had intermediate pretest probability of CAD. Mean eCCr was 64.7±18.5 mL/min/1.73 m².

Cardiovascular events were evaluated during follow-up period of 819±529 days (median 837 days). There were four cases of cardiac death (0.6%), three cases of non-fatal MI (0.5%), 11 cases of unstable angina (1.8%) and 11 cases of late revascularization (1.8%). Primary composite events including cardiac death, non-fatal MI, unstable angina and late revascularization occurred in 28 patients (4.5%), and composite hard events including cardiac death and non-fatal MI occurred in seven patients (1.1%). Annualized all- and hard-event rates were 2.00% and 0.49%, respectively. Fifteen patients (2.4%) were died, and mean annualized death rate was 1.06% (Table 2). Clinical parameters predicting cardiovascular events were assessed using multivariable Cox regression analyses (Table 3). Independent predictors for primary composite cardiac events were male sex (hazard ratio [HR], 2.40; 95% confidence interval [CI], 1.01-5.69; P=0.046) and low eCCr (<60 mL/min/1.73 m²) (HR, 3.07; 95% CI, 1.22-7.74; P=0.017). Diabetes mellitus had a marginal significance in this model (P=0.060). eCCr was the only independent predictor for secondary composite hard events (HR, 17.6; 95% CI, 1.44-215.7; P=0.025). Primary composite event rates proportionally increased with decrease of eCCr: event rates were 1.3%, 3.2≥, and 7.6% in subjects with eCCr ≥90 mL/min/1.73 m², 60-89 mL/min/1.73 m² and <60 mL/min/1.73 m², respectively (P=0.006) (Fig. 1). In ROC curve analysis, the sensitivity and specificity for detection of primary composite cardiac events were 53.5% and 77.3%, respectively with eCCr 60 mL/min/1.73 m² as the best cut-off value (Fig. 2). In Kaplan-Meier survival curve, cumulative primary and secondary composite event free survival rates were significantly lower in patients with low eCCr (<60 mL/min/1.73 m²) compared to those with high eCCr (≥60 mL/min/1.73 m²) (log-rank P<0.05 for each) (Fig. 3).