Methods

This is an observational cohort study in consecutive symptomatic patients without known history of CAD from January 2009 to May 2012. This study was performed under approval from the institutional review board. Patients were excluded if they had established diagnosis of aortic stenosis undergoing transcatheter aortic valve replacement, ischemic electrocardiogram findings diagnostic of an acute coronary syndrome, an elevated initial troponin level, hemodynamic instability or established diagnosis of CAD documented by coronary angiography, history of coronary angioplasty with or without stenting and/or coronary artery bypass graft surgery. All patients had both non–contrast-enhanced CACS testing and contrast-enhanced CCTA on the same day of evaluation. Baseline characteristics were retrieved on the day of the scans by dedicated research study personnel. Complete follow-up data were not available for 16% of patients (151 of 956); however, they were alive according to the social security death index. The patients in the final cohort and the excluded patients were not significantly different in mean age, proportion of male gender, incidence of diabetes mellitus, smoking history, and CACS (both as continuous variables and as categorical variables); however, those in the final cohort had higher rates of hypertension (p = 0.009), dyslipidemia (p = 0.041), and ≤50% stenosis (p = 0.007 for limited disease and 0.014 for extensive disease).

CACS was acquired by a 64-slice multidetector CT scanner (Philips Brilliance, Best, The Netherlands) immediately before the CCTA studies. Images were acquired during a single breath-hold using prospective electrocardiographic gating with imaging triggered at 75% of the RR interval (collimation 8 × 2.5 mm, voltage 120 keV, current 75 mAs). Reconstructed axial images of 2.5-mm thickness were displayed for review. The computer software automatically defined the presence of calcified lesions as those >130 Hounsfield units and calculated the CACS with overread by a cardiologist. CACS results were categorized into 4 groups: CACS = 0, CACS 1 to 100, CACS 101 to 400, and CACS >400.

CCTA was performed with a 64-slice multidetector CT scanner (Philips Brilliance, Best, The Netherlands) after CACS testing. The voltage and tube current used were 120 kV and 500 to 900 mA, respectively. The protocol to process and obtain coronary images was in accordance with the guidelines set by the Society of Cardiovascular Computed Tomography.

The left main coronary, left anterior descending, left circumflex, right coronary artery, and their major branches were evaluated. The coronary plaque with degree of stenosis was quantified and categorized as normal CCTA, ≤50% stenosis (nonobstructive), and >50% stenosis (obstructive). In patients with CAD, those with 1-vessel involvement were defined as limited disease and those with 2-vessel disease, 3-vessel disease, or involvement of left main coronary artery were categorized as extensive disease. To examine the severity of CCTA stenosis, we grouped the patients into 5 groups: normal CCTA findings, limited ≤50% stenosis, extensive ≤50% stenosis, limited >50% stenosis, and extensive >50% stenosis.

The clinical end point in this study was major adverse cardiac events (MACE), which were defined as cardiac death, nonfatal myocardial infarction (MI), and late revascularization. Cardiac death was defined as death due to MI, congestive heart failure, or arrhythmia or any unknown causes of death not explained by noncardiac etiologies. The diagnosis of MI was defined as chest pain associated with typical electrocardiogram findings and a troponin I ≥0.10 ng/dl. Late revascularization was defined as revascularization after 60 days and included coronary artery bypass graft surgery and coronary angioplasty with or without stenting. In patients who had multiple cardiac events, only 1 was counted toward MACE.

Follow-up cardiac events were collected by chart review, telephone interview, and confirmation with social security death index. Research personnel asked specific, scripted questions regarding death, subsequent visits to the emergency department or readmission to the hospital for evaluation of chest pain symptoms, MI, cardiac catheterization, or coronary revascularization (angioplasty, stenting, or bypass procedures). The time from the day of CACS and CCTA assessment to a cardiac event or final contact encounter in those without cardiac events was used for outcome analyses.

Descriptive statistics for studied variables are presented as mean ± SD for normally distributed continuous variables, median with interquartile range for non-normally distributed continuous variables and frequency with percentage for categorical variables. Variables were compared with independent Student t tests for normally distributed continuous data, Wilcoxon-Mann-Whitney U tests for non-normally distributed continuous data, and chi-square test for categorical data.

Follow-up data were examined as annualized MACE rate categorized into different CACS and CCTA groups specified previously. Cumulative MACE rate as a function of time was investigated using Kaplan–Meier curve analysis. Differences in MACE-free survival curves between CCTA and CACS groups were compared using log-rank test. To assess influence of CACS and CCTA stenosis on MACE, univariate and multivariate Cox regression analysis was used. All potential independent predictors with p <0.10 in univariate analysis were included into multivariate Cox regression models. The regression analysis results are presented as hazard ratios (HRs) and 95% confidence intervals (CIs).

Performance of different predictive models for MACE with clinical risk factors, CACS, and CCTA stenosis were evaluated by comparison of global chi-square score of each predictive model using ANOVA F tests. The function of each predictive model over time was built with Cox regression analysis. Predictive coefficient is presented as chi-square of the model. The baseline model (clinicals) included all traditional cardiovascular risk factors (age, male gender, hypertension, diabetes mellitus, dyslipidemia and smoking). Additional models comprised clinicals plus CCTA (categorized into normal CCTA, limited ≤50% stenosis, extensive ≤50% stenosis, limited >50% stenosis, and extensive >50% stenosis) or clinicals plus CCTA plus log (CACS+1) data. All statistical analysis was performed with IBM SPSS/PASW Statistics 20 (SPSS Inc., Chicago, Illinois). All tests were 2 tailed with p <0.05 considered statistically significant.

Results

The final cohort comprised 805 patients. Baseline clinical and CT characteristics are summarized in Table 1 . Distribution of CACS in different CCTA stenosis categories is shown in Figure 1 . The proportion of patients in higher CACS categories increased in CCTA groups with more stenosis. In the 0 CACS group, there were 8% of patients (29 of 354) who had CAD detected with CCTA. This comprised 5% (8 of 354) of the 0 CACS group with limited ≤50% stenosis, 2% (6 of 354) with extensive ≤50% stenosis, and 1% (5 of 354) with limited >50% stenosis. Mean radiation dose for CACS was 2.5 mSv and for CCTA was 11.7 ± 4.8 mSv.

Distribution of CACS in different CCTA stenosis and extent of disease categories.

Mean follow-up duration after the scans was 2.3 ± 0.9 years. MACE occurred in 25 patients (1.4% per year), including 9 cardiac deaths, 7 nonfatal MIs, and 9 late coronary revascularizations. Patients who developed MACE were older (63 ± 13 vs 57 ± 13 years; p = 0.048) and had a higher rate of diabetes mellitus (32% vs 13%; p = 0.014) than those without MACE. Median CACS of patients with MACE were greater than those without MACE (318 vs 3; p <0.001). Correspondingly, there was a greater proportion of patients in higher CACS and CCTA categories in the MACE group compared to the group without MACE (p <0.001).

Patients with CACS = 0 had no occurrence of MACE. Patients with CACS >0, in all categories, had significantly higher annualized MACE rate than those with CACS = 0 as shown in Figure 2 . Annualized MACE rate was 0.1% in the normal CCTA group. Patients with ≤50% stenosis assessed by CCTA had higher annualized MACE rate than those with normal CCTA (1.4% vs 0.1%; p = 0.009). Patients with >50% stenosis detected by CCTA had higher annualized MACE rate than both ≤50% stenosis and normal CCTA groups (4.5% vs 1.4%; p = 0.002 and 4.5% vs 0.1%; p <0.001, respectively), as shown in Figure 2 . Further classification based on extent of the disease is shown in Figure 2 .

Annualized MACE rate with associated survival curves categorized by CACS (A, D) , CCTA stenosis (B, E) , and CCTA stenosis with extent of the disease (C, F) .

There were 29 patients with noncalcified coronary plaque (CCTA stenosis with 0 CACS) in our cohort. None of the patients with 0 CACS developed MACE during the follow-up period. Within the normal CCTA group, patients with CACS 1 to 100 had significantly higher annualized MACE rate than patients with CACS = 0 (p <0.001). This is due to 1 patient with CACS of 29 and normal CCTA who had late coronary revascularization. Within the ≤50% stenosis group, patients with CACS >100 showed comparable annualized MACE rate to patients with CACS 1 to 100 (1.6%/year vs 1.5%/year). Within the obstructive group, patients with CACS >100 had an annualized MACE rate approximately 2.5 times higher than patients with CACS 1 to 100 (5.4%/year vs 2.1%/year).

Prognostic performance of CACS was evaluated with Kaplan–Meier curve analysis. Patients with more severe CACS categories had a lower MACE-free survival rate (log-rank p <0.001), as shown in Figure 2 . Patients with CACS = 0 had a significantly higher MACE-free survival rate than all categories with CACS >0 (log-rank p <0.05). Patients with CACS >400 had significantly lower MACE-free survival rate than CACS 1 to 100 (log-rank p = 0.002) but not significantly lower than CACS 101 to 400 (log-rank p = 0.134).

Correspondingly in CCTA, patients with more severe CCTA stenosis had lower MACE-free survival rates (log-rank p <0.001). Those with normal CCTA had a significantly higher MACE-free survival rate than both ≤50% stenosis (log-rank p = 0.009) and >50% stenosis (log-rank p <0.001), as shown in Figure 2 . Patients with >50% stenosis had significantly lower MACE-free survival rate than those with ≤50% stenosis (log-rank p = 0.001). MACE-free survival rate was lowest in extensive >50% stenosis group ( Figure 2 ).

Univariate Cox analysis showed significant association between MACE and older age (HR 1.036; 95% CI 1.004 to 1.068; p = 0.026), history of diabetes mellitus (HR 2.423; 95% CI 1.051 to 5.584; p = 0.038), log (CACS+1) (HR 3.110; 95% CI 1.975 to 4.899; p <0.001), CACS 1 to 100 (HR 11.266; 95% CI 1.383 to 91.773; p = 0.023), CACS 101 to 400 (HR 10.980; 95% CI 2.314 to 159.759; p = 0.006), CACS > 400 (HR 42.881; 95% CI 5.555 to 330.990; p <0.001), extensive ≤50% stenosis detected by CCTA (HR 7.644; 95% CI 1.649 to 35.437; p = 0.009), limited >50% stenosis (HR 10.980; 95% CI 2.126 to 56.703; p = 0.004), and extensive >50% stenosis (HR 53.812; 95% CI 11.339 to 255.373; p <0.001). In multivariate analysis adjusted for clinical risk factors, all CT findings remained significant (p <0.05) except for limited ≤50% stenosis (p = 0.305). With further adjustment for clinical risk factors and CCTA stenosis, as summarized in Table 2 , CACS as continuous variables and categorical variables remained significantly associated with MACE; however, CCTA stenosis became statistically insignificant after adjustment with clinical risk factors and CACS.

Table 2

Multivariate association with major adverse cardiac events

Predictors	Adjusted for clinical risk factors		Adjusted for clinical risk factors and CT findings
	HR (95%CI)	p-value	HR (95%CI)	p-value
CACS
Log(CACS+1)	3.245(1.975,5.333)	<0.001	2.465(1.220,4.984)	0.012
CACS = 0	Ref	–	Ref	–
CACS 1-100	11.569(1.382,96.842)	0.024	18.053(1.192,273.384)	0.037
CACS 101-400	20.408(2.342, 177.832)	0.006	21.220(1.231,365.816)	0.035
CACS > 400	45.479(5.330,388.034)	<0.001	33.111(1.833,598.122)	0.018
CCTA stenosis
None	Ref	–	Ref	–
≤50% ∗	2.801(0.391,20.078)	0.305	0.357(0.033,3.834)	0.395
≤50% †	7.284(1.475,35.976)	0.015	0.705(0.089,5.563)	0.740
>50% ∗	10.219(1.817,57.462)	0.008	0.994(0.113,8.704)	0.996
>50% †	49.989(9.676,258.263)	<0.001	3.804(0.429,33.761)	0.230

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