To assess the value of coronary computed tomographic angiography (CCTA) in the prediction of cardiac events in asymptomatic patients, 451 consecutive asymptomatic patients who underwent CCTA from December 2003 to November 2007 were retrospectively analyzed. The primary end point of the study was the occurrence of cardiac events, defined as cardiac death, nonfatal myocardial infarction, unstable angina requiring hospitalization, and late revascularization (>90 days after CCTA) during a median follow-up period of 27.5 months. Secondary end points were the prevalence of nonobstructive coronary lesions and the number of patients reclassified regarding their cardiovascular risk. Two hundred twenty-nine patients (54%) had nonobstructive coronary lesions, and 107 patients (24%) obstructive coronary artery disease. During follow-up, there were 2 cases of unstable angina and 8 revascularizations for stable angina. Patients with obstructive coronary artery disease had a significantly higher event rate than those without obstructive CAD (risk ratio 13.9, 95% confidence interval 4.0 to 48.0). In 217 patients (48%), the clinically assessed cardiovascular risk could be reclassified by CCTA from intermediate or high to low risk. In conclusion, although the event rate was low in asymptomatic patients, CCTA could reliably predict further cardiac events and could reclassify 2/3 of patients regarding their cardiovascular risk.
In recent years, coronary computed tomographic angiography (CCTA) has emerged as a widely used imaging modality for the detection or exclusion of obstructive coronary artery disease (CAD), replacing invasive coronary angiography in certain situations. In addition, evidence is emerging that CCTA may also have a prognostic role in the prediction of subsequent cardiac events. Patients with intermediate pretest probability of CAD or symptomatic patients with uninterpretable or equivocal stress test results are considered appropriately investigated by CCTA. Most studies investigating the accuracy and prognostic value of CCTA are undertaken on this patient group. The detection of CAD in asymptomatic patients was ranked as an “uncertain” indication for the use of CCTA in the 2006 appropriateness criteria for cardiac computed tomography. Among others, the radiation exposure associated with CCTA is a major reason for this ranking. However, recent technical improvements and the rigorous use of dose-saving algorithms are resulting in a very efficacious reduction in radiation dose applied to patients, already reaching the dose range of a calcium-scoring scan, approximately equivalent to the annual natural background radiation exposure. This might allow expanding the indications for CCTA to the coronary risk assessment of asymptomatic patients in the near future, as has been performed so far with calcium scoring. Because data regarding CCTA in this patient group are unavailable, we retrospectively analyzed in this study the outcomes of asymptomatic patients who underwent CCTA with regard to prevalence of obstructive CAD and the incidence of subsequent cardiac events.
Methods
This study included all asymptomatic patients who underwent CCTA at our institution from December 1, 2003, to November 30, 2007, for assessment of cardiovascular risk. All patients had been seen by referring cardiologists, who ordered the test mainly because of elevated cardiovascular risk profiles. Excluded from the analysis were all patients with known CAD, patients complaining of angina pectoris or nonanginal chest pain as defined by Diamond and Forrester, and patients having other symptoms that may be caused by cardiac disease, such as arrhythmias or dyspnea (New York Heart Association class ≥II). Furthermore, we excluded asymptomatic patients with abnormal or equivocal stress test results. Written informed consent was obtained from all patients before examination.
A structured interview was performed before examination, and information about age, height and weight, history of cardiac disease, and present complaints was collected. The following cardiac risk factors were recorded: (1) presence and degree of arterial hypertension (for binary analysis, systolic blood pressure >40 mm Hg or treatment with antihypertensive medication was considered abnormal), (2) diabetes mellitus (defined as fasting blood glucose >7 mmol/L or the use of oral antidiabetic therapy or insulin), (3) smoking (defined as current smoking or previous smoking within the past year), and (4) a positive family history (defined as the presence of CAD in first-degree relatives aged <55 years in men or <65 years in women). In addition, laboratory tests for total cholesterol, low-density lipoprotein and high-density lipoprotein fraction, and triglycerides were performed (for binary analysis, total blood cholesterol >240 mg/dl or treatment with cholesterol-lowering medication was considered abnormal). From these data, the Framingham risk score with the established categorical model using low-density lipoprotein cholesterol according to Wilson et al was calculated. Coronary risk was classified as low in patients with Framingham scores <6, intermediate in those with scores of 6 to 20, and high in those with scores >20. The study design was approved by the local ethics committee.
The detailed multislice computed tomographic scanning protocol is described elsewhere. Images for calcium scoring were acquired by a non-contrast-enhanced sequential scan and analyzed with a commercially available software package (Siemens CalciumScore; Siemens Healthcare, Erlangen, Germany). For CCTA, a bolus-timing test scan using 10 to 20 ml of contrast (Imeron 350 [iomeprol]; Bracco Altana Pharma, GmbH, Konstanz, Germany; iodine content 350 mg/cm 3 ) followed by a 50-ml saline chaser was used. After administration of 80 to 140 ml of contrast individually adjusted to the selected table feed and scan range at a rate of 4 to 6 ml/s followed by a 50-ml saline chaser, the coronary computed tomographic angiographic images were acquired. Electrocardiographically gated tube current modulation was used in patients with stable sinus rhythm for the reduction of radiation dose exposure. Different computed tomographic system configurations were used during the study period: a 16-slice system from December 2003 to September 2004, a 64-slice single-source system from October 2004 to September 2006, and a 64-slice dual-source system from October 2006 to October 2007 (all from Siemens Healthcare). The radiation dose estimate was calculated by multiplying the dose-length product by a thorax-specific conversion coefficient of 0.014 mSv / (mGy × cm) according to a report of the American Association of Physicists in Medicine Task Group 23 of the Diagnostic Imaging Council CT Committee.
For image analysis, the coronary artery tree was segmented into 15 segments according to the modified American Heart Association classification. Each segment with a diameter >1.5 mm was evaluated by 2 experienced readers (1 radiologist and 1 cardiologist). Any disagreement was settled by consensus. The degree of stenosis was rated visually using 4 groups: no relevant stenosis (<25%), mild stenosis (25% to 49%), moderate stenosis (50% to 74%), and severe stenosis (≥75%). If a moderate or severe stenosis could not be excluded because of artifacts, the segment was classified as equivocal. In addition, for each segment, the presence of calcium and the presence of noncalcified plaques were assessed. Noncalcified plaques were defined as any discernible structure in the coronary artery wall with a computed tomographic density less than the contrast-enhanced coronary lumen but greater than the surrounding connective tissue. Plaques meeting these criteria but additionally showing calcification were classified as mixed plaques.
Follow-up information was gathered by clinical visits, telephone contact, or questionnaires sent by mail. We verified all reported events by hospital records or contact with the attending physician. The primary end point of the study was a combined end point including cardiac death (including death without definitive noncardiac cause), nonfatal myocardial infarction, unstable angina pectoris requiring hospitalization, or coronary revascularization later than 90 days after CCTA (either by bypass surgery or percutaneous coronary intervention), whichever occurred first. Nonfatal myocardial infarction was defined on the basis of the criteria of typical acute chest pain and persistent ST-segment elevation or positive cardiac enzymes. Unstable angina pectoris was defined according to the guidelines of the European Society of Cardiology as typical acute chest pain with negative cardiac enzymes, if CAD could not be excluded as the cause of symptoms. Deaths from clearly noncardiac causes were not counted as events. For differentiation between CCTA-triggered and CCTA-independent revascularization procedures, we did not include early revascularizations (<90 days after CCTA) in the end point for follow-up analysis but considered it as an additional adjustment factor in the multivariate analysis.
Categorical variables are expressed as frequencies and percentages, and continuous variables are expressed as mean ± SD. Comparisons were performed using Fisher’s exact test or Welch’s t test. Event-free survival was analyzed using the Kaplan-Meier method, differences were assessed using the log-rank test, and nested models were compared by their likelihood ratios. Statistical significance was accepted for bilateral p values <0.05. The statistical package R version 2.6.1 (R Development Core Team, Vienna, Austria) including the package Design (Frank Harrell, Vanderbilt University, Nashville, Tennessee) was used for statistical analysis.
Results
During the study period, 474 asymptomatic patients underwent CCTA. Of these, 451 patients could be contacted for follow-up, resulting in a follow-up rate >95%. The median duration of follow-up was 27.5 months (interquartile range 17.2 to 40.4). The mean age was 58.6 ± 9.9 years, and 74% were men. The patient characteristics and coronary risk factor profile mirrored a study population of low to intermediate risk for CAD, with a mean Framingham risk score of 10.6 ± 7.1. According to the Framingham risk score, 150 patients (33%) had low cardiovascular risk, 252 (56%) had intermediate risk, and 49 (11%) had high risk. In 449 patients, the indication for CCTA was the exclusion of CAD in asymptomatic patients; 2 patients with oligosymptomatic mitral regurgitation were scanned during preoperative workup. The detailed patient characteristics are listed in Table 1 .
| Variable | Value |
|---|---|
| Age (years) | 58.7 ± 10 |
| Men | 334 (74%) |
| Body mass index (kg/m 2 ) | 26.1 ± 3.8 |
| Hypertension ⁎ | 226 (50%) |
| Smokers | 177 (39%) |
| Diabetes mellitus | 37 (8%) |
| Not insulin dependent | 29 (6%) |
| Insulin dependent | 8 (2%) |
| Hypercholesterolemia † | 260 (58%) |
| Family history of coronary artery disease | 156 (35%) |
| Framingham risk score | 10.6 ± 7.1 |
| <6 | 150 (33%) |
| 6–20 | 252 (56%) |
| >20 | 49 (11%) |
⁎ Systolic blood pressure >140 mm Hg or treatment with antihypertensive medication.
† Total cholesterol >240 mg/dl or treatment with cholesterol-lowering medication.
Calcium scoring was performed in 434 patients (96%). Of these, 151 (35%) had no coronary calcification, 157 (36%) had mild calcification (Agatston score <100), 77 (18%) had moderate calcification (Agatston score 100 to 400), and 49 (13%) had severe coronary calcification (Agatston score > 400). The mean Agatston score was 15.9 ± 14.6.
Normal coronary arteries without evidence of atherosclerotic plaque or coronary stenosis were seen in 115 patients (25%), and atherosclerosis without luminal narrowing >25% was present in 73 patients (16%). In 156 patients (35%), mild CAD with maximal luminal stenosis <50% was present, while in 94 (21%) and 13 (3%) patients, moderate and severe CAD with luminal stenoses of 50% to 74% and ≥75% was present, respectively. Accordingly, obstructive CAD could be ruled out in 344 patients (76%) by CCTA. Fifty-eight patients (13%) had 1-vessel disease, 29 (6%) had 2-vessel disease, and 18 (4%) had 3-vessel disease. Thirty-nine patients (9%) had obstructive lesions either in the left main coronary artery or the proximal left anterior descending coronary artery. Coronary computed tomographic angiographic images of representative patients are depicted in Figure 1 .
The median radiation dose exposures associated with CCTA were 4.2 mSv (interquartile range 3.9 to 4.5) for the 16-slice scanner, 7.9 mSv (interquartile range 7.1 to 10.4) for the 64-slice single-source scanner, and 5.7 mSv (interquartile range 3.7 to 9.1) for the 64-slice dual-source scanner.
The rate of cardiac events during follow-up was low. There was no cardiac death or myocardial infarction, and 2 patients were admitted to the hospital because of unstable angina pectoris 9 and 56 months after the exclusion of obstructive CAD by CCTA. In addition, 8 patients with obstructive CAD on CCTA were treated with percutaneous coronary intervention because of stable angina pectoris 4 months to 5 years after CCTA (see Table 2 ). There was no significant difference in any single clinical risk factor and in the Framingham score between patients with and without cardiac events (13 ± 10 vs 10 ± 7 for patients with vs without cardiac events, p = 0.14). For calcium scoring, there was a significant difference (Agatston score 83.9 ± 59.3 vs 15.5 ± 14.3 for patients with vs without cardiac events, p = 0.015), but the best computed tomographic parameter for predicting cardiac events was the presence of obstructive CAD (p <0.001): the event rate of patients with obstructive CAD of 3.1% (95% confidence interval [CI] 1.6% to 6.2%) was significantly higher than the event rate of 0.2% (95% CI 0.1% to 0.9%) in patients without obstructive CAD, resulting in a risk ratio of 12.6 (95% CI 2.7 to 59.7). To exclude confounding effects from the early coronary intervention, we repeated the analysis after the exclusion of patients who underwent invasive angiography <90 days after CCTA; this yielded very similar results, with an annual event rate of 2.5% compared to 0.2% and a risk ratio of 13.9 (95% CI 4.0 to 48.0) between patients with obstructive CAD and those without it. In a multivariate analysis including the presence of obstructive CAD on CCTA, calcium scoring, clinical risk factors, and the presence of a coronary intervention <90 days after CCTA as an additional adjustment factor, only the presence of obstructive CAD remained significant. The Kaplan-Meyer plot for event-free survival after CCTA is depicted in Figure 2 . For a summary of the predictive value of different computed tomographic parameters and the Framingham score refer to Table 3 .
| Follow-Up Events | Obstructive CAD | p Value | |
|---|---|---|---|
| No (n = 344) | Yes (n = 107) | ||
| Cardiac death | 0 | 0 | |
| Myocardial infarction | 0 | 0 | |
| Unstable angina pectoris | 2 (0.6%) | 0 | 0.86 |
| Coronary bypass surgery | 0 | 0 | |
| Percutaneous coronary intervention | 2 (0.6%) | 8 (7%) | <0.001 |
| All cardiac events | 2 (0.6%) | 8 (7%) | <0.001 |
| Noncardiac death | 1 (0.3%) | 3 (3%) | 0.04 |
| Variable | Late Events | c Index | p Value | |
|---|---|---|---|---|
| No (n = 441) | Yes (n = 10) | |||
| Computed tomographic parameters | ||||
| Presence of obstructive coronary artery disease | 99 (22%) | 8 (80%) | 0.82 ± 0.05 | <0.001 |
| Most severe stenosis | 0.84 ± 0.03 | <0.001 | ||
| Normal coronary arteries | 115 (26%) | 0 | ||
| Nonstenotic plaque | 73 (16%) | 0 | ||
| 25%–50% | 154 (35%) | 2 (20%) | ||
| 51%–75% | 87 (20%) | 7 (70%) | ||
| >75% | 12 (3%) | 1 (10%) | ||
| Number of coronary arteries narrowed | 0.83 ± 0.08 | <0.001 | ||
| 1 | 56 (13%) | 2 (20%) | ||
| 2 | 26 (6%) | 3 (30%) | ||
| 3 | 15 (3%) | 3 (30%) | ||
| Left main/proximal left anterior descending coronary artery narrowed | 38 (9%) | 1 (14%) | 0.50 ± 0.05 | 0.99 |
| Calcium score | 15.1 ± 13.9 | 147 ± 111.18 | 0.74 ± 0.06 | 0.015 |
| 0 | 151 (34%) | 0 | ||
| 0.1–100 | 154 (34%) | 3 (30%) | ||
| 100–400 | 73 (17%) | 4 (40%) | ||
| >400 | 47 (11%) | 2 (20%) | ||
| Framingham risk score | 10 ± 7 | 13 ± 10 | 0.59 ± 0.10 | 0.14 |
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