Author + information
- Received May 1, 2006
- Revision received July 24, 2006
- Accepted July 27, 2006
- Published online January 2, 2007.
- Gabija Pundziute, MD⁎,†,1,
- Joanne D. Schuijf, MSc⁎,‡,1,
- J. Wouter Jukema, MD, PhD⁎,‡,
- Eric Boersma, PhD§,
- Albert de Roos, MD, PhD∥,
- Ernst E. van der Wall, MD, PhD⁎,‡ and
- Jeroen J. Bax, MD, PhD⁎,⁎ ()
- ↵⁎Reprint requests and correspondence:
Dr. Jeroen J. Bax, Department of Cardiology, Leiden University Medical Center, Albinusdreef 2, 2333 ZA Leiden, the Netherlands.
Objectives This study sought to determine the prognostic value of multislice computed tomography (MSCT) coronary angiography in patients with known or suspected coronary artery disease (CAD).
Background It is expected that MSCT will be used increasingly as an alternative imaging modality in the diagnosis of patients with suspected CAD. Data on the prognostic value of MSCT, however, are currently not available.
Methods A total of 100 patients (73 men, age 59 ± 12 years) who were referred for further cardiac evaluation due to suspicion of significant CAD underwent additional MSCT coronary angiography to evaluate the presence and severity of CAD. Patients were followed up for the occurrence of: 1) cardiac death, 2) nonfatal myocardial infarction, 3) unstable angina requiring hospitalization, and 4) revascularization.
Results Coronary plaques were detected in 80 (80%) patients. During a mean follow-up of 16 months, 33 events occurred in 26 patients. In patients with normal coronary arteries on MSCT, the first-year event rate was 0% versus 30% in patients with any evidence of CAD on MSCT. The observed event rate was highest in the presence of obstructive lesions (63%) and when obstructive lesions were located in the left main (LM)/left anterior descending (LAD) coronary arteries (77%). Nonetheless, an elevated event rate was also observed in patients with nonobstructive CAD (8%). In multivariate analysis, significant predictors of events were the presence of CAD, obstructive CAD, obstructive CAD in LM/LAD, number of segments with plaques, number of segments with obstructive plaques, and number of segments with mixed plaques.
Conclusions Multislice computed tomography coronary angiography provides independent prognostic information over baseline clinical risk factors in patients with known and suspected CAD. An excellent prognosis was noted in patients with a normal MSCT.
In patients presenting with suspected or known coronary artery disease (CAD), assessment of prognosis is essential in selecting appropriate patient management. Currently, extensive data are available on the prognostic value of myocardial perfusion imaging with single-photon emission computed tomography (SPECT). A normal SPECT study has been shown to indicate a good clinical outcome with an annual death or infarct rate of <1% per year, whereas the likelihood to develop cardiac events is significantly increased when perfusion abnormalities are detected (1,2). Similarly, coronary artery calcium score assessed by electron beam computed tomography (EBCT) or, less frequently, by multislice computed tomography (MSCT), has been used for risk stratification in patients with known or suspected CAD, and a calcium score <100 has been associated with excellent outcome, with an increase in the event rate paralleling the increase in calcium score (3,4).
More recently, noninvasive coronary angiography techniques (magnetic resonance imaging, EBCT, and MSCT) have been introduced which allow direct visualization of coronary artery lesions. At present, MSCT appears to be the most robust technique for this purpose, and it is expected that this technique will be increasingly used as an alternative first-line imaging modality in the diagnosis of patients presenting with chest pain suspect for CAD. Multislice computed tomography allows detection of both obstructive and nonobstructive lesions, and noncalcified lesions are also visualized. Although the diagnostic accuracy of MSCT has been demonstrated, data on the prognostic value of MSCT are not available. Accordingly, the aim of this study was to determine the prognostic value of MSCT in patients with known or suspected CAD.
Patients and study protocol
The study population consisted of consecutive patients who presented to the outpatient clinic and were referred for further evaluation (using exercise electrocardiogram, perfusion imaging, or invasive coronary angiography) of suspected CAD (chest pain complaints, elevated risk profile, or abnormal test results). In all patients, MSCT coronary angiography was performed in addition to the standard clinical workup. Subsequent clinical management was based on the latter; MSCT findings were not included in the diagnostic/therapeutic workup.
Only patients without previous coronary bypass grafting who were in sinus rhythm and without contraindications to iodinated contrast media were included, resulting in the exclusion of 5 patients because of potential contrast allergy (n = 3) and atrial fibrillation (n = 2), respectively. Follow-up was successful in all patients. All patients gave written informed consent to the study protocol, which was approved by the local ethics committee.
A structured interview and clinical history were acquired, and the following cardiac risk factors were assessed before the MSCT examination: 1) diabetes mellitus (defined as a fasting glucose level of ≥7 mmol/l or the need for insulin or oral hypoglycemic agents) (5); 2) hypercholesterolemia (defined as a total cholesterol level ≥5 mmol/l or treatment with lipid-lowering drugs) (6); 3) hypertension (defined as blood pressure ≥140/90 mm Hg or the use of antihypertensive medication) (7); 4) obesity (body mass index ≥30 kg/m2) (8); 5) positive family history of CAD (defined as the presence of CAD in first-degree relatives younger than 55 [male] or 65 [female] years of age) (9); and 6) smoking (defined as previous or current smoking).
MSCT data acquisition
All examinations were performed using Toshiba Multislice Aquilion systems (Toshiba Medical Systems, Tokyo, Japan). If the heart rate was ≥65 beats/min, additional oral beta-blockers (metoprolol, 50 mg, single dose, 1 h before scan) were provided if tolerated. First, a prospectively triggered coronary calcium scan was performed before MSCT angiography with identical parameters for 16- and 64-slice MSCT systems: collimation 4 × 3.0 mm, gantry rotation time 500 ms, tube voltage and tube current 120 kV and 200 mA, respectively. The temporal window was set at 75% after the R-wave for electrocardiographically triggered prospective reconstruction.
Sixteen-slice MSCT coronary angiography was performed according to the protocol described elsewhere (10). The following parameters were applied for 64-slice MSCT coronary angiography: collimation of 64 × 0.5 mm; tube rotation time of 400, 450, or 500 ms, depending on the heart rate; tube current 300 mA at 120 kV. Nonionic contrast material was administered in the antecubital vein with an amount of 80 to 105 ml, depending on the total scan time, and a flow rate of 5 ml/s (Iomeron 400, Bracco Altana Pharma, Konstanz, Germany). Automated detection of peak enhancement in the aortic root was used for timing of the scan. All images were acquired during an inspiratory breath hold of approximately 10 s, with simultaneous registration of the patient’s electrocardiogram. With the aid of a segmental reconstruction algorithm, data of 1, 2, or 3 consecutive heartbeats were used to generate a single image.
To evaluate the presence of coronary artery plaques, reconstructions in diastole (typically 75% of the cardiac cycle) were generated with a slice thickness of 0.5 mm at an increment of 0.3 mm. If motion artefacts were present, additional reconstructions were made in different time points of the R-R interval. Axial data sets were transferred to a remote workstation (Vitrea 2, Vital Images, Plymouth, Minnesota) for postprocessing and subsequent evaluation.
MSCT data analysis
Coronary artery calcium score
The coronary artery calcium score was assessed with the application of dedicated software (Vitrea 2). Coronary artery calcium was identified as a dense area in the coronary artery exceeding the threshold of 130 HU. An overall Agatston score was recorded for each patient.
Coronary plaque assessment
For the current study, all MSCT angiograms were evaluated within a time frame of 2 weeks by 2 experienced observers unaware of the clinical history of the patients, using a standard analysis (see later text). In case of disagreement, a joint reading was performed and a consensus decision was reached. Coronary arteries were divided into 17 segments according to the modified American Heart Association classification (11). Only segments with a diameter >1.5 mm (as measured on the MSCT coronary angiogram) were included. First, each segment was classified as interpretable or not. Predefined, patients were excluded from the analysis in case of: 1) an uninterpretable proximal or mid segment, or 2) more than 3 uninterpretable segments in general.
Then, the interpretable segments were evaluated for the presence of any atherosclerotic plaque using axial images and curved multiplanar reconstructions. Coronary plaques were defined as structures >1 mm2within and/or adjacent to the coronary artery lumen, which could be clearly distinguished from the vessel lumen and the surrounding pericardial tissue, as previously described (12). One coronary plaque was assigned per coronary segment. Subsequently, the type of plaque was determined using the following classification: 1) noncalcified plaques, plaques having lower density compared with the contrast-enhanced vessel lumen; 2) calcified plaques, plaques with high density; and 3) mixed plaques, plaques with noncalcified and calcified elements within a single plaque. Finally, it was determined whether the lesion was obstructive or not, using a threshold of 50% luminal narrowing. For each patient, the number of diseased coronary segments, number of segments with obstructive lesions, and number of each type of plaque was calculated. Patients without coronary artery calcium or coronary plaques on MSCT were considered normal; an abnormal MSCT was defined in the presence of ≥1 coronary plaque. Abnormal patients were further classified as having obstructive coronary plaques (≥50% luminal narrowing) in 1 or more coronary arteries, as well as having obstructive coronary lesions in the left main (LM) and/or left anterior descending (LAD) coronary arteries.
Follow-up information was obtained by either clinical visits or telephone interviews. Hospital records of all patients were screened for the occurrence of clinical events to confirm the obtained information. Clinical end points were the occurrence of: 1) cardiac death, 2) nonfatal infarction, 3) unstable angina requiring hospitalization, or 4) revascularization. Cardiac death was defined as death caused by acute myocardial infarction, ventricular arrhythmias, or refractory heart failure. Nonfatal myocardial infarction was defined based on criteria of typical chest pain, elevated cardiac enzyme levels, and typical changes on the electrocardiogram (13).
Categorical baseline characteristics are expressed as numbers and percentages, and compared between 2 groups with the chi-square test. Continuous variables are expressed as mean (standard deviation) and compared with the 2-tailed ttest for independent samples. When not normally distributed, continuous variables are expressed as medians (25th to 75th percentile range) and compared using a nonparametric Mann-Whitney test.
To identify the association between MSCT variables and outcomes, Cox regression analysis was used. A composite end point of cardiac death, nonfatal infarction, unstable angina requiring hospitalization, and revascularization was used. First, univariate analysis of baseline clinical characteristics and MSCT variables was performed to identify potential predictors. Hazard ratios were calculated with 95% confidence intervals as an estimate of the risk associated with a particular variable. To determine independent predictors of the composite end point, multivariate analysis of MSCT variables with p ≤ 0.05 in the univariate analysis was performed, which was corrected for the baseline characteristics with p ≤ 0.5 in the univariate analysis.
Cumulative event rates as a function over time were obtained by the Kaplan-Meier method. Event curves of the composite end point (cardiac death, nonfatal infarction, unstable angina requiring hospitalization, revascularization) and hard cardiac events (cardiac death, nonfatal infarction, and unstable angina requiring hospitalization) were compared using the log-rank test.
Statistical analyses were performed using SPSS software (version 12.0, SPSS Inc., Chicago, Illinois) and SAS software (version 6.12, SAS Institute Inc., Cary, North Carolina), and p values < 0.05 were considered statistically significant.
In total, 104 consecutive patients were enrolled in the present study. In 4 patients, an elevated and/or irregular heart rate during MSCT data acquisition rendered the MSCT data set uninterpretable, and these patients were excluded from the analysis. As a result, 100 patients (73 men, mean age 59 ± 12 years) were included in the study (15 patients were included in a previous study on the diagnostic accuracy of MSCT in direct comparison with invasive angiography ). Baseline characteristics are provided in Table 1.Briefly, 65 patients (65%) presented with suspected CAD at the time of MSCT, whereas CAD was known in the remaining 35 patients (35%) (33 patients had previous myocardial infarction, 31 patients had previous percutaneous coronary intervention). In total, 55 patients underwent 16-slice MSCT and 45 underwent 64-slice MSCT.
The MSCT characteristics are provided in Table 2.Only coronary segments with sufficient lumen diameter for evaluation of the presence of plaques were included in the analysis. After exclusion of 33 (2%) coronary segments with stents and 19 (1%) nonevaluable segments because of motion artifacts, plaque burden was evaluated in 1,298 segments. CAD was completely absent in 20 patients. In the remaining 80 patients, 345 coronary segments with plaques were observed, of which 47 (14%) contained noncalcified plaques, 109 (31%) mixed plaques, and 189 (55%) calcified plaques. In 71 (21%) segments of 32 (32%) patients, plaques were regarded as obstructive (≥50% luminal narrowing). Thirty-two (9%) segments with obstructive lesions in 23 (23%) patients were located in the LM and/or LAD coronary artery. In Figure 1,examples of different MSCT observations, including normal coronary arteries, nonobstructive CAD, and obstructive CAD in the LM, are shown.
During a mean follow-up of 16 months (median 13 months, interquartile range 5 to 39 months), 33 events occurred in 26 patients (with 7 events occurring repeatedly). One patient (1%) died of acute myocardial infarction. Nonfatal myocardial infarction occurred in 3 patients (3%), and unstable angina requiring hospitalization occurred in 4 patients (4%, with 1 also undergoing revascularization). A total of 24 patients (24%) underwent coronary revascularization; percutaneous coronary intervention was performed in 17 patients, whereas the remaining 7 patients underwent coronary artery bypass grafting. The decision for revascularization was based on worsening angina and/or the presence of ischemia on noninvasive testing.
Predictors of events
Baseline and clinical characteristics of patients with and without events are described in Table 1. Patients presenting with events during follow-up were significantly older (p = 0.03) and had worse clinical condition, as indicated by an elevated European System for Cardiac Operative Risk Evaluation value (p = 0.01). No significant differences in risk factors for CAD and use of medication were observed.
Differences in MSCT characteristics of patients with and without events are summarized in Table 2. Patients with events had more extensive atherosclerosis on MSCT, as reflected by a higher coronary calcium score and a higher number of segments showing (obstructive) plaques. Also, relatively more mixed and calcified plaques were observed as compared with patients without events.
In Table 3,the univariate analysis of both clinical and MSCT characteristics to predict events is summarized. In the multivariate analysis (Table 4),MSCT characteristics that were significant during univariate analysis were corrected for baseline characteristics with p ≤ 0.5 during univariate analysis, whereas the type of scanner (16- vs. 64-slice MSCT) used was also included in the analysis. As indicated in Table 4, the remaining significant independent predictors of cardiac events in the multivariate analysis were the presence of coronary plaques, obstructive CAD, LM/LAD disease, number of coronary segments with plaques, number of coronary segments with obstructive plaques, and number of coronary segments with mixed plaques.
Kaplan-Meier survival curves are provided in Figures 2 to 5.⇓⇓⇓As can be derived from Figure 2, no events occurred in patients with normal coronary arteries on MSCT, whereas a first-year event rate (including all events) of 30% was observed in patients with any CAD on MSCT (log-rank p value = 0.005). Excluding revascularizations resulted in a first-year hard cardiac event rate of 5% in patients with CAD on MSCT, as compared with 0% in patients with completely absent CAD on MSCT (log-rank p value = 0.19) (Fig. 3).
In Figure 4, the relationship between the severity of CAD and the occurrence of events was further explored, showing an increased event rate in patients with obstructive CAD (63%) compared with patients without CAD (0%) or nonobstructive CAD (8%) (log-rank p value <0.001). Finally, LM/LAD disease was found to be associated with the highest event rate (77%), as shown in Figure 5(log-rank p value <0.001).
In the present study, MSCT coronary angiography provided independent prognostic information for predicting cardiac events. Patients with completely absent CAD on MSCT coronary angiography had an excellent prognosis (0% event rate), whereas an increased event rate (30%) was observed in patients with CAD on MSCT. Furthermore, the risk of cardiac events increased with the extent of CAD as observed on MSCT, and patients with obstructive lesions (particularly in the LM and LAD) were shown to be at the greatest risk for cardiac events. Even after correction for baseline clinical variables such as age and risk factors, MSCT variables reflecting coronary plaque burden, including the severity, extent, and location of atherosclerosis, remained independent predictors of cardiac events.
The prognostication and subsequent management of patients with known or suspected CAD in current practice relies on initial clinical evaluation, with the low-risk patients being reassured and the high-risk patients being referred for invasive angiography (14). However, the majority of these patients are in the intermediate risk group, in whom prognosis and subsequent management is less well defined. Accordingly, these patients need additional testing with 1 or more of the established noninvasive modalities, which include exercise electrocardiography, stress SPECT imaging, or stress echocardiography (14). All these techniques aim at detecting ischemia. Exercise electrocardiography is not an ideal modality because of the suboptimal accuracy, and imaging of stress-induced perfusion abnormalities or systolic wall motion abnormalities may be preferred; indeed, average sensitivity and specificity of 87% and 73% to detect CAD have been reported for SPECT versus 82% and 84% for stress echocardiography (15,16). In addition, these tests proved to be predictive of future cardiac events when abnormalities were found and were associated with a low risk for events when the test results were normal (17–19).
Multislice computed tomography coronary angiography is a highly accurate, noninvasive imaging technique for the diagnosis of CAD; in particular, the negative predictive value of MSCT approaches 100%, allowing CAD to be ruled out (20,21).
The current study explored the prognostic value of MSCT in a symptomatic patient population with known or suspected CAD and a high prevalence of conventional risk factors. Consequently, the pretest likelihood of CAD was high in this population, and even in patients without known disease, CAD was present on MSCT in 69%. Not surprisingly, therefore, high cardiac event rates were observed. Most importantly, however, a 100% event-free survival was noted in patients without any abnormalities on MSCT, highlighting an excellent negative predictive value of a normal MSCT. This finding is of major clinical relevance, because these patients may indeed be safely reassured without need for further testing. Patients with coronary atherosclerosis identified on MSCT were shown to have a worse prognosis. More detailed analysis showed that although the risk of events was considerably higher in patients with obstructive CAD, patients with nonobstructive CAD still were at elevated risk as compared with patients without CAD. Indeed, previous studies support the notion that plaque composition (in addition to stenosis severity) is predictive of events. Moreover, Mann et al. (22) showed in a postmortem study that lipid core size and minimal cap thickness, 2 major determinants of plaque vulnerability, were not related to absolute plaque size or degree of stenosis. Accordingly, vulnerable plaques may occur across the full spectrum of severity of stenosis, underlining that also nonobstructive lesions may contribute to coronary events (23,24). Because less obstructive plaques are more frequent than severely obstructive plaques, coronary occlusion and myocardial infarction may in fact most frequently arise from mild to moderate stenoses (23,25–28). Pooling of these angiographic studies showed that 68% of myocardial infarctions were attributable to so-called “angiographically silent” lesions (luminal narrowing <50%), whereas only 14% could be assigned to a severe stenotic lesion (>70%) (29). In line with these observations, multivariate analysis of the possible predictors of cardiac events in the present study showed that nonobstructive CAD was indeed an independent predictor of future cardiac events. Of interest, the presence of mixed plaques, which may represent less advanced and possibly less stabilized atherosclerosis as compared with dense calcified lesions (30), was shown to be an independent predictor as well. However, further investigations are clearly needed to support these observations.
Nonetheless, considering individual lesions, the likelihood of progression to coronary occlusion (and subsequent myocardial infarction) remains highest for severe obstructive lesions (23,25,26). Indeed, prospective evaluation of nonbypassed coronary segments, as was performed in the CASS (Coronary Artery Surgery Study), showed that during a 5-year follow-up only 0.7% and 2.3% of segments with narrowing of respectively <5% and 5% to 49% resulted in coronary occlusion (25). In contrast, occlusion occurred in 10.1% and even 23.6% of lesions with narrowing 50% to 80% and 81% to 95%, respectively. In agreement, high event rates were observed for patients with obstructive CAD in the present study. More detailed analysis showed that hazard ratios were highest for patients with obstructive CAD in either the LM or LAD coronary arteries. Indeed previous studies showed that patients with severe proximal LAD disease are at high risk (31–33); for example, Califf et al. (34) reported a 59% event-free survival at 5 years in patients with 3-vessel disease and proximal LAD disease. Accordingly, early identification of these patients with MSCT will be crucial to optimize therapy.
The prognostic value of MSCT in the present study was evaluated in patients presenting with a wide spectrum of different conditions, including patients with no previous history of CAD and patients with previous myocardial infarction and revascularization. Accordingly, treatment strategies may have differed substantially within the studied population, and future studies will need to address the prognostic role of MSCT coronary angiography in more homogeneous patient populations. Also, the study population was small, and some clinically relevant predictors may not have reached statistical significance. Studies in larger cohorts (with longer follow-up) are clearly warranted to confirm these initial results.
This is the first study to show the independent prognostic value of MSCT coronary angiography over baseline clinical risk factors in patients presenting with chest pain. An excellent prognosis (0% event rate) was noted in patients with a normal MSCT. The presence of CAD (either nonobstructive or obstructive atherosclerotic lesions) was associated with an event rate of 30%. The event rate was highest in the presence of obstructive lesions and when lesions were located in the LM/LAD coronary arteries. Future studies are needed to further define the prognostic value of MSCT.
↵1 Drs. Pundziute and Schuijf contributed equally to this article and are shared first authors.
Supported by the Training Fellowship of the European Society of Cardiology and the Huygens scholarship, the Hague, the Netherlands (Dr. Pundziute) and The Netherlands Heart Foundation, the Hague, the Netherlands, grant 2002B105 (Dr. Schuijf).
Frank Bengel, MD, served as the Guest Editor for this article.
- Abbreviations and Acronyms
- coronary artery disease
- electron beam computed tomography
- left anterior descending coronary artery
- left main coronary artery
- multislice computed tomography
- single-photon emission computed tomography
- Received May 1, 2006.
- Revision received July 24, 2006.
- Accepted July 27, 2006.
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