Prognostic value of extensive coronary calcium quantities in symptomatic malesa 5-year follow-up study
Stefan Möhlenkampa,*,
Nils Lehmannb,
Axel Schmermunda,
Heiko Pumpc,
Susanne Moebusb,
Dietrich Baumgarta,
Rainer Seibelc,
Dietrich H.W Grönemeyerd,
Karl-Heinz Jöckelb and
Raimund Erbela
a Clinic of Cardiology, University Clinic Essen, Hufelandstrasse 55, 45122 Essen, Germany
b Institute of Medical Informatics, Biometry and Epidemiology, University Clinic Essen, Essen, Germany
c Institute of Diagnostic and Interventional Radiology, University Witten/Herdecke, Mülheim, Germany
d Department of Radiology and MicroTherapy, University Witten/Herdecke, Bochum, Germany
* Corresponding author. Tel.: +49-201-723-2339; fax: +49-201-723-5951
E-mail address: stefan.moehlenkamp{at}uni-essen.de
Received 8 November 2002;
accepted 20 November 2002
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Abstract
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Aims Coronary calcium scores (CSs) have been shown to predict future events in patients presenting for first-time evaluation of CAD. Long-term outcome data on symptomatic subjects with advanced CAD are limited. In this study, we evaluated the prognostic value of very high coronary CSs in symptomatic males undergoing angiography and analyzed the impact of event definitions on identification of risk predictors.
Methods and results Fifty consecutive symptomatic males with electron beam computed tomography (EBT)-based CSs >1000 were matched 1:2 by age with symptomatic males with scores between 4001000 and 100400. All 150 patients underwent coronary angiography. CAD risk factors were ascertained. Events were analyzed after 5 years for: (1) hard coronary events (coronary death and myocardial infarction); (2) overall hard events (adding stroke and non-coronary deaths); and (3) all events (including long-term revascularizations). During follow-up, 17 deaths, two infarctions and three strokes occurred in 21 patients; 38 patients underwent 43 revascularizations. Events occurred earlier and more frequently in patients with scores >1000. Left main disease was the only independent predictor of hard coronary events (hazard ratio, 4.5; 95% confidence interval, 1.117.8). Left main disease (4.3; 1.413.0) and CSs (1.7; 1.12.5) independently predicted overall hard events. Only CSs>90thpercentile independently predicted all events (2.5; 1.34.8).
Conclusions Symptomatic males with extensive CSs carry an even higher risk for future events than other symptomatic males with advanced CAD. In these patients, EBT-based calcified plaque burden and angiographic indices of disease severity may have a complementary role in predicting future cardiovascular events.
Key Words: Electron beam computed tomography Coronary calcification Prognostic value Follow-up Coronary angiography
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1. Introduction
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The extent of coronary calcium as determined by electron beam computed tomography (EBT) reflects the overall extent of histologic1 and clinical coronary atherosclerosis.24 While very high degrees of calcified coronary atherosclerosis are uncommon in young individuals, the prevalence of coronary calcium increases substantially with age.5 For any given age, asymptomatic individuals presenting for first-time evaluation of CAD usually have a low to moderate calcified plaque burden,5 while symptomatic patients with a high pre-angiographic likelihood for significant CAD are expected to have substantially higher coronary calcium quantities.3,4 The calcium score (CS) parallels the increasing prevalence of clinical coronary artery disease increasing with age and it may be used to estimate the degree of angiographic lumen narrowing irrespective of age and gender.6 However, the role of calcium quantification for risk assessment especially in an elderly high-risk population remains controversial.7,8
Studies on the prognostic value of coronary calcium quantification have been performed in mixed middle-aged populations.916 In symptomatic males and females with previously unknown CAD, EBT-based coronary calcium was identified as a strong predictor of future events independent of angiographic findings13,14 with a CS of 100 being a useful threshold for risk prediction. However, the prognostic value of calcium quantification has not been studied in the increasingly prevalent group of high-risk symptomatic males with extensive coronary atherosclerosis undergoing coronary angiography.
In this study, we evaluated the prognostic value of CS-quantities, angiographic disease severity and conventional risk factor status in symptomatic males with extensive coronary atherosclerosis. We also assessed the influence of endpoint definition on identification of predictors of future events and therefore defined three groups of endpoints: (1) hard coronary events, i.e. myocardial infarction (MI) and coronary death; (2) overall hard events, i.e. additional strokes and non-coronary deaths and (3) all events, additional long-term revascularization procedures.
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2. Methods
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2.1. Patients
All symptomatic males, including those with previously established CAD, who were referred for coronary angiography to our tertiary referral center between March 1994 and December 1997 and who had extensive degrees of EBT-based coronary calcifications, i.e. an Agatston score >1000, were included. Because CS of 100 and 400 have previously been suggested as clinically useful cutpoints,17 these subjects were matched 1:2 by age (±3 years) with symptomatic males from our database with severe, i.e. score of 4001000, and moderate, i.e. score of 100400, degrees of calcification who had also undergone coronary angiography. Patients were excluded from the study if they had had coronary artery bypass grafts (CABG) at the time of the EBT study. Eligible patients were included based on scanner availability irrespective of clinical or previous angiographic findings.
2.2. Cardiovascular risk factors
Risk factors for coronary atherosclerosis were determined as previously reported,18 including age, family history, smoking status, arterial hypertension, diabetes mellitus, hypercholesterolemia and body mass index (kg/m2). Lipid levels were determined as previously described.18 Total cholesterol levels were measured in 90%, HDL-cholesterol in 87% and LDL-cholesterol in 84% of 150 patients. Medication was recorded at the time of discharge.
2.3. Electron beam computed tomography
EBT studies were performed as previously described.18 In brief, subjects were placed supine on the table of a C-150 EBT scanner (Imatron Inc., South San Francisco, CA, USA) and were acquired with an image acquisition time of 100ms, a slice thickness of 3mm and a 2630cm2field of view. Thirty to forty contiguous slices were obtained down to the apex of the heart with ECG-triggering at 80% of the RR-interval. The Agatston score was determined manually.18 The score is the product of the area of a hyperattenuating focus
4 pixels with CT densities
130 HU and a factor of 14 derived from the peak intensity of this focus. In addition to the CS-groups, i.e. 100400, 4001000 and >1000, we also analyzed the total CS as a continuous variable. Further, each CS was assigned to a percentile group according to a previously published large population-based study,5 i.e. <50th, 50th75th, 75th90th and >90th percentiles. EBT scans were evaluated without knowledge of angiographic findings. Referring physicians and patients were informed about the calcium scan result after work-up at our center. The EBT scanner is located at different institutions (HP, RMMS, DHWG) and access to this test was limited to certain times each week.
2.4. Coronary angiography
Coronary angiograms were visually assessed and decisions for revascularization made by experienced readers with no knowledge of the EBT scan result. Stenoses, including major side branches, were classified into: (1) no evidence of luminal narrowing; (2) stenosis <50%; (3) stenosis
50 and <75%; (4) stenosis
75 and <100% and (5) occlusion. The left main coronary artery (LCA) was evaluated separately. Angiographic- or intravascular ultrasound (IVUS)-based left main narrowing above 30% area or diameter stenosis was considered clinically relevant. The mean angiographic stenosis was calculated based on the maximal stenosis within each vascular territory, i.e.
.
2.5. Follow-up
Follow-up information could be obtained in 149 patients (99.3%) from a telephone survey 59±13 months (range, 3584 months) after the EBT-study. One patient (total CS of 1360) could not be contacted but is known to be alive at the time of final follow-up according to mandatory city registries. Based on angiographic findings, he was recommended for CABG, but it is unknown whether he ever underwent surgery. In all subjects, we enquired about coronary events since the EBT scan, i.e. MI, stroke, CABG and PTCA. Short-term index-revascularizations were distinguished from long-term procedures by a cut-off period of 6 months after the EBT study. By that time all patients had undergone complete revascularization that was indicated based on index CAD severity. When patients had died during follow-up, relatives were asked about specific circumstances of death. Physicians' and hospital records and also death certificates (available in all but two subjects) were used to confirm patient- or relative-derived information.
2.6. Endpoints
In the relevant EBT-literature, study endpoints are heterogeneously defined. To assess the influence of clinically relevant different endpoints we distinguished three event categories: (1) hard coronary events, i.e. coronary death and MI; (2) overall hard events, i.e. all patients from (1) and additionally non-coronary deaths and stroke and (3) all events including soft revascularization procedures, i.e. all patients from (2) and additionally long-term CABG or PTCA, defined as revascularization procedures occurring at
6 months after the EBT-study.
2.7. Statistics
KaplanMeier survival distribution function estimates were calculated for cardiovascular hard, overall hard and all events with respect to CS groups (CS
1000,
,
). We further analyzed the time-to-event data for the three endpoints by the method of proportional hazards (Cox regression).19 The matched triplet design regarding age (one patient with
matched to one patient each with
and
, age approximately ±2 years) was taken into account by frequency matching the patients in strata ranging from age <50 years, 5074 by 5 years, to
75 years.20 For each parameter (risk factors, angiographic variables and EBT-based CS), we calculated the single factor hazard ratio (HR), its 95% confidence interval (95% CI) and the associated P-value using univariate analysis. All P-values given in the context of Cox modeling relate to the Wald
2-statistic. Factors not reported for all 150 patients have been excluded from the analysis. Factors revealing significant association with time-to-event in the univariate analysis
were included in a multiple stepwise selection procedure, where factors enter the multivariate model when
(score
2-statistic) and stay when
(Wald
2-statistic). Out of the different CS measures, i.e. total CS, CS>90th percentile,
, and
, only the factor showing the strongest deviation from the null hypothesis of no association with time-to-event in the univariate analysis entered the factor selection process. For the selected multivariate model the relevant factors' (adjusted) HRs along with the respective 95% CIs and P-values were calculated as well as the P-value for the overall model fit. The proportional hazards assumption underlying Cox's model was confirmed for the respective selected models with stratification taken into account.21 Association of dichotomous factors with the pre-defined CS groups was explored by means of the CochranMantelHaenszel statistics, while for continuous and ordinal factors the KruskalWallis test with respect to CS group was applied. Statistical computing was done with SAS, for Cox regression we used the SAS procedure PHREG.22
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3. Results
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3.1. Patient demographics and risk factors at index evaluation
In the three groups of patients, risk factor assessment demonstrated a typical distribution with a positive family history in one quarter of patients, arterial hypertension in two-thirds and diabetes mellitus in 1224% of patients (Table 1). Patients with the lowest scores tended to have less diabetes mellitus. About 60% of patients were (mostly former) smokers. Total, LDL- and HDL-cholesterol levels were not statistically different between the groups. The average number of risk factors per patient was 3.1. A history of MI was present in about 40% of patients as was a previous PTCA.
3.2. Coronary calcium quantities and angiographic disease severity
CSs across the three groups were significantly associated with angiographic disease severity (Table 2), as per maximum stenosis (
,
) and mean stenosis (
,
). Left main disease occurred more frequently in patients with
compared to the other groups (Table 2). With increasing scores, a higher number of diseased vessels was found (Table 2).
3.3. Revascularization procedures
PTCA was performed in 36, 44 and 44% of patients in groups 100400, 4001000 and >1000, respectively
. An additional 10, 18 and 28% of patients in the groups underwent short-term CABG
. Thus, at the time of the EBT study 78, 80 and 94% of patients in the groups, respectively, already had a history of MI or PTCA or required revascularization during the index evaluation
.
3.4. Long-term events during follow-up
During the follow-up period, 65 events occurred in 53 (35%) of 150 patients: 17 deaths (11%) including 10 cardiovascular deaths (7%), 2 MI (1%), and 3 strokes (2%) occurred in 21 (14%) patients and 43 long-term revascularization procedures occurred in 38 (25%) patients (Table 3). Two patients, both alive, were recommended for CABG but decided against surgery. Patients with overall hard events had a score of 1465±1202 compared to 826±825 in those without events
. Mean age was 66±8 and 61±8 years
and the rate of left main disease was 24 and 6%, respectively
. Mean percent-stenosis was 54±24 and 49±26%
, maximum stenosis was 85±23 and 78±29%
. In 81 and 52% of patients with overall hardevents, the CS was >75th and >90th percentile, respectively.
3.5. Event-free survival and predictors of future events
In all three event categories, events generally occurred earlier and more frequently in patients with
compared to the other groups (Fig. 1ac). For the category all events, the difference in event-free survival between CS-groups was statistically significant (Fig. 1c).
Angiographic- and EBT-based parameters (but not risk factor status, history of events or revascularization procedures) were predictive of future events (Fig. 2). Hard coronary events were significantly predicted only by the presence of left main disease both in univariate analysis and in the multiple stepwise procedure (Figs. 2a and 3a). An increased HR for total CS and CS >90th percentile failed to reach statistical significance in this event category (Fig. 2a). Overall hard events were predicted by both angiographic and EBT-based parameters in univariate analysis: left main disease, total CS, CS >90th percentile and a
, but not
(Fig. 2b). In the multiple stepwise procedure, the presence of left main disease and total CS remained independently predictive for future events (Fig. 3b). When revascularization procedures were additionally considered as events, total CS,
and a CS>90th percentile were predictive of events (Fig. 2c). An increased HR for the presence of left main disease failed to reach statistical significance
. Stenoses in other arterial segments (as per maximum stenosis (Fig. 2c) or mean percent-stenosis (
,
,
)) revealed significantly increased HRs in univariate analysis, but were discarded in the multiple model selection process when adjusted for CS>90th percentile (Fig. 3c).

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Fig. 3 HRs with 95%-CI for independent predictive factors of event-free survival, selected by stepwise Cox regression: hard coronary events (top), overall hard events (middle) and all events including revascularizations (bottom). Graph details as in Fig. 2
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4. Discussion
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In this study, we show that in high-risk symptomatic males, the non-invasive quantification of coronary calcification by EBT predicts future events independent of and in addition to disease severity assessed by coronary angiography. Identification of independent predictors of future events depends on the chosen endpoints; while the presence of left main disease was the only identified predictor of hard coronary events, i.e. coronary death and MI, CS-quantities were an additional independent predictor of hard events when non-cardiac deaths and strokes were included. When revascularization procedures were additionally considered as events, only EBT-based indices of CAD severity remained independently associated with patients' prognosis. Therefore, we suggest that a
or a CS>90th percentile may be useful additional thresholds for clinical risk appraisal in symptomatic males with extensive coronary atherosclerosis.
To date, two reports have been published on the long-term prognostic value of CT-based coronary artery calcium quantification in patients undergoing coronary angiography.13,14 Detrano et al.13 reported 30 months event rates in a multicenter group of 491 patients undergoing EBT and angiographic evaluation. They too found a moderate correlation of calcified plaque with angiographic disease severity and CSs were also an independent predictor of CAD-related events. Similarly, Keelanet al.14 recently reported EBT-based CSs to be a powerful predictor for future hard events independent of angiographic findings. In both studies, each performed in patients mostly presenting for first-time evaluation of CAD, angiographic disease severity was not of independent prognostic value, which may in part be attributable to endpointcriteria. Independent of endpoint definition, quantitative EBT-based visualization of calcified plaque appears to be of particular prognostic value in early stages of CAD, when vascular remodeling may preclude accurate disease quantification based on angiographic lumenography.13,14 Our findings suggest that both angiography-based and EBT-based quantities of coronary atherosclerosis are of independent and prognostically complementary value, once the disease has progressed beyond compensatory vascular remodeling.
In our population, the presence of left main disease was the only predictor of future hard coronary events, independent of calcium quantities, risk factor status or revascularization procedures. In univariate analysis, the increased HR of a CS>90th percentile just failed to reach statistical significance in this event category, which may be attributable to the limited absolute number of hard coronary events during the follow-up period. However, CSs had independent prognostic value for overall hard events and all events, indicating that patients with severe coronary atherosclerosis may be more likely to experience (fatal) complications from co-morbidities compared to other symptomatic males with less severe coronary atherosclerosis. This is consistent with the concept that coronary plaque quantification may provide an estimate for the individual arterial age,23 which may prove to be a useful adjunct to the limited predictive value of conventional risk assessment particularly in older symptomatic males.
The event rates in our study are substantially higher compared to the above-mentioned EBTstudies,13,14 which may be attributed to older age, exclusion of females, higher CSs and more severe angiographic disease as well as a high rate of previous events in our study. While all our patients had CSs above 100, Detrano et al.13 and Keelan et al.14 reported a significantly better outcome for patients with CSs below 100 with a relative risk of 3.2 for patients with scores above this threshold.14 Georgiou et al.15 included a high rate of symptomatic subjects at the low end of the spectrum of CSs
. In their patients that presented with chest pain in the emergency department, but who had no routine angiographic work-up, the annualized event rate (including cardiac death, non-fatal MI, CABG, PTCA, stroke and hospitalization for angina) was 0.6% when the EBT scan was negative and increased to 6, 10 and 14% when CS were between 1100, 100400 and >400, respectively. Similar to our findings, these long-term outcome studies in symptomatic subjects support a graded relationship between the extent of CS quantities and the incidence of future cardiovascular events. According to our data, the rate of events continues to rise beyond a
compared to CS below this threshold in elderly high-risk symptomatic men.
A graded relationship between (absolute) CSs and future events is further supported by recently published preliminary data on 5-year mortality in 10,377 asymptomatic individuals.24 After adjustment for risk factors, the relative risk for patients with a score >1000 was 4.03 compared to individuals with a score <10.24 Mortality progressively increased with CS between 10100, 100400 and 4001000.24 Wayhs et al.16 reported an annualized rate of MI and coronary death of 25% in asymptomatic subjects with
compared to an annual rate of 1015% in an historic group of symptomatic patients with severe abnormalities on SPECT perfusion images. Their event rate in asymptomatic individuals is even higher than our outcome data in symptomatic males of similar age, which supports the relative importance of the degree of subclinical coronary atherosclerosis over symptoms for cardiovascular risk assessment and challenges current distinctions between primary and secondary preventive strategies.
We found CSs above the 75th and 90th percentile in 81 and 52% of patients with overall hard events. This is comparable to the percentile distribution reported by Raggi et al.25 in patients with MI. However, they included patients with MI only, patients were substantially younger (mean age about 55) and consisted of initially asymptomatic mixed gender subjects with a significantly lower mean CS. Consistent with other reports,15 an age- and gender-adjusted 75th percentile was identified to be a clinically useful threshold associated with hard events.25 In our study, patients above the 90th percentile had an even higher rate of events compared to our other symptomatic males, indicating the 90th percentile to be an additional clinically useful threshold beyond which risk for future events increases even further.
Our study does not support the hypothesis that very high amounts of coronary calcium would indicate generally stable atherosclerosis. Coronary calcium is frequently detectable in the vicinity of ruptured plaque,26 and substantial evidence points towards a role of coronary calcium in acute coronary syndromes.27 Although other studies found no evidence for a destabilizing role of coronary calcification in an individual plaque,28,29 CSs appear not only to be useful in predicting severe angiographic disease,4,6 but also to permit identification ofthose individuals that will most likely continue being exposed to potentially unstable, non-calcified atherosclerotic alterations within the vessel wall.
4.1. Study limitations
Multiple sources of bias may be present in this clinical observational study. Especially, we cannot exclude the possibility that patients with lower CS were the ones with atypical or non-cardiac chest pain but a conspicuous risk factor constellation, leading to angiographic work-up despite a lower factual than anticipated risk for future events. However, this possible selection bias seems an unlikely explanation for the strong associations observed because risk factors were potential predictors in the stepwise procedure.
Most investigators use visual analysis of angiographic images when applying angiography as a reference standard for evaluating a non-invasive diagnostic test.2,3,6,13,14,18 Keelan et al.14 used a segment-based approach to quantify overall angiographic disease burden but still found that only age and coronary calcium quantities independently predicted hard events. We are nonetheless aware that the use of quantitative coronary angiography and an angiographic risk estimate weighted for proximal disease might have improved the predictive power of angiographic variables in all endpoint categories.
Based on this study alone, we would not recommend EBT scanning for all symptomatic males. Further studies in larger patient cohorts are required to demonstrate its independent prognostic value when other clinical variables such as left ventricular function or novel risk factors and/or other imaging modalities such as nuclear stress tests are included in the pre-angiographic work-up. This study, performed in patients with advanced coronary atherosclerosis, rather aims at a better understanding of the potential predictive role of coronary calcium quantification across the entire spectrum of CAD severity.
Finally, our data are not readily applicable in a general symptomatic or asymptomatic population and also not in women. Patients seen in our tertiary referral center presumably have a comparatively high pre-angiographic likelihood for significant CAD and hence future risk. However, recently published data in asymptomatic individuals support a substantially increased risk for future events in subjects with CS above 1000, comparable to the event rate observed in our study.16,24
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5. Conclusions
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In symptomatic males with advanced coronary atherosclerosis undergoing coronary angiography, EBT-based CS quantification provides prognostic information on future events. Depending on endpoint definition, prognostic information is independent of and/or complementary to angiographic indices of CAD severity. Symptomatic males with extensive coronary calcification, i.e. a
or a CS>90th percentile, have an even higher risk for future events compared to other symptomatic males with CAD. Quantification of coronary atherosclerosis may be a helpful adjunct tool for risk assessment even in symptomatic subjects with advanced CAD.
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Acknowledgments
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The authors are indebted to Stefanie Schaar and Holger Heibel for their help in collecting the data and to the staff at the EBT-scanner facilities for their help in performing the studies.
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