(Circulation. 2000;101:850.)
© 2000 American Heart Association, Inc.
Clinical Investigation and Reports |
Identification of Patients at Increased Risk of First Unheralded Acute Myocardial Infarction by Electron-Beam Computed Tomography
Presented in part at the 48th Meeting of the American College of Cardiology, New Orleans, La, March 7–11, 1999. Tracy Q. Callister, Paolo Raggi, Nicholas J. Lippolis, Donald J. Russo. How should we use coronary artery calcium scores to predict events? J Am Coll Cardiol. 1999;33:414A. Abstract.
From EBT Research Foundation (T.Q.C., P.R., N.J.L., D.J.R.) and Vanderbilt University (B.C.), Nashville, Tenn; Baylor College of Medicine, Houston, Tex (Z.-X.H., J.J.M.); and Christ Hospital and Medical Center and Rush Medical College, Oak Lawn, Ill (A.Z.).
Correspondence to Paolo Raggi, MD, FACP, FACC, Director, EBT Research Foundation, 64 Valleybrook Dr, Hendersonville, TN 37075. E-mail praggi{at}attglobal.net
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Background—There is a clear relationship between absolute calcium scores (CS) and severity of coronary artery disease. However, hard coronary events have been shown to occur across all ranges of CS.
Methods and Results—We conducted 2 analyses: in group A, 172 patients underwent electron-beam CT (EBCT) imaging within 60 days of suffering an unheralded myocardial infarction. In group B, 632 patients screened by EBCT were followed up for a mean of 32±7 months for the development of acute myocardial infarction or cardiac death. The mean patient age and prevalence of coronary calcification were similar in the 2 groups (53±8 versus 52±9 years and 96% each). In group B, the annualized event rate was 0.11% for subjects with CS of 0, 2.1% for CS 1 to 99, 4.1% for CS 100 to 400, and 4.8% for CS >400, and only 7% of the patients had CS >400. However, mild, moderate, and extensive absolute CSs were distributed similarly between patients with events in both groups (34%, 35%, and 27%, respectively, in group A and 44%, 30%, and 22% in group B). In contrast, the majority of events in both groups occurred in patients with CS >75th percentile (70% in each group).
Conclusions—Coronary calcium is present in most patients who suffer acute coronary events. Although the event rate is greater for patients with high absolute CSs, few patients have this degree of calcification on a screening EBCT. Conversely, the majority of events occur in individuals with high CS percentiles. Hence, CS percentiles constitute a more effective screening method to stratify individuals at risk.
Key Words: calcium • tomography • myocardial infarction • coronary disease
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Introduction |
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Despite a significant reduction in coronary artery disease (CAD) mortality, during the past decade the incidence of acute myocardial infarction (AMI) has continued to rise in the United States.1 Several studies have shown the potential for aggressive lipid-lowering therapy to influence CAD outcome,2 3 but our ability to predict and prevent the majority of events remains limited. Kannel4 recently suggested that to maximize the cost-effectiveness of primary prevention, it is necessary to target high-risk candidates by use of multifactorial risk-stratification approaches and more sophisticated diagnostic technologies than those currently in use. At present, the possibility that electron-beam CT (EBCT) may provide such an opportunity is being investigated. Coronary artery calcium has long been identified as a marker of underlying CAD,5 6 7 8 9 and EBCT is extremely sensitive for the detection and quantification of the extent of coronary artery calcification (CAC). Measures of CAC expressed as calcium scores (CSs) show a close correlation with the atherosclerotic plaque burden,10 11 12 13 and the simple presence of CAC on a screening EBCT test has been reported to be associated with high odds ratios for developing a variety of cardiovascular events.14 However, although a clear correlation exists between increasing absolute CS, severity of coronary luminal stenosis,15 and subsequent revascularization procedures,14 16 previous investigations consistently showed that patients suffered coronary events across all ranges of absolute CSs.16 17 18 19 20 Indeed, it is likely that age- and sex-adjusted CS values may be more appropriate than absolute CS to assess the individual risk, because they may better reflect the underlying individual atherogenic process.
In this study, we compared the value of absolute and relative CSs, based on expected values for age- and sex-matched control subjects, for predicting hard cardiac events. We performed EBCT scanning in 2 distinct patient groups. (1) Group A consisted of 172 patients who had suffered an AMI as their first clinical manifestation of CAD and who underwent EBCT imaging shortly after their acute events. In this group, the imaging was conducted to estimate the extent of plaque burden that could have been identified had EBCT scanning been performed before the patients suffered an AMI. (2) A telephone survey for the occurrence of hard events was conducted in 632 patients who had originally been referred for a screening EBCT by their primary care physicians because of the presence of risk factors for CAD (group B). The average follow-up was 32±7 months. In both groups, absolute CSs and percentiles were calculated.
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Methods |
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Patient Selection
One hundred seventy-two patients who had suffered an AMI with no previous clinical manifestation of CAD were enrolled in group A. The diagnosis of AMI was based on standard clinical and ECG criteria as well as a characteristic rise and fall in plasma creatine kinase MB fraction.21 22 Patients who had Q-wave and non–Q-wave AMIs were included. The mean and median times between AMI and EBCT imaging were 31 and 35 days, respectively (range, 3 to 60 days). Because of potential interference with the CS calculations, patients who had undergone coronary angioplasty and stent placement in the peri-infarction period were excluded, whereas plain angioplasty was allowed. This part of the study was performed to assess the presence and extent of CAC that could have been identified had these patients undergone an EBCT screening test before suffering a nonfatal AMI.
Six hundred thirty-two asymptomatic patients, referred for EBCT screening by primary care physicians because of the presence of risk factors for CAD, constituted the cohort for the second portion of our study (group B). None of the subjects were self-referred. Clinical follow-up for cardiac events was conducted via telephone interview after a mean period of 32±7 months (range, 24 to 48 months) from the initial screening. Follow-up was completed in all patients. Diagnosis of AMI was confirmed by means of medical record review and the same clinical, laboratory, and ECG criteria as used for the post-AMI patients described above. Sudden cardiac death or death due to AMI was verified through review of the death certificates or hospital records and was performed by an investigator blinded to the results of the EBCT screening scan.
Data on risk factors for CAD were collected by a cardiac nurse before the initial EBCT imaging procedure. Arterial hypertension was defined by current use of antihypertensive medications or known but untreated hypertension. Current smoking was necessary for the definition of positive smoking status. Hypercholesterolemia was defined as currently receiving cholesterol-lowering medications or the presence of known but untreated hypercholesterolemia. Patients currently receiving insulin or oral hypoglycemic agents were classified as diabetic. A family history of premature CAD was considered present if CAD had occurred in a first- or second-degree relative at <55 years of age.
All patients gave informed consent to participate in the study, and the internal review boards of our institutions approved the research protocol.
Imaging Protocol
All patients underwent EBCT imaging with an Imatron C-100 or
C-150 scanner, those in group A within 6 weeks of AMI. Images were
obtained with 100-ms scan time and 3-mm single-slice thickness, with a
total of 40 slices starting at the level of the carina and proceeding
to the level of the diaphragm. Tomographic imaging was
electrocardiographically triggered to 80% of the R-R interval.
Coronary calcification was defined as a plaque of 
4
consecutive pixels (area=1.37 mm2) with a
density of 130 HU. Quantitative CSs were calculated according to the
method described by Agatston et al.23 All EBCT scans were
reviewed in random order by 3 separate investigators, and because
calcium scoring was performed only once on each patient,
interinvestigator score variability was not calculated.
Statistical Analysis
Four absolute CS categories were considered: zero, mild score
(CS=1 to 99), moderate score (CS=100 to 400), and severe score (>400).
CSs were also expressed as age- and sex-adjusted CS percentiles derived
from a group of 9728 subjects who underwent EBCT imaging at 1 center
(EBT Research Foundation, Nashville, Tenn; Table 1
). These patients had a
distribution of risk factors for CAD similar to those of the patients
in the study groups: systemic hypertension, 47%; diabetes mellitus,
11%; smoking, 43%; hypercholesterolemia,
56%; and family history of CAD, 69% (see Table 2 for comparison).
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For patients in the prospective cohort, the absolute event rates, risk ratios, and relative risk of events were calculated in each CS and risk factor quartile. The quartiles of CS percentile were created by subdividing the population into 4 numerically equal groups. The event rate was derived by assigning to each numerically balanced quartile group the observed number of events in each quartile. Risk factor quartile groups were created by including the following risk factors: men >45 years old, women >55 years old, current smoking, systemic hypertension, diabetes mellitus, hypercholesterolemia, and family history of premature CAD.
ANOVA and 2-sample t tests were used to compare the means of
continuous variables. 
2 analysis
and the 2-sample test on proportions were used to compare categorical
variables. All cited probability values are 2-tailed, and a value
of P<0.05 was considered statistically significant. All
data are expressed as mean±SD.
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Results |
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Post-AMI Cohort
The clinical characteristics of group A patients are shown in Table 2
. The overall mean CS was 367±535, and this was similar
in the 126 men (389±559) and 46 women (307±534). The median CS for
the entire group was 160. EBCT imaging showed CAC in 165 patients
(96%). Four women and 3 men did not have CAC, and although their mean
age was lower than that of patients with CAC, this difference did not
reach statistical significance (47±8 versus 53±8;
P=0.058). Of note, all patients without CAC at the time of
AMI were smokers.
The individual CSs were mild (1 to 99) in 34%, moderate (100 to 400)
in 35%, and severe (>400) in 27% of the subjects (Table 3; P=NS for all comparisons by
2 analysis).
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Table 3 shows the distribution of CS percentiles found in study
patients in relation to the age- and sex-adjusted values
presented in Table 1. The majority of group A patients
(87%) had a CS >50th percentile for age and sex, 70% showed a CS
>75th percentile, and 42% showed a CS >90th percentile. All
comparisons of observed and expected prevalence of CSs were highly
statistically significant (87% versus 50%, 70% versus 25%, and 42%
versus 10%; P<0.001).
Prospective Cohort
The clinical characteristics of group B patients are shown in
Table 2. In this cohort, 50% of patients were men, and 54% had
CAC on the screening EBCT. The mean CS for the entire cohort was
101±254; median, 3.1.
During 32±7 months, 27 patients (4%) had either a fatal cardiac event (n=8) or nonfatal AMI (n=19). Of these 27 patients, 26 (96%) had CAC on the initial EBCT, and their mean and median CSs were statistically greater than in the 605 individuals without events (303±441 versus 92±240, P<0.001, and 141 versus 2.4, P<0.001, respectively).
Prevalence of mild, moderate, and severe CS and CS percentiles for the
patients in group B are shown in Table 3. As in the
retrospective analysis, 
2/3 of the events occurred in
patients with mild to moderate absolute CS values (74% in group B
versus 69% in group A, P=NS), and 1/4 occurred in
patients with severe CS (22% in group B versus 27% in group A;
P=NS). These results are compatible with angiographic and
pathological findings demonstrating that the majority of patients who
suffer an AMI or sudden cardiac death have nonobstructive
coronary artery lesions.24 25 26
The annualized event rate was 0.11% for the 292 subjects with a CS of 0, compared with 2.1% for those with a CS of 1 to 99, 4.1% for those with a CS of 100 to 400, and 4.8% for those with a CS >400. Although 22% of the events occurred in patients with a CS >400, only 7% of the entire cohort showed a CS in this range, and the majority of events occurred in patients with mild or moderate CSs. Hence, although a larger absolute CS identified a population at high risk of events, these values reflected only a small segment of the population at risk and would therefore not constitute an optimal screening method.
Conversely, as shown in the retrospective group, the majority of patients who suffered an acute AMI in group B had a CS percentile value in the upper range of normal (85% >50th percentile, 70% >75th percentile, and 41% >90th percentile). Again, the comparisons of observed and expected prevalence of CS percentiles were all highly statistically significant (85% versus 50%, 70% versus 25%, and 41% versus 10%; P<0.001).
Limiting the analysis to patients who showed a CS >75th percentile demonstrated that a much greater proportion of events occurred in patients in this quartile group than in all other lower quartile groups considered together (19 events in 181 patients versus 8 events in 451 patients; P<0.001).
Risk Analysis of Prospective Patient Cohort
Table 4 shows a comparison of total
number of events, annualized absolute event rates, and odds ratios for
an event in the 27 prospective patients identified according to
quartiles of CS percentiles and risk factors. The risk ratio for events
in the highest risk factor quartile was 6.5-fold greater than in the
lowest quartile (13/2=6.5). In contrast, the risk ratio for patients in
the highest CS quartile (ie, CS >75th percentile) was 19 times that of
patients in the lowest quartile (19/1=19). Furthermore, the odds ratios
for events in the upper 2 quartiles of CS percentiles were
substantially greater than in the respective risk factor quartiles (6.2
and 21.5 versus 3.1 and 7.0, respectively), although there was some
overlapping of the CIs. The annualized relative risk of events (Table 5) ranged from 0.09 to 1.05 (12-fold
difference) between the lowest and the highest quartiles in patients
identified according to risk factors and from 0.045 to 2.7 (59-fold
difference) when the grouping was done according to CS quartiles. This
analysis suggests that although traditional risk factors for
CAD are very valuable predictors, percentiles of CS are a substantially
better means of identifying patients at risk of hard coronary
events.
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Discussion |
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Calcification of the coronary arteries, identified and measured on EBCT imaging, is highly prevalent in patients suffering an acute AMI and strongly predictive of hard events. This study demonstrates that CS percentiles, based on patient age and sex, are better predictors than absolute CS values and categorical risk factors for CAD. In this regard, Wilson et al27 recently showed that the presence of categorical risk factors for CAD is as predictive of cardiovascular events as the measurement of such continuous variables as systolic hypertension and LDL cholesterol levels. Therefore, the assumptions made in this study about the relative ability of risk factor categories to predict events in comparison to CS categories are pertinent.
As previously shown, CAC is present with a very high prevalence in patients who suffer a coronary event,16 25 26 28 29 indicating that this is a true marker of CAD. However, previous studies showed an apparent paradox: patients with high CSs were shown to be at high risk of hard events, but only a small portion of the population would show high CS, and events were evenly distributed across all ranges of absolute CS.16 19 Our study suggests that high CS percentiles are highly prevalent in patients suffering a hard event independent of the absolute CS and that these measurements may allow a better segregation of the portion of an asymptomatic population that may benefit from therapeutic interventions.
The process of coronary calcification is currently believed to be an active process similar in many aspects to true bone formation.30 31 32 33 34 Some investigators view this process as a repair mechanism to the damage caused by various noxious stimuli.17 A larger-than-expected amount of coronary calcium might indicate the presence of an aggressive damage of the arterial wall requiring either a faster or a more extensive repair. In this context, the amount of coronary calcium relative to the patient’s age and sex could be seen as an indicator of plaque activity rather than plaque quiescence.
Rosamond et al1 showed that in recent years, the incidence
of AMI has continued to increase even though the mortality rate from
AMI has declined. Hence, primary prevention of CAD must remain the
focus of public health policies of industrialized nations. The
Framingham equations36 37 provide a
population-based method to assess the median risk of developing CAD but
do not allow discernment of the individual’s risk. The National
Cholesterol Education Program (NCEP)-II
guidelines38 provide a very helpful aid for the prevention
of CAD in people at risk, but published data suggest a maximum 3- to
5-fold increase in estimated risk between patients with the lowest and
the highest risk profiles.39 40 41 Sophisticated computer
simulations have been attempted to improve on the predictive ability of
these models, but with poor applicability to the everyday clinical
practice.39 Furthermore, according to the NCEP-II
guidelines, 21.1 million Americans (17% of the adult population)
need treatment for the presence of risk factors for CAD.42
However, even when more liberal treatment criteria are applied, as
suggested in the recent Air Force/Texas Coronary
Atherosclerosis Prevention Study (AFCAPS/TexCAPS)
trial,3 only 37% of the AMIs are prevented. Conversely,
our EBCT analysis suggests that a larger number of hard events
could be addressed by implementation of this screening strategy. If
patients with CS >75th percentile were treated, 70% of the events
could potentially be prevented, and if patients with CS >90th
percentile were treated, 40% of the events could be prevented.
Hence, EBCT screening for coronary calcification should improve
the practicing physician’s ability to stratify individuals at high
risk of events, to whom aggressive treatment of traditional risk
factors for CAD can be more appropriately directed.
Of note, the data presented in this study confirm previous observations pertaining to the absence of CAC on EBCT imaging in a percentage of young smokers who suffer an acute coronary event.16 26 28 29 43 Similar findings have been reported in pathological studies conducted in young individuals who died of cardiac arrest or AMI.44 45 46 This indicates that prudence should be used in characterizing the absence of CAC or the presence of small amounts of CAC in young smokers as a nonthreatening marker for acute coronary events.
Study Limitations
Our postevent imaging analysis in group A was limited to
nonfatal AMI cases. However, nonfatal AMI is the most prevalent
clinical manifestation of coronary heart disease in men and the
second most prevalent in women, and its incidence continues to rise in
recent years.1 47 48 We can only conjecture that the
amount of CAC found in patients who die of an acute coronary
event is at least as extensive as, if not greater than, the amount
found in patients who suffer a nonfatal event. Interestingly, in the
prospective group, the patients who died had a larger amount of
coronary calcification than those who suffered a nonfatal AMI
(median CS, 391 versus 75, P<0.04). Finally, the presence
of risk factors for CAD was not directly assessed but rather inferred
from current medical regimens or patient self-reporting.
Conclusions
The incidence of cardiovascular events is greatly
increased in the presence of CAC. Although high CSs portend a high risk
of events, only a relatively small portion of the AMIs occur in this
fraction of the population, and the majority of events occur in
patients with mild to moderate amounts of CAC. Conversely, high age-
and sex-adjusted CS percentiles appear to be closely related to the
occurrence of subsequent hard events, and we suggest that this
measurement should be used in the assessment of the risk of a hard
event in asymptomatic individuals undergoing EBCT
screening.
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Acknowledgments |
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This study was supported in part by the Dean’s Fund for Faculty Research, Owen Graduate School of Management, Vanderbilt University.
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Footnotes |
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Guest Editor for this article was Bruce Brundage, MD, Bend Memorial Clinic, Bend, Ore.
Drs Callister and Russo own publicly traded shares of Imatron Inc, South San Francisco, Calif, the maker of electron-beam computed tomography scanners.
Received May 14, 1999; revision received September 14, 1999; accepted September 29, 1999.
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