CLINICAL STUDY: RISK FACTORS
Electron beam tomography and national cholesterol education program guidelines in asymptomatic women
Harvey S. Hecht, MD, FACC*  and
H. Robert Superko, MD, FACC
* Arizona Heart Institute and Foundation, Phoenix, Arizona, USA
Heart and Vascular Institute, Morristown, New Jersey, USA
Berkeley HeartLab, Berkeley, California, USA
Manuscript received September 8, 2000;
revised manuscript received November 22, 2000,
accepted January 24, 2001.
Reprint requests and correspondence: Dr. Harvey S. Hecht, Arizona Heart Institute, 2632 North 20th Street, Phoenix, Arizona 85006
hhecht{at}aol.com
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Abstract
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OBJECTIVES
This investigation was designed to determine the relationship between National Cholesterol Education Program (NCEP) ATP-II lipid guidelines and subclinical atherosclerosis, defined by electron beam tomography (EBT) calcified coronary plaque, in asymptomatic women.
BACKGROUND
NCEP guidelines are used to identify women at increased risk for coronary artery disease (CAD) on the basis of low density lipoprotein cholesterol (LDLC) and high density lipoprotein cholesterol (HDLC) values. The relationship of the guidelines to subclinical atherosclerosis is unknown.
METHODS
A total of 304 asymptomatic women underwent lipid and EBT evaluation and were classified as: 1) NCEP higher risk, with LDLC  130 mg/dl and/or HDLC <35 mg/dl, or lower risk with LDLC <130 mg/dl and HDLC 35 mg/dl; and 2) EBT+ if any calcified plaque was noted or EBT– if there was no calcified plaque.
RESULTS
Forty-two percent of patients were EBT+, with a mean score of 227 and percentile of 73%; 58% were EBT–. Women who were EBT+ had significantly higher total cholesterol, LDLC and triglycerides than EBT– women, but only with ages  55 years; women >55 years demonstrated no differences. NCEP higher risk women made up 53.5% of the EBT+ and 37.7% of the EBT– groups; NCEP lower risk women accounted for 46.5% of the EBT+ and 62.3% of the EBT– groups. Assuming a higher risk in subjects with EBT–defined subclinical CAD than in those without, only 58.6% of the total group would be correctly identified by NCEP guidelines as either higher or lower risk, with correct identification of 65.5% of the younger and 52.2% of the older women. There was no correlation between either calcium percentile or score and any lipid measurement.
CONCLUSIONS
This study demonstrates the shortcomings of employing NCEP guidelines to identify asymptomatic women with subclinical CAD, particularly women >55 years, and suggests increased utilization of EBT for primary prevention in the female population.
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Abbreviations and Acronyms
| | CAD | = coronary artery disease | | EBT | = electron beam tomography | | HDLC | = high density lipoprotein cholesterol | | LDLC | = low density lipoprotein cholesterol | | NCEP | = National Cholesterol Education Program | | SD | = standard deviation | | TC | = total cholesterol | | TG | = triglycerides |
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Coronary artery disease (CAD) is the leading cause of death of American women (1). Yet, it receives far less attention than breast cancer, for which routine screening by mammography is routinely performed. American Heart Association statistics reveal that breast cancer killed 41,943 women in 1997, compared to 502,938 for CAD (1). The delayed development of CAD in women may lead to a false sense of security regarding the number of pre and post menopausal women who have subclinical CAD and may benefit from primary prevention. Once women manifest CAD, they fare worse than men; 42% of women who have heart attacks die within a year compared to 24% of men (1).
The foundation of CAD primary prevention is the identification and modification of the classic CAD risk factors and treatment of lipid disorders according to the National Cholesterol Education Program (NCEP) ATP-II guidelines (2). Dietary intervention is recommended for low density lipoprotein cholesterol (LDLC) 130 mg/dl and 2 risk factors and drug therapy for LDLC 160 mg/dl. High density lipoprotein cholesterol (HDLC) <35 mg/dl is also considered to pose increased risk.
Electron beam tomography (EBT) evaluation of calcified coronary plaque burden has been validated by an increasing body of evidence supporting its correlation with total plaque volume (3–13), obstructive CAD (6–13) and clinical prognosis (14–18). Unlike mammography, EBT has not yet been recommended for screening the general population (19), but has been suggested as a tool to identify asymptomatic individuals who may benefit from specific practice guidelines (20).
This investigation was designed to determine whether the NCEP guidelines for defining higher and lower risk accurately identify subclinical atherosclerosis in both younger and older women, as defined by EBT evidence of calcified plaque. Further, the relationship between the levels of conventional blood lipid measurements and the absolute and age-corrected amount of calcified plaque was evaluated.
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Methods
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Subjects.
Three hundred nineteen consecutive asymptomatic women undergoing EBT at the Arizona Heart Institute, self-referred out of personal concern for CAD risk, filled out a medical history questionnaire and were evaluated. Hypertension was defined by current or recommended use of antihypertensive medications for blood pressure control. Smoking was defined as current tobacco usage and diabetes by current or recommended use of diet or medication to reduce blood sugar. Family history of CAD was defined as CAD in first-degree male relatives 55 years of age or female relatives 65 years. Body mass index was calculated as weight (kg)/height (m)2.
In order to explore the potential effects of younger and older age, the group was divided into women 55 and >55 years of age. The age of 55 years was selected because women presenting to emergency departments with chest pain are more likely to be misdiagnosed if they are 55 years of age, and, women >55 years of age are likely to be postmenopausal (21). Fifteen women were on lipid-lowering drug therapy (statins, fibrates or niacin) and were excluded, resulting in a final population of 304 women.
Imaging.
Electron beam tomography was performed using an Imatron C-150 (San Francisco, California) scanner. Forty contiguous 3-mm slices were acquired during a single breathhold beginning at the carina with a 350 mm scan field, 100 ms/slice scan time and triggered at 80% of the R-R interval. Two contiguous pixels with attenuation coefficient >130 Hounsfield units were the minimum requirement for a calcium deposit. The coronary artery score, corresponding to the amount of plaque, was calculated with the Agatston (22) method by a technologist and reviewed by a physician blinded to all clinical data. The calcium percentile, an age- and gender-corrected index of plaque burden prematurity (17,23) shown to be powerfully related to prognosis (17), was derived from the University of Illinois database of 19,200 asymptomatic men and women by assigning a percentile comparing an individual’s calcium score to database subjects of identical age and gender. For example, a 60-year-old woman in the 75th percentile has more calcium than 74% and less than 25% of 60-year-old women in the database.
Subjects with calcium scores >0 were classified as EBT+; those without detectable coronary calcium were classified as EBT–.
Laboratory.
Fasting total cholesterol (TC) and triglycerides (TG) were determined using enzymatic methods on samples drawn on the same day as the EBT. High density lipoprotein cholesterol was measured after precipitation of apo B containing particles with phosphotungstate. Low density lipoprotein cholesterol was calculated using the Friedewald equation. The Framingham risk score was used to determine each subject’s computed risk (24).
Subjects were classified as NCEP higher or lower risk as follows: NCEP higher risk = LDLC 130 and/or HDLC <35 mg/dl; NCEP lower risk = LDLC <130 and HDLC 35 mg/dl.
Statistical analysis.
Tests of significance between groups were determined by using Student t test with the level of significance set at p < 0.05 (two-tailed). Chi-square analysis was used to test for differences between dichotomous variable groups. The STATVIEW (v.4.1) (Berkeley, California) statistical package was used for all analyses.
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Results
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Demographics, mean (± SD) plasma lipid values and mean (± SD) EBT results of the total population are shown in Table 1. A family history of premature CAD was common and was found in 50.7%. A history of hypertension was present in 17.8%, smoking in 7.2% and diabetes in 2.6%. The mean lipid values were not abnormal and were well within NCEP guidelines. The mean EBT calcium score of 96.1 was in the moderate range and the average subject was in the 31st percentile. NCEP higher risk was noted in 47.7% of the women and lower risk in 52.3%.
EBT+ versus EBT–.
EBT+ and EBT– women are compared in Table 1; 42% were EBT+ and 58% were EBT–. The EBT+ group was older (p = 0.0001) and more likely to have a history of hypertension (p = 0.005) compared with the EBT– group. There were no significant differences between EBT+ and EBT– groups for body mass index, diabetes, smoking history or family history of CAD. Total cholesterol (p = 0.0004), LDLC (p= 0.005) and TG (p = 0.02) were significantly higher in the EBT+ compared with the EBT– group. In the EBT+ group, 53.5% were classified as NCEP higher risk and 46.5% as NCEP lower risk. In the EBT– group, 62.3% were classified as NCEP lower risk and 37.7% as NCEP higher risk. Assuming a higher risk in subjects with EBT-defined subclinical CAD than in those without, correct identification by NCEP guidelines of either higher or lower risk was noted in 58.6% of the women.
The Framingham risk score was significantly higher in the EBT+ versus EBT– group in the total cohort of women, but was heavily influenced by the age difference. With age removed from the Framingham risk calculation, there was no significant difference between groups. The mean calcium score in the EBT+ group was 227, in the moderately severe range. The mean calcium percentile was 73%, and 90% of the subjects had scores that were in the 53rd percentile or higher (mean –1 SD).
The analysis of women 55 years of age is presented in Table 2. The total cholesterol (p = 0.04) and LDLC (p = 0.02) were significantly higher in the EBT+ group compared with the EBT– group. There were no significant differences in HDLC or age. The percentage of individuals classified as NCEP higher risk was significantly higher and the percentage of subjects classified as NCEP lower risk was significantly lower in the EBT+ compared with the EBT– group (p = 0.01), but 42.4% of the lower risk group were EBT+. Framingham risk scores were significantly higher in the EBT+ group (p = 0.004), primarily attributed to differences in LDLC. A history of hypertension was noted more frequently in the EBT+ compared with the EBT– group (p = 0.006). Other potential contributors to CAD risk, including a family history of CAD, diabetes mellitus and cigarette smoking, were not significantly different. Correct identification by NCEP guidelines of either higher or lower risk was observed in 65.5% of the younger group.
The analysis of women >55 years of age is presented in Table 3. The EBT+ group was significantly older than the EBT– group (p = 0.0004), but there were no significant differences in any lipid measurements or other potential contributors to CAD risk between the groups, and the Framingham risk scores were similar. NCEP higher and lower risk lipid profiles were equally distributed between the EBT+ and EBT– groups and were  50% in each category. Correct identification by NCEP guidelines of either higher or lower risk was noted in 52.2% of the >55 years of age cohort.
In the entire group of women, age was significantly related to coronary calcium score (r = 0.35, p < 0.0001) and the calcium scores were higher in women >55 compared with 55 years of age (279 ± 503 vs. 75.5 ± 106.1, p < 0.02). Further analysis revealed that the relationship of age to calcium score was significant in the >55 years of age group (r = 0.33, p < 0.0001) but not in the 55 years of age group (r = 0.07, p = 0.39). The calcium percentiles were significantly higher in the younger compared with the older women (83.8 ± 13.9 vs. 69.8 ± 20.8, p < 0.0005).
Calcium percentile, calcium score and lipid levels.
In the EBT+ group there were no significant correlations between calcium percentile and LDLC (r = 0.06, p = 0.49) (Fig. 1), HDLC (r = 0.03, p = 0.73) (Fig. 2), TC/HDLC (r = 0.001, p = 0.99) or TG (r = 0.04, p = 0.70). A similar absence of significant correlation was noted between calcium score and LDLC (r = 0.10, p = 0.29), HDLC (r = 0.17, p = 0.06), TC/HDLC (r = 0.001, p = 0.99) and TG (r = 0.11, p = 0.23).
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Figure 1 Correlation of electron beam tomography (EBT) calcium percentile and low density lipoprotein cholesterol (LDLC) in EBT+ women. r = 0.06, p= 0.49.
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Figure 2 Correlation of electron beam tomography (EBT) calcium percentile and high density lipoprotein cholesterol (HDLC) in EBT+ women. r = 0.03, p= 0.73.
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Discussion
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This investigation, for the first time, defines the relationship between NCEP higher and lower risk lipid guidelines and subclinical atherosclerosis in asymptomatic women as determined by EBT. It also demonstrates that the amount and prematurity of calcified plaque are not related to levels of the conventional lipid parameters.
General population.
As expected, EBT+ women were significantly older than the EBT– cohort and age accounted for a large portion of the difference in the Framingham risk scores between the groups. When age was eliminated from the Framingham risk calculation there was no significant difference between groups. Standard cardiovascular risk factors, including the presence of diabetes mellitus, smoking, hypertension and family history of CAD did not explain the difference between EBT+ and EBT– women. Although total and LDL cholesterol were significantly higher in the EBT+ compared with the EBT– group, the number of women with coronary calcification who would have been placed into the NCEP lower risk group (46.5%) is troubling from the clinical standpoint. The definition of NCEP lower risk used in this analysis employed an LDLC cut point of 130 mg/dl. If an LDLC cut point of 160 mg/dl (the value above which NCEP recommends drug therapy) had been used instead, a significantly greater number of women (75.2%, p = 0.0001) would have been classified as lower risk, yet exhibit evidence of CAD as represented by coronary calcification. Moreover, those women classified as lower risk had calcium scores and percentiles indistinguishable from those classified as higher risk.
Older versus younger women.
Analyses of women 55 and >55 years of age reveal that statistically significant differences between EBT+ and EBT– cohorts exist primarily in the younger age group, and are limited to higher total cholesterol and LDLC in the EBT+ group, accompanied by a higher incidence of NCEP higher risk and a lower incidence of NCEP lower risk subjects. A history of hypertension was reported in significantly more EBT+ younger than older women. Even in the younger cohort, however, only 57.6% of the EBT+ group was identified by NCEP higher risk lipid guidelines. In the older group there were no significant differences between the EBT+ and EBT– groups in any lipid measurement, NCEP higher and lower risk distribution, Framingham risk scores or demographic variables. Only 52.1% of the older EBT+ women were identified by NCEP guidelines. The calcium scores were lower in the 55 year cohort but the calcium percentiles were significantly higher, suggesting a more aggressive process in the younger group.
Relevance of EBT.
The importance of these findings is dependent on the relevance of EBT calcified plaque to CAD. The past decade has seen a proliferation of documentation, by postmortem studies (3–5), angiography (5–13) and intravascular ultrasound (25,26), of the direct proportionality of calcified plaque to total coronary plaque burden and obstructive CAD. This has been accompanied by reports substantiating the poorer prognosis (14–18) and likelihood of ischemia (27) associated with both increasing calcium score and increasing calcium percentile (17), as well as the superiority of EBT findings to conventional risk factors (17). The assumption that a population of women with a mean calcium score of 227 and percentile of 73% (i.e., the EBT+ group in this study) is at higher risk than a population of women with 0 scores is supported by all published studies as well as the recent ACC/AHA Consensus statement on EBT (19): "A negative test may be consistent with a low risk of a cardiovascular event in the next 2 to 5 years ... A high calcium score may be consistent with moderate to high risk of a cardiovascular event within the next 2 to 5 years." Dissemination of the concept that calcified plaque is not itself a risk factor, but rather reflects the effect or lack thereof of all risk factors on the endothelium, is crucial to identifying subjects who should be targeted for primary prevention.
The crucial role played by NCEP guidelines in promoting awareness of the need to identify and treat lipid disorders is incontrovertible. However, the lack of close correlation between the conventional lipid parameters that are incorporated into the NCEP higher and lower risk guidelines and the presence or absence of subclinical CAD suggests a possible role for other contributing factors. Investigation into LDL subclass distribution differences, Lp(a), homocysteine, infectious and inflammatory etiologies may provide some of the missing links (28–30).
The striking lack of correlation between any of the standard lipid measurements and the amount and percentile of calcified plaque (Figs. 1 and 2 and Results section), although counterintuitive, is consistent with arteriographic investigations of CAD patients, unselected for abnormal lipids, that have revealed no correlation between LDLC and disease severity (31,32) and further strengthens the necessity for identifying the agents that promote plaque development at levels of lipids not conventionally thought to be associated with CAD. It reinforces the observations from large clinical trials that report outcome improvements <40% in response to LDLC (33,34) and HDLC treatment (35) and the Framingham observation that 80% of people who develop CAD have the same total cholesterol as those who do not develop CAD (36).
Clinical implications.
Guidelines, by their nature, extrapolate conclusions from large population-based studies to decision making in individual patients, in whom such conclusions may or may not be relevant. Application of the NCEP higher and lower risk lipid guidelines to this population of asymptomatic women would not identify subclinical atherosclerosis, and therefore would result in neither dietary nor drug treatment of 47% of the individuals who have it. Moreover, those women who would not be treated, those with lower LDLC and higher HDLC levels, have similar amounts of total and age-corrected calcified plaque as those for whom treatment would be recommended. Conversely, treatment would be recommended for 37.7% of women who have no EBT evidence for subclinical atherosclerosis.
Of the total population, only 58.6% would be correctly identified as being either at higher or lower risk by the NCEP guidelines, using calcified plaque as the reference point. Women 55 years of age appear to be better served by the guidelines than those >55 years of age, with correct identification of 65.5% in the younger group compared with 52.2% in the older cohort. The shortcomings of using conventional lipid parameters are supported by Kuller et al. (37), who noted that treatment decisions such as lipid-lowering therapy based only on LDLC (130 mg/dl) and HDLC (<60 mg/dl) levels before menopause excluded the majority of women who had high calcium scores 10 years later and included many who had minimal risk of high coronary calcium scores. It appears reasonable, therefore, to incorporate the results of EBT evaluation into the decision-making process in individual patients to more appropriately allocate treatment to women who have already demonstrated unequivocal evidence for subclinical atherosclerosis. The underappreciated magnitude of CAD in women, far exceeding breast cancer, may warrant wider scale implementation of EBT in the asymptomatic population.
Study limitations.
Several factors may affect interpretation of the results of this investigation. First, this study did not measure clinical outcomes. However, there are considerable data supporting the direct relationship of EBT-determined plaque burden to coronary atherosclerosis (3–13) and documentation of the relationship between increasing plaque burden and increased CAD event risk (14–18). Second, there may be women who are at risk on the basis of exclusively soft, noncalcified plaque who are EBT–. However, these patients represent a small fraction of those who experience coronary events (17,26). Third, the bias implicit in the self-referral nature of a population concerned about CAD risk may result in conclusions that are not applicable to the population as a whole. However, they are valid for this population, reflect the concerns of women oriented towards primary prevention and are free from any selection criteria biases, particularly related to hypercholesterolemia. Fourth, questionnaire-based demographics may not be entirely accurate. However, EBT+ and EBT– groups would be equally affected.
Conclusions.
This study demonstrates the potential shortcomings of using NCEP guidelines to identify women with subclinical atherosclerosis, as defined by EBT, who should be targeted for aggressive primary prevention. Postmenopausal women at risk appear to be particularly difficult to identify by conventional risk-factor analysis. Use of EBT may have a significant impact in the treatment of the leading cause of death in the female population.
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Abstract
Methods