Coronary Calcium Screening 7

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71

Coronary Calcium Screening

An Epidemiologic Perspective

C

HRISTOPHER

J. O’D

ONNELL

,

MD

,

MPH AND

U

DO

H

OFFMANN

,

MD

From: Contemporary Cardiology: CT of the Heart:

Principles and Applications

Edited by: U. Joseph Schoepf © Humana Press, Inc., Totowa, NJ

7

INTRODUCTION

Because coronary artery disease (CAD) is the most frequent cause of death in industrialized nations (1) and the available tools for prediction of CAD onset are imperfect, there is a need for new methods to screen apparently healthy individuals to identify those at increased risk. Current risk prediction of CAD is based on the patient’s age and sex as well as on the presence and extent of established, modifiable coronary risk factors such as hypertension, hyperlipidemia, diabetes mellitus, and ciga- rette smoking. Risk prediction algorithms such as the Framingham Heart Study coronary risk score have been shown feasible and valid for CAD risk prediction in the United States population (2). As a consequence, those traditional risk factors and/or risk-factor algorithms have been incorporated into treat- ment guidelines for hyperlipidemia (3) and hypertension.(4).

However, coronary risk scores can explain only 70% of the overall risk for CAD and are more sensitive than specific.

Consequently, there is need to develop new strategies to identify patients at high risk, specifically among patients who appear to be at intermediate (i.e., 6–20% 10-yr risk) or low risk accord- ing to traditional risk factors (5,6).

Recently developed fast computed tomography (CT) techniques such as multidetector-row CT (MDCT) and electron beam CT (EBCT) now offer the opportunity to noninvasively detect and quantify coronary artery plaque burden (Figs. 1–4).

The conduct of both techniques and their similarities and differences are described in detail elsewhere in this book. These CT scanners are capable of nearly freezing the motion of the heart as a result of very fast image acquisition and synchroni- zation to ECG signals. Both have been shown to be highly sensitive for the detection of calcified coronary atherosclerotic plaques. A typical report from either MDCT or EBCT contains the Agatston score, a semiquantitative measure that is based on the area and a weighted density factor for coronary calcium.

In the past decade, a large number of studies have been conducted to examine the predictive value of CT coronary artery calcium (CAC) as a predictor for coronary risk. In addition, this technique has been shown to be capable of following the natural history of coronary atherosclerosis and tracking the

dynamics of coronary calcification under drug treatment. In this chapter, we review the strengths and limitations of available original research and discuss consensus statements of the American College of Cardiology/American Heart Association (ACC/AHA) regarding the use of CAC as an adjunct to established risk factors. We also provide insight into ongoing research and propose studies that could help to facilitate evidence-based practice guidelines.

CORONARY CALCIFICATION AND CORONARY ARTERY DISEASE

Experts agree that CT testing can determine whether calcifications are present in the walls of the coronary arteries. If calcification of any amount is present, it follows that atherosclerosis is present in the coronary artery. Hence, patients with no symptoms but with detectable calcification can be said to have coronary artery disease not detectable by the usual clinical tests (“subclinical atherosclerosis”). However, there is contro- versy regarding the relation of the calcification score to the prevalence of CAD and the incidence of cardiac events such as unstable angina, myocardial infarction, and sudden cardiac death.

Early studies by Rumberger (6a) showed that there is a lin- ear relationship between the amount of calcium and the overall amount of atherosclerotic plaque. Logically, a number of studies have shown that high Agatston scores are associated with the presence and number of obstructive coronary artery lesions.

While the technique appears to be quite sensitive, there is no one-to-one correlation, and the location of calcification and stenosis may be different. Two meta-analyses evaluated the diagnostic accuracy of CAC (EBCT) for the detection of significant coronary artery stenosis as compared to coronary angiography. In both studies, the overall sensitivity and speci- ficity of CAC were 80–90% and 40–50%, with a maximum joint value of 75%, respectively (7,8). Moreover, the summary odds ratios were increased 20-fold (95% confidence interval [CI], 5 to 88) indicating that the odds of having a significant coronary artery stenosis are 20 times higher if calcium was detected. However, the generalizability of these studies is limited—most of the patients were middle-aged men. Apart from a small number of studies where most patients were referred to angiography as a result of chest pain, the indication for coronary angiography was not specified. However, most likely almost all patients were symptomatic for CAD or had known

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72 O’DONNELL AND HOFFMANN

CAD. Consequently, the prevalence of disease (CAD) was very high in the study populations (with one exception >50%, in about a third of the studies 70–95%), and the clinically important question “What is the probability of having/not having significant CAD given a positive/negative test?” (positive pre-

dictive value/negative predictive value) is difficult to answer.

In addition, most studies were designed only as observational studies, and blinding was not mentioned as a quality criterion in all but two of the analyzed studies. In summary, the available information is still limited, and the results cannot be general- Fig. 1. A cross-sectional image through the aorta and the origin of the

left coronary artery (dashed arrow). A moderate amount of calcification can be easily identified as bright signals (solid arrows).

Fig. 2. A cross-sectional image through the aorta; a moderate amount of calcification can be easily identified as bright signals (arrows).

Fig. 3. A cross-sectional image through the aorta (Ao), the left ventricle (LV) and the right atrium (RA). Left image: high image quality, no image artifacts, aortic valve calcification. Right image: image artifacts in the right coronary artery (solid arrow) and mitral valve calcification (dashed arrow).

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ized. As a consequence, the use of CAC for the accurate prediction of prevalent significant CAD has not been implemented into clinical guidelines.

PREDICTIVE VALUE OF CORONARY CALCIFICATION FOR CARDIOVASCULAR EVENTS

Clinicians are currently interested in the role of CAC in prediction of cardiovascular events. Since a large proportion of all cardiovascular events occur in asymptomatic patients, it is justified to differentiate asymptomatic persons from symptomatic patients with known CAD.

CORONARY CALCIFICATION IN ASYMPTOMATIC PERSONS

A small number of prospective studies have evaluated the prediction of cardiac events by coronary calcification. In a recent meta-analysis of prospective studies, there was an increased risk for a combined outcome (nonfatal myocardial infarction [MI], congenital heart disease [CHD], death, or revascularization) associated with a calcium score elevated above a median value (risk ratio 8.7 [95% CI, 2.7–28.1]). The relative risk of hard endpoints (MI or death) was also increased (risk ratio 4.2 [95% CI 1.6–11.3]) (9). Three more recent prospective studies have added data from more than 20,000 patients to the meta-analysis. In 5635 asymptomatic, low-to- medium-risk men and women self-referred for EBCT, there were 224 events, of which only 61 were “hard” endpoints (MI

or death) after 37 ± 12 mo of follow-up. After adjustment for risk factors ascertained by questionnaire, there were statistically increased risks associated with the presence of CAC for hard events in men (95% CI, 3.9 [1.2–13]) and no significantly increased risks in women (95% CI, 1.5 [0.2–10]) (10). In a second prospective study of all-cause mortality in 10,377 self- referred men and women, there were 249 deaths in approx 60 mo of follow-up. Increasing CAC scores were associated with significantly increased relative risks for death, and receiver operating characteristics (ROC) curves were significantly greater for CAC score added to risk factors compared with risk factors alone (p < 0.001) (11). In a third prospective study of 5585 men and women recruits in whom an EBCT test was obtained to decide upon eligibility for inclusion in a random- ized controlled lipid lowering trial, there were 122 events, of which 43 were hard events after over 50 mo of follow-up.

Overall, there were statistically increased risks for hard events (9.9 [5.2–18.9]) as well as all endpoints associated with a high CAC score. In an analysis of the incremental predictive ability of CAC over Framingham risk score in a subset of 1817 subjects in whom risk factors was measured, there was a several- fold increase in risk for cardiovascular endpoints in the highest compared with the lowest tertile of CAC score (12).

LIMITATIONS OF THE AVAILABLE DATA

While there is consistency across the available studies for an association of CAC scores with the presence of significant CAD Fig. 4. A cross-sectional image through the aorta and the left atrium. Left image: high image quality, no image artifacts, arrow pointing at the circumflex and the left coronary artery. Right image: image artifacts in the circumflex, the left coronary artery, and the aortic valve (arrows).

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and the risk of cardiovascular events, a number of method- ological concerns make it difficult to interpret study results and apply them to clinical practice. Importantly, there are concerns regarding study generalizability/external validity, validity of the risk factor measures, and resultant multivariable models used in the studies. In addition, the conclusions are drawn from relatively small numbers of hard cardiovascular outcomes (all together numbering only several hundred).

A major limiting factor of most studies has been the inclusion of self-referred patients. None of the available evidence for CAC screening has been drawn from community-based cohorts representative of typical populations which might be considered for screening. Subjects studied to date have a high prevalence of subclinical CAD and CAD risk factors, often making them different from persons in the community of a similar age and sex. The baseline characteristics of many of these cohorts suggest that patient populations already at substantially elevated risk have been studied. Thus, data from these studies may not be representative of apparently healthy low- and medium-risk groups for whom screening may be more relevant. Moreover, the self-referred subjects to date may differ significantly in other unmeasured characteristics that accompany health-seeking behaviors.

In the available studies, data are limited for young persons, women, and non-Caucasians. Much of the data to date have been derived largely from middle-aged Caucasian men. As a consequence of this selection bias, age- and gender-specific CAC thresholds for younger individuals for subjects below 40 yr of age, women, and non-Caucasian populations may be relatively unreliable due to lack of statistical power (small sample sizes, insufficient numbers of events) or wholly unavailable. Potentially important racial differences in prevalence of CAC have been noted in the Multiethnic Study of Atherosclerosis (MESA) (13); in particular, the prevalence of CAC appears to be lower in African Americans and other major ethnic groups in the United States (14–16).

Another significant concern pertains to the method of ascer- tainment of risk factor data. It has been suggested that a high CAC score predicts coronary risk independently and probably incrementally to traditional coronary risk factors and coronary risk scores. ROC curve analyses are often provided to bolster the case for CAC screening over and above risk factors. How- ever, in virtually every available study, blood pressure determi- nations, lipid levels, and other risk factors are obtained retrospectively by questionnaire, self-report from the study patient, and/or review of the medical record. There is a substantial risk of misclassification in self-reported risk-factor data.

Therefore, calculations of Framingham coronary risk or other multivariable risk models using self-reported risk factors algorithms would tend to underestimate the risk conferred by risk factors (bias towards the null) and lead to a more favorable comparison of CAC scores with risk factors. Standardized research methods that mirror office-based methods for mea- surement of blood pressure, lipid levels, and diabetes have not been employed in the available studies. By way of contrast, prospective epidemiologic cohort studies such as the Framingham Heart Study and the Multiethnic Study of Athero-

sclerosis are recording risk factor data prospectively. A final set of concerns pertains to study follow-up and outcomes. First, the level of completion of follow-up is inconsistent across studies, with some studies having less than 90% follow-up. For example, in one of the largest recent studies, only a 64% fol- low-up was achieved (10). Losses to follow-up can raise ques- tions about the validity of study findings. A second concern is the focus of the available studies on either combined hard (i.e., MI and death) and/or soft (i.e., revascularization using percu- taneous coronary interventions or coronary artery bypass sur- gery) outcomes. Soft intervention outcomes are often used, but may not be appropriate because neither the study patients nor their physicians were blinded to the CAC score. Thus, given the fact that many patients were self-referred and not part of a blinded study, there is a substantial risk that soft outcomes may be contaminated by intervention bias introduced by knowledge of the CAC test results. No study with cardiovascular mortality as a primary outcome has been reported to date, and in virtually all available studies, there have been too few cardiovascular deaths to reliably examine the association of CAC. The recent study of Shaw et al. shares many of the limitations of the other self-referral studies, but it did report a positive association of CAC score with all-cause mortality (11). One strength of the Shaw study was its demonstration of consistent, statistically significant increases in mortality across increasing CAC scores in a large cohort. Nevertheless, mortality data were drawn from the National Death Index, and no further data on cause of death or on non-fatal outcomes were ascertained (11).

Interestingly, there is a small and growing body of evidence in population-based cohorts that calcification of the aorta predicts risk for CAD and other cardiovascular diseases independent of measured risk factors. The prevalence of calcified lesions detected on thoracic and abdominal radiographs like that of coronary calcium, increases steeply with age (17). A number of recent studies have demonstrated that thoracic and abdominal aortic calcifications are independent, prospective predictors of CVD. Calcification of the aortic arch detected by plain antero-posterior radiographs predicts an increased risk of cardiovascular diseases in men and women (18). In the Framingham Heart Study, the presence and extent of abdominal aortic calcification detected by lateral lumbar radiographs is a predictor of CVD, CVD mortality, and CHD in middle- aged men and women (mean age 60 yr), independent of age and actually measured cardiovascular risk factors (17). Abdominal aortic calcification would likely be detected quite reliably and accurately by CT imaging, and further study of the prognostic value of such CT findings in addition to or instead of coronary calcium is clearly warranted.

ADDITIONAL QUESTIONS SURROUNDING CAC SCREENING

A number of additional concerns have arisen surrounding CAC screening and are summarized in Table 1. First, the CT test does lead to significant exposure to radiation. The test exposes the patient to a limited amount of ionizing radiation (0.7 to 3 mSv) that is equivalent to 25–100% of the natural background radiation exposure that an individual in the United

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States receives per year (2.5 to 3 mSv). This is less than the dose received during a diagnostic cardiac catheterization (approx 4.5 mSv) and only a fraction of the occupational exposure limit for a radiation worker in the United States (50 mSv/y). Although the available data suggest that these risks are extremely low from such exposure (19), for some individuals even this low risk may be considered unacceptably high. Second, several recent studies have demonstrated that there is a high prevalence of potentially clinically important findings that are incidentally detected on CT scans (20,21). Such incidental findings may provoke significant anxiety in the patient and may require

additional exposure to radiation or even invasive testing in order to confirm or exclude a potentially serious diagnosis such as an aortic aneurysm or malignancy. Third, as mentioned above, unbiased data on age-adjusted coronary calcium thresholds are not yet available, because the available data are derived from cohorts that may or may not be representative of general screening subjects. Moreover, simple thresholds (such as an Agatston score of 400) that do not adjust for age may overestimate risk in older persons and underestimate risk in younger persons (Fig. 5) (22). A fourth and related concern is the fact that many different CT scan machines are now available (including both Fig. 5. 90th Percentile Agatston scores derived from large numbers of men and women screened with electron beam CT. Data from ref. 22.

Table 1

Suggested Guidelines and Implications for Coronary Artery Calcium Scoring (Adapted From Partner’s HealthCare System 2002 Guidelines) Guidelines for ordering a CT test for coronary calcium

Coronary calcium screening is not recommended for asymptomatic individuals at low risk.

Coronary calcium screening will be performed only upon a physician’s request.

Patients should be informed that most insurers do not reimburse for coronary screening. The out-of-pocket expense for a multidetector-row CT test for coronary calcium is $350–$450.

A positive calcium score might be valuable in determining whether a patient who appears to be at intermediate congenital heard disease (CHD) risk is actually at high risk. However, we do not currently recommend coronary calcium scoring for this group.

Ongoing research will better define the clinical subgroups, such as elderly asymptomatic persons or those with a strong family history, in whom the management of other risk factors might be modified according to the calcium score.

Guidelines for Interpreting a CT Test for Coronary Calcium

Some patients and physicians will choose to obtain coronary calcium studies despite the lack of consensus for these studies. We recognize that clinicians who might not have ordered the test themselves are increasingly faced with the test “results” and asked for their advice. Therefore the following comments are provided from the recent ACC/AHA consensus document:

In the absence of coronary calcium (i.e., a “negative” CT test)

Atherosclerotic plaque, including unstable plaque, is very unlikely, although it is possible that significant coronary atherosclerosis may not be detected.

Significant luminal obstructive disease is highly unlikely.

Angiographically normal coronary arteries occur in the majority of such patients.

The absence of calcium may be consistent with a low risk of CHD events over the next 2 to 5 yr.

For a test that is positive for coronary calcium:

The presence of calcium confirms the presence of a coronary atherosclerotic plaque.

The greater the amount of calcium, the greater the likelihood of occlusive coronary artery disease, although there is not a one-to-one relationship, and findings may not be site specific.

The total amount of calcium correlates best with the total amount of atherosclerotic plaque, although the true “plaque burden” is underestimated.

A high calcium score (e.g., Agatston score > 400) may be consistent with moderate–high risk of CHD events over the next 2–5 yr.

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EBCT and MDCT machines) and standardized scanning and scoring algorithms have not been implemented across machine types. Moreover, there is a small but significant level of mea- surement variability consistently seen across all scanner types, and the degree of variability may differ. Fifth, all CAC scoring to date has been conducted using the Agatston score. While the Agatston score has provided an invaluable reference score for research to date, newer mass-based scoring techniques may substantially reduced the misclassification introduced by image noise. A final concern regarding CT scanning is its currently high cost. The cost for the test ranges from $375–$450, and the test is not currently covered by most health insurance providers.

CRITICAL EVIDENCE NEEDED FOR CLINICAL GUIDELINES

Both risks and benefits must be considered for any potential screening test. The benefits would include potential for reduc- tion of risk provided by an accurate diagnosis of increased risk and the potential benefits from early detection of incidental findings (e.g., small lung cancers). The risks include the morbidity and mortality risk of an incorrect diagnosis (negative or positive), risks of radiation exposure, morbidity and mortality from detection of benign incidental findings, and high costs of potentially unnecessary testing. The current body of studies suggests that there may be a role for CAC screening, but to date there are no strong unbiased data for or against CAC screening over and above traditional risk-factor assessments in the general population. The limitations of existing studies can be addressed only by prospective, observational studies conducted in unbiased, population-based cohorts of both Caucasian and non- Caucasian men and women. It has been suggested that coronary calcium screening may be most beneficial in persons at intermediate coronary risk (5,6). At least 40% of the population of middle-aged men and women may fall into this category (5).

In the proposed studies, risk-factor measurements should be office-based rather than self-reported. Ideally, measures of risk factors as well as coronary calcification would be conducted in as blinded a manner as possible. Several such population-based studies are currently underway. These studies include the Framingham Heart Study and the Multiethnic Study of Athero- sclerosis. Final recommendations regarding use of CT calcium awaits the completion of these studies.

CONCLUSION

Coronary atherosclerosis underlies CHD and is influenced by the interaction of multiple risk factors over time in a suscep- tible host. Traditional risk-prediction models, such as the Framingham risk score, are reasonable predictors of CHD risk.

Interest in CAC screening is aimed at improving the prediction of risk for future clinical events. Future studies will need to ascertain the incremental benefit of CAC measures over traditional risk factors and the cost effectiveness of incorporating such measures into global risk-assessment algorithms.

In the future, CAC tests may play an important role in assessment of patients at intermediate risk for CHD events.

Higher-risk individuals may be candidates for more aggres- sive pharmacological risk-factor modification using combi-

nations of lipid-lowering agents, anti-platelet therapies, and angiotensin-converting enzyme inhibitors. While the optimal indications for the use of noninvasive tests for clinical moni- toring of the response to therapy remain to be determined, existing expert consensus statements such as that provided by the ACC/AHA in 2000 provide cogent standards for the present time. CAC testing has not yet been reliably shown to add incremental information for risk stratification in general- izable patient cohorts, and ongoing studies should address the important outstanding questions regarding the appropriate types of men and women in whom to consider coronary calcium screening.

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