Coronary artery calcium screening: implications for clinical practice

For reprint orders, please contact: reprints@futuremedicine.com REVIEW Coronary artery calcium screening: implications for clinical practice E Ferramosca, MD, A Bellasi, MD, Carlo Ratti, MD, Paolo Raggi, MD, FACP, FACC Author for correspondence Tulane University School of Medicine, 1430 Tulane Avenue SL48, New Orleans, Tel.: +1 504 588 5492; Fax: +1 504 587 4237; praggi@tulane.edu Cardiovascular disease is the most common cause of death in the Western hemisphere, and in the majority of cases the event announcing the presence of atherosclerosis is either sudden death or a disabling myocardial infarction or stroke. Although traditional risk factors are present in most individuals suffering a cardiovascular event, the prognostic ability of risk factors to predict events in the short term is limited. The focus of research has therefore turned to the application of noninvasive modalities to image the atherosclerotic plaque in its preclinical stages. Measurements of coronary artery calcium serve as a quantitative reflection of the severity of coronary artery disease, and greater calcium burdens correlate with more advanced disease. Coronary artery calcium has been shown in several studies to add prognostic value to traditional risk factors in patients at intermediate risk, and in this group of patients it may be cost effective. There is, however, an inherent danger in raising the cost of care by increasing downstream unnecessary testing if such screening were to be applied to low-risk individuals. This article is a systematic review of the most relevant literature regarding the utilization of coronary artery calcium screening as a tool to refine risk assessment and to evaluate the efficacy of therapy for atherosclerosis. Keywords: cardiac, computed tomography, coronary artery disease, coronary calcium, outcome, prevention During the past several years a number of new noninvasive technologies have been developed to detect subclinical atherosclerosis. Tests such as electron beam computed tomography (EBCT) and multi-detector computed tomography (MDCT) allow the detection and quantification of coronary artery calcium (CAC), a marker of atherosclerosis, in a much more accurate fashion than fluoroscopy or conventional and digital radiography [1,2]. Numerous studies have correlated the extent of coronary calcium measured by computed tomography (CT) with angiographic findings and found a fair specificity and sensitivity for detection of obstructive luminal disease [3 5]. Nonetheless, the best use of coronary calcium screening is the assessment of the extent of plaque burden which provides an indication of the probability of coronary stenosis. In a histological study, Mautner and colleagues examined 1298 segments from 50 heart specimens and observed that 93% of arteries with greater than 75% stenosis harbored CAC [6]. Conversely, only 14% of arteries with a luminal stenosis of less than 25% harbored CAC. CAC deposition is intimately associated with the development of coronary atherosclerotic plaques. Although it is detectable by CT only in advanced stages of vascular disease, its deposition begins very early in response to vessel wall injury by various noxious stimuli [7]. Furthermore, calcification of the atherosclerotic plaque occurs via an active process of mineralization with deposition of hydroxyapatite crystals and not simple mineral precipitation [8,9]. Findings in numerous studies indicate that CAC accumulates in different amounts and at different ages in the two genders, although it is clear that in both men and women the extent increases with age. Despite the fact that women show an approximate 10 year delay in CAC development compared with men, this difference disappears at the age of 70 years [10]. In view of its nature as a marker of atherosclerosis, CAC detected with CT screening may help refine risk assessment conducted by means of risk-factor analysis especially in the gray area of intermediate risk. In the following sections, the evidence available in the current medical literature on utilization of CAC for risk stratification of symptomatic as well as asymptomatic individuals shall be reviewed, and therapeutic effectiveness will be subsequently discussed. Coronary calcium screening in asymptomatic individuals The approach to cardiovascular risk assessment with tools such as the Framingham or PROCAM algorithms [11,12], requires the consideration of the combined effect of multiple risk factors such as age, hypertension, hyperlipidemia, smoking and diabetes mellitus. These assessments, however, provide reliable data on the median risk of coronary heart disease in a population with a defined risk profile [13,14], but 10.1517/14796678.1.2.215 2005 Future Medicine Ltd ISSN 1479-6678 Future Cardiology (2005) 1(2), 215 223 215

REVIEW Ferramosca, Bellasi, Ratti & Raggi do not allow a clear discernment of the risk of a single individual. Since CAC is an accurate marker of atherosclerosis, many investigators have tried to validate its prognostic value for cardiovascular events both singly and in addition to traditional risk factors. Rumberger and colleagues reported a strong correlation between coronary calcium scores (CS) measured on EBCT with histological calcium measurements [4]. Increases in plaque area were invariably associated with greater amounts of CAC [4]. Low or negative CS have correspondingly been found to be associated with low atherosclerotic plaque burdens and low overall disease severity. Interestingly, the absence of visible CAC on a screening EBCT has been associated with an extremely low risk of cardiac events at least in the short to intermediate term, less than 0.5% yearly. In fact, the negative predictive value of a negative EBCT scan has been reported to range from 84 to 100% [15,16]. A well-rooted opinion considers coronary calcification a stabilizing phenomenon of the atherosclerotic plaque. Indeed, limited in vivo and in vitro studies of stenotic coronary artery segments showed that calcified plaques are less elastic and probably less prone to rupture than areas rich in lipid [17,18]. Nonetheless, other reports demonstrated that calcified lesions approached by interventional catheter-based techniques are more prone to dissection [19]. At this stage of our understanding of the pathophysiology of vascular calcification, it seems prudent to state that it is not clear whether presence of calcium in a individual plaque renders it more or less stable. However, it is quite obvious that the presence of extensive calcium deposits in a subject increases that individual s probability of cardiovascular events several fold. Hence, the calcified patient is at high risk for events, and the focus of prevention has changed from the high-risk plaque to the high-risk patient. A study of 98 asymptomatic subjects (mean age: 62 ± 10 years) with very high coronary CS (greater than 1000) provides good supportive evidence for this theory [20]. The individuals in this study did not undergo any further test driven by the results of the EBCT scan, but were monitored for the occurrence of myocardial infarction and death for an average of 17 ± 1 month (range: 4 to 36 months) after undergoing EBCT screening. During the follow-up period they suffered 35 hard events, mostly within the first 28 months of follow-up, at the extremely high rate of 25% yearly. Patients with hard events had significantly greater CS than patients without events, while age and risk factor distribution did not differ. The authors concluded that a high CS (greater than 1000), on a screening EBCT in an asymptomatic person, portends a very high risk of coronary events in the short term and appears to be greater than the risk associated with a severe perfusion abnormality on myocardial scintigraphy [20]. Hence, extensive calcification of the coronary tree is a harbinger of poor prognosis and it should not be seen as protective against dramatic events. Several investigators analyzed the contribution of coronary calcium screening to risk prediction. Arad and colleagues published two reports each involving over 1100 patients screened by EBCT and followed for 19 months and 36 months, respectively [15,21]. The investigators enrolled mostly self-referred patients and reported on the association of CAC with both soft and hard coronary events. The relative risk of events in the upper two quartiles of CS ranged from 15 to 22 times that of patients in the lower quartiles. In a direct comparison, the area under the receiver operating characteristic (ROC) curve for prediction of events was greater when using CS than that obtained employing risk factors alone [15]. These studies were partly criticized for having included self-referred patients and having reported a mixture of soft events including: hospital admission for unstable angina and revascularizations, and hard events such as death, myocardial infarction and stroke. Wong and colleagues followed 926 asymptomatic individuals for an average of 3.3 years after an EBCT screening scan [22]. The two highest quartiles of CS were associated with a 4.5- and 8.8-fold increase in risk of coronary artery disease compared with those in the lowest quartile. In a cross-sectional prospective study conducted in Rotterdam, Holland, the investigators researched the association of a history of myocardial infarction with findings on a screening EBCT [23]. Of the 2013 patients enrolled in the study, 229 had had a prior myocardial infarction. Compared with subjects in the lowest CS category (0 100), men in the highest CS category (above 2000) demonstrated an age-adjusted odds ratio for myocardial infarction of 7.7, while for women the odds ratio was 6.7. Kondos and colleagues followed a cohort of 4151 men and 1484 women for an average of 37 ± 13 months [24]. The authors were able to determine that men had an 216 Future Cardiology (2005) 1(2)

Coronary artery calcium screening REVIEW eightfold greater chance of suffering a hard event if they were in the top quartile of CS compared with the lowest quartile, and a magnitude greater chance of suffering soft and hard events combined. Women did not sustain enough hard events, but when hard and soft events were combined (defined as clinically indicated revascularizations), subjects in the top quartile of CS had a relative risk ten times higher than women in the lowest quartile to suffer an event. In both genders a gradual increase in risk was noted as the score increased [24]. Despite these encouraging results, a frequent criticism directed toward the use of coronary calcium CT screening is that it has not firmly established that coronary calcium adds incremental value to prediction of hard cardiovascular events beyond established cardiac risk factors. Such tenets were supported by reports such as an early study by Detrano and colleagues [25]. In that study of 1196 older subjects with high pretest probability of disease, the investigators reported that the area under the ROC curve (AUC) did not differ between risk factors and CAC, nor did the AUC described by risk factors increase when the calcium information was added to a logistic model containing the Framingham risk data [25]. However, other researchers have investigated whether coronary calcium is a better predictor of events than traditional risk factors, or whether calcium adds incremental prognostic value to traditional risk factors and have reached conclusions contradictory to those of Detrano and colleagues. Raggi and colleagues compared the ability of coronary calcium and traditional risk factors to predict myocardial infarction and death in a cohort of 676 intermediate-risk individuals referred by primary care physicians for EBCT calcium screening [26]. During a followup period of 3 years, 30 hard events were recorded. ROC curves were used to ascertain the ability of the different methods (EBCT calcium screening and conventional risk factors) to predict myocardial infarction or death. Age- and sex-specific CS were the best predictive model for the occurrence of hard coronary events and added incremental prognostic information to conventional risk factors for coronary artery disease [26]. Shaw and colleagues reported on allcause mortality in 10,377 asymptomatic subjects followed for an average of 5 ± 3.5 years after undergoing an EBCT screening test [27]. At the end of the follow-up period, a total of 249 deaths were recorded (death rate 2.4%) with very similar rates for men (2.3%), and women (2.5%). In both genders, CAC was an independent predictor of death (p < 0.001), and the risk increased proportionally to the baseline CS: a fourfold increase in relative risk was measured for an increase in CS from 10 to greater than 1000. In multivariable models the addition of CS information to risk factors for coronary artery disease significantly increased the ability to predict death (p < 0.001), demonstrating that coronary calcium adds incremental prognostic information to the presence of risk factors [27]. In a recent publication, Greenland and colleagues reported on 1312 patients, 45 years of age or older, assessed for the occurrence of hard cardiovascular events after 8.5 years from CT screening [28]. The presence of CAC was predictive of events (HR = 3.9 compared to no CAC), and added incremental prognostic information to risk factors in patients with a baseline Framingham risk of hard events at 10 years greater than 10%. Hence, both reports by Shaw and colleagues [27] and Greenland and colleagues [28], highlighted the important point that CAC may be a useful tool in clinical management and add prognostic information in the intermediate-risk patient and therefore, should not be used in very low or very high-risk groups for a more cost-effective use. Table 1 summarizes some of the data from the studies discussed above. In a meta-analysis of several studies of coronary calcium screening in asymptomatic subjects, O Malley and colleagues concluded that the risk of hard and soft events is increased 8.7-fold and the risk of hard events is increased 4.5-fold in the presence of CAC [29]. In a more recent meta-analysis [30], Pletcher and colleagues estimated that the relative risk of a hard event ranged between two and 17 for patients with CAC, but varied significantly among studies. Such heterogeneity may be due to the differences among studies in the way an outcome was adjudicated (blinded or not), measurement of risk factors (direct or by patient history), CT technical settings, and/or proportion of female subjects enrolled in the study. An example of a patient who might benefit from CAC screening is presented here. A 55 year-old man presents for a regular physical exam at his primary care physician s office. This patient has a smoking history of 20 years, a total serum cholesterol level of 224 mg/dl, a blood pressure of 130/80 mmhg and a family history of premature coronary artery disease. The patient s Framingham risk for hard coronary events at www.futuremedicine.com 217

REVIEW Ferramosca, Bellasi, Ratti & Raggi Table 1. Summary of multiple studies performed in asymptomatic subjects that investigated the association of coronary artery calcium and the occurrence of cardiovascular events. Primary author No. of patients Mean follow-up (years) Type of events Arad Y 1173 1.5 Stroke, myocardial infarction, death and revascularizations No. of events Refs 26 [15] Detrano R 1196 3.4 Myocardial infarction and death 46 [25] Arad Y 1172 3.6 Myocardial infarction, death and revascularizations 39 [21] Raggi P 676 2.5 Myocardial infarction and death 30 [26] Wong N 926 3.3 Stroke, myocardial infarction, death and revascularizations 41 [22] Shaw L 10,377 5 All-cause death 249 [27] Vliegenthart R 2013 N/A Myocardial infarction 229 [23] Kondos G 5635 3 Myocardial infarction, death and 224 [24] revascularizations Greenland P 1029 7.0 Myocardial infarction and death 84 [28] Total 22,197 827 10 years is calculated at 16%, i.e., intermediate risk. Using a Bayesian model, the pre- and posttest probability of cardiovascular events can be estimated, based on the quantity of CAC revealed by the CT screening test. If the patient were to undergo a screening test for CAC and the test were negative, the post-test risk could be considered lower, on the order of 5 to 6% at 10 years, than estimated based on risk factors alone [31]. In this case, simple risk-factor modification may suffice to address his risk of cardiovascular disease. If however, the test revealed a coronary CS of greater than the 50th percentile for the age and gender of this patient, the posttest risk would be elevated to 27% at 10 years. In the latter case, very aggressive lifestyle changes and medical therapy should be initiated [31]. As stated, the studies outlined above have analyzed the impact of CAC as a predictor of events in subjects at intermediate pretest probability of disease. It remains to be determined whether CAC might be a useful predictor even in subjects at high risk. An example of high-risk individuals is provided by diabetic patients, who are considered coronary artery disease equivalents given their extremely high incidence of cardiovascular events. CAC has been described to be more abundant in diabetic patients and its extent is similar to that found in nondiabetic individuals symptomatic for coronary artery disease. In a large observational study, Raggi and colleagues showed that the presence of any degree of CAC in patients with diabetes mellitus portends a higher risk for all-cause mortality than in nondiabetic patients [32]. Additionally, the absence of CAC indicated a low short-term risk of death for diabetic patients, as well as subjects without diabetes, with approximately 99% survival at 5 years in both groups. Hence, the absence of measurable atherosclerosis appears to be an important modifier of outcome, even in the presence of established severe risk factors for atherosclerosis such as diabetes mellitus [25]. These observations need to be expanded and if confirmed in subsequent studies, may open a new venue to risk assessment in asymptomatic subjects independent of the underlying risk profile. Coronary calcium screening to perform risk assessment in symptomatic patients Coronary calcium screening has been employed to assess risk of cardiovascular events in symptomatic individuals besides the asymptomatic subjects. An early publication that 218 Future Cardiology (2005) 1(2)

Coronary artery calcium screening REVIEW demonstrated the prognostic value of coronary calcification in symptomatic patients was released by Margolis and colleagues [33]. Using fluoroscopy on 800 patients referred for angiography, the authors noted an increased 5 year mortality rate in subjects with compared to those without CAC (87 and 58%, respectively). This association was independent of age, gender and number of angiographically diseased vessels [33]. More recently, Detrano and colleagues examined the prognostic value of CAC detected by EBCT for predicting cardiovascular events in 491 patients undergoing cardiac angiography [34]. They described a strong association between CS and coronary heart disease-related events (cardiac deaths and nonfatal myocardial infarction), during a 2.5 year follow-up. Subjects with a median CS greater than 75 were six times as likely to experience a coronary event as those with a score below this CS level and event frequency increased significantly across ascending quartiles of CS [34]. Logistic regression models demonstrated that CS was the only independent predictor of events unlike angiographic stenosis or patient s age. These findings were replicated and the notion confirmed by Keelan and colleagues in a study of 288 symptomatic patients submitted to EBCT and coronary angiography within a few weeks of each other [35]. The mean follow-up was longer (6.9 versus 2.5 years), and the median CS was higher (160 versus 75) than in the study by Detrano and colleagues [34]. The relative risk of a hard event was 3.2-fold higher in subjects with a CS of greater than or equal to 100 compared with those with a CS of less than 100. In a multivariable model only CS and age were independent predictors of an event [35]. Möhlenkamp and colleagues assessed the risk associated with a very high CS (greater than 1000) as opposed to a moderate CS (100 400) or moderate high CS (400 1000) in patients with stable symptoms of CAD [36]. The follow-up of these 150 patients lasted 5 years. Patients with very high CS suffered more frequent events such as all-cause death, cardiac death, stroke, nonfatal myocardial infarction and revascularizations, and at an earlier time than any patient in the other categories of CS. Presence of left main coronary artery stenosis at angiography and CS were independent predictors of hard events. Finally, Schmermund and colleagues followed 300 patients with recent onset (less than 3 months) of angina symptoms to verify whether CAC adds prognostic information to known risk factors for atherosclerosis, exercise stress testing and coronary angiography results [37]. A complete follow-up of 3.5 years was possible on 85% of the original cohort. Major adverse cardiac events (MACEs) including death, nonfatal myocardial infarction and revascularizations, were predicted well by the clinical characteristics of the subjects. Nonetheless, a CS of greater than 100 was independently predictive of MACE and remained independently predictive after corrction for age and clinical characteristics with an estimated relative risk of 4.4. It appears therefore, rather clear that CAC adds substantial prognostic information even in patients with stable symptoms of coronary artery disease. Another intriguing application of CAC screening is its use in the emergency room setting, mostly as a tool to exclude the presence of coronary artery disease with a high negative predictive value. Laudon and colleagues reported an initial observation on 105 patients, women 40 65 years of age and men 30 55 years of age, who presented to the emergency room with anginalike chest pain [38]. All patients underwent EBCT for detection of CAC, and 100 patients underwent other cardiac tests such as the standard treadmill stress test, imaging stress test or angiographic studies. CAC showed both a sensitivity and a negative predictive value of 100%, and a specificity of 63% compared with all other cardiac tests for detection of coronary artery disease. All 53 patients with a negative EBCT scan (CS = 0) remained free of cardiac events during a follow-up period of 4 months [30]. Georgiou and colleagues followed 192 subjects who presented to the emergency room with chest pain and had no evidence of myocardial ischemia and/or injury by either electrocardiogram (ECG) or serum markers [39]. All patients were managed according to standard emergency room protocols, but were also submitted to an EBCT test for CAC screening. The emergency room physicians and the treating physicians were kept blinded to the results of EBCT testing. At the end of a follow-up period of 50 months, absolute CSs were shown to effectively differentiate risk with cardiac events (30 hard events and 28 soft events), occurring at a rate of 0.6% per year in patients with no CAC and approximately 14% in those with a CS greater than 400 (Figure 1). The mean CS for those who did not suffer a cardiac event was 240 ± 698, as compared with 595 ± 636 for those who suffered a hard event [39]. In Cox regression models, CAC was a predictor of events independent of age, race, gender and risk factors for coronary artery disease. www.futuremedicine.com 219

REVIEW Ferramosca, Bellasi, Ratti & Raggi Figure 1. Graded increase in risk of hard events in low-risk symptomatic patients submitted to coronary calcium screening in the emergency room. Annual event rate % 16 14 12 10 8 6 4 2 0 0 1 100 101 400 >400 Calcium score Reproduced with kind permission from [39]. McLaughlin and colleagues evaluated the predictive value of a negative EBCT test in patients who presented to the emergency room with chest pain and no ECG changes suggestive of myocardial ischemia [40]. Out of 134 subjects, 48 (36%) had a negative EBCT scan. Excluding one cardiac event in a cocaine user, there were no events in the group without CAC within 30 days of follow-up. The remaining 86 individuals (64%) had a positive EBCT scan with a mean CS of 243. Of these, seven suffered an event (8%), and their mean CS was 322. All the above studies confirm the high negative predictive value of the absence of CAC in low-risk symptomatic patients either in the emergency room setting or in daily clinical practice. A positive CAC test should instead be taken as an indication of substantial risk when the absolute or percentile CS exceeds the two upper quartiles. This approach could potentially provide a substantial cost saving by inducing avoidance of unnecessary further testing, while concentrating resources of those individuals in greatest need of invasive testing. Additionally, knowledge of the presence of atherosclerosis even in the absence of luminal stenosis should help both patients and physicians in steering a more aggressive treatment of all underlying risk factors. Conclusions & future perspective CAC screening has been the center of an animated debate for a long time. Evidence has accumulated that CAC screening can be a useful tool to improve risk prediction for asymptomatic subjects with intermediate pretest probability as well as symptomatic patients, at low pretest probability of disease. This view is supported by expert opinion [41,42] and in part by large professional associations such as the European Society of Cardiology (ESC) and the American College of Cardiology/American Heart Association (ACC/AHA), or the National Cholesterol Education Program (NCEP-III) [43 45]. The latter, in agreement with the position expressed in the Prevention V report of the ACC/AHA [44], recognized that a high CS score carries predictive power for major coronary events in persons with multiple risk factors. In such patients a concomitantly high CS places subjects in the range of a coronary heart disease risk equivalent. Nonetheless, the NCEP-III did not recommend indiscriminate screening for CAC in asymptomatic persons, particularly in persons without multiple risk factors. Furthermore, NCEP-III specified that a referral for screening should always be provided by a physician and that CAC should be used to evoke a follow-up invasive test only in exceptional cases. The ESC remarked again that CAC should not be used as a marker for underlying coronary luminal stenosis, but rather as a tool to improve risk assessment in the individual patient [43]. The ESC further acknowledged that the prognostic relevance of CAC has been demonstrated in several prospective studies, not only in asymptomatic individuals, but also in patients undergoing coronary angiography. Nonetheless, screening for CAC should be reserved to individuals at intermediate risk and in men greater than 45 years of age and women greater than 55 years of age. The ESC further endorsed the recommendation of the Society of Atherosclerosis Imaging [101] to perform CAC screening as the initial test in older individuals (greater than 65 years) with atypical chest discomfort and no known risk factors for atherosclerosis nor prior history of coronary artery disease [46]. In the absence of CAC, such individuals would not need any further testing. Finally, the decision to perform CAC screening and the interpretation of the results should be reserved to a physician properly trained in this field. It is the opinion of the authors that although CAC imaging may find its best application in screening populations at intermediate risk of cardiovascular events, some evidence indicates that high-risk subjects might also benefit from screening and risk stratification with this tool, though further 220 Future Cardiology (2005) 1(2)

Coronary artery calcium screening REVIEW investigation is certainly necessary on this particular issue. In general, aggressive therapy aimed at risk reduction is probably justified in patients in the top quartiles of CS independent of the risk profile. Indeed, the information derived from this type of screening could be used to refine the level of an individual s risk calculated on the basis of traditional algorithms allowing to match the intensity of therapy to the risk profile of the individual. Further research must confirm that CAC screening is cost effective, as evidence is accumulating that this approach plays an important role for risk assessment of selected populations. Executive summary Epidemiology Coronary artery disease remains the first cause of morbidity and mortality in the 21st century in spite of extraordinary diagnostic and therapeutic advancements. Though traditional risk factors are present in the majority of individuals suffering a cardiovascular event, our ability to predict outcome in the short-term based on the presence of risk factors is limited. The focus of research has therefore turned to imaging of atherosclerosis in its pre-clinical stages hoping to affect the natural history of the disease. Coronary artery calcium (CAC) is a sensitive marker of atherosclerotic disease infiltrating the arterial wall and recent research has centered on its role as a predictor of cardiovascular events. Pathophysiology of coronary artery calcium Calcium is deposited in the atherosclerotic plaque via active metabolic processes that involve bone-specific enzymes and osteoblast-like cells. Its deposition, in the form of crystals of hydroxyapatite, is dependent upon many of the mechanisms that initiate the atherosclerotic damage of the vessel wall. In histopathological studies, the extent of arterial calcification has been shown to correlate closely with the severity of coronary artery disease. This notion has been at the core of the utilization of coronary calcium as a potential predictor of events. Clinical evidence of the effectiveness of coronary calcium as a marker of risk In multiple outcome studies, the absence of coronary calcium on computed tomography (CT) screening has been associated with an extremely low risk of cardiac events in the short to intermediate term (< 0.5%/year). The negative predictive value of a negative CT scan has been reported to range from 84 to 100%. It is not yet clear whether the presence of calcium in a individual plaque renders it more or less stable. However, it is obvious that presence of extensive calcium deposits in a subject increases that individual's probability of cardiovascular events several fold. Several studies of asymptomatic individuals at intermediate risk of coronary artery disease screened for the presence of coronary calcium, showed that the risk of myocardial infarction and death is 10 20 times higher in the presence of large amounts of calcium compared to little or no calcium. Some investigators have also demonstrated that coronary calcium adds incremental prognostic significance to traditional risk factors. In symptomatic patients at low to intermediate risk of coronary disease, the presence of calcium in the coronary arteries increases the risk of events two- to threefold. Absence of coronary calcium on a CT performed in the emergency department is associated with an extremely low risk of events (approximately 0.2%/year) in the short term. Future perspective Several professional organizations have issued guidelines on appropriate use of calcium screening that include mostly screening of intermediate risk asymptomatic individuals and low-risk symptomatic patients. It remains to be determined whether CAC might be a useful predictor of events in subjects at high risk. In general, aggressive therapy aimed at risk reduction is currently justified in patients in the top quartiles of calcium score independent of the baseline risk profile. Further research must confirm that CAC screening is cost effective as evidence is accumulating that this approach plays an important role for risk assessment of selected populations. www.futuremedicine.com 221

REVIEW Ferramosca, Bellasi, Ratti & Raggi Bibliography Papers of special note have been highlighted as either of interest ( ) or of considerable interest ( ) to readers. 1. Blankenhorn DH, Stern D: Calcification of the coronary arteries. Am. J. Roentgenol. 81(5), 772 777 (1959). 2. Reinmuller R, Lipton MJ: Detection of coronary artery calcification by computed tomography. Dynam. Cardiovasc. Imaging 1, 139 145 (1987). 3. Agatston AS, Janowitz WR, Hildner FJ et al.: Quantification of coronary artery calcium using ultrafast computed tomography. J. Am. Coll. Cardiol. 15(4), 827 832 (1990). 4. Rumberger JA, Sheedy PF, Breen JF et al.: Coronary calcium, as determined by electron beam computed tomography, and coronary disease on arteriogram. Circulation 91(5), 1363 1367 (1995). 5. Tannenbaum SR, Kondos GT, Veselik KE et al.: Detection of calcific deposits in coronary arteries by ultrafast computed tomography and correlation with angiography. Am. J. Cardiol. 63(12), 870 873 (1989). 6. 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