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THEMED ARTICLE y Cardiac Imaging & Diagnostic Techniques
Review
Role of coronary artery calcium in cardiovascular risk assessment Expert Rev. Cardiovasc. Ther. 12(1), 87–94 (2014)
Nirmal Sunkara, Nathan D Wong and Shaista Malik* Division of Cardiology, Department of Medicine, University of California, 333 City Drive West, Suite 400, Orange, CA 92868, USA *Author for correspondence: [email protected]
Coronary artery disease (CAD) is associated with substantial morbidity and mortality worldwide. Despite many advances in prevention and therapy for CAD, a third to one-half of cardiovascular events occur in those with no prior symptoms. Assessing subclinical disease using coronary artery calcium (CAC) has been shown to provide additional risk stratification and to improve prediction of cardiovascular events over traditional strategies such as the Framingham Risk Score. In this review, we aim to cover the current data available on utilization of CAC as a tool in the general population as well as in targeted subgroups such as those with diabetes and metabolic syndrome. For this review, the authors performed thorough Pubmed and Medline searches using keywords coronary artery calcification, X-ray computed tomography, multidetector computed tomography, CAD, diabetes mellitus and metabolic syndrome. Based on the authors’ review of literature, they believe that CAC is an excellent risk stratification imaging modality, especially in patients with diabetes and metabolic syndrome; behavioral changes in patients and therapeutic interventions based on CAC scoring are cost-effective. KEYWORDS: calcium • coronary artery calcification • coronary artery disease • diabetes mellitus • metabolic syndrome • multidetector computed tomography • risk • X-ray computed tomography
Despite recent reductions in total mortality from coronary artery disease (CAD), up to half of initial CAD events are fatal. In the classically described population pyramid, a significant number of total events related to CAD still happen in the risk category deemed to be at intermediate risk based on traditional risk assessment scores such as the Framingham risk score in the USA and Muenster European risk scoring. The age of initiation and the rate of progression of atherosclerosis varies markedly among individuals and has been difficult to predict with traditional cardiovascular risk assessment markers. It has thus been proposed that at every level of exposure to traditional risk factors, due to genetic variability in an individuals’ susceptibility to develop atherosclerosis and thrombus formation, vulnerability to an acute cardiac event varies greatly, thereby adding the concepts of vulnerable patient and vulnerable blood to the well-known vulnerable plaque [1]. Early detection of atherosclerosis before symptoms occur can provide a major opportunity to
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treat those vulnerable to prevent many cardiovascular events. The search remains for a riskstratifying test that can predefine many if not most of the patients in the intermediate risk category prior to having their first event. Several newer imaging modalities as well as novel biomarkers have recently been proposed to help reclassify patients and identify those at highest risk. In this paper, we discuss the prognostic importance of coronary calcium and its clinical utility in the intermediate-risk population, especially the two risk groups of patients with diabetes and metabolic syndrome (MetS) who make up a vast majority of the at-risk population and thereby have the greatest burden for CAD events and how measuring coronary calcium may impact on physician and patient behavior in these groups. Coronary artery calcium & cardiac risk
In 1959, Blankenhorn and Stern described the importance of coronary artery calcium (CAC) as a marker of coronary atherosclerosis [2].
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They described three major patterns of coronary calcium based on radiographic appearance, small discrete punctuate areas, dense blocky areas and diffuse punctuate areas. Coronary calcium later measured by digital subtraction fluoroscopy in asymptomatic patients was shown to correlate (p < 0.05) with age, smoking history (relative risk [RR]: 1.30), diabetes history (RR: 1.24) and family history (RR: 1.26), all traditional risk factors for CAD [3]. Then came ultrafast computed tomography (CT), which showed that in patients with known CAD, measured total CAC was 3- to 6-times greater (p < 0.01) and the probability of CAC 30–40% greater (p < 0.01) [4]. Ultrafast CT was then shown to be superior to fluoroscopy as a tool for detecting and quantifying CAC by Agatston et al. [5]. Thus, CAC as measured by CT in these early studies was shown to have excellent sensitivity and specificity for presence of atherosclerotic plaque. In atherosclerosis, lipid accumulation, cell proliferation and extracellular matrix proliferation are involved with histopathologic progression from the initial fatty streak with aggregation of lipid-laden macrophages and T lymphocytes in the innermost arterial wall layer to the intermediate lesion with macrophages and proliferating smooth muscle cells, which then evolve into the more complex fibrous plaques [6]. Calcification starts with the exposure of hydroxyapatite in the matrix vesicles to osteoid and to bone matrix proteins that are found in atherosclerotic plaques, but not in normal vessel wall. Osteopontin, which is synthesized by vascular smooth muscle cells, macrophages and endothelial cells, has calcium-binding sites, is regulated by cytokines and binds readily to hydroxyapatite and is found at the sites of early calcification. The amount of coronary calcium reported as the Agatston score has since been shown in many published studies to provide prognostic information over and above the standard risk factors. Agatston score is calculated by multiplying the lesion area in millimeter squared by a density factor between 1 and 4 [5]. With a CAC more than 300, patients previously classified as intermediate Framingham risk were reclassified as high risk, with an observed 2.8% annual rate or a 28% 10-year rate of cardiac death or myocardial infarction. Pooled data from six studies examining the predictors of cardiac death or myocardial infarction in 27,622 patients showed that, compared with a CAC of zero, there was a significant increase in RR with CAC between 100 and 400 (RR: 4.3), CAC between 400 and 1000 (RR: 7.2) and CAC more than 1000 (RR: 10.8) [7]. Similar findings were noted in the Rotterdam study participants when addition of CAC scoring to the Framingham Risk score led to the reclassification of 22% of the study participants into a more accurate risk category. In the group of patients initially categorized as intermediate risk based on their Framingham score, a total of 52% were reclassified after addition of CAC scoring, 30% into the low-risk category and 22% into the high-risk category. In the group initially considered low risk, the addition of CAC scoring moved 11% into the intermediate-risk group and 1% into the high-risk group. Among the high-risk patients, CAC scoring led to the reclassification of 29% into the intermediate-risk group and 5% into 88
the low-risk group [8]. This was further established by the Multi-Ethnic Study of Atherosclerosis (MESA) study and as illustrated in FIGURE 1 [9], irrespective of the risk category of the patient based on traditional risk factors, the incidence of coronary heart disease (CHD)-related events is higher in those with higher calcium scores. CAC scoring has the best area under receiver operating curve for risk estimation of CAD in addition to the traditional risk factors among the newly studied biomarkers and imaging modalities. CAC has also shown the highest Net Reclassification Improvement (NRI) among all the newer imaging modalities and biomarkers in re-risk-stratifying patients for prediction of cardiovascular events [10]. In this study of comparison of novel risk markers for improvement of risk assessment by Yeboah et al., the NRI in hazard ratio with addition to the traditional risk factors was shown to be 0.659 with CAC, 0.024 with brachial flow-mediated dilation, 0.036 with anklebrachial index, 0.102 with carotid intima–media thickness, 0.160 with addition of family history and 0.079 with addition of high-sensitivity CRP [10]. NRI for CAC was 25% (95% CI: 16–34%) in the MESA study [11]. This improvement in risk classification was more balanced among intermediate-risk individuals (0.29 for events and 0.26 for nonevents). Though the prevalence of cardiovascular disease differs between ethnic groups, a high CAC score was still shown to be predictive of events irrespective of the ethnic group [12]. Based on this multitude of evidence, measurement of CAC is given an appropriate use recommendation with a appropriateness score of 7 (9 being the highest) in asymptomatic individuals and also as being reasonable for cardiovascular risk assessment in asymptomatic adults at intermediate risk (10–20% 10-year risk) and a Class IIb recommendation for measurement of CAC for cardiovascular risk assessment in persons at low-to-intermediate risk (6–10% 10-year risk) [8,13]. CAC in asymptomatic patients with metabolic syndrome
MetS is defined according to the National Cholesterol Education Program Adult Treatment Panel III criteria [14] as requiring the presence of ‡3 of the following: • increased waist circumference (>40 in [>102 cm] for men; >35 in [>88 cm] for women); • elevated triglycerides (‡150 mg/dl [1.69 mmol/l]) or on therapy for treatment of hypertriglyceridemia; • low high-density lipoprotein cholesterol (400 and RF ≥3 RF = 0 RF ≥3
Figure 1. Bar diagram showing increased hazard ratio for all-cause mortality with increasing calcium score over traditional risk factors. CAC: Coronary artery calcium; RF: Risk factor. Data taken from [9].
summary odds ratio of 0.56 (95% CI: 0.53–0.60). Hyperglycemia can cause endothelial dysfunction, impaired fibrinolysis, increased platelet aggregation, plaque instability, dysfunctional arterial remodeling and fibrotic and calcified coronary arteries. All these changes lead to vascular aging, which led to the proposed suggestion that diabetics should be considered equivalent to those without diabetes who are about 15 years older [29]. Diabetic patients commonly do not present with typical symptoms of CAD and the prevalence of silent CAD has ranged from 20 to 50% in reported studies and has been shown to be associated with higher mortality [30]. Despite recent advances in care and reductions in overall CAD mortality, diabetics still have a higher age- and sex-adjusted mortality (286.4/10,000 person-years) compared with nondiabetics (84.6/10,000 person-years). In the Collaborative Atorvastatin Diabetes study, even after reduction of LDL cholesterol to 80 mg/dl, diabetics aged 45– 70 years with no previous CAD still had a 1.5% CAD event rate [31]. Diabetics in the COURAGE trial both in the medical treatment and PCI arms had a CAD event rate of 5%, which is higher than the reported event rate in nondiabetics. These findings suggest that even in intensely treated diabetics, there is still a residual risk of CAD mortality that is greater than the nondiabetic population [32]. These findings would seem to highlight the need for improved methods to stratify residual risk within populations undergoing intensive medical management. Recent consensus, citing lack of evidence, contrasts the American Diabetes Association recommendation to screen diabetics for CAD with two or more atherogenic factors and suggests that there may be a high-risk subset of diabetics who will benefit from screening such as those who are medically difficult to control or those in whom there is very high suspicion for CAD [33,34]. 89
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Figure 2. Survival in individuals with and without diabetes based on coronary calcium score. Mortality increased with increasing calcium score in diabetic and non-diabetic individuals, and a significant interaction of coronary calcium score with diabetes was seen in a risk-adjusted model (p < 0.00001).
CAC has been shown to have better sensitivity and specificity compared with other modes of noninvasive studies in patients with diabetes. In the PREDICT study, in patients with diabetes, CAC was shown to be a highly significant, independent predictor of events (p < 0.001), with a doubling in CAC score associated with a 32% increase in risk of events (29% after adjustment) in those with diabetes [35]. In a study of 91 patients, CAC had a higher diagnostic ability than either treadmill-ECG or technetium-stress for the detection of obstructive angiographic CAD with a RR of 4.53 for CAC compared with 1.72 for treadmill-ECG and 1.96 for technetium-stress [36]. In a comparison study by Kajinami et al. of fast CT, ECG and thallium exercise testing to coronary angiography in 251 symptomatic patients, sensitivity and specificity of ECG were 74 and 73%, thallium exercise testing 83 and 60%, respectively, and CAC had a sensitivity and specificity of 77 and 86% [37]. In patients with diabetes, the presence of any coronary calcium predicts risk for all-cause mortality and more importantly, its absence indicates a low risk of mortality in this high-risk population. Thus, the use of CAC in this population can help improve risk assessment in these high-risk patients. The CAC score in patients with diabetes without established CAD is similar to that of nondiabetic subjects with known CAD [38,39]. Also, interestingly, diabetic women with high calcium score have been shown to have similar atherosclerotic burden and extent of coronary artery calcification as men, and the advantage women have seems to have been abolished [40]. Five-year survival was shown to be similar for diabetics and nondiabetics with no coronary calcium. With increasing CAC scores, mortality increased in diabetics and nondiabetics, with the highest mortality seen with CAC score >400. In a riskadjusted model, diabetics had a greater increase in mortality 90
with each level of CAC score compared with nondiabetic individuals (p < 0.00001) [41]. The predictive value of calcium scoring is not diminished in those with diabetes as shown in FIGURE 2; increasing calcium scores result in greater mortality, an association that is also seen in those without diabetes. Interestingly, there are no significant differences between the survival curves in those with and without diabetes who had a zero calcium score (FIGURE 3) [42]. Effectiveness of CAC scoring: the costs & potential benefits through behavioral change
Among patients with suspected CAD, CAC can potentially serve as a gatekeeper for downstream medical testing and invasive procedures, given that it has shown to help predict future events. CAD has substantial burden on the health care system, with the greatest financial effects in the initial diagnosis and final phases of life. There is also a concern of adding potential additional costs to the health care system by adding CAC into the mix of screening and diagnostic modalities for CAD. Frequent presentation of CAD with initial manifestation of sudden cardiac death represents an unsolved problem necessitating better means for screening for CAD. A costeffective screening test would be one which can reliably identify a high-risk subgroup for aggressive follow-up that would constitute only a small proportion of the total screened population. Shaw et al. [43] showed that CAC scanning identified a highrisk subgroup of subjects with CAC scores ‡400. This high-risk subgroup, which constituted only 8.2% of the study population, had substantially increased medical costs and downstream testing. The subgroup at the highest risk, by virtue of CAC scores ‡1000 had a marked increase in medical costs, but only constituted 2.2% of the study population. Conversely, downstream medical costs were very low among the large pool of subjects with low CAC scores in this study. These findings suggested that CAC may play an important role in promoting Expert Rev. Cardiovasc. Ther. 12(1), (2014)
more efficient, selective testing patterns in asymptomatic individuals at risk for CAD. In the EISNER study, a randomized controlled trial of CAC scores in asymptomatic patients compared with usual care, randomization to CAC scanning was associated with superior CAD risk factor control without increasing downstream medical testing [44]. The baseline CAC correlated directly with the degree of reduction of blood pressure, total cholesterol and serum LDL levels. There was also a reduction in waist size and weight loss noted in patients with elevated CAC scores. Patients with an elevated CAC scores had a decrease in their composite Framingham Risk Scores at 4 years. The normal CAC group showed a 25% reduction in medication and a 37% reduction in procedure costs. Similarly, the St Francis Heart Study Randomized Clinical Trial (involving 1005 patients) showed that statin therapy (atorvastatin at a dose of 20 mg/day) in patients with a CAC score above 400 resulted in a 42% reduction in the RR and a 6.3% reduction in the absolute risk of coronary events, which showed a positive trend, albeit statistically insignificant [45]. In a more recent study, it is shown that risk perception scores were significantly higher in the positive (1 to >400) CAC group compared with the 0 CAC group (p = 0.045). Healthpromoting behaviors increased in all groups over time (p < 0.001). Risk reduction medication use increased in all groups with significant increase in lipid and aspirin intake [46]. In a study of comparative effectiveness and cost–effectiveness of CT screening for CAC in asymptomatic individuals in the Rotterdam study, CAC screening was found to be cost-effective compared with current practice, statin therapy and current guidelines [47]. In the Prospective Army Coronary Calcium project, the marginal cost–effectiveness of a calcium scan, assuming a 30% improvement in survival associated with primary prevention among at-risk men, was modeled to be US $37,633 per quality-adjusted life-year saved [48]. Role of remeasurement & follow-up of calcium scores
Studies so far have shown that there are worsening outcomes with continuing progression of coronary calcium and worsening calcium score [49,50]. Among 4609 consecutive asymptomatic individuals, progression of CAC was significantly associated with mortality regardless of the method used to assess progression (p < 0.0001) [49]. Progression was very limited and did not predict mortality in patients with baseline CAC = 0. Though there may be some increase in calcification with plaque stabilization, this is where the location, type and characteristics of coronary calcium in the repeat scans are helpful to differentiate stabilization versus worsening disease. More recently, in the Multiethnic Study of Atherosclerosis, both incidence and progression of CAC were associated with increases in risk of CHD events; the association of progression of CAC with CHD events also remained after adjusting for baseline CAC score. Among participants with baseline CAC, those with annual progression of ‡300 U had adjusted HRs of 3.8 (1.5–9.6) for total and 6.3 (1.9–21.5) for hard CHD compared with those www.expert-reviews.com
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Figure 3. Kaplan–Meier survival curves of patients with diabetes and nondiabetes showing no significant difference in survival when the calcium score is zero. Reproduced with permission from [42] Elsevier Inc. (2004).
without progression [50]. In addition, also in the Multiethnic Study of Atherosclerosis, we showed progression of CAC to predict CHD events both in those with MetS and diabetes [25]. Also, in the BELLES trial, Raggi et al. studied aggressive versus moderate lipid-lowering therapy in the postmenopausal women and identified that though there is a positive trend toward less progression in CAC with aggressive lipid-lowering therapy, it was not statistically significant [51]. Indeed, the 2007 ACCF/AHA consensus document on CAC scoring stated that clinical monitoring of CAC progression through serial fast CT scanning is not recommended [7] and appropriate use criteria classify the repeat use of coronary CT scanning as ‘inappropriate’ in asymptomatic patients with known CAD and previous CT scanning [52]. Though the guidelines do not recommend repeat scans, based on the studies above, there may be some benefit to certain patient subpopulations. CAC in symptomatic patients or patients with established CAD
Irrespective of the presence or absence of diabetes, or MetS, this has been a controversial topic. Theoretically, when patients present with symptoms suggestive of angina chest pain but with indeterminate EKG and are found to have a CAC of 0, the presence of any significant coronary stenosis should be unlikely. As stated by an American Heart Association writing group, with a CAC score of zero in symptomatic patients, the risk of a cardiovascular event in the next 2–5 years is quite low (0.1/100 person-years) [7]. A positive CT study (defined as presence of any CAC) is nearly 100% specific for atheromatous coronary plaque [53]. In a study of 221 patients presenting to the emergency room in such a clinical setting, the presence of CAC (a total calcium score >0) and increasing score quartiles were strongly related to the occurrence of hard cardiac events including myocardial infarction and death (p < 0.001) and all 91
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cardiovascular events (p < 0.001) [54]. In a study of 1031 patients in the emergency department with chest pain, 61% were noted to have a CAC of 0, which predicted both a normal SPECT scan as well as excellent short-term outcome [55]. Further studies need to be done to assess the utility of calcium scoring in the outpatient setting as well as in the emergency department setting, as a gatekeeper test for further downstream testing. Conclusion
In summary, CAC as done using a 64-slice multidetector CT scanner is a low radiation, noncontrast screening modality, which has consistently shown utility in providing usable CV prognostic information. Diabetes is a major risk factor for CAD and considered a CAD equivalent; however, those with diabetes represent a spectrum of risk for CAD. CAC scoring has been shown in studies to be valuable in further risk stratifying this traditionally assumed high-risk group. Similarly, CAC has shown to further risk stratify those with MetS by further reclassifying them into higher or lower risk groups. Appropriate risk assessment in those with diabetes and/or MetS is crucial in determining the most cost-effective and intensive therapeutic approach. CAC directed appropriate risk assessment and reclassification has the potential for higher treatment intensity and improved patient adherence. Patient behavior and physician practice modification as a result of CAC risk stratification has been associated with greater cost– effectiveness and improved outcomes.
Expert commentary & five-year view
Coronary calcium scoring is a low radiation screening modality, which has proven utility as a reclassification tool for improving risk assessment of CDA-related events compared with risk assessment using traditional risk factors alone. This improves provider ability to direct clinical intensification on appropriate patients. A calcium score of zero may indicate an event-free period of 3–4 years, a higher calcium score in asymptomatic patients likely serves as a motivator for patients in inducing lifestyle changes and promoting a healthier lifestyle. In the next 5 years, calcium scoring may show that by improving targeted use of clinical resources and avoiding unnecessary testing, there will be improved cost–effectiveness in CAD prevention. Future studies will continue to provide better understanding of utility and impact of calcium scoring in preventive cardiology. Financial & competing interests disclosure
ND Wong is a consultant for Re-Engineering Healthcare, Inc. and receives research funding through the University of California, CA, USA from Bristol Myers-Squibb. The authors have no other relevant affiliations or financial involvement with any organization or entity with a financial interest in or financial conflict with the subject matter or materials discussed in the manuscript. This includes employment, consultancies, honoraria, stock ownership or options, expert testimony, grants or patents received or pending, or royalties. No writing assistance was utilized in the production of this manuscript.
Key issues • A third to a half of all cardiovascular disease-related events occur in people with no prior symptoms. • Diabetes is considered a coronary artery disease (CAD) equivalent when estimating risk for future CAD events; however people with diabetes represent a spectrum of risk for CAD. • Coronary artery calcium scoring provides additional risk stratification and improve prediction of cardiovascular events over traditional risk stratification strategies. • Coronary artery calcium further stratifies patients with diabetes and metabolic syndrome to determine appropriate intensity of therapeutic approaches.
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Arad Y, Spadaro LA, Roth M, Newstein D, Guerci AD. Treatment of asymptomatic adults with elevated coronary calcium scores with atorvastatin, vitamin C, and vitamin E: the St. Francis Heart Study randomized clinical trial. J. Am. Coll. Cardiol. 46(1), 166–172 (2005).
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Johnson JE. Risk perception, psychological well-being and health-promoting behaviors in persons informed of a coronary artery calcium score. Dissertations 304 (2012).
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van Kempen BJH, Spronk S, Koller MT et al. Comparative effectiveness and cost-effectiveness of computed tomography screening for coronary artery calcium in asymptomatic individuals. J. Am. Coll. Cardiol. 58(16), 1690–1701 (2011).
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Taylor AJ, Bindeman J, Feuerstein I, Cao F, Brazaitis M, O’Malley PG. Coronary calcium independently predicts incident premature coronary heart disease over measured cardiovascular risk factors: mean three-year outcomes in the prospective army coronary calcium (PACC) project. J. Am. Coll. Cardiol. 46(5), 807–814 (2005).
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Budoff MJ, Hokanson JE, Nasir K et al. Progression of coronary artery calcium predicts all-cause mortality. JACC Cardiovasc. Imaging 3(12), 1229–1236 (2010). Budoff MJ, Young R, Lopez VA et al. Progression of coronary calcium and incident coronary heart disease events: the multi-ethnic study of atherosclerosis. J. Am. Coll. Cardiol. 61, 1231–1239 (2013).
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Raggi P, Davidson M, Callister TQ et al. Aggressive versus moderate lipid-lowering therapy in hypercholesterolemic post menopausal women beyond endorsed lipid lowering with EBT scanning (BELLES). Circulation 112(4), 563–571 (2005).
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Budoff MJ, Achenbach S, Blumenthal RS et al. Assessment of coronary artery disease by cardiac computed tomography a scientific statement from the American Heart Association Committee on Cardiovascular Imaging and Intervention, Council on Cardiovascular Radiology and Intervention, and Committee on Cardiac Imaging, Council on Clinical Cardiology. Circulation 114(16), 1761–1791 (2006).
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Kennedy J, Shavelle R, Wang S, Budoff M, Detrano RC. Coronary calcium and standard risk factors in symptomatic patients referred for coronary angiography. Am. Heart J. 135(4), 696–702 (1998).
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Expert Rev. Cardiovasc. Ther. 12(1), (2014)
THEMED ARTICLE y Cardiac Imaging & Diagnostic Techniques
Review
Role of coronary artery calcium in cardiovascular risk assessment Expert Rev. Cardiovasc. Ther. 12(1), 87–94 (2014)
Nirmal Sunkara, Nathan D Wong and Shaista Malik* Division of Cardiology, Department of Medicine, University of California, 333 City Drive West, Suite 400, Orange, CA 92868, USA *Author for correspondence: [email protected]
Coronary artery disease (CAD) is associated with substantial morbidity and mortality worldwide. Despite many advances in prevention and therapy for CAD, a third to one-half of cardiovascular events occur in those with no prior symptoms. Assessing subclinical disease using coronary artery calcium (CAC) has been shown to provide additional risk stratification and to improve prediction of cardiovascular events over traditional strategies such as the Framingham Risk Score. In this review, we aim to cover the current data available on utilization of CAC as a tool in the general population as well as in targeted subgroups such as those with diabetes and metabolic syndrome. For this review, the authors performed thorough Pubmed and Medline searches using keywords coronary artery calcification, X-ray computed tomography, multidetector computed tomography, CAD, diabetes mellitus and metabolic syndrome. Based on the authors’ review of literature, they believe that CAC is an excellent risk stratification imaging modality, especially in patients with diabetes and metabolic syndrome; behavioral changes in patients and therapeutic interventions based on CAC scoring are cost-effective. KEYWORDS: calcium • coronary artery calcification • coronary artery disease • diabetes mellitus • metabolic syndrome • multidetector computed tomography • risk • X-ray computed tomography
Despite recent reductions in total mortality from coronary artery disease (CAD), up to half of initial CAD events are fatal. In the classically described population pyramid, a significant number of total events related to CAD still happen in the risk category deemed to be at intermediate risk based on traditional risk assessment scores such as the Framingham risk score in the USA and Muenster European risk scoring. The age of initiation and the rate of progression of atherosclerosis varies markedly among individuals and has been difficult to predict with traditional cardiovascular risk assessment markers. It has thus been proposed that at every level of exposure to traditional risk factors, due to genetic variability in an individuals’ susceptibility to develop atherosclerosis and thrombus formation, vulnerability to an acute cardiac event varies greatly, thereby adding the concepts of vulnerable patient and vulnerable blood to the well-known vulnerable plaque [1]. Early detection of atherosclerosis before symptoms occur can provide a major opportunity to
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treat those vulnerable to prevent many cardiovascular events. The search remains for a riskstratifying test that can predefine many if not most of the patients in the intermediate risk category prior to having their first event. Several newer imaging modalities as well as novel biomarkers have recently been proposed to help reclassify patients and identify those at highest risk. In this paper, we discuss the prognostic importance of coronary calcium and its clinical utility in the intermediate-risk population, especially the two risk groups of patients with diabetes and metabolic syndrome (MetS) who make up a vast majority of the at-risk population and thereby have the greatest burden for CAD events and how measuring coronary calcium may impact on physician and patient behavior in these groups. Coronary artery calcium & cardiac risk
In 1959, Blankenhorn and Stern described the importance of coronary artery calcium (CAC) as a marker of coronary atherosclerosis [2].
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They described three major patterns of coronary calcium based on radiographic appearance, small discrete punctuate areas, dense blocky areas and diffuse punctuate areas. Coronary calcium later measured by digital subtraction fluoroscopy in asymptomatic patients was shown to correlate (p < 0.05) with age, smoking history (relative risk [RR]: 1.30), diabetes history (RR: 1.24) and family history (RR: 1.26), all traditional risk factors for CAD [3]. Then came ultrafast computed tomography (CT), which showed that in patients with known CAD, measured total CAC was 3- to 6-times greater (p < 0.01) and the probability of CAC 30–40% greater (p < 0.01) [4]. Ultrafast CT was then shown to be superior to fluoroscopy as a tool for detecting and quantifying CAC by Agatston et al. [5]. Thus, CAC as measured by CT in these early studies was shown to have excellent sensitivity and specificity for presence of atherosclerotic plaque. In atherosclerosis, lipid accumulation, cell proliferation and extracellular matrix proliferation are involved with histopathologic progression from the initial fatty streak with aggregation of lipid-laden macrophages and T lymphocytes in the innermost arterial wall layer to the intermediate lesion with macrophages and proliferating smooth muscle cells, which then evolve into the more complex fibrous plaques [6]. Calcification starts with the exposure of hydroxyapatite in the matrix vesicles to osteoid and to bone matrix proteins that are found in atherosclerotic plaques, but not in normal vessel wall. Osteopontin, which is synthesized by vascular smooth muscle cells, macrophages and endothelial cells, has calcium-binding sites, is regulated by cytokines and binds readily to hydroxyapatite and is found at the sites of early calcification. The amount of coronary calcium reported as the Agatston score has since been shown in many published studies to provide prognostic information over and above the standard risk factors. Agatston score is calculated by multiplying the lesion area in millimeter squared by a density factor between 1 and 4 [5]. With a CAC more than 300, patients previously classified as intermediate Framingham risk were reclassified as high risk, with an observed 2.8% annual rate or a 28% 10-year rate of cardiac death or myocardial infarction. Pooled data from six studies examining the predictors of cardiac death or myocardial infarction in 27,622 patients showed that, compared with a CAC of zero, there was a significant increase in RR with CAC between 100 and 400 (RR: 4.3), CAC between 400 and 1000 (RR: 7.2) and CAC more than 1000 (RR: 10.8) [7]. Similar findings were noted in the Rotterdam study participants when addition of CAC scoring to the Framingham Risk score led to the reclassification of 22% of the study participants into a more accurate risk category. In the group of patients initially categorized as intermediate risk based on their Framingham score, a total of 52% were reclassified after addition of CAC scoring, 30% into the low-risk category and 22% into the high-risk category. In the group initially considered low risk, the addition of CAC scoring moved 11% into the intermediate-risk group and 1% into the high-risk group. Among the high-risk patients, CAC scoring led to the reclassification of 29% into the intermediate-risk group and 5% into 88
the low-risk group [8]. This was further established by the Multi-Ethnic Study of Atherosclerosis (MESA) study and as illustrated in FIGURE 1 [9], irrespective of the risk category of the patient based on traditional risk factors, the incidence of coronary heart disease (CHD)-related events is higher in those with higher calcium scores. CAC scoring has the best area under receiver operating curve for risk estimation of CAD in addition to the traditional risk factors among the newly studied biomarkers and imaging modalities. CAC has also shown the highest Net Reclassification Improvement (NRI) among all the newer imaging modalities and biomarkers in re-risk-stratifying patients for prediction of cardiovascular events [10]. In this study of comparison of novel risk markers for improvement of risk assessment by Yeboah et al., the NRI in hazard ratio with addition to the traditional risk factors was shown to be 0.659 with CAC, 0.024 with brachial flow-mediated dilation, 0.036 with anklebrachial index, 0.102 with carotid intima–media thickness, 0.160 with addition of family history and 0.079 with addition of high-sensitivity CRP [10]. NRI for CAC was 25% (95% CI: 16–34%) in the MESA study [11]. This improvement in risk classification was more balanced among intermediate-risk individuals (0.29 for events and 0.26 for nonevents). Though the prevalence of cardiovascular disease differs between ethnic groups, a high CAC score was still shown to be predictive of events irrespective of the ethnic group [12]. Based on this multitude of evidence, measurement of CAC is given an appropriate use recommendation with a appropriateness score of 7 (9 being the highest) in asymptomatic individuals and also as being reasonable for cardiovascular risk assessment in asymptomatic adults at intermediate risk (10–20% 10-year risk) and a Class IIb recommendation for measurement of CAC for cardiovascular risk assessment in persons at low-to-intermediate risk (6–10% 10-year risk) [8,13]. CAC in asymptomatic patients with metabolic syndrome
MetS is defined according to the National Cholesterol Education Program Adult Treatment Panel III criteria [14] as requiring the presence of ‡3 of the following: • increased waist circumference (>40 in [>102 cm] for men; >35 in [>88 cm] for women); • elevated triglycerides (‡150 mg/dl [1.69 mmol/l]) or on therapy for treatment of hypertriglyceridemia; • low high-density lipoprotein cholesterol (400 and RF ≥3 RF = 0 RF ≥3
Figure 1. Bar diagram showing increased hazard ratio for all-cause mortality with increasing calcium score over traditional risk factors. CAC: Coronary artery calcium; RF: Risk factor. Data taken from [9].
summary odds ratio of 0.56 (95% CI: 0.53–0.60). Hyperglycemia can cause endothelial dysfunction, impaired fibrinolysis, increased platelet aggregation, plaque instability, dysfunctional arterial remodeling and fibrotic and calcified coronary arteries. All these changes lead to vascular aging, which led to the proposed suggestion that diabetics should be considered equivalent to those without diabetes who are about 15 years older [29]. Diabetic patients commonly do not present with typical symptoms of CAD and the prevalence of silent CAD has ranged from 20 to 50% in reported studies and has been shown to be associated with higher mortality [30]. Despite recent advances in care and reductions in overall CAD mortality, diabetics still have a higher age- and sex-adjusted mortality (286.4/10,000 person-years) compared with nondiabetics (84.6/10,000 person-years). In the Collaborative Atorvastatin Diabetes study, even after reduction of LDL cholesterol to 80 mg/dl, diabetics aged 45– 70 years with no previous CAD still had a 1.5% CAD event rate [31]. Diabetics in the COURAGE trial both in the medical treatment and PCI arms had a CAD event rate of 5%, which is higher than the reported event rate in nondiabetics. These findings suggest that even in intensely treated diabetics, there is still a residual risk of CAD mortality that is greater than the nondiabetic population [32]. These findings would seem to highlight the need for improved methods to stratify residual risk within populations undergoing intensive medical management. Recent consensus, citing lack of evidence, contrasts the American Diabetes Association recommendation to screen diabetics for CAD with two or more atherogenic factors and suggests that there may be a high-risk subset of diabetics who will benefit from screening such as those who are medically difficult to control or those in whom there is very high suspicion for CAD [33,34]. 89
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Figure 2. Survival in individuals with and without diabetes based on coronary calcium score. Mortality increased with increasing calcium score in diabetic and non-diabetic individuals, and a significant interaction of coronary calcium score with diabetes was seen in a risk-adjusted model (p < 0.00001).
CAC has been shown to have better sensitivity and specificity compared with other modes of noninvasive studies in patients with diabetes. In the PREDICT study, in patients with diabetes, CAC was shown to be a highly significant, independent predictor of events (p < 0.001), with a doubling in CAC score associated with a 32% increase in risk of events (29% after adjustment) in those with diabetes [35]. In a study of 91 patients, CAC had a higher diagnostic ability than either treadmill-ECG or technetium-stress for the detection of obstructive angiographic CAD with a RR of 4.53 for CAC compared with 1.72 for treadmill-ECG and 1.96 for technetium-stress [36]. In a comparison study by Kajinami et al. of fast CT, ECG and thallium exercise testing to coronary angiography in 251 symptomatic patients, sensitivity and specificity of ECG were 74 and 73%, thallium exercise testing 83 and 60%, respectively, and CAC had a sensitivity and specificity of 77 and 86% [37]. In patients with diabetes, the presence of any coronary calcium predicts risk for all-cause mortality and more importantly, its absence indicates a low risk of mortality in this high-risk population. Thus, the use of CAC in this population can help improve risk assessment in these high-risk patients. The CAC score in patients with diabetes without established CAD is similar to that of nondiabetic subjects with known CAD [38,39]. Also, interestingly, diabetic women with high calcium score have been shown to have similar atherosclerotic burden and extent of coronary artery calcification as men, and the advantage women have seems to have been abolished [40]. Five-year survival was shown to be similar for diabetics and nondiabetics with no coronary calcium. With increasing CAC scores, mortality increased in diabetics and nondiabetics, with the highest mortality seen with CAC score >400. In a riskadjusted model, diabetics had a greater increase in mortality 90
with each level of CAC score compared with nondiabetic individuals (p < 0.00001) [41]. The predictive value of calcium scoring is not diminished in those with diabetes as shown in FIGURE 2; increasing calcium scores result in greater mortality, an association that is also seen in those without diabetes. Interestingly, there are no significant differences between the survival curves in those with and without diabetes who had a zero calcium score (FIGURE 3) [42]. Effectiveness of CAC scoring: the costs & potential benefits through behavioral change
Among patients with suspected CAD, CAC can potentially serve as a gatekeeper for downstream medical testing and invasive procedures, given that it has shown to help predict future events. CAD has substantial burden on the health care system, with the greatest financial effects in the initial diagnosis and final phases of life. There is also a concern of adding potential additional costs to the health care system by adding CAC into the mix of screening and diagnostic modalities for CAD. Frequent presentation of CAD with initial manifestation of sudden cardiac death represents an unsolved problem necessitating better means for screening for CAD. A costeffective screening test would be one which can reliably identify a high-risk subgroup for aggressive follow-up that would constitute only a small proportion of the total screened population. Shaw et al. [43] showed that CAC scanning identified a highrisk subgroup of subjects with CAC scores ‡400. This high-risk subgroup, which constituted only 8.2% of the study population, had substantially increased medical costs and downstream testing. The subgroup at the highest risk, by virtue of CAC scores ‡1000 had a marked increase in medical costs, but only constituted 2.2% of the study population. Conversely, downstream medical costs were very low among the large pool of subjects with low CAC scores in this study. These findings suggested that CAC may play an important role in promoting Expert Rev. Cardiovasc. Ther. 12(1), (2014)
more efficient, selective testing patterns in asymptomatic individuals at risk for CAD. In the EISNER study, a randomized controlled trial of CAC scores in asymptomatic patients compared with usual care, randomization to CAC scanning was associated with superior CAD risk factor control without increasing downstream medical testing [44]. The baseline CAC correlated directly with the degree of reduction of blood pressure, total cholesterol and serum LDL levels. There was also a reduction in waist size and weight loss noted in patients with elevated CAC scores. Patients with an elevated CAC scores had a decrease in their composite Framingham Risk Scores at 4 years. The normal CAC group showed a 25% reduction in medication and a 37% reduction in procedure costs. Similarly, the St Francis Heart Study Randomized Clinical Trial (involving 1005 patients) showed that statin therapy (atorvastatin at a dose of 20 mg/day) in patients with a CAC score above 400 resulted in a 42% reduction in the RR and a 6.3% reduction in the absolute risk of coronary events, which showed a positive trend, albeit statistically insignificant [45]. In a more recent study, it is shown that risk perception scores were significantly higher in the positive (1 to >400) CAC group compared with the 0 CAC group (p = 0.045). Healthpromoting behaviors increased in all groups over time (p < 0.001). Risk reduction medication use increased in all groups with significant increase in lipid and aspirin intake [46]. In a study of comparative effectiveness and cost–effectiveness of CT screening for CAC in asymptomatic individuals in the Rotterdam study, CAC screening was found to be cost-effective compared with current practice, statin therapy and current guidelines [47]. In the Prospective Army Coronary Calcium project, the marginal cost–effectiveness of a calcium scan, assuming a 30% improvement in survival associated with primary prevention among at-risk men, was modeled to be US $37,633 per quality-adjusted life-year saved [48]. Role of remeasurement & follow-up of calcium scores
Studies so far have shown that there are worsening outcomes with continuing progression of coronary calcium and worsening calcium score [49,50]. Among 4609 consecutive asymptomatic individuals, progression of CAC was significantly associated with mortality regardless of the method used to assess progression (p < 0.0001) [49]. Progression was very limited and did not predict mortality in patients with baseline CAC = 0. Though there may be some increase in calcification with plaque stabilization, this is where the location, type and characteristics of coronary calcium in the repeat scans are helpful to differentiate stabilization versus worsening disease. More recently, in the Multiethnic Study of Atherosclerosis, both incidence and progression of CAC were associated with increases in risk of CHD events; the association of progression of CAC with CHD events also remained after adjusting for baseline CAC score. Among participants with baseline CAC, those with annual progression of ‡300 U had adjusted HRs of 3.8 (1.5–9.6) for total and 6.3 (1.9–21.5) for hard CHD compared with those www.expert-reviews.com
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Figure 3. Kaplan–Meier survival curves of patients with diabetes and nondiabetes showing no significant difference in survival when the calcium score is zero. Reproduced with permission from [42] Elsevier Inc. (2004).
without progression [50]. In addition, also in the Multiethnic Study of Atherosclerosis, we showed progression of CAC to predict CHD events both in those with MetS and diabetes [25]. Also, in the BELLES trial, Raggi et al. studied aggressive versus moderate lipid-lowering therapy in the postmenopausal women and identified that though there is a positive trend toward less progression in CAC with aggressive lipid-lowering therapy, it was not statistically significant [51]. Indeed, the 2007 ACCF/AHA consensus document on CAC scoring stated that clinical monitoring of CAC progression through serial fast CT scanning is not recommended [7] and appropriate use criteria classify the repeat use of coronary CT scanning as ‘inappropriate’ in asymptomatic patients with known CAD and previous CT scanning [52]. Though the guidelines do not recommend repeat scans, based on the studies above, there may be some benefit to certain patient subpopulations. CAC in symptomatic patients or patients with established CAD
Irrespective of the presence or absence of diabetes, or MetS, this has been a controversial topic. Theoretically, when patients present with symptoms suggestive of angina chest pain but with indeterminate EKG and are found to have a CAC of 0, the presence of any significant coronary stenosis should be unlikely. As stated by an American Heart Association writing group, with a CAC score of zero in symptomatic patients, the risk of a cardiovascular event in the next 2–5 years is quite low (0.1/100 person-years) [7]. A positive CT study (defined as presence of any CAC) is nearly 100% specific for atheromatous coronary plaque [53]. In a study of 221 patients presenting to the emergency room in such a clinical setting, the presence of CAC (a total calcium score >0) and increasing score quartiles were strongly related to the occurrence of hard cardiac events including myocardial infarction and death (p < 0.001) and all 91
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cardiovascular events (p < 0.001) [54]. In a study of 1031 patients in the emergency department with chest pain, 61% were noted to have a CAC of 0, which predicted both a normal SPECT scan as well as excellent short-term outcome [55]. Further studies need to be done to assess the utility of calcium scoring in the outpatient setting as well as in the emergency department setting, as a gatekeeper test for further downstream testing. Conclusion
In summary, CAC as done using a 64-slice multidetector CT scanner is a low radiation, noncontrast screening modality, which has consistently shown utility in providing usable CV prognostic information. Diabetes is a major risk factor for CAD and considered a CAD equivalent; however, those with diabetes represent a spectrum of risk for CAD. CAC scoring has been shown in studies to be valuable in further risk stratifying this traditionally assumed high-risk group. Similarly, CAC has shown to further risk stratify those with MetS by further reclassifying them into higher or lower risk groups. Appropriate risk assessment in those with diabetes and/or MetS is crucial in determining the most cost-effective and intensive therapeutic approach. CAC directed appropriate risk assessment and reclassification has the potential for higher treatment intensity and improved patient adherence. Patient behavior and physician practice modification as a result of CAC risk stratification has been associated with greater cost– effectiveness and improved outcomes.
Expert commentary & five-year view
Coronary calcium scoring is a low radiation screening modality, which has proven utility as a reclassification tool for improving risk assessment of CDA-related events compared with risk assessment using traditional risk factors alone. This improves provider ability to direct clinical intensification on appropriate patients. A calcium score of zero may indicate an event-free period of 3–4 years, a higher calcium score in asymptomatic patients likely serves as a motivator for patients in inducing lifestyle changes and promoting a healthier lifestyle. In the next 5 years, calcium scoring may show that by improving targeted use of clinical resources and avoiding unnecessary testing, there will be improved cost–effectiveness in CAD prevention. Future studies will continue to provide better understanding of utility and impact of calcium scoring in preventive cardiology. Financial & competing interests disclosure
ND Wong is a consultant for Re-Engineering Healthcare, Inc. and receives research funding through the University of California, CA, USA from Bristol Myers-Squibb. The authors have no other relevant affiliations or financial involvement with any organization or entity with a financial interest in or financial conflict with the subject matter or materials discussed in the manuscript. This includes employment, consultancies, honoraria, stock ownership or options, expert testimony, grants or patents received or pending, or royalties. No writing assistance was utilized in the production of this manuscript.
Key issues • A third to a half of all cardiovascular disease-related events occur in people with no prior symptoms. • Diabetes is considered a coronary artery disease (CAD) equivalent when estimating risk for future CAD events; however people with diabetes represent a spectrum of risk for CAD. • Coronary artery calcium scoring provides additional risk stratification and improve prediction of cardiovascular events over traditional risk stratification strategies. • Coronary artery calcium further stratifies patients with diabetes and metabolic syndrome to determine appropriate intensity of therapeutic approaches.
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Expert Rev. Cardiovasc. Ther. 12(1), (2014)
