Chapter 15 Coronary Calcium Scoring for Individualized, Disease-Guided Management: Evidence Is Accumulating

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1 Chapter 15 Coronary Calcium Scoring for Individualized, Disease-Guided Management: Evidence Is Accumulating GEEVAR ZACHARIAH JAMES K.J. INTRODUCTION Coronary artery calcium (CAC) is virtually pathognomonic of coronary atherosclerosis, and histopathologic studies have shown that the area of calcification has a direct relationship to coronary atherosclerotic plaque area 1, 2. There is a linear relationship between coronary calcification and total coronary plaque burden on a segmental and entire coronary vessel basis. Roughly 20% of the atherosclerotic plaque burden in the coronary vascular bed is calcified 3. Calcification of the atherosclerotic plaque first appears in the lipid core of the atheroma and occurs by an active process. The initiating mechanisms are not clearly understood but apoptosis of smooth muscle cells seems to be an important step, which then serves as a nidus for calcification 3. CAC assesses the burden of atherosclerosis in a patient truly reflecting the effect of all risk factors in his lifetime. Global risk scores such as the Framingham Risk Score (FRS) or the Pooled Cohort Equation (PCE), however, provide only cardiovascular risk estimates based on mean risk factor distributions across a population and do not assess the atherosclerotic burden or the disease burden. CAC score is a direct measure of disease burden and that is why it is a powerful predictor of risk with a very high negative predictive value. Findings of atherosclerosis by means of CAC represent the best time to intervene with lifestyle changes and medicines 4. EVOLUTION OF CAC SCORING The association between vascular calcification and vascular disease has been known to anatomists and pathologists for several hundred years. Radiologic detection of coronary artery calcification in vivo by fluoroscopy was described in the late 1950s and an association between the presence of CAC and the risk of cardiovascular events was subsequently demonstrated 5. The development of electron beam computed tomographic scanning (EBCT) in the early 1980s permitted noninvasive and quantitative detection of CAC for the first time. Since 1999, the temporal resolution of multidetector row or multislice CT scanners (MDCT or MSCT) has improved sufficiently to permit imaging of the beating heart with no or little motion artefact. The early studies examining the diagnostic and prognostic value of CAC scanning have been conducted with EBCT. However, EBCT has now become obsolete and newest studies of CAC have been performed with 64- detector MDCT which is considered as state-of-theart technology 5. The most widely used and best-established measure of CAC for assessment of the diagnostic and prognostic value of EBCT CAC scanning is the Agatston score. In this method, calcified lesions above a threshold value of 130 Hounsfield Units (HU) and area 1 mm 2 (3 adjacent pixels) are detected based on their density and area. The area of calcification in each of the slices is calculated and multiplied by a weighting factor. All axial scores are then summed 3. CAC scoring was not initially accepted as a screening tool for asymptomatic patients within the cardiovascular community 5. Guidelines for the clinical use of CAC scoring was first published in 1999 (see ref 6 ). However, the 2010 American College of Cardiology/American Heart Association (ACC/AHA) guidelines on screening for coronary artery disease indicated that measurement of 115

2 116 SECTION II Preventive Cardiology CAC is reasonable (level of evidence B) for cardiovascular risk assessment in asymptomatic adults at Framingham intermediate risk (10% 20% 10-year risk) 7. The guidelines noted that measurement of CAC may be reasonable for patients at low to intermediate risk (6% 10% 10-year risk). It was not recommended for patients at low ( 6%, 10-year risk) or high risk 7. Examinations performed to quantify CAC generally impart a lower radiation dose than examinations performed for coronary CT angiography. A typical dose of radiation is to the tune of 1 2 msv (see ref 5 ). CAC AND CORONARY ARTERY STENOSIS In general, CAC is a better marker of the extent of coronary atherosclerosis than the severity of stenosis. Studies have shown relationships between CAC and histologic, intracoronary ultrasonic and angiographic measures of coronary artery atherosclerosis and plaque burden 2, 8, 9. CAC, however, has a low sensitivity to detect plaques without calcification 8. Extensive CAC may be present before the plaque burden overwhelms vascular remodelling, begins to encroach upon the vessel lumen, and leads to clinically relevant stenosis. CAC detected by CT is highly sensitive for the presence of 50% angiographic stenosis but only moderately specific. In a review of 16 studies, the sensitivity and specificity of EBCT were 91% and 49%, respectively 10. Both sensitivity and specificity for the presence of 50% angiographic stenosis vary with the amount of CAC; with more marked CAC, sensitivity falls but specificity increases. Diagnostic accuracy can be improved by the use of age- and gender-specific threshold values 5. The ACCURACY trial confirmed the high sensitivity but low specificity of any CAC for obstructive disease ( 50% stenosis), with sensitivity falling and specificity rising with greater CAC 11. The sensitivity/specificity for CAC 0, 100 and 400 were 98%/42%, 88%/71% and 60%/88%, respectively. In Multi-Ethnic Study of Atherosclerosis (MESA) in the USA of 6814 men and women without clinical cardiovascular disease and diabetes, CAC scores were higher in men compared to women and increased progressively with age 12. Absence of CAC is highly predictive of the absence of significant (greater than 50%) coronary artery stenosis. Patients with no CAC had a probability of significant coronary stenosis of less than 1% (see ref 13 ). CAC AND MYOCARDIAL ISCHAEMIA The relationship between silent ischaemia, detected by stress testing, and CAC has been evaluated in a number of studies. In one report, 1195 patients without known CHD underwent both stress radionuclide myocardial perfusion imaging (rmpi) and CAC scanning 14. Among the 76 patients with stress-induced ischaemia, the CAC score was 0 in 95%, 100 in 88% and 400 in 68%. The frequency of ischaemia on rmpi was less than 2% overall in patients with CAC scores 100. Moreover, in a review of 222 asymptomatic men and women in the population-based MESA study, increasing CAC correlated with a progressive reduction in hyperaemic myocardial blood flow 15. CAC AND PROGNOSIS IN ASYMPTOM- ATIC INDIVIDUALS Several large prospective trials studying the prognostic value of CAC scoring involving population and clinical cohorts have been published A number of meta-analysis and systemic reviews have also been published evaluating the prognostic value of CAC scoring in asymptomatic individuals 7, In one of the earliest studies, in over 10,000 asymptomatic patients who underwent both cardiac risk factor assessment and CAC scoring, CAC score was a significant independent predictor of all-cause mortality after adjustment for family history, hyperlipidaemia, hypertension, smoking and diabetes 26. Similar findings were demonstrated in a study of over 25,000 asymptomatic individuals who underwent both cardiac risk factor assessment and CAC scoring 20. The CAC score predicted allcause mortality independent of and more accurately than standard coronary artery disease risk factors. Risk-adjusted relative risk ratios (for allcause mortality) were 2.2, 4.5, 6.4, 9.2, 10.4 and 12.5 for CAC scores of , , , , and 1000, respectively, when compared to a score of 0. In a MESA cohort of 5878 participants, adding CAC to traditional risk factors including age, sex, tobacco use, systolic blood pressure, antihypertensive medication use, total and HDL cholesterol, race and ethnicity resulted in reclassification of 26% of the cohort and significantly improved the classification of risk 27. There have been numerous recent reports regarding the prognostic value of CAC in asymptomatic individuals. In a large single centre cohort of 9715 asymptomatic patients, Shaw et al. found that CAC

3 Chapter 15 Coronary Calcium Scoring for Individualized, Disease-Guided Management MACE includes cardiac or all cause mortality, MI, UA hospitalization or leading to revascularisation or late revascularisation 3 months, stroke, TIA MACE % (Median Values) % 0.4% None Mild Risk CAC 0.7% Moderate Risk CAC 1.6% High Risk CAC CAC 0 CAC 1 99 CAC CAC 400 Figure 15-1 Median rates of major adverse cardiovascular events (% per year) from seven registries. Note: CAC, coronary artery calcium; MACE, major adverse cardiovascular events; MI, myocardial infarction; TIA, transient ischemic attack; UA, unstable angina. (Reprinted from Journal of Cardiovascular Computed Tomography, 11/2, Hecht et al., Clinical indications for coronary artery calcium scoring in asymptomatic patients: Expert consensus statement from the Society of Cardiovascular Computed Tomography, , 2017, Published by Elsevier Inc. on behalf of Society of Cardiovascular Computed Tomography.) score was highly predictive of all-cause mortality ( P.001). The relative hazard for all-cause mortality ranged from 1.68 for a CAC score of 1 10 ( P.001) to 6.26 for a score of 1000 or greater ( P.001) 28. Fig shows median rates of major adverse cardiovascular events (% per year) from seven registries. The cumulative sample size is 84,182 and end points were cardiac or all-cause mortality, myocardial infarction, unstable angina hospitalization, late revascularization 3 months, stroke and transient ischaemic attacks. A synthesis of these findings shows that there is a direct proportional relation between CAC and clinical outcomes stratified by the CAC categories 0, 1 99, and 400 (Agatston units). Annualized major adverse cardiac events (MACE) rates ranged from 0.1% to 1.6% for those with zero to high risk CAC scores 4. When compared to individuals with CAC score 0, those with high CAC score were found to have relative risk ratios as high as 20%. 29 MACE rates increase proportionally with more extensive CAC scores, but also increase further among individuals with intermediate FRS or PCE risk estimates. Thus, higher event rates are observed in diabetes, the elderly, smokers, hypertensives and other high-risk patient subsets irrespective of the CAC scores. In individuals with a strong family history of coronary heart disease, CAC score identifies the highest risk cases. Long-term follow-up of more than 10 years has also shown prognostic value of CAC scoring. When compared for detectable calcium with CAC score of 0, a cumulative RR ratio of 0.29 ( P.0001) was obtained showing a 70% reduced risk of MACE for those with absent compared to detectable calcium. Those with CAC 0 had an extremely low-event rates of coronary heart disease of 0.1% per year 30. After comparing multiple negative risk markers over long-term follow-up, Blaha and colleagues reported a low-cardiovascular disease event rate in individuals with CAC 0 (4.0% rate of CVD and 2.2% rate of CHD after 10.3 years). This was much lower rate than when a normal ankle-brachia index, low-risk carotid intima-media thickness (CIMT), flow-mediated dilation or high-sensitivity C-reactive protein (hscrp) was used 31. In MESA study, 38% of the diabetic population had a CAC score of 0, making them low risk on follow-up 32. Most studies evaluating the predictive value of CAC have used absolute values of the Agatston score. However, in one study, an Agatston score 75th percentile for age and gender was a better predictor of future cardiac events than the absolute score 33. CAC SCORE AND hscrp The CAC score and hscrp appear to contribute independently to risk stratification for cardiovascular events. This was illustrated in a cohort of 1461 patients without known CHD who were followed for 6.4 years 34. The relative risk for those with the highest quartile hscrp and highest tertile CAC scores

4 118 SECTION II Preventive Cardiology ( 4.05 and 142.1) was 7.5-fold greater than the risk for those with lower hscrp ( 4.05) and the lowest tertile CAC ( 3.7). Another study in 4129 individuals showed that CAC and hscrp independently predicted coronary events and deaths 35. The net reclassification improvement was higher for CAC (23.8%) than for CRP (10.5%). CAC SCORE AND CAROTID INTIMA- MEDIA THICKNESS (CIMT) The predictive value of CAC and CIMT often differ, with CAC more strongly associated with risk of incident cardiovascular disease and CIMT more strongly associated with risk of incident stroke. In a report from MESA of 6698 subjects (aged years) initially free of cardiovascular disease followed over a maximum of 5.3 years, the association of CAC and CIMT with incident cardiovascular disease was evaluated 36. CAC was associated with the risks of incident CHD and total cardiovascular disease more strongly than CIMT. CIMT was a modestly better predictor of stroke than CAC. INCORPORATING CAC SCORING INTO PREVENTION GUIDELINES AND RECOMMENDATION FOR STATINS The PCE, which was developed as a more contemporary risk score than FRS, was used in both the 2013 ACC/AHA Cholesterol Guidelines and the 2016 United States Preventive Services Task Force (USP- STF) guidelines. But limitations of these risk scores like high dependency on age criteria and overestimation of risk based on observed versus predicted events were noted across all racial and ethnic groups 37. This overestimation can be overcome in part by identifying the prevalence of low CAC (CAC 0) and reclassifying high-risk patients defined by PCE into much lower risk stratum. In a recent study from MESA, Nasir et al., reported a 10.3 year followup of 4758 enrollees in whom 247 (5.2%) atherosclerotic cardiovascular disease (ASCVD) events occurred. In those who had statin therapy based on the PCE (PCE 7.5%), 41% had CAC 0 and in those individuals, there were only 5.2 ASCVD events/1000 patient years, compared to 10.5/1000 person years in those with any CAC 38. Similar results were reported from the Framingham Heart Study of 2435 statin-naïve individuals followed for 9.4 years ( n 74 ASCVD events) reported by Pursnani et al. 39. These studies showed that based on zero CAC, down-reclassification to a lower risk strata can be done for statin-eligible patient based on PCE. Up-reclassification into a statin-benefit group was evaluated in a separate MESA analysis by Yeboah et al. who reported that 4185 of 5185 statin-naïve individuals had a recalibrated PCE risk 7.5% (thus not recommended for statins). Excluding diabetic individuals, guideline recommended CAC thresholds (i.e. CAC 300 or 75th percentile for age, sex and ethnicity) reclassified 6.8% of this group to a higher risk statin-eligible risk stratum. The observed 10-year ASCVD event rate for those with a PCE risk 7.5% who were reclassified to a higher risk strata based on CAC was 13.3%. CAC was the most effective tool for upwardly reclassifying otherwise lowrisk patients 40. Yeboah et al. also looked at the improvement in discrimination gained by adding four nontraditional cardiovascular risk markers, CAC, ankle-brachial index (ABI), hscrp and family history of ASCVD to PCE in participants of MESA 41. After 10 years of follow-up, 320 (6.2%) ASCVD events occurred. CAC score, ABI and FH were independent predictors of ASCVD events in the multivariable Cox models. CAC score modestly improved the discriminative ability of the PCE compared with other nontraditional risk markers. The superiority of the CAC score was consistent across all possible ASCVD strata and they concluded that CAC score is superior for improving ASCVD risk prediction and may be useful in individuals in whom quantitative ASCVD risk-based treatment decision-making may be uncertain. However, ultimate use of CAC in the clinical setting for risk assessment demands consideration of additional variables such as cost-effectiveness, radiation exposure and patient preference. CAC AS A GUIDE TO TREATMENT CAC is the most useful test for identification of early atherosclerosis. It is even more powerful in deciding whether treatment is needed. Absence of atherosclerosis potentially obviates the need for anti-atherosclerotic therapies such as aspirin, statin and ACE inhibitors. A recent study demonstrated that a CAC score of 0 confers a 15-year warranty period against mortality in individuals at low to intermediate risk, unaffected by age or sex 42. The 2013 ACC/AHA Cholesterol Guideline strongly emphasizes the importance of shared decision management (SDM) before initiating statin therapy to discuss patient preferences, adverse effects and the potential for ASCVD risk reduction benefits 43. It is appropriate to include the option of CAC testing, explaining its potential role in allowing for no treatment when it is unlikely to result in

5 Chapter 15 Coronary Calcium Scoring for Individualized, Disease-Guided Management 119 net benefit. All patients without clinical ASCVD or diabetes who are years of age and with an estimated 10-year ASCVD risk of 5% or higher based on the PCE (i.e., statins considered or statinrecommended groups) should have a SDM. SDM should detail a discussion regarding any potential adverse effects of statins including myalgia, diabetes, cognitive impairment as well as the values and preferences that patients place on either taking or avoiding statin therapy. Safety concerns regarding radiation exposure and implications of incidental findings should be discussed Cholesterol guideline supports consideration of CAC in order to further ascertain risk when the physician recommendation or patient decision regarding statin therapy is uncertain. For a physician, CAC may be most useful in the 10-year ASCVD 5% 15% risk group in which CAC 0 and low CAC scores would largely refine risk downward to lowest or low strata 4. Downward risk reclassification may be considered with 0 or low CAC scores in 15% 20% 10-year risk group, but there is little role for risk reclassification in the 10-year ASCVD 20% risk group. In the 10-year ASCVD 5% risk group, patients like young patients with strong family history of premature CAD, young patients with renal disease, or inflammatory diseases, erectile dysfunction or obstructive sleep apnoea may be the candidates for CAC evaluation 4. CAC to guide statin use: CAC scoring is useful to guide the initiation and the intensity of statin therapy. High-intensity statin therapy is recommended in patients with a CAC 300 or above the 75th percentile for age/gender/race. Moderate- to high-intensity statin treatment is recommended for patients with CAC In patients with CAC 1 99, moderate-intensity statin therapy is recommended for those with CAC percentile 75% and moderate to high intensity for those with CAC percentile 75%. Patients with CAC 0 are considered to be at lowest risk and statins are not uniformly recommended, exceptions being familial hypercholesterolaemia or diabetes 4. CAC to guide aspirin use: In patients with CAC 100, bleeding risks outweigh benefits of aspirin therapy in the absence of other risk factors. In the MESA study, individuals with CAC scores 100 had an estimated net benefit from aspirin regardless of their traditional risk status 28. Individuals with score of zero were unlikely to benefit irrespective of gender and age. Aspirin therapy should be considered for patients with CAC 100, in the absence of bleeding contraindications 4. ROLE OF CAC IN TREATMENT ADHER- ENCE AND A HEALTHY LIFESTYLE A targeted literature review of observational studies showed that in patients with high risk for CVD, the majority of patients do not attain recommended LDL-C goals, highlighting worldwide suboptimal hyperlipidaemia management 44. A systemic review has shown that CAC screening significantly improve risk perception and medication adherence among asymptomatic adults 25. Early Identification of Subclinical Atherosclerosis by Noninvasive Imaging Research (EISNER) trial studied the impact of CAC scanning on future CAD risk relative to that of conventional medical practice. This largest RCT comparing CAC scanning ( n 1424) to a no-scan strategy ( n 713) showed that after 4 years of follow-up, the CAC scan group had lower systolic blood pressure ( P.02), LDL cholesterol ( P.04) and reductions in waist circumference ( P.01) for those with greater abdominal girth measurements. Mean FRS score increased in the no-scan group compared to baseline FRS, but remained essentially unchanged in the scan group ( vs , P.003). Increasing baseline CAC score was associated with a proportionally greater improvement in most CAD risk factors at follow-up. Moreover, nearly half of the scan group had 0 CAC and the 4-year costs of care were 30% lower when compared to the no scan group ( P.001) 45. COST-EFFECTIVENESS OF CAC Treating all is not cost-effective and people are less compliant if there are no personal benefits. Roberts et al. selected participants in the MESA study with intermediate ATP III FRSs of 6% 20%, LDL-cholesterol levels 160 mg/dl and not on statins and developed a model to test cost-effectiveness of statin treatment in patients with CAC 1 and CAC 100, with different intensities of statins based on the CAC score. They compared CAC-based treatment strategies to a treat all strategy and to treatment according to the Adult Treatment Panel III (ATP III) guidelines. They found that CAC scanning in intermediate-risk patients is more effective and cost saving 46. Blaha et al. identified 950 participants in the MESA study who satisfied the entry criteria of JUPITER Study (MESA JUPITER population) and compared coronary heart disease and cardiovascular disease event rates and multivariable-adjusted hazard ratios after stratifying by burden of CAC (scores of 0, or 100). Median

6 120 SECTION II Preventive Cardiology follow-up was 5.8 years. About 47% of patients in the MESA JUPITER population had CAC scores of 0 and in this group, rates of coronary heart disease events were 0 8 per 1000 person-years. About 74% of all coronary events were in the 239 (25%) of participants with CAC scores of more than 100. For coronary heart disease, the predicted 5-year number needed to treat (NNT) was 549 for CAC score 0, 94 for scores 1 100, and 24 for scores greater than 100. Interestingly hscrp was not associated with coronary heart disease events after multivariable adjustment. They concluded that focusing of treatment on the subset of individuals with measurable atherosclerosis could allow for more appropriate allocation of resources 47. ROLE OF SERIAL CAC SCANNING A meta-analysis from four controlled clinical trials which compared effect of statin therapy to placebo or varying intensity statin therapy did not show significant effect on CAC and suggested that statin therapy did not impact CAC progression 48. On the contrary, a recent post hoc analysis of eight prospective randomized serial coronary intravascular ultrasound (IVUS) trials seems to suggest that statins promoted coronary calcification, hypothesized as a means of stabilizing atherosclerotic plaque 49. However, these findings have not been corroborated by other studies using virtual histology IVUS. However, there is evidence that prognosis worsens with increased CAC on repeat scanning and the increase in CAC is proportional to the rate of increase in cardiovascular risk 50. Expert consensus is that in patients for whom the development or progression of CAC would support intensification or alteration in preventive management, it may be appropriate to consider repeat CAC scanning at an interval of 5 years for patients with 0 CAC and a 3- to 5-year interval for patients with 0 CAC 4. Since serial studies of CAC are of unproven clinical value, routine quantification of CAC progression is not recommended. RECOMMENDATIONS FOR USE OF CAC SCORING It is appropriate to perform CAC testing in the context of shared decision-making for asymptomatic individuals without clinical ASCVD who are years of age in the 5% 20% 10-year ASCVD risk group and selectively in the 5% ASCVD group, such as those with a family history of premature coronary artery disease 4. The best management approach for asymptomatic patients with a high CAC score (e.g. CAC 400) is uncertain ACC/AHA guidelines on screening for CHD suggest consideration of stress testing in such individuals, particularly if they are sedentary where absence of symptoms does not imply absence of ischaemia 5. Serial CAC scanning to monitor progression or regression of disease is not recommended since the utility of such an approach is unknown 5. The use of statins and other primary prevention modalities should not be based upon the findings on CAC screening and conversely, pharmacologic risk factor management should not be withheld if CAC is absent 5. There is as yet no evidence that basing the decision to implement or intensify preventive measures (such as resetting goal LDL to 70 mg/dl in patients in whom CAC is the only manifestation of CAD) on the presence and quantity of CAC leads to an improvement in outcomes 5. CONCLUSION Coronary artery calcification assesses the burden of atherosclerosis in an individual, truly reflecting the effect of all risk factors in his lifetime unlike global risk scores such as the PCE which provide only cardiovascular risk estimates. CAC is virtually pathognomonic of coronary atherosclerosis. It is a better marker of extent of coronary atherosclerosis than severity of stenosis. Findings of atherosclerosis by means of CAC represent the best time to intervene with lifestyle changes and medicines. Large number of prospective cohort studies in the population as well as in clinical registries has shown prognostic value of CAC in predicting coronary heart disease events. CAC is highly sensitive for the presence of 50% angiographic stenosis but only moderately specific. Absence of CAC is highly predictive of the absence of significant coronary artery stenosis. CAC can overcome many of the limitations of the risk scores like PCE and can help to reclassify low CAC score individuals to lower risk. It can improve the discriminative ability of the PCE compared with other nontraditional risk markers like ankle-brachial index, high-sensitivity CRP and positive family history. It is a valuable tool in the context of shared decision-making for asymptomatic individuals without clinical ASCVD who are years of age in the 5% 20% 10-year ASCVD risk group and selectively in the 5% ASCVD group, such as those

7 Chapter 15 Coronary Calcium Scoring for Individualized, Disease-Guided Management 121 with a family history of premature coronary artery disease. In addition, CAC screening considerably improve risk perception and adherence to medications and preventive lifestyle. However, serial CAD evaluation has not been shown to be useful. Finally, CAC is a cost-effective tool when used in a prespecified patient population. REFERENCES 1. Sangiorgi, G., Rumberger, J. A., Severson, A., Edwards, W. D., Gregoire, J., Fitzpatrick, L. A., et al. ( 1998 ). Arterial calcification and not lumen stenosis is highly correlated with atherosclerotic plaque burden in humans: A histologic study of 723 coronary artery segments using non decalcifying methodology. Journal of the American College of Cardiology, 31, Rumberger, J. A., Simons, D. B., Fitzpatrick, L. A., Sheedy, P. F., & Schwartz, R. S. ( 1995 ). Coronary artery calcium areas by electron-beam computed tomography and coronary atherosclerotic plaque area: A histopathologic correlative study. Circulation, 92, Kalra, D. K., Heo, R., Valenti, V., Nakazato, R., & Min, J. K. ( 2014 ). Role of computed tomography for diagnosis and risk stratification of patients with suspected or known coronary artery disease. Arteriosclerosis, Thrombosis, and Vascular Biology, 34 ( 6 ), Hecht, H., Blaha, M. J., Berman, D.S., Nasir, K., Budoff, M., Leipsic, J., et al. ( 2017 ). Clinical indications for coronary artery calcium scoring in asymptomatic patients: Expert consensus statement from the Society of Cardiovascular Computed Tomography. Journal of Cardiovascular Computed Tomography, 11, Gerber, T. C., & Kramer, C. M. ( 2017 ). Diagnostic and prognostic implications of coronary artery calcification detected by computer tomography. In C. D. Brian & I. L. Susanna (Ed.). UpToDate. [Retrieved August 29, 2017]. 6. Rumberger, J. A., Brundage, B. H., Rader, D. J., & Kondos, G. ( 1999 ). Electron beam CT coronary calcium scanning: A review and guidelines for use in asymptomatic individuals. Mayo Clinic Proceedings, 74, Greenland, P., Alpert, J. S., Beller, G. A., Benjamin, E. J., Budoff, M. J., Fayad, Z. A., et al. ( 2010 ) ACCF/AHA guideline for assessment of cardiovascular risk in asymptomatic adults: A report of the American College of Cardiology Foundation/American Heart Association Task Force on Practice Guidelines. Journal of the American College of Cardiology, 56, e Baumgart, D., Schmermund, A., Goerge, G., Haude, M., Ge, J., Adamzik, M., et al. ( 1997 ). Comparison of electron beam computed tomography with intracoronary ultrasound and coronary angiography for detection of coronary atherosclerosis. Journal of the American College of Cardiology, 30, Kajinami K, Seki H, Takekoshi N, & Mabuchi H. ( 1997 ). Coronary calcification and coronary atherosclerosis: Site by site comparative morphologic study of electron beam computed tomography and coronary angiography. Journal of the American College of Cardiology, 29, O Rourke, R. A., Brundage, B. H., Froelicher, V. F., Greenland, P., Grundy, S. M., Hachamovitch, R., et al. ( 2000 ). American College of Cardiology/American Heart Association Expert Consensus document on electronbeam computed tomography for the diagnosis and prognosis of coronary artery disease. Circulation, 102, Budoff, M. J., Hokanson, J. E., Nasir, K., Shaw, L. J., Kinney, G. L., Chow, D., et al. ( 2010 ). Progression of coronary artery calcium predicts all-cause mortality. JACC Cardiovascular Imaging, 3, McClelland, R. L., Chung, H., Detrano, R., Post, W., & Kronmal, R. A. ( 2006 ). Distribution of coronary artery calcium by race, gender, and age: Results from the Multi-Ethnic Study of Atherosclerosis (MESA). Circulation, 113, Haberl, R., Becker, A., Leber, A., Knez, A., Becker, C., Lang, C., et al. ( 2001 ). Correlation of coronary calcification and angiographically documented stenoses in patients with suspected coronary artery disease: Results of 1,764 patients. Journal of the American College of Cardiology, 37, Berman, D. S, Wong, N. D., Gransar, H., Miranda-Peats, R., Dahlbeck, J., Hayes, S. W., et al. ( 2004 ). Relationship between stress-induced myocardial ischemia and atherosclerosis measured by coronary calcium tomography. Journal of the American College of Cardiology, 44, Wang, L., Jerosch-Herold, M., Jacobs, D. R. Jr., Shahar, E., Detrano, R., Folsom, A. R., et al. ( 2006 ). Coronary artery calcification and myocardial perfusion in asymptomatic adults: The MESA (Multi-Ethnic Study of Atherosclerosis). Journal of the American College of Cardiology, 48, Detrano, R., Guerci, A. D., Carr, J. J., Bild, D. E., Burke, G., Folsom, A. R., et al. ( 2008 ). Coronary calcium as a predictor of coronary events in four racial or ethnic groups. New England Journal of Medicine, 358, Hoffmann, U., Massaro, J. M., D Agostino, R. B., Sr., Kathiresan, S., Fox, C. S., O Donnell, C. J., et al. ( 2016 ). Cardiovascular event prediction and risk reclassification by coronary, aortic, and valvular calcification in the Framingham Heart Study. Journal of the American Heart Association, Baber, U., Mehran, R., Sartori, S., Schoos, M. M., Sillesen, H., Muntendam, P., et al. ( 2015 ). Prevalence, impact, and predictive value of detecting subclinical coronary and carotid atherosclerosis in asymptomatic adults: The BioImage study. Journal of the American College of Cardiology, 65, Erbel, R., Möhlenkamp, S., Moebus, S., Schmermund, A., Lehmann, N., Stang, A., et al., Heinz Nixdorf Recall Study Investigative G. ( 2010 ). Coronary risk stratification, discrimination, and reclassification improvement based on quantification of subclinical coronary atherosclerosis: The Heinz Nixdorf Recall Study. Journal of the American College of Cardiology, 56, Budoff, M. J., Shaw, L. J., Liu, S. T., Weinstein, S. R., Mosler, T. P., Tseng, P. H., et al. ( 2007 ). Long-term prognosis associated with coronary calcification: Observations from a registry of 25,253 patients. Journal of the American College of Cardiology, 49,

8 122 SECTION II Preventive Cardiology 21. Pletcher, M. J., Tice, J. A., Pignone, M., & Browner, W. S. ( 2004 ). Using the coronary artery calcium score to predict coronary heart disease events: A systematic review and meta-analysis. Archives of Internal Medicine, 164, Greenland, P., Bonow, R. O, Brundage, B. H, Budoff, M. J., Eisenberg, M. J., Grundy, S. M., et al. ( 2007 ). ACCF/ AHA 2007 clinical expert consensus document on coronary artery calcium scoring by computed tomography in global cardiovascular risk assessment and in evaluation of patients with chest pain. Journal of the American College of Cardiology, 49, Perrone-Filardi, P., Achenbach, S., Möhlenkamp, S., Reiner, Z., Sambuceti, G., Schuijf, J. D., et al. ( 2011 ). Cardiac computed tomography and myocardial perfusion scintigraphy for risk stratification in asymptomatic individuals without known cardiovascular disease: A position statement of the working group on nuclear cardiology and cardiac CT of the European Society of Cardiology. European Heart Journal, 32, Peters, S. A., den Ruijter, H. M., Bots, M. L., & Moons, K. G. ( 2012 ). Improvements in risk stratification for the occurrence of cardiovascular disease by imaging subclinical atherosclerosis: A systematic review. Heart, 98, Mamudu, H. M., Paul, T. K., Veeranki, S. P., & Budoff, M. ( 2014 ). The effects of coronary artery calcium screening on behavioral modification, risk perception, and medication adherence among asymptomatic adults: A systematic review. Atherosclerosis, 236, Shaw, L. J., Raggi, P., Schisterman, E., Berman, D. S., & Callister, T. Q. ( 2003 ). Prognostic value of cardiac risk factors and coronary artery calcium screening for allcause mortality. Radiology, 228, Polonsky, T. S., McClelland, R. L., Jorgensen, N. W., Bild, D. E., Burke, G. L., Guerci, A. D., et al. ( 2010 ). Coronary artery calcium score and risk classification for coronary heart disease prediction. JAMA, 303, Shaw, L. J., Giambrone, A. E., Blaha, M. J., Knapper, J. T., Berman, D. S., Bellam, N., et al. ( 2015 ). Long-term prognosis after coronary artery calcification testing in asymptomatic patients: A cohort study. Annals of Internal Medicine, 163, Goel, R., Garg, P., Achenbach, S., Gupta, A., Song, J. J., Wong, N. D., et al. ( 2012 ). Coronary artery calcification and coronary atherosclerotic disease. Cardiology Clinics, 30, Nakanishi, R., Li, D., Blaha, M. J., Whelton, S. P., Matsumoto, S., Alani, A., et al. ( 2015 ). The relationship between coronary artery calcium score and the longterm mortality among patients with minimal or absent coronary artery risk factors. International Journal of Cardiology, 185, Blaha, M. J., Cainzos-Achirica, M., Greenland, P., McEvoy, J. W., Blankstein, R., Budoff, M. J., et al. ( 2016 ). Role of coronary artery calcium score of zero and other negative risk markers for cardiovascular disease: The Multi-Ethnic Study of Atherosclerosis (MESA). Circulation, 133, Malik, S., Budoff, M. J., Katz, R., Blumenthal, R. S., Bertoni, A. G., Nasir, K., et al. ( 2011 ). Impact of subclinical atherosclerosis on cardiovascular disease events in individuals with metabolic syndrome and diabetes: The multi-ethnic study of atherosclerosis. Diabetes Care, 34, Raggi, P., Callister, T. Q., Cooil, B., He, Z. X., Lippolis, N. J., Russo, D. J., et al. ( 2000 ). Identification of patients at increased risk of first unheralded acute myocardial infarction by electron-beam computed tomography. Circulation, 101, Park, R., Detrano, R., Xiang, M., Fu P, Ibrahim, Y., LaBree, L., et al. ( 2002 ). Combined use of computed tomography coronary calcium scores and C-reactive protein levels in predicting cardiovascular events in nondiabetic individuals. Circulation, 106, Möhlenkamp, S., Lehmann, N., Moebus, S., Schmermund, A., Dragano, N., Stang, A., et al. ( 2011 ). Quantification of coronary atherosclerosis and inflammation to predict coronary events and all-cause mortality. Journal of the American College of Cardiology, 57, Folsom, A. R., Kronmal, R. A., Detrano, R. C., O Leary, D. H., Bild, D. E., Bluemke, D. A., et al. ( 2008 ). Coronary artery calcification compared with carotid intima-media thickness in the prediction of cardiovascular disease incidence: The Multi-Ethnic Study of Atherosclerosis (MESA). Archives of Internal Medicine, 168, Cook NR, & Ridker PM. ( 2016 ). Calibration of the pooled cohort equations for atherosclerotic cardiovascular disease: An update. Annals of Internal Medicine, 165, Nasir, K., Bittencourt, M. S., Blaha, M. J., Blankstein, R., Agatson, A. S., Rivera, J. J., et al. ( 2015 ). Implications of coronary artery calcium testing among statin candidates according to American College of cardiology/ American Heart Association cholesterol management guidelines: MESA (Multi-Ethnic Study of Atherosclerosis). Journal of the American College of Cardiology, 66, Pursnani, A., Massaro, J. M., D Agostino, R. B., Sr., O Donnell, C. J., & Hoffmann, U. ( 2015 ). Guidelinebased statin eligibility, coronary artery calcification, and cardiovascular events. JAMA, 314, Yeboah, J., Polonsky, T. S., Young, R., McClelland, R. L., Delaney, J. C., Dawood, F., et al. ( 2015 ). Utility of nontraditional risk markers in individuals ineligible for statin therapy according to the 2013 American College of Cardiology/American Heart Association cholesterol guidelines. Circulation, 132, Yeboah, J., Young, R., McClelland, R. L., Delaney, J. C., Polonsky, T. S., Dawood, F. Z., et al. ( 2016 ). Utility of nontraditional risk markers in atherosclerotic cardiovascular disease risk assessment. Journal of the American College of Cardiology, 67, Valenti V, Ó Hartaigh, B., Heo, R., Cho, I., Schulman- Marcus, J., Gransar, H., et al. ( 2015 ). A 15-year warranty period for asymptomatic individuals without coronary artery calcium: A prospective follow-up of 9,715 individuals. JACC Cardiovascular Imaging, 8, Martin, S. S., Sperling, L. S., Blaha, M. J., Wilson, P. W., Gluckman, T. J., Blumenthal, R. S., et al. ( 2015 ). Clinician-patient risk discussion for atherosclerotic

9 Chapter 15 Coronary Calcium Scoring for Individualized, Disease-Guided Management 123 cardiovascular disease prevention: Importance to implementation of the 2013 ACC/AHA guidelines. Journal of the American College of Cardiology, 65, Mitchell, S., Roso, S., Samuel, M., & Pladevall-Vila, M. ( 2016 ). Unmet need in the hyperlipidaemia population with high risk of cardiovascular disease: A targeted literature review of observational studies. BMC Cardiovascular Disorders, 16, Rozanski, A., Gransar, H., Shaw, L. J., Miranda-Peats, L., Wong, N. D., Rana, J. S., et al. ( 2011 ). Impact of coronary artery calcium scanning on coronary risk factors and downstream testing the EISNER (Early Identification of Subclinical Atherosclerosis by Noninvasive Imaging Research) prospective randomized trial. Journal of the American College of Cardiology, 57, Roberts, E. T., Horne, A., Martin, S. S., Blaha, M. J., Blankstein, R., Budoff, M. J. et al. ( 2015 ). Costeffectiveness of coronary artery calcium testing for coronary heart and cardiovascular disease risk prediction to guide statin allocation: The Multi-Ethnic Study of Atherosclerosis (MESA). PLoS one, 10, e Blaha, M. J., Budoff, M. J., DeFilippis, A. P., Blankstein, R., Rivera, J. J., Agatston, A., et al. ( 2011 ). Associations between C-reactive protein, coronary artery calcium, and cardiovascular events: Implications for the JUPI- TER population from MESA, a population-based cohort study. Lancet, 378, Oudkerk M, Stillman AE, Halliburton SS, et al., European society of cardiac R and North American society for cardiovascular Imaging. ( 2008 ). Coronary artery calcium screening: Current status and recommendations from the European Society of Cardiac Radiology and North American Society for Cardiovascular Imaging. European Radiology, 18, Puri, R., Nicholls, S. J., Shao, M., Kataoka, Y., Uno, K., Kapadia, SR., et al. ( 2015 ). Impact of statins on serial coronary calcification during atheroma progression and regression. Journal of the American College of Cardiology, 65, Budoff, M. J., Young, R., Lopez, V. A., Kronmal, R. A., Nasir, K., Blumenthal, R. S., et al. ( 2013 ). Progression of coronary calcium and incident coronary heart disease events: MESA (Multi-Ethnic Study of Atherosclerosis). Journal of the American College of Cardiology, 61,

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