1. Clinical Trial Results. org Long-Term Prognosis Associated with Coronary Calcification Matthew J. Budoff, MD, Leslee J. Shaw, PhD, Sandy T. Liu, Steven R. Weinstein, Tristen P. Mosler, Philip H. Tseng, Ferdinand R. Flores, Tracy Q. Callister, MD, Paolo Raggi, MD, Daniel S. Berman, MD Published in JACC May 8, 2007 Long-Term Prognosis Associated with Coronary Calcification

2. Clinical Trial Results. org Primary prevention interventions are often focused on patients who are classified as intermediate-risk or high-risk.Primary prevention interventions are often focused on patients who are classified as intermediate-risk or high-risk. Stratification into risk groups is helpful but can be imprecise when large proportions of patients are considered to be at “intermediate” risk.Stratification into risk groups is helpful but can be imprecise when large proportions of patients are considered to be at “intermediate” risk. Intermediate-risk patients receive cholesterol therapy that can range from no therapy to a low-density lipoprotein target <100 mg/dl.Intermediate-risk patients receive cholesterol therapy that can range from no therapy to a low-density lipoprotein target <100 mg/dl. Primary prevention interventions are often focused on patients who are classified as intermediate-risk or high-risk.Primary prevention interventions are often focused on patients who are classified as intermediate-risk or high-risk. Stratification into risk groups is helpful but can be imprecise when large proportions of patients are considered to be at “intermediate” risk.Stratification into risk groups is helpful but can be imprecise when large proportions of patients are considered to be at “intermediate” risk. Intermediate-risk patients receive cholesterol therapy that can range from no therapy to a low-density lipoprotein target <100 mg/dl.Intermediate-risk patients receive cholesterol therapy that can range from no therapy to a low-density lipoprotein target <100 mg/dl. Budoff, et al. JACC 2007; 49: 1860-70 Long-Term Prognosis Associated with Coronary Calcification: Background

3. Clinical Trial Results. org More effective assessment of coronary heart disease (CHD) risk might improve the outcome, cost- effectiveness, and safety of primary prevention efforts.More effective assessment of coronary heart disease (CHD) risk might improve the outcome, cost- effectiveness, and safety of primary prevention efforts. This study aimed to develop risk-adjusted multivariable models that include risk factors and coronary artery calcium (CAC) scores measured with electron-beam tomography (EBT) in asymptomatic patients for the prediction of all-cause mortality.This study aimed to develop risk-adjusted multivariable models that include risk factors and coronary artery calcium (CAC) scores measured with electron-beam tomography (EBT) in asymptomatic patients for the prediction of all-cause mortality. More effective assessment of coronary heart disease (CHD) risk might improve the outcome, cost- effectiveness, and safety of primary prevention efforts.More effective assessment of coronary heart disease (CHD) risk might improve the outcome, cost- effectiveness, and safety of primary prevention efforts. This study aimed to develop risk-adjusted multivariable models that include risk factors and coronary artery calcium (CAC) scores measured with electron-beam tomography (EBT) in asymptomatic patients for the prediction of all-cause mortality.This study aimed to develop risk-adjusted multivariable models that include risk factors and coronary artery calcium (CAC) scores measured with electron-beam tomography (EBT) in asymptomatic patients for the prediction of all-cause mortality. Long-Term Prognosis Associated with Coronary Calcification: Background Cont. Budoff, et al. JACC 2007; 49: 1860-70

4. Clinical Trial Results. org Long-Term Prognosis Associated with Coronary Calcification: Study Design Assessment of all-cause mortality A cohort of 25,253 consecutive, asymptomatic individuals referred by their primary physician for CAC scanning to assess cardiovascular risk 6.8 ± 3 yrs. follow-up 6.8 ± 3 yrs. follow-up CAC Score 044% 044% 1-1014% 1-1014% 11-10020% 11-10020% 101-40013% 101-40013% 401-10006% 401-10006% >10004% >10004% CAC scanning Budoff, et al. JACC 2007; 49: 1860-70

5. Clinical Trial Results. org Of the 25,253 patients, the average age was 56 ± 11 years with more than half being male and having a family history of premature coronary artery disease (CAD).Of the 25,253 patients, the average age was 56 ± 11 years with more than half being male and having a family history of premature coronary artery disease (CAD). The prevalence of cardiac risk factors was as follows: family history of premature CAD (58%), hypercholesterolemia (18%), hypertension (15%), smoking (9%), and diabetes (4%).The prevalence of cardiac risk factors was as follows: family history of premature CAD (58%), hypercholesterolemia (18%), hypertension (15%), smoking (9%), and diabetes (4%). Of the 25,253 patients, the average age was 56 ± 11 years with more than half being male and having a family history of premature coronary artery disease (CAD).Of the 25,253 patients, the average age was 56 ± 11 years with more than half being male and having a family history of premature coronary artery disease (CAD). The prevalence of cardiac risk factors was as follows: family history of premature CAD (58%), hypercholesterolemia (18%), hypertension (15%), smoking (9%), and diabetes (4%).The prevalence of cardiac risk factors was as follows: family history of premature CAD (58%), hypercholesterolemia (18%), hypertension (15%), smoking (9%), and diabetes (4%). Long-Term Prognosis Associated with Coronary Calcification: Clinical Characteristics Budoff, et al. JACC 2007; 49: 1860-70

6. Clinical Trial Results. org In the overall cohort, the average CAC score was 146 ± 443.In the overall cohort, the average CAC score was 146 ± 443. In subsets with more extensive CAC scores, patients were older and had more frequent cardiac risk factors. Nearly one-half of the patients with CAC scores ≥ 1000 were male (p<0.0001), hypertensive (p<0.0001), hyperlipidemic (p<0.0001), or had a family history of premature CAD (p=0.052).In subsets with more extensive CAC scores, patients were older and had more frequent cardiac risk factors. Nearly one-half of the patients with CAC scores ≥ 1000 were male (p<0.0001), hypertensive (p<0.0001), hyperlipidemic (p<0.0001), or had a family history of premature CAD (p=0.052). In the overall cohort, the average CAC score was 146 ± 443.In the overall cohort, the average CAC score was 146 ± 443. In subsets with more extensive CAC scores, patients were older and had more frequent cardiac risk factors. Nearly one-half of the patients with CAC scores ≥ 1000 were male (p<0.0001), hypertensive (p<0.0001), hyperlipidemic (p<0.0001), or had a family history of premature CAD (p=0.052).In subsets with more extensive CAC scores, patients were older and had more frequent cardiac risk factors. Nearly one-half of the patients with CAC scores ≥ 1000 were male (p<0.0001), hypertensive (p<0.0001), hyperlipidemic (p<0.0001), or had a family history of premature CAD (p=0.052). Long-Term Prognosis Associated with Coronary Calcification: Clinical Characteristics Budoff, et al. JACC 2007; 49: 1860-70

7. Clinical Trial Results. org Figure 1. Cumulative Survival by Coronary Calcium Score Time to Follow-up (Years) 0 (n=11,044) 1-10 (n=3,567) 11-100 (n=5,032) 101-299 (n=2,616) 300-399 (n=561) 400-699 (n=955) 700-999 (n=514) 1,000+ (n=964)  2 =1363, p<0.0001 for variable overall and for each category subset. Cumulative Survival 0.02.04.06.08.010.012.0 0.70 0.75 0.80 0.85 0.90 0.95 1.00 Long-Term Prognosis Associated with Coronary Calcification: Outcomes Budoff, et al. JACC 2007; 49: 1860-70

8. Clinical Trial Results. org 0.02.04.06.08.010.012.0 0.70 0.75 0.80 0.85 0.90 0.95 1.00 Time to Follow-up (Years) Cumulative Survival 0 Vessel (n=24,340) 1 Vessel (n=596) 2 Vessel (n=143) 3 Vessel (n=28) Left Main (n=146)  2 =251, p<0.0001 Figure 2. Cumulative Survival by the Coronary Calcium Extent in the Number of Vascular Territories Long-Term Prognosis Associated with Coronary Calcification: Outcomes Budoff, et al. JACC 2007; 49: 1860-70

9. Clinical Trial Results. org Time to Follow-up (Years) Cumulative Survival 0 Vessel (n=19,302) 1 Vessel (n=2,563) 2 Vessel (n=1,432) 3 Vessel (n=848) 3 Vessel + LM (n=195)  2 =182, p<0.0001 for the variable and for each category subset. Figure 3. Cumulative Survival in Patients with No Significant Calcium Score but with CAC Scores in the Range of 11-100 0.002.004.006.008.0010.0012.00 0.80 0.85 0.90 0.95 1.00 Long-Term Prognosis Associated with Coronary Calcification: Outcomes Budoff, et al. JACC 2007; 49: 1860-70

10. Clinical Trial Results. org 0.002.004.006.008.0010.0012.00 Time to Follow-up (Years) 0.75 0.80 0.85 0.90 0.95 1.00 0.001.002.003.004.005.00 Time to Follow-up (Years) 0.75 0.80 0.85 0.90 0.95 1.00 Near- and Long-Term Survival from 2 EBT Centers: Nashville and Los Angeles n=10,377 n=25,257 99.4% 97.8% 95.2% 90.4% 81.8% 99.4% 97.8% 94.5% 93.0% 76.9%  2 =1503, p<0.0001, interaction p<o.0001 Long-Term Prognosis Associated with Coronary Calcification: Outcomes Budoff, et al. JACC 2007; 49: 1860-70

11. Clinical Trial Results. org Survival rate (%) CAC Score Long-Term Prognosis Associated with Coronary Calcification: Outcomes 5-year and 12-year Survival from 2 EBT Centers: Nashville and Los Angeles Budoff, et al. JACC 2007; 49: 1860-70

12. Clinical Trial Results. org 0.00.20.40.60.81.0 1 - Specificity 0.0 0.2 0.4 0.6 0.8 1.0 Sensitivity 5a. Incremental Value of Agatston Score over the Total Number of Cardiac Risk Factors p<0.0001 0.611 (0.585-0.637) 0.813 (0.794-0.832) 0.00.20.40.60.81.0 1 - Specificity 0.0 0.2 0.4 0.6 0.8 1.0 p<0.0001 0.771 (0.750-0.793) 0.813 (0.794-0.832) 5b. Incremental Value of Agatston Score over the Age ROC analysis for other indivduals risk factors were less from 0.586 for sex, 0.440 for family history, 0.573 for smoking, 0.577 fpr diabetes, 0.518 for ethnicity, 0.484 for hyperlipidemia, and 0.562 for hypertension. Figure 5. Receiver Operating Characteristics Curves Noting the Incremental Value of the Total Agatston Scores Over and Above the Total Number of Clinical Risk Factors as well as Age. These curves note the available data revealing the highest area under the curve for clinical risk factors. In both cases, the addition of the Agatston score resulted in a significant improvement in the area under the curve (p<0.0001 for the total number of risk factors and for age) Long-Term Prognosis Associated with Coronary Calcification: Outcomes Budoff, et al. JACC 2007; 49: 1860-70

13. Clinical Trial Results. org The majority of patients in this study that were referred for calcium scanning had cardiac risk factors and, therefore, are not representative of the general population.The majority of patients in this study that were referred for calcium scanning had cardiac risk factors and, therefore, are not representative of the general population. There was incomplete information related to cardiovascular risk factors, because these measures were taken by survey rather than being measured.There was incomplete information related to cardiovascular risk factors, because these measures were taken by survey rather than being measured. The majority of patients in this study that were referred for calcium scanning had cardiac risk factors and, therefore, are not representative of the general population.The majority of patients in this study that were referred for calcium scanning had cardiac risk factors and, therefore, are not representative of the general population. There was incomplete information related to cardiovascular risk factors, because these measures were taken by survey rather than being measured.There was incomplete information related to cardiovascular risk factors, because these measures were taken by survey rather than being measured. Long-Term Prognosis Associated with Coronary Calcification: Limitations Budoff, et al. JACC 2007; 49: 1860-70

14. Clinical Trial Results. org Information on subsequent therapy after calcium scanning is unknown. It was previously demonstrated that patients with higher calcium burdens are more likely to maintain statin therapy over 3-5 years. Therefore, higher calcium scores are confounded by improved anti-athersoclerotic therapies that would possible lower cardiovascular mortality.Information on subsequent therapy after calcium scanning is unknown. It was previously demonstrated that patients with higher calcium burdens are more likely to maintain statin therapy over 3-5 years. Therefore, higher calcium scores are confounded by improved anti-athersoclerotic therapies that would possible lower cardiovascular mortality. Also, the National Death Index data do not include the cause of death. Therefore, this study’s models include mortality possibly unrelated to athersoclerotic disease.Also, the National Death Index data do not include the cause of death. Therefore, this study’s models include mortality possibly unrelated to athersoclerotic disease. Information on subsequent therapy after calcium scanning is unknown. It was previously demonstrated that patients with higher calcium burdens are more likely to maintain statin therapy over 3-5 years. Therefore, higher calcium scores are confounded by improved anti-athersoclerotic therapies that would possible lower cardiovascular mortality.Information on subsequent therapy after calcium scanning is unknown. It was previously demonstrated that patients with higher calcium burdens are more likely to maintain statin therapy over 3-5 years. Therefore, higher calcium scores are confounded by improved anti-athersoclerotic therapies that would possible lower cardiovascular mortality. Also, the National Death Index data do not include the cause of death. Therefore, this study’s models include mortality possibly unrelated to athersoclerotic disease.Also, the National Death Index data do not include the cause of death. Therefore, this study’s models include mortality possibly unrelated to athersoclerotic disease. Long-Term Prognosis Associated with Coronary Calcification: Limitations Cont. Budoff, et al. JACC 2007; 49: 1860-70

15. Clinical Trial Results. org Long-Term Prognosis Associated With Coronary Calcification: Summary This large observational data series shows the CAC provides independent incremental information in addition to traditional risk factors in the prediction of all-cause mortality.This large observational data series shows the CAC provides independent incremental information in addition to traditional risk factors in the prediction of all-cause mortality. The results marked a difference in survival at 6.8 years as the CAC scores increase from 0 to >1,000, which supports the notion that increasing coronary atherosclerosis is a strong and independent predictor of future cardiac events/The results marked a difference in survival at 6.8 years as the CAC scores increase from 0 to >1,000, which supports the notion that increasing coronary atherosclerosis is a strong and independent predictor of future cardiac events/ Furthermore, the study shows that CAC provides independent and incremental prognostic information in addition to traditional risk factors in the prediction of all-cause mortality.Furthermore, the study shows that CAC provides independent and incremental prognostic information in addition to traditional risk factors in the prediction of all-cause mortality. This large observational data series shows the CAC provides independent incremental information in addition to traditional risk factors in the prediction of all-cause mortality.This large observational data series shows the CAC provides independent incremental information in addition to traditional risk factors in the prediction of all-cause mortality. The results marked a difference in survival at 6.8 years as the CAC scores increase from 0 to >1,000, which supports the notion that increasing coronary atherosclerosis is a strong and independent predictor of future cardiac events/The results marked a difference in survival at 6.8 years as the CAC scores increase from 0 to >1,000, which supports the notion that increasing coronary atherosclerosis is a strong and independent predictor of future cardiac events/ Furthermore, the study shows that CAC provides independent and incremental prognostic information in addition to traditional risk factors in the prediction of all-cause mortality.Furthermore, the study shows that CAC provides independent and incremental prognostic information in addition to traditional risk factors in the prediction of all-cause mortality. Budoff, et al. JACC 2007; 49: 1860-70