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Clinical Trial Results . orgClinical Trial Results . org

Long-Term Prognosis Associated with Coronary Calcification


Matthew J. Budoff, MD, Leslee J. Shaw, PhD, Sandy T. Liu, Matthew J. Budoff, MD, Leslee J. Shaw, PhD, Sandy T. Liu, Steven R. Weinstein, Tristen P. Mosler, Philip H. Tseng, Steven R. Weinstein, Tristen P. Mosler, Philip H. Tseng,

Ferdinand R. Flores, Tracy Q. Callister, MD, Paolo Raggi, MD, Ferdinand R. Flores, Tracy Q. Callister, MD, Paolo Raggi, MD, Daniel S. Berman, MDDaniel S. Berman, MD

Published in JACCPublished in JACC

May 8, 2007May 8, 2007




• Primary prevention interventions are often focused on Primary prevention interventions are often focused on patients who are classified as intermediate-risk or high-risk.patients who are classified as intermediate-risk or high-risk.

• Stratification into risk groups is helpful but can be imprecise Stratification into risk groups is helpful but can be imprecise when large proportions of patients are considered to be at when large proportions of patients are considered to be at “intermediate” risk.“intermediate” risk.

• Intermediate-risk patients receive cholesterol therapy that Intermediate-risk patients receive cholesterol therapy that can range from no therapy to a low-density lipoprotein can range from no therapy to a low-density lipoprotein target <100 mg/dl.target <100 mg/dl.

• Primary prevention interventions are often focused on Primary prevention interventions are often focused on patients who are classified as intermediate-risk or high-risk.patients who are classified as intermediate-risk or high-risk.

• Stratification into risk groups is helpful but can be imprecise Stratification into risk groups is helpful but can be imprecise when large proportions of patients are considered to be at when large proportions of patients are considered to be at “intermediate” risk.“intermediate” risk.

• Intermediate-risk patients receive cholesterol therapy that Intermediate-risk patients receive cholesterol therapy that can range from no therapy to a low-density lipoprotein can range from no therapy to a low-density lipoprotein target <100 mg/dl.target <100 mg/dl.

Budoff, et al. JACC 2007; 49: 1860-70 Budoff, et al. JACC 2007; 49: 1860-70

Long-Term Prognosis Associated with Coronary Calcification: Background

Long-Term Prognosis Associated with Coronary Calcification: Background


• More effective assessment of coronary heart disease More effective assessment of coronary heart disease (CHD) risk might improve the outcome, cost-(CHD) risk might improve the outcome, cost-effectiveness, and safety of primary prevention efforts.effectiveness, and safety of primary prevention efforts.

• This study aimed to develop risk-adjusted multivariable This study aimed to develop risk-adjusted multivariable models that include risk factors and coronary artery models that include risk factors and coronary artery calcium (CAC) scores measured with electron-beam calcium (CAC) scores measured with electron-beam tomography (EBT) in asymptomatic patients for the tomography (EBT) in asymptomatic patients for the prediction of all-cause mortality. prediction of all-cause mortality.

• More effective assessment of coronary heart disease More effective assessment of coronary heart disease (CHD) risk might improve the outcome, cost-(CHD) risk might improve the outcome, cost-effectiveness, and safety of primary prevention efforts.effectiveness, and safety of primary prevention efforts.

• This study aimed to develop risk-adjusted multivariable This study aimed to develop risk-adjusted multivariable models that include risk factors and coronary artery models that include risk factors and coronary artery calcium (CAC) scores measured with electron-beam calcium (CAC) scores measured with electron-beam tomography (EBT) in asymptomatic patients for the tomography (EBT) in asymptomatic patients for the prediction of all-cause mortality. prediction of all-cause mortality.

Long-Term Prognosis Associated with Coronary Calcification: Background Cont.

Long-Term Prognosis Associated with Coronary Calcification: Background Cont.



Long-Term Prognosis Associated with Coronary Calcification: Study Design

Long-Term Prognosis Associated with Coronary Calcification: Study Design

Assessment of all-cause mortalityAssessment of all-cause mortalityAssessment of all-cause mortalityAssessment of all-cause mortality

A cohort of 25,253 consecutive, asymptomatic individuals referred by their primary A cohort of 25,253 consecutive, asymptomatic individuals referred by their primary physician for CAC scanning to assess cardiovascular risk physician for CAC scanning to assess cardiovascular risk

A cohort of 25,253 consecutive, asymptomatic individuals referred by their primary A cohort of 25,253 consecutive, asymptomatic individuals referred by their primary physician for CAC scanning to assess cardiovascular risk physician for CAC scanning to assess cardiovascular risk

6.8 6.8 ± 3± 3 yrs. follow-up yrs. follow-up 6.8 6.8 ± 3± 3 yrs. follow-up yrs. follow-up

CAC ScoreCAC Score00

44%44%

CAC ScoreCAC Score00

44%44%

CAC ScoreCAC Score1-101-1014%14%




CAC ScoreCAC Score101-400101-400

13%13%


13%13%


6%6%


6%6%

CAC ScoreCAC Score>1000>10004%4%

CAC ScoreCAC Score>1000>10004%4%

CAC scanning CAC scanning



• Of the 25,253 patients, the average age was 56 Of the 25,253 patients, the average age was 56 ±± 11 years with more than half being male and 11 years with more than half being male and having a family history of premature coronary having a family history of premature coronary artery disease (CAD).artery disease (CAD).

• The prevalence of cardiac risk factors was as The prevalence of cardiac risk factors was as follows: family history of premature CAD (58%), follows: family history of premature CAD (58%), hypercholesterolemia (18%), hypertension hypercholesterolemia (18%), hypertension (15%), smoking (9%), and diabetes (4%). (15%), smoking (9%), and diabetes (4%).

• Of the 25,253 patients, the average age was 56 Of the 25,253 patients, the average age was 56 ±± 11 years with more than half being male and 11 years with more than half being male and having a family history of premature coronary having a family history of premature coronary artery disease (CAD).artery disease (CAD).

• The prevalence of cardiac risk factors was as The prevalence of cardiac risk factors was as follows: family history of premature CAD (58%), follows: family history of premature CAD (58%), hypercholesterolemia (18%), hypertension hypercholesterolemia (18%), hypertension (15%), smoking (9%), and diabetes (4%). (15%), smoking (9%), and diabetes (4%).

Long-Term Prognosis Associated with Coronary Calcification: Clinical Characteristics




• In the overall cohort, the average CAC score was 146 In the overall cohort, the average CAC score was 146 ±± 443. 443.

• In subsets with more extensive CAC scores, patients In subsets with more extensive CAC scores, patients were older and had more frequent cardiac risk factors. were older and had more frequent cardiac risk factors. Nearly one-half of the patients with CAC scores Nearly one-half of the patients with CAC scores ≥ ≥ 1000 were male (p<0.0001), hypertensive (p<0.0001), 1000 were male (p<0.0001), hypertensive (p<0.0001), hyperlipidemic (p<0.0001), or had a family history of hyperlipidemic (p<0.0001), or had a family history of premature CAD (p=0.052).premature CAD (p=0.052).

• In the overall cohort, the average CAC score was 146 In the overall cohort, the average CAC score was 146 ±± 443. 443.

• In subsets with more extensive CAC scores, patients In subsets with more extensive CAC scores, patients were older and had more frequent cardiac risk factors. were older and had more frequent cardiac risk factors. Nearly one-half of the patients with CAC scores Nearly one-half of the patients with CAC scores ≥ ≥ 1000 were male (p<0.0001), hypertensive (p<0.0001), 1000 were male (p<0.0001), hypertensive (p<0.0001), hyperlipidemic (p<0.0001), or had a family history of hyperlipidemic (p<0.0001), or had a family history of premature CAD (p=0.052).premature CAD (p=0.052).





Figure 1.Figure 1. Cumulative Survival by Coronary Calcium ScoreCumulative Survival by Coronary Calcium ScoreFigure 1.Figure 1. Cumulative Survival by Coronary Calcium ScoreCumulative Survival by Coronary Calcium Score

Time to Follow-up (Years)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.

Cu

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0.0 2.0 4.0 6.0 8.0 10.0 12.0

0.70

0.75

0.80

0.85

0.90

0.95

1.00

Long-Term Prognosis Associated with Coronary Calcification: Outcomes




0.0 2.0 4.0 6.0 8.0 10.0 12.0

0.70

0.75

0.80

0.85

0.90

0.95

1.00


Cu

mu

lati

ve S

urv

ival

Cu

mu

lati

ve S

urv

ival 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.Figure 2. Cumulative Survival by the Coronary Calcium Extent in the Cumulative Survival by the Coronary Calcium Extent in the Number of Vascular TerritoriesNumber of Vascular Territories






Cu

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Cu

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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 Figure 3. Cumulative Survival in Patients with No Significant Calcium Score but with CAC Scores in the Range of 11-100Score but with CAC Scores in the Range of 11-100

0.00 2.00 4.00 6.00 8.00 10.00 12.00

0.80

0.85

0.90

0.95

1.00





0.00 2.00 4.00 6.00 8.00 10.00 12.00


0.75

0.80

0.85

0.90

0.95

1.00

0.00 1.00 2.00 3.00 4.00 5.00


0.75

0.80

0.85

0.90

0.95

1.00

Near- and Long-Term Survival from 2 EBT Centers: Nashville and Los AngelesNear- and Long-Term Survival from 2 EBT Centers: Nashville and Los Angelesn=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





99.4% 97.8%95.2%

90.4%

81.8%

99.4% 97.8%94.5% 93.0%

76.9%

0%

20%

40%

60%

80%

100%

0-10 11-100 101-400 401-1,000 >1,000

5 yr

12 yr

99.4% 97.8%95.2%

90.4%

81.8%

99.4% 97.8%94.5% 93.0%

76.9%

0%

20%

40%

60%

80%

100%

0-10 11-100 101-400 401-1,000 >1,000

5 yr

12 yr

Su

rviv

al r

ate

(%

)S

urv

iva

l ra

te (

%)

CAC ScoreCAC Score



5-year and 12-year Survival from 2 EBT Centers: Nashville and Los Angeles5-year and 12-year Survival from 2 EBT Centers: Nashville and Los Angeles



0.0 0.2 0.4 0.6 0.8 1.0

1 - Specificity1 - Specificity

0.0

0.2

0.4

0.6

0.8

1.0

Sen

siti

vity

5a. Incremental Value of Agatston Score over the Total 5a. Incremental Value of Agatston Score over the Total Number of Cardiac Risk FactorsNumber of Cardiac Risk Factors

p<0.0001

0.611 (0.585-0.637)

0.813(0.794-0.832)

0.0 0.2 0.4 0.6 0.8 1.0

1 - Specificity1 - 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 Age5b. 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)





• The majority of patients in this study that were The majority of patients in this study that were referred for calcium scanning had cardiac risk referred for calcium scanning had cardiac risk factors and, therefore, are not representative of factors and, therefore, are not representative of the general population.the general population.

• There was incomplete information related to There was incomplete information related to cardiovascular risk factors, because these cardiovascular risk factors, because these measures were taken by survey rather than being measures were taken by survey rather than being measured.measured.

• The majority of patients in this study that were The majority of patients in this study that were referred for calcium scanning had cardiac risk referred for calcium scanning had cardiac risk factors and, therefore, are not representative of factors and, therefore, are not representative of the general population.the general population.

• There was incomplete information related to There was incomplete information related to cardiovascular risk factors, because these cardiovascular risk factors, because these measures were taken by survey rather than being measures were taken by survey rather than being measured.measured.

Long-Term Prognosis Associated with Coronary Calcification: Limitations

Long-Term Prognosis Associated with Coronary Calcification: Limitations



• Information on subsequent therapy after calcium scanning Information on subsequent therapy after calcium scanning is unknown. It was previously demonstrated that patients is unknown. It was previously demonstrated that patients with higher calcium burdens are more likely to maintain with higher calcium burdens are more likely to maintain statin therapy over 3-5 years. Therefore, higher calcium statin therapy over 3-5 years. Therefore, higher calcium scores are confounded by improved anti-athersoclerotic scores are confounded by improved anti-athersoclerotic therapies that would possible lower cardiovascular therapies that would possible lower cardiovascular mortality.mortality.

• Also, the National Death Index data do not include the Also, the National Death Index data do not include the cause of death. Therefore, this study’s models include cause of death. Therefore, this study’s models include mortality possibly unrelated to athersoclerotic disease.mortality possibly unrelated to athersoclerotic disease.

• Information on subsequent therapy after calcium scanning Information on subsequent therapy after calcium scanning is unknown. It was previously demonstrated that patients is unknown. It was previously demonstrated that patients with higher calcium burdens are more likely to maintain with higher calcium burdens are more likely to maintain statin therapy over 3-5 years. Therefore, higher calcium statin therapy over 3-5 years. Therefore, higher calcium scores are confounded by improved anti-athersoclerotic scores are confounded by improved anti-athersoclerotic therapies that would possible lower cardiovascular therapies that would possible lower cardiovascular mortality.mortality.

• Also, the National Death Index data do not include the Also, the National Death Index data do not include the cause of death. Therefore, this study’s models include cause of death. Therefore, this study’s models include mortality possibly unrelated to athersoclerotic disease.mortality possibly unrelated to athersoclerotic disease.

Long-Term Prognosis Associated with Coronary Calcification: Limitations Cont.

Long-Term Prognosis Associated with Coronary Calcification: Limitations Cont.



Long-Term Prognosis Associated With Coronary Calcification: Summary

Long-Term Prognosis Associated With Coronary Calcification: Summary

• This large observational data series shows the CAC provides This large observational data series shows the CAC provides independent incremental information in addition to traditional risk factors independent incremental information in addition to traditional risk factors in the prediction of all-cause mortality.in the prediction of all-cause mortality.

• The results marked a difference in survival at 6.8 years as the CAC 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 scores increase from 0 to >1,000, which supports the notion that increasing coronary atherosclerosis is a strong and independent increasing coronary atherosclerosis is a strong and independent predictor of future cardiac events/predictor of future cardiac events/

• Furthermore, the study shows that CAC provides independent and Furthermore, the study shows that CAC provides independent and incremental prognostic information in addition to traditional risk factors in incremental prognostic information in addition to traditional risk factors in the prediction of all-cause mortality.the prediction of all-cause mortality.

• This large observational data series shows the CAC provides This large observational data series shows the CAC provides independent incremental information in addition to traditional risk factors independent incremental information in addition to traditional risk factors in the prediction of all-cause mortality.in the prediction of all-cause mortality.

• The results marked a difference in survival at 6.8 years as the CAC 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 scores increase from 0 to >1,000, which supports the notion that increasing coronary atherosclerosis is a strong and independent increasing coronary atherosclerosis is a strong and independent predictor of future cardiac events/predictor of future cardiac events/

• Furthermore, the study shows that CAC provides independent and Furthermore, the study shows that CAC provides independent and incremental prognostic information in addition to traditional risk factors in incremental prognostic information in addition to traditional risk factors in the prediction of all-cause mortality.the prediction of all-cause mortality.


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