1. The Prognostic Value of Coronary Artery Calcium in the PROMISE Trial (PROspective Multicenter Imaging Study for Evaluation of Chest Pain)
Matthew J. Budoff, Thomas Mayrhofer, Maros Ferencik, Daniel O. Bittner, Kerry L. Lee, Michael T. Lu, Adrian Coles, James Jang, Mayil Krishnam, Pamela S. Douglas, Udo Hoffmann, on behalf of the PROMISE Investigators
Supported by R01HL098237, R01HL098236, R01HL98305 and R01HL from the National Heart, Lung, and Blood Institute

2. - Research contracts (Ame1ican Heart Association Fellow to Faculty Award)

3. Acknowledgments and Disclosures
The PROMISE trial was funded by the National Heart, Lung, and Blood Institute (NHLBI) grants R01 HL098237, R01 HL098236, R01 HL098305, and R01 HL098235
We are grateful for the contributions of the study participants and study team
Dr. Budoff reports receiving grants from the National Institutes of Health and General Electric outside of the submitted work. Dr. Ferencik reports receiving grant support from the American Heart Association. Dr. Douglas reports receiving grant support from HeartFlow and service on a data and safety monitoring board for GE HealthCare outside the submitted work. Dr. Hoffmann reports receiving grants from American College of Radiology Imaging Network and HeartFlow Inc. during the conduct of the study, and from Siemens Healthcare outside the submitted work. The other authors report no potential conflicts of interest.

4. Background
Coronary artery calcium (CAC) is an established predictor of future major adverse atherosclerotic cardiovascular events in asymptomatic individuals.
CAC has been recommended for use as the initial test in stable chest pain/suspected CAD
Limited data exist as to how CAC compares to functional testing in estimating prognosis in symptomatic patients.

5. Objectives
We determined the predictive value of CAC for major adverse cardiovascular events (MACE) in a large cohort of symptomatic low-intermediate risk patients in the PROMISE trial.
We evaluated the comparative prognostic ability of CAC to functional testing (FT).

6. Methods: Patient Inclusions and Exclusions
Randomized (n=10003)
Anatomic testing strategy (CTA) (n=4996)
Functional testing strategy (n=5007)
Received other test as 1st test (n=154)
No testing (n=156)
No CAC score (n=477)
Received other test as 1st test (n=67)
No test or test before randomization (n=248)
Allocation
Received CAC as 1st test (n=4209)
Received functional tests as 1st test (n=4692)
Test results: indeterminate/ incomplete data (n=90)
Follow up
Median follow-up (month):
26.5 (18.2, 34.5)
Median follow-up (months):
25.5 (17.7, 33.8)
Analysis
Analyzed (n=4209)
Analyzed (n=4602)

7. Methods: Patient Inclusions and Exclusions
Randomized (n=10003)
Anatomic testing strategy (CTA) (n=4996)
Functional testing strategy (n=5007)
Received other test as 1st test (n=154)
No testing (n=156)
No CAC score (n=477)
Received other test as 1st test (n=67)
No test or test before randomization (n=248)
Allocation
Received CAC as 1st test (n=4209)
Received functional tests as 1st test (n=4692)
Test results: indeterminate/ incomplete data (n=90)
Follow up
Median follow-up (month):
26.5 (18.2, 34.5)
Median follow-up (months):
25.5 (17.7, 33.8)
Analysis
Analyzed (n=4209)
Analyzed (n=4602)

8. Methods: Patient Inclusions and Exclusions
Randomized (n=10003)
Anatomic testing strategy (CTA) (n=4996)
Functional testing strategy (n=5007)
Received other test as 1st test (n=154)
No testing (n=156)
No CAC score (n=477)
Received other test as 1st test (n=67)
No test or test before randomization (n=248)
Allocation
Received CAC as 1st test (n=4209)
Received functional tests as 1st test (n=4692)
Test results: indeterminate/ incomplete data (n=90)
Follow up
Median follow-up (month):
26.5 (18.2, 34.5)
Median follow-up (months):
25.5 (17.7, 33.8)
Analysis
Analyzed (n=4209)
Analyzed (n=4602)

9. Classifications of CAC and Functional Tests
Anatomical
Functional
Test Strata
CAC
ETT
Stress MPI
Stress Echo
Severely abnormal
Severe Calcification CAC Score >400
Ischemic ECG
+ severe arrhythmia or hypotension
Severe inducible Ischemia Large territory OR 2 territories
Moderately abnormal
Moderate Calcification
CAC Score
Early ischemic ECG
Moderate inducible ischemia or mixed defect
1 coronary territory OR Normal imaging with early positive TM/symptoms/arrhythmia/hypoten
sion
Moderate inducible ischemia or
mixed defect
1 coronary territory OR Normal imaging with early positive
TM/symptoms/arrhythmia/hypot ension
Mildly abnormal
Mild Calcification CAC Score 1-99
Late ischemic ECG
Late positive ECG with normal perfusion or fixed perfusion defect
Late positive ECG with no ischemia on Echo
Normal
CAC Score 0

10. Methods: Outcomes
The primary endpoint was all-cause death, myocardial infarction or unstable angina hospitalization (UAP).
Median follow-up of 26.1 months.
We used Cox regression models to calculate hazard ratios and c-statistic to determine predictive and discriminatory value.

11. Results – Baseline Characteristics
Variables
Coronary Artery Calcium
(N=4209)
Functional Testing
(N=4602)
P-Value
Age – mean ± SD, y
60.6 ± 8.2
61.0 ± 8.3
0.034
Female – n (%)
2141 (50.9%)
2458 (53.4%)
0.018
Hypertension – n (%)
2731 (64.9%)
2999 (65.2%)
0.788
Diabetes – n (%)
878 (20.9%)
999 (21.7%)
0.335
Dyslipidemia – n (%)
2865 (68.1%)
3127 (67.9%)
0.909
Current or past smoking – (%)
2164 (51.4%)
2367 (51.4%)
1.000
Fam. hx of premature CAD – (%)
1389 (33.1%)
1426 (31.1%)
0.046
Mean no. of risk factors
2.4 ± 1.1
0.669
Framingham risk score
0.265
Low risk (<6%)
Intermediate risk (6-20%)
High risk (>20%)
269 (6.4%)
2164 (51.5%)
1768 (42.1%)
325 (7.1%)
2302 (50.1%)
1971 (42.9%)

12. Results – Baseline Characteristics
Variables
Coronary Artery Calcium
(N=4209)
Functional Testing
(N=4602)
P-Value
Age – mean ± SD, y
60.6 ± 8.2
61.0 ± 8.3
0.034
Female – n (%)
2141 (50.9%)
2458 (53.4%)
0.018
Hypertension – n (%)
2731 (64.9%)
2999 (65.2%)
0.788
Diabetes – n (%)
878 (20.9%)
999 (21.7%)
0.335
Dyslipidemia – n (%)
2865 (68.1%)
3127 (67.9%)
0.909
Current or past smoking – (%)
2164 (51.4%)
2367 (51.4%)
1.000
Fam. hx of premature CAD – (%)
1389 (33.1%)
1426 (31.1%)
0.046
Mean no. of risk factors
2.4 ± 1.1
0.669
Framingham risk score
0.265
Low risk (<6%)
Intermediate risk (6-20%)
High risk (>20%)
269 (6.4%)
2164 (51.5%)
1768 (42.1%)
325 (7.1%)
2302 (50.1%)
1971 (42.9%)

13. Results – Baseline Characteristics
Variables
Coronary Artery Calcium
(N=4209)
Functional Testing
(N=4602)
P-Value
Age – mean ± SD, y
60.6 ± 8.2
61.0 ± 8.3
0.034
Female – n (%)
2141 (50.9%)
2458 (53.4%)
0.018
Hypertension – n (%)
2731 (64.9%)
2999 (65.2%)
0.788
Diabetes – n (%)
878 (20.9%)
999 (21.7%)
0.335
Dyslipidemia – n (%)
2865 (68.1%)
3127 (67.9%)
0.909
Current or past smoking – (%)
2164 (51.4%)
2367 (51.4%)
1.000
Fam. hx of premature CAD – (%)
1389 (33.1%)
1426 (31.1%)
0.046
Mean no. of risk factors
2.4 ± 1.1
0.669
Framingham risk score
0.265
Low risk (<6%)
Intermediate risk (6-20%)
High risk (>20%)
269 (6.4%)
2164 (51.5%)
1768 (42.1%)
325 (7.1%)
2302 (50.1%)
1971 (42.9%)

14. Distribution of Test Results
Anatomic Testing (N=4209)
Functional Testing (N=4602)
Initial Test Results
Frequency
Event Rate
HR* (95% CI)
P-value
Normal (CAC =0, FT = normal)
34.6%
1.4%
78.0%
2.1%
Mild (CAC 1-99, FT =
mild)
31.8%
2.3%
1.51
(0.86–2.65)
0.147
9.4%
0.94
(0.47–1.89)
0.867
Moderate (CAC 100-
400, FT moderate)
18.3%
5.2%
3.14
(1.81–5.44)
<0.001
4.7%
6.0%
2.65
(1.46–4.83)
0.001
Severe (CAC >400, FT
15.2%
6.4%
3.56
7.9%
9.6%
3.88
Severe)
(1.99–6.36)
(2.58–5.85)
*Adjusted for age, sex, CAD risk equivalent (history of either diabetes mellitus, peripheral artery disease, or cerebrovascular disease), and
the prespecification of the intended functional test (if randomly assigned to the functional testing arm)

15. Distribution of Test Results
Anatomic Testing (N=4209)
Functional Testing (N=4602)
Initial Test Results
Frequency
Event Rate
HR* (95% CI)
P-value
Normal (CAC =0, FT = normal)
34.6%
1.4%
78.0%
2.1%
Mild (CAC 1-99, FT =
mild)
31.8%
2.3%
1.51
(0.86–2.65)
0.147
9.4%
0.94
(0.47–1.89)
0.867
Moderate (CAC 100-
400, FT moderate)
18.3%
5.2%
3.14
(1.81–5.44)
<0.001
4.7%
6.0%
2.65
(1.46–4.83)
0.001
Severe (CAC >400, FT
15.2%
6.4%
3.56
7.9%
9.6%
3.88
Severe)
(1.99–6.36)
(2.58–5.85)
*Adjusted for age, sex, CAD risk equivalent (history of either diabetes mellitus, peripheral artery disease, or cerebrovascular disease), and
the prespecification of the intended functional test (if randomly assigned to the functional testing arm)

16. Distribution of Test Results
Anatomic Testing (N=4209)
Functional Testing (N=4602)
Initial Test Results
Frequency Event Rate HR* P-value Frequency Event Rate
(95% CI)
T = 34.6% 1.4% 78.0% 2.1%
= 31.8% 2.3% % 2.1%
HR*
15.8% of MACE in those with normal CAC
P-value
(95% CI)
Normal (CAC =0, F normal)
vs.
56.8% of MACE in those with normal FT
Mild (CAC 1-99, FT
0.94
0.867
mild)
(0.86–2.65)
(0.47–1.89)
Moderate (CAC 100-
400, FT moderate)
3.14
(1.81–5.44)
2.65
(1.46–4.83)
18.3%
5.2%
<0.001
4.7%
6.0%
0.001
Severe (CAC >400, FT
3.56
3.88
15.2%
6.4%
<0.001
7.9%
9.6%
<0.001
Severe)
(1.99–6.36)
(2.58–5.85)
*Adjusted for age, sex, CAD risk equivalent (history of either diabetes mellitus, peripheral artery disease, or cerebrovascular disease), and
the prespecification of the intended functional test (if randomly assigned to the functional testing arm)

17. Distribution of Test Results
Anatomic Testing (N=4209)
Functional Testing (N=4602)
Initial Test Results
Frequency
Event Rate
HR* (95% CI)
P-value
Normal (CAC =0, FT = normal)
34.6%
1.4%
78.0%
2.1%
Mild (CAC 1-99, FT =
mild)
31.8%
2.3%
1.51
(0.86–2.65)
0.147
9.4%
0.94
(0.47–1.89)
0.867
Moderate (CAC 100-
400, FT moderate)
18.3%
5.2%
3.14
(1.81–5.44)
<0.001
4.7%
6.0%
2.65
(1.46–4.83)
0.001
Severe (CAC >400, FT
15.2%
6.4%
3.56
7.9%
9.6%
3.88
Severe)
(1.99–6.36)
(2.58–5.85)
*Adjusted for age, sex, CAD risk equivalent (history of either diabetes mellitus, peripheral artery disease, or cerebrovascular disease), and
the prespecification of the intended functional test (if randomly assigned to the functional testing arm)

18. Distribution of Test Results
Anatomic Testing (N=4209)
Functional Testing (N=4602)
HR*
Initial Test Res
ults Frequency Event Rate HR* P-value Frequency Event Rate
(95% CI) (9
FT = 34.6% 1.4% 78.0% 2.1%
FT = 31.8% 2.3% % 2.1%
84.2% of MACE in those with abnormal CAC 5% CI)
P-value
Normal (CAC =0,
vs.
normal)
43.2% of MACE in those with abnormal FT
Mild (CAC 1-99,
mild)
0.94
0.867
(0.86–2.65) (0.47–1.89)
Moderate (CAC 100-
400, FT moderate)
3.14
(1.81–5.44)
2.65
(1.46–4.83)
18.3%
5.2%
< % 6.0%
< % 9.6%
0.001
Severe (CAC >400, FT
3.56
3.88
15.2%
6.4%
<0.001
Severe)
(1.99–6.36)
(2.58–5.85)
*Adjusted for age, sex, CAD risk equivalent (history of either diabetes mellitus, peripheral artery disease, or cerebrovascular disease), and
the prespecification of the intended functional test (if randomly assigned to the functional testing arm)

19. Sensitivity and Specificity of CAC vs. FT for MACE
A positive CAC was significantly more sensitive than a positive FT for predicting events (84% vs. 43%, p<0.001)
Conversely, an abnormal FT was significantly more specific than positive CAC for predicting events (79% vs. 35%, p<0.001).
Increasing the CAC cutpoint improves specificity, at the expense of sensitivity.
A cutpoint of ≥100 increased specificity to 67%, while reducing sensitivity to 61%
A CAC cutpoint of >400 increase specificity to 85%, while reducing sensitivity to 31%.

20. Kaplan-Meier Curves for CAC and FT

21. Kaplan-Meier Curves for CAC and FT
Discriminatory ability for MACE – c-statistics AUC CAC 0.67 vs. FT 0.64

22. Sensitivity Analyses
C statistics for FT and CAC were also similar for other outcomes, including:
Secondary (CV death, MI, UAP) and tertiary (CV death, MI) outcomes
Severe CAC defined as >300
Normal CAC defined as ≤10

23. Limitations
Post-hoc evaluation of CAC testing, as the design of the PROMISE Trial was CTA versus FT.
Only 4209 patients underwent CAC scanning, while underwent CTA testing in PROMISE.
Quantification of ischemia was not routinely performed in PROMISE

24. Conclusions
CAC and FT had modest and similar discriminatory capacity for future MACE in stable outpatients presenting with suspected CAD.
Most patients experiencing MACE have measurable CAC at baseline while less than half have any abnormalities on FT.
An abnormal FT was more specific for MACE, leading to overall similarly modest discriminatory abilities of both tests.
Given the high sensitivity of CAC, these findings may represent a testing strategy of CAC first, followed by FT or CTA.

25. Thank you!

26. The Prognostic Value of Coronary Artery Calcium in the PROMISE Study.
Matthew J. Budoff, Thomas Mayrhofer, Maros Ferencik, Daniel O. Bittner, Kerry L. Lee, Michael T. Lu, Adrian Coles, James Jang, Mayil Krishnam, Pamela S. Douglas, Udo Hoffmann.
The Prognostic Value of Coronary Artery Calcium in the PROMISE Study.
Published simultaneously with ESC Congress 2017