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 R01HL098235 from the National Heart, Lung, and Blood Institute

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

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.

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.

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).

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)

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)

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)

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 100-399 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

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.

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%)

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%)

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%)

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)

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)

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% 1.51 0.147 9.4% 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)

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)

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% 1.51 0.147 9.4% 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% <0.001 4.7% 6.0% <0.001 7.9% 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)

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%.

Kaplan-Meier Curves for CAC and FT

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

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

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 4589 underwent CTA testing in PROMISE. Quantification of ischemia was not routinely performed in PROMISE

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.

Thank you!

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