CAC, CORONARY CALCIUM ACC2009

1. Signs of Subclinical Coronary Atherosclerosis Measured as Coronary Artery Calcification Improve Risk Prediction of Hard Events Beyond Traditional Risk Factors in an Unselected General Population: The Heinz Nixdorf Recall Study – 5-Year Outcome Data Raimund Erbel 1 , Stefan Möhlenkamp 1 , Susanne Moebus 1 , Axel Schmermund 4 , Nils Lehmann 1 , Nico Dragano 3 , Andreas Stang 5 , Dietrich Grönemeyer 2 , Rainer Seibel 2 , Hagen Kälsch 1 , Martina Bröcker-Preuß 1 , Klaus Mann 1 , Johannes Siegrist 3 , Karl-Heinz Jöckel 1 , for the Heinz Nixdorf Recall Study Investigative Group 1 University Duisburg-Essen, 2 University Witten-Herdecke, 3 University Düsseldorf, 4 Cardioangiological Center Bethanien, Frankfurt, 5 University Halle-Wittenberg, Germany

2. Presenter Disclosure Information < Raimund Erbel, MD, FACC, FESC, FAHA > The following relationships exist related to this presentation: Research Grant Company Imatron-GE modest level

5. Electron-beam Computed Tomography for Non-Invasive Imaging of Subclinical Coronary Atherosclerosis - < 20 s scan time - 1-1.3 mSv X-ray exposure - 100 ms acquisition time - standardized protocols: Agatston-Score - 15-20 min total time - 0.94 Kappa value for inter- institutional variation Imaging of coronary artery calcification as a specific sign of atherosclerosis Agatston et al. JACC 15:827-32, 1990 Hunold P et al Radiology 226:145-52, 2003 Schmermund et al . Z Kardiol 92:I/385,2003

6. Aim of the Study Funded by the Heinz Nixdorf Foundation (chairman: G Schmidţ) International Advisory Board: Th Meinertz, (chair) supported by German Foundation of Research … coronary calcium as a sign of subclinical coronary atherosclerosis improves risk prediction for cardiovascular events in comparison to risk factors Heinz Nixdorf Recall Study (HNR) R isk Factors, E valuation of Coronary Cal cium and L ifestyle Initiated in 1999 and started in 2000

10. 0.8 % lost to follow-up 1.9 % alive, no information about AMI n = 4487 without CAD 4370 study cohort: 4137 participants (53% females) missing values for Framingham risk factors, ATPIII variables and calcium scores (n=233) Study Cohort Median observation time: 5.03 yrs (mean: 5.12 ± 0.26 yrs)

11. no primary endpoint n=4044 (53% females) primary endpoint n=93 (30% females) non-fatal MI : n=64 (30% females) * coronary death: n=29 (31% females) *: MI-Group includes 1 subject who survived sudden cardiac death (died 2 days later from cerebral bleeding) Study Cohort 4137 (53% females) n=107 non-coronary deaths (43% females) 450/100.000 per year observed versus 300 – 500/100.000 predicted based on German PROCAM / MONICA data Primary Endpoints

12. Age [yrs] Systolic BP [mmHg] Total Cholesterol [mmol/l] HDL-Cholesterol [mmol/l] Smoking (active or former) [%] Diabetes [%] ATP III <10% 10-20% >20% 62±8 145±25 6.1±0.9 1.3±0.4 70.8% 16.9% 15.4% 38.5% 46.1% 59±8* 138±19* 5.9±1.0 1.3±0.4 70.0% 8.5%* 30.0% 38.6% 31.4% Men Women events n=65 no events n=1891 64±8 135±23 6.5±1.1 1.6±0.5 42.9% 17.9% 42.8% 28.6% 28.6% 59±8* 128±21 6.1±1.0* 1.7±0.4 43.6% 6.0%* 71.5% 20.0% 8.5% events n=28 no events n=2153 Demographics / Risk Factors * * * : p < 0.05 Data = mean±SD or %

13. ATP III Categories Data = Event Rates (95%CI) Event Rates stratified by ATP III Categories 0 8 12 20 Event Rate in 5 Years [%] 16 4 low inter- mediate high All Subjects low inter- mediate high Men Women low inter- mediate high p=0.0003 P<0.0001 p=0.03 p=0.08 P=0.003 p=0.17 p=0.06 P=0.0007 p=0.10 51.5% 28.8% 19.7% 29.6% 38.6% 31.9% 71.2% 20.1% 8.8%

14. CAC Categories Data = Event Rates (95%CI) Event Rates stratified by CAC Score Categories 72.9% 16.8% 10.3% 85.0% 10.5% 4.5% 0 8 12 20 Event Rate in 5 Years [%] 16 4 <100 100-399 ≥ 400 Men <100 100-399 ≥ 400 Women <100 100-399 ≥ 400 All Subjects p=0.0002 p<0.0001 p=0.0004 p=0.002 p<0.0001 p=0.02 p=0.48 p<0.0001 p=0.004 59.4% 23.8% 16.8%

15. Relative Risks (Men) * adjusted for ATP III category CAC Score Categories Crude Relative Risk (95%CI) Adjusted* Relative Risk (95%CI) 0-99 1.00 1.00 100-399 2.77 (1.48-5.19) 2.53 (1.35-4.74)  400 5.31 (2.96-9.53) 4.65 (2.60-8.30) Doubling of CAC Scores (Log 2 (CAC+1)) 1.32 (1.20-1.45) 1.30 (1.18-1.43) Quartiles of CAC Scores 1st (0-4.4) 1.00 2nd (4.4-55.55) 3.39 (0.94-12.24) 3.16 (0.88-11.29) 3rd (55.55-239.2) 6.39 (1.90-21.44) 5.69 (1.72-18.80) 4th (>239.2) 11.09 (3.42-35.92) 9.48 (2.97-30.22)

16. Relative Risks (Women) * adjusted for ATP III category CAC Score Categories Crude Relative Risk (95%CI) Adjusted* Relative Risk (95%CI) 0-99 1.00 1.00 100-399 1.42 (0.42-4.81) 1.07 (0.29-3.97)  400 8.90 (3.94-20.11) 5.89 (2.46-14.08) Doubling of CAC Scores (log 2 (CAC+1)) 1.25 (1.11-1.42) 1.20 (1.06-1.37) Quartiles of CAC Scores 1st (=0) 1.00 2nd + 3rd (>0-37.9) 1.12 (0.39-3.23) 0.90 (0.31-2.61) 4th (>37.9) 3.16 (1.33-7.48) 2.12 (0.81-5.55)

17. ROC Curve Analysis / C-Statistics ATPIII categories log(CAC+1) ATPIII cat. + log(CAC+1) All Subjects **: p=0.0001 versus ATPIII *: p=0.009 versus ATPIII Sensitivity 1 - Specificity 0.0 0.2 0.4 0.6 0.8 1.0 0.0 0.2 0.4 0.6 0.8 1.0 ATPIII log(CAC+1) ATPIII + log(CAC+1) 0.754 ** 0.740 * 0.667

18. ROC Curve Analysis / C-Statistics **: p < 0.0001 vs ATPIII *: p = 0.004 vs ATPIII Men **: p = 0.18 vs ATPIII *: p = 0.80 vs ATPIII Women Men Women 0.0 0.2 0.4 0.6 0.8 1.0 0.0 0.2 0.4 0.6 0.8 1.0 Sensitivity 1 - Specificity ATPIII log(CAC+1) ATPIII + log(CAC+1) 0.727 ** 0.724 * 0.602 0.0 0.2 0.4 0.6 0.8 1.0 0.0 0.2 0.4 0.6 0.8 1.0 1 - Specificity ATPIII log(CAC+1) ATPIII + log(CAC+1) 0.660 0.677 * 0.723 ** Sensitivity

19. Events Stratified by ATP III & CAC Categories All Subjects Data = Event Rates (95%CI) Low risk Intermediate risk High risk ATP III CAC 87.3% 9.3% 3.4% 62.9% 23.1% 14.1% 49.8% 27.4% 22.9% 51.5% 28.8% 19.7% 0 8 12 20 Event Rate in 5 Years [%] 16 4 <100 100-399 ≥ 400 <100 100-399 ≥ 400 <100 100-399 ≥ 400

20. 0 10 20 % 10-year risk ATPIII Score Risk Assessment CAC Score high risk Intermediate risk low risk Reclassification of ATP III Risk Categories Using CAC Scheme according to Wilson PWF et al JACC 41:1889 – 1906, 2003 with HNR data 23.1 % 51.5% 28.8% 19.7% 62.9 % 14.1 %

23. „ ... we are still living in a world where almost 1/3 of the patients who die ... die suddenly before we were even aware that these people were ill or that their lives were in jeopardy. So it seems to me that the most important problem we face is to find a way of recognizing these people before they drop dead and tell us that they were sick “ In: Coronary Heart Disease, 3rd Int. Symposium Frankfurt, Kaltenbach M, Lichtlen P, Balcon R, Bussmann WD (eds) Thieme, Stuttgart 1978; 83 Mason Sones in Frankfurt 1978 Risk factors alone seem not be reliable enough