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Signs of Subclinical Coronary Atherosclerosis Measured as Coronary Artery Calcification Improve Risk Prediction of 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 3 Duisburg-Essen, 2 University Witten-Herdecke, University Düsseldorf, 4 Cardioangiological Center Bethanien, Frankfurt, 5 University Halle-Wittenberg, Germany

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

Background Acute onset of coronary syndromes still combined with - up to 50 % Background Acute onset of coronary syndromes still combined with - up to 50 % rate of sudden deaths Fox CS et al AHA: Heart Disease and Stroke Circulation 110: 522 -7, 2004 Update 2009 at a glance - 60 % of deaths outside the hospital with no improvement over the last 10 years (MONICA/KORA) Löwel H et al Dtsch Ärztebl 103: A 616 -22, 2006 - prevention at top of list of measures to reduce case fatality from CAD Chambless et al (MONICA study) Circulation 96: 3849 -59, 1997

Background: Risk Classification FRS/NCEP ATP III 35 % Low Risk Hard CVE or all Background: Risk Classification FRS/NCEP ATP III 35 % Low Risk Hard CVE or all CV Events < 10% 10 -year Life Style Change Reassessment after 5 years Imaging techniques - CAC Screening 40 % Intermediate risk 25 % High Risk Diabetes, stroke, aortic aneurysma, PAD 10 – 20% 10 -year > 20% 10 - year - Ultrasound - Carotis Ankle-Brachial-Index (ABI) Stress EKG (M 45 – 60 J) hs C-reactive Protein Greenland P et al Grundy SM + INTENSIFIED THERAPY of all risk factors Circulation 104: 1863 -1867, 2001 JACC 46: 173 – 5, 2005

Electron-beam Computed Tomography for Non-Invasive Imaging of Subclinical Coronary Atherosclerosis - < 20 s Electron-beam Computed Tomography for Non-Invasive Imaging of Subclinical Coronary Atherosclerosis - < 20 s scan time - 1 -1. 3 m. Sv X-ray exposure - 100 ms acquisition time - standardized protocols: Agatston-Score - 15 -20 min total time Imaging of coronary artery calcification as a specific sign of atherosclerosis - 0. 94 Kappa value for interinstitutional variation 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

Aim of the Study Heinz Nixdorf Recall Study (HNR) Risk Factors, Evaluation of Coronary Aim of the Study Heinz Nixdorf Recall Study (HNR) Risk Factors, Evaluation of Coronary Calcium and Lifestyle …coronary calcium as a sign of subclinical coronary atherosclerosis improves risk prediction for cardiovascular events in comparison to risk factors Initiated in 1999 and started in 2000 Funded by the Heinz Nixdorf Foundation (chairman: G Schmidţ) International Advisory Board: Th Meinertz, (chair) supported by German Foundation of Research

Methods I: - prospective, population-based cohort study according to GEP - random samples from Methods I: - prospective, population-based cohort study according to GEP - random samples from resident registration offices - 4814 men and women, aged 45 – 75 years (response: 56%) between 12/2000 and 6/2003 - urban population with 1. 5 million inhabitants in an big city area of 8 million people - study certified and recertified according to ISO 9001: 2000 Schmermund A et al Am Heart J 144: 212 -18, 2002 Stang A et al Eur J Epidemiol 20: 489 -96, 2005 Dragano N et al Eur J Cardvasc Prev Rehab 14: 568 -74, 2007

Methods II: Risk Factors and CAC - blood pressure measurement [OMRON 705 CP] - Methods II: Risk Factors and CAC - blood pressure measurement [OMRON 705 CP] - blood samples taken for measurement of total cholesterol, LDL-C, HDL-C (enzymatic methods), - ATP III: low, intermediate and high risk categories <10%, 10– 20%, >20% 10 -year risk for hard events, - electron beam CT (GE-Imatron, San Francisco), - coronary artery calcification scoring (Agatston score) for low, intermediate and high risk categories: < 100, 100 – 399, ≥ 400 calcium score. EBCT results not open to participants or physicians Stang A et al Am J Epidemiol 164: 85 -94, 2006 Erbel R et al Atherosclerosis 197: 662 -72, 2008 Schmermund A et Atherosclerosis 185: 177 -82, 2006 Greenland P et al Circulation 115: 402 -26, 2007

Methods III: Sample Size Calculation and Statistical Methods - Primary hypothesis: > 2. 5 Methods III: Sample Size Calculation and Statistical Methods - Primary hypothesis: > 2. 5 relative risk of 4 th versus 1 st quartile of coronary artery calcification - Primary endpoint: fatal and non fatal myocardial infarction - Pre-specified follow-up time: 5 years - one-sided test; : 5% , : 10% - calculation of means, relative risk with 2 -sided 95%CI and c-statistics (ROC/AUC) Endpoint committee: C Bode, Freiburg (chairman) K. Berger, Münster; HR. Figulla, Jena; C. Hamm, Bad Nauheim; P. Hanrath, Aachen ; W. Köpcke, Münster; Ringelstein, Münster, C. Weimar, Essen; A. Zeiher, Frankfurt

Study Cohort n = 4487 without CAD 0. 8 % lost to follow-up 1. Study Cohort n = 4487 without CAD 0. 8 % lost to follow-up 1. 9 % alive, no information about AMI 4370 missing values for Framingham risk factors, ATPIII variables and calcium scores (n=233) study cohort: 4137 participants (53% females) Median observation time: 5. 03 yrs (mean: 5. 12 ± 0. 26 yrs)

Primary Endpoints Study Cohort 4137 (53% females) primary endpoint n=93 (30% females) non-fatal MI Primary Endpoints Study Cohort 4137 (53% females) primary endpoint n=93 (30% females) non-fatal MI : n=64 (30% females)* coronary death: n=29 (31% females) no primary endpoint n=4044 (53% females) n=107 non-coronary deaths (43% females) *: MI-Group includes 1 subject who survived sudden cardiac death (died 2 days later from cerebral bleeding) 450/100. 000 per year observed versus 300 – 500/100. 000 predicted based on German PROCAM / MONICA data

Demographics / Risk Factors Men Women events n=65 no events n=1891 62± 8 59± Demographics / Risk Factors Men Women events n=65 no events n=1891 62± 8 59± 8* 64± 8 59± 8* Systolic BP [mm. Hg] 145± 25 138± 19* 135± 23 128± 21 Total Cholesterol [mmol/l] 6. 1± 0. 9 5. 9± 1. 0 6. 5± 1. 1 6. 1± 1. 0* HDL-Cholesterol [mmol/l] 1. 3± 0. 4 1. 6± 0. 5 1. 7± 0. 4 Smoking (active or former) [%] 70. 8% 70. 0% 42. 9% 43. 6% Diabetes [%] 16. 9% 8. 5%* 17. 9% 6. 0%* ATP III 15. 4% 38. 5% 46. 1% 30. 0% 38. 6% 31. 4% 42. 8% 28. 6% 71. 5% 20. 0% 8. 5% Age [yrs] <10% 10 -20% >20% events no events n=28 n=2153 * * : p < 0. 05 Data = mean±SD or % *

Event Rates stratified by Event Rate in 5 Years [%] ATP III Categories 20 Event Rates stratified by Event Rate in 5 Years [%] ATP III Categories 20 All Subjects Men Women 16 P<0. 0001 P=0. 003 P=0. 0007 12 p=0. 03 51. 5% 28. 8% 19. 7% p=0. 0003 p=0. 17 29. 6% 38. 6% 31. 9% p=0. 08 p=0. 10 71. 2% 20. 1% 8. 8% p=0. 06 8 4 0 low inter- high mediate ATP III Categories Data = Event Rates (95%CI)

Event Rates stratified by Event Rate in 5 Years [%] CAC Score Categories 20 Event Rates stratified by Event Rate in 5 Years [%] CAC Score Categories 20 16 All Subjects Men Women 72. 9% 16. 8% 10. 3% p<0. 0001 59. 4% 23. 8% 16. 8% p<0. 0001 85. 0% 10. 5% 4. 5% p<0. 0001 p=0. 0004 12 p=0. 0002 p=0. 004 p=0. 48 8 4 0 <100 100 -399 ≥ 400 CAC Categories Data = Event Rates (95%CI)

Relative Risks (Men) CAC Score Categories Crude Relative Risk (95%CI) 0 -99 100 -399 Relative Risks (Men) CAC Score Categories Crude Relative Risk (95%CI) 0 -99 100 -399 400 1. 00 2. 77 5. 31 Doubling of CAC Scores (Log 2(CAC+1)) Quartiles of CAC Scores 1 st (0 -4. 4) 2 nd (4. 4 -55. 55) 3 rd (55. 55 -239. 2) 4 th (>239. 2) Adjusted* Relative Risk (95%CI) (1. 48 -5. 19) (2. 96 -9. 53) 1. 00 2. 53 4. 65 (1. 35 -4. 74) (2. 60 -8. 30) 1. 32 (1. 20 -1. 45) 1. 30 (1. 18 -1. 43) 1. 00 3. 39 6. 39 11. 09 (0. 94 -12. 24) (1. 90 -21. 44) (3. 42 -35. 92) 3. 16 5. 69 9. 48 (0. 88 -11. 29) (1. 72 -18. 80) (2. 97 -30. 22) * adjusted for ATP III category

Relative Risks (Women) CAC Score Categories Crude Relative Risk (95%CI) Adjusted* Relative Risk (95%CI) Relative Risks (Women) CAC Score Categories Crude Relative Risk (95%CI) Adjusted* Relative Risk (95%CI) 0 -99 100 -399 400 1. 42 (0. 42 -4. 81) 8. 90 (3. 94 -20. 11) 1. 00 1. 07 (0. 29 -3. 97) 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) 1. 00 1. 12 (0. 39 -3. 23) 3. 16 (1. 33 -7. 48) 0. 90 (0. 31 -2. 61) 2. 12 (0. 81 -5. 55) Quartiles of CAC Scores 1 st (=0) 2 nd + 3 rd (>0 -37. 9) 4 th (>37. 9) * adjusted for ATP III category

ROC Curve Analysis / C-Statistics 1. 0 All Subjects Sensitivity 0. 8 0. 754 ROC Curve Analysis / C-Statistics 1. 0 All Subjects Sensitivity 0. 8 0. 754 ** 0. 667 0. 740 * ATPIII categories log(CAC+1) ATPIII cat. + log(CAC+1) 0. 4 ATPIII log(CAC+1) ATPIII + log(CAC+1) 0. 2 **: p=0. 0001 versus ATPIII *: p=0. 009 versus ATPIII 0. 0 0. 2 0. 4 0. 6 1 - Specificity 0. 8 1. 0

ROC Curve Analysis / C-Statistics Men Women 0. 8 0. 727 ** 0. 602 ROC Curve Analysis / C-Statistics Men Women 0. 8 0. 727 ** 0. 602 0. 724 * 0. 4 ATPIII log(CAC+1) ATPIII + log(CAC+1) 0. 2 Sensitivity 1. 0 0. 8 Sensitivity 1. 0 0. 723 ** 0. 660 0. 677 * 0. 4 ATPIII log(CAC+1) ATPIII + log(CAC+1) 0. 2 0. 0 0. 2 0. 4 0. 6 1 - Specificity 0. 8 0. 0 1. 0 0. 2 0. 4 0. 6 1 - Specificity 0. 8 Men Women **: p < 0. 0001 vs ATPIII **: p = 0. 18 vs ATPIII *: p = 0. 004 vs ATPIII *: p = 0. 80 vs ATPIII 1. 0

Events Stratified by ATP III & CAC Categories Event Rate in 5 Years [%] Events Stratified by ATP III & CAC Categories Event Rate in 5 Years [%] All Subjects 20 16 51. 5% 87. 3% 9. 3% 3. 4% 28. 8% 62. 9% 23. 1% 14. 1% 19. 7% 49. 8% 27. 4% 22. 9% <100 100 -399 ≥ 400 Low risk Intermediate risk High risk 12 CAC ATP III 8 4 0 Data = Event Rates (95%CI)

Reclassification of ATP III Risk Categories Using CAC Score high risk Intermediate risk low Reclassification of ATP III Risk Categories Using CAC Score high risk Intermediate risk low risk 51. 5% 28. 8% 19. 7% 14. 1 % 23. 1 % 62. 9 % 0 10 20 % 10 -year risk ATPIII Score Risk Assessment Scheme according to Wilson PWF et al JACC 41: 1889 – 1906, 2003 with HNR data

Conclusion Coronary Artery Calcium Score - is a strong predictor of acute coronary events, Conclusion Coronary Artery Calcium Score - is a strong predictor of acute coronary events, - improves risk prediction beyond traditional risk factors, - may be valid more in men than in women, - can be used for reclassification of individuals at intermediate ATP III risk, - is not recommended in ATP III graded low risk subjects, - may improve risk prediction in ATPIII high risk individuals

u University Clinic Essen, University Duisburg-Essen • Department of Cardiology (R Erbel, Chairman, S u University Clinic Essen, University Duisburg-Essen • Department of Cardiology (R Erbel, Chairman, S Möhlenkamp) • IMIBE (KH Jöckel, Vicechairman, S Moebus: study coordinator) • Department of Endocrinology (K Mann) • Division of Laboratory Research (K Mann, M Bröcker-Preuß) • Institute of Health Economics (J Wasem) u University Düsseldorf • Institute of Medical Sociology ( J Siegrist, N Dragano) u Alfried Krupp Hospital (Th Budde) u University Witten/Herdecke - Bochum/Mülheim/R • Institute of Radiology and Microtherapy (D Grönemeyer) • Institute of Diagnostic and Interventional Radiology (R Seibel) Funded by the Heinz Nixdorf Foundation (chairman: G Schmidt) International Advisory Board: T Meinertz, (chair), by the German Foundation of Research, DFG.

Mason Sones in Frankfurt 1978 „. . . we are still living in a Mason Sones in Frankfurt 1978 „. . . 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“ Risk factors alone seem not be reliable enough In: Coronary Heart Disease, 3 rd Int. Symposium Frankfurt, Kaltenbach M, Lichtlen P, Balcon R, Bussmann WD (eds) Thieme, Stuttgart 1978; 83