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Presented by Terje R. Pedersen, M.D. Oslo, Norway

Presented by Terje R. Pedersen, M.D. Oslo, Norway. Norway n=425. 187. UK n=187. Finland n=221. Ireland n=17. Sweden n=401. 292. Germany n=292. 330. Denmark n=330. Patients Randomized by Country. Rossebø et al. NEJM 2008;359 (Epub ahead of print). SEAS Steering Committee.

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Presented by Terje R. Pedersen, M.D. Oslo, Norway

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  1. Presented by Terje R. Pedersen, M.D. Oslo, Norway

  2. Norway n=425 187 UK n=187 Finland n=221 Ireland n=17 Sweden n=401 292 Germany n=292 330 Denmark n=330 Patients Randomized by Country Rossebø et al. NEJM 2008;359 (Epub ahead of print).

  3. SEAS Steering Committee Terje R. Pedersen (Chairman) Anne B. Rossebø (Coordinator) Kurt Boman John Chambers Kenneth Egstrup Eva Gerdts Christa Gohlke-Bärwolf Ingar Holme (Statistician) Antero Y. Kesäniemi Christoph Nienaber Simon Ray Terje Skjærpe Kristian Wachtell Ronnie Willenheimer Nonvoting members: Philippe Brudi (MSP) William Malbecq (MSD statistician) Rossebø et al. NEJM 2008;359 (Epub ahead of print).

  4. SEAS Study Design Randomized Double-blind Placebo-controlled Multicentre 4 weeks placebo/diet run-in Simvastatin 40 mg + ezetimibe 10 mg or placebo Median duration: 4.5 years (minimum follow-up 4 years) Rossebø et al. NEJM 2008;359 (Epub ahead of print).

  5. SEAS: Primary End Point Major Cardiovascular (CV) Events: CV death Aortic valve replacement surgery (AVR) CHF as a result of progression of AS Non-fatal myocardial infarction CABG PCI Hospitalized unstable angina Non-hemorrhagic stroke PCI = percutaneous coronary intervention CHF= congestive heart failure CABG = coronary-artery bypass grafting Rossebø et al. NEJM 2008;359 (Epub ahead of print).

  6. SEAS: Secondary End Points Aortic Valve Events Aortic valve replacement CHF as a result of progression of AS CV death Ischemic CV Events CV death Nonfatal MI CABG PCI Hospitalized unstable angina Nonhemorrhagic stroke Rossebø et al. NEJM 2008;359 (Epub ahead of print).

  7. Other Objectives Echocardiography Safety Rossebø et al. NEJM 2008;359 (Epub ahead of print).

  8. Patient Definition Men and women Age 45 - 85 years Asymptomatic Valvular AS: Aortic valve thickening on echocardiographic evaluation Doppler jet velocity ≥2.5 - ≤4.0 m/sec Normal LV systolic function Rossebø et al. NEJM 2008;359 (Epub ahead of print).

  9. Exclusion Criteria Statin therapy or indication for statins Coronary heart disease Other important valvular disease: Significant mitral valve stenosis or regurgitation Severe or predominant aortic regurgitation Rheumatic valvular disease or AV prosthesis or subvalvular (hypertrophic, obstructive cardiomyopathy) or supravalvular AS Diabetes mellitus Other conditions precluding participation Rossebø et al. NEJM 2008;359 (Epub ahead of print).

  10. Baseline Characteristics Rossebø et al. NEJM 2008;359 (Epub ahead of print).

  11. Baseline Medications Rossebø et al. NEJM 2008;359 (Epub ahead of print).

  12. Baseline Lipids and Lipoproteins Rossebø et al. NEJM 2008;359 (Epub ahead of print).

  13. Baseline Echocardiography Rossebø et al. NEJM 2008;359 (Epub ahead of print).

  14. LDL-Cholesterol Intention-to-Treat Population 150 Placebo 125 100 75 Mean (mg/dL) ±SE 50 Ezetimibe/Simvastatin 10/40 mg 25 0 0 0.5 1 1.5 2 2.5 3 3.5 4 4.5 5 5.5 Year Rossebø et al. NEJM 2008;359 (Epub ahead of print).

  15. Primary End Point MCE Intention-to-Treat Population 50 Placebo 40 Hazard ratio: 0.96, P=0.591 30 Patients with first event (%) Ezetimibe/Simvastatin 10/40 mg 20 10 0 0 1 2 3 4 5 Years in study No. at risk Ezetimibe/Simvastatin 10/40 mg 906 817 713 618 53 Placebo 884 791 696 586 56 Rossebø et al. NEJM 2008;359 (Epub ahead of print).

  16. Second End Point: Aortic Valve Events 50 Intention-to-Treat Population 40 Placebo 30 Hazard ratio: 0.97, P=0.732 Patients with first event (%) Ezetimibe/Simvastatin 10/40 mg 20 10 0 No. at risk 0 1 2 3 4 5 Years in study Ezetimibe/Simvastatin 10/40 mg 914 836 732 635 55 895 814 725 611 58 Placebo Rossebø et al. NEJM 2008;359 (Epub ahead of print).

  17. Aortic Valve Replacement 896 816 728 618 61 50 Intention-to-Treat Population 40 Placebo Hazard ratio: 1.00, P=0.968 30 Patients with first event (%) Ezetimibe/Simvastatin 10/40 mg 20 10 0 0 1 2 3 4 5 Years in study No. at risk Ezetimibe/Simvastatin 10/40 mg 915 837 734 640 55 Placebo Rossebø et al. NEJM 2008;359 (Epub ahead of print).

  18. Peak Aortic - Jet Velocity Intention-to-Treat Population 0.75 0.60 Ezetimibe/Simvastatin 10/40 mg 0.45 Change from baseline (m/sec) mean (±SE) 0.30 0.15 Placebo 0.00 Year 1 Year 2 Last follow-up Time Rossebø et al. NEJM 2008;359 (Epub ahead of print).

  19. Second End Point: Ischemic CV Events 30 Intention-to-Treat Population Hazard ratio: 0.78, P=0.024 Placebo 20 Patients with first event (%) 10 Ezetimibe/Simvastatin 10/40 mg 0 0 1 2 3 4 5 Years in study No. at risk Ezetimibe/Simvastatin 10/40 mg 917 867 823 769 76 Placebo 898 838 788 729 76 Rossebø et al. NEJM 2008;359 (Epub ahead of print).

  20. Coronary Artery Bypass Grafting 30 Intention-to-Treat Population Hazard ratio: 0.68, P=0.015 20 Patients with first event (%) Placebo 10 Ezetimibe/Simvastatin 10/40 mg 0 0 1 2 3 4 5 Years in study No. at risk Ezetimibe/Simvastatin 10/40 mg 925 887 848 797 80 Placebo 909 862 819 761 80 Rossebø et al. NEJM 2008;359 (Epub ahead of print).

  21. Clinical Adverse Events (AE) All Patients as Treated Population Rossebø et al. NEJM 2008;359 (Epub ahead of print).

  22. Clinical Adverse Events All Patients as Treated Population Rossebø et al. NEJM 2008;359 (Epub ahead of print).

  23. Clinical Adverse Events All Patients as Treated Population Rossebø et al. NEJM 2008;359 (Epub ahead of print).

  24. Fatal Cancer 20 Intention-to-Treat Population 15 Hazard ratio: 1.67 P=0.05 Unadjusted P=0.06 With Log-rank continuity correction Cumulative percentage 10 Ezetimibe/Simvastatin 10/40 mg n=39 (4.1%) 5 n=23 (2.5%) Placebo 0 0 1 2 3 4 5 Years in study No. at risk Ezetimibe/Simvastatin 10/40 mg 930 912 884 855 89 Placebo 916 890 865 835 94 Rossebø et al. NEJM 2008;359 (Epub ahead of print).

  25. Incident Cancer All Patients as Treated Population Rossebø et al. NEJM 2008;359 (Epub ahead of print). All differences are non-significant

  26. All-cause Mortality 30 Intention-to-Treat Population Hazard ratio: 1.04, P=0.799 20 Ezetimibe/Simvastatin 10/40 mg Cumulative percentage 10 Placebo 0 0 1 2 3 4 5 Years in study No. risk Ezetimibe/Simvastatin 10/40 mg 930 912 884 855 89 Placebo 916 890 865 835 94 Rossebø et al. NEJM 2008;359 (Epub ahead of print).

  27. Major CV Events - Components # of Events Placebo Ezetimibe/Simvastatin 355 333 56 47 278 267 23 25 26 17 100 69* 17 8 8 5 29 33 ITT Population End Points Hazard ratio (95% CI) Major CV Events CV Death AVR CHF Nonfatal MI CABG PCI Hospitalized UAP Nonhematological stroke *P=0.02 vs. placebo 0.1 1.0 10.0 Favours Placebo Favours Ezetimibe/Simvastatin 10/40 mg Rossebø et al. NEJM 2008;359 (Epub ahead of print).

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