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Presented by Terje R. Pedersen Oslo Disclosure:

Presented by Terje R. Pedersen Oslo Disclosure: Research grants and/or speaker- / consulting fees from Merck, MSP, Astra-Zeneca, Pfizer. 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.

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Presented by Terje R. Pedersen Oslo Disclosure:

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  1. Presented by Terje R. Pedersen Oslo Disclosure: Research grants and/or speaker- / consulting fees from Merck, MSP, Astra-Zeneca, Pfizer

  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

  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

  4. Study Design Randomized Double blind Placebo controlled Multicenter 4 Weeks placebo/diet run-in Simvastatin 40 mg + ezetimibe 10 mg or placebo Median duration: 4.5 year (minimum follow-up 4 years)

  5. Primary Endpoint Major Cardiovascular Events: Cardiovascular 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

  6. Secondary Endpoints Aortic Valve Events Aortic Valve Replacement CHF as a result of progression of AS Cardiovascular death Ischemic Cardiovascular Events Cardiovascular death Nonfatal MI CABG PCI Hospitalized unstable angina Nonhemorrhagic stroke

  7. Other Objectives Echocardiography Safety

  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

  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

  10. Baseline Characteristics

  11. Baseline Medications

  12. Baseline Lipids and Lipoproteins

  13. Baseline Echocardiography

  14. LDL-Cholesterol Intention to Treat Population 150 Placebo 125 100 75 Mean (mg/dL) ±SE 50 EZ/Simva 10/40 mg 25 0 0 0.5 1 1.5 2 2.5 3 3.5 4 4.5 5 5.5 Year

  15. Primary Endpoint MCE Intention to Treat Population 50 Placebo 40 Hazard ratio: 0.96, p=0.591 30 Percentage of Patients With First Event EZ/Simva 10/40 mg 20 10 0 0 1 2 3 4 5 Years in Study No. at Risk EZ/Simva 10/40 mg 906 817 713 618 53 Placebo 884 791 696 586 56

  16. 2nd EP: Aortic Valve Events 50 Intention to Treat Population 40 Placebo 30 Hazard ratio: 0.97, p=0.732 Percentage of Patients With First Event EZ/Simva 10/40 mg 20 10 0 No. at Risk 0 1 2 3 4 5 Years in Study EZ/Simva 10/40 mg 914 836 732 635 55 895 814 725 611 58 Placebo

  17. Aortic Valve Replacement 50 Intention to Treat Population 40 Placebo Hazard ratio: 1.00, p=0.968 30 Percentage of Patients With First Event 20 EZ/Simva 10/40 mg 10 0 0 1 2 3 4 5 Years in Study No. at risk EZ/Simva 10/40 mg 915 837 734 640 55 Placebo 896 816 728 618 61

  18. Peak Aortic - Jet Velocity Intention to Treat Population 0.75 0.60 0.45 Change from Baseline (m/sec) Mean (±SE) EZ/Simva 10/40 mg 0.30 0.15 Placebo 0.00 Year 1 Year 2 Last Follow-up Time

  19. 2nd EP: Ischemic CV Events 30 Intention to Treat Population Hazard ratio: 0.78, p=0.024 Placebo 20 EZ/Simva 10/40 mg 10 0 0 1 2 3 4 5 Years in Study Percentage of Patients With First Event No. at risk EZ/Simva 10/40 mg 917 867 823 769 76 Placebo 898 838 788 729 76

  20. Coronary Artery Bypass Grafting (CABG) Intention to Treat Population Hazard ratio: 0.68, p=0.015 20 Percentage of Patients With First Event Placebo 10 EZ/Simva 10/40 mg 0 0 1 2 3 4 5 Years in Study No. at risk EZ/Simva 10/40 mg 925 887 848 797 80 Placebo 909 862 819 761 80 30

  21. Clinical Adverse Events (AE) All Patients as Treated Population

  22. Clinical Adverse Events (AE) All Patients as Treated Population

  23. Clinical Adverse Events (AE) All Patients as Treated Population

  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 EZ/Simva 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 EZ/Simva 10/40 mg 930 912 884 855 89 Placebo 916 890 865 835 94

  25. Incident Cancer All Patients as Treated Population All differences are non-significant

  26. All Cause Mortality 30 Intention to Treat Population Hazard ratio: 1.04, p=0.799 20 EZ/Simva 10/40 mg Cumulative Percentage 10 Placebo 0 0 1 2 3 4 5 Years in Study No. risk EZ/Simva 10/40 mg 930 912 884 855 89 Placebo 916 890 865 835 94

  27. Major CV Events - Components # of Events Placebo EZ/Simva 355 333 56 47 278 267 23 25 26 17 100 69* 17 8 8 5 29 33 ITT Population Hazard Ratio (95% CI) Endpoints Major CV Events CV Death AVR CHF Nonfatal MI CABG PCI Hospitalized UAP Non hem. Stroke *p=0.02 vs Placebo 0.1 1.0 10.0 Favors EZ/Simva 10/40 mg Favors Placebo

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