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

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

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

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)

Rossebø et al. NEJM. 2008;359 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

Rossebø et al. NEJM. 2008;359 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

Rossebø et al. NEJM. 2008;359 Other Objectives Echocardiography Safety

Rossebø et al. NEJM. 2008;359 Patient Definition Men and Women Age 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 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 Baseline Characteristics Placebo Simva + Ezetimibe n= 929n= 944 Age (years) Women (%) SBP (mm Hg) DBP (mm Hg)82 Smoker (%)1820 Ex-smoker (%)3735 Never smoker (%)45 BMI (kg/m 2)

Rossebø et al. NEJM. 2008;359 Baseline Medications Placebo Simva + Ezetimibe n= 929n= 944 ACE inhibitors A-II blockers Ca antagonists Beta-blockers Aspirin Diuretics

Rossebø et al. NEJM. 2008;359 Baseline Lipids and Lipoproteins Fasting Serum Lipid and Lipoprotein Levels at Baseline (n=1,873) Concentration (mmol/L) Concentration (mg/dl) Total Cholesterol LDL Cholesterol HDL Cholesterol Triglycerides Apolipoprotein B (g/L) Values given as mean ± SD; LDL = low-density lipoprotein; HDL = high-density lipoprotein

Rossebø et al. NEJM. 2008;359 Baseline Echocardiography Mean Values Placebo Simva + Ezetimibe n= 929n= 944 Transaortic Peak velocity (m/sec) Peak gradient (mmHg) Mean gradient (mmHg) Aortic valve area (cm 2 ) Bicuspid valve (%)6.35.0

Rossebø et al. NEJM. 2008;359 LDL-Cholesterol Intention to Treat Population Year Mean (mg/dL) ±SE EZ/Simva 10/40 mg Placebo

Rossebø et al. NEJM. 2008;359 Primary Endpoint MCE Intention to Treat Population Years in Study Percentage of Patients With First Event EZ/Simva 10/40 mg Placebo EZ/Simva 10/40 mg No. at Risk Hazard ratio: 0.96, p=

Rossebø et al. NEJM. 2008;359 2nd EP: Aortic Valve Events Years in Study Placebo EZ/Simva 10/40 mg No. at Risk Intention to Treat Population EZ/Simva 10/40 mg Placebo Hazard ratio: 0.97, p=0.732 Percentage of Patients With First Event

Rossebø et al. NEJM. 2008;359 Aortic Valve Replacement Placebo Intention to Treat Population Years in Study EZ/Simva 10/40 mg No. at risk Hazard ratio: 1.00, p= Percentage of Patients With First Event EZ/Simva 10/40 mg Placebo

Rossebø et al. NEJM. 2008;359 Peak Aortic - Jet Velocity Intention to Treat Population EZ/Simva 10/40 mg Placebo Year 1Year 2Last Follow-up Time Change from Baseline (m/sec) Mean (±SE)

Rossebø et al. NEJM. 2008;359 2nd EP: Ischemic CV Events Placebo EZ/Simva 10/40 mg No. at risk Percentage of Patients With First Event Intention to Treat Population Years in Study Hazard ratio: 0.78, p=0.024 EZ/Simva 10/40 mg Placebo

Rossebø et al. NEJM. 2008;359 Coronary Artery Bypass Grafting (CABG) 30 Years in Study Placebo EZ/Simva 10/40 mg No. at risk Percentage of Patients With First Event Intention to Treat Population Hazard ratio: 0.68, p=0.015 EZ/Simva 10/40 mg Placebo

Rossebø et al. NEJM. 2008;359 Clinical Adverse Events (AE) PlaceboEZ/ Simva N=929N=943* nnp= Any serious AE (SAE) Drug discon. due to SAE7977 All Patients as Treated Population

Rossebø et al. NEJM. 2008;359 Clinical Adverse Events (AE) PlaceboEZ/ Simva N=929N=943* nnp= Any serious AE (SAE) Drug discon. due to SAE7977 Musculoskeletal AE Myopathy / Rhabdo00 All Patients as Treated Population

Rossebø et al. NEJM. 2008;359 Clinical Adverse Events (AE) PlaceboEZ/ Simva N=929N=943* nnp= Any serious AE (SAE) Drug discon. due to SAE7977 Musculoskeletal AE Myopathy / Rhabdo00 New cancer Recurrent, same site53 Cancer, total All Patients as Treated Population

Rossebø et al. NEJM. 2008;359 Fatal Cancer Placebo EZ/Simva 10/40 mg No. at risk P=0.05 Unadjusted P=0.06 With Log-rank continuity correction Years in Study Hazard ratio: 1.67 Cumulative Percentage EZ/Simva 10/40 mg Placebo Intention to Treat Population n=23 (2.5%) n=39 (4.1%)

Rossebø et al. NEJM. 2008;359 Incident Cancer Site Placebo (N=929) EZ/simva (N=943) nn Lip, oral pharynx, Oesophagus 1 1 Stomach15 Large bowel / intestine89 Pancreas14 Liver gallbladder, bile ducts32 Lung107 Other respiratory01 Skin (any)818 Breast58 Prostate1321 Kidney2 2 Bladder7 7 Genital4 4 Hemathological5 7 Other/unspecified7 12 All differences are non-significant All Patients as Treated Population

Rossebø et al. NEJM. 2008;359 All Cause Mortality Intention to Treat Population Placebo EZ/Simva 10/40 mg No. risk Years in Study Hazard ratio: 1.04, p= EZ/Simva 10/40 mg Placebo Cumulative Percentage

Rossebø et al. NEJM. 2008;359 Major CV Events - Components ITT Population Major CV Events CV Death AVR CHF Nonfatal MI CABG PCI Hospitalized UAP Non hem. Stroke Endpoints Favors PlaceboFavors EZ/Simva 10/40 mg Hazard Ratio (95% CI) # of Events Placebo EZ/Simva * *p=0.02 vs Placebo