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

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

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

2 Patients Randomized by Country 187 330 292 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

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 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

6 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

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

8 Rossebø et al. NEJM. 2008;359 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 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

10 Rossebø et al. NEJM. 2008;359 Baseline Characteristics Placebo Simva + Ezetimibe n= 929n= 944 Age (years)67.467.7 Women (%)38.838.5 SBP (mm Hg)144146 DBP (mm Hg)82 Smoker (%)1820 Ex-smoker (%)3735 Never smoker (%)45 BMI (kg/m 2) 26.826.9

11 Rossebø et al. NEJM. 2008;359 Baseline Medications Placebo Simva + Ezetimibe n= 929n= 944 ACE inhibitors16.014.7 A-II blockers10.510.1 Ca antagonists17.216.6 Beta-blockers28.825.6 Aspirin28.025.0 Diuretics24.722.1

12 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 Cholesterol5.74222 LDL Cholesterol3.60139 HDL Cholesterol1.4958 Triglycerides1.42126 Apolipoprotein B- 1.31 (g/L) Values given as mean ± SD; LDL = low-density lipoprotein; HDL = high-density lipoprotein

13 Rossebø et al. NEJM. 2008;359 Baseline Echocardiography Mean Values Placebo Simva + Ezetimibe n= 929n= 944 Transaortic Peak velocity (m/sec)3.103.09 Peak gradient (mmHg)39.639.3 Mean gradient (mmHg)23.022.7 Aortic valve area (cm 2 )1.271.29 Bicuspid valve (%)6.35.0

14 Rossebø et al. NEJM. 2008;359 LDL-Cholesterol Intention to Treat Population 00.511.522.533.544.555.5 Year 0 25 50 75 100 125 150 Mean (mg/dL) ±SE EZ/Simva 10/40 mg Placebo

15 Rossebø et al. NEJM. 2008;359 Primary Endpoint MCE Intention to Treat Population 012345 Years in Study 0 10 20 30 40 50 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=0.591 90681771361853 88479169658656

16 Rossebø et al. NEJM. 2008;359 2nd EP: Aortic Valve Events Years in Study Placebo EZ/Simva 10/40 mg No. at Risk 91483673263555 89581472561158 Intention to Treat Population EZ/Simva 10/40 mg Placebo 012345 0 10 20 30 40 50 Hazard ratio: 0.97, p=0.732 Percentage of Patients With First Event

17 Rossebø et al. NEJM. 2008;359 Aortic Valve Replacement Placebo89681672861861 50 Intention to Treat Population 012345 Years in Study 0 10 20 30 40 EZ/Simva 10/40 mg No. at risk Hazard ratio: 1.00, p=0.968 915 837 734 640 55 Percentage of Patients With First Event EZ/Simva 10/40 mg Placebo

18 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 0.00 0.15 0.30 0.45 0.60 0.75 Change from Baseline (m/sec) Mean (±SE)

19 Rossebø et al. NEJM. 2008;359 2nd EP: Ischemic CV Events Placebo EZ/Simva 10/40 mg No. at risk 917 898 867 838 823 788 769 729 76 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 012345 0 10 20 30

20 Rossebø et al. NEJM. 2008;359 Coronary Artery Bypass Grafting (CABG) 30 Years in Study Placebo EZ/Simva 10/40 mg No. at risk 925 909 887 862 848 819 797 761 80 Percentage of Patients With First Event Intention to Treat Population Hazard ratio: 0.68, p=0.015 EZ/Simva 10/40 mg Placebo 012345 0 10 20

21 Rossebø et al. NEJM. 2008;359 Clinical Adverse Events (AE) PlaceboEZ/ Simva N=929N=943* nnp= Any serious AE (SAE)463468 Drug discon. due to SAE7977 All Patients as Treated Population

22 Rossebø et al. NEJM. 2008;359 Clinical Adverse Events (AE) PlaceboEZ/ Simva N=929N=943* nnp= Any serious AE (SAE)463468 Drug discon. due to SAE7977 Musculoskeletal AE1811650.28 Myopathy / Rhabdo00 All Patients as Treated Population

23 Rossebø et al. NEJM. 2008;359 Clinical Adverse Events (AE) PlaceboEZ/ Simva N=929N=943* nnp= Any serious AE (SAE)463468 Drug discon. due to SAE7977 Musculoskeletal AE1811650.28 Myopathy / Rhabdo00 New cancer651020.01 Recurrent, same site53 Cancer, total701050.01 All Patients as Treated Population

24 Rossebø et al. NEJM. 2008;359 Fatal Cancer Placebo EZ/Simva 10/40 mg No. at risk 930 916 912 890 884 865 855 835 89 94 P=0.05 Unadjusted P=0.06 With Log-rank continuity correction 012345 Years in Study 0 5 10 15 20Hazard ratio: 1.67 Cumulative Percentage EZ/Simva 10/40 mg Placebo Intention to Treat Population n=23 (2.5%) n=39 (4.1%)

25 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

26 Rossebø et al. NEJM. 2008;359 All Cause Mortality Intention to Treat Population Placebo EZ/Simva 10/40 mg No. risk 930 916 912 890 884 865 855 835 89 94 Years in Study Hazard ratio: 1.04, p=0.799 012345 0 10 20 30 EZ/Simva 10/40 mg Placebo Cumulative Percentage

27 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 0.11.010.0 Favors PlaceboFavors EZ/Simva 10/40 mg Hazard Ratio (95% CI) # of Events Placebo EZ/Simva 355 56 278 23 26 100 17 8 29 333 47 267 25 17 69* 8 5 33 *p=0.02 vs Placebo

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