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

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Presentation on theme: "Presented by Terje R. Pedersen, M.D. Oslo, Norway."— Presentation transcript:

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

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 (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 Placebo Simvastatin + 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 Rossebø et al. NEJM 2008;359 (Epub ahead of print).

11 Baseline Medications Placebo Simvastatin + Ezetimibe n= 929n= 944 ACE inhibitors16.014.7 A-II blockers10.510.1 Ca antagonists17.216.6 Beta-blockers28.825.6 ASA28.025.0 Diuretics24.722.1 Rossebø et al. NEJM 2008;359 (Epub ahead of print).

12 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 Rossebø et al. NEJM 2008;359 (Epub ahead of print).

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

14 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 Ezetimibe/Simvastatin 10/40 mg Placebo Rossebø et al. NEJM 2008;359 (Epub ahead of print).

15 Primary End Point MCE Intention-to-Treat Population 012345 Years in study 0 10 20 30 40 50 Patients with first event (%) Ezetimibe/Simvastatin 10/40 mg Placebo Ezetimibe/Simvastatin 10/40 mg No. at risk Hazard ratio: 0.96, P=0.591 90681771361853 88479169658656 Rossebø et al. NEJM 2008;359 (Epub ahead of print).

16 Second End Point: Aortic Valve Events Years in study Placebo Ezetimibe/Simvastatin 10/40 mg No. at risk 91483673263555 89581472561158 Intention-to-Treat Population Ezetimibe/Simvastatin 10/40 mg Placebo 012345 0 10 20 30 40 50 Hazard ratio: 0.97, P=0.732 Patients with first event (%) Rossebø et al. NEJM 2008;359 (Epub ahead of print).

17 Aortic Valve Replacement 89681672861861 50 Intention-to-Treat Population 012345 Years in study 0 10 20 30 40 Ezetimibe/Simvastatin 10/40 mg No. at risk Hazard ratio: 1.00, P=0.968 915 837 734 640 55 Patients with first event (%) Ezetimibe/Simvastatin 10/40 mg Placebo Rossebø et al. NEJM 2008;359 (Epub ahead of print). Placebo

18 Peak Aortic - Jet Velocity Intention-to-Treat Population Ezetimibe/Simvastatin 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) Rossebø et al. NEJM 2008;359 (Epub ahead of print).

19 Second End Point: Ischemic CV Events Placebo Ezetimibe/Simvastatin 10/40 mg No. at risk 917 898 867 838 823 788 769 729 76 Patients with first event (%) Intention-to-Treat Population Years in study Hazard ratio: 0.78, P=0.024 Ezetimibe/Simvastatin 10/40 mg Placebo 012345 0 10 20 30 Rossebø et al. NEJM 2008;359 (Epub ahead of print).

20 Coronary Artery Bypass Grafting 30 Years in study Placebo Ezetimibe/Simvastatin 10/40 mg No. at risk 925 909 887 862 848 819 797 761 80 Patients with first event (%) Intention-to-Treat Population Hazard ratio: 0.68, P=0.015 Ezetimibe/Simvastatin 10/40 mg Placebo 012345 0 10 20 Rossebø et al. NEJM 2008;359 (Epub ahead of print).

21 Clinical Adverse Events (AE) Placebo Ezetimibe/ Simvastatin N=929N=943* nnP=P= Any serious AE (SAE)463468 Drug discontinuation due to SAE 7977 All Patients as Treated Population Rossebø et al. NEJM 2008;359 (Epub ahead of print).

22 Clinical Adverse Events Placebo Ezetimibe/ Simvastatin N=929N=943 nnP=P= Any SAE463468 Drug disconuation due to SAE 7977 Musculoskeletal AE1811650.28 Myopathy / rhabdomyolysis00 All Patients as Treated Population Rossebø et al. NEJM 2008;359 (Epub ahead of print).

23 Clinical Adverse Events Placebo Ezetimibe/ Simvastatin N=929N=943 nnP=P= Any SAE463468 Drug disconuation due to SAE 7977 Musculoskeletal AE1811650.28 Myopathy / rhabdomyolysis00 New cancer651020.01 Recurrent cancer, same site53 Cancer (total )701050.01 All Patients as Treated Population Rossebø et al. NEJM 2008;359 (Epub ahead of print).

24 Fatal Cancer Placebo Ezetimibe/Simvastatin 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 20 Hazard ratio: 1.67 Cumulative percentage Ezetimibe/Simvastatin 10/40 mg Placebo Intention-to-Treat Population n=23 (2.5%) n=39 (4.1%) Rossebø et al. NEJM 2008;359 (Epub ahead of print).

25 Incident Cancer Site Placebo (N=929) Ezetimibe/simvastatin (N=943) nn Lip, oral pharynx, oesophagus1 1 Stomach15 Large bowel / intestine89 Pancreas14 Liver, gallbladder, bile ducts32 Lung107 Other respiratory01 Skin (any)818 Breast58 Prostate1321 Kidney2 2 Bladder7 7 Genital4 4 Hematological5 7 Other/unspecified7 12 All differences are non-significant All Patients as Treated Population Rossebø et al. NEJM 2008;359 (Epub ahead of print).

26 All-cause Mortality Intention-to-Treat Population Placebo Ezetimibe/Simvastatin 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 Ezetimibe/Simvastatin 10/40 mg Placebo Cumulative percentage Rossebø et al. NEJM 2008;359 (Epub ahead of print).

27 Major CV Events - Components ITT Population Major CV Events CV Death AVR CHF Nonfatal MI CABG PCI Hospitalized UAP Nonhematological stroke End Points 0.11.010.0 Favours Placebo Favours Ezetimibe/Simvastatin 10/40 mg Hazard ratio (95% CI) # of Events Placebo Ezetimibe/Simvastatin 355 56 278 23 26 100 17 8 29 333 47 267 25 17 69* 8 5 33 *P=0.02 vs. placebo Rossebø et al. NEJM 2008;359 (Epub ahead of print).

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