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

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Presentation transcript:

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

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 (Epub ahead of print).

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).

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).

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).

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).

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

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 (Epub ahead of print).

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).

Baseline Characteristics Placebo Simvastatin + 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 (Epub ahead of print).

Baseline Medications Placebo Simvastatin + Ezetimibe n= 929n= 944 ACE inhibitors A-II blockers Ca antagonists Beta-blockers ASA Diuretics Rossebø et al. NEJM 2008;359 (Epub ahead of print).

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

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

LDL-Cholesterol Intention-to-Treat Population Year Mean (mg/dL) ±SE Ezetimibe/Simvastatin 10/40 mg Placebo Rossebø et al. NEJM 2008;359 (Epub ahead of print).

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

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

Aortic Valve Replacement Intention-to-Treat Population Years in study Ezetimibe/Simvastatin 10/40 mg No. at risk Hazard ratio: 1.00, P= Patients with first event (%) Ezetimibe/Simvastatin 10/40 mg Placebo Rossebø et al. NEJM 2008;359 (Epub ahead of print). Placebo

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

Second End Point: Ischemic CV Events Placebo Ezetimibe/Simvastatin 10/40 mg No. at risk Patients with first event (%) Intention-to-Treat Population Years in study Hazard ratio: 0.78, P=0.024 Ezetimibe/Simvastatin 10/40 mg Placebo Rossebø et al. NEJM 2008;359 (Epub ahead of print).

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

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

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

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

Fatal Cancer Placebo Ezetimibe/Simvastatin 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 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).

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).

All-cause Mortality Intention-to-Treat Population Placebo Ezetimibe/Simvastatin 10/40 mg No. risk Years in study Hazard ratio: 1.04, P= Ezetimibe/Simvastatin 10/40 mg Placebo Cumulative percentage Rossebø et al. NEJM 2008;359 (Epub ahead of print).

Major CV Events - Components ITT Population Major CV Events CV Death AVR CHF Nonfatal MI CABG PCI Hospitalized UAP Nonhematological stroke End Points Favours Placebo Favours Ezetimibe/Simvastatin 10/40 mg Hazard ratio (95% CI) # of Events Placebo Ezetimibe/Simvastatin * *P=0.02 vs. placebo Rossebø et al. NEJM 2008;359 (Epub ahead of print).