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

Transcription

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 UK n=187 Norway n=425 Finland n=221 Ireland n= Germany n= Denmark n=330 Sweden n=401

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)

4 Study Design Randomized Double blind 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 years Asymptomatic Valvular AS: Aortic valve thickening on echocardiographic evaluation Doppler jet velocity 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 Simva + Ezetimibe n= 929 n= 944 Age (years) Women (%) SBP (mm Hg) DBP (mm Hg) Smoker (%) Ex-smoker (%) Never smoker (%) BMI (kg/m 2)

11 Baseline Medications Simva + Ezetimibe n= 929 n= 944 ACE inhibitors A-II blockers Ca antagonists Beta-blockers Aspirin Diuretics

12 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

13 Baseline Echocardiography Transaortic Mean Values Simva + Ezetimibe n= 929 n= 944 Peak velocity (m/sec) Peak gradient (mmhg) Mean gradient (mmhg) Aortic valve area (cm 2 ) Bicuspid valve (%)

14 LDL-Cholesterol Intention to Treat Population Mean (mg/dl) ±SE Year

15 Primary Endpoint MCE 50 Intention to Treat Population Percentage of Patients With First Event Hazard ratio: 0.96, p=0.591 No. at Risk Years in Study

16 2nd EP: Aortic Valve Events 50 Intention to Treat Population Percentage of Patients With First Event Hazard ratio: 0.97, p=0.732 No. at Risk Years in Study

17 Aortic Valve Replacement 50 Intention to Treat Population Percentage of Patients With First Event Hazard ratio: 1.00, p= No. at risk Years in Study

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

19 2nd EP: Ischemic CV Events 30 Intention to Treat Population Percentage of Patients With First Event Hazard ratio: 0.78, p=0.024 No. at risk Years in Study

20 Coronary Artery Bypass Grafting (CABG) 30 Intention to Treat Population Percentage of Patients With First Event Hazard ratio: 0.68, p= No. at risk Years in Study

21 Clinical Adverse Events (AE) All Patients as Treated Population EZ/ Simva N=929 N=943* n n p= Any serious AE (SAE) Drug discon. due to SAE 79 77

22 Clinical Adverse Events (AE) All Patients as Treated Population EZ/ Simva N=929 N=943* n n p= Any serious AE (SAE) Drug discon. due to SAE Musculoskeletal AE Myopathy / Rhabdo 0 0

23 Clinical Adverse Events (AE) All Patients as Treated Population EZ/ Simva N=929 N=943* n n p= Any serious AE (SAE) Drug discon. due to SAE Musculoskeletal AE Myopathy / Rhabdo 0 0 New cancer Recurrent, same site 5 3 Cancer, total

24 Fatal Cancer 20 Intention to Treat Population Cumulative Percentage No. at risk Hazard ratio: 1.67 P=0.05 Unadjusted P=0.06 With Log rank continuity correction Years in Study n=39 (4.1%) n=23 (2.5%)

25 Incident Cancer All Patients as Treated Population Site Lip, oral pharynx, Oesophagus Stomach Large bowel / intestine Pancreas Liver gallbladder, bile ducts Lung Other respiratory Skin (any) Breast Prostate Kidney Bladder Genital Hemathological Other/unspecified (N=929) n EZ/simva (N=943) n All differences are non-significant

26 All Cause Mortality 30 Intention to Treat Population Cumulative Percentage Hazard ratio: 1.04, p= Years in Study No. risk

27 Major CV Events - Components Endpoints # of Events EZ/Simva ITT Population Hazard Ratio (95% CI) Major CV Events CV Death AVR CHF Nonfatal MI CABG PCI Hospitalized UAP Non hem. Stroke * *p=0.02 vs Favors Favors