Presented byTerje R. Pedersen
OsloDisclosure:
Research grants and/or speaker- / consulting fees fromMerck, MSP, Astra-Zeneca, Pfizer
Patients Randomized by Country
187
330
292
Denmark n=330
Sweden n=401
Norway n=425UK 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
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 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
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= 929 n= 944
Age (years) 67.4 67.7
Women (%) 38.8 38.5
SBP (mm Hg) 144 146
DBP (mm Hg) 82 82
Smoker (%) 18 20
Ex-smoker (%) 37 35
Never smoker (%) 45 45
BMI (kg/m2) 26.8 26.9
Rossebø et al. NEJM. 2008;359
Baseline Medications
Placebo Simva + Ezetimibe
n= 929 n= 944
ACE inhibitors 16.0 14.7
A-II blockers 10.5 10.1
Ca antagonists 17.2 16.6
Beta-blockers 28.8 25.6
Aspirin 28.0 25.0
Diuretics 24.7 22.1
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 5.74 222
LDL Cholesterol 3.60 139
HDL Cholesterol 1.49 58
Triglycerides 1.42 126
Apolipoprotein B - 1.31 (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= 929 n= 944
Transaortic
Peak velocity (m/sec) 3.10 3.09
Peak gradient (mmHg) 39.6 39.3
Mean gradient (mmHg) 23.0 22.7
Aortic valve area (cm2) 1.27 1.29
Bicuspid valve (%) 6.3 5.0
Rossebø et al. NEJM. 2008;359
LDL-Cholesterol
Intention to Treat Population
0 0.5 1 1.5 2 2.5 3 3.5 4 4.5 5 5.5
Year
0
25
50
75
100
125
150
Me
an
(m
g/d
L)
±SE
EZ/Simva 10/40 mg
Placebo
Rossebø et al. NEJM. 2008;359
Primary Endpoint MCEIntention to Treat Population
0 1 2 3 4 5Years in Study
0
10
20
30
40
50P
erce
nta
ge
of
Pat
ien
ts W
ith
F
irst
Eve
nt
EZ/Simva 10/40 mg
Placebo
Placebo
EZ/Simva 10/40 mg
No. at Risk
Hazard ratio: 0.96, p=0.591
906 817 713 618 53
884 791 696 586 56
Rossebø et al. NEJM. 2008;359
2nd EP: Aortic Valve Events
Years in Study
PlaceboEZ/Simva 10/40 mgNo. at Risk
914 836 732 635 55 895 814 725 611 58
Intention to Treat Population
EZ/Simva 10/40 mg
Placebo
0 1 2 3 4 50
10
20
30
40
50
Hazard ratio: 0.97, p=0.732
Per
cen
tag
e o
f P
atie
nts
Wit
h
Fir
st E
ven
t
Rossebø et al. NEJM. 2008;359
Aortic Valve Replacement
Placebo 896 816 728 618 61
50Intention to Treat Population
0 1 2 3 4 5Years in Study
0
10
20
30
40
EZ/Simva 10/40 mgNo. at risk
Hazard ratio: 1.00, p=0.968
915
837
734
640
55
Per
cen
tag
e o
f P
atie
nts
Wit
h
Fir
st E
ven
t
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 1 Year 2 Last Follow-up
Time
0.00
0.15
0.30
0.45
0.60
0.75
Ch
ang
e fr
om
Bas
elin
e (m
/sec
) M
ean
(±S
E)
Rossebø et al. NEJM. 2008;359
2nd EP: Ischemic CV Events
PlaceboEZ/Simva 10/40 mgNo. at risk
917 898
867 838
823 788
769 729
76 76
Per
cen
tag
e o
f P
atie
nts
Wit
h
Fir
st E
ven
tIntention to Treat Population
Years in Study
Hazard ratio: 0.78, p=0.024
EZ/Simva 10/40 mg
Placebo
0 1 2 3 4 50
10
20
30
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
80
Per
cen
tag
e o
f P
atie
nts
Wit
h
Fir
st E
ven
tIntention to Treat Population
Hazard ratio: 0.68, p=0.015
EZ/Simva 10/40 mg
Placebo
0 1 2 3 4 50
10
20
Rossebø et al. NEJM. 2008;359
Clinical Adverse Events (AE)
Placebo EZ/ Simva
N=929 N=943*
n n p=
Any serious AE (SAE) 463 468
Drug discon. due to SAE 79 77
All Patients as Treated Population
Rossebø et al. NEJM. 2008;359
Clinical Adverse Events (AE)
Placebo EZ/ Simva
N=929 N=943*
n n p=
Any serious AE (SAE) 463 468
Drug discon. due to SAE 79 77
Musculoskeletal AE 181 165 0.28
Myopathy / Rhabdo 0 0
All Patients as Treated Population
Rossebø et al. NEJM. 2008;359
Clinical Adverse Events (AE)
Placebo EZ/ Simva
N=929 N=943*
n n p=
Any serious AE (SAE) 463 468
Drug discon. due to SAE 79 77
Musculoskeletal AE 181 165 0.28
Myopathy / Rhabdo 0 0
New cancer 65 102 0.01
Recurrent, same site 5 3
Cancer, total 70 105 0.01
All Patients as Treated Population
Rossebø et al. NEJM. 2008;359
Fatal Cancer
PlaceboEZ/Simva 10/40 mgNo. at risk
930 916
912 890
884 865
855 835
89 94
P=0.05 UnadjustedP=0.06 With Log-rank continuity correction
0 1 2 3 4 5Years in Study
0
5
10
15
20
Hazard ratio: 1.67
Cu
mu
lati
ve P
erce
nta
ge
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)
n n
Lip, oral pharynx, Oesophagus
1 1
Stomach 1 5 Large bowel / intestine 8 9 Pancreas 1 4 Liver gallbladder, bile ducts 3 2Lung 10 7Other respiratory 0 1Skin (any) 8 18 Breast 5 8Prostate 13 21 Kidney 2 2
Bladder 7 7
Genital 4 4
Hemathological 5 7
Other/unspecified 7 12
All differences are non-significant
All Patients as Treated Population
Rossebø et al. NEJM. 2008;359
All Cause Mortality
Intention to Treat Population
PlaceboEZ/Simva 10/40 mgNo. risk
930 916
912 890
884 865
855 835
89 94
Years in Study
Hazard ratio: 1.04, p=0.799
0 1 2 3 4 50
10
20
30
EZ/Simva 10/40 mg
PlaceboCu
mu
lati
ve P
erce
nta
ge
Rossebø et al. NEJM. 2008;359
Major CV Events - ComponentsITT Population
Major CV Events
CV Death
AVR
CHF
Nonfatal MI
CABG
PCI
Hospitalized UAP
Non hem. Stroke
Endpoints
0.1 1.0 10.0
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