Terje R. Pedersen, M.D.

1
Presented by Terje R. Pedersen, M.D. Oslo, Norway
2
Patients Randomized by Country
Rossebø et al. NEJM 2008359 (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 2008359 (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 2008359 (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 2008359 (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 2008359 (Epub ahead of
print).
7
Other Objectives

• Echocardiography
• Safety

Rossebø et al. NEJM 2008359 (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 2008359 (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 2008359 (Epub ahead of
print).
10
Baseline Characteristics
Placebo Simvastatin 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 2008359 (Epub ahead of
print).
11
Baseline Medications
Placebo Simvastatin 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
ASA 28.0 25.0
Diuretics 24.7 22.1
Rossebø et al. NEJM 2008359 (Epub ahead of
print).
12
Baseline Lipids and Lipoproteins
Fasting serum lipid and lipoprotein levels at baseline (n1,873) Fasting serum lipid and lipoprotein levels at baseline (n1,873) Fasting serum lipid and lipoprotein levels at baseline (n1,873)
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 Values given as mean SD Values given as mean SD
Rossebø et al. NEJM 2008359 (Epub ahead of
print).
13
Baseline Echocardiography
Mean Values Mean Values
Placebo Simvastatin Ezetimibe
n 929 n 944
Transaortic
Peak velocity (m/sec) 3.10 3.09
Peak gradient (mm Hg) 39.6 39.3
Mean gradient (mm Hg) 23.0 22.7
Aortic valve area (cm2) 1.27 1.29
Bicuspid valve () 6.3 5.0
Rossebø et al. NEJM 2008359 (Epub ahead of
print).
14
LDL-Cholesterol
Intention-to-Treat Population
150
Placebo
125
100
75
Mean (mg/dL) SE
50
Ezetimibe/Simvastatin 10/40 mg
25
0
0
0.5
1
1.5
2
2.5
3
3.5
4
4.5
5
5.5
Year
Rossebø et al. NEJM 2008359 (Epub ahead of
print).
15
Primary End Point MCE
Intention-to-Treat Population
50
Placebo
40
Hazard ratio 0.96, P0.591
30
Patients with first event ()
Ezetimibe/Simvastatin 10/40 mg
20
10
0
0
1
2
3
4
5
Years in study
No. at risk




Ezetimibe/Simvastatin 10/40 mg
906
817
713
618
53
Placebo
884
791
696
586
56
Rossebø et al. NEJM 2008359 (Epub ahead of
print).
16
Second End Point Aortic Valve Events
Rossebø et al. NEJM 2008359 (Epub ahead of
print).
17
Aortic Valve Replacement
50
Intention-to-Treat Population
40
Placebo
Hazard ratio 1.00, P0.968
30
Patients with first event ()
Ezetimibe/Simvastatin 10/40 mg
20
10
0
0
1
2
3
4
5
Years in study





No. at risk
Ezetimibe/Simvastatin 10/40 mg
915
837
734
640
55
Placebo
Rossebø et al. NEJM 2008359 (Epub ahead of
print).
18
Peak Aortic - Jet Velocity
Intention-to-Treat Population
0.75
0.60
Ezetimibe/Simvastatin 10/40 mg
0.45
Change from baseline (m/sec) mean (SE)
0.30
0.15
Placebo
0.00
Year 1
Year 2
Last follow-up
Time
Rossebø et al. NEJM 2008359 (Epub ahead of
print).
19
Second End Point Ischemic CV Events
Intention-to-Treat Population
30
Hazard ratio 0.78, P0.024
Placebo
20
Patients with first event ()
10
Ezetimibe/Simvastatin 10/40 mg
0
0
1
2
3
4
5
Years in study
No. at risk





Ezetimibe/Simvastatin 10/40 mg
917
867
823
769
76
Placebo
898
838
788
729
76
Rossebø et al. NEJM 2008359 (Epub ahead of
print).
20
Coronary Artery Bypass Grafting
30
Intention-to-Treat Population
Hazard ratio 0.68, P0.015
20
Patients with first event ()
Placebo
10
Ezetimibe/Simvastatin 10/40 mg
0
0
1
2
3
4
5
Years in study
No. at risk





Ezetimibe/Simvastatin 10/40 mg
925
887
848
797
80
Placebo
909
862
819
761
80
Rossebø et al. NEJM 2008359 (Epub ahead of
print).
21
Clinical Adverse Events (AE)
All Patients as Treated Population
Placebo Ezetimibe/ Simvastatin
N929 N943
n n P

Any serious AE (SAE) 463 468
Drug discontinuation due to SAE 79 77
Rossebø et al. NEJM 2008359 (Epub ahead of
print).
22
Clinical Adverse Events
All Patients as Treated Population
Placebo Ezetimibe/ Simvastatin
N929 N943
n n P

Any SAE 463 468
Drug disconuation due to SAE 79 77

Musculoskeletal AE 181 165 0.28
Myopathy / rhabdomyolysis 0 0
Rossebø et al. NEJM 2008359 (Epub ahead of
print).
23
Clinical Adverse Events
All Patients as Treated Population
Placebo Ezetimibe/ Simvastatin
N929 N943
n n P

Any SAE 463 468
Drug disconuation due to SAE 79 77

Musculoskeletal AE 181 165 0.28
Myopathy / rhabdomyolysis 0 0

New cancer 65 102 0.01
Recurrent cancer, same site 5 3
Cancer (total ) 70 105 0.01
Rossebø et al. NEJM 2008359 (Epub ahead of
print).
24
Fatal Cancer
20
Intention-to-Treat Population
15
Hazard ratio 1.67
P0.05 Unadjusted P0.06 With Log-rank continuity
correction
Cumulative percentage
10
Ezetimibe/Simvastatin 10/40 mg
n39 (4.1)
5
n23 (2.5)
Placebo
0
0
1
2
3
4
5
Years in study
No. at risk




Ezetimibe/Simvastatin 10/40 mg
930
912
884
855
89
Placebo
916
890
865
835
94
Rossebø et al. NEJM 2008359 (Epub ahead of
print).
25
Incident Cancer
All Patients as Treated Population
Site Placebo(N929) Ezetimibe/simvastatin(N943)
Site n n
Lip, oral pharynx, oesophagus 1 1
Stomach 1 5
Large bowel / intestine 8 9
Pancreas 1 4
Liver, gallbladder, bile ducts 3 2
Lung 10 7
Other respiratory 0 1
Skin (any) 8 18
Breast 5 8
Prostate 13 21
Kidney 2 2
Bladder 7 7
Genital 4 4
Hematological 5 7
Other/unspecified 7 12
Rossebø et al. NEJM 2008359 (Epub ahead of
print).
All differences are non-significant
26
All-cause Mortality
30
Intention-to-Treat Population
Hazard ratio 1.04, P0.799
20
Ezetimibe/Simvastatin 10/40 mg
Cumulative percentage
10
Placebo
0
0
1
2
3
4
5
Years in study
No. risk





Ezetimibe/Simvastatin 10/40 mg
930
912
884
855
89
Placebo
916
890
865
835
94
Rossebø et al. NEJM 2008359 (Epub ahead of
print).
27
Major CV Events - Components
ITT Population
End Points
Hazard ratio (95 CI)
Major CV Events
CV Death
AVR
CHF
Nonfatal MI
CABG
PCI
Hospitalized UAP
Nonhematological stroke
0.1
1.0
10.0
P0.02 vs. placebo
Favours Placebo
Favours Ezetimibe/Simvastatin 10/40 mg
Rossebø et al. NEJM 2008359 (Epub ahead of
print).