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

Presented byTerje R. Pedersen, M.D.

Oslo, Norway

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 (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)


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)


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 strokePCI = percutaneous coronary intervention

CHF= congestive heart failure

CABG = coronary-artery bypass grafting


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


Other Objectives

Echocardiography

Safety


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


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


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


Baseline Medications


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


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


Baseline Echocardiography

Mean Values


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 5.0Rossebø et al. NEJM 2008;359 (Epub ahead of print).

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

Ezetimibe/Simvastatin 10/40 mg

Placebo


Primary End Point MCE


0 1 2 3 4 5Years in study

0

10

20

30

40

50

Pat

ien

ts w

ith

fir

st e

ven

t (%

)


Placebo

Placebo


No. at risk

Hazard ratio: 0.96, P=0.591

906 817 713 618 53

884 791 696 586 56


Second End Point: Aortic Valve Events

Years in study

PlaceboEzetimibe/Simvastatin 10/40 mgNo. at risk

914 836 732 635 55 895 814 725 611 58



Placebo

0 1 2 3 4 50

10

20

30

40

50


Pat

ien

ts w

ith

fir

st e

ven

t (%

)


Aortic Valve Replacement

896 816 728 618 61

50Intention-to-Treat Population


0

10

20

30

40


No. at risk


915

837

734

640

55

Pat

ien

ts w

ith

fir

st e

ven

t (%

)


Placebo

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

Peak Aortic - Jet Velocity



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)


Second End Point: Ischemic CV Events

PlaceboEzetimibe/Simvastatin 10/40 mg

No. at risk

917 898

867 838

823 788

769 729

76 76

Pat

ien

ts w

ith

fir

st e

ven

t (%

)


Years in study



Placebo

0 1 2 3 4 50

10

20

30


Coronary Artery Bypass Grafting

30

Years in study

Placebo


No. at risk

925

909

887

862

848

819

797

761

80

80

Pat

ien

ts w

ith

fir

st e

ven

t (%

)Intention-to-Treat Population



Placebo

0 1 2 3 4 50

10

20


Clinical Adverse Events (AE)

Placebo Ezetimibe/ Simvastatin

N=929 N=943*

n n P=

Any serious AE (SAE) 463 468

Drug discontinuationdue to SAE 79 77

All Patients as Treated Population


Clinical Adverse Events


N=929 N=943

n n P=

Any SAE 463 468

Drug disconuationdue to SAE 79 77

Musculoskeletal AE 181 165 0.28

Myopathy / rhabdomyolysis 0 0



Clinical Adverse Events


N=929 N=943

n n P=

Any SAE 463 468

Drug disconuationdue 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



Fatal Cancer

PlaceboEzetimibe/Simvastatin 10/40 mg

No. at risk

930 916

912 890

884 865

855 835

89 94

P=0.05 UnadjustedP=0.06 With Log-rank continuity correction


0

5

10

15

20

Hazard ratio: 1.67

Cu

mu

lati

ve p

erce

nta

ge


Placebo


n=23 (2.5%)

n=39 (4.1%)


Incident Cancer

Site

Placebo(N=929)

Ezetimibe/simvastatin(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

Hematological 5 7

Other/unspecified 7 12

All differences are non-significant



All-cause Mortality


Placebo


No. risk

930

916

912

890

884

865

855

835

89

94

Years in study


0 1 2 3 4 50

10

20

30


PlaceboCu

mu

lati

ve p

erce

nta

ge


Major CV Events - Components

ITT Population

Major CV Events

CV Death

AVR

CHF

Nonfatal MI

CABG

PCI

Hospitalized UAP

Nonhematological stroke

End Points

0.1 1.0 10.0

Favours PlaceboFavours 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


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

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