presented by terje r. pedersen oslo disclosure: research grants and/or speaker- / consulting fees...

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)



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)


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


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


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 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


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

Aspirin 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; LDL = low-density lipoprotein; HDL = high-density lipoprotein


Baseline Echocardiography

Mean Values


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


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


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


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


EZ/Simva 10/40 mg

Placebo

0 1 2 3 4 50

10

20

30

40

50


Per

cen

tag

e o

f P

atie

nts

Wit

h

Fir

st E

ven

t


Aortic Valve Replacement

Placebo 896 816 728 618 61

50Intention to Treat Population


0

10

20

30

40

EZ/Simva 10/40 mgNo. at risk


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


Peak Aortic - Jet Velocity


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)


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


EZ/Simva 10/40 mg

Placebo

0 1 2 3 4 50

10

20

30


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


EZ/Simva 10/40 mg

Placebo

0 1 2 3 4 50

10

20


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



Placebo EZ/ Simva

N=929 N=943*

n n p=



Musculoskeletal AE 181 165 0.28

Myopathy / Rhabdo 0 0




Placebo EZ/ Simva

N=929 N=943*

n n p=



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



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

5

10

15

20

Hazard ratio: 1.67

Cu

mu

lati

ve P

erce

nta

ge

EZ/Simva 10/40 mg

Placebo


n=23 (2.5%)

n=39 (4.1%)


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 Cause Mortality


PlaceboEZ/Simva 10/40 mgNo. risk

930 916

912 890

884 865

855 835

89 94

Years in Study


0 1 2 3 4 50

10

20

30

EZ/Simva 10/40 mg

PlaceboCu

mu

lati

ve P

erce

nta

ge


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

presented by terje r. pedersen oslo disclosure: research grants and/or speaker- / consulting fees...

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