Scandinavian Simvastatin Survival Study (4S) The Lancet, Vol 344, November 19, 1994.

Scandinavian Scandinavian Simvastatin Survival Simvastatin Survival

Study (4S)Study (4S)

Scandinavian Scandinavian Simvastatin Survival Simvastatin Survival

Study (4S)Study (4S)

The Lancet, Vol 344, November 19, 1994The Lancet, Vol 344, November 19, 1994

ObjectivesObjectivesObjectivesObjectives

Randomized trial of cholesterol lowering in Randomized trial of cholesterol lowering in 4,444 patients with CAD: The Scandinavian 4,444 patients with CAD: The Scandinavian Simvastatin Survival Study.Simvastatin Survival Study.

To investigate whether long-term simvastatin To investigate whether long-term simvastatin therapy reduces total mortality and coronary therapy reduces total mortality and coronary events in post-MI and or angina patients with events in post-MI and or angina patients with total cholesterol between 212-309 mg/dL. total cholesterol between 212-309 mg/dL.


DesignDesignDesignDesign

Double-blind, randomized, placebo-controlledDouble-blind, randomized, placebo-controlled 94 centers in 5 countries94 centers in 5 countries 4,444 men and women 35 to 70 years of age4,444 men and women 35 to 70 years of age Inclusion Criteria: Prior MI and/or angina Inclusion Criteria: Prior MI and/or angina

pectorispectoris Total Cholesterol: Total Cholesterol: 212-309 mg/dL212-309 mg/dL Follow-up: until 440 deaths occurred.Follow-up: until 440 deaths occurred.


EndpointsEndpointsEndpointsEndpoints Primary:Primary: Total MortalityTotal Mortality Secondary:Secondary: Major adverse coronary events Major adverse coronary events

Coronary deathsCoronary deaths Nonfatal MIsNonfatal MIs

Tertiary:Tertiary: Effect on:Effect on: PTCA/CABG proceduresPTCA/CABG procedures Survival without atherosclerotic Survival without atherosclerotic

event (event-free survival)event (event-free survival) Any coronary eventAny coronary event Non-MI acute CHD eventsNon-MI acute CHD events


Treatment ScheduleTreatment Schedule

Simvastatin 20 mg/day orSimvastatin 20 mg/day ormatching placebomatching placebo

Increased to 40 mg/day if TC exceededIncreased to 40 mg/day if TC exceeded200 mg/dL200 mg/dL

Study Goal:Study Goal:TC 116-200 mg/dLTC 116-200 mg/dL


Dosage TitrationDosage TitrationDosage TitrationDosage Titration


2 0 m g /d a y6 3 %

4 0 m g /d a y3 7 %

2 ,2 2 1s im v a sta tin 2 0 m g /d a y

2 ,2 2 3p la ceb o p a tien ts

4 ,4 4 4ra n d o m ized p a tien ts

Baseline CharacteristicsBaseline CharacteristicsBaseline CharacteristicsBaseline Characteristics

M e a n a g e ( y e a r s ) - m e n 5 8 . 1 5 8 . 2

M e a n a g e ( y e a r s ) - w o m e n 6 0 . 5 6 0 . 5

A n g in a o n ly 2 1 % 2 1 %

M I o n ly 6 2 % 6 3 %

B o t h a n g in a a n d M I 1 7 % 1 6 %

H y p e r t e n s io n 2 6 % 2 6 %

S m o k e r 2 7 % 2 4 %

T C ( m g / d L ) 2 6 0 2 6 0

L D L ( m g / d L ) 1 8 0 1 8 0

M e a n a g e ( y e a r s ) - m e n 5 8 . 1 5 8 . 2

M e a n a g e ( y e a r s ) - w o m e n 6 0 . 5 6 0 . 5

A n g in a o n ly 2 1 % 2 1 %

M I o n ly 6 2 % 6 3 %

B o t h a n g in a a n d M I 1 7 % 1 6 %

H y p e r t e n s io n 2 6 % 2 6 %

S m o k e r 2 7 % 2 4 %

T C ( m g / d L ) 2 6 0 2 6 0

L D L ( m g / d L ) 1 8 0 1 8 0

PlaceboPlacebo(n=2223)(n=2223)

SimvastatinSimvastatin(n=2221)(n=2221)


Primary Endpoint: Overall SurvivalPrimary Endpoint: Overall SurvivalPrimary Endpoint: Overall SurvivalPrimary Endpoint: Overall Survival

80828486889092949698

100

0 1 2 3 4 5 6

SimvastatinPlacebo

Years since randomizationYears since randomization

% S

urv

ivin

g%

Su

rviv

ing

30% risk reduction

p = 0.0003


Coronary MortalityCoronary MortalityCoronary MortalityCoronary Mortality

111

189

0

50

100

150

200

Placebo imvastatin

42% Risk Reduction42% Risk Reductionp<0.00001p<0.00001

Nu

mb

er

of

de

ath

sN

um

be

r o

f d

ea

ths


Cardiovascular MortalityCardiovascular MortalityCardiovascular MortalityCardiovascular Mortality

Coronary 189 111 42%

-Definite acute MI 63 30

-Probable acute MI 5 5

-Sudden death 78 46

-Other 43 30

Cerebrovascular 12 14

Other cardiovascular 6 11

All cardiovascularAll cardiovascular 207207 136136 35%35%

Cause of deathCause of deathPlaceboPlacebo(n=2223)(n=2223)


RiskRiskReductionReduction


All Cause MortalityAll Cause MortalityAll Cause MortalityAll Cause Mortality

C o r o n a r y 1 8 9 1 1 1 4 2 %

N o n c o r o n a r yv a s c u la r

1 8 2 5

N o n - c a r d io v a s c u la r 4 9 4 6

- C a n c e r 3 5 3 3

- S u ic id e 4 5

- T r a u m a 3 1

- O t h e r 7 7

Cause of deathCause of deathPlaceboPlacebo(n=2223)(n=2223)


RiskRiskReductionReduction

All DeathsAll Deaths 256256 182182 30%30%


Causes of DeathCauses of Death

111

131433352518

189

Placebo Simvastatin

Other Cancer Other Cardiovascular Coronary

11.5%11.5%

8.2%8.2%


60

70

80

90

100

0 1 2 3 4 5 6

SimvastatinPlacebo

Coronary Death and Nonfatal MICoronary Death and Nonfatal MI


% o

f p

atie

nts

wit

ho

ut

even

ts%

of

pat

ien

ts w

ith

ou

t ev

ents

34% 34% Risk ReductionRisk Reduction

p<0.00001p<0.00001


Need for PTCA/CABGNeed for PTCA/CABGNeed for PTCA/CABGNeed for PTCA/CABG

70

75

80

85

90

95

100

0 1 2 3 4 5 6

SimvastatinPlacebo


% o

f p

atie

nts

wit

ho

ut

% o

f p

atie

nts

wit

ho

ut

PT

CA

/CA

BG

PT

CA

/CA

BG

37%37%Risk Risk

ReductionReductionp<0.00001p<0.00001


Endpoint by GenderEndpoint by Gender

12.8

6

29.4

21.7

8.56.6

20.5

14.5

0

5

10

15

20

25

30

35

Male Female Male Female

Total Mortality Major Coronary Events

% I

ncid

en

ce

PlaceboSimvastatin

12.8

6

29.4

21.7

8.56.6

20.5

14.5

0

5

10

15

20

25

30

35

Male Female Male Female


% I

ncid

en

ce

PlaceboSimvastatin


Endpoints by AgeEndpoints by Age

8.1

14.8

27.6 28.3

5.2

11

17.6

21

0

5

10

15

20

25

30

35

<60 yrs >60 yrs <60 yrs >60 yrs


% I

nci

den

ce

PlaceboSimvastatin

8.1

14.8

27.6 28.3

5.2

11

17.6

21

0

5

10

15

20

25

30

35

<60 yrs >60 yrs <60 yrs >60 yrs


% I

nci

den

ce

PlaceboSimvastatin


Event-Free SurvivalEvent-Free SurvivalEvent-Free SurvivalEvent-Free Survival

50

60

70

80

90

100

110

0 1 2 3 4 5 6

SimvastatinPlacebo

Survival without atherosclerotic eventSurvival without atherosclerotic event


% o

f p

atie

nts

ali

ve w

ith

ou

t%

of

pat

ien

ts a

live

wit

ho

ut

an a

ther

osc

lero

tic

even

tan

ath

ero

scle

roti

c ev

ent

26%26%RiskRisk

ReductionReductionp<0.00001p<0.00001


Cholesterol ParametersCholesterol ParametersCholesterol ParametersCholesterol Parameters

-38

-28

8

-50

-40

-30

-20

-10

0

10

20

LDL TC HDL

Me

an

% c

ha

ng

eM

ea

n %

ch

an

ge

Simvastatin 20 mg, week 6Simvastatin 20 mg, week 6

p<0.0001p<0.0001


Changes in Lipoprotein Levels Changes in Lipoprotein Levels Changes in Lipoprotein Levels Changes in Lipoprotein Levels

-25

-35

8

-10

1 17 7

-50

-40

-30

-20

-10

0

10

20

TC LDL HDL TGs

% C

ha

ng

e

Simvastatin

Placebo

Simvastatin vs placebo, at study endSimvastatin vs placebo, at study end


Safety ProfileSafety ProfileSafety ProfileSafety Profile

N o n f a t a l c a n c e r 6 1 5 7

A S T 3 x U L N 2 3 2 0

A L T 3 x U L N 3 3 4 9

C P K 1 0 x U L N 1 6

R h a b d o m y o l is is 0 1

# of patients with# of patients withPlaceboPlacebo(n=2223)(n=2223)



Summary of Key End-point ResultsSummary of Key End-point ResultsSummary of Key End-point ResultsSummary of Key End-point Results

Simvastatin BetterSimvastatin Better

Total mortalityTotal mortality

CAD mortalityCAD mortality

Major coronary Major coronary eventsevents

PTCA/CABGPTCA/CABG

Event-freeEvent-freesurvivalsurvival

0.20.2 0.40.4 0.60.6 0.80.8 1.01.0 1.21.2

p=0.0003p=0.0003

p<0.00001p<0.00001

p<0.00001p<0.00001

p<0.00001p<0.00001

p<0.00001p<0.00001

Relative risk (95% CI)Relative risk (95% CI)ReducedReduced IncreasedIncreased


Placebo BetterPlacebo Better

Overall Risk of Death

30% Only trial to date with cholesterol lowering agent to definitivelyshow reduction in total or coronary mortality

Risk of Coronary Death 42% Cardiovascular disease is the world’s leading cause of deathaccounting for one-fourth of all deaths

Risk of Major CoronaryEvents 34%

Includes death from coronary disease and non-fatal heart attacks

Risk of RevascularizationProcedures 37%

Includes percutaneous coronary angioplasties (PTCA) and coronaryartery bypass grafts (CABG).

Event - free Survival 26% Finished the study without suffering any coronary events or otheratheroscleotic events such as stroke

LDL Cholesterol38%*

Human atherosclerotic plaques primarily contain LDL cholesterol

HDL Cholesterol8%*

High concentrations of HDL may protect against coronary heartdisease.

Total Cholesterol28%*

Simvastatin is the most effective cholesterol-lowering agent availableat recommended doses

EndpointEndpoint CommentCommentRelative Relative RiskRisk

* After 6 weeks of treatment with 20mg* After 6 weeks of treatment with 20mg

4S Summary4S Summary4S Summary4S Summary

Improved survivalImproved survival Reduced coronary mortalityReduced coronary mortality Reduced major coronary eventsReduced major coronary events Reduced need for PTCA and CABG Reduced need for PTCA and CABG

Improved event-free survivalImproved event-free survival Substantially reduced TC and LDLSubstantially reduced TC and LDL

Compared with Placebo, Simvastatin:Compared with Placebo, Simvastatin:


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Scandinavian Simvastatin Survival Study (4S) The Lancet, Vol 344, November 19, 1994.

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