4S Study Ppt

Scandinavian Simvastatin Survival

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

ObjectivesObjectivesObjectives

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


DesignDesignDesign

•• DoubleDouble--blind, randomized, placeboblind, randomized, placebo--controlledcontrolled−− 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: 212Total Cholesterol: 212--309 mg/dL309 mg/dL−− FollowFollow--up: until 440 deaths occurred.up: until 440 deaths occurred.


EndpointsEndpointsEndpoints•• Primary:Primary: Total MortalityTotal Mortality•• Secondary:Secondary: Major adverse coronary eventsMajor 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 (eventevent (event--free survival)free survival)•• Any coronary eventAny coronary event•• NonNon--MI acute CHD eventsMI 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 116TC 116--200 mg/dL200 mg/dL


Dosage TitrationDosage TitrationDosage Titration


20 mg/day63%

40 mg/day37%

2,221simvastatin 20 mg/day

2,223placebo patients

4,444randomized patients

Baseline CharacteristicsBaseline CharacteristicsBaseline Characteristics

Mean age (years)-men 58.1 58.2

Mean age (years)-women 60.5 60.5

Angina only 21% 21%

MI only 62% 63%

Both angina and MI 17% 16%

Hypertension 26% 26%

Smoker 27% 24%

TC (mg/dL) 260 260

LDL (mg/dL) 180 180

Mean age (years)-men 58.1 58.2

Mean age (years)-women 60.5 60.5

Angina only 21% 21%

MI only 62% 63%

Both angina and MI 17% 16%

Hypertension 26% 26%

Smoker 27% 24%

TC (mg/dL) 260 260

LDL (mg/dL) 180 180

PlaceboPlacebo(n=2223)(n=2223)

SimvastatinSimvastatin(n=2221)(n=2221)


Primary 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

urvi

ving

% S

urvi

ving

30% risk reduction

p = 0.0003


Coronary MortalityCoronary MortalityCoronary Mortality

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

Num

ber o

f dea

ths

Num

ber o

f dea

ths


111

189

0

50

100

150

200

Placebo Simvastatin

Cardiovascular 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 Mortality

Coronary 189 111 42%

Noncoronaryvascular

18 25

Non-cardiovascular 49 46

-Cancer 35 33

-Suicide 4 5

-Trauma 3 1

-Other 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 pat

ient

s w

ithou

t eve

nts

% o

f pat

ient

s w

ithou

t eve

nts

34% 34% Risk ReductionRisk Reduction

p<0.00001p<0.00001


Need 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 pat

ient

s w

ithou

t%

of p

atie

nts

with

out

PTC

A/C

AB

GPT

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

% In

cide

nce

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


% In

cide

nce

PlaceboSimvastatin


Endpoints by AgeEndpoints by Age

8.1

14.8

27.6 28.3

5.2

11

17.621

0

5

10

15

20

25

30

35

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


% In

cide

nce

PlaceboSimvastatin

8.1

14.8

27.6 28.3

5.2

11

17.621

0

5

10

15

20

25

30

35

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


% In

cide

nce

PlaceboSimvastatin


Event-Free SurvivalEventEvent--Free SurvivalFree 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 pat

ient

s al

ive

with

out

% o

f pat

ient

s al

ive

with

out

an a

ther

oscl

erot

ic e

vent

an a

ther

oscl

erot

ic e

vent

26%26%RiskRisk

ReductionReductionp<0.00001p<0.00001


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

-25

-35

8

-10

1 17 7

-50-40-30-20-10

01020

TC LDL HDL TGs

% C

hang

e

SimvastatinPlacebo

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


Safety ProfileSafety ProfileSafety Profile

Nonfatal cancer 61 57

AST 3x ULN 23 20

ALT 3x ULN 33 49

CPK 10x ULN 1 6

Rhabdomyolisis 0 1

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



Summary of Key End-point ResultsSummary of Key EndSummary of Key End--point Resultspoint ResultsSimvastatin BetterSimvastatin Better

Total mortalityTotal mortality

CAD mortalityCAD mortality

Major coronary Major coronary eventsevents

PTCA/CABGPTCA/CABG

EventEvent--freefreesurvivalsurvival

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 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 eventImproved event--free survivalfree survival•• Substantially reduced TC and LDLSubstantially reduced TC and LDL

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


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