Scandinavian Scandinavian Simvastatin Simvastatin Survival Study Survival Study (4S) (4S) The Lancet, Vol 344, November 19, 1994 The Lancet, Vol 344, November 19, 1994
Jun 03, 2015
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.
The Lancet, Vol 344, November 19, 1994The Lancet, Vol 344, November 19, 1994
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.
The Lancet, Vol 344, November 19, 1994The Lancet, Vol 344, November 19, 1994
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
The Lancet, Vol 344, November 19, 1994The Lancet, Vol 344, November 19, 1994
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
The Lancet, Vol 344, November 19, 1994The Lancet, Vol 344, November 19, 1994
Dosage TitrationDosage TitrationDosage TitrationDosage Titration
The Lancet, Vol 344, November 19, 1994The Lancet, Vol 344, November 19, 1994
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
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)
The Lancet, Vol 344, November 19, 1994The Lancet, Vol 344, November 19, 1994
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
The Lancet, Vol 344, November 19, 1994The Lancet, Vol 344, November 19, 1994
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
The Lancet, Vol 344, November 19, 1994The Lancet, Vol 344, November 19, 1994
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)
SimvastatinSimvastatin(n=2221)(n=2221)
RiskRiskReductionReduction
The Lancet, Vol 344, November 19, 1994The Lancet, Vol 344, November 19, 1994
All Cause MortalityAll 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)
SimvastatinSimvastatin(n=2221)(n=2221)
RiskRiskReductionReduction
All DeathsAll Deaths 256256 182182 30%30%
The Lancet, Vol 344, November 19, 1994The Lancet, Vol 344, November 19, 1994
Causes of DeathCauses of Death
111
131433352518
189
Placebo Simvastatin
Other Cancer Other Cardiovascular Coronary
11.5%11.5%
8.2%8.2%
The Lancet, Vol 344, November 19, 1994The Lancet, Vol 344, November 19, 1994
60
70
80
90
100
0 1 2 3 4 5 6
SimvastatinPlacebo
Coronary Death and Nonfatal MICoronary Death and Nonfatal MI
Years since randomizationYears since randomization
% 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
The Lancet, Vol 344, November 19, 1994The Lancet, Vol 344, November 19, 1994
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
Years since randomizationYears since randomization
% 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
The Lancet, Vol 344, November 19, 1994The Lancet, Vol 344, November 19, 1994
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
Total Mortality Major Coronary Events
% I
ncid
en
ce
PlaceboSimvastatin
The Lancet, Vol 344, November 19, 1994The Lancet, Vol 344, November 19, 1994
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
Total Mortality Major Coronary Events
% 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
Total Mortality Major Coronary Events
% I
nci
den
ce
PlaceboSimvastatin
The Lancet, Vol 344, November 19, 1994The Lancet, Vol 344, November 19, 1994
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
Years since randomizationYears since randomization
% 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
The Lancet, Vol 344, November 19, 1994The Lancet, Vol 344, November 19, 1994
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
The Lancet, Vol 344, November 19, 1994The Lancet, Vol 344, November 19, 1994
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
The Lancet, Vol 344, November 19, 1994The Lancet, Vol 344, November 19, 1994
Safety ProfileSafety 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)
SimvastatinSimvastatin(n=2221)(n=2221)
The Lancet, Vol 344, November 19, 1994The Lancet, Vol 344, November 19, 1994
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
The Lancet, Vol 344, November 19, 1994The Lancet, Vol 344, November 19, 1994
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 RiskRelative Risk
* 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:
The Lancet, Vol 344, November 19, 1994The Lancet, Vol 344, November 19, 1994