Scandinavian Simvastatin Survival Study (4S)

ScandinavianScandinavian
Simvastatin SurvivalSimvastatin Survival
Study (4S)Study (4S)
The Lancet, Vol 344, November 19, 1994The Lancet, Vol 344, November 19, 1994

ObjectivesObjectives
• Randomized trial of cholesterol lowering inRandomized trial of cholesterol lowering in
4,444 patients with CAD: The Scandinavian4,444 patients with CAD: The Scandinavian
Simvastatin Survival Study.Simvastatin Survival Study.
• To investigate whether long-term simvastatinTo investigate whether long-term simvastatin
therapy reduces total mortality and coronarytherapy reduces total mortality and coronary
events in post-MI and or angina patients withevents in post-MI and or angina patients with
total cholesterol between 212-309 mg/dL.total cholesterol between 212-309 mg/dL.

DesignDesign
• 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 anginaInclusion 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.

EndpointsEndpoints
• 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 atheroscleroticSurvival 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 or
matching placebomatching placebo
Increased to 40 mg/day if TC exceededIncreased to 40 mg/day if TC exceeded
200 mg/dL200 mg/dL
Study Goal:Study Goal:
TC 116-200 mg/dLTC 116-200 mg/dL

Dosage TitrationDosage Titration
2 0 m g / d a y
6 3 %
4 0 m g / d a y
3 7 %
2 , 2 2 1
s i m v a s t a t i n 2 0 m g / d a y
2 , 2 2 3
p l a c e b o p a t i e n t s
4 , 4 4 4
r a n d o m i z e d p a t i e n t s

Baseline CharacteristicsBaseline Characteristics
M e a n a g e (y e a rs )-m e n 5 8 .1 5 8 .2
M e a n a g e (y e a rs )-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 th a n g in a a n d M I 1 7 % 1 6 %
H y p e rte 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 Survival
80
82
84
86
88
90
92
94
96
98
100
0 1 2 3 4 5 6
Simvastatin
Placebo
Years since randomizationYears since randomization
%Surviving%Surviving
30%
risk reduction
p = 0.0003

Coronary MortalityCoronary Mortality
111
189
0
50
100
150
200
Placebo imvastatin
42% Risk Reduction42% Risk Reduction
p<0.00001p<0.00001
NumberofdeathsNumberofdeaths

Cardiovascular 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 death
PlaceboPlacebo
(n=2223)(n=2223)
(n=2221)(n=2221)
RiskRisk
ReductionReduction

All Cause MortalityAll Cause Mortality
C o ro n a ry 1 8 9 1 1 1 4 2 %
N o n c o ro n a ry
v a s c u la r
1 8 2 5
N o n -c a rd 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 ra u m a 3 1
-O th e r 7 7
Cause of deathCause of death
PlaceboPlacebo
(n=2223)(n=2223)
(n=2221)(n=2221)
RiskRisk
ReductionReduction
All DeathsAll Deaths 256256 182182 30%30%

Causes of DeathCauses of Death
111
1314
3335
2518
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
Simvastatin
Placebo
Coronary Death and Nonfatal MICoronary Death and Nonfatal MI
%ofpatientswithoutevents%ofpatientswithoutevents
34%34%
Risk ReductionRisk Reduction
p<0.00001p<0.00001

Need for PTCA/CABGNeed for PTCA/CABG
70
75
80
85
90
95
100
0 1 2 3 4 5 6
Simvastatin
Placebo
%ofpatientswithout%ofpatientswithout
PTCA/CABGPTCA/CABG
37%37%
RiskRisk
ReductionReduction
p<0.00001p<0.00001

Endpoint by GenderEndpoint by Gender
12.8
6
29.4
21.7
8.5
6.6
20.5
14.5
0
5
10
15
20
25
30
35
Male Female Male Female
Total Mortality Major Coronary Events
%Incidence
Placebo
Simvastatin

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
%Incidence
Placebo
Simvastatin

Event-Free SurvivalEvent-Free Survival
50
60
70
80
90
100
110
0 1 2 3 4 5 6
Simvastatin
Placebo
Survival without atherosclerotic eventSurvival without atherosclerotic event
%ofpatientsalivewithout%ofpatientsalivewithout
anatheroscleroticeventanatheroscleroticevent
26%26%
RiskRisk
ReductionReduction
p<0.00001p<0.00001

Cholesterol ParametersCholesterol Parameters
-38
-28
8
-50
-40
-30
-20
-10
0
10
20
LDL TC HDL
Mean%changeMean%change
Simvastatin 20 mg, week 6Simvastatin 20 mg, week 6
p<0.0001p<0.0001

Changes in Lipoprotein LevelsChanges in Lipoprotein Levels
-25
-35
8
-10
1 1
7 7
-50
-40
-30
-20
-10
0
10
20
TC LDL HDL TGs
%Change
Simvastatin
Placebo
Simvastatin vs placebo, at study endSimvastatin vs placebo, at study end

Safety ProfileSafety Profile
N o n fa ta 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 lis is 0 1
# of patients with# of patients with
PlaceboPlacebo
(n=2223)(n=2223)
(n=2221)(n=2221)

Summary of Key End-point ResultsSummary of Key End-point Results
Simvastatin BetterSimvastatin Better
Total mortalityTotal mortality
CAD mortalityCAD mortality
Major coronaryMajor coronary
eventsevents
PTCA/CABGPTCA/CABG
Event-freeEvent-free
survivalsurvival
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)
Reduced Increased
Placebo BetterPlacebo Better

• Overall Riskof Death 30% Only trial to date with cholesterol lowering agent to definitively
showreduction in total or coronary mortality
• Riskof CoronaryDeath 42% Cardiovascular disease is theworld’s leading cause of death
accounting for one-fourth of all deaths
• Riskof MajorCoronary
Events 34%
Includes death from coronary disease and non-fatal heart attacks
• Riskof Revascularization
Procedures 37%
Includes percutaneous coronary angioplasties (PTCA) andcoronary
artery bypass grafts (CABG).
• Event-freeSurvival 26% Finished the study without suffering any coronary events orother
atheroscleotic events such as stroke
• LDL Cholesterol
38%*
Human atherosclerotic plaques primarily contain LDL cholesterol
• HDL Cholesterol
8%*
Highconcentrations of HDL may protect against coronary heart
disease.
• Total Cholesterol
28%*
Simvastatin is the most effective cholesterol-lowering agentavailable
at recommended doses
EndpointEndpoint CommentComment
Relative RiskRelative Risk
* After 6 weeks of treatment with 20mg* After 6 weeks of treatment with 20mg

4S Summary4S Summary
• Improved survivalImproved survival
• Reduced coronary mortalityReduced coronary mortality
• Reduced major coronary eventsReduced major coronary events
• Reduced need for PTCA and CABGReduced 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:

Scandinavian Simvastatin Survival Study (4S)

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