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ScandinavianScandinavian
Simvastatin SurvivalSimvastatin Survival
Study (4S)Study (4S)
The Lancet, Vol 344, November 19, 1...
ObjectivesObjectives
• Randomized trial of cholesterol lowering inRandomized trial of cholesterol lowering in
4,444 patien...
DesignDesign
• Double-blind, randomized, placebo-controlledDouble-blind, randomized, placebo-controlled
− 94 centers in 5 ...
EndpointsEndpoints
• Primary:Primary: Total MortalityTotal Mortality
• Secondary:Secondary: Major adverse coronary eventsM...
Treatment ScheduleTreatment Schedule
Simvastatin 20 mg/day orSimvastatin 20 mg/day or
matching placebomatching placebo
Inc...
Dosage TitrationDosage Titration
The Lancet, Vol 344, November 19, 1994The Lancet, Vol 344, November 19, 1994
2 0 m g / d ...
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...
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
Simva...
Coronary MortalityCoronary Mortality
111
189
0
50
100
150
200
Placebo imvastatin
42% Risk Reduction42% Risk Reduction
p<0....
Cardiovascular MortalityCardiovascular Mortality
Coronary 189 111 42%
-Definite acute MI 63 30
-Probable acute MI 5 5
-Sud...
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...
Causes of DeathCauses of Death
111
1314
3335
2518
189
Placebo Simvastatin
Other Cancer Other Cardiovascular Coronary
11.5%...
60
70
80
90
100
0 1 2 3 4 5 6
Simvastatin
Placebo
Coronary Death and Nonfatal MICoronary Death and Nonfatal MI
Years since...
Need for PTCA/CABGNeed for PTCA/CABG
70
75
80
85
90
95
100
0 1 2 3 4 5 6
Simvastatin
Placebo
Years since randomizationYear...
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
Tota...
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
T...
Event-Free SurvivalEvent-Free Survival
50
60
70
80
90
100
110
0 1 2 3 4 5 6
Simvastatin
Placebo
Survival without atheroscl...
Cholesterol ParametersCholesterol Parameters
-38
-28
8
-50
-40
-30
-20
-10
0
10
20
LDL TC HDL
Mean%changeMean%change
Simva...
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 TG...
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...
Summary of Key End-point ResultsSummary of Key End-point Results
Simvastatin BetterSimvastatin Better
Total mortalityTotal...
• Overall Riskof Death 30% Only trial to date with cholesterol lowering agent to definitively
showreduction in total or co...
4S Summary4S Summary
• Improved survivalImproved survival
• Reduced coronary mortalityReduced coronary mortality
• Reduced...
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Scandinavian Simvastatin Survival Study (4S)

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Scandinavian Simvastatin Survival Study (4S)

  1. 1. ScandinavianScandinavian Simvastatin SurvivalSimvastatin Survival Study (4S)Study (4S) The Lancet, Vol 344, November 19, 1994The Lancet, Vol 344, November 19, 1994
  2. 2. 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. The Lancet, Vol 344, November 19, 1994The Lancet, Vol 344, November 19, 1994
  3. 3. 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. The Lancet, Vol 344, November 19, 1994The Lancet, Vol 344, November 19, 1994
  4. 4. 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 The Lancet, Vol 344, November 19, 1994The Lancet, Vol 344, November 19, 1994
  5. 5. 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 The Lancet, Vol 344, November 19, 1994The Lancet, Vol 344, November 19, 1994
  6. 6. Dosage TitrationDosage Titration The Lancet, Vol 344, November 19, 1994The Lancet, Vol 344, November 19, 1994 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
  7. 7. 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) The Lancet, Vol 344, November 19, 1994The Lancet, Vol 344, November 19, 1994
  8. 8. 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 The Lancet, Vol 344, November 19, 1994The Lancet, Vol 344, November 19, 1994
  9. 9. Coronary MortalityCoronary Mortality 111 189 0 50 100 150 200 Placebo imvastatin 42% Risk Reduction42% Risk Reduction p<0.00001p<0.00001 NumberofdeathsNumberofdeaths The Lancet, Vol 344, November 19, 1994The Lancet, Vol 344, November 19, 1994
  10. 10. 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) SimvastatinSimvastatin (n=2221)(n=2221) RiskRisk ReductionReduction The Lancet, Vol 344, November 19, 1994The Lancet, Vol 344, November 19, 1994
  11. 11. 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) SimvastatinSimvastatin (n=2221)(n=2221) RiskRisk ReductionReduction All DeathsAll Deaths 256256 182182 30%30% The Lancet, Vol 344, November 19, 1994The Lancet, Vol 344, November 19, 1994
  12. 12. 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% The Lancet, Vol 344, November 19, 1994The Lancet, Vol 344, November 19, 1994
  13. 13. 60 70 80 90 100 0 1 2 3 4 5 6 Simvastatin Placebo Coronary Death and Nonfatal MICoronary Death and Nonfatal MI Years since randomizationYears since randomization %ofpatientswithoutevents%ofpatientswithoutevents 34%34% Risk ReductionRisk Reduction p<0.00001p<0.00001 The Lancet, Vol 344, November 19, 1994The Lancet, Vol 344, November 19, 1994
  14. 14. Need for PTCA/CABGNeed for PTCA/CABG 70 75 80 85 90 95 100 0 1 2 3 4 5 6 Simvastatin Placebo Years since randomizationYears since randomization %ofpatientswithout%ofpatientswithout PTCA/CABGPTCA/CABG 37%37% RiskRisk ReductionReduction p<0.00001p<0.00001 The Lancet, Vol 344, November 19, 1994The Lancet, Vol 344, November 19, 1994
  15. 15. 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 The Lancet, Vol 344, November 19, 1994The Lancet, Vol 344, November 19, 1994
  16. 16. 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 The Lancet, Vol 344, November 19, 1994The Lancet, Vol 344, November 19, 1994
  17. 17. 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 Years since randomizationYears since randomization %ofpatientsalivewithout%ofpatientsalivewithout anatheroscleroticeventanatheroscleroticevent 26%26% RiskRisk ReductionReduction p<0.00001p<0.00001 The Lancet, Vol 344, November 19, 1994The Lancet, Vol 344, November 19, 1994
  18. 18. 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 The Lancet, Vol 344, November 19, 1994The Lancet, Vol 344, November 19, 1994
  19. 19. 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 The Lancet, Vol 344, November 19, 1994The Lancet, Vol 344, November 19, 1994
  20. 20. 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) SimvastatinSimvastatin (n=2221)(n=2221) The Lancet, Vol 344, November 19, 1994The Lancet, Vol 344, November 19, 1994
  21. 21. 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 The Lancet, Vol 344, November 19, 1994The Lancet, Vol 344, November 19, 1994 Placebo BetterPlacebo Better
  22. 22. • 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
  23. 23. 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: The Lancet, Vol 344, November 19, 1994The Lancet, Vol 344, November 19, 1994

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