Scandinavian

Simvastatin Survival
Study (4S)

The Lancet, Vol 344, November 19, 1994

 Objectives

• Randomized trial of cholesterol lowering in

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

The Lancet, Vol 344, November 19, 1994

 Design
• Double-blind, randomized, placebo-controlled
− 94 centers in 5 countries
− 4,444 men and women 35 to 70 years of age
− Inclusion Criteria: Prior MI and/or angina
pectoris
− Total Cholesterol: 212-309 mg/dL
− Follow-up: until 440 deaths occurred.

The Lancet, Vol 344, November 19, 1994

 Endpoints
• Primary: Total Mortality
• Secondary: Major adverse coronary events
• Coronary deaths
• Nonfatal MIs
• Tertiary: Effect on:
• PTCA/CABG procedures
• Survival without atherosclerotic
event (event-free survival)
• Any coronary event
• Non-MI acute CHD events
The Lancet, Vol 344, November 19, 1994
 Treatment Schedule

Simvastatin 20 mg/day or
matching placebo

Increased to 40 mg/day if TC exceeded

200 mg/dL

Study Goal:
TC 116-200 mg/dL
The Lancet, Vol 344, November 19, 1994
 Dosage Titration

4,444
randomized patients

2,221 2,223
simvastatin 20 mg/day placebo patients

20 mg/day 40 mg/day
63% 37%

The Lancet, Vol 344, November 19, 1994

 Baseline Characteristics
Placebo Simvastatin
(n=2223) (n=2221)
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
The Lancet, Vol 344, November 19, 1994
 Primary Endpoint: Overall Survival

100
98
96
94
92
% Surviving

90
88 30%
86 Simvastatin risk reduction
84 p = 0.0003
Placebo
82
80
0 1 2 3 4 5 6
Years since randomization

The Lancet, Vol 344, November 19, 1994

 Coronary Mortality
200
189
42% Risk Reduction
Number of deaths

150 p<0.00001

100 111

50

0
Placebo Simvastatin

The Lancet, Vol 344, November 19, 1994

 Cardiovascular Mortality
Placebo Simvastatin Risk
Cause of death (n=2223) (n=2221) Reduction
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 cardiovascular 207 136 35%

The Lancet, Vol 344, November 19, 1994

 All Cause Mortality
Placebo Simvastatin Risk
Cause of death (n=2223) (n=2221) Reduction
Coronary 189 111 42%

Noncoronary 18 25
vascular
Non-cardiovascular 49 46

-Cancer 35 33

-Suicide 4 5

-Trauma 3 1

-Other 7 7

All Deaths 256 182 30%

The Lancet, Vol 344, November 19, 1994
 Causes of Death

11.5%

8.2%
189
111

18 25
35 33
14 13
Placebo Simvastatin

Other Cancer Other Cardiovascular Coronary

The Lancet, Vol 344, November 19, 1994

 Coronary Death and Nonfatal MI

100
% of patients without events

90

80 34%
Risk Reduction
70
p<0.00001 Simvastatin
Placebo
60
0 1 2 3 4 5 6
Years since randomization

The Lancet, Vol 344, November 19, 1994

 Need for PTCA/CABG

100
Simvastatin
% of patients without

95
Placebo
PTCA/CABG

90

85 37%
80
Risk
Reduction
75 p<0.00001

70
0 1 2 3 4 5 6
Years since randomization

The Lancet, Vol 344, November 19, 1994

 Endpoint by Gender

35
29.4
30 Placebo
25 Simvastatin
% Incidence

20.5 21.7
20
14.5
15 12.8

10 8.5
6 6.6
5
0
Male Female Male Female
Total Mortality Major Coronary Events

The Lancet, Vol 344, November 19, 1994

 Endpoints by Age

35
30 Placebo 27.6 28.3
Simvastatin
25
% Incidence

21
20 17.6
14.8
15
11
10 8.1
5.2
5
0
<60 yrs >60 yrs <60 yrs >60 yrs
Total Mortality Major Coronary Events

The Lancet, Vol 344, November 19, 1994

 Event -Free Survival
Event-Free
Survival without atherosclerotic event

110
Simvastatin
% of patients alive without

100
an atherosclerotic event

Placebo
90

80 26%
Risk
70
Reduction
60 p<0.00001
50
0 1 2 3 4 5 6
Years since randomization
The Lancet, Vol 344, November 19, 1994
 Changes in Lipoprotein Levels
Simvastatin vs placebo, at study end
20
8 7 7
10
1 1
0
% Change

-10
-10
-20
-30 -25 Simvastatin
-40 -35 Placebo
-50
TC LDL HDL TGs
The Lancet, Vol 344, November 19, 1994
 Safety Profile
Placebo Simvastatin
# of patients with (n=2223) (n=2221)
Nonfatal cancer 61 57

AST 3x ULN 23 20

ALT 3x ULN 33 49

CPK 10x ULN 1 6

Rhabdomyolisis 0 1

The Lancet, Vol 344, November 19, 1994

 Summary of Key End-point Results
End-point
Simvastatin Better Placebo Better
Total mortality p=0.0003

CAD mortality p<0.00001

Major coronary
events p<0.00001

PTCA/CABG p<0.00001

Event-free p<0.00001
survival
0.2 0.4 0.6 0.8 1.0 1.2
Relative risk (95% CI)
Reduced
Reduced Increased
Increased
The Lancet, Vol 344, November 19, 1994
Endpoint
• Overall Risk of Death
• Risk of Coronary Death
• Risk of Major Coronary
Events
• Risk of Revascularization
Procedures
• Event - free Survival
• LDL Cholesterol
• HDL Cholesterol
* After
• Total 6 weeks of treatment with 20mg
Cholesterol
28%*
Relative Comment
Risk
30% Only trial to date with cholesterol lowering agent to definitively
showreduction in total or coronary mortality
42% Cardiovascular disease is the world’s leading cause of death
accounting for one-fourth of all deaths
Includes death from coronary disease and non-fatal heart attacks
34%
Includes percutaneous coronary angioplasties (PTCA) and coronary
artery bypass grafts (CABG).
37%
26% Finished the study without suffering any coronary events or other
atheroscleotic events such as stroke
Human atherosclerotic plaques primarily contain LDL cholesterol
38%*
High concentrations of HDL may protect against coronary heart
disease.
8%*
Simvastatin is the most effective cholesterol-lowering agent available
at recommended doses
 4S Summary
Compared with Placebo, Simvastatin:

• Improved survival
• Reduced coronary mortality
• Reduced major coronary events
• Reduced need for PTCA and CABG
Improved event-free survival
• Substantially reduced TC and LDL

The Lancet, Vol 344, November 19, 1994