1. Scandinavian Simvastatin Survival Study (4S)
The Lancet, Vol 344, November 19, 1994

2. 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 mg/dL.
The Lancet, Vol 344, November 19, 1994

3. 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: mg/dL
Follow-up: until 440 deaths occurred.
The Lancet, Vol 344, November 19, 1994

4. Endpoints Coronary deaths Nonfatal MIs PTCA/CABG procedures
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

5. Increased to 40 mg/day if TC exceeded
Treatment Schedule
Simvastatin 20 mg/day or
matching placebo
Increased to 40 mg/day if TC exceeded
200 mg/dL
Study Goal:
TC mg/dL
The Lancet, Vol 344, November 19, 1994

6. Dosage Titration
The Lancet, Vol 344, November 19, 1994

7. Baseline Characteristics
Placebo
(n=2223)
Simvastatin
(n=2221)
The Lancet, Vol 344, November 19, 1994

8. Primary Endpoint: Overall Survival
30%
risk reduction
% Surviving
p =
Years since randomization
The Lancet, Vol 344, November 19, 1994

9. Coronary Mortality 42% Risk Reduction p<0.00001 Number of deaths
The Lancet, Vol 344, November 19, 1994

10. Cardiovascular Mortality
Placebo
(n=2223)
Simvastatin
(n=2221)
Risk
Reduction
Cause of death
All cardiovascular
207
136
35%
The Lancet, Vol 344, November 19, 1994

11. All Cause Mortality Placebo (n=2223) Simvastatin (n=2221) Risk
Reduction
Cause of death
All Deaths
256
182
30%
The Lancet, Vol 344, November 19, 1994

12. Causes of Death
11.5%
8.2%
The Lancet, Vol 344, November 19, 1994

13. Coronary Death and Nonfatal MI
34%
Risk Reduction
% of patients without events
p<
Years since randomization
The Lancet, Vol 344, November 19, 1994

14. Need for PTCA/CABG 37% Risk Reduction % of patients without PTCA/CABG
Years since randomization
The Lancet, Vol 344, November 19, 1994

15. Endpoint by Gender
The Lancet, Vol 344, November 19, 1994

16. Endpoints by Age
The Lancet, Vol 344, November 19, 1994

17. % of patients alive without an atherosclerotic event
Event-Free Survival
Survival without atherosclerotic event
26%
Risk
Reduction
% of patients alive without
an atherosclerotic event
p<
Years since randomization
The Lancet, Vol 344, November 19, 1994

18. Cholesterol Parameters
Simvastatin 20 mg, week 6
Mean % change
p<0.0001
The Lancet, Vol 344, November 19, 1994

19. Changes in Lipoprotein Levels
Simvastatin vs placebo, at study end
The Lancet, Vol 344, November 19, 1994

20. Safety Profile Placebo (n=2223) Simvastatin (n=2221)
# of patients with
The Lancet, Vol 344, November 19, 1994

21. Summary of Key End-point Results
Simvastatin Better
Placebo Better
Total mortality
p=0.0003
CAD mortality
p<
Major coronary
events
p<
PTCA/CABG
p<
Event-free
survival
p<
0.2
0.4
0.6
0.8
1.0
1.2
Relative risk (95% CI)
Reduced
Increased
The Lancet, Vol 344, November 19, 1994

22. Endpoint
Relative Risk
Comment
* After 6 weeks of treatment with 20mg

23. 4S Summary Improved survival Reduced coronary mortality
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