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

2. ObjectivesObjectives  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

3. DesignDesign  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

4. EndpointsEndpoints  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. 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

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 Years since randomization % Surviving 30% risk reduction p = 0.0003 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 All cardiovascular 20713635% Cause of death Placebo(n=2223)Simvastatin(n=2221)RiskReduction The Lancet, Vol 344, November 19, 1994

11. All Cause Mortality Cause of death Placebo(n=2223) Simvastatin(n=2221) RiskReduction All Deaths 25618230% 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 Years since randomization % of patients without events 34% Risk Reduction p<0.00001 The Lancet, Vol 344, November 19, 1994

14. Need for PTCA/CABG Years since randomization % of patients without PTCA/CABG 37%RiskReduction p<0.00001 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. Event-Free Survival Survival without atherosclerotic event Years since randomization % of patients alive without an atherosclerotic event 26%RiskReduction p<0.00001 The Lancet, Vol 344, November 19, 1994

18. Cholesterol Parameters Mean % change Simvastatin 20 mg, week 6 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 # of patients with Placebo(n=2223)Simvastatin(n=2221) The Lancet, Vol 344, November 19, 1994

21. Summary of Key End-point Results Simvastatin Better Total mortality CAD mortality Major coronary events PTCA/CABG Event-freesurvival 0.20.40.60.81.01.2 p=0.0003 p<0.00001 p<0.00001 p<0.00001 p<0.00001 Relative risk (95% CI) Reduced Increased The Lancet, Vol 344, November 19, 1994 Placebo Better

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

23. 4S Summary  Improved survival  Reduced coronary mortality  Reduced major coronary events  Reduced need for PTCA and CABG Improved event-free survival  Substantially reduced TC and LDL Compared with Placebo, Simvastatin: The Lancet, Vol 344, November 19, 1994