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 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

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 116-200 mg/dL The Lancet, Vol 344, November 19, 1994

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

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

Primary Endpoint: Overall Survival 30% risk reduction % Surviving p = 0.0003 Years since randomization The Lancet, Vol 344, November 19, 1994

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

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

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

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

Coronary Death and Nonfatal MI 34% Risk Reduction % of patients without events p<0.00001 Years since randomization The Lancet, Vol 344, November 19, 1994

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

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

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

% 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<0.00001 Years since randomization The Lancet, Vol 344, November 19, 1994

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

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

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

Summary of Key End-point Results 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 survival p<0.00001 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

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

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