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

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

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

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

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

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 Years since randomization % Surviving 30% risk reduction p = The Lancet, Vol 344, November 19, 1994

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

Cardiovascular Mortality All cardiovascular % Cause of death Placebo(n=2223)Simvastatin(n=2221)RiskReduction The Lancet, Vol 344, November 19, 1994

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

Need for PTCA/CABG Years since randomization % of patients without PTCA/CABG 37%RiskReduction p< 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

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

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

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

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

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