Scandinavian Simvastatin Survival Study (4S)

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Scandinavian Simvastatin Survival Study (4S)
The Lancet, Vol 344, November 19, 1994
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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
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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
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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
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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
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Dosage Titration
The Lancet, Vol 344, November 19, 1994
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Baseline Characteristics
Placebo (n2223)
Simvastatin (n2221)
The Lancet, Vol 344, November 19, 1994
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Primary Endpoint Overall Survival
30 risk reduction
Surviving
p 0.0003
Years since randomization
The Lancet, Vol 344, November 19, 1994
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Coronary Mortality
42 Risk Reduction
plt0.00001
Number of deaths
The Lancet, Vol 344, November 19, 1994
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Cardiovascular Mortality
Placebo (n2223)
Simvastatin (n2221)
Risk Reduction
Cause of death
All cardiovascular
207
136
35
The Lancet, Vol 344, November 19, 1994
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All Cause Mortality
Placebo (n2223)
Simvastatin (n2221)
Risk Reduction
Cause of death
All Deaths
256
182
30
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Causes of Death
11.5
8.2
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Coronary Death and Nonfatal MI
34 Risk Reduction
of patients without events
plt0.00001
Years since randomization
The Lancet, Vol 344, November 19, 1994
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Need for PTCA/CABG
of patients without PTCA/CABG
37 Risk Reduction
plt0.00001
Years since randomization
The Lancet, Vol 344, November 19, 1994
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Endpoint by Gender
The Lancet, Vol 344, November 19, 1994
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Endpoints by Age
The Lancet, Vol 344, November 19, 1994
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Event-Free Survival
Survival without atherosclerotic event
26 Risk Reduction
of patients alive without an atherosclerotic
event
plt0.00001
Years since randomization
The Lancet, Vol 344, November 19, 1994
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Cholesterol Parameters
Simvastatin 20 mg, week 6
Mean change
plt0.0001
The Lancet, Vol 344, November 19, 1994
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Changes in Lipoprotein Levels
Simvastatin vs placebo, at study end
The Lancet, Vol 344, November 19, 1994
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Safety Profile
Placebo (n2223)
Simvastatin (n2221)
of patients with
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Summary of Key End-point Results
Simvastatin Better
Placebo Better
Total mortality
p0.0003
CAD mortality
plt0.00001
Major coronary events
plt0.00001
PTCA/CABG
plt0.00001
Event-free survival
plt0.00001
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
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Endpoint
Comment
Relative Risk
After 6 weeks of treatment with 20mg
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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