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Evevident
Original paper
1994LancetCardiology

4S

Scandinavian Simvastatin Survival Study

RCTSecondary Prevention

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Overview

Simvastatin cut all-cause mortality in patients with coronary disease, the first trial to prove statins save lives.

Clinical takeaway

4S was the landmark secondary-prevention trial that showed lowering cholesterol with simvastatin reduces all-cause mortality, coronary death, and major coronary events in patients with established coronary heart disease.

Key result

All-cause mortality: RR 0.70 (95% CI 0.58-0.85), p=0.0003.

Practice impact

Launched the modern era of statin therapy for secondary prevention.

Evidence

Study design

Randomized, double-blind, placebo-controlled trial

Enrollment

4,444

Follow-up

Median 5.4 years

Geography

Scandinavia

Clinical question

In patients with coronary heart disease and elevated cholesterol, does lowering cholesterol with simvastatin reduce mortality?

Population

  • History of angina pectoris or prior myocardial infarction
  • Serum total cholesterol 5.5-8.0 mmol/L (~213-310 mg/dL)

Intervention

Simvastatin 20-40 mg daily

Comparator

Placebo

Primary outcome

All-cause mortality

Simvastatin reduced all-cause mortality compared with placebo.

RR / 0.7 / CI 0.58-0.85 / p=0.0003

Key results

  • All-cause mortality: RR 0.70 (95% CI 0.58-0.85), p=0.0003
  • Coronary deaths and major coronary events markedly reduced
  • Reduced need for coronary revascularization
  • No excess in non-cardiovascular mortality

Harms

  • No excess in non-cardiovascular mortality was reported in the seed data.

Clinical Use

When to cite

  • When explaining why statins are foundational for secondary prevention
  • When asked for the classic trial showing statins save lives

Practice impact

  • First trial to prove statins reduce mortality
  • Established statins as cornerstone of secondary prevention
  • Drove cholesterol lowering into routine coronary care

Applicability

  • Most applicable to patients with established coronary heart disease
  • Useful as the classic mortality-benefit statin trial

Limitations

  • Predominantly middle-aged patients; few women and elderly patients
  • Pre-dates modern background therapy such as widespread aspirin and revascularization
  • Entry required elevated cholesterol, unlike later broad-eligibility statin trials

Common misinterpretations

  • Do not reduce the lesson to LDL lowering alone; the clinical point is mortality and event reduction.

Related evidence

JUPITER - Later Trial

Citation

Randomised trial of cholesterol lowering in 4444 patients with coronary heart disease: the Scandinavian Simvastatin Survival Study (4S). Lancet. 1994;344(8934):1383-1389.