Randomised Trial of Cholesterol Lowering in 4444 Patients with Coronary Heart Disease: The 4S Trial

The Scandinavian Simvastatin Survival Study (4S) randomized 4,444 patients with established coronary heart disease and elevated cholesterol to simvastatin 20–40 mg daily or placebo, followed for a median of 5.4 years. It was the first trial to demonstrate that cholesterol-lowering with a statin significantly reduced total mortality.

Simvastatin reduced total cholesterol by 25% and LDL-C by 35%, with an 8% increase in HDL-C. Total mortality was reduced by 30% (HR 0.70, p=0.0003), major coronary events by 34%, and coronary revascularization by 37%. No excess of non-cardiovascular deaths was observed.

The 4S trial was a watershed event in cardiovascular medicine. Prior to 4S, statins were used to lower cholesterol as a risk factor, but the mortality benefit was debated — some researchers worried that cholesterol lowering might cause harm through cancer or other mechanisms. 4S resolved that debate unequivocally: in high-risk secondary prevention patients with established CHD, statin therapy reduces mortality. This finding transformed statin prescribing from a risk-reduction strategy into an established survival therapy.

The 4S population had LDL-C of 135–250 mg/dL at entry — above the current treatment threshold for secondary prevention patients. The trial established the principle; subsequent trials (CARE, LIPID, PROVE-IT) filled in the evidence for lower-cholesterol secondary prevention patients and higher-intensity targets.

We rate the evidence strong. The landmark trial establishing that statin therapy reduces mortality in established coronary disease — one of the most important cardiovascular trials ever conducted.