4S (Scandinavian Simvastatin Survival Study)

Throughout the late 1980s, cardiologists had a plausible reason to lower cholesterol in patients with coronary disease but no proof that doing so reduced mortality. Trials with earlier lipid-lowering agents, including clofibrate, gemfibrozil, and bile-acid resins, had suggested reductions in coronary events but had not demonstrated a convincing effect on all-cause mortality. Some analyses even suggested possible harm from non-cardiovascular causes. The statins offered more potent LDL reduction than earlier agents, but their effect on hard outcomes remained unproven when the 4S trial began enrolling.

The Scandinavian Simvastatin Survival Study enrolled 4,444 patients with angina or a previous myocardial infarction and serum cholesterol of 5.5 to 8.0 mmol/L despite a lipid-lowering diet. Patients were randomized, double-blind, to simvastatin or placebo and followed for a median of 5.4 years. Total cholesterol fell 25 percent, LDL cholesterol 35 percent, and HDL cholesterol rose 8 percent, with few adverse effects.

There were 182 deaths (8 percent) on simvastatin and 256 (12 percent) on placebo, a 30 percent reduction; coronary deaths fell from 189 to 111, a 42 percent reduction. Major coronary events fell from 28 to 19 percent of patients, and the reduction was also significant in women and in patients aged 60 or more. There was no excess of noncardiovascular deaths (46 against 49), and the need for revascularization procedures fell by 37 percent.

The report, by the 4S study group, appeared in the Lancet on November 19, 1994; Terje Pedersen of Aker Hospital in Oslo led the group's later publications. Before 4S, drug treatment of high cholesterol had been controversial for lack of survival evidence; afterward, a statin became the expected treatment for patients with coronary disease.

The following year, WOSCOPS extended statin evidence into primary prevention, showing that pravastatin reduced coronary events in men with elevated cholesterol but no prior heart disease. Together, 4S and WOSCOPS made statins the main drug treatment for lowering cardiovascular risk. Later trials, including CARE and LIPID, confirmed the secondary prevention benefit at lower baseline LDL levels and progressively broadened the treated population.