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The Scandinavian Simvastatin Survival Study (4S)

In the first part of our new series on pivotal studies that influence current practice, we look at this coronary heart disease secondary prevention study

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Pedersen T, Kjekshus J, Berg K et al. The Scandinavian Simvastatin Survival Study: Randomised trial of cholesterol lowering in 4,444 patients with coronary heart disease. Lancet 1994;344:1383-9

Study design: RCT

Evidence level: 1b

Key message

In patients with established coronary artery disease and total cholesterol levels of 5.5-8.0mmol/l, the addition of simvastatin to regular medical therapy results in a 30% reduction in total mortality relative to placebo, with no effect on non-cardiac mortality.


Lipid-lowering therapy with a statin is now part of the standard treatment of patients with coronary heart disease (CHD).


Epidemiological evidence demonstrated a powerful association between hypercholesterolaemia and CHD, with early studies of cholesterol lowering for both primary and secondary prevention demonstrating reduced CHD events. Nevertheless, drug treatment for hypercholesterolaemia remained controversial as no mortality outcome data were available, and an increase in the risk of non-cardiac death from cancer or violence had been reported. This trial was designed to study the effects of long-term treatment with simvastatin (a 3-hydroxy-3-methylglutaryl coenzyme A [HMGCoA] reductase inhibitor) on mortality and morbidity in patients with CHD.


Patients: 4,444 patients at 94 Scandinavian centres.

Inclusion criteria: Compliance with two-week placebo run-in, and:

• age 35-70 years, with previous myocardial infarction (MI) or angina

• fasting cholesterol level of 5.5-8.0mmol/l after dietary advice

• fasting triglyceride level below 2.5mmol/l after dietary advice.


• Dietary advice and simvastatin 20mg daily, increased to 40mg daily if total cholesterol exceeded 5.2mmol/l (n=2,221)

• Dietary advice and matching placebo (n=2,223)

Primary endpoint: Total mortality.

Secondary endpoint: ‘Major coronary events' such as coronary deaths, definite or probable hospital-verified non-fatal MI, resuscitated cardiac arrest, definite silent MI verified by ECG.

Other endpoints: Myocardial revascularisation – coronary artery bypass graft or percutaneous coronary intervention.

Follow-up: Mean follow-up of 5.6 years.


41248474Treatment with simvastatin was associated with reductions in serum total cholesterol, LDL and triglycerides, but a significant increase in HDL cholesterol. For a summary of clinical endpoints see box below.


This trial demonstrated for the first time that in patients with overt CHD, the addition of simvastatin to standard medical therapy significantly reduced mortality and morbidity. The 10-year follow-up data is now available for this study and, although more than 80% of the two groups were ultimately on open-label statin therapy, the survival benefit of an initial five-year statin treatment persisted, with no increase in cancer deaths up to a median follow-up of 10.4 years.

Subsequent trials – such as LIPID (NEJM 1998;339:1349-57), CARE (NEJM 1996;335:1001-9) and HPS (Lancet 2002;360:7-22) – have confirmed the beneficial effects of statin therapy. In a meta-analysis of 14 such trials (including more than 90,000 patients), statin therapy reduced the five-year incidence of major coronary events, myocardial revascularisation, and stroke by about one-fifth per mmol/l reduction in LDL cholesterol. The absolute benefits of statin therapy were largely independent of initial lipid profile, but were determined by the absolute risk of adverse vascular events and the absolute reduction in LDL achieved.


Only 19% of patients were women, and the mortality rate for women in the placebo group was half that of men. Nevertheless, simvastatin reduced the risk of major adverse events in women to roughly the same extent as in men, and the benefits of treating women have been confirmed in meta-analyses.

This is an extract from the Oxford Handbook of Key Clinical Evidence, which provides doctors with a quick route to the salient details of the trials that have most influenced clinical practice.The book is published by Oxford University Press and edited by Harrison, Kulkarni, Baguneid and Prendergast (ISBN 9780199234073) price £27.95. Pulse readers can buy the book at a 20% discount from the OUP using the promotion code webkce10 (offer expires 30 June 2010)

Simvastatin CPD questions

This article is part of the Pulse Plus series on lipid management. Please click here to read the full series.

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