The Scandinavian Simvastatin Survival Study (also known as the 4S study), was a multicentre, randomized, double-blind, placebo-controlled clinical trial, which provided the initial data that supported the use of the

cholesterol-lowering drug Lipid-lowering agents, also sometimes referred to as hypolipidemic agents, cholesterol-lowering drugs, or antihyperlipidemic agents are a diverse group of pharmaceuticals that are used to lower the level of lipids and lipoproteins such as cholester ...

simvastatin Simvastatin, sold under the brand name Zocor among others, is a statin, a type of lipid-lowering medication. It is used along with exercise, diet, and weight loss to decrease elevated lipid levels. It is also used to decrease the risk of hear ...

, in people with a moderately raised

cholesterol Cholesterol is any of a class of certain organic molecules called lipids. It is a sterol (or modified steroid), a type of lipid. Cholesterol is biosynthesized by all animal cells and is an essential structural component of animal cell mem ...

and

coronary heart disease Coronary artery disease (CAD), also called coronary heart disease (CHD), ischemic heart disease (IHD), myocardial ischemia, or simply heart disease, involves the reduction of blood flow to the heart muscle due to build-up of atherosclerotic pla ...

(CHD); that is people who had previously had a

heart attack A myocardial infarction (MI), commonly known as a heart attack, occurs when blood flow decreases or stops to the coronary artery of the heart, causing damage to the heart muscle. The most common symptom is chest pain or discomfort which may tr ...

angina Angina, also known as angina pectoris, is chest pain or pressure, usually caused by ischemia, insufficient blood flow to the Cardiac muscle, heart muscle (myocardium). It is most commonly a symptom of coronary artery disease. Angina is typical ...

. The study was sponsored by the pharmaceutical company

Merck Merck refers primarily to the German Merck family and three companies founded by the family, including: * the Merck Group, a German chemical, pharmaceutical and life sciences company founded in 1668 ** Merck Serono (known as EMD Serono in the Unite ...

and enrolled 4,444 people from 94 centres in

Scandinavia Scandinavia; Sámi languages: /. ( ) is a subregion#Europe, subregion in Northern Europe, with strong historical, cultural, and linguistic ties between its constituent peoples. In English usage, ''Scandinavia'' most commonly refers to Denmark, ...

. Before the 4S study, it was not proven that lowering cholesterol could prolong life in people who had CHD. The study concluded that

secondary prevention Preventive healthcare, or prophylaxis, consists of measures taken for the purposes of disease prevention.Hugh R. Leavell and E. Gurney Clark as "the science and art of preventing disease, prolonging life, and promoting physical and mental hea ...

with simvastatin in a high risk group with CHD reduced overall mortality by 30%. Published in ''

The Lancet ''The Lancet'' is a weekly peer-reviewed general medical journal and one of the oldest of its kind. It is also the world's highest-impact academic journal. It was founded in England in 1823. The journal publishes original research articles, ...

'' in 1994, it is considered a "landmark paper".

Objective

The 4S multicentre, randomized, double-blind, placebo-controlled clinical trial enrolled 4,444 people chosen from 7,027 people who had been followed up for two months after being given dietary advice. The objective of the study was to assess the effect of a

called

mortality Mortality is the state of being mortal, or susceptible to death; the opposite of immortality. Mortality may also refer to: * Fish mortality, a parameter used in fisheries population dynamics to account for the loss of fish in a fish stock throug ...

and morbidity in people with a history of a previous

, who also had a moderately raised cholesterol; between 5.5 and 8.0 mmol/L. A second objective was to investigate whether the incidence of major coronary artery disease events (fatal and nonfatal myocardial infarction and sudden death) could be reduced with simvastatin.

Study details

The participants, all at high risk of death from CHD and death in general, were selected from 94 clinical centers in Denmark, Finland, Iceland, Norway, and Sweden from 1988 to 1989, and were aged between 35 and 70 years, with the average age being 59. Of the 4,444 people enrolled in the study, 3,617 were men and 827 women, 2,223 were randomly assigned a

placebo A placebo ( ) is a substance or treatment which is designed to have no therapeutic value. Common placebos include inert tablets (like sugar pills), inert injections (like Saline (medicine), saline), sham surgery, and other procedures. In general ...

and 2,221 were given 20 to 40 mg of simvastatin daily. The plan was to follow the participants for a minimum of three years or until such a time as total mortality reached 440 deaths. In practice, the study carried for a median period of 5.4 years.

Results

After 5.4 years, compared to the group that were given placebo, the simvastatin group demonstrated a 35% reduction in

LDL-C Low-density lipoprotein (LDL) is one of the five major groups of lipoprotein that transport all fat molecules around the body in extracellular water. These groups, from least dense to most dense, are chylomicrons (aka ULDL by the overall densit ...

and 30% reduction in overall mortality. The risk of hospital-verified non-fatal myocardial infarction reduced by 37% and fatal and non-fatal cerebrovascular events (

stroke A stroke is a medical condition in which poor blood flow to the brain causes cell death. There are two main types of stroke: ischemic, due to lack of blood flow, and hemorrhagic, due to bleeding. Both cause parts of the brain to stop functionin ...

and

TIA TIA or Tia may refer to: Aviation * Tampa International Airport, US, IATA code TPA * Texas International Airlines, US, ICAO code * Tirana International Airport Nënë Tereza, Albania, IATA code * Trans International Airlines, former U.S. airl ...

) lessened by 28%. 30 people would need to be treated with simvastatin to prevent one death;

number needed to treat The number needed to treat (NNT) or number needed to treat for an additional beneficial outcome (NNTB) is an epidemiological measure used in communicating the effectiveness of a health-care intervention, typically a treatment with medication. The ...

around 30. There were no extra deaths from other non-cardiac causes such as

cancer Cancer is a group of diseases involving abnormal cell growth with the potential to invade or spread to other parts of the body. These contrast with benign tumors, which do not spread. Possible signs and symptoms include a lump, abnormal b ...

or trauma. The trial also showed benefits in diabetes, women and older people. A follow-up of treatment with simvastatin for up to eight years was published in 2000. Ten years after the start of the 4S trial, a follow-up study published on 28 August 2004 in ''The Lancet'', revealed that of those 2,221 people who continued to take simvastatin, there was a further reduction in number of deaths from CHD when compared to those who had switched from placebo to statin at the five year mark. The overall mortality also reduced by 15% at the 10 year mark.

Conclusion

The study concluded that

with simvastatin in a high risk group with CHD reduced overall mortality by 30%. Non-fatal CHD events and fatal and non-fatal cerebrovascular events were reduced without an increase in risk of cancer.

Response

Published in ''

'' in 1994, the 4S trial, had an immediate influence on medical opinion, and is considered a "landmark paper". Several other large multicenter clinical trials followed, leading to widespread use of simvastatin. Data from the 4S trial has frequently been used to analyse the cost-effectiveness of simvastatin in secondary prevention.

Objective

Study details

Results

Conclusion

Response

See also

References

Further reading