Scandinavian Simvastatin Survival Study

Template:Infobox project 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, simvastatin, in people with a moderately raised cholesterol and coronary heart disease (CHD); that is people who had previously had a heart attack or angina. The study was sponsored by the pharmaceutical company Merck and enrolled 4,444 people from 94 centres in Scandinavia.<ref name="Nawarskas">Template:Cite book</ref><ref name="Design1993">Template:Cite journal</ref>

Before the 4S study, it was not proven that lowering cholesterol could prolong life in people who had CHD.<ref name="Aung2012">Template:Cite book</ref> The study concluded that secondary prevention with simvastatin in a high risk group with CHD reduced overall mortality by 30%.<ref name=Aung2012/> Published in The Lancet in 1994, it is considered a "landmark paper".<ref name=Aung2012/><ref name="Reynolds2006">Template:Cite book</ref>

ObjectiveEdit

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.<ref name=Design1993/> The objective of the study was to assess the effect of a cholesterol-lowering drug called simvastatin on mortality and morbidity in people with a history of a previous heart attack or angina, who also had a moderately raised cholesterol; between 5.5 and 8.0 mmol/L.<ref name=Nawarskas/><ref name="Thompson">Template:Cite book</ref><ref name="Scandinavian1994">Template:Cite journal</ref>

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.<ref name=Design1993/>

Study detailsEdit

The participants, all at high risk of death from CHD and death in general,<ref name=Thompson/> 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.<ref name=Design1993/><ref name="Pedersen">Template:Cite journal</ref> Of the 4,444 people enrolled in the study, 3,617 were men and 827 women,<ref name=Thompson/> 2,223 were randomly assigned a placebo and 2,221 were given 20 to 40 mg of simvastatin daily.<ref name="Nawarskas" /> The plan was to follow the participants for a minimum of three years or until such a time as total mortality reached 440 deaths.<ref name=Design1993/><ref name=Thompson/> In practice, the study carried for a median period of 5.4 years.<ref name=Aung2012/>

ResultsEdit

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After 5.4 years, compared to the group that were given placebo, the simvastatin group demonstrated a 35% reduction in LDL-C and 30% reduction in overall mortality.<ref name=Nawarskas/><ref name=Aung2012/> The risk of hospital-verified non-fatal myocardial infarction reduced by 37% and fatal and non-fatal cerebrovascular events (stroke and TIA) lessened by 28%.<ref name=Nawarskas/> 30 people would need to be treated with simvastatin for about five years, to prevent one death; number needed to treat around 30.<ref name=Aung2012/> There were no extra deaths from other non-cardiac causes such as cancer or trauma.<ref name=Aung2012/><ref name=Thompson2009/> The trial also showed benefits in diabetes, women and older people.<ref name=Aung2012/>

A follow-up of treatment with simvastatin for up to eight years was published in 2000.<ref name=Pedersen/> 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.<ref name=Pedersen/><ref name="Medscape">{{#invoke:citation/CS1|citation |CitationClass=web }}</ref> The overall mortality also reduced by 15% at the 10 year mark.<ref name=Aung2012/><ref name=Pedersen/>

ConclusionEdit

The study concluded that secondary prevention 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.<ref name=Aung2012/>

ResponseEdit

Published in The Lancet in 1994, the 4S trial, had an immediate influence on medical opinion,<ref name="Thompson2009">Template:Cite journal</ref> and is considered a "landmark paper".<ref name=Aung2012/><ref name="Reynolds2006" /><ref name="Jameson2015">Template:Cite book</ref> Several other large multicenter clinical trials followed, leading to widespread use of simvastatin.<ref name=Aung2012/>

Data from the 4S trial has frequently been used to analyse the cost-effectiveness of simvastatin in secondary prevention.<ref name="Topol2007">Template:Cite book</ref><ref name="Jönsson">Template:Cite journal</ref>

ReferencesEdit

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