Scandinavian Simvastatin Survival Study

Scandinavian Simvastatin Survival Study
Scandinavian Simvastatin Survival Study
	Simvastatin 3D
Type of project	Multicenter clinical trial
Country	Scandinavian countries
Established	1990s
Disestablished	1990s
Funding	Merck
Status	Completed

Last updated January 20, 2025

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.^[1]^[2]

Before the 4S study, it was not proven that lowering cholesterol could prolong life in people who had CHD.^[3] The study concluded that secondary prevention with simvastatin in a high risk group with CHD reduced overall mortality by 30%.^[3] Published in The Lancet in 1994, it is considered a "landmark paper".^[3]^[4]

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.^[2] 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.^[1]^[5]^[6]

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.^[2]

Study details

The participants, all at high risk of death from CHD and death in general,^[5] 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.^[2]^[7] Of the 4,444 people enrolled in the study, 3,617 were men and 827 women,^[5] 2,223 were randomly assigned a placebo and 2,221 were given 20 to 40 mg of simvastatin daily.^[1] The plan was to follow the participants for a minimum of three years or until such a time as total mortality reached 440 deaths.^[2]^[5] In practice, the study carried for a median period of 5.4 years.^[3]

Results

Atheroma blocking an artery lumen Atheroma.jpg — Atheroma blocking an artery lumen

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.^[1]^[3] 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%.^[1] 30 people would need to be treated with simvastatin for about five years, to prevent one death; number needed to treat around 30.^[3] There were no extra deaths from other non-cardiac causes such as cancer or trauma.^[3]^[9] The trial also showed benefits in diabetes, women and older people.^[3]

A follow-up of treatment with simvastatin for up to eight years was published in 2000.^[7] 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.^[7]^[10] The overall mortality also reduced by 15% at the 10 year mark.^[3]^[7]

Conclusion

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.^[3]

Response

Published in The Lancet in 1994, the 4S trial, had an immediate influence on medical opinion,^[9] and is considered a "landmark paper".^[3]^[4]^[11] Several other large multicenter clinical trials followed, leading to widespread use of simvastatin.^[3]

Data from the 4S trial has frequently been used to analyse the cost-effectiveness of simvastatin in secondary prevention.^[12]^[13]

Related Research Articles

Coronary artery disease (CAD), also called coronary heart disease (CHD), or ischemic heart disease (IHD), is a type of heart disease involving the reduction of blood flow to the cardiac muscle due to a build-up of atheromatous plaque in the arteries of the heart. It is the most common of the cardiovascular diseases. CAD can cause stable angina, unstable angina, myocardial ischemia, and myocardial infarction.

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

<span class="mw-page-title-main">Heart Protection Study</span>

The Heart Protection Study was a randomized controlled trial run by the Clinical Trial Service Unit, and funded by the Medical Research Council (MRC) and the British Heart Foundation (BHF) in the United Kingdom. It studied the use of the cholesterol lowering drug, simvastatin 40 mg and vitamin supplementation in people who were at risk of cardiovascular disease. It was led by Jane Armitage, an epidemiologist at the Clinical Trial Service Unit.

<span class="mw-page-title-main">Atorvastatin</span> Cholesterol-lowering medication

Atorvastatin is a statin medication used to prevent cardiovascular disease in those at high risk and to treat abnormal lipid levels. For the prevention of cardiovascular disease, statins are a first-line treatment. It is taken by mouth.

<span class="mw-page-title-main">Simvastatin</span> Lipid-lowering medication

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 heart problems in those at high risk. It is taken by mouth.

<span class="mw-page-title-main">Fluvastatin</span> Chemical compound

Fluvastatin is a member of the statin drug class, used to treat hypercholesterolemia and to prevent cardiovascular disease.

Coronary thrombosis is defined as the formation of a blood clot inside a blood vessel of the heart. This blood clot may then restrict blood flow within the heart, leading to heart tissue damage, or a myocardial infarction, also known as a heart attack.

Acute coronary syndrome (ACS) is a syndrome due to decreased blood flow in the coronary arteries such that part of the heart muscle is unable to function properly or dies. The most common symptom is centrally located pressure-like chest pain, often radiating to the left shoulder or angle of the jaw, and associated with nausea and sweating. Many people with acute coronary syndromes present with symptoms other than chest pain, particularly women, older people, and people with diabetes mellitus.

A myocardial infarction (MI), commonly known as a heart attack, occurs when blood flow decreases or stops in one of the coronary arteries of the heart, causing infarction to the heart muscle. The most common symptom is retrosternal chest pain or discomfort that classically radiates to the left shoulder, arm, or jaw. The pain may occasionally feel like heartburn. This is the dangerous type of Acute coronary syndrome.

<span class="mw-page-title-main">Dalcetrapib</span> Chemical compound

DalCor is currently conducting the Dal-GenE-2 confirmatory trial with dalcetrapib and placebo in North America under a Special Protocol Assessment (SPA) agreement with the U.S. Food and Drug Administration (FDA).

The JUPITER trial was a clinical trial aimed at evaluating whether statins reduce heart attacks and strokes in people with normal cholesterol levels.

Polycap is a specific five-in-one fixed dose combination polypill created by Cadila Pharmaceuticals Limited of Ahmedabad, India that combines moderate levels of five different medications in a single, one-a-day pill aimed at reducing/preventing heart attacks and strokes.

Reperfusion therapy is a medical treatment to restore blood flow, either through or around, blocked arteries, typically after a heart attack. Reperfusion therapy includes drugs and surgery. The drugs are thrombolytics and fibrinolytics used in a process called thrombolysis. Surgeries performed may be minimally-invasive endovascular procedures such as a percutaneous coronary intervention (PCI), which involves coronary angioplasty. The angioplasty uses the insertion of a balloon and/or stents to open up the artery. Other surgeries performed are the more invasive bypass surgeries that graft arteries around blockages.

Management of acute coronary syndrome is targeted against the effects of reduced blood flow to the affected area of the heart muscle, usually because of a blood clot in one of the coronary arteries, the vessels that supply oxygenated blood to the myocardium. This is achieved with urgent hospitalization and medical therapy, including drugs that relieve chest pain and reduce the size of the infarct, and drugs that inhibit clot formation; for a subset of patients invasive measures are also employed. Basic principles of management are the same for all types of acute coronary syndrome. However, some important aspects of treatment depend on the presence or absence of elevation of the ST segment on the electrocardiogram, which classifies cases upon presentation to either ST segment elevation myocardial infarction (STEMI) or non-ST elevation acute coronary syndrome (NST-ACS); the latter includes unstable angina and non-ST elevation myocardial infarction (NSTEMI). Treatment is generally more aggressive for STEMI patients, and reperfusion therapy is more often reserved for them. Long-term therapy is necessary for prevention of recurrent events and complications.

The HDL-Atherosclerosis Treatment Study, also known as HATS, was a three-year double-blind trial involving 160 people with coronary heart disease (CHD) who had a low HDL and near normal LDL. The study compared a combination of simvastatin and niacin with antioxidant vitamin therapy. Using angiography, coronary artery stenosis progressed when using placebo or antioxidant alone, and regressed with the combination of simvastatin and niacin. The study demonstrated a 90% reduction in CHD death, nonfatal heart attacks, stroke, or revascularization for worsening angina. It was published in 2001.

The West of Scotland Coronary Prevention Study was a landmark randomized controlled trial, published in 1995, that investigated the effects of pravastatin, a cholesterol-lowering drug, on primary prevention of coronary heart disease (CHD) in men with hypercholesterolemia. Conducted in the early 1990s, this study provided critical evidence on the benefits of statins in reducing cardiovascular events in individuals without a history of CHD. It concluded that statin treatment reduced CHD events by 31% after nearly five years of treatment.

The Pravastatin or Atorvastatin Evaluation and Infection Therapy–Thrombolysis in Myocardial Infarction 22 trial, also known as PROVE-IT TIMI 22, was a randomized, double-blind, clinical trial that recruited 4,162 people admitted within 10 days of an acute coronary event and randomised them to the lipid-lowering drugs pravastatin (40 mg) or atorvastatin (80 mg) and a 10-day course of the antibiotic gatifloxacin or placebo. The participants enrolled at 349 sites across Australia, Europe, and North America between November 2000 and December 2001, and the study concluded that statin treatment for secondary prevention reduced coronary heart disease (CHD) events and that atorvastatin had a more marked effect than pravastatin. The study was published in The New England Journal of Medicine and reported at the American College of Cardiology Annual Scientific Session in 2004.

Atherothrombosis Intervention in Metabolic Syndrome with Low HDL/High Triglycerides: Impact on Global Health Outcomes was a randomized control trial designed to assess the efficacy of niacin (extended-release) added to statin therapy in reducing cardiovascular events in patients with established atherosclerotic cardiovascular disease (ASCVD). These patients had well-controlled low-density lipoprotein (LDL) cholesterol but persistently low high-density lipoprotein (HDL) cholesterol and elevated triglycerides. 3,414 patients with established ASCVD were enrolled. The mean follow-up period was three years. The trial was stopped early due to a lack of efficacy and a trend towards an increase in the incidence of ischemic stroke.

References

1 2 3 4 5 Frishman, William H.; Cheng-Lai, Angela; Nawarskas, James (2005). "11. Lipd-lowering drugs". Current Cardiovascular Drugs. Springer Science & Business Media. p. 307. ISBN 1-57340-221-4.
1 2 3 4 5 "Design and baseline results of the Scandinavian Simvastatin Survival Study of patients with stable angina and/or previous myocardial infarction". The American Journal of Cardiology . 71 (5): 393–400. 15 February 1993. doi:10.1016/0002-9149(93)90438-i. ISSN 0002-9149. PMID 8430625.
1 2 3 4 5 6 7 8 9 10 11 12 Myat, Aung; Gershlick, A. H.; Gershlick, Tony (2012). Landmark Papers in Cardiovascular Medicine. Oxford University Press. p. 31. ISBN 978-0-19-959476-4.
1 2 Reynolds, L. A.; Tansey, E. M., eds. (2006). Cholesterol, atherosclerosis and coronary disease in the UK, 1950–2000; Wellcome Witnesses to Twentieth Century Medicine (PDF). Vol. 27. London: Wellcome Trust Centre for the History of Medicine at UCL. ISBN 978-085484-107-3.
1 2 3 4 Thompson, Andrew; Shergill, Iqbal S.; Temple, N. (2011). Ethics, Medical Research, and Medicine: Commercialism versus Environmentalism and Social Justice. Springer Science & Business Media. ISBN 978-94-010-0794-8.
↑ Scandinavian Simvastatin Survival Study Group (19 November 1994). "Randomised trial of cholesterol lowering in 4444 patients with coronary heart disease: the Scandinavian Simvastatin Survival Study (4S)". The Lancet . 344 (8934): 1383–1389. doi:10.1016/S0140-6736(94)90566-5. ISSN 0140-6736. PMID 7968073. S2CID 5965882.
1 2 3 4 Pedersen, Terje R.; Wilhelmsen, Lars; Færgeman, Ole; Strandberg, Timo E.; Thorgeirsson, Gudmundur; Troedsson, Linda; Kristianson, Johan; Berg, Kåre; Cook, Thomas J.; Haghfelt, Torben; Kjekshus, John (1 August 2000). "Follow-up study of patients randomized in the scandinavian simvastatin survival study (4S) of cholesterol lowering". The American Journal of Cardiology. 86 (3): 257–262. doi:10.1016/S0002-9149(00)00910-3. ISSN 0002-9149. PMID 10922429.
↑ "Atheroma". Scientific Animations. Retrieved 7 April 2020.
1 2 Thompson, G. R. (1 February 2009). "History of the cholesterol controversy in Britain". QJM: An International Journal of Medicine. 102 (2): 81–86. doi:10.1093/qjmed/hcn158. ISSN 1460-2725. PMID 19042967.
↑ Wood, Shelley (27 August 2004). "Ten-year outcomes from 4S study" . Medscape. Retrieved 2 April 2020.
↑ Jameson, J. Larry; Groot, Leslie J. De (2015). Endocrinology: Adult and Pediatric. Elsevier Health Sciences. p. 730. ISBN 978-0-323-32195-2.
↑ Topol, Eric J.; Califf, Robert M. (2007). Textbook of Cardiovascular Medicine. Lippincott Williams & Wilkins. p. 752. ISBN 978-0-7817-7012-5.
↑ Jönsson, B.; Johannesson, M.; Kjekshus, J.; Olsson, A. G.; Pedersen, T. R.; Wedel, H. (July 1996). "Cost-effectiveness of cholesterol lowering. Results from the Scandinavian Simvastatin Survival Study (4S)". European Heart Journal . 17 (7): 1001–1007. doi: 10.1093/oxfordjournals.eurheartj.a014994 . ISSN 0195-668X. PMID 8809516.