Title

a. Randomized trial of cholesterol lowering in 4444 patients with coronary heart disease: The Scandinavian Simvastatin Survival Study (4S)
b. Baseline serum cholesterol and treatment effect in the Scandinavian Simvastatin Survival Study (4S).
c. Reducing the risk of coronary events: evidence from the Scandinavian Simvastatin Survival Study (4S).
d. Cholesterol lowering therapy in women and elderly patients with myocardial infarction or angina pectoris.
Findings from the Scandinavian Simvastatin Survival Trial (4S).
e. Cost effectiveness of simvastatin treatment to lower cholesterol levels in patients with coronary heart disease.
f. Lipoprotein changes and reduction in the incidence of major coronary heart disease events in the Scandinavian
Simvastatin Survival Study (4S).
g. Effect of simvastatin on ischemic signs and symptoms in the Scandinavian Simvastatin Survival Study (4S)

Purpose

• To assess the effect of simvastatin therapy on mortality and morbidity of patients with coronary artery disease and
serum cholesterol 5.5-8.0 mmol/L.
• To determine the cost effectiveness of lowering cholesterol in relationship to age, sex, and the cholesterol level from the
4S study.
• To determine which baseline lipoproteins are predictive of coronary events.
• To determine which changes in lipoproteins accounted for the reduction in coronary events in the 4S.
• To determine effect of lipid intervention with simvastatin on noncoronary ischemic symptoms and signs over 5.4 years

Design

Randomized, double blind, placebo controlled, multicenter.

Patients

4444 patients, aged 35-70 years, with a history of angina pectoris or myocardial infarction, and serum cholesterol 5.5-8.0 mmol/L, (213-309 mg per deciliter) and serum triglyceride £ 2.5 mmol/L were included. Premenopausal women, patients with secondary hypercholesterolemia, patients with myocardial infarction within 6 months, congestive heart failure, planned coronary artery surgery, or angioplasty were excluded.

Follow-up

Clinical follow-up for 4.9-6.3 years (median 5.4 years)

Treatment regimen

Simvastatin 20 mg/d or placebo. If serum cholesterol did not reach the target range of 3.0-5.2 mmol/L by simvastatin 20 mg/d, the dose was increased to 40 mg/d. If necessary, dose was decreased to 10 mg/d.

Additional therapy

Dietary advice

Results

• Lipid concentrations changed only little in the placebo group, whereas simvastatin resulted in - 25%, -35%, +8%, and
-10% change from baseline of total, LDL, and HDL cholesterol, and triglycerides.
• After 1 year, 72% of the simvastatin group had achieved total cholesterol < 5.2 mmol/L.
• During the follow-up, mortality was 12% in the placebo and 8% in the simvastatin group (RR 0.70, p=0.0003).
• Coronary mortality was 8.5% vs 5.0%, respectively (RR 0.58).
• 28% of the placebo and 19% of the simvastatin group had 1 or more major coronary events (coronary death, myocardial
infarction, or resuscitated cardiac arrest (RR 0.66, p<0.00001).
• The relative risk of having any coronary event in the simvastatin group was 0.73 (p < 0.00001).
• Simvastatin also reduced the risk of undergoing coronary artery bypass surgery or angioplasty (RR 0.63, p < 0.00001).
The overall rates of adverse effects were not different between the groups.
• Simvastatin significantly reduced the risk of major coronary events in all quartiles of baseline total, HDL, and LDL cholesterol, by a similar amount in each quartile.
• A recent post hoc analysis showed that patients ³ 65 years of age who received simvastatin had a reduced relative risk (RR) for clinical events. The RRs (95% confidence intervals) were 0.66 (0.40-0.90) for all cause mortality; 0.57
(0.39-0.83) for coronary heart disease mortality; and 0.66 (0.52-0.84) for major coronary events. The RR was also reduced for any atherosclerotic related events and revascularization procedures. In women the RRs were 1.16 (0.68- 1.99), 0.86 (0.42-1.74), and 066 (0.48-0.91) for all cause mortality, coronary heart disease mortality, and major coronary events. Any atherosclerotic related event and revascularization procedures also were reduced in women on
simvastatin.
• The cost of each year of life gained ranged from $ 3,800 for 70 year old men with cholesterol levels of 309 mg/dL to $ 27,400 for 35 year old women with 213 mg/dL. With indirect costs included, the costs ranged from youngest patients exhibiting a savings in money while 70 year old women with 213 cholesterol levels cost $ 13,300 per year of life gained.
• Simvastatin reduced cholesterol by 25% and LDL cholesterol by 34%. Three fourths of patients on simvastatin had reduction of LDL cholesterol by 30%; a quarter had reduction by > 45%. Reduction in coronary events on simvastatin correlated with on-treatment levels and changes in total, LDL cholesterol, and apolipoprotein B. There
was less of a correlation with triglyceride levels. Each 1% reduction in LDL cholesterol reduced coronary risk by 1.7%. There was no evidence for any % reduction or on-treatment threshold below which further reduction of LDL cholesterol did not have benefit.
• Risk of claudication, bruits, and angina were decreased by simvastatin. The risk of new or worsening carotid bruits was significantly decreased. Fatal plus nonfatal cerebral events (stroke or transient ischemic attacks) was reduced by 28% with simvastatin. New or worsening intermittent claudication was decreased by 38% with the statin; new or worsening angina was decreased by 26%.

Conclusion

• Long term therapy with simvastatin is safe and effective in improvement of survival and reduction of the rate of
coronary events.
• Simvastatin produced similar reductions in relative risk for major coronary events in women vs men and in elderly vs
younger patients.
• In patients with coronary artery disease, simvastatin is cost effective.
• The beneficial effect of simvastatin on major coronary events was dependent upon the magnitude of reduction in LDL
cholesterol, without a threshold below which reduction was no longer beneficial.
• Cholesterol lowering with simvastatin 20-40 mg/day retards progression of atherosclerosis throughout the vascular
system.