Randomised trial of cholesterol lowering in 4444 patients with coronary heart disease: the Scandinavian Simvastatin Survival Study (4S)

BACKGROUND Lowering the blood cholesterol level may reduce the risk of coronary heart disease. This double-blind study was designed to determine whether the administration of pravastatin to men with hypercholesterolemia and no history of myocardial infarction reduced the combined incidence of nonfatal myocardial infarction and death from coronary heart disease. METHODS We randomly assigned 6595 men, 45 to 64 years of age, with a mean (+/- SD) plasma cholesterol level of 272 +/- 23 mg per deciliter (7.0 +/- 0.6 mmol per liter) to receive pravastatin (40 mg each evening) or placebo. The average follow-up period was 4.9 years. Medical records, electrocardiographic recordings, and the national death registry were used to determine the clinical end points. RESULTS Pravastatin lowered plasma cholesterol levels by 20 percent and low-density-lipoprotein cholesterol levels by 26 percent, whereas there was no change with placebo. There were 248 definite coronary events (specified as nonfatal myocardial infarction or death from coronary heart disease) in the placebo group, and 174 in the pravastatin group (relative reduction in risk with pravastatin, 31 percent; 95 percent confidence interval, 17 to 43 percent; P < 0.001). There were similar reductions in the risk of definite nonfatal myocardial infarctions (31 percent reduction, P < 0.001), death from coronary heart disease (definite cases alone: 28 percent reduction, P = 0.13; definite plus suspected cases: 33 percent reduction, P = 0.042), and death from all cardiovascular causes (32 percent reduction, P = 0.033). There was no excess of deaths from noncardiovascular causes in the pravastatin group. We observed a 22 percent reduction in the risk of death from any cause in the pravastatin group (95 percent confidence interval, 0 to 40 percent; P = 0.051). CONCLUSIONS Treatment with pravastatin significantly reduced the incidence of myocardial infarction and death from cardiovascular causes without adversely affecting the risk of death from noncardiovascular causes in men with moderate hypercholesterolemia and no history of myocardial infarction.

https://www.nejm.org/doi/pdf/10.1056/NEJM199511163332001

Prevention of coronary heart disease with pravastatin in men with hypercholesterolemia. West of Scotland Coronary Prevention Study Group

In a randomized, double-blind five-year trial, we tested the efficacy of simultaneously elevating serum levels of high-density lipoprotein (HDL) cholesterol and lowering levels of non-HDL cholesterol with gemfibrozil in reducing the risk of coronary heart disease in 4081 asymptomatic middle-aged men (40 to 55 years of age) with primary dyslipidemia (non-HDL cholesterol greater than or equal to 200 mg per deciliter [5.2 mmol per liter] in two consecutive pretreatment measurements). One group (2051 men) received 600 mg of gemfibrozil twice daily, and the other (2030 men) received placebo. Gemfibrozil caused a marked increase in HDL cholesterol and persistent reductions in serum levels of total, low-density lipoprotein (LDL), and non-HDL cholesterol and triglycerides. There were minimal changes in serum lipid levels in the placebo group. The cumulative rate of cardiac end points at five years was 27.3 per 1,000 in the gemfibrozil group and 41.4 per 1,000 in the placebo group--a reduction of 34.0 percent in the incidence of coronary heart disease (95 percent confidence interval, 8.2 to 52.6; P less than 0.02; two-tailed test). The decline in incidence in the gemfibrozil group became evident in the second year and continued throughout the study. There was no difference between the groups in the total death rate, nor did the treatment influence the cancer rates. The results are in accord with two previous trials with different pharmacologic agents and indicate that modification of lipoprotein levels with gemfibrozil reduces the incidence of coronary heart disease in men with dyslipidemia.

https://www.nejm.org/doi/pdf/10.1056/NEJM198711123172001?listPDF=true

Helsinki Heart Study: primary-prevention trial with gemfibrozil in middle-aged men with dyslipidemia. Safety of treatment, changes in risk factors, and incidence of coronary heart disease

Aetiology confronts two distinct issues: the determinants of individual cases, and the determinants of incidence rate. If exposure to a necessary agent is homogeneous within a population, then case/control and cohort methods will fail to detect it: they will only identify markers of susceptibility. The corresponding strategies in control are the 'high-risk' approach, which seeks to protect susceptible individuals, and the population approach, which seeks to control the causes of incidence. The two approaches are not usually in competition, but the prior concern should always be to discover and control the causes of incidence.

/pdf/sick-individuals-and-sick-populations-1nnq1p0k8s.pdf

Sick individuals and sick populations

Background Although it is generally accepted that lowering elevated serum levels of low-density lipoprotein (LDL) cholesterol in patients with coronary heart disease is beneficial, there are few data to guide decisions about therapy for patients whose primary lipid abnormality is a low level of high-density lipoprotein (HDL) cholesterol. Methods We conducted a double-blind trial comparing gemfibrozil (1200 mg per day) with placebo in 2531 men with coronary heart disease, an HDL cholesterol level of 40 mg per deciliter (1.0 mmol per liter) or less, and an LDL cholesterol level of 140 mg per deciliter (3.6 mmol per liter) or less. The primary study outcome was nonfatal myocardial infarction or death from coronary causes. Results The median follow-up was 5.1 years. At one year, the mean HDL cholesterol level was 6 percent higher, the mean triglyceride level was 31 percent lower, and the mean total cholesterol level was 4 percent lower in the gemfibrozil group than in the placebo group. LDL cholesterol levels...

https://www.nejm.org/doi/pdf/10.1056/NEJM199908053410604

Gemfibrozil for the Secondary Prevention of Coronary Heart Disease in Men with Low Levels of High-Density Lipoprotein Cholesterol

A double-blind intervention trial was started in 1965 to test the hypothesis that the incidence of ischaemic heart disease in middle-aged men can be reduced by lowering raised serum cholesterol levels. It was carried out in 3 European centres-Edinburgh, Budapest, and Prague. Serum cholesterol was to be lowered by the drug clofibrate (ethyl chlorophenoxyisobutyrate) which was considered to be free from serious side effects. Studies were carried out on 15 745 males, aged 30 to 59 at entry, for an average of 5-3 years, accumulating 83 534 years of experience. The treatment group, of about 5000, Group I, was a randomly chosen half of the men in the upper third of the serum cholesterol distribution in some 30 000 volunteers. The comparable control group, Group II, comprised the other 5000 men of the upper third of the cholesterol distribution, and these were given a placebo. A further control group, Group III, of 5000 men, was selected randomly from the lower third of the cholesterol distribution. These numbers were chosen in order to be 90 per cent certain of detecting a 30 per cent reduction in the incidence of ischaemic heart disease should this occur. Subjects with manifest heart or other major disease were excluded from the trial. No attempt was made to correct other 'risk factors' for IHD, but their presence was monitored and considered in the analysis. Investigators and participants in the trial were unaware of the groups to which individual men belonged. A mean reduction of approximately 9 per cent of the initial serum cholesterol levels was achieved in the treatment group (ranging from 7 to 11% in the 3 centres); this was less than the 15 per cent fall expected. In Edinburgh, during treatment, serum triglyceride concentrations in Group I resembled those naturally occurring in Group III. The incidence ofIHO was lower by 20 per cent in the clofibrate group compared with the high cholesterol controls (P <0.05); this fall was confined to non-fatal myocardial infarcts which were reduced by 25 per cent. The incidence offatal heart attacks was similar in the 2 high cholesterol groups and there was no significant difference in the incidence of angina. Group III showed substantially lower rates of ischaemic heart disease. The reduction of myocardial infarction in the clofibrate-treated group was greatest in men with the highest levels, and greatest reduction in serum cholesterol. Men with a substantial reduction of cholesterol concentration, who smoked, and also had above average blood pressure levels showed the most benefit. The numbers of deaths, and crude mortality rates from all causes in the clofibrate-treated group significantly exceeded those in the high cholesterol control group (P < 0.05), though the age-standardised mortality rates did not differ significantly between the 3 groups. The numbers of deaths from 'other

/pdf/a-co-operative-trial-in-the-primary-prevention-of-ischaemic-3mcmu1qk82.pdf

T. Strasser

Papers

A Co-operative trial in the primary prevention of ischaemic heart disease using clofibrate: Report1 from the Committee of Principal Investigators