WHO Cooperative Clofibrate Trial
Type Diet/Drug (Stage): rug (1º)
Study Category: The Prevention Trials (1946-1973)
Year Begun: 1962
Location: Edinburgh, Prague, and Budapest
Principal Investigator(s): Committee of Principal Investigators (M. Oliver Chairman)
External Resource: View URL
This classic early WHO trial beginning in 1962 evaluated clofibrate use for the primary prevention of ischemic heart disease in hypercholesterolemic men. The effectiveness of clofibrate in reducing hypercholesterolaemia and hypertriglyceridaemia was already shown but not whether it would reduce the incidence of ischemic heart disease and mortality. The study was designed to last five years but was extended because of the excess early mortality and became a study of the long-term effects of clofibrate, with an average follow-up of 13.2 years.
The study population included men age 30-59 from Edinburgh, Prague and Budapest. The subjects were selected based on a preliminary determination of serum cholesterol in the upper third of the distribution of cholesterol. Subjects were randomly split into a control group, which received olive oil capsules, and a treatment group, which received 1.6 grams of clofibrate. A second control group was chosen from the lowest third of the distribution of cholesterol, which also received olive oil capsules. 15,745 subjects were admitted to the trial and 10,703 completed the first 5 years. The subjects were examined in 6-month intervals for the first 2 years and every year for the following 3 years. After the first five-year period, the study population was followed to ascertain causes and rate of death. In the 2-year follow-up examinations, the men were asked about changes in habits, about adherence to the drug therapy, and about symptoms or side affects. If chest pain was mentioned, men had an ECG to check for myocardial infarction. Blood was also taken to check lipid levels as well as adherence to the drug regimen. Between annuals, at 6th month intervals, a postal questionnaire was sent.
After the first five years the results showed 25% more all-cause deaths in the clofibrate-treated group than in the control group. This result led the researchers to continue the follow-up, however the drug was only used for the first five years. In 1984, the results after the second follow-up, with average 13.2 years participation, revealed that mortality risks in the treatment group and the control group were equalizing. For the whole study the treatment group now had 11% more all-cause deaths than the control group (II) compared to the 25% found after the first five years. Measuring only deaths from IHD (Ischemic Heart Disease), there was no excess mortality for the treatment group, but after drug treatment ended both the control group and the treatment group saw an increase in IHD mortality.
This early study of cholesterol lowering with clofibrate showed no reduction in mortality from IHD, but a reduction in the number of non-fatal myocardial infarctions. The increased all-cause death rate during clofibrate treatment did not continue after treatment was stopped. (FB/HB)
Committee of Principal Investigators. “A cooperative trial in the prevention of ischemic heart disease using clofibrate.” (1978) Br Heart J, 40:1069-1118.
Heady, J.A. “A cooperative trial on the primary prevention of ischemic heart disease using clofibrate: design, methods, and progress.” (1973) Bull WHO, 48: 243-256.
Committee of Principal Investigators. “WHO cooperative trial on primary prevention of ischemic heart disease with clofibrate to lower serum cholesterol: final mortality follow-up.” (1984) The Lancet, 2(8403): 600-604.