Creatinine 90.47 (μmol/l) (10.74) Alkaline phosphatase 90.40 91.82 93.39 94.35 SD in parentheses "Gall bladder disease or gallstones that required hospitalization. Ulcer that required hospitalization. "Cholecystectomies for gallstones. "Both groups of diagnoses are partially based on patient history without objective documentation (X-ray, ultrasound). 60 Discussion Helsinki Heart Study Ethical Committee In the two recent large primary prevention trials which have demonstrated beneficial effect of cholesterol regulation in CHD incidence (the WHO trial and the LRC-CPPT) the issue of safety has been very important, especially with respect to the WHO investigation. In that study there were significantly (28 per cent) more deaths from all causes in the clofibrate group than in the high cholesterol control group, both during the trial and in the 4-year post-trial follow up (Committee of Principal Investigators 1978, 1980). The significant excess of deaths (35) was due to a group of non-cardiovascular diseases, most notably diseases of the liver, gall bladder and small and large intestines. While the treatment groups did not differ significantly with regard to cancer mortality or morbidity, the rates were higher for the clofibrate group. There was also a significant (more than two-fold) excess of cholecystectomies in the clofibrate group and gastrointestinal side-effects and diarrhoea were reported significantly more often among the clofibrate-treated patients. In the LRC-CPPT both study groups were similar with respect to the incidence of mortality from all causes. The incidences of fatal and non-fatal malignant neoplasms were also similar. However, various cancers of the gastro-intestinal tract were somewhat more prevalent in the cholestyramine group. There was a greater incidence of hospitalizations and of surgery and procedures relating to the nervous system in the treated group. In overall reasons for hospitalizations there was no difference between cholestyramine and control treatment, nor was there any excess of gall bladder disease or cholecystectomy in the cholestyramine group. Table 9 presents a comparison of the three primary prevention studies on the basis of several safety parameters. After an average of 3.8 years of study experience, the overall mortality among those subjects taking either medication in the Helsinki Heart Study is 1.2 per cent. This figure is only half the projected rate of 2-4 per cent which is based on 1981 mortality figures for the same age group in Finland (Central Statistical Office of Finland 1983). There has been no significant excess in the incidence of malignant neoplasms, gall bladder disease, cholecystectomies, or diseases of the liver or small and large intestines (Table 4). In both the WHO trial and the LRC-CPPT, the incidence for the active treatment group was greater than for the respective control. However in the Helsinki Heart Study, levels of these complaints in the active treatment group and control are virtually identical. As in both the previous trials, there was no significant overall excess of hospitalization or surgery in either group in the HHS. In addition, however, unlike the cholestyramine group in the LRC-CPPT, neither group in the HHS showed any significant excess in the number of hospitalizations relating to the respiratory system or of surgical procedures involving the nervous system. Nor was there any greater incidence of cancers of the gastro-intestinal tract. Overall, the Helsinki Heart Study to date has demonstrated that the medications involved, which include gemfibrozil and placebo, are safe. At this stage of the study the differences appear to favour gemfibrozil over both clofibrate and cholestyramine results. Whilst minor increases in side-effects might be anticipated because of the additional period that the study has to run, there is no reason to anticipate that these comparative findings will have changed by the time that the Helsinki Heart Study is completed. References Central Statistical Office of Finland (1983). Causes of Death in Finland. VIB: 136 Helsinki. Helsinki Heart Study Interim Report 61 Committee of Principal Investigators, WHO Clofibrate Trial. (1978). WHO cooperative trial on primary prevention of ischaemic heart disease using clofibrate. British Heart Journal 40, 1069-1118. Committee of Principal Investigators, WHO Clofibrate Trial (1980). WHO cooperative trial on primary prevention of ischaemic heart disease using clofibrate to lower serum cholesterol: mortality follow-up. Lancet 2, 379–385. Kaplan, E. L. and Meier, P. (1958). Nonparametric estimation from incomplete observations. Journal of the American Statistical Association 53, 457-481. Lipid Research Clinics Program (1984). The Lipid Research Clinics Coronary Primary Prevention Trial Results. I. Reduction in the incidence of coronary heart disease. II. The relationship of reduction in incidence of coronary heart disease to cholesterol lowering. Journal of the American Medical Association 251, 351-364 and 365-374. Manninen, V. (1983). Clinical results with gemfibrozil and background to the Helsinki Heart Study. American Journal of Cardiology 52, 35B-38B. Manninen, V., Mänttäri, M., Nikkilä, E. A. and Gorringe, J. A. L. (1982). Helsinki Heart Study. Research and Clinical Forums 4(2), 9-20. Mänttäri, M. (1984). Helsinki Heart Study. Baseline characteristics and feasibility of the intervention program. Academic Dissertation, University of Helsinki. This is in response to your letter regarding S. 1200, the Process As you know, as a component of the Department of Health and Human |