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Coronary Heart Disease Prevention in Type II Primary Hyperlipoproteinaemia

The value of a dietary or drug-induced reduction in plasma cholesterol concentration as a preventive measure in coronary heart disease (CHD) has been debated for many years. The inconclusive results of early clinical trials emphasized the practical problems involved in the test of the hypothesis and the inescapability of rigorous attention to study design (Rinzler 1968, Dayton et al. 1969). Although diet is the preferred means of intervention, feasibility studies undertaken in the 1960s by the US National Heart Institute (later to become the National Heart, Lung and Blood Institute NHLBI) demonstrated the impracticality of this approach in the general community (National Diet-Heart Study 1968, NHLBI Task Force on Arteriosclerosis 1971) and attention was focused on drug therapy as an alternative procedure. A clinical trial of cholesterol-lowering drug therapy for prevention of CHD was planned as a major component of the Lipid Research Clinics programme of the NHLBI, along with population and clinical studies which were to prove of value in the trial design. The anion exchange resin cholestyramine was selected for this purpose, since 10 years of clinical experience had established its efficacy and safety in doses of 16 to 24 g/day (Bergen et al. 1959), and an effective placebo was available. In order to provide a reasonable chance of demonstration of therapeutic effect on CHD incidence within 7 years, the trial was restricted to men aged 35-59 years with type II hyperlipoproteinaemia, defined from population data as a serum cholesterol concentration greater than 6.8 mmol/l (264 mg/dl) (Lipid Metabolism Branch of NHLBI 1980). Half the participants received cholestyramine 24 g/day, while the remainder were given a placebo in a random, double-blind manner. The study ran between July 1973 and August 1983. Its findings and implications were presented to the Society's Forum on Lipids in Clinical Medicine on 26 June 1984 by Dr Robert Levy (New York) with commentary by Professor Michael Oliver (Edinburgh). Few men with hypercholesterolaemia, and aware of their high risk of CHD, were expected to accept the 50% probability of prescription of no more than an inert substance for 7 years, especially among those already on a cholesterol-lowering diet. Thus, in an attempt to improve compliance 'Report of meeting of the Forum on Lipids in Clinical Medicine, 31 May 1984. Accepted 10 October 1984 and standardize diet, all men were prescribed a diet estimated to reduce plasma cholesterol by about 4%. A double-blind trial of cholestyramine in type II hyperlipoproteinaemia (Levy et al. 1973) had demonstrated an average 21 % reduction in plasma cholesterol at a dose of 16 g/day (less than used in the prevention trial). Assuming, therefore, 28% and 4% reductions in plasma cholesterol in treatment and control groups respectively, and an instantaneous effect of cholesterol reduction on CHD risk, then from the Framingham Study (Kannel et al. 1971) the respective 7-year incidence rates of non-fatal myocardial infarction and fatal CHD combined (the primary endpoint) were anticipated to be 39/1000 and 87/1000. Neither assumption was recognized as reasonable, however. Non-compliance would reduce the effectiveness of therapy, and the time for treatment to achieve maximum effect (F) would be years rather than days. These problems had been examined by the Biometrics Research Branch of the National Heart Institute, and tables (National Diet-Heart Study 1968, Halperin et al. 1968) were available for allowance for F and non-compliance (assumed in the absence of data to be 3 years and 5% per year respectively). The adjusted incidence rate for the cholestyramine-plus-diet group was 56/1000, and the minimum sample required to provide a 90% chance of demonstration of statistical significance at P=0.01 was estimated to be 3550. With this target in mind, recruitment commenced through physician and laboratory referral. After 9 months, however, only 74 (2%) participants had entered the trial. From then on recruitment was intensified, and the 12 Lipid Research Clinics sought alternative ways to identify candidates. Occupational groups, complete communities and blood banks were screened for eligible men. Advertisements were placed in the media. Mailing lists were employed, and recruitment resources were shared with other major studigs such as the Multiple Risk Factor Intervention Trial. In all, 436 679 age-eligible men responded to this drive, but it is impossible to define the baseline population from which these men were drawn. For example, 23 355 respondents were seen in response to a mailing campaign involving more than 650000 letters. Another 113000 men were obtained from 19 blood banks with an estimated turnover of more than 240000 per year. Community screening in Iowa achieved a 25% response yielding a further 12000 potential participants.