Copyright © 1994 by the European Society of Cardiology.
© 1994 The European Society of Cardiology
Three-year follow-up of the Oxford Cholesterol Study: assessment of the efficacy and safety of simvastatin in preparation for a large mortality study
*MRC/ICRF Clinical Trial Service Unit, Nuffield Department of Clinical Medicine Radcliffe Infirmary, Oxford
Department of Cardiology John Radcliffe Hospital, Oxford
Department of Chemical Pathology and Metabolic Disorders St Thomas' Hospital, London, U.K.
Received 20 July 1993; revised 30 September 1993; .
Coresspondence: Oxford Cholesterol Study, MRC/ICRF Clinical Trial Service Unit, Harkneas Building, Radcliffe Infinnary, Oxford OX2 6HE, U.K.
Abstract
We report the results of a randomized single-centre study designed to assess the effects of simvastatin on blood lipids, blood biochemistry, haematology and other measures of safety and tolerability in preparation for a large-scale multicentre mortality study. Six hundred and twenty-one individuals considered to be at increased risk of coronary heart disease were randomized, following a 2-month placebo ‘run-in’ period, to receive 40 mg daily simvastatin, 20 mg daily simvastatin or matching placebo. Their mean age was 63 years, 85% were male, 62% had a history of prior myocardial infarction (MI), and the mean baseline total cholesterol was 7·0 mmol. 1–1. Median follow-up in the present report is 3·4 years.
Eight weeks after randomization, 40 mg daily simvastatin had reduced non-fasting total cholesterol by 29·2% ± 1·1 (2·03 ± 0·08 mmol. 1–1)and 20 mg daily simvastatin had reduced it by 26·8% ± 1·0 (1·87 ± 0·07 mmol. 1–1). Almost all of tile difference in total cholesterol at 8 weeks was due to the reduction in LDL cholesterol (40·8±1·6 and 38·2%±1·4 among patients allocated 40mg and 20mg of simvastatin daily respectively), but simvastatin also reduced triglycerides substantially (19·0% and 17·3%) and produced a small increase in HDL cholesterol (6·4% and 4·8%). These effects were largely sustained over the next 3 years, with 40 mg daily simvastatin producing a slightly greater reduction in total cholesterol at 3 years (25·7%±1·9 reduction) than did 20 mg daily simvastatin (22·2%±1·8).
There were no differences between the treatment groups in the numbers of reports of ‘possible adverse effects’ of treatment or of a range of different symptoms or conditions (including those related to sleep or mood) recorded at regular clinic follow-up. Mean levels of alanine aminotransferase, aspartate aminotransferase and creatine kinase were slightly increased by treatment, but there were no significant difference between the treatment groups in the numbers of patients with significantly elevated levels. A slightly lower platelet count in the simvasatin group was the only haematological difference from placebo, with no difference in the numbers of patients with low platelet counts.
In summary, the simvastatin regimens studied produced large sustained reductions in total cholesterol, LDL cholesterol and triglyceride and small increases in HDL cholesterol. They were well tolerated, with no evidence of serious side-effects during the first 3 years of this study. Consequently, simvastatin provides an opportunity to conduct large randomized studies that assess the effects of cholesterol lowering on total mortality and on cause-spec mortality. Even with such an effective cholesterol lowering treatment, however such mortality studies will still need to be prolonged and to involve some tens of thousands of patients at substantial risk of coronary heart disease if clear evidence is to emerge.
Key Words: Cholesterol lowering • simvastatin • randomized trial
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