Three-year follow-up of the Oxford Cholesterol Study: assessment of the efficacy and safety of simvastatin in preparation for a large mortality study

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.l-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.l-1) and 20 mg daily simvastatin had reduced it by 26.8% +/- 1.0 (1.87 +/- 0.07 mmol.l-1). Almost all of the 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 40 mg and 20 mg 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 differences between the treatment groups in the numbers of patients with significantly elevated levels. A slightly lower platelet count in the simvastatin 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.(ABSTRACT TRUNCATED AT 400 WORDS)

A systematic review and economic evaluation of statins for the prevention of coronary events

“…Studies that were excluded from any meta-analysis of clinical outcomes because they had not published such data in usable form were 4D, for which only preliminary data were available, indicating a nonsignificant reduction in the primary end-point of combined cardiac death, non-fatal MI and stroke, 104 and the Oxford Cholesterol Study, which collected data on the number of patients who suffered all-cause, CHD and other vascular mortality, non-fatal MI and stroke, but only published these data in an interim report which did not attribute such outcomes to treatment groups. 101 Mondillo 2003 did not report any clinical outcomes other than walking distances. 105 Many studies were also too small to show a statistically significant effect in relation to nonfatal outcomes.…”

“…These were the Aronow, Mohler and Mondillo studies in patients with intermittent claudication 21,105,118 and the Oxford Cholesterol Study in patients at increased risk of CHD because of a history of MI, angina pectoris, stroke, TIA, PAD, treated diabetes mellitus or treated hypertension. 101 The Mohler study specifically measured quality of life, using the Short-Form 36 (SF-36); it did not find any significant difference between treatment groups. 21 This study also used the Walking Impairment Questionnaire (WIQ) and the Low Level Physical Activity Recall (LOPAR) questionnaire.…”

“…Thus, three of the four fluvastatin studies (FLARE, FLORIDA, LIPS) used the maximum dose of 80 mg; the LiSA study increased the starting dose of 40 mg to 80 mg 6 weeks after randomisation if the decrease in LDL-C was less than 30%. 93 Similarly, all but two of the pravastatin studies used the maximum dose of 40 mg; in the remaining two (PLAC II and PMSG), the dose could be increased to 40 mg in participants whose LDL-C levels had not responded to the starting dose of 20 mg. 95,96 Three of the simvastatin studies (Aronow 2003, 101 By contrast, the atorvastatin studies generally used doses well below the maximum dose of 80 mg: ASCOT-LLA and CARDS used a fixed dose of 10 mg, 102,103 and the 4D study a fixed dose of 20 mg. 84 Only the small DALI 86 and Mohler 21 studies used an 80-mg dose: each had two treatment arms, one on a fixed dose of 10 mg and the other on 80 mg.…”

Complications of Statin Therapy and Their Management

“…18 Typically with standard doses, little or no effect is seen on gamma glutamyl transferase, alkaline phosphatase and bilirubin. 19 , though a small percentage of patients experience an increase in liver enzymes like alanine and aspartate transaminase. 1 The increases in transaminase are seen within first six months of therapy with statins.…”

Effects of treatment with simvastatin and pravastatin on cognitive function in patients with hypercholesterolaemia.

“…The present results are supported by negative findings in a double-blind, placebo-controlled study of the effects of simvastatin and pravastatin on EEG and subjective sleep parameters in hyperlipidaemic patients [12], and in a double-blind, placebo-controlled study of EEG evoked potentials, mood, sleep and cognitive performance in healthy volunteers receiving a higher dose of simvastatin (40 mg day-) [4]. Also, there were no significant differences between simvastatin and placebo in Profile of Mood States scores in the 600 patient, double-blind, placebo-controlled, Oxford Cholesterol Study [13] (personal communication). On the basis of the current data it is concluded that these two chemically distinct HMG CoA reductase inhibitors, which are both effective in reducing LDL cholesterol, are without substantive effects on cognitive function as assessed by a range of psychometric procedures.…”