The Anatomy of a Clinical Trial

Publisher： Karger

E-ISSN： 1423-0151|11|2|17-30

ISSN： 1011-7571

Source： Medical Principles and Practice, Vol.11, Iss.2, 2002-11, pp. : 17-30

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Abstract

Objective: Treatment of hyperlipidemia to reduce the risk of ischemic heart disease was, prior to the statin era, disappointingly limited in its ability to yield the benefits expected from the strong relationship known to exist between serum cholesterol and coronary death. Three primary prevention trials, using clofibrate, cholestyramine and gemfibrozil, had achieved modest reductions in fatal and nonfatal coronary events but none was able to extend life overall or even to reduce cardiovascular mortality; and combined analyses of the three raised disquiet over potential links between cholesterol reduction, cancer and aggressive or violent behaviour. The time was therefore ripe to determine whether statins could help prevent that first and all important myocardial infarction. Methods: The West of Scotland Coronary Prevention Study recruited 6,595 45- to 64-year-old men with no history of prior myocardial infarction and with low-density lipoprotein cholesterol in the range 4–6 mmol/l (155–232 mg/dl). Subjects who had undergone coronary revascularisation or had been hospitalised for angina pectoris in the previous 12 months were excluded, as were those with significant electrocardiographic abnormalities. Participants were randomised to receive pravastatin 40 mg/day or matching placebo and were followed for an average of 4.9 years. Results: Treatment with pravastatin reduced the combined risk of fatal and nonfatal myocardial infarction by 31%. Cardiovascular death overall fell by 32% and the need for coronary revascularisation procedures was reduced by 37%. All of these endpoint benefits were statistically significant. Because there was no increase in non-cardiovascular mortality, the reduction in death from any cause also proved to be statistically significant (p = 0.051 by log rank test and p = 0.037 after adjustment for baseline risk factors). Conclusions: The West of Scotland Coronary Prevention Study is the first to show that cholesterol reduction with pravastatin helps avoid the first myocardial infarction, reduces coronary mortality and extends life. Ongoing exploration of the study database continues to unearth additional surprisingly beneficial effects of the treatment and permits authoritative decision-making on the effective use of lipid-lowering drugs.