Statins in the 21st century: end of the simple story?

The development of the HMG-CoA reductase inhibitors (the statins) has lead to important advances in the management of cardiovascular disease. There have several landmark mortality and morbidity clinical trials with the statins. The 4S (Scandinavian Simvastatin Survival Study) was the first large-scale randomised cholesterol-lowering trial to show a decrease in mortality. In patients with coronary heart disease and relatively high cholesterol, simvastatin decreased mortality, hospital stays, the risk of undergoing myocardial revascularisation, stroke and transient ischaemic attack. The CARE (Cholesterol and Recurrent Events) trial showed that lowering average cholesterol levels after myocardial infarction with pravastatin reduced a composite primary end point of coronary mortality and myocardial infarction, coronary bypass surgery, angioplasty and strokes. The LIPID (Long-term Intervention with Pravastatin in Ischaaemic Disease) study showed that lowering average cholesterol levels after previous myocardial infarction or unstable angina reduced mortality. WOSCOPS (The West of Scotland Coronary Prevention Study) was the first trial to demonstrate the benefit of pravastatin, as primary prevention for cardiovascular disease, in men with high cholesterol levels. AFCAPS/Tex CAPS (The Air Force/Texas Coronary Atherosclerosis Prevention Study) showed that the benefits of lowering cholesterol levels were also evident in healthy men and women who initially had average cholesterol levels. Rather surprisingly the reductions in mortality and morbidity with statins are only associated with small improvements in coronary angiographic findngs. A preliminary study indicated than lovastatin prevented restenosis, but larger and better-controlled studies indicate that the statins do not have beneficial effects in restenosis. Effects other than lipid-lowering or as a consequence of their lipid-lowering may contribute to the beneficial effects of statins. These effects include improvement in vascular endothelial function, cardiac remodelling, changes in blood rheology, anti-oxidant, anti-inflammatory and antihypertensive actions.