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Stroke is a major cause of mortality and morbidity. The epidemiologic association between elevated serum cholesterol and stroke risk is controversial. However, recent secondary prevention studies with 3-hydroxy-3-methylglutaryl coenzyme A reductase inhibitors (statins) have demonstrated a significant reduction in ischemic stroke without an increase in hemorrhagic stroke. Statins probably reduce stroke by a variety of mechanisms, including modulation of precerebral atherothrombosis in the aorta and the carotid artery, thus preventing plaque disruption and artery-to-artery thromboembolism. Statins also improve endothelial homeostasis by increasing the bioavailability of nitric oxide, which orchestrates the paracrine antiatherosclerotic functions of the endothelium. Studies in experimental models of ischemic stroke show that statin therapy reduces brain infarct size and improves neurologic outcome by directly upregulating brain endothelial nitric oxide synthase. Putative anti-inflammatory actions of statins may also contribute to neuroprotection and stroke prevention. Although the clinical benefit of statins largely depends on lowering low-density lipoprotein cholesterol, accumulating data indicate that many of the pleiotropic effects of statins are attributable to the cellular consequences of depletion of intermediates in the cholesterol biosynthetic pathway (isoprenoids). These molecules play fundamental roles in cell growth, signal transduction, and mitogenesis. In addition to reducing stroke risk, emerging data suggest that statins may reduce dementia. Further studies are needed to fully address the role of statins in the prevention of stroke in patients without established vascular disease and the role of cholesterol modulation in the treatment of dementia. [ABSTRACT FROM AUTHOR]

Multiple randomized controlled trials (RCTs) have established the efficacy of statins for the prevention of cardiovascular disease. The benefits observed are often framed in terms of percentage reductions in low-density lipoprotein (LDL) cholesterol from baseline or percentage reductions between control and treatment groups, although epidemiologic data suggest that the absolute intergroup difference in LDL cholesterol (ΔLDLControl-Rx) is the more informative measure. A systematic review of large-scale trials of statins versus placebo, usual care, or active (lower dose statin) control was conducted to calculate updated summary estimates of risk reduction in coronary artery disease and all-cause mortality. Meta–regression analysis was used to ascertain the relations of different LDL cholesterol metrics to outcomes. In 20 eligible RCTs, there were significant overall reductions for coronary artery disease (odds ratio 0.72, 95% confidence interval 0.67 to 0.78) and mortality (odds ratio 0.89, 95% confidence interval 0.84 to 0.94), but with substantial variability in trial results. ΔLDLControl-Rx was the strongest determinant of coronary artery disease risk reduction, particularly after excluding active-comparator studies, and was independent of baseline LDL cholesterol. In contrast, baseline LDL cholesterol edged out ΔLDLControl-Rx as the strongest determinant of mortality, but neither was significant after the exclusion of active-comparator studies. The exclusion of 3 RCTs involving distinct populations, however, rendered ΔLDLControl-Rx the predominant determinant of mortality reduction. In conclusion, these findings underscore the primacy of absolute reductions in LDL cholesterol in the design and interpretation of RCTs of lipid-lowering therapies and in framing treatment recommendations on the basis of the proved coronary benefits of these drugs. [Copyright &y& Elsevier]