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HMG-CoA Reductase Inhibitors

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HMG-CoA Reductase Inhibitors
Hypertension, age, smoking, obesity and diabetes mellitus are risk factors for both stroke and cardiovascular disease. Although hypercholesterolaemia is a characteristic risk factor for cardiovascular disease, there appears to be only a weak correlation between elevated serum cholesterol levels and stroke. Results from clinical trials are equivocal; a number of studies report an association between cholesterol levels and ischaemic stroke but this is not supported by other clinical trials. HMG-CoA reductase inhibitors (statins) have proven effective in preventing cardiovascular disease. Despite there being no firm correlation between cholesterol levels and stroke risk, these agents have also been associated with a reduction in nonfatal strokes.

It is important to note that these positive results have been obtained in middle-aged patients with ischaemic heart disease (IHD). Therefore it has been hypothesised that the beneficial effects of HMG-CoA reductase inhibitors may be related to a beneficial cholesterol lowering effect on the carotid or coronary vasculature. Alternatively, it is possible that HMG-CoA reductase inhibitors may act via cholesterol independent effects on the cerebral vasculature. The role of HMG-CoA reductase inhibitors in elderly patients, among whom stroke occurs most frequently, remains to be defined.

Stroke and cardiovascular disease share similar risk factors including hypertension, smoking, obesity, diabetes mellitus and age. This adds weight to the viewpoint that atherosclerosis is an important factor in the pathogenesis of stroke. Hypertension, the most important risk factor for stroke, is linked more to haemorrhagic than to ischaemic stroke. Lowering of either systolic or diastolic blood pressure has been shown to reduce the risk of stroke in a number of clinical trials. Reducing raised systolic blood pressure in the elderly is as effective on the incidence of stroke as treating hypertension in middle-aged people. In contrast with cardiovascular disease, males and females are equally at risk of having a stroke and are at least 10 years older when the event occurs. In addition, increasing blood pressure is more strongly linked with the incidence of stroke and increasing cholesterol levels are less so. Interestingly, approximately one-third of patients with ischaemic stroke have clinical signs of cardiovascular disease [i.e. angina pectoris or a history of myocardial infarction (MI)]. Conversely, patients with a history of MI have a 2.5 times greater risk of stroke than healthy controls.

The association between hypercholesterolaemia and the development of both haemorrhagic and ischaemic stroke is unclear and the results of clinical studies are equivocal. While a number of clinical trials demonstrate an association between cholesterol and ischaemic stroke this association is not confirmed by other studies (see table 1).

No association between serum cholesterol levels and the incidence of stroke was reported in a meta-analysis of 45 prospective cohort studies which included 13 000 strokes. However, inconsistencies in distinguishing between the various subtypes of stroke may have affected interpretation of these data. On the other hand an association between haemorrhagic stroke and low cholesterol levels has not been definitively shown. Several studies including the Multiple risk Factor Intervention Trial (MRFIT) and the Honolulu Heart Program reported a 0.3 and 2.2% higher risk of haemorrhagic stroke in the lowest cholesterol level quintiles. However, there was no significant association between cholesterol levels and haemorrhagic stroke in a review of 7 Asian cohorts (1044 strokes). Furthermore, in patients with IHD and low cholesterol levels the risk of haemorrhagic stroke was negligible in a primarily Caucasian population, according to data from the Cholesterol And Recurrent Events (CARE) stroke study.

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