Fast track — ArticlesEffects of cholesterol-lowering with simvastatin on stroke and other major vascular events in 20 536 people with cerebrovascular disease or other high-risk conditions
Introduction
Observational studies in different populations indicate a strong continuous positive relation between coronary heart disease risk and blood cholesterol concentration that extends well below the range commonly seen in Western populations.1, 2, 3, 4, 5 Little association has been found in observational studies between blood total cholesterol concentrations and the risk of any type of stroke, but there does appear to be a positive association with ischaemic stroke risk (particularly at younger ages).6, 7, 8, 9, 10, 11 It has been suggested, however, that this might be counterbalanced by a weak negative association with haemorrhagic stroke risk (perhaps especially among people with higher blood pressure).8, 9, 10, 11
In the randomised trials of cholesterol-lowering drugs or diets that were conducted before the introduction of the statins, blood cholesterol concentrations were typically reduced by only about 0·5 mmol/L (19 mg/dL) and coronary events reduced by only about 10–15%.11 The stroke risk did not appear to be altered in a meta-analysis of those trials (relative risk 1·0), but the 95% CI (0·8–1·6) includes the possibility of a 10–15% reduction in stroke.12 More recently, in previous trials of statin therapy, LDL cholesterol concentrations were typically reduced by about 1·0 mmol/L (39 mg/dL) and coronary events reduced by about 20–25%.11 Although there were too few strokes during each of those trials13, 14, 15, 16, 17, 18 to allow reliable assessment of the effects on stroke risk, meta-analyses did indicate that statin therapy reduces the risk not just of coronary events but also of strokes.11, 19, 20 This observation was supported by the finding that cholesterol-lowering with statin therapy slowed the progression of carotid atherosclerosis.21, 22, 23 More definitive evidence was required, however, about the magnitude of any effects of cholesterol-lowering on stroke subtypes and about the effects on stroke in different circumstances.24, 25 The large randomised Heart Protection Study (HPS) prospectively aimed to assess reliably the effects on stroke incidence of a substantial LDL cholesterol reduction maintained for several years in a wide range of individuals at substantial risk of vascular disease.
Section snippets
Methods
Details of the study have been reported previously26, 27, 28 (see also http://www.hpsinfo.org), and are summarised below.
Patient enrolment
Between July, 1994, and May, 1997, 3280 people aged 40–80 years with a history of cerebrovascular disease were randomised, along with a further 17256 high-risk patients who did not have diagnosed cerebrovascular disease (table 1).27 Among the participants known to have cerebrovascular disease, previous ischaemic strokes were reported at study entry by 2070 (63%), transient cerebral ischaemic attacks by 1504 (46%), and carotid endarterectomy or angioplasty by 343 (10%), with overlap between
Discussion
Due to its large size and the types of high-risk patient studied, much larger numbers of participants suffered a stroke during HPS than in any other randomised trial of cholesterol-lowering therapy. Consequently, the present study is able to resolve many of the remaining uncertainties about the effects of statin therapy on the incidence of stroke.24, 25 In particular, it shows that cholesterol-lowering statin therapy rapidly produces a definite and substantial reduction in ischaemic stroke,
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Collaborators and participating hospitals are listed at http://image.thelancet.com/extras/04art2126webappendix.pdf