Elsevier

The Lancet

Volume 363, Issue 9411, 6 March 2004, Pages 757-767
The Lancet

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Effects of cholesterol-lowering with simvastatin on stroke and other major vascular events in 20 536 people with cerebrovascular disease or other high-risk conditions

https://doi.org/10.1016/S0140-6736(04)15690-0Get rights and content

Summary

Background

Lower blood cholesterol concentrations have consistently been found to be strongly associated with lower risks of coronary disease but not with lower risks of stroke. Despite this observation, previous randomised trials had indicated that cholesterol-lowering statin therapy reduces the risk of stroke, but large-scale prospective confirmation has been needed.

Methods

3280 adults with cerebrovascular disease, and an additional 17256 with other occlusive arterial disease or diabetes, were randomly allocated 40 mg simvastatin daily or matching placebo. Subgroup analyses were prespecified of first “major vascular event” (ie, non-fatal myocardial infarction or coronary death, stroke of any type, or any revascularisation procedure) in prior disease subcategories. Subsidiary outcomes included any stroke, and stroke subtype. Comparisons are of all simvastatin-allocated versus all placebo-allocated participants (ie, “intention-to-treat”), which yielded an average difference in LDL cholesterol of 1·0 mmol/L (39 mg/dL) during the 5-year treatment period.

Findings

Overall, there was a highly significant 25% (95% CI 15–34) proportional reduction in the first event rate for stroke (444 [4·3%] simvastatin vs 585 [5·7%] placebo; p<;0·0001), reflecting a definite 28% (19–37) reduction in presumed ischaemic strokes (p<0·0001) and no apparent difference in strokes attributed to haemorrhage (51 [0·5%] vs 53 [0·5%]; rate ratio 0·95 [0·65–1·40]; p=0·8). In addition, simvastatin reduced the numbers having transient cerebral ischaemic attacks alone (2·0% vs 2·4%; p=0·02) or requiring carotid endarterectomy or angioplasty (0·4% vs 0·8%; p=0·0003). The reduction in stroke was not significant during the first year, but was already significant (p=0·0004) by the end of the second year. Among patients with pre-existing cerebrovascular disease there was no apparent reduction in the stroke rate, but there was a highly significant 20% (8–29) reduction in the rate of any major vascular event (406 [24·7%] vs 488 [29·8%]; p=0·001). The proportional reductions in stroke were about one-quarter in each of the other subcategories of participant studied, including: those with coronary disease or diabetes; those aged under or over 70 years at entry; and those presenting with different levels of blood pressure or lipids (even when the pretreatment LDL cholesterol was below 3·0 mmol/L [116 mg/dL]).

Interpretation

Much larger numbers of people in the present study suffered a stroke than in any previous cholesterol-lowering trial. The results demonstrate that statin therapy rapidly reduces the incidence not only of coronary events but also of ischaemic strokes, with no apparent effect on cerebral haemorrhage, even among individuals who do not have high cholesterol concentrations. Allocation to 40 mg simvastatin daily reduced the rate of ischaemic strokes by about one-quarter and so, after making allowance for noncompliance in the trial, actual use of this regimen would probably reduce the stroke rate by about a third. HPS also provides definitive evidence that statin therapy is beneficial for people with pre-existing cerebrovascular disease, even if they do not already have manifest coronary disease.

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,

References (51)

  • ChenZ et al.

    Serum cholesterol concentration and coronary heart disease in population with low cholesterol concentrations

    BMJ

    (1991)
  • Cholesterol, diastolic blood pressure, and stroke: 13000 strokes in 450000 people in 45 prospective cohorts

    Lancet

    (1995)
  • Blood pressure, cholesterol, and stroke in eastern Asia

    Lancet

    (1998)
  • Cholesterol, coronary heart disease, and stroke in the Asia Pacific region

    Int J Epidemiol

    (2003)
  • H Iso et al.

    Serum cholesterol levels and six-year mortality from stroke in 350977 men screened for the multiple risk factor intervention trial

    N Engl J Med

    (1989)
  • IribarrenC et al.

    Serum total cholesterol and mortality: confounding factors and risk modification in Japanese-American men

    JAMA

    (1995)
  • LawMR et al.

    Quantifying effect of statins on low density lipoprotein cholesterol, ischaemic heart disease, and stroke: systematic review and meta-analysis

    BMJ

    (2003)
  • HebertPR et al.

    An overview of trials of cholesterol lowering and risk of stroke

    Arch Intern Med

    (1995)
  • WhiteHD et al.

    Pravastatin therapy and the risk of stroke

    N Engl J Med

    (2000)
  • Randomised trial of cholesterol lowering in 4444 patients with coronary heart disease: the Scandinavian Simvastatin Survival Study (4S)

    Lancet

    (1994)
  • JF Plehn et al.

    Reduction of stroke incidence after myocardial infarction with pravastatin: the Cholesterol and Recurrent Events (CARE) Study

    Circulation

    (1999)
  • The Post Coronary Artery Bypass Graft Trial Investigators

    The effect of aggressive lowering of low-density lipoprotein cholesterol levels and low-dose anticoagulation on obstructive changes in saphenous-vein coronary-artery bypass grafts

    N Engl J Med

    (1997)
  • J Shepherd et al.

    Prevention of coronary heart disease with pravastatin in men with hypercholesterolemia

    N Engl J Med

    (1995)
  • JR Downs et al.

    Primary prevention of acute coronary events with lovastatin in men and women with average cholesterol levels: results of AFCAPS/TexCAPS

    JAMA

    (1998)
  • HebertPR et al.

    Cholesterol lowering with statin drugs, risk of stroke, and total mortality: an overview of randomized trials

    JAMA

    (1997)
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