Throughout the usual LDL cholesterol range in Western populations, lower blood concentrations
are associated with lower cardiovascular disease risk. In such populations, therefore,
reducing LDL cholesterol may reduce the development of vascular disease, largely irrespective
of initial cholesterol concentrations.
20,536 UK adults (aged 40-80 years) with coronary disease, other occlusive arterial
disease, or diabetes were randomly allocated to receive 40 mg simvastatin daily (average
compliance: 85%) or matching placebo (average non-study statin use: 17%). Analyses
are of the first occurrence of particular events, and compare all simvastatin-allocated
versus all placebo-allocated participants. These "intention-to-treat" comparisons
assess the effects of about two-thirds (85% minus 17%) taking a statin during the
scheduled 5-year treatment period, which yielded an average difference in LDL cholesterol
of 1.0 mmol/L (about two-thirds of the effect of actual use of 40 mg simvastatin daily).
Primary outcomes were mortality (for overall analyses) and fatal or non-fatal vascular
events (for subcategory analyses), with subsidiary assessments of cancer and of other
major morbidity.
All-cause mortality was significantly reduced (1328 [12.9%] deaths among 10,269 allocated
simvastatin versus 1507 [14.7%] among 10,267 allocated placebo; p=0.0003), due to
a highly significant 18% (SE 5) proportional reduction in the coronary death rate
(587 [5.7%] vs 707 [6.9%]; p=0.0005), a marginally significant reduction in other
vascular deaths (194 [1.9%] vs 230 [2.2%]; p=0.07), and a non-significant reduction
in non-vascular deaths (547 [5.3%] vs 570 [5.6%]; p=0.4). There were highly significant
reductions of about one-quarter in the first event rate for non-fatal myocardial infarction
or coronary death (898 [8.7%] vs 1212 [11.8%]; p<0.0001), for non-fatal or fatal stroke
(444 [4.3%] vs 585 [5.7%]; p<0.0001), and for coronary or non-coronary revascularisation
(939 [9.1%] vs 1205 [11.7%]; p<0.0001). For the first occurrence of any of these major
vascular events, there was a definite 24% (SE 3; 95% CI 19-28) reduction in the event
rate (2033 [19.8%] vs 2585 [25.2%] affected individuals; p<0.0001). During the first
year the reduction in major vascular events was not significant, but subsequently
it was highly significant during each separate year. The proportional reduction in
the event rate was similar (and significant) in each subcategory of participant studied,
including: those without diagnosed coronary disease who had cerebrovascular disease,
or had peripheral artery disease, or had diabetes; men and, separately, women; those
aged either under or over 70 years at entry; and--most notably--even those who presented
with LDL cholesterol below 3.0 mmol/L (116 mg/dL), or total cholesterol below 5.0
mmol/L (193 mg/dL). The benefits of simvastatin were additional to those of other
cardioprotective treatments. The annual excess risk of myopathy with this regimen
was about 0.01%. There were no significant adverse effects on cancer incidence or
on hospitalisation for any other non-vascular cause.
Adding simvastatin to existing treatments safely produces substantial additional benefits
for a wide range of high-risk patients, irrespective of their initial cholesterol
concentrations. Allocation to 40 mg simvastatin daily reduced the rates of myocardial
infarction, of stroke, and of revascularisation by about one-quarter. After making
allowance for non-compliance, actual use of this regimen would probably reduce these
rates by about one-third. Hence, among the many types of high-risk individual studied,
5 years of simvastatin would prevent about 70-100 people per 1000 from suffering at
least one of these major vascular events (and longer treatment should produce further
benefit). The size of the 5-year benefit depends chiefly on such individuals' overall
risk of major vascular events, rather than on their blood lipid concentrations alone.