Elsevier

The Lancet

Volume 360, Issue 9326, 6 July 2002, Pages 7-22
The Lancet

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MRC/BHF Heart Protection Study of cholesterol lowering with simvastatin in 20 536 high-risk individuals: a randomised placebocontrolled trial

https://doi.org/10.1016/S0140-6736(02)09327-3Get rights and content

Summary

Background

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.

Methods

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.

Findings

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 nonfatal 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 noncoronary 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.

Interpretation

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.

Introduction

Observational studies in different populations indicate a continuous positive relationship between coronary heart disease risk and blood LDL cholesterol concentration that extends well below the range currently seen in Western populations, without any definite “threshold” below which a lower concentration is not associated with lower risk.1, 2, 3, 4, 5 This relationship is approximately linear when coronary disease risk is plotted on a logarithmic (or “doubling”) scale, which implies that the proportional reduction in risk associated with a given absolute difference in usual LDL cholesterol concentration is similar throughout the range that has been studied. Hence, the absolute size of the risk reduction produced by lowering LDL cholesterol may be determined more by an individual's overall risk of cardiovascular disease than by just their initial blood lipid concentrations. If this is the case, then the benefits of treatment may be greatest in those who, as a consequence of their previous medical history (eg, occlusive arterial disease or diabetes) or some other factors (eg, age), are at greatest risk.

Recently, large randomised trials have shown that lowering LDL cholesterol with 3-hydroxy-3-methylglutaryl-coenzyme A (HMG-CoA) reductase inhibitors (“statins”) reduces coronary mortality and morbidity in some types of high-risk patient.6, 7, 8, 9, 10, 11 Typically in those trials, an average reduction in LDL cholesterol of about 1 mmol/L maintained for about 5 years produced a reduction in non-fatal myocardial infarction and coronary death of about one-quarter (which is about half the effect associated epidemiologically with a long-term difference of 1 mmol/L in people without diagnosed vascular disease2, 4). But, even after those trials, there was still only limited evidence about the effects of such treatment in many specific types of high-risk patient—in particular, those without diagnosed coronary disease who have diabetes or non-coronary occlusive arterial disease; those who are female or elderly; and those with belowaverage LDL cholesterol concentrations for Western populations.12, 13, 14, 15 Moreover, although those trials did not find any excess of non-coronary deaths or major morbidity, further evidence was still needed of the longterm effects of lowering LDL cholesterol on cause-specific mortality and on cancers of particular sites.16, 17, 18, 19, 20, 21, 22

The Heart Protection Study aimed to help resolve some of those remaining uncertainties by assessing the longterm effects of cholesterol-lowering therapy on vascular and non-vascular mortality and major morbidity in a wide range of circumstances. To do this reliably, it included large numbers of people at substantial risk of death from both vascular and other causes, and involved a substantial LDL cholesterol reduction maintained for several years.

Section snippets

Patients and methods

Details of the study objectives, design, and methods have been reported previously12, 23 (including the protocol on the study website: http://www.hpsinfo.org), and are summarised below. As well as comparing the effects of cholesterollowering therapy versus matching placebo in 20 536 randomised participants (which is the subject of the present report), a “2X2 factorial” design was used to allow the separate assessment of antioxidant vitamin supplementation (see accompanying report24).

Patient enrolment

63 603 people attended the initial screening clinic visit, and 32 145 were potentially eligible and agreed to enter the prerandomisation run-in phase of the study (figure 1).23 Of those who entered run-in, 36% were not subsequently randomised: 26% chose not to enter the trial or did not seem likely to be compliant for 5 years, 5% were considered by their own doctors to have a clear indication for (or, rarely, contraindication to) statin therapy, 3% had elevated concentrations of liver enzymes,

Benefits for a wide range of high-risk patients

The results of the Heart Protection Study demonstrate that lowering LDL cholesterol with a statin produces a substantial reduction in the incidence of major vascular events among a much wider range of high-risk individuals than had previously been shown to benefit from such treatment. In particular, it demonstrates substantial benefit not only in those already known to have coronary disease, but also in those without diagnosed coronary disease who have cerebrovascular disease, or peripheral

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