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Heart Protection Study

(a) Heart Protection Study Collaborative Group.
(b) Collins R, Armitage J, Parish S, Sleigh P, Peto R; Heart Protection Study Collaborative Group.

(a) MRC/BHF Heart Protection Study of cholesterol lowering with simvastatin in 20,536 high-risk individuals: a randomised placebo-controlled trial
(b) MRC/BHF Heart Protection Study of cholesterol-lowering with simvastatin in 5963 people with diabetes: a randomised placebo-controlled trial

(a) Lancet. 2002 Jul 6;360(9326):7-22. Related Articles, Links
(b) Lancet. 2003 Jun 14;361(9374):2005-16. Related Articles, Links

Coronary heart disease, other occlusive artery disease, diabetes, hypertension

To determine whether LDL-cholesterol lowering with simvastatin reduces cardiovascular events in high risk patients (established occlusive artery disease, diabetes or hypertension) irrespective of pretreatment lipid concentrations

Study design
Randomized, double-blind, placebo controlled trial conducted in 69 centres in UK. 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

Mean follow-up was 5 years

20,536 UK adults (aged 40-80 years) with coronary disease, other occlusive arterial disease, diabetes, or treated hypertension, with total cholesterol concentrations above 3.5mmol/l, who were not indicated to statin therapy by their own physician

Treatment regimen
Patients were randomly assigned to receive treatment with simvastatin, 40 mg/d, or matching placebo

Concomitant therapy

Among patients randomised to simvastatin, the average compliance was 85%; in placebo-trated patients, the average non-study statin use was 17%. Therefore, the "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).
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.
In summary, 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.