Elsevier

The Lancet

Volume 366, Issue 9493, 8–14 October 2005, Pages 1267-1278
The Lancet

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Efficacy and safety of cholesterol-lowering treatment: prospective meta-analysis of data from 90 056 participants in 14 randomised trials of statins

https://doi.org/10.1016/S0140-6736(05)67394-1Get rights and content

Summary

Background

Results of previous randomised trials have shown that interventions that lower LDL cholesterol concentrations can significantly reduce the incidence of coronary heart disease (CHD) and other major vascular events in a wide range of individuals. But each separate trial has limited power to assess particular outcomes or particular categories of participant.

Methods

A prospective meta-analysis of data from 90 056 individuals in 14 randomised trials of statins was done. Weighted estimates were obtained of effects on different clinical outcomes per 1·0 mmol/L reduction in LDL cholesterol.

Findings

During a mean of 5 years, there were 8186 deaths, 14 348 individuals had major vascular events, and 5103 developed cancer. Mean LDL cholesterol differences at 1 year ranged from 0·35 mmol/L to 1·77 mmol/L (mean 1·09) in these trials. There was a 12% proportional reduction in all-cause mortality per mmol/L reduction in LDL cholesterol (rate ratio [RR] 0·88, 95% CI 0·84–0·91; p<0·0001). This reflected a 19% reduction in coronary mortality (0·81, 0·76–0·85; p<0·0001), and non-significant reductions in non-coronary vascular mortality (0·93, 0·83–1·03; p=0·2) and non-vascular mortality (0·95, 0·90–1·01; p=0·1). There were corresponding reductions in myocardial infarction or coronary death (0·77, 0·74–0·80; p<0·0001), in the need for coronary revascularisation (0·76, 0·73–0·80; p<0·0001), in fatal or non-fatal stroke (0·83, 0·78–0·88; p<0·0001), and, combining these, of 21% in any such major vascular event (0·79, 0·77–0·81; p<0·0001). The proportional reduction in major vascular events differed significantly (p<0·0001) according to the absolute reduction in LDL cholesterol achieved, but not otherwise. These benefits were significant within the first year, but were greater in subsequent years. Taking all years together, the overall reduction of about one fifth per mmol/L LDL cholesterol reduction translated into 48 (95% CI 39–57) fewer participants having major vascular events per 1000 among those with pre-existing CHD at baseline, compared with 25 (19–31) per 1000 among participants with no such history. There was no evidence that statins increased the incidence of cancer overall (1·00, 0·95–1·06; p=0·9) or at any particular site.

Interpretation

Statin therapy can safely reduce the 5-year incidence of major coronary events, coronary revascularisation, and stroke by about one fifth per mmol/L reduction in LDL cholesterol, largely irrespective of the initial lipid profile or other presenting characteristics. The absolute benefit relates chiefly to an individual's absolute risk of such events and to the absolute reduction in LDL cholesterol achieved. These findings reinforce the need to consider prolonged statin treatment with substantial LDL cholesterol reductions in all patients at high risk of any type of major vascular event.

Introduction

Results of observational studies in different populations indicate a continuous positive relationship between coronary heart disease (CHD) risk and blood cholesterol concentrations that extends well below the range seen in many developed populations, without any definite threshold below which a lower cholesterol concentration is not associated with lower risk.1, 2 Despite this evidence, there has been substantial uncertainty about the effects on mortality and major morbidity of lowering blood cholesterol by drugs or diets.3, 4, 5, 6, 7, 8, 9

Definitive assessment of whether a substantial reduction in LDL cholesterol concentrations would be beneficial was facilitated by the development of potent cholesterol-lowering drugs, such as the 3-hydroxy-3-methylglutaryl coenzyme A (HMG-CoA) reductase inhibitors (statins).10 But discussion among the principal investigators of ongoing large-scale randomised trials of these treatments suggested that some uncertainties about their effects were likely to persist unless there was a systematic meta-analysis of the findings; although the individual trials might be large enough to show effects on the aggregate of all coronary events, they might well over estimate or under estimate any effects on coronary death or on other specific vascular or non-vascular outcomes, especially when particular subgroups of participants were considered. Hence, in 1994, the decision was made to undertake periodic meta-analyses of individual participant data on mortality and morbidity from all relevant large-scale randomised trials of lipid-modifying treatments whose first results would be reported subsequently. This report is of the results from the first cycle of such meta-analyses, and involves only trials of statins.

Section snippets

Study eligibility

A protocol for the Cholesterol Treatment Trialists' (CTT) Collaboration was agreed in November, 1994, before the results of any of the relevant trials became available, and was published the next year.11 Properly randomised trials were eligible for inclusion if: (i) the main effect of at least one of the trial interventions was to modify lipid levels; (ii) the trial was unconfounded with respect to this intervention (ie, no other differences in risk factor modification between the relevant

Results

For the first cycle of analyses, individual participant data were available from 14 trials of statin therapy (table),13, 14, 15, 16, 17, 18, 19, 20, 21, 22, 23, 24, 25, 26 but not from one other eligible trial.27 Data were obtained on 90 056 participants, of whom 42 131 (47%) had pre-existing CHD, 21 575 (24%) were women, 18 686 (21%) had a history of diabetes, and 49 689 (55%) had a history of hypertension. The mean pre-treatment LDL cholesterol was 3·79 mmol/L, and ranged from 3·03 mmol/L in

Discussion

The main objective of this collaboration is to provide reliable assessments of the major benefits and risks of lipid-modifying treatments, and this first cycle of meta-analyses has specifically addressed the effects of lowering LDL cholesterol with statins. We aimed to minimise both systematic and random errors by bringing together individual participant data from all eligible large randomised trials comparing statin therapy versus control, and by prespecifying the main analyses.11 Furthermore,

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