Fast track — ArticlesEfficacy and safety of cholesterol-lowering treatment: prospective meta-analysis of data from 90 056 participants in 14 randomised trials of statins
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.
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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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Collaborators listed at end of paper