Elsevier

The Lancet

Volume 385, Issue 9976, 11–17 April 2015, Pages 1397-1405
The Lancet

Articles
Efficacy and safety of LDL-lowering therapy among men and women: meta-analysis of individual data from 174 000 participants in 27 randomised trials

https://doi.org/10.1016/S0140-6736(14)61368-4Get rights and content

Summary

Background

Whether statin therapy is as effective in women as in men is debated, especially for primary prevention. We undertook a meta-analysis of statin trials in the Cholesterol Treatment Trialists' (CTT) Collaboration database to compare the effects of statin therapy between women and men.

Methods

We performed meta-analyses on data from 22 trials of statin therapy versus control (n=134 537) and five trials of more-intensive versus less-intensive statin therapy (n=39 612). Effects on major vascular events, major coronary events, stroke, coronary revascularisation and mortality were weighted per 1·0 mmol/L reduction in LDL cholesterol and effects in men and women compared with a Cox model that adjusted for non-sex differences. For subgroup analyses, we used 99% CIs to make allowance for the multiplicity of comparisons.

Findings

46 675 (27%) of 174 149 randomly assigned participants were women. Allocation to a statin had similar absolute effects on 1 year lipid concentrations in both men and women (LDL cholesterol reduced by about 1·1 mmol/L in statin vs control trials and roughly 0·5 mmol/L for more-intensive vs less-intensive therapy). Women were generally at lower cardiovascular risk than were men in these trials. The proportional reductions per 1·0 mmol/L reduction in LDL cholesterol in major vascular events were similar overall for women (rate ratio [RR] 0·84, 99% CI 0·78–0·91) and men (RR 0·78, 99% CI 0·75–0·81, adjusted p value for heterogeneity by sex=0·33) and also for those women and men at less than 10% predicted 5 year absolute cardiovascular risk (adjusted heterogeneity p=0·11). Likewise, the proportional reductions in major coronary events, coronary revascularisation, and stroke did not differ significantly by sex. No adverse effect on rates of cancer incidence or non-cardiovascular mortality was noted for either sex. These net benefits translated into all-cause mortality reductions with statin therapy for both women (RR 0·91, 99% CI 0·84–0·99) and men (RR 0·90, 99% CI 0·86–0·95; adjusted heterogeneity p=0·43).

Interpretation

In men and women at an equivalent risk of cardiovascular disease, statin therapy is of similar effectiveness for the prevention of major vascular events.

Funding

UK Medical Research Council, British Heart Foundation, Australian National Health and Medical Research Council, European Community Biomed Program.

Introduction

There is general agreement that statins reduce both cardiovascular events and mortality,1, 2, 3, 4 but uncertainty remains regarding the extent of their effectiveness in women compared with men,5 especially for primary prevention.5, 6, 7, 8, 9, 10, 11 Few studies have reported independently significant cardiovascular benefits in women,5, 12, 13, 14, 15 and much of the resulting uncertainty has been attributed to the under-representation of women in statin trials and a lack of sex-specific analyses in cardiovascular research.16, 17

Previous meta-analyses of the effects of statin therapy in women have reached conflicting conclusions. The authors of a 2010 meta-analysis concluded that, among individuals without known cardiovascular disease, statins might not be as effective in women as in men,10 whereas those of a more recent meta-analysis in 2012 (which included mainly patients receiving statins for primary prevention, but also included some patients receiving statins for secondary prevention) concluded that statins are effective in both sexes.15 Investigators in both studies, however, were able to access information only from a subset of the relevant trials and used published data, thereby limiting the reliability of their findings. Perhaps as a result of this uncertainty, a recent review concluded that a large trial of statin therapy for primary prevention in women is needed.11

The Cholesterol Treatment Trialists' (CTT) Collaboration has previously reported meta-analyses of individual data from 22 trials of standard statin regimens versus control and five trials of more-intensive (ie, higher dose) versus less-intensive (ie, lower dose) regimens; findings from these analyses showed that the proportional benefits of statin therapy for major vascular events were similar irrespective of baseline risk of vascular disease.4 In that study, findings from a subsidiary analysis suggested that the proportional effects of statins on major vascular events did not differ in women and men of equivalent baseline risk of vascular disease. The purpose of the present meta-analysis is to provide a more detailed assessment of the effects of statin therapy on particular vascular and non-vascular outcomes in men and women in the settings of both primary and secondary prevention.

Section snippets

Study design and outcomes

We did a meta-analysis of studies included in the CTT Collaboration database reported up to 2010; the database includes trials of statin therapy versus control and trials that compared statin regimens of differing intensity. A protocol for the CTT Collaboration was agreed in November, 1994, before the results of any of the relevant trials became available.18 Randomised trials were eligible for inclusion if the main effect of at least one of the trial interventions was to reduce LDL cholesterol,

Results

Individual participant data were available from 27 trials of statin therapy: 22 trials examining statin therapy versus control, and five trials examining more-intensive statin therapy versus less-intensive therapy (table 1).2, 23 The median duration of follow-up among survivors was 4·9 years (IQR 4·5–5·3), ranging from 2·0 years20, 24, 25 to 7·0 years.26 Among all trials, 46 675 (26·8%) of 174 149 randomly assigned participants were women. Compared with men, women were older (mean age 65·1 vs

Discussion

To our knowledge, this analysis of individual patient data from more than 174 000 people represents the largest meta-analysis to date comparing statin efficacy by sex, and is the only such analysis to adjust in detail for cardiovascular risk (panel). It is widely accepted that reduction of LDL cholesterol with statin therapy reduces the risk of major coronary events, coronary revascularisation, and ischaemic stroke, and that the absolute benefits of statin therapy are determined chiefly by the

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