Elsevier

The Lancet

Volume 360, Issue 9350, 21–28 December 2002, Pages 2001-2008
The Lancet

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Oestrogen therapy for prevention of reinfarction in postmenopausal women: a randomised placebo controlled trial*

https://doi.org/10.1016/S0140-6736(02)12001-0Get rights and content

Summary

Background

Results of observational studies suggest that hormone replacement therapy (HRT) could reduce the risk of coronary heart disease (CHD), but those of randomised trials do not indicate a lower risk in women who use oestrogen plus progestagen. The aim of this study was to ascertain whether or not unopposed oestrogen reduces the risk of further cardiac events in postmenopausal women who survive a first myocardial infarction.

Methods

The study was a randomised, blinded, placebo controlled, secondary prevention trial of postmenopausal women, age 50–69 years (n=1017) who had survived a first myocardial infarction. Individuals were recruited from 35 hospitals in England and Wales. Women received either one tablet of oestradiol valerate (2 mg; n=513) or placebo (n=504), daily for 2 years. Primary outcomes were reinfarction or cardiac death, and all-cause mortality. Analyses were by intention-to-treat. Secondary outcomes were uterine bleeding, endometrial cancer, stroke or other embolic events, and fractures.

Findings

Frequency of reinfarction or cardiac death did not differ between treatment groups at 24 months (rate ratio 0·99, 95% Cl 0·70–1·41, p=0·97). Similarly, the reduction in all-cause mortality between those who took oestrogen and those on placebo was not significant (0·79, 0·50–1·27, p=0·34). The relative risk of any death (0·56, 0·23–1·33) and cardiac death (0·33, 0·11–1·01) was lowest at 3 months post-recruitment.

Interpretation

Oestradiol valerate does not reduce the overall risk of further cardiac events in postmenopausal women who have survived a myocardial infarction.

Published online Dec 17, 2002 http://image.thelancet.com/extras/02artll268web.pdf

Introduction

Data from observational studies suggest that hormone replacement therapy (HRT) reduces the risk of coronary heart disease. Results of a meta-analysis1 indicate a relative risk of 0·70 for ever users of oestrogen as HRT, with a slightly lower risk (0·66) for users of combined therapy (oestrogen plus progestagen). Such risk reductions seem plausible, since studies show potentially advantageous changes in lipid profiles,2, 3 vessel walls,4 fibrinogen and antithrombin III concentrations,5, 6 and insulin secretion7 in women on HRT. However, possibly unfavourable effects, such as altered triglyceride8 and factor VII concentrations,9 have also been reported. Studies that used angiography or carotid ultrasonography have provided contradictory evidence. Increased survival in ever users of oestrogen with greater than 70% coronary artery stenosis was noted in one observational study.10 Findings of three randomised trials,11, 12, 13, 14 however, showed no beneficial effect on progression of coronary arteriosclerosis, although those of another trial15 indicated a slower rate of progression in healthy postmenopausal women who took unopposed oestrogen (17β oestradiol) rather than placebo. Results of a small trial16 indicate no effect of conjugated oestrogen on recurrence of ischaemic events.

The results of the Heart and Estrogen/progestin Replacement Study (HERS), a randomised controlled trial17 of HRT in women with coronary heart disease that used the clinical end-points of non-fatal myocardial infarction or cardiac death, indicate no overall difference between intervention groups. HERS compared 2763 women with coronary disease allocated to either conjugated equine oestrogen plus medroxyprogesterone acetate or placebo. A significantly increased risk of cardiac events in the first year of treatment was noted in women given active treatment, followed by a reduced risk in years 3–5 that was not sustained with further follow-up.18 Results of smaller trials of women with ischaemic heart disease,19 or who had recently had a cerebrovascular event,20 also showed no cardiac benefit from HRT.

The Women's Health Initiative randomised controlled trials of primary prevention assessed two hormonal components-namely, oestrogen alone in women who had undergone hysterectomy, and oestrogen plus progestagen in those who had not. The combined treatment component, which was stopped early, showed a significantly increased risk of coronary heart disease, an effect that was greatest in the first year.21 Results are not yet available for the unopposed oestrogen component, which is still being assessed.22

Almost all randomised trials with clinical cardiac endpoints have investigated combined hormone therapies. The oEStrogen in the Prevention of Relnfarction Trial (ESPRIT) was, therefore, designed to assess the effect of unopposed oestradiol valerate on risk of another cardiac event or death in postmenopausal women who had just survived their first myocardial infarction.

Section snippets

Participants

All women aged 50–69 years admitted to coronary care units or general medical wards in participating hospitals in England and Wales between July, 1996, and February, 2000, were eligible for inclusion provided that they met the diagnostic criteria for myocardial infarction, they were discharged alive from hospital within 31 days of admission, and they had not had a previous documented myocardial infarction or any other exclusion condition-ie, use of HRT or vaginal bleeding in the 12 months

Results

The figure shows the trial profile. 1017 women were randomly assigned to active treatment (n=513) or placebo (n=504). At the time of admission the mean age of participants was 62·6 years, 97% (n=985) were white, 53% (n=540) were smokers, 24% (n=245) reported having had a hysterectomy, and 15% (n=153) had been told they had diabetes (table 1). Both groups had similar baseline characteristics, including those identified a priori as potential confounders.

Compliance with treatment was poor, and was

Discussion

The findings of ESPRIT indicate no overall difference in the frequency of reinfarction or cardiac death between individuals treated with unopposed oestrogen or placebo. Furthermore, although the rate of death from all causes was lower at 24 months in the active treatment group than in the placebo group, because of the slightly lower rate of cardiac deaths, this finding was not significant. The results of ESPRIT, showing no clear benefit of oestrogen for clinical cardiac outcomes, are consistent

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