N=2603
Long term safety of unopposed oestrogen used by women surviving myocardial infarction: 14 year
follow-up of the ESPRIT randomised controlled trial.
Nicola Cherry1, Roseanne McNamee2, Anthony Heagerty3, Henry Kitchener4, Philip Hannaford5
1
Division of Preventive Medicine, University of Alberta
2
School of Community-based medicine, University of Manchester
3
Cardiovascular Research Group, University of Manchester
4
Institute of Cancer Sciences, University of Manchester
5
School of Medicine and Dentistry, University of Aberdeen
Correspondence to:
Dr Nicola Cherry
Division of Preventive Medicine
University of Alberta
Edmonton, Alberta
T6G 2T4
Canada
nicola.cherry@ualberta.ca
1 780 492 7851
Safety of unopposed estrogen in the ESPRIT trial.
1
N=241
Objective: To compare health outcomes during 14 year observational follow-up in women initially
randomised to unopposed estrogen or placebo.
Design: At recruitment to the Estrogen for the Prevention of Re-Infarction Trial (ESPRIT) women were
assigned to estradiol valerate: 2mg or placebo treatment for 2 years.
Setting. Women were recruited from 35 hospitals in the north west of England and Wales in July 1996February 2000.
Sample. Women aged 50-69 surviving their first myocardial infarction
Methods: All women were followed by data linkage to UK mortality and cancer records; mean follow-up
14.1 and 12.6 years respectively. In an intention to treat analysis Hazard Ratios (HRs) were computed,
overall and stratified by age at recruitment.
Outcome measures: Death (all cause, cardiac disease, stroke or cancer) and cancer incidence (any,
breast or endometrium).
Results: There were 418 deaths in 1017 women randomised. The all-cause mortality Hazards Ratio of
1.07 (95%CI 0.88-1.29) indicated no significant difference between treatment groups. Women aged 5059 years at recruitment had lower HRs than women aged 60-69 years for all outcomes except ischemic
heart disease. Amongst 149 incident cancers there were 7 cases of breast cancer in the intervention arm
and 15 in the placebo; HR 0.47 (95%CI 0.19-1.15). There were no deaths from endometrial cancer but 3
incident cases, 1 in the active arm and 2 in placebo.
Conclusions: These results suggest that unopposed oestrogen may be safely used for a short duration
by women surviving a first myocardial infarction.
Keywords: estrogen, cancer, randomised controlled trial
2
Introduction
The ESPRIT trial [1] was designed to investigate whether estrogen (estradiol valerate) reduced the risk of
re-infarction, cardiac death or all cause mortality in postmenopausal women recruited at the time of
hospital admission for a first myocardial infarction (MI). Few other trials of the health effects of
hormone replacement therapy (HRT) have used estrogen without progesterone (unopposed estrogen) in
women with an intact uterus. The recent Cochrane review [2] lists only two (EPAT [3] and PEPI [4]), both
of which used surrogate markers of disease rather than clinical outcomes. The largest trial of unopposed
estrogen (Women’s Health Initiative Estrogen-Alone Trial (WHI E-A)[5]), which recruited women in good
health, initially included women with an intact uterus in the unopposed estrogen arm but later changed
the protocol because of concerns about endometrial hyperplasia [6]. The ESPRIT trial used estrogen
without progesterone for all women in the treatment arm, including those with an intact uterus,
because of concern about the safety of using progesterone in women with recent MI. The follow-up
described in this report was planned primarily to determine whether this use of unopposed estrogen
was detrimental, specifically whether there was any evidence of excess endometrial cancer that might
be attributed to the intervention.
Recently published data from the WHI E-A trial has demonstrated a protective effect of unopposed
conjugated equine estrogens (CEE) on invasive breast cancer in women of all ages in that trial and, in
younger women (aged 50-59 years at enrolment), on incidence of coronary heart disease (CHD), MI and
death (all causes), with a trend towards more adverse outcomes in those over 60 years [7]. Although
smaller than WHI E-A, ESPRIT, with 1017 subjects randomized, is larger than any other trial using
unopposed oestrogen. Continued follow-up of the women recruited provided the opportunity to assess
whether the WHI-E-A results on incident breast cancer and death from all causes, stratified by age, were
found also in women recruited in a different country and exposed to a different type of estrogen
(estadiol valerate rather than CEE used in the WHI E-A).
Methods
As described in the earlier report [1], 1017 women age 50-69 years who had survived a first MI were
recruited at the time of their hospitalization for MI from 35 collaborating hospitals in the north west of
England and Wales between July 1996 and February 2000. Women who reported a history of cancer or
use of hormone replacement therapy in the previous 12 months were excluded. Subjects were
randomized to receive either one tablet of estradiol valerate (2mg; n=513) or placebo (n=504), daily for
2 years. Each subject was followed up through their family physician at 3, 6, 12, 18 and 24 months from
date of recruitment, with follow-up of the last recruit ending on February 2nd 2002. The outcome of this
initial ‘active’ follow-up has been reported previously [1].
3
Given the unconventional use of unopposed estrogen in women with an intact uterus (373/513 in the
active treatment arm), strict trial procedures sought to maximise the notification of all episodes of
vaginal bleeding, and provide effective management of such episodes [1]. Women with vaginal bleeding
during the trial were clinically assessed and, if appropriate, had a pipelle endometrial biopsy followed by
a 14 day course of medroxyprogesterone acetate 20mg, increased to 3 courses each lasting 14 days if
the biopsy showed complex hyperplasia. When women with an intact uterus stopped active or placebo
treatment, at two years after study entry or earlier, those who had not previously been investigated for
vaginal bleeding were offered an endometrial biopsy. Women in the active arm who had not had a
hysterectomy were also sent a letter each year for 5 years after stopping treatment to remind them to
seek medical attention if they experienced vaginal bleeding. There was no attempt after the end of the 2
year intervention period to obtain information from women or their physicians about medication
(including use of estrogen) or health events. However, all 1017 women were flagged at recruitment on
the UK National Health Service central register so that deaths and cancers could be notified through
record linkage. The analyses reported here are based on these notifications.
Follow-up for this paper was to 31st December 2010 for cancer incidence (mean follow-up 12.6 years
range 10.9-14.5) and to 30 June 2012 for mortality (mean follow-up 14.1 years range 12.4-16.0). Cancer
incidence, vital status and cause of death were determined from data routinely collected by the Office
of National Statistics for England and Wales, and by parallel systems in Scotland for women who had
moved there after recruitment into the study. Cancer incidence data are routinely collected by regional
cancer boards and forwarded to the national register with some delay (hence the shorter follow-up for
this endpoint). Mortality is reported centrally with cause of death (both underlying and ‘mentioned’ i.e.
a condition that contributed to but did not cause the death) on the death certificate coded routinely
using the World Health Organization’s International Classification of Diseases (ICD) codes, version 9 until
2000 and version 10 in subsequent years. For this follow-up the outcomes of interest were death (all
cause), and deaths from ischemic heart disease (ICD-9 410-414; ICD-10 I20-I25), any cardiac diagnosis
(ICD-9 codes 393-398, 410-414, 415-417, 420-429; ICD-10 I05-I09, I20-I25, I26-I28, I30-I52), stroke (ICD
9: 430-438, ICD-10: I160-168), any cancer (ICD-9 140-209, ICD-10 C00-C97), breast cancer (ICD-9 174;
ICD-10 C50) and endometrial cancer (ICD-9 182; ICD-10 C54.1). Incidence of cancer in this analysis, for
any cancer, breast cancer and endometrial cancer, was taken from cancer notifications with the same
ICD codes as those in the mortality analysis.
Analysis
Hazard ratios (HRs) comparing treatment arms were estimated using Cox regression. In the all-cause
mortality analysis data for those still alive at the end of follow-up period were treated as censored
observations; for analysis of specific causes or cancer incidence, censoring was at the end of the followup period or time of death if earlier. All HRs were adjusted for age at risk, using six 5-year age bands (5055 to 75-80). A binary variable indicated the randomised treatment arm; thus each analysis was by the
intention to treat during the two year intervention phase. Each outcome was considered separately. For
mortality, the analysis was first by underlying cause and then by ‘any mention’ on the death certificate.
For cancer incidence, the time to event for ‘any cancer’ was taken as time to the first cancer, if more
than one had occurred: in situ and benign neoplasms were excluded. 95% confidence intervals (95%CI)
4
were calculated. For each outcome the effect of treatment group was estimated for all women and then
stratified by age at recruitment (age 50-59 years (n=301) or 60-69 years (n=716)): again adjustment was
made in 5 year bands for age at risk. Tests of whether the HRs differed significantly between the two
age groups were based on a test of interaction between age and treatment in the regression model.
Results
1) Mortality
There were 418 deaths among the 1017 women recruited to ESPRIT, 214 among the 513 in the
treatment arm, 204 among the 504 in the placebo arm (Table 1). The overall HR for all cause mortality
was 1.07 (95% CI: 0.88-1.29) (Table 2). Heart disease was recorded as the underlying cause for 177
(42.3%) of the 418 deaths and as either the underlying cause or as a condition mentioned elsewhere on
the death certificate (‘any mention’ in the tables) in 269 (64.4%) deaths. Estimates of hazard ratios
(Table 2) for all women showed no significant detrimental or protective effect of treatment, although
the ratios were above unity for heart disease and stroke. When stratified by age, women recruited at
age 50-59 years had lower hazard ratios (except for IHD) than those aged 60-69 years at recruitment
although none of the differences between age groups was significant (p>0.05).
There were 5 deaths attributed to breast cancer (1 in the active treatment group, 4 in placebo) as the
underlying cause. There were 7 women with ‘any mention’ of breast cancer on the death certificate, 3 in
the active arm, and 4 in placebo. Endometrial cancer was not reported on any death certificate, either as
an underlying or ‘mentioned’ cause. Although not an outcome specified a priori, three death certificates
with codes for ovarian cancer (ICD-9 183.0; ICD-10 C56) were noted, all in the active arm (p=0.25,
Fisher’s exact test)
2) Cancer incidence
There were 149 incident malignant cancers among 142 women, plus 13 in situ or benign tumours (none
breast or genital; excluded from the analysis). The HR was close to unity for any cancer (all types) among
all 1017 women, with lower HRs for those under 60 years of age at recruitment (Table 2). There were 22
incident cases of breast cancer, 7 in the treatment group and 15 in placebo. HRs for breast cancer were
below unity for the treatment arm overall and for both younger and older women when examined
separately, with women aged 50-59 years having the smallest risk estimate (0.33). For the group as a
whole, the (two sided) probability of an HR of 0.47 or smaller, under the null hypothesis, was 0.097,
having adjusted for age at risk.
There were 3 incident cases of endometrial cancer (1 in the active arm and 2 in placebo), giving an HR
of 0.52 (95%CI 0.05-5.80) and one cervical cancer (placebo). Five ovarian cancers were listed, 4 in the
active arm (p=0.37, Fisher’s exact test).
5
Discussion
Main Findings:
This follow-up of ESPRIT was primarily to investigate whether any harm had been done by using
unopposed estrogen in women with an intact uterus. No harm has been demonstrated. Although during
the trial more than half of the women in the active arm with a uterus reported bleeding, no woman was
diagnosed with endometrial cancer during active follow-up [1]. The unexpected observation of more
ovarian cancer in the treatment arm is consistent with chance and has not been reported in other trials
As in the initial report, there was no significant difference between women in the active and treatment
arms on any of the outcomes considered. In the current analysis, the lowest HR (0.47, suggesting a
protective effect of active treatment) was for incident breast cancer, with the likelihood of such an
effect arising by chance being <0.10. For all the outcomes (except IHD as underlying cause) considered in
this extended ESPRIT follow-up, the HR for women aged 50-59 years at recruitment was lower than for
older women.
Strengths and Limitations:
Since all of the women were flagged for death and cancers at the NHS Central registries, we should have
captured all such events occurring in the trial participants; in effect there was no loss to follow-up.
Although our study had limited statistical power for some of the endpoints included in the analysis it
had 80% power to detect a 20% decrease in all cause mortality. The observation on endometrial cancer
was based on only 373 women with an intact uterus in the active arm and 399 in the placebo. We did
not obtain during the observational extended follow-up of the original trial participants data on nonfatal clinical events other than cancer incidence. It cannot, therefore, add to reports of other outcomes
(e.g. gall bladder disease, venous thrombo-embolism, non-fatal stroke) that have been associated with
unopposed estrogen elsewhere [2]. Neither could we assess whether over time unopposed oestrogen
affects the risk of non-fatal myocardial re-infarction. Data were not available about use of hormone
replacement therapy after the formal trial ended. Some women may have subsequently used these
products although the number is probably small due to the widespread publicity that occurred in the
Summer of 2002 concerning the premature cessation of the oestrogen plus progestin trial of the
Women’s Health Initiative (6), leading to regulatory advice in the UK to avoid long-term use [8]The
absence of adverse effect on the endometrium in this study is likely to be, in large part, a reflection of
the management of bleeding during and at the end of the active intervention [1]. Eight women found to
have atypical hyperplasia during the trial were immediately started on a 3 month course of cyclical
medroxyprogesterone acetate: all endometrial abnormalities resolved and none of the women required
a hysterectomy during the 2 years of the trial. The conclusion of no adverse effect, therefore, should
not be generalized to situations without such active management. The unexpected observation of more
ovarian cancer in the treatment arm is consistent with chance and has not been reported in other trials.
6
Interpretation
In its most recent follow-up, the WHI E-A found a significantly reduced HR for breast cancer in those
randomized to unopposed estrogen (0.77: 95% CI 0.62-0.95) [7]. The size of the protective effect was
much the same at 10.7 years as at 7.1 years but with more events increasing the trial’s power, a
stronger conclusion of benefit was possible. Younger women in the active treatment arm of the WHI E-A
study had a similar reduction in risk of breast cancer as older women. In a recently reported trial from
Denmark, 192 women aged 45-52 years who had undergone hysterectomy were randomly assigned to
take taking unopposed estrogen (N=95) or to no treatment (N=97) and followed up for death,
cardiovascular disease and cancer for 16 years [9]. Those on unopposed estrogen as their active
treatment were reported to have an HR (0.63: 95% CI 0.23-1.78) for breast cancer similar to that in the
WHI E-A trial. The lower breast cancer incidence in the women in ESPRIT is consistent with these earlier
reports.
The WHI E-A also showed greater benefit of active treatment in younger than in older women at 10.7
years of follow-up. Rates were lower for incident CHD, MI and death (all causes) [7]. The incident data
for CHD and MI is not comparable with ESPRIT, where all the women had been recruited post-MI, but
the lower HR for death from all causes was seen in younger women in both studies.
The WHI E-A found an increased risk of stroke at 7.1 years [5], but by 10.7 years there was no significant
increase in the active intervention group, overall or in any age specific group [7]. In ESPRIT, clinical
reports of stroke were somewhat higher in the intervention arm at the end of 2 years (risk ratio 1.64
95%CI 0.60-4.47) [1]. Non-fatal strokes were not identified in the follow-up reported here but there was
only a small excess of deaths in which stroke appeared as an underlying or ‘mentioned’ cause among
those assigned to estrogen, again consistent with the findings from the larger US trial.
Conclusion.
The ESPRIT trial was set up to examine whether estrogen prevented re-infarction in post-menopausal
women. The results both of the initial trial and of this extended follow-up did not suggest important
deficit in cardiac events/mortality in the intervention arm and do not support the use of estrogen for
prevention of cardiac mortality in this group. Importantly, there was no evidence that use of unopposed
estrogen was harmful: its use by women with an intact uterus did not result in an excess risk of
endometrial cancer. As such, if estrogen is indicated in elderly women with heart disease for reasons
such as the control of menopausal symptoms, the use of unopposed estrogen may be safely considered.
A recent Cochrane review concluded that ‘for women in their 50s without a uterus taking estrogen-only
HT for 5-6 years appears relatively safe and there may even be some health benefits’ [2]. Our results
support this conclusion, even for women with a uterus, provided that there are processes in place for
the investigation and management of any vaginal bleeding arising among users.
7
Acknowledgements: None
Disclosure of interests: PH has received research grants from Schering AG and hospitality and speakers
fees from Schering Health Care Limited.
Contributions to authorship: N. Cherry, R. McNamee and P. Hannaford were responsible for the design
of the original study, with A. Heagerty contributing to decisions on cardiac aspects of the study and H.
Kitchener to the design and implementation of the gynaecological protocol. During the follow-up
reported here N. Cherry and then P. Hannaford received notifications on deaths and incident cancers. R.
McNamee carried out the statistical analyses. All authors contributed to the writing of the report.
Ethics Approval: The trial, including follow-up via the Central Registry, was approved by the central
ethics committee of the Royal College of General Practitioners, the research ethics committee of the
University of Manchester and the local research ethics committees of the 35 collaborating hospitals in
the north west of England and north east Wales.
Funding: The initial trial was funded by the UK National Health Services Research and Development
Programme on Cardiovascular Disease and Stroke though a grant to the University of Manchester.
Medication (active and placebo) used as the intervention was supplied without charge by Schering Ag.
Additional support came from Schering Health Care Limited. Continued follow-up is supported by the
University of Aberdeen. None of the funders have been involved with the collection, analysis and
interpretation of data reported here.
Trial registration: The trial was registered by ISRCTN: Number 59274741
8
References
1) The Esprit team. Oestrogen therapy for the prevention of reinfarction in postmenopausal
women: a randomized placebo controlled trial Lancet 2002; 360:2001-8.
2) Marjoribanks J, Farquhar C, Roberts H, Lethaby A. Long term hormone therapy for
perimenopausal and postmenopausal women. Cochrane Database of Systematic Reviews 2012,
Issue 7.
3) Hodis HN, Mack WJ, Lobo RA, Shoupe D, Sevanian A Mahrer PR et al. Estrogen in the prevention
of atherosclerosis: a randomized, double-blind, placebo controlled trial. Annals of Internal
Medicine 2001; 135; 939-53.
4) Writing group for the PEPI trial Effects of estrogen or estrogen/progestin regimes on heart
disease risk factors in postmenopausal women. JAMA 1995;273:199-208.
5) Anderson GL, Limacher M, Assaf AR, et al. Effects of conjugated equine estrogen in
postmenopausal women with hysterectomy: the Women’s Health initiative randomized
controlled trial. JAMA. 2004; 291:1701-1712.
6) Writing group for the Women’s Health Initiative Investigators. Risks and benefits of estrogen
plus progestin in healthy postmenopausal women. JAMA. 2002; 288:321-333.
7) LaCroix AZ, Chlebowski RT, Manson JE, Aragaki AK, Johnson KC Margolis KL et al for the WHI
investigators. Health outcomes after stopping conjugated equine estrogens among
postmenopausal women with prior hysterectomy: a randomized controlled trial. JAMA 2011;
305:1305-14.
8) Medicines Control Agency (MCA) Committee on Safety of Medicines. New product information
for hormone replacement therapy. Curr Probl Pharmacovigilance 2002; 28: 1-2.
9) Schierbeck LL, Rejnmark l, Tofteng CL, Stilgren L, Eiken P Moselilde L et al Effect of hormone
replacement therapy on cardiovascular events in recently postmenopausal women: randomized
trial. BMJ 2012 Oct 9;345:e6409. doi: 10.1136/bmj.e6409.
9
Table 1: Outcome by treatment group and age at recruitment
Age
50-59
Outcome
60-69
All ages
Active
Placebo
Active
Placebo
Active
Placebo
N=167
N=134
N=346
N=370
N=513
N=504
N
%
N
%
N
%
N
%
N
%
N
%
46
27.5
39
29.1
168
48.6
165
44.6
214
41.7
204
40.5
Ischemic heart disease (IHD)
23
13.8
14
10.5
66
19.1
58
15.7
89
17.3
72
14.3
Any heart disease
24
14.4
16
11.9
73
21.1
64
17.3
97
18.9
80
15.9
Stroke
2
1.2
2
1.5
13
3.8
11
3.0
15
2.9
13
2.6
Cancer – all sites
10
6.0
11
8.2
28
8.1
28
7.6
38
7.4
39
7.7
Ischemic heart disease (IHD)
31
18.6
20
14.9
95
27.5
89
24.1
126
24.6
109
21.6
Any heart disease
32
19.2
27
20.2
109
31.5
101
27.3
141
27.5
128
25.4
Stroke
3
1.8
5
3.7
22
6.4
16
4.3
25
4.9
21
4.2
Cancer – all sites
13
7.8
11
8.2
33
9.5
34
9.2
46
9.0
45
8.9
All sites
15
9.0
17
12.7
55
15.9
55
14.9
70
13.7
72
14.3
Breast cancer
*to 30/6/2012
2
1.2
5
3.7
5
1.4
10
2.7
7
1.4
15
3.0
Death*
All causes
Underlying cause
Any mention
Cancer Incidence**
**to 31/12/2010
10
Table 2: Hazard ratio (active/placebo) by age at recruitment (adjusted for age at risk)
Age
50-59
60-69
All Ages
Outcome
HR
95% CI
HR
95% CI
HR
95% CI
0.90
0.59-1.38
1.11
0.90-1.38
1.07
0.88-1.29
Ischemic heart disease (IHD)
1.23
0.63-2.41
1.23
0.87-1.76
1.24
0.91-1.70
Any heart disease
1.14
0.60-2.16
1.24
0.89-1.73
1.22
0.91-1.64
Stroke
0.73
0.10-5.21
1.29
0.58-2.88
1.18
0.56-2.49
Cancer – all sites
0.71
0.30-1.67
1.09
0.65-1.84
0.91
0.62-1.52
Ischemic heart disease (IHD)
1.19
0.67-2.08
1.16
0.87-1.54
1.18
0.91-1.52
Any heart disease
0.91
0.54-1.51
1.18
0.90-1.54
1.12
0.88-1.42
Stroke
0.45
0.11-1.89
1.51
0.79-2.88
1.22
0.68-2.18
Cancer – all sites
0.91
0.41-2.04
1.06
0.65-1.71
1.03
0.68-1.55
All sites
0.70
0.35-1.40
1.08
0.74-1.57
0.97
0.70-1.35
Breast cancer
0.33
0.06-1.68
0.54
0.19-1.59
0.47
0.19-1.15
Death
All causes
Underlying cause
Any mention
Cancer Incidence
11