Interpretation
The impact of oestrogen-only and
combined HRT on all-cause mortality was reported separately in only a
few previous studies. The Women’s Health Initiative
Trials19 found that combined or oestrogen only HRT for
a median of 5.6 years was not associated with all-cause, cardiovascular,
or cancer mortality, and Stram et al. (2011)23 found a
reduced risk of death in younger users of combined HRT but not in older
postmenopausal women.. Our results partly agree with these two studies
but there were some major differences. WHI was a randomized control
trial consisting of 13,816 postmenopausal HRT users versus placebo, and
Stram et al. (2011) used
survey data from California Teachers Cohort Study. The mean age of women
in both studies was around 63 years, which is more than a decade away
from menopausal transition age. WHI investigated only one single dose of
oral HRT, whereas the participants in this study took various doses and
preparations of oral and transdermal HRT, and were followed up for
longer.
Pooled analysis of 26,708 women from 30 trials by Salpeter et al.(2004)42 showed that HRT reduced total mortality by
39% in women of mean age 54 years at baseline, but not in older women
(mean age 66 years). Our results on combined HRT agree with
Ettinger et al.(1996),15 Hunt et al.(1987),16Grodstein et al.(1997)17, and Salpeter et al.(2009)18 who also reported a reduced risk of all-cause
death in HRT users with a variation from 27% to 46%. However, this
study found a lower reduction of hazards of death than the
above-mentioned studies. Several factors may have caused the difference.
Firstly, this study estimated hazards using big health data from primary
care while most other studies used survey or register data. Secondly, we
analyzed combined and oestrogen-only HRT separately, while most other
studies did not. Other possible causes of lower reduction of hazards in
this study in comparison to others is that the majority of observational
studies did not have age- matched controls, and some of them were
criticized for healthy users selection bias.17 In this
study, both cases and controls have the same age and similar health
characteristics at study entry. In addition, this study estimated
hazards of mortality by adjusting for a wide range of important
confounders while most other studies adjusted for demographical and/or
lifestyle variables only. However, in unadjusted analysis, we found
greater reduction of hazards of all-cause mortality in both
oestrogen-only and combined HRT users.
This study found no significant interactions of HRT type or age at
initiation with other morbidities or lifestyle factors such as
hypertension or smoking, which means that the effect of HRT on the
hazards of all-cause mortality were the same across different patient
subgroups. This study found that a history of both oophorectomy and
hysterectomy was associated with significantly improved survival. In
addition, our result agrees with the findings of Drever et al.(1995)43 in
respect to significant survival variation due to deprivation. Finally,
this study found significant heterogeneity in patients’ survival between
GP practices.
Current NICE clinical guidelines44 in the UK recommend
offering combined HRT to symptomatic women with a uterus, and
oestrogen-only HRT to women without a uterus after discussing the
benefits and risks. According to the NICE, benefits of HRT include
prevention of osteoporotic fractures, colorectal cancer, and
cardiovascular disease if the therapy starts before the age of 60 years,
and the risks include slight increase of CHD, stroke, and thromboembolic
events. All-cause mortality studies were not reviewed by NICE yet. In
this study, combined HRT users had lower incidence of type 2 diabetes,
heart failure, and somewhat less osteoporosis,
and oestrogen-only users developed
more hypertension and CHD events than the non-users during follow-up.
Although the current NICE guideline states that oestrogen-only HRT is
associated with little or no change in the risk of breast cancer and
combined HRT can be associated with increased risk of breast cancer, we
observed the increased incidence of breast cancer for both types of HRT.
However, this did not translate into increased mortality in HRT users.
This may be because women are more likely to die from cardiovascular
disease, osteoporosis, and dementia than from breast cancer, and so
benefits in these conditions will offset risks from rarer
conditions.45 It is, therefore, important to
disseminate a balanced information on the potential benefits and risks
of HRT and not to overestimate the possible risks, to allow women and
their GPs to make an informed choice.