HRT associated with increased risk of stroke Print E-mail

The below comment in the British Medical Journal clearly indicates that Hormone Replacement Therapy "significantly increase[s] the risk of total stroke, non-fatal stroke, stroke leading to death or disability, and ischaemic stroke and [is] associated with a trend to more fatal stroke". Comes as no surprise, but surely this is the final nail in the HRT coffin! Fifty years of the Hazards, Risks and Tricks of the menopause industry, are more than "enough"!

Scroll down to read the research article - Lynette
---------
 2005; 330 (12 February)

HRT is associated with increased risk of stroke

Hormone replacement therapy (HRT) does not protect postmenopausal women from stroke, but rather increases the risk, particularly of ischaemic stroke. On page 342, Bath and Gray report the results of a meta-analysis of 28 randomised controlled trials with 39 769 participants. Hormone replacement therapy significantly increased the risk of total stroke, non-fatal stroke, stroke leading to death or disability, and ischaemic stroke and was associated with a trend to more fatal stroke. They found no evidence of the association with haemorrhagic stroke or transient ischaemic attack.

Credit: SHEILA TERRY/SPL
^^^^^^^^^^^^^^^^^^^^^^^^


 2005;330:342 (12 February)

Primary care

Association between hormone replacement therapy and subsequent stroke:a meta-analysis

Philip M W Bath, Stroke Association professor of stroke medicine1, Laura J Gray, medical statistician1 1 Division of Stroke Medicine, Institute of Neuroscience, Queen's Medical Centre,University of Nottingham,Nottingham NG7 2UH
Correspondence to: P M W Bath philip.bath{at}nottingham.ac.uk

Abstract:Objectives To review completed trials assessing effect of hormone replacement therapy on subsequent risk of stroke,assessing stroke by
pathological type,severity,and outcome.

Table 1 Effect of hormone replacement therapy on stroke and its type and outcome,and transient ischaemic attack Design Systematic review of randomised controlled trials identified from the Cochrane Library,Embase,and Medline;reviews;and reference lists of relevant papers.
Studies reviewed 28 trials,with 39 769 subjects,were identified.
Review measures Rates for cerebrovascular events analysed with a random
effects model.Sensitivity analyses for heterogeneity included phase of
prevention (primary or secondary),type of hormone replacement therapy
(oestrogen alone or combined with progesterone),type of oestrogen
(estradiol or conjugated equine oestrogen),size of trial (< 5000 or > 5000
patients),length of follow up (£ 3 years or > 3 years),sex (women only or
men only),and trial quality (high or low).
Results Hormone replacement therapy was associated with significant
increases in total stroke (odds ratio 1.29 (95% confidence interval 1.13 to
1.47), n = 28),non-fatal stroke (1.23 (1.06 to 1.44), n = 21),stroke
leading to death or disability (1.56 (1.11 to 2.20), n = 14),ischaemic
stroke (1.29 (1.06 to 1.56), n = 16),and a trend to more fatal stroke (1.28
(0.87 to 1.88), n = 22).It was not associated with haemorrhagic stroke
(1.07 (0.65 to 1.75), n = 17) or transient ischaemic attack (1.02 (0.78 to
1.34), n = 22). Statistical heterogeneity was not present in any analysis.
Conclusions Hormone replacement therapy was associated with an increased
risk of stroke,particularly of ischaemic type.Among subjects who had a
stroke, those taking hormone replacement therapy seemed to have a worse
outcome.Hormone replacement therapy cannot be recommended for the primary
or secondary prevention of stroke.

Introduction

Sex steroid hormones are believed to provide women with endogenous
protection against cerebrovascular events—premenopausal women have a lower
risk of stroke than men of the same age,1 2 and the incidence of stroke in
women increases rapidly after the menopause,3 coincident with diminished
circulating levels of oestrogen and progesterone.As a result,hormone
replacement therapy has been used widely for vascular prophylaxis in
parallel with its known effects in reducing menopausal symptoms and bone
loss.However,two meta-analyses of observational studies have suggested
that hormone replacement therapy may increase risk of stroke,especially
ischaemic stroke.4 5 Furthermore,the results of randomised controlled
trials have given conflicting results,with studies either finding no
benefit or apparent hazard.A recent non-systematic review of randomised
controlled trials found that hormone replacement therapy was associated with
an increased risk of stroke.6

The aim of this study was to review systematically the evidence from
completed randomised controlled trials of hormone replacement therapy and
subsequent stroke risk,in particular assessing stroke by pathological type,severity,and outcome.

Methods
Literature search—We identified publications from searches of the Cochrane
Library,Embase,Medline (to May 2004),previous reviews,7-10 and reference
lists from identified articles.

Study selection—We included completed,published,and non-confounded
randomised controlled trials that compared hormone replacement therapy with
a control group and that reported stroke events,or where such events could
be calculated.Trials could include participants of either sex since early
studies assessed the role of hormone replacement therapy in preventing
vascular events in men.We excluded publications not in English or where
event numbers were given for stroke and transient ischaemic attack combined
and not separately.

Quality assessment—We assessed studies for quality of randomisation,
blinding, reporting of withdrawals, generation of random numbers,and
concealment of allocation.Trials scored one point for each area addressed,
therefore receiving a score between 0 and 5 (highest level of quality).11

Data abstraction—All data were independently extracted by LJG and PMWB.
Disparities were resolved by discussion.

Study characteristics—We recorded information on trial size,treatment
regimen (oestrogen alone or plus progesterone), length of follow up,and
outcome.Outcomes included stroke events (fatal and non-fatal), type of
stroke (ischaemic, haemorrhagic, not known),and functional outcome
(combined death and disability or dependency). Where data were available, we
also recorded the number of transient ischaemic attacks (not included in the
overall stroke outcome) and data related to intention to treat analyses.

Quantitative data synthesis
We analysed data using Stata (version 7) and Cochrane Review Manager
(version 4.2). We assessed the effect of hormone replacement therapy on
dichotomous outcomes from the odds ratio calculated with a random effects
model since we expected the trials to be heterogeneous.

We used pre-specified sensitivity analyses to explain any heterogeneity,
including phase of stroke prevention (primary or secondary), type of hormone
replacement therapy (oestrogen only or oestrogen plus progesterone), type of
oestrogen (estradiol or conjugated equine oestrogen), size of trial (£ 5000
or > 5000 patients), length of follow up (£ 3 years or > 3 years), sex, and
quality of trial (high (5) or low (< 5)). We assessed interactions between
subgroups and treatment.We examined publication bias using Eggers test.12

Results
Study characteristics
We identified 28 trials with 39 769 subjects for inclusion in our study (fig
1, table A on bmj.com).w1-w28 The trials varied in size between 59
subjectsw17 and 16 608.w26 Fifteen trials investigated primary prevention of
stroke,w5-w7 w9-w12 w14 w17-w19 w22 w24 w26 w28 and 12 studied patients with
prior vascular events (stroke,w1-w3 w21 ischaemic heart disease,w4 w8 w15
w16 w20 w23 w25 and venous thromboembolismw13). The average age of patients
varied from 55 to 71.Three trials included men,with one trial of men
exclusively.w1-w3 Three trials required that women should not have had a
hysterectomy.w9 w20 w26 Follow up varied from 0.7 to 6.8 years.Twelve
trials studied hormone replacement therapy with oestrogen alone, and 16
studied oestrogen plus progesterone.All trials,apart from five,w6 w14-w16
w27 were placebo controlled.Eleven trials,all small,did not record any
stroke events.

Fig 1 Results of literature search for randomised controlled trials of
hormone replacement therapy (HRT) that reported stroke events

We excluded 12 trials (fig 1, table B on bmj.com), eight because they did
not report vascular events,w30-w35 w37 w38 two because they did not
distinguish between stroke and transient ischaemic attacks (total n =
685),w36 w39 and one because it did not have a control group.w40 The women's
international study of long duration oestrogen after the menopause (WISDOM,
n = 5664) was closed early after the release of data from the dual therapy
arms of the women's health initiative trialw29; its data are yet to be
published.

Data quality
Trials varied in their quality score11 from 2 to 5, median 5 (maximum
score). All trials included were randomised, and 96% of trials gave adequate
details of withdrawals.

Quantitative data synthesis
Stroke occurred in 2% of the participants randomised to no hormone
replacement therapy, and this rate was significantly increased by a third
(number needed to harm 147) in those randomised to hormone replacement
therapy (table 1, fig 2). This increase in stroke resulted from an excess of
ischaemic strokes but not primary intracerebral haemorrhage, as was seen in
the women's health initiative dual trial.w26 An early increase in stroke
occurred during the first six months of treatment in Viscoli et al's trial
of secondary stroke prevention,w21 analogous to the early increase in
coronary events seen in a trial of secondary prevention of coronary heart
disease.w20 Both therapy arms of the women's health initiative trial
(oestrogen alone and in combination with progesterone) were stopped
prematurely because of therapy being associated with hazard.w26 w28

Fig 2 Effects of hormone replacement therapy (HRT) on stroke events

A poor outcome after stroke, judged as combined death and dependency, was
increased by half with hormone replacement therapy; we also found a
non-significant increase in fatal stroke. This relation between hormone
replacement therapy and severe stroke was present individually in three
trials.w20 w21 w26 Hormone replacement therapy did not alter the rate of
transient ischaemic attack (table 1). We found no statistical heterogeneity
for any of the stroke outcomes.

Table 2 shows the results of our sensitivity analyses on several prognostic
factors for the total stroke outcome. These results seem to be driven by the
large women's health initiative trial, with significant effects being seen
for the subgroups that included this study. However, we found no significant
heterogeneity between trials examining primary versus secondary stroke
prevention, oestrogen alone versus combination hormone replacement therapy,
conjugated equine oestrogen versus estradiol, shorter versus longer follow
up, smaller versus larger trials, those including exclusively men versus
women alone, and high versus lower quality. We found no significant
publication bias for the "all stroke" outcome (Eggers test P = 0.19).

Table 2 Sensitivity analyses of the effect of hormone replacement therapy
on total stroke

Discussion
This systematic review supports the results of individual trials and
previous reviews finding that hormone replacement therapy does not reduce
the risk of stroke in postmenopausal women. Indeed, it was associated with
an overall 29% increase in the risk of stroke. This effect was driven by an
increase in ischaemic but not haemorrhagic stroke. Importantly, the severity
of stroke was increased with hormone replacement therapy, since the
frequency of a poor functional outcome, judged as combined death and
disability or dependency, was 56% higher in those randomised to therapy.
Similarly, fatal stroke was non-significantly increased.

Possible explanations for results
Why hormone replacement therapy should increase ischaemic stroke and its
severity when biological plausibility and some previous observational
studies suggested it might protect against cerebrovascular events remains
unclear. Firstly, it is possible that the results of the studies we reviewed
are wrong, but this is unlikely since in none of the studies did hormone
replacement therapy reduce stroke—25 trials had neutral results, and three
found that therapy increased stroke risk.

Secondly, the trials used either oestrogen alone or combination hormone
replacement therapy. Although long term therapy with oestrogen alone can
promote uterine cancer, this would not explain an increase in stroke. In
contrast, adding a progestogen could have had detrimental effects since
progestogens can promote atherogenesis and vasoconstriction.13 This is
particularly relevant for medroxyprogesterone acetate, which was used in
most of the trials of combination therapy. However, we found no
heterogeneity between trials of oestrogen alone and combination therapy,
suggesting that oestrogen itself, given as estradiol or conjugated equine
oestrogen, might be the culprit.

Thirdly, within-class differences in hormone replacement therapy may mean
that the most appropriate type of oestrogen has yet to be tested adequately;
the trials assessed either conjugated equine oestrogens or estradiol but not
other types such as phytoestrogen.14 However, there was no evidence for
statistical heterogeneity between the trials with respect to type of
oestrogen.

Fourthly, the dose of oestrogen (and progestogen if present) may have been
too high. The usual starting doses of conjugated equine oestrogen and
estradiol in Britain in postmenopausal women are 0.625 mg and 1 mg
respectively, although the dose may be titrated up if menopausal vasomotor
symptoms persist. These doses are below those used in several of the trials.

Fifthly, the delivery route may be important since substantial
pharmacological differences exist between oral and transdermal
administration of oestrogen, especially regarding hepatic first pass
metabolism.

Lastly, several of the trials may have been too short, with a median length
of less than three years, contrasting with the earlier observational
studies. Of note, the trials by Simon et al and Viscoli et al showed an
early vascular hazard that disappeared later.w20 w21 The hazard during the
first year of treatment seems to reflect the development of a thrombophilic
state that may not persist. This raises the possibility that an extended
follow up would have revealed long term benefit. An analogous situation
exists with statin treatment, whereby benefit was found in trials with
longer rather than shorter follow up.15 Nevertheless, the women's health
initiative trial, the largest of the trials we reviewed, had follow up for
more than five years and yet found no beneficial effect on stroke risk in
either of its therapy arms.

Conclusions
We have found that the use of hormone replacement therapy is associated with
an increased risk of stroke, typically ischaemic in type and severe in
nature. Hormone replacement therapy cannot be recommended for the primary or
secondary prevention of stroke.


What is already known on this topic

Postmenopausal women have a greater risk of stroke than premenopausal women

Hormone replacement therapy has been used widely for vascular prophylaxis
and to reduce menopausal symptoms and bone loss

Some randomised controlled trials have shown that hormone replacement
therapy may increase the risk of stroke

What this study adds

Hormone replacement therapy is associated with an increased risk of stroke,
especially of ischaemic type

Hormone replacement therapy cannot be recommended for the primary or
secondary prevention of stroke

------------------------------------
Details of the search strategy used, of the trials identified in the search,
and of references w1-w40 are on bmj.com

Contributors: PMWB conceived of the study, collated data, and drafted the
paper and is guarantor. LJG collated data, performed statistical analyses,
and revised the paper.

Funding: PMWB is Stroke Association professor of stroke medicine. LJG is
funded, in part, by the Stroke Association (TSA 01/03) and BUPA Foundation.
The Division of Stroke Medicine receives core funding from the Stroke
Association.

Completing interests: None declared.

Ethical approval: None required.

Amendment

This is Version 2 of the paper. In this version table 1 has been corrected
to show the control event rate for the outcome "Death or dependency" as
0.53% [not 0.1%]. Also, in the discussion, in the section "Possible
explanations for results," the second sentence now reads: "Firstly, it is
possible that the results of the studies we reviewed are wrong, but this is
unlikely since in none of the studies did hormone replacement therapy reduce
stroke—25 [not 11] trials had neutral results, and three found that therapy
increased stroke risk."

References
Barrett-Connor E, Bush TL. Estrogen and coronary heart disease in women.
JAMA 1991;265: 1861-7.[Abstract]
Kannel WB, Thom TJ. Incidence, prevalence and mortality of cardiovascular
disease. In: Schlant RC, Alexander RW, eds. The heart. New York:
McGraw-Hill, 1994: 185-97.
Wenger N, Speroff L, Packard B. Cardiovascular health and disease in women.
N Engl J Med 1993;329: 247-56.[Free Full Text]
Paganini-Hill A. Hormone replacement therapy and stroke: risk, protection or
no effect? Maturitas 2001;38: 243-61.[CrossRef][ISI][Medline]
Nelson HD, Humphrey LL, Hygren P, Teutsch SM, Allan JD. Postmenopausal
hormone replacement therapy. Scientific review. JAMA 2002;288:
872-81.[Abstract/Free Full Text]
Beral V, Banks E, Reeves G. Evidence from randomised trials on the long-term
effects of hormone replacement therapy. Lancet 2002;360:
942-4.[CrossRef][ISI][Medline]
Wren BG. Megatrials of hormonal replacement therapy. Drugs Aging 1998;12:
343-8.[ISI][Medline]
Zec RF, Trivedi MA. Effects of hormone replacement therapy on cognitive
aging and dementia risk in postmenopausal women: a review of ongoing
large-scale, long-term clinical trials. Climacteric 2002;5:
122-34.[ISI][Medline]
Collins P. Clinical cardiovascular studies of hormone replacement therapy.
Am J Cardiol 2002;90(suppl): 30-4F.
Salpeter SR, Walsh JME, Greyber E, Ormiston TM, Salpeter EE. Mortality
associated with hormone replacement therapy in younger and older women. J
Gen Intern Med 2004;19: 791-804.[CrossRef][ISI][Medline]
Moher D, Pham B, Jones A, Cook DJ, Jadad AR, Moher M, et al. Does quality of
reports of randomised trials affect estimates of intervention efficacy
reported in meta-analyses? Lancet 1998;352: 609-13.[CrossRef][ISI][Medline]
Egger M, Davey Smith G, Schneider M, Minder C. Bias in meta-analysis
detected by a simple, graphical test. BMJ 1997;315: 629-34.[Abstract/Free
Full Text]
Badimon L, Bayes-Genis A. Effects of progestogens on thrombosis and
atherosclerosis. Hum Reprod Update 1999;5: 191-9.[Abstract/Free Full Text]
Glazier MG, Bowman MA. A review of the evidence for the use of
phytoestrogens as a replacement for traditional estrogen replacement
therapy. Arch Intern Med 2001;161: 1161-72.[Abstract/Free Full Text]
Collins R, Armitage J. High-risk elderly patients prosper from
cholesterol-lowering therapy [commentary]. Lancet 2002;360:
1618-9.[CrossRef][ISI][Medline]
(Accepted 1 December 2004)