BMJ  2005;330:342 (12 February), doi:10.1136/bmj.38331.655347.8F (published 7 January 2005)

Primary care

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

¹ Division of Stroke Medicine, Institute of Neuroscience, Queen's Medical Centre, University of Nottingham, Nottingham NG7 2UH

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.

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 or transient ischaemic attack and not separately.

Quality assessment—We assessed studies for quality of randomisation, blinding, reporting of withdrawals, generation of random numbers, and concealment of allocation.

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.¹¹

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 subjects^w17 and 16 608.^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.

View larger version (20K): [in this window] [in a new window]   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), 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} one because it did not have a control group,^w40 and one because its data are yet to be published (see table B on bmj.com).^w29

Data quality
Trials varied in their quality score¹² 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 was significantly increased by a third (number needed to harm 147) in those randomised to hormone replacement therapy (fig 2, table). 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

View larger version (51K): [in this window] [in a new window]   Fig 2 Effects of hormone replacement therapy (HRT) on stroke events

 

View this table: [in this window] [in a new window]   Effect of hormone replacement therapy on stroke and its type and outcome, and transient ischaemic attack

 

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). We found no statistical heterogeneity for any of the stroke outcomes.

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

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.

We must therefore conclude that 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

This is the abridged version of an article that was posted on bmj.com on 7 January 2005: http://bmj.com/cgi/doi/10.1136/bmj.38331.655347.8F

Contributors: See bmj.com

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.

References

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2. 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.
3. Wenger N, Speroff L, Packard B. Cardiovascular health and disease in women. N Engl J Med 1993;329: 247-56.[Free Full Text]
4. Paganini-Hill A. Hormone replacement therapy and stroke: risk, protection or no effect? Maturitas Journal of the Climacteric and Postmenopause 2001;38: 243-61.[CrossRef][Web of Science][Medline]
5. 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]
6. 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][Web of Science][Medline]
7. Wren BG. Megatrials of hormonal replacement therapy. Drugs Aging 1998;12: 343-8.[CrossRef][Web of Science][Medline]
8. 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.[Web of Science][Medline]
9. Collins P. Clinical cardiovascular studies of hormone replacement therapy. Am J Cardiol 2002;90(suppl): 30-4F.
10. 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][Web of Science][Medline]
11. 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]
12. 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][Web of Science][Medline]

(Accepted 1 December 2004)

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