Association between hormone replacement therapy and subsequent stroke:
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《英国医生杂志》
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@nottingham.ac.uk
Abstract
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
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
Barrett-Connor E, Bush TL. Estrogen and coronary heart disease in women. JAMA 1991;265: 1861-7.
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.
Paganini-Hill A. Hormone replacement therapy and stroke: risk, protection or no effect? Maturitas 2001;38: 243-61.
Nelson HD, Humphrey LL, Hygren P, Teutsch SM, Allan JD. Postmenopausal hormone replacement therapy. Scientific review. JAMA 2002;288: 872-81.
Beral V, Banks E, Reeves G. Evidence from randomised trials on the long-term effects of hormone replacement therapy. Lancet 2002;360: 942-4.
Wren BG. Megatrials of hormonal replacement therapy. Drugs Aging 1998;12: 343-8.
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.
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.
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.
Egger M, Davey Smith G, Schneider M, Minder C. Bias in meta-analysis detected by a simple, graphical test. BMJ 1997;315: 629-34.
Badimon L, Bayes-Genis A. Effects of progestogens on thrombosis and atherosclerosis. Hum Reprod Update 1999;5: 191-9.
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.
Collins R, Armitage J. High-risk elderly patients prosper from cholesterol-lowering therapy . Lancet 2002;360: 1618-9.(Philip M W Bath, Stroke Association prof)
Correspondence to: P M W Bath philip.bath@nottingham.ac.uk
Abstract
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
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
Barrett-Connor E, Bush TL. Estrogen and coronary heart disease in women. JAMA 1991;265: 1861-7.
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.
Paganini-Hill A. Hormone replacement therapy and stroke: risk, protection or no effect? Maturitas 2001;38: 243-61.
Nelson HD, Humphrey LL, Hygren P, Teutsch SM, Allan JD. Postmenopausal hormone replacement therapy. Scientific review. JAMA 2002;288: 872-81.
Beral V, Banks E, Reeves G. Evidence from randomised trials on the long-term effects of hormone replacement therapy. Lancet 2002;360: 942-4.
Wren BG. Megatrials of hormonal replacement therapy. Drugs Aging 1998;12: 343-8.
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.
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.
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.
Egger M, Davey Smith G, Schneider M, Minder C. Bias in meta-analysis detected by a simple, graphical test. BMJ 1997;315: 629-34.
Badimon L, Bayes-Genis A. Effects of progestogens on thrombosis and atherosclerosis. Hum Reprod Update 1999;5: 191-9.
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.
Collins R, Armitage J. High-risk elderly patients prosper from cholesterol-lowering therapy . Lancet 2002;360: 1618-9.(Philip M W Bath, Stroke Association prof)