Hormone replacement therapy is not recommended for menopausal symptoms in women with increased risk of stroke or history of stroke.
The recommendation attaches a relative high value on preventing a severe adverse event (stroke) compared to improvement of symptoms for which other interventions can also be used.
A meta-regression analysis 3 included 31 RCTs comparing HRT users to nonusers (n=40 521). There was significant heterogeneity of treatment effect between younger versus older HRT initiators for all-cause mortality (I²=89.7%), cardiac mortality (I²=75.2%), and CHD events (I²=67.3%). Both groups experienced an increase in stroke, TIA and systemic embolism (1112/18 774 in the HRT group versus 734/18 070 in the control group; OR 1.52; 95% CI 1.38 to 1.67). When performing the meta-regression, as age increased the treatment effect of HRT was increased for stroke, TIA and systemic embolism.
A meta-analysis 4 assessing the risk of vascular events included 15 observational studies at moderate risk of bias with follow-up of 3 to 20.25 years. When compared to transdermal oestrogen therapy (ET), oral ET was associated with increased risk of a first episode of venous thromboemolism (RR 1.63; 95% C, 1.40 to 1.90; I² 53%), deep venous thrombosis (RR 2.09; 95% CI 1.35 o 3.23; I² 0 %), and possibly stroke (RR 1.24; 95% CI,1.03 to 1.48; a single case-controlled study), but not myocardial infarction (RR 1.17; 95% CI 0.80 to 1.71; I² 74%).
A systematic review and meta-analysis 1 including 28 studies with a total of 39 769 subjects reviewed completed randomised controlled trials assessing effect of hormone replacement therapy on subsequent risk of stroke.
Hormone replacement therapy (HT) was associated with significant increases in total stroke (OR 1.29; 95% confidence interval 1.13 to 1.47, n = 28), non-fatal stroke (1.23; 95% CI 1.06 to 1.44, n = 21), stroke leading to death or disability (1.56; 95% CI 1.11 to 2.20, n = 14), ischaemic stroke (1.29; 95% CI 1.06 to 1.56, n = 16), and a trend to more fatal stroke (1.28; 95% CI 0.87 to 1.88, n = 22). It was not associated with haemorrhagic stroke (1.07; 95% CI 0.65 to 1.75, n = 17) or transient ischaemic attack (1.02; 95% CI 0.78 to 1.34, n = 22).
A Cochrane review [Abstract] 2 included 22 studies involving 43 637 women. Nearly 70% of the data was derived from two studies (HERS 1998; WHI 1998). Most participants were postmenopausal American women with at least some degree of comorbidity, and mean participant age in most studies was over 60 years. None of the studies focused on perimenopausal women. Combined continuous HT increased the risk of stroke (after 3 years' use: from 6 per 1000 to between 6 and 12 per 1000; RR 1.46, )5% CI 1.02 to 2.09; 2 trials, n=17 585). Oestrogen-only HT increased the risk of stroke (after 7 years' use: from 24 per 1000 to between 25 and 40 per 1000; RR 1.33, 95% CI 1.06 to 1.67; 1 trial, n=10 739).
A national historical cohort of women aged 51 to 70 years was established by linking 5 Danish registries 5. Of the 980 003 included women, 20 199 suffered a stroke (78% ischemic, 12% hemorrhagic, and 10% subarachnoid hemorrhage). In total, 36% of women used hormone therapy. Current use conferred a relative rate of 1.16 (95% CI 1.12 to 1.22). Compared with never users, the rate ratio of all stroke was increased: with continuous (1.29, 95% CI 1.21 to 1.37), cyclic combined estrogen/progestin (1.11, 95% CI 1.04 to 1.20), and estrogen only oral therapy (1.18, 95% CI 1.10-1.26). The increased risk was because of ischemic stroke, but not hemorrhagic stroke. Transdermal application of hormone therapy was not associated with risk of stroke.
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