Menopausal hormone 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 menopausal hormone therapy (HT) users to nonusers (n=40 521). There was significant heterogeneity of treatment effect between younger versus older HT 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 HT was increased for stroke, TIA and systemic embolism. In this meta-analysis, all different formulations of systemic HT studied were pooled and studied as HT.
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 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.
A systematic review 6 included 33 studies (6 trials and 27 prospective observational studies) with a total of 2 588 327 women. Overall, the evidence did not support the concerns that oral or transdermal HT increases heart disease risk. Observational data showed a beneficial cardioprotective effect even with low doses of oral HT, but there were no clinical trials. Furthermore, the current data suggested that oral and transdermal HT, in dose-dependent manner and irrespective of HT formulation, increased thromboembolic risk, as well as risk of stroke. However, transdermal estrogen with <50μg/day of estrogen combined with micronized progesterone appeared to be the safer choice with respect to thrombotic and stroke risk. The timing of HT initiation and duration may be important factors to consider when prescribing HT especially in women with adverse cardiometabolic profile and pre-existing conditions.
A nested case-control study 7 of ischemic stroke included all French women aged 51 to 62 years between 2009 and 2011 without history of cardiovascular disease or contraindication to hormone therapy. A national database was used. 3144 hospitalized stroke cases were identified and were matched for age and zip code to 12 158 controls. Compared with nonusers, the adjusted ORs of stroke were1.58 (95% CI 1.01 to 2.49) in oral estrogen users and 0.83 (95% CI 0.56 to 1.24) in transdermal estrogens users (P<0.01). There was no association of stroke with use of progesterone (OR 0.78; 95% CI 0.49 to 1.26), pregnanes (OR 1.00; 95% CI 0.60 to 1.67), and nortestosterones (OR, 1.26; 95% CI 0.62 to 2.58), whereas norpregnanes increased stroke risk (OR 2.25; 95% CI 1.05 to 4.81).
Population based nested case-control study 8 in the United Kingdom using the General Practice Research Database included all women in the database aged 50-79 years between 1987 and 2006. There were 15 710 cases of stroke matched to 59 958 controls. Exposure to menopausal hormone therapy (HT) was categorised into oestrogens only, oestrogens plus progestogen, progestogen only, and tibolone. The adjusted rate ratio of stroke associated with current use of transdermal HT was 0.95 (95% CI 0.75 to 1.20) relative to no use. The risk of stroke was not increased with use of low oestrogen dose patches (rate ratio 0.81, 95% CI 0.62 to 1.05) compared with no use, whereas the risk was increased with high dose patches (rate ratio 1.89, 95% CI 1.15 to 3.11). Current users of oral HT had a higher rate of stroke than non-users (rate ratio 1.28, 95% CI 1.15 to 1.42) with both low dose and high dose.
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