Transdermal and oral hormone replacement therapy and the risk of stroke: a nested case-control study. BMJ 340:c2519

McGill Pharmacoepidemiology Research Unit, Center for clinical epidemiology, Jewish General Hospital, Department of Epidemiology and Biostatistics, McGill University, Montreal, Canada H3T 1E2.
BMJ (online) (Impact Factor: 17.45). 06/2010; 340(jun03 4):c2519. DOI: 10.1136/bmj.c2519
Source: PubMed


To determine the risk of stroke associated with oral and transdermal routes of administration of hormone replacement therapy.
Population based nested case-control study. Setting About 400 general practices in the United Kingdom contributing to the General Practice Research Database. Participants Cohort of all women in the database aged 50-79 years between 1 January 1987 and 31 October 2006 who were members of a practice that fulfilled predefined quality criteria and without a diagnosis of stroke before cohort entry. For each case of stroke occurring during follow-up, up to four controls were selected from among the cohort members in the risk sets defined by the case. Exposure to hormone replacement therapy (HRT) was categorised into oestrogens only, oestrogens plus progestogen, progestogen only, and tibolone. Oestrogens were further subdivided according to the route of administration (oral v transdermal) and dose (high v low). Main outcome measures Rate ratio of stroke associated with current use of oral and transdermal HRT compared with no use. Current use was considered as a prescription whose duration included the index date.
There were 15,710 cases of stroke matched to 59 958 controls. The rate of stroke in the cohort was 2.85 per 1000 per year. The adjusted rate ratio of stroke associated with current use of transdermal HRT 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(0.62 to 1.05)) compared with no use, whereas the risk was increased with high dose patches (rate ratio 1.89 (1.15 to 3.11)). Current users of oral HRT had a higher rate of stroke than non-users (rate ratio 1.28 (1.15 to 1.42)) with both low dose and high dose.
The use of transdermal HRT containing low doses of oestrogen does not seem to increase the risk of stroke. The presence of residual confounding, however, cannot be entirely excluded in the interpretation of this finding.

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    • "There are no trial data directly comparing stroke risk with varying types and doses of estrogen as existing clinical trials were based on single regimens of HRT. Data from available observational studies are conflicting since some of them indicate a similar stroke risk between subjects using high and low doses of estrogen while other studies show a dose–response association [132–134]. Clinical trial results show that the use of either estrogen plus progestin or estrogen alone (taken orally) increases stroke risk in post-menopausal women [134–136]. "
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    • "Furthermore, the type of progestin may also and again be a determinant factor since combinations with 19-norpregnanes were found to be associated with an increased VTE risk even when the oestrogen is given by the transdermal route (Canonico et al., 2007). More recently, transdermal HT did not appear to increase the risk of stroke in another independent case/control study, especially with regimens using low doses of oestrogens (Renoux et al., 2010). Thus, although these findings should be confirmed by randomized clinical trials, they strongly suggest that both the route of oestrogen administration and the type of progestin may be important determinants of the overall benefit–risk profile of HT. "
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    • "One additional report from the WHI ancillary study of coronary artery calcium showed that women with vasomotor symptoms who were given estrogen more immediately after the onset of menopause and for a shorter duration had a reduced calcified-plaque burden (Allison et al., 2010). Finally, a new large case-control study based on UK general practices showed that estrogen alone or combined with a progestogen is not a risk factor for stroke if the estrogen is used at low doses and administered transdermally (Renoux et al., 2010). "
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