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

Objectives To determine the risk of stroke associated with oral and transdermal routes of administration of hormone replacement therapy. Design 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. Results 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. Conclusions 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.