Use of hormone replacement therapy and risk of venous thromboembolism

Problem

During menopause in women, hormone replacement therapy (HRT) is used to relieve adverse symptoms. Although HRT treatments are effective in managing menopausal symptoms, some have been shown to have an increased risk of venous thromboembolism (VTE).Previous studies have shown an increased VTE risk associated with the use of oral HRTs, but none were sufficiently powered to provide a full comparison between different components, doses or regimens. There is also only limited information about the different transdermal hormonal therapies, which in general have shown no association with VTE risk. These knowledge gaps have been noted in the National Institute of Health and Clinical Excellence guideline on menopause. Our study investigated VTE risks for all types of HRT prescribed in the UK.

Approach

A nested case-control study based on the general female population, using records from UK general practices within Clinical Practice Research Datalink. Cases were 32,069 female patients aged 40 to 79 with clinical records of primary VTE diagnosed between 1990 and 2017, matched by age, year of birth and practice to 148,274 female controls alive and registered with the same practice at the time of case diagnosis (index date). Women with previous VTE were excluded. Exposure to different HRT preparations was based on prescriptions in the year before the index date. Effects of duration and the length of any gap since last use were investigated. Conditional logistic regression was applied to calculate odds ratios adjusted for smoking, ethnicity, body-mass index and co-morbidities associated with increased risk of VTE and use of HRT.

Findings

2390 (7%) cases and 8084 (5%) controls were exposed to either oral or transdermal hormonal therapy. 83% of exposed cases and 78% of exposed controls were prescribed oral-only therapy and 16% and 21% were prescribed transdermal-only therapy. Compared to no use, oral therapy was associated with increased VTE risk (adjusted odds ratio 1.54, 95% confidence interval 1.45 to 1.64). The risk was increased for all oral preparations and was highest for conjugated equine oestrogen with medroxyprogesterone acetate (1.80, 1.53 to 2.12). Higher oestrogen doses were consistently associated with higher VTE risks than lower doses. There was no detected difference between unopposed or sequential or cyclical regimens. For all available preparations or regimens, transdermal therapy was not associated with increased VTE risk (overall, 0.98, 0.87 to 1.12).

Consequences

In this large general population-based study, oral hormonal therapy was associated with increased VTE risk, whereas there were no increased risks for transdermal preparations. The detailed findings could help doctors and patients in their choice of hormonal therapy particularly in patients with increased VTE risk.