Objectives: To assess risk of venous thromboembolism associated with different types of hormone replacement therapy.
Design: Two nested case-control studies.
Setting: UK general practices contributing to QResearch or Clinical Practice Research Datalink, and linked to hospital, mortality and social deprivation data.
Participants: 80,396 female cases aged 40 to 79 years, with a primary diagnosis of venous thromboembolism between 1998 and 2017, matched by age, general practice and index date to 391,494 female controls.
Main outcome measures: Venous thromboembolism recorded on either general practice, mortality or hospital records. Odds ratios were adjusted for demographics, smoking, alcohol, comorbidities, recent medical events and other prescribed medications.
Results: Overall, 5795 cases (7.2%) and 21670 controls (5.5%) had been exposed to hormone replacement therapy within 90 days prior to the index date. 82% of exposed cases and 72% of exposed controls used oral therapy, which was associated with a significantly increased venous thromboembolism risk compared with no exposure (adjusted odds ratio 1.58, 95% confidence interval 1.52 to 1.64), both for oestrogen-only (1.40, 1.32 to 1.48) and combined preparations (1.73, 1.65 to 1.81). Oestradiol had a lower risk compared with conjugated equine oestrogen, both for oestrogen-only (0.85, 0.76 to 0.95) and for combined preparations (0.83, 0.76 to 0.91).
Compared with no exposure, conjugated equine oestrogen with medroxyprogesterone acetate had the highest risk (2.10, 1.92 to 2.31) and oestradiol with dydrogesterone had the lowest risk (1.18, 0.98 to 1.42). Transdermal preparations were not associated with venous thromboembolism risk, and this was consistent over different dosages and regimens (overall, 0.93, 0.87 to 1.01).
Conclusions: The study provides information for clinicians and menopausal women, highlighting that, with respect to venous thromboembolism risk, transdermal treatment is the safest form of hormone replacement therapy. This appears underused, with overwhelming preference still being for oral preparations.