A protocol for a nested case-control study assessing cardiovascular disease risk associated with menopausal hormone therapy use

Menopausal hormone therapy (MHT) is prescribed to women with moderate to severe menopausal symptoms. The relationship between MHT and cardiovascular disease remains controversial. Evidence from randomised controlled trials and observational studies has been inconsistent, partly due to differences in treatment formulations, routes of administration, and timing of initiation. This nested case-control study aims to provide detailed and comparable estimates of cardiovascular disease (CVD) risks associated with MHT use in the UK (both overall and for myocardial infarction, ischaemic stroke and transient ischaemic attack). We will use data from the Clinical Practice Research Datalink (CPRD). Women aged 40 years or over with a first diagnosis of CVD between 1998 and 2024 (cases) will be matched by age and general practice to up to five female controls with no prior record of CVD at the case’s index date. MHT exposure will be defined using primary care prescriptions for the full range of oestrogen-only and oestrogen–progestogen treatments historically available through the NHS. Use will be classified by type of hormone, route of administration, dosage and age of initiation (before or after 51 years). Conditional logistic regression will estimate odds ratios for CVD outcomes associated with current and past MHT use, treatment duration, and time since discontinuation. Models will be adjusted for lifestyle factors, deprivation, ethnicity, comorbidities, and concurrent medications. Subgroup analyses will explore potential effect modification by age, body mass index and health status. Analyses will also be carried out for women from Black and Asian ethnic population groups.