Certain hormone treatments linked to increased heart disease risk

Certain hormone replacement therapy (HRT) tablets containing both oestrogen and progestogen are associated with a higher risk of heart disease and rare but serious blood clots known as venous thromboembolism (VTE) in women around the age of menopause, according to a study from Sweden that has been published in The BMJ.

Another HRT tablet called tibolone was associated with an increased risk of heart disease, heart attack and stroke, but not blood clot.

The researchers’ findings are based on data from 138 emulated trials (observational studies that mimic clinical trials), involving 919,614 healthy women in Sweden aged 50–58 between 2007 and 2020 who had not used hormone therapy in the previous two years.

The research excluded women with a history of heart disease, stroke, narrowed arteries or cancer, and who had undergone surgery to remove their ovaries, a hysterectomy or sterilisation.

Using monthly prescription records, the women were assigned to one of eight menopausal hormone treatment groups: oral combined continuous, oral combined sequential, oral unopposed oestrogen, oral oestrogen with local progestin, tibolone, transdermal combined, transdermal unopposed oestrogen, or no menopausal hormone therapy.

Hospital records were then used to track cardiovascular events over two years, and other potentially influential factors such as age, education level, region of residence, high blood pressure and diabetes were taken into account.

During this monitoring period, 24,089 cardiovascular events were recorded among the 919,614 women in the study.

Compared with not starting menopausal hormone therapy, starting oral combined continuous therapy or tibolone was associated with an increased risk of ischemic heart disease. This translates to approximately 11 new cases of ischaemic heart disease per 1000 women who start treatment with oral combined continuous therapy or tibolone over one year.

No increased risk of cardiovascular disease was found for transdermal treatments, which include skin patches, gels and creams.

An increased risk of blood clots was also found for oral combined continuous, oral combined sequential, oral unopposed oestrogen and transdermal combined therapy. “If 1000 women started each of these treatments and were observed for a year, we would expect to see seven new cases of venous thromboembolism across all groups,” the study authors said.

Tibolone was also linked to an increased risk of stroke and heart attack, but not blood clots.

These are observational findings, so no firm conclusions can be drawn about causality, and the authors point to limitations including a lack of data on menopausal status and the possibility that other unmeasured factors, such as smoking and body mass index, may have affected their results.

However, by using an emulated target trial design they reduced the bias common to observational studies, and use of registry data allowed them to distinguish between different types of hormone therapies, including differences in administration, regimens and combinations of hormones.

As such, the authors said, “These findings highlight the diverse effects of different hormone combinations and administration methods on the risk of cardiovascular disease.”

Future research should investigate the potential various effects on the risk of cardiovascular disease based on different progestogens used in menopausal hormone therapy, they said.

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