Specific HRT tablets linked to increased risk of heart disease and blood clots

Certain hormone replacement therapy (HRT) tablets containing both estrogen 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, finds a study from Sweden published by The BMJ today.

Another HRT tablet called tibolone was associated with an increased risk of heart disease, heart attack and stroke, but not blood clots, “highlighting the diverse effects of different hormone combinations and administration methods on the risk of cardiovascular disease,” say the researchers.

HRT is used to relieve menopausal symptoms such as hot flushes and night sweats and different treatments are available depending on symptoms.

Some previous trials have suggested a link between menopausal hormone therapy and an increased risk of cardiovascular disease, but information on risks linked to different types of therapy during menopausal transition age is lacking.

To address this, researchers set out to assess the effect of contemporary menopausal hormone therapy on the risk of cardiovascular disease according to the route of administration and combination of hormones.

Their 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. They 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 sterilization.

Using monthly prescription records, the women were assigned to one of eight menopausal hormone treatment groups: oral combined continuous, oral combined sequential, oral unopposed estrogen, oral estrogen with local progestin, tibolone, transdermal combined, transdermal unopposed estrogen, 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 ischemic heart disease per 1,000 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 estrogen, and transdermal combined therapy. “If 1,000 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,” say the authors.

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, they say: “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 add.