Oral Hormone Replacement Therapy Raises Blood Clot Risk

Key Points

• Oral hormone replacement therapy was associated with a higher risk of venous thromboembolism (VTE) among women aged 50–69 in a large Danish study.
• The increased VTE risk occurred regardless of oral therapy dose or treatment duration.
• Higher risks of ischemic stroke and myocardial infarction appeared mainly with high-dose oral estradiol used for more than 1 year.
• Transdermal hormone therapy did not show a general increase in thrombotic risk across dose, duration, or regimen.
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Oral Hormone Replacement Therapy and Thromboembolic Risk

Oral hormone replacement therapy was associated with an increased risk of venous thromboembolism, while the risk of ischemic stroke and myocardial infarction appeared more limited to prolonged use of high-dose oral therapy, according to a large Danish observational study published in The BMJ.

Menopausal hormone therapy can relieve symptoms such as hot flushes and night sweats. However, clinicians must consider thrombotic risks when selecting treatment. The study examined whether these risks varied according to the route of administration, dose, treatment duration, and age at treatment initiation.

Researchers used Danish health registry data from 2003 through 2021 involving women aged 50–69 years. They identified 9,807 women with VTE, 18,460 with ischemic stroke, and 11,974 with myocardial infarction. Each group was compared with women without the respective thrombotic condition.

Prescription data allowed the researchers to assess different menopausal hormone therapy regimens while accounting for sociodemographic factors, medication use, and pre-existing conditions.

How Did Oral and Transdermal Therapy Differ?

Among women who had not received hormone therapy, VTE, ischemic stroke, and myocardial infarction occurred at rates of 15.8, 20.3, and 13.0 cases per 10,000 person-years, respectively.

Oral estrogen therapy, either alone or combined with progestin, increased the absolute annual rates by 0.09% for VTE, 0.06% for ischemic stroke, and 0.03% for myocardial infarction. This translated to approximately one additional VTE case for every 1,055 women treated for 1 year.

The VTE association remained consistent across oral therapy doses and treatment durations. In contrast, the increased risks of ischemic stroke and myocardial infarction occurred primarily among women receiving high-dose oral estradiol above 1 mg/day for more than 1 year, with risk increasing alongside longer treatment.

Transdermal hormone therapy, including patches, gels, and sprays, showed no general increase in thrombotic risk regardless of dose, duration, regimen, or active ingredients. Researchers noted one exception: combined transdermal cyclic therapy was associated with a higher myocardial infarction rate, although the estimate relied on limited data.

What Do These Findings Mean for Clinical Practice?

The findings highlight the importance of considering the route of hormone therapy administration when assessing thrombotic risk in menopausal patients.

However, the observational design means the study cannot establish a cause-and-effect relationship. Researchers also lacked information about menopause age, body mass index, and smoking. In addition, the predominantly Danish population may limit how broadly the findings apply to more ethnically diverse populations.

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For HCPs, the results provide further evidence that treatment route, dose, and duration should form part of individualized discussions about menopausal hormone therapy and thrombotic risk.

Source:

BMJ Group