Study reveals CV Risk Profiles of Different Hormone Therapies and their Clinical Implications for Menopausal Treatment

Cardiovascular diseases are the leading cause of death globally. Despite developing at a later stage than men, women develop cardiovascular diseases during the midlife period that coincide with the menopausal period. This phase of life is characterized by a decrease in estrogen and an increase in follicle-stimulating hormone concentrations that affect the neuroendocrine system. This condition is treated by systemic menopausal hormonal therapy. Systemic menopausal therapy that contains estrogen mitigates the vasomotor symptoms. However, research has shown that systemic menopausal therapy can affect cardiovascular health. Due to knowledge gaps between the effects of menopausal therapy on cardiovascular health, researchers conducted a trial to assess the impact of contemporary menopausal hormone therapy on the risk of cardiovascular disease according to the route of administration and combination of hormones.

A Nationwide register-based emulated target trial was carried out from Swedish national registries involving 9,19,614 women aged 50-58 who did not use hormone therapy in the previous two years. A total of 138 nested trials were conducted beginning each month from July 2007 until December 2018. For every trial, the prescription registry data of that particular month was used to identify women who had not used hormone therapy in the previous two years. These identified women were assigned to one of eight treatment groups: oral combined continuous, oral combined sequential, oral unopposed estrogen, oral estrogen with local progestin, tibolone, transdermal combined, transdermal unopposed estrogen, or non-initiators of menopausal hormone therapy.

Hazard ratios with 95% confidence intervals were calculated for venous thromboembolism, ischemic heart disease, cerebral infarction, and myocardial infarction, both individually and as part of a composite cardiovascular disease outcome. Contrasting initiators assessed treatment effects to non-initiators in observational analogs of "intention-to-treat" analyses and continuous users to never users in "per protocol" analyses.

Findings:

• The trial included 77 512 women who were initiators of any menopausal hormone therapy and 842 102 women who were non-initiators.
• Out of them, 24 089 women had an event recorded during the follow-up:

10 360 (43.0%)	ischemic heart disease event
4098 (17.0%)	cerebral infarction event
4312 (17.9%)	myocardial infarction event
9196 (38.2%) had a	venous thromboembolic event

• When compared to non-initiators, tibolone was associated with an increased risk of cardiovascular disease in intention-to-treat analyses.
• An increased risk of ischemic heart disease was seen with the initiators of tibolone or oral estrogen-progestin therapy.
• Venous thromboembolism risk was increased in oral continuous estrogen-progestin therapy, sequential therapy, and estrogen-only therapy.
• Tibolone usage was associated with an increased risk of cerebral infarction and myocardial infarction as per protocol analyses.

The study concluded that menopausal therapy is associated with increased cardiovascular disease outcomes, with estrogen-progestin therapy causing heart disease and venous thromboembolism, while tibolone was associated with ischemic heart disease, cerebral infarction, and myocardial infarction but not venous thromboembolism. The choice of hormonal therapy should be individualized based on the patient’s cardiovascular risk profile. Clinicians should consider cardiovascular health and tailor it according to the patient’s needs.

Further reading: Contemporary menopausal hormone therapy and risk of cardiovascular disease: Swedish nationwide register based emulated target trial. doi:https://doi.org/10.1136/bmj-2023-078784.