Tibolone use in menopausal hormone therapy may be associated with a 52% increased risk of cardiovascular disease, according to a recent study.

The study utilized a Swedish nationwide register-based emulated target trial to investigate the cardiovascular disease (CVD) risks associated with contemporary menopausal hormone therapy (MHT). Investigators examined 919,614 women aged 50 to 58 years who had no history of MHT use in the prior 2 years. The study, published in BMJ, spanned from July 2007 to December 2018, employing 138 nested trials initiated monthly. Women were categorized into eight MHT treatment groups, including oral and transdermal regimens, or a noninitiator cohort.

Over a 2-year follow-up, 24,089 cardiovascular events were recorded: 10,360 cases of ischemic heart disease (43.0%), 4,098 cerebral infarctions (17.0%), 4,312 myocardial infarctions (17.9%), and 9,196 venous thromboembolisms (VTE) (38.2%). Among the 77,512 MHT initiators, tibolone users exhibited the highest overall CVD risk, with a hazard ratio (HR) of 1.52 (95% confidence interval [CI] = 1.11–2.08). In disease-specific analyses, tibolone was associated with increased risks of ischemic heart disease (HR = 1.46, 95% CI = 1.00–2.14), cerebral infarction (HR = 1.97, 95% CI = 1.02–3.78), and myocardial infarction (HR = 1.94, 95% CI = 1.01–3.73).

Oral estrogen-progestin therapies were linked to elevated VTE risks: continuous combined therapy (HR = 1.61, 95% CI = 1.35–1.92) and sequential combined therapy (HR = 2.00, 95% CI = 1.61–2.49). Notably, transdermal therapies were not associated with increased risks for any of the cardiovascular outcomes assessed.

The trial design emulated a randomized trial, aligning treatment initiation and follow-up at time zero to reduce selection and immortal time biases. This study highlights the heterogeneous cardiovascular risks of MHT regimens. Oral estrogen-progestin combinations demonstrated significant associations with both VTE and CVD, whereas tibolone increased arterial thrombotic risks without affecting VTE. These findings emphasized the need for tailored MHT approaches and further research into progestin-specific effects on cardiovascular outcomes.

Full disclosures can be found in the published study.