Randomized trials and observational studies on the effects of menopausal hormone therapy (MHT) have reported an increased risk of cardiovascular disease (CVD). However, these reports might not reflect use of contemporary menopausal hormone therapy, built on today’s guidelines. This study aims to update current knowledge on the association between the use of contemporary MHT and the risk of ischemic heart disease (IHD), myocardial infarction (MI), cerebral infarction and venous thromboembolism (VTE).
We emulated a target trial using combined data from the national prescription register, patient register, and death register in Sweden. Eligible women were those between 50-58 years of age during follow-up (2007-2020) and without a previous history of any cardiovascular event, cancer or MHT use. The was designed as a series of “trials” where eligible women were categorized as either non-initiators or initiators of any type of MHT, oral combined continuous, oral combined sequential, oral estrogen, tibolone, transdermal estrogen and transdermal combined. We estimated the hazard ratios (HRs) of IHD, MI, cerebral infarction and VTE separately, for initiators versus non-initiators.
A total of 55,525,123 person “trials” were generated including 963 408 eligible women, of which 76 983 were initiators. Compared with non-initiators, initiators of oral estrogen were associated with an increased HR of IHD: 1.26 (95% CI: 1.09-1.47), Cerebral infarction: 3.12 (2.70-3.61), and VTE 1.77 (1.54-2.04), but not with MI. Transdermal estrogen therapy was associated with a decreased HR of IHD: 0.68 (0.56-0.81), MI 0.46 (0.38-0.56), and VTE 0.75 (0.63-0.89). Between 2007 and 2020 we observed a shift towards the usage of transdermal estrogen products, resulting in a 50% decrease of oral estrogen usage.
Our findings show that oral estrogen poses a higher risk of IHD, Cerebral infarction and VTE compared to transdermal therapy, which aligns with previous randomized trials. Oral estrogen in contrast to transdermal estrogen undergoes first-pass metabolism in the liver which in turn increase the synthesis of procoagulant factors and, as a result, increase the risk of IHD, Cerebral infarction and VTE.
The observed decrease in the use of oral estrogen agrees with revised guidelines for MHT, and is likely to have caused a significant reduction in the incidence of CVD attributed to MHT.
