Menopausal Hormone Therapy May Bolster Heart Health

Menopausal hormone therapy (MHT) may have heart benefits for some women with vasomotor symptoms, though effects vary by timing of initiation and race, a target trial emulation of observational data suggested.

Among perimenopausal and recently postmenopausal women with no history of cardiovascular disease (CVD), initiation of MHT was associated with a 22% reduction in CVD events (adjusted HR 0.78, 95% CI 0.62-0.98), reported Samar El Khoudary, PhD, MPH, of the Virginia Commonwealth University School of Public Health in Richmond, and co-authors.

Of note, those who initiated MHT within 10 years of menopause onset were estimated to have a 27% reduction in CVD risk (aHR 0.73, 95% CI 0.58-0.93), but there was no benefit when MHT was initiated more than 10 years after menopause onset (aHR 1.53, 95% CI 0.66-3.52), they wrote in JAMA Internal Medicine.

Race also played a factor, with initiation of MHT indicating a protective effect for Black women (aHR 0.51, 95% CI 0.33-0.81), but no clear benefit for other races.

“We hope these findings help inform conversations between women and their healthcare providers about the potential benefits and risks of menopause hormone therapy for vasomotor symptoms,” El Khoudary told MedPage Today.

However, the authors noted that, “given the lack of consistent CVD benefit and the overall risk-benefit balance, these findings should not be used to support the use of MHT for CVD prevention.”

Roughly 70% to 80% of women experience vasomotor symptoms, like hot flashes or night sweats, most often during perimenopause or menopause.

Earlier this year, the FDA approved label changes for six hormone replacement therapies that remove boxed warnings for CVD, breast cancer, and probable dementia. For more than two decades, the boxed warnings cautioned that hormone therapy increased the risks of blood clots, strokes, and other health issues based on findings from the pivotal Women’s Health Initiative (WHI) study.

In the current study, the authors observed an increased breast cancer risk among MHT initiators compared with non-initiators (aHR 1.41, 95% CI 1.00-1.98, P=0.02), but there was no significant difference between groups for venous thromboembolism events (aHR 1.00, 95% CI 0.39-2.58, P=0.99).

“Notably, our study differs from the WHI because it includes younger women who initiated MHT during perimenopause or early postmenopause,” they noted.

In an accompanying commentary, Regina Castaneda, MD, and Stephanie Faubion, MD, MBA, both of the Mayo Clinic in Jacksonville, Florida, wrote that the cardiovascular effects of MHT for those “in the early stages of the menopause transition remain poorly characterized,” in part because the existing evidence is limited by “the heterogeneity of hormone therapy preparations and routes of delivery used across studies.”

In this study, the MHT used included systemic oral or transdermal estrogen with or without progestogens, including oral contraceptives. Castaneda and Faubion said this type of hormone exposure “warrants discussion, given that the formulations used in contraceptives, characterized by higher estrogen doses and synthetic progestins, differ meaningfully from those used in postmenopausal hormone therapy regimens.”

The study authors reported no statistically significant interaction by type of hormone therapy, but Castaneda and Faubion pointed out that the analysis “was potentially underpowered to detect meaningful differences” on that front.

Still, they concluded that this study “establishes a timely foundation and provides strong observational evidence” that the timing of MHT and identity of patients have an effect on CVD risk among perimenopausal and recently postmenopausal women with vasomotor symptoms, though randomized controlled trials are still needed.

For this study, El Khoudary and colleagues used cohort data from the multicenter Study of Women’s Health Across the Nation (SWAN), which has been following more than 3,000 women who were 42 to 52 years old in 1996 or 1997, up until 2017 (study visit 16 of 18) to emulate a sequence of target trials. They compared women who initiated MHT versus women who did not at each visit, and followed the patients for CVD events.

Eligible participants had self-reported vasomotor symptoms within the last 2 weeks and were CVD-free with no prior MHT use. The primary outcomes were self-reported CVD events, including myocardial infarction, stroke, heart failure, and revascularization, as well as CVD-related deaths, pulled from death certificates. A total of 224 fatal and nonfatal CVD events occurred over the 20-year follow-up.

Of the 2,737 women who reported vasomotor symptoms, 755 initiated MHT (mean age 53.7), with a mean 3.7 years of use. Sixty percent of participants were white, 23.9% were Black, and 16.2% were other races and ethnicities. Those who initiated MHT had a mean follow-up time of 9.6 years compared with 11.8 years among non-initiators. Initiators were more likely to be white, college educated, financially secure, have health insurance, and not be taking a lipid-lowering medication.

The authors noted that their study was limited by its observational nature and the potential for residual confounding.