HRT for Menopause and CV Risk: Two Observational Studies Provide Insights

Two new observational studies add to the growing evidence base on cardiovascular risks associated with hormone replacement therapy (HRT) taken by women around the time of menopause.

Specifically, the impact of HRT on overall CV risk among those with vasomotor symptoms—namely, hot flashes and night sweats—varies depending on when treatment is initiated and for how long, with racial and ethnic differences also apparent, according to one study.

The second showed that the risk of thromboembolism is increased across the board for women taking oral, but not transdermal, HRT. Yet the risks of ischemic stroke and MI only seem to go up when women use high-dose, oral HRT for longer than a year.

In the years since the Women’s Health Initiative (WHI) trials dashed hopes that hormone replacement in postmenopausal women could help prevent cardiovascular disease, new data have emerged showing that it doesn’t affect long-term mortality, with risks varying by type of HRT. Still other studies have hinted at lower coronary artery calcium scores with HRT, and the recent removal of a “black-box” warning has enabled greater use for women who can benefit.

In combination, the recently released studies reinforce the already existing recommendations to consider age, time since menopause, and underlying CVD risk factors when deciding whether to use HRT, JoAnn E. Manson, MD, DrPH (Brigham and Women’s Hospital, Boston, MA), a lead investigator for the WHI trials, commented to TCTMD.

Manson, who was not involved in the new research, said “sometimes calculating a PREVENT risk score can be a benefit in identifying the more appropriate candidates for hormone therapy.

“If a woman has a really high PREVENT risk score, [we] probably would want to avoid hormone therapy,” she continued. “But women with very low scores would be particularly good candidates in addition to taking into account age, time since menopause, and obviously whether there’s an indication for treatment such as bothersome vasomotor symptoms.”

Importantly, “women really need to share in decision-making because very often the decisions will depend on whether a woman is favorably disposed to treatment [and] whether she’s more concerned about this endpoint versus another endpoint,” Manson said.

“Now that the black-box warning has been removed, there’s more impetus for a personalized decision-making because the [label] was sort of one-size-fits-all,” she added. “It put all types of hormone therapy in the same category, [which] made it seem like hormone therapy was bad for all women regardless of their risk factor profile.”

SWAN Findings

For the first study, published online recently in JAMA Internal Medicine, Ziyuan Wang, PhD (University of Pittsburgh School of Public Health, PA), and colleagues looked at 2,737 women from the Study of Women’s Health Across the Nation (SWAN) who had vasomotor symptoms, including 755 (mean age 53.7 years) who initiated HRT over the 20 years of follow-up.

Compared with women who did not initiate HRT, those who did saw a lower overall risk for CVD (adjusted HR 0.78; 95% CI 0.62-0.98). When stratified by when HRT began, this benefit was observed in women who initiated HRT within 10 years of menopause (adjusted HR 0.73; 95% CI 0.58-0.93) but not those who started more than 10 years after the onset of menopause (adjusted HR 1.53; 95% CI 0.66-3.52; P for interaction = 0.02).

Additionally, HRT showed a protective effect in Black women (adjusted HR 0.51; 95% CI 0.33-0.81), but not in white women (adjusted HR 1.07; 95% CI 0.77-1.49) or those whose race was categorized as “other” (adjusted HR 0.64; 95% CI 0.25-1.67; P for interaction = 0.007).

Manson said these findings are very similar to what investigators observed in WHI data.

“It provides further reassurance about treating vasomotor symptoms with menopausal hormone therapy early in menopause but raises some concerns and caution about hormone therapy being for vasomotor symptoms initiated later in menopause, such as after 10 years,” she said. “Sometimes those symptoms of hot flashes and night sweats are not specifically due to menopause. They may not be the usual vasomotor symptoms due to declining estrogen, because those are likely to occur earlier in menopause.”

These other causes might be a marker for increased risk of cardiovascular disease, and these women don’t generally do well on HRT, according to Manson. “The convergence of the findings in SWAN, which is an observational study, and the Women’s Health Initiative, provides reassurance about the credibility of those findings.”

In an accompanying editorial, Regina Castaneda, MD, and Stephanie S. Faubion, MD (both Mayo Clinic, Jacksonville, FL), say the study “establishes a timely foundation and provides strong observational evidence that the effect on CVD risk of hormone therapy initiation among perimenopausal and recently postmenopausal women with [vasomotor symptoms] varies by time since menopause and race and ethnicity.

“However, this study also highlights that the definitive trials needed to guide clinical decision-making and advance the health of millions of women have yet to be conducted,” they add.

One of the biggest challenges of observational reports in this space to date has been the “heterogeneity of hormone therapy preparations and routes of delivery used across studies,” the editorialists argue. Specifically, WHI used oral conjugated estrogen with or without medroxyprogesterone acetate, and while these formulations were also used during the SWAN study period, they are less frequently used in contemporary practice.

Now, physicians tend to prescribe “lower-dose transdermal estradiol and micronized progesterone, which carry substantially different pharmacokinetic profiles, hepatic first-pass effects, and potentially distinct cardiovascular and thrombotic risk profiles compared with conjugated estrogen and medroxyprogesterone acetate,” Castaneda and Faubion write. The current study also includes hormonal contraceptives, “a methodological caveat that 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.”

Danish Data

In another study published online recently in the BMJ, Julie Berggreen, MD (Steno Diabetes Centre Copenhagen, Denmark), and colleagues show that oral HRT in menopausal women (ages 50-69 years) in Denmark is associated with an increased risk for thromboembolism, with high-dose therapy used for more than 1 year additionally tied to greater risks for ischemic stroke and MI. 

Using Danish health registries, the researchers analyzed data on 9,807 women with venous thromboembolism (VTE), 18,460 with ischemic stroke, and 11,974 with MI between 2003 and 2021. Women were excluded if they had a medical history of venous thrombosis, arterial thrombosis, cancer, liver disease, thrombophilia, oophorectomy, infertility treatment, endometriosis, or polyendocrine metabolic ovarian syndrome.

Among women who had not used menopausal HRT, the rates of VTE, ischemic stroke, and MI were 15.8, 20.3, and 13.0 per 10,000 person-years, respectively. Compared with women who were not using oral HRT (estrogen therapy alone or combined with progestin), current users had higher rates of VTE (HR 1.6; 95% CI 1.5-1.8), ischemic stroke (HR 1.3; 95% CI 1.2-1.4), and MI (HR 1.2; 95% CI 1.1-1.3). These translated to absolute risk increases per year of 0.09%, 0.06%, and 0.03%, respectively, as well as corresponding numbers need to harm for 1 year of use of 1,055, 1,642, and 3,846.

Oral estradiol consistently increased the risk of VTE, with use of doses greater than 1 mg/day for more than 1 year linked to increased risks of ischemic stroke and MI with longer treatment. Comparing greater than 5 years of use to none, the risks of ischemic stroke (HR 1.8; 95% CI 1.4-2.2) and MI (HR 1.8; 95% CI 1.4-2.4) increased substantially.

These increases in risk were not observed among women who used transdermal estradiol, except for a greater risk of MI for those on transdermal combined cyclic therapy compared with nonusers (HR 2.1; 95% CI 1.1-4.1).

In an accompanying editorial, the study’s senior author, Amani Meaidi, MD, PhD (Copenhagen University Hospital of North Zealand, Denmark), argues that much remains unknown about menopause and its ideal treatment.

“These findings do not support describing menopausal hormone therapy as simply safe or unsafe; the results instead suggest that there is no single risk profile for hormone therapy,” she writes. “Risk may depend on the therapy prescribed, the method of use, the dosage, and duration of treatment.”

Future research needs to “capture heterogeneity rather than exploring average treatment effects alone,” Meaidi says. “We need evidence that distinguishes between formulations, doses, and methods of use, while also accounting for the characteristics and baseline risks of the women receiving hormone therapy. Equally importantly, we need to understand why women experience menopause so differently in the first place.”

In the past, women were “unnecessarily frightened away from effective treatment,” but that doesn’t mean that the next era of menopause care should make “uncertainty disappear from the conversation,” she continues. “Women deserve to know when treatment is likely to help, what risks may be relevant to them, and where evidence remains uncertain. Clinicians need the same information, and researchers need to ask more fundamental questions about menopause itself.”

Manson, speaking with TCTMD, cautioned against relying too much on observational studies to guide decisions about HRT in menopausal women but noted that randomized trials in this space will be a hard sell moving forward.

“We’re still hoping to do a randomized trial of transdermal estradiol micronized progesterone, because that is the contemporary formulation being used and it’s more similar to what women naturally make,” she said. A large-scale RCT will help lend greater understanding of “the associations with cardiovascular disease, breast cancer, diabetes, many of these chronic diseases, but it’s going to be a challenge to get funding for a trial of that nature because it’s probably a trial of 30,000 to 35,000 women.”

For now, Manson said, “the evidence is reassuring enough that [HRTs] can be used for their FDA-approved indications.”