Studies examine drug management of vasomotor symptoms in menopause
An analysis of data from the Women's Health Initiative looked at estrogen and progesterone, while an industry-funded phase 3 trial considered a nonhormonal drug in the dual neurokinin-targeted therapy class.
Both estrogen alone and estrogen plus progesterone reduced vasomotor symptoms without significantly affecting risk for atherosclerotic cardiovascular disease (ASCVD) among postmenopausal women ages 50 to 59 years, a study found.
Researchers conducted a secondary analysis of two randomized clinical trials from the Women's Health Initiative (WHI) that evaluated hormone therapy and included postmenopausal women ages 50 to 79 years at 40 U.S. clinical centers from November 1993 to September 2012. Participants took conjugated equine estrogen (CEE), 0.625 mg/d, or CEE with medroxyprogesterone acetate (MPA), 2.5 mg/d, versus placebo and were assessed for ASCVD, defined as a composite of nonfatal myocardial infarction, hospitalization for angina, coronary revascularization, ischemic stroke, peripheral artery disease, carotid artery disease, or CVD death. Results were published Sept. 15 by JAMA Internal Medicine.
Of 27,347 included postmenopausal women, CEE alone reduced symptoms by 41% across all age groups (overall relative risk [RR], 0.59; 95% CI, 0.53 to 0.66). However, in the CEE plus MPA trial, symptom reduction was attenuated with age (RR, 0.41 [95% CI, 0.35 to 0.48] for ages 50 to 59 years, 0.72 [95% CI, 0.61 to 0.85] for ages 60 to 69 years, and 1.20 [95% CI, 0.91 to 1.59] for ages 70 to 79 years; interaction P for trend<0.001). Both CEE alone and CEE plus MPA appeared to have neutral effects on ASCVD in women ages 50 to 59 years who had moderate or severe vasomotor symptoms (hazard ratios [HRs], 0.85 [95% CI, 0.53 to 1.35] and 0.84 [95% CI, 0.44 to 1.57], respectively).
While the estimated risk was higher for CEE alone than for CEE plus MPA in women ages 60 to 69 years with vasomotor symptoms, there was no clear signal of harm (HRs, 1.31 [95% CI, 0.90 to 1.90] and 0.84 [95% CI, 0.51 to 1.39], respectively). However, women ages 70 years and older with vasomotor symptoms had increased risks of ASCVD with both CEE alone (HR, 1.95 [95% CI, 1.06 to 3.59]; 217 excess events per 10,000 person-years; interaction P for trend=0.03) and CEE plus MPA (HR, 3.22 [95% CI, 1.36 to 7.63]; 382 excess events per 10,000 person-years; interaction P for trend=0.02).
The findings support guideline recommendations of prescribing hormone treatment for vasomotor symptoms in women ages 50 to 59 years, using caution if initiating hormones in women ages 60 to 69 years, and avoiding hormones in women ages 70 years and older, the authors said.
An accompanying editor's note pointed out that the WHI data are old and that doses and formulations of hormone therapy have changed since the trials were done, among other limitations. However, they wrote that this updated analysis provides the best available evidence that use of hormone therapy for vasomotor symptoms does not increase risk of ASCVD among women in their 50s but substantially increases risk among those in their 70s, with the effects among women in their 60s remaining unclear.
“These new analyses from the WHI offer valuable guidance for understanding the impact on cardiovascular risk of menopausal HT [hormone therapy] for treatment of VMS [vasomotor symptoms] in women over time,” the editor's note concluded.
A second, unrelated study, published Sept. 8 by JAMA Internal Medicine, found that elinzanetant, a dual neurokinin-targeted therapy, significantly reduced the frequency of daily moderate to severe vasomotor symptoms of menopause at 12 weeks compared to placebo.
The phase 3 study, which was conducted by Bayer, was a randomized double-blind, placebo-controlled clinical trial done at 83 sites in North America and Europe from Aug. 27, 2021, to Feb. 12, 2024. Six hundred twenty-eight postmenopausal women ages 40 to 65 seeking treatment for moderate to severe vasomotor symptoms were randomly assigned to receive once-daily oral elinzanetant, 120 mg, or matching placebo for 52 weeks. The primary outcome was mean change from baseline to week 12 in frequency of daily moderate to severe symptoms, and secondary end points included changes over 52 weeks in measures evaluating sleep disturbance and the effect on menopause-related quality of life. Exploratory end points included mean changes over 50 weeks in frequency and severity of daily moderate to severe symptoms. Elinzanetant has not yet been approved by the FDA.
Overall, 313 women received elinzanetant and 315 received placebo (mean ages, 54.6 years and 54.9 years, respectively). At week 12, the mean change from baseline in daily moderate to severe symptom frequency was −5.4 (95% CI, −6.3 to −4.5) for elinzanetant and −3.5 (95% CI, −4.1 to −2.9) for placebo. The least-squares mean difference for elinzanetant versus placebo was −1.6 (95% CI, −2.0 to −1.1) (P<0.001). Descriptive analyses showed numerical advantages for elinzanetant versus placebo, and the drug was not associated with hepatotoxic effects, endometrial hyperplasia, or meaningful changes in bone density or bone turnover markers. Treatment-related adverse events (AEs) were more common with elinzanetant than placebo (30.4% vs 14.6%), with the most frequent being somnolence, fatigue, and headache.
An accompanying editorial stated that while hormone therapy, specifically estrogen, remains the most effective treatment for menopause symptoms, many women are not candidates because of contraindications or personal preference.
“Based on the 52-week data for women experiencing a broad range of VMS frequency, elinzanetant appears to be effective in reducing VMS frequency without serious AEs,” the editorial stated. “While further safety data are needed, especially for effects on the liver, initial results are promising. Elinzanetant will add to the nonhormonal pharmacologic armamentarium for treatment of VMS, providing an important novel option.”