Early initiation of menopausal hormone therapy improved some markers of CVD, but had no effect on the progression of atherosclerosis 4 years, according to new data from the KEEPS study.
Researchers conducted the randomized, double blind, placebo-controlled trial to determine whether hormone therapy was associated with cardioprotective effects in women who recently entered menopause.
The study population included women aged 42 to 58 years who were between 6 and 36 months from their last menses, had no history of CVD, and had plasma follicle-stimulating hormone levels ≥35 IU/L and/or estradiol levels <147 pmol/L.
Participants were randomly assigned one of three therapies: oral conjugated equine estrogens (Premarin, Pfizer) 0.45 mg/day (n=230); transdermal 17 beta-estradiol (Climara, Bayer HealthCare) 50 mcg/day (n=222); or placebo (n=275). Those assigned oral conjugated equine estrogens and transdermal 17 beta-estradiol also received oral progesterone (Prometrium, Abbott Laboratories) 200 mg twice monthly.
The primary outcome was change in carotid artery intima-media thickness. Secondary outcomes included changes in markers of CVD risk. Participants were followed for 4 years, at which point carotid artery intima-media thickness was available for 79.8% of participants, of whom 63.8% of all participants were still receiving study medications.
Similar atherosclerosis progression
The researchers reported a similar increase in carotid artery intima-media thickness during follow-up in all three hormone therapy groups, at a mean rate of 0.0076 mm/year.
The difference in rates of change between the oral conjugated equine estrogen group and the placebo group was 0.0008 mm/year (95% CI, –0.0012 to 0.0029); the difference in rates of change between the estradiol group and the placebo group was 0.0005 mm/year (95% CI, –0.0016 to 0.0026).
Change in coronary artery calcium score was also similar between the hormone therapy groups (risk difference for oral conjugated equine estrogen group vs. placebo group, –3.6 percentage points (95% CI, –11.4 to 4.1); risk difference for estradiol group vs. placebo group, –2.1 percentage points (95% CI, –10 to 5.7).
Some CV risk factors affected
Compared with women assigned placebo, those assigned oral conjugated equine estrogen showed increased HDL (mean difference, 2.75 mg/dL; 95% CI, 1.27-4.22), decreased LDL (mean difference, –5.1 mg/dL; 95% CI, –8.73 to –1.47), increased C-reactive protein (mean difference, 10.48 nmol/L; 95% CI, 4.95-15.91) and increased sex hormone-binding globulin (mean difference, 38.71 nmol/L; 95% CI, 34.98-42.44) during follow-up.
Compared with women assigned placebo, those assigned estradiol showed decreased total cholesterol (mean difference, –5.52 mg/dL; 95% CI, –9.76 to –1.28), decreased non-HDL (mean difference, –4.23 mg/dL; 95% CI, –7.86 to –0.61) and decreased Homeostasis Model Assessment of Insulin Resistance (HOMA-IR) score (mean difference, –0.23; 95% CI, –0.43 to –0.04) during follow-up.
The researchers reported no between-group differences in BP or interleukin-6 levels.
Vaginal bleeding was more common among women assigned estrogen compared with placebo (P<.001). Other adverse events, including serious adverse events, did not differ based on treatment.
“The North American Menopause Society and other groups support the use of [menopausal hormone therapy] for relief of menopausal symptoms in women at low risk for known complications of this therapy. Results of KEEPS are consistent with this recommendation and provide novel information that, in recently menopausal women at low cardiovascular risk, 4 years of [menopausal hormone therapy] neither increases nor decreases atherosclerosis progression as measured by [carotid intima-media thickness] or [coronary artery calcium] score. To the extent that these imaging methods predict CVD events, our findings suggest that [menopausal hormone therapy] neither is a risk nor is protective in the population studied,” S. Mitchell Harman, MD, PhD, of the Kronos Longevity Research Institute and the Phoenix Veterans Affairs Health Care System, and colleagues concluded.
Disclosure: The study was funded by the NIH and the Aurora Foundation. Some study medications were donated by Abbott Pharmaceuticals and Bayer HealthCare. See the full study for a list of the researchers’ relevant financial disclosures.