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Date of release: 27 June, 2016

Cardiovascular results from the ELITE study

The results from the ELITE (Early versus Late Intervention Trial with Estradiol) study have been long awaited because of its desired methodology. This was a single-center, randomized, double-blind, placebo-controlled trial in which serial carotid arterial measurements were obtained non-invasively [1]. Participants were 643 healthy postmenopausal women without diabetes and without clinical evidence of cardiovascular disease who had had no regular menses for at least 6 months or who had surgically induced menopause. At the time of randomization, participants were stratified according to the number of years past menopause: less than 6 years or 10 or more years. Participants were randomly assigned to receive oral 17β-estradiol (1 mg daily) or matching placebo. Women in the estradiol group who had a uterus also received micronized progesterone (45 mg) as a 4% vaginal gel (for 10 days per month), whereas women in the placebo group who had a uterus received matching placebo gel. The intima-media thickness at the right distal common carotid artery (CIMT) was measured every 6 months during a median 5-year follow-up period. As a secondary endpoint, cardiac CT was performed when participants completed the randomly assigned regimen. Among women who were less than 6 years past menopause at the time of randomization, the mean CIMT increased by 0.0078 mm per year in the placebo group versus 0.0044 mm per year in the estradiol group (p = 0.008). Among women who were 10 or more years past menopause at the time of randomization, the rates of CIMT progression in the placebo and estradiol groups were similar (0.0088 and 0.0100 mm per year, respectively; p = 0.29). CT values of coronary-artery calcium, total stenosis, and plaque did not differ significantly between the placebo group and the estradiol group in either postmenopause stratum.

Comment

Another recent randomized study addressed the cardiovascular effects of postmenopausal hormone therapy (MHT) in healthy women. The KEEPS (Kronos Early Estrogen Prevention Study) trial recruited recently menopausal women (participants were within 3 years since their last menstrual period, mean age 52.7 years), and followed them during 4 years of treatment with either low-dose oral conjugated estrogens (0.45 mg/day) or patch estradiol (50 μg/day) with oral progesterone (200 mg for 12 days per month) or placebo [2]. MHT had no significant effect on CIMT progression, or on the CAC (coronary artery calcification) score. However, time since menopause (years) was significantly associated with CIMT (correlation coefficient = 0.075, p = 0.029).

The differences between KEEPS and ELITE are therefore as follows: ELITE participants were a little older at enrollment, since at baseline the early postmenopause stratum had a mean age of 55.4 years, mean 3.5 years since menopause. KEEPS did not have a late postmenopause strata as in the ELITE (mean age around 63 years, time since menopause around 14 years). Also, medications and regimens were different in the two studies as outlined above, and follow-up was mean 5 years in ELITE, but only 4 years in KEEPS. The WHI (Women's Health Initiative) trial addressed the same issue of progression of arterial atherosclerosis in hormone users, but once again the characteristics of the studied population were not similar to KEEPS or ELITE [3]. Only the ‛young’ age group (50-59 years old) underwent coronary CT tests, the mean age was 55.1 years at randomization and 64.8 years at CAC measurement. All women were hysterectomized and conjugated equine estrogen (0.625 mg/day) was the drug that was used and compared to placebo. Among women who had not used MHT before enrollment in the WHI, those who had a history of bilateral oophorectomy had more than a two-fold higher odds of the presence of any CAC.

The above three studies, as well as several previous ones, pointed at a favorable cardiac outcome of MHT in women younger than 60 at initiation of therapy. Hormone users have a much slower progression of atherosclerosis and development of plaques at the coronary and carotid arteries. However, it seems that some hormonal combinations may not be associated with this benefit. Also, different study protocols may lead to inconsistent findings. Nevertheless, the clinical data from major observational and randomized trials clearly point at a small reduction in the risk for coronary events in the ‛young’ postmenopausal hormone users.

Amos PInes


Sackler School of Medicine, Tel-Aviv University, Tel-Aviv, Israel



    References

  1. Hodis HN, Mack WJ, Henderson VW, et al. Vascular effects of early versus late postmenopausal treatment with estradiol. N Engl J Med 2016;374:1221-31


    http://www.ncbi.nlm.nih.gov/pubmed/27028912

  2. Harman SM, Black DM, Naftolin F, et al. Arterial imaging outcomes and cardiovascular risk factors in recently menopausal women: a randomized trial. Ann Intern Med 2014;161:249-60


    http://www.ncbi.nlm.nih.gov/pubmed/25069991

  3. Allison MA, Manson JE, Langer RD, et al. Oophorectomy, hormone therapy, and subclinical coronary artery disease in women with hysterectomy: the Women's Health Initiative coronary artery calcium study. Menopause 2008;15:639-47


    http://www.ncbi.nlm.nih.gov/pubmed/18458645