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Hormone therapy ‘timing hypothesis’ gains ground in ELITE

Publish date: December 12, 2014

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ELITE findings jibe with WHI results

The results from the ELITE study are consistent with what we found in the Women’s Health Initiative. Last year, my collaborators from the Women’s Health Initiative and I reported that among the subgroup of women treated with conjugated equine estrogens alone, women who entered the study at age 50-59 years showed a net reduction, compared with the placebo-treated controls, in both total mortality and by a composite tally of death plus nonfatal events that included coronary heart disease, stroke, and five other adverse outcomes (JAMA 2013;310:1358-68). Women aged 60-69 years on estrogen alone had a virtually identical number of events as the placebo group, and women aged 70-79 years had a substantial excess of deaths and composite events, compared with their placebo counterparts. This age-based difference in response was statistically significant, and a remarkable pattern that we did not see in women who received with estrogen plus systemic treatment with medroxyprogesterone.

It was clear that age, as well as time from the start of menopause, played a role in the estrogen-alone arm of the Women’s Health Initiative.

^{Whitney McKnight/Frontline Medical News}

Dr. JoAnn E. Manson

These findings prompted me and my associates to formulate an algorithm and mobile app for managing menopausal symptoms and deciding whether or not a postmenopausal woman is a good candidate for hormonal therapy (Menopause 2014; 22:1-7). We do not endorse hormone therapy for any purpose other than suggesting it as an option to consider for postmenopausal women who experience moderate to severe hot flashes, night sweats, or both. Among these women, we suggest that hormone therapy is a reasonable option for women who are 10 or fewer years removed from menopause onset and if their 10-year risk for an atherosclerotic cardiovascular disease event is 5% or less as calculated by the 2013 risk calculator developed by the American Heart Association and American College of Cardiology. If these women 10 or fewer years out from their menopause start have a 6%-10% 10-year risk we also endorse hormone therapy as an option, but in a transdermal formulation. For women more than 10 years out from menopause, and for those with a greater than 10% 10-year risk, we suggest avoiding hormone therapy.

Dr. JoAnn E. Manson is professor of medicine and chief of preventive medicine at Harvard University and Brigham and Women’s Hospital, both in Boston. She had no disclosures. She made these comments in a lecture at the American Heart Association Scientific Sessions. Dr. Manson has served as lead investigator from the Women’s Health Initiative since the study began.

AT THE AHA SCIENTIFIC SESSIONS

References

CHICAGO– The “timing hypothesis” of estrogen’s ability to slow progression of atherosclerotic disease in relatively young postmenopausal women received a boost in results from a randomized trial with 643 participants.

The trial, designed about a decade ago to test the timing hypothesis, produced results showing that systemic treatment with 17beta-estradiol alone (plus topical progesterone) slowed progression of carotid intima-media thickness compared with placebo in women fewer than 6 years out from menopause, while the same treatment had no effect compared with placebo in women 10 or more years removed from menopause, Dr. Howard N. Hodis said at the American Heart Association Scientific Sessions.

Dr. Howard Hodis

The new results “support the timing hypothesis, whereby women who start hormone therapy within 6 years of menopause show a significant slowing of subclinical carotid-artery atherosclerosis, whereas women who are more than 10 years postmenopausal when starting hormone therapy show no difference from placebo,” said Dr. Hodis, professor of medicine and director of the atherosclerosis research unit at the University of Southern California, Los Angeles. The findings “are consistent with the majority of the literature” that previously reported evidence supporting a net benefit from hormone therapy when started in women who are young, and not long after they entered menopause, he added.

The ELITE (Early Versus Late Intervention Trial With Estradiol) investigators enrolled 643 postmenopausal women at the University of Southern California and stratified them into two subgroups: women fewer than 6 years removed from the onset of menopause, and women 10 or more years out from menopause. The average age of women in the younger group was about 55 years, and they averaged just under 4 years since menopause onset. Women in the older group averaged about 64 years and were an average of about 14 years removed from menopause onset.

Dr. Hodis and his associates randomized women within each of the two subgroups to daily treatment with 1 mg oral, micronized 17beta-estradiol or placebo. Women treated with estradiol who had an intact uterus also applied a micronized progesterone gel on 12 days out of every cycle, while those who received a daily placebo also applied a placebo gel. The study’s primary endpoint was the rate of change in the intima-media thickness (IMT) of the common carotid artery, measured once every 6 months. Compliance with the assigned regimens reached or exceeded 98% among all women in the study.

During 6 years of follow-up, the rate of increase in carotid IMT among the women who entered the study at least 10 years after the start of menopause tracked nearly identically between those on hormone therapy and those on placebo, with a difference between the two arms that was not statistically significant. In contrast, the women who began hormone therapy fewer than 6 years after menopause onset showed a statically significant difference in the rate of change in their carotid IMT, depending on their treatment assignment. After 6 years, the average increase in carotid IMT was roughly 40% less in women who received hormone therapy, compared with those randomized to placebo. The difference in IMT change between the older women and the younger women was also statistically significant, Dr. Hodis reported.

Dr. Hodis had no disclosures.

mzoler@frontlinemedcom.com

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