ELITE was designed to specifically test the timing hypothesis, 643 postmenopausal women have been randomized to a 2×2, double-blind, placebo-controlled, single-center trial according to time-since-menopause. Women without pre-existing clinical cardiovascular disease <6 years- and >10 years-since-menopause were randomized to oral estradiol (1 mg/d) or placebo (with vaginal progesterone gel or placebo for 10 days each month) in each stratum. The primary trial end point is CIMT progression measured every 6 months. The secondary trial end point is rate of cognitive decline. Based on the wealth of evidence that accumulated since 2003 in support of the initial ELITE proposal to the NIH of the timing hypothesis, a 3-year extension of the trial was awarded. The three specific aims of the ELITE extension include: 1) increased randomized treatment for an average of 5 years; 2) addition of a secondary vascular end point using non-contrast and contrast cardiac computed tomography to non-invasively measure coronary artery calcium and coronary artery lesions; and, 3) addition of a third cognitive assessment to extend measurement of cognitive decline over an average of 5 years. Primary trial results from ELITE are expected in 2013. The primary trial end point is progression of CIMT measured every year by the same methodology and technology as used in ELITE. Although women were screened for coronary artery calcium at baseline and excluded if their Agatston score was >50 U, repeat coronary artery calcium measurements will be determined at end of study and progression and incident coronary artery calcium determined as a secondary end point.
ELITE was funded by the National Institutes of Health; enrollment initiated in 2004.
Registered in clinicaltrials.gov NCT00114517
Methods and baseline cardiovascular data from the Early versus Late Intervention Trial with Estradiol testing the menopausal hormone timing hypothesis.
Hodis HN, Mack WJ, Shoupe D, Azen SP, Stanczyk FZ, Hwang-Levine J, Budoff MJ, Henderson VW.
Menopause. 2015 Apr;22(4):391-401.
This study aims to present methods and baseline data from the Early versus Late Intervention Trial with Estradiol (ELITE), the only clinical trial designed to specifically test the timing hypothesis of postmenopausal hormone therapy (HT). The timing hypothesis posits that HT effects depend on the temporal initiation of HT relative to time since menopause.
ELITE is a randomized, double-blind, placebo-controlled trial with a 2 × 2 factorial design. Six hundred forty-three healthy postmenopausal women without cardiovascular disease were randomized to oral estradiol or placebo for up to 6 to 7 years according to time since menopause (<6 or ≥10 y). Carotid artery intima-media thickness (CIMT) and cardiac computed tomography were conducted to determine HT effects on subclinical atherosclerosis across menopause strata.
Participants in the early and late postmenopausal strata were well-separated by mean age (55.4 vs 65.4 y) and median time since menopause (3.5 vs 14.3 y). Expected risk factors (age, blood pressure, and body mass index) were associated with CIMT at baseline in both strata. In the early postmenopausal group, but not in the late postmenopausal group, we observed significant associations between CIMT and factors that may play a role in the responsiveness of atherosclerosis progression according to timing of HT initiation. These include low-density lipoprotein cholesterol, high-density lipoprotein cholesterol, sex hormone-binding globulin, and serum total estradiol.
The ELITE randomized controlled trial is timely and unique. Baseline data indicate that ELITE is well-positioned to test the HT timing hypothesis in relation to atherosclerosis progression and coronary artery disease.
Vascular Effects of Early versus Late Postmenopausal Treatment with Estradiol.
Hodis HN, Mack WJ, Henderson VW, Shoupe D, Budoff MJ, Hwang-Levine J, Li Y, Feng M, Dustin L, Kono N, Stanczyk FZ, Selzer RH, Azen SP; ELITE Research Group.
N Engl J Med. 2016 Mar 31;374(13):1221-31.
Data suggest that estrogen-containing hormone therapy is associated with beneficial effects with regard to cardiovascular disease when the therapy is initiated temporally close to menopause but not when it is initiated later. However, the hypothesis that the cardiovascular effects of postmenopausal hormone therapy vary with the timing of therapy initiation (the hormone-timing hypothesis) has not been tested.
A total of 643 healthy postmenopausal women were stratified according to time since menopause (<6 years [early postmenopause] or ≥10 years [late postmenopause]) and were randomly assigned to receive either oral 17β-estradiol (1 mg per day, plus progesterone [45 mg] vaginal gel administered sequentially [i.e., once daily for 10 days of each 30-day cycle] for women with a uterus) or placebo (plus sequential placebo vaginal gel for women with a uterus). The primary outcome was the rate of change in carotid-artery intima-media thickness (CIMT), which was measured every 6 months. Secondary outcomes included an assessment of coronary atherosclerosis by cardiac computed tomography (CT), which was performed when participants completed the randomly assigned regimen.
After a median of 5 years, the effect of estradiol, with or without progesterone, on CIMT progression differed between the early and late postmenopause strata (P=0.007 for the interaction). 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 measures of coronary-artery calcium, total stenosis, and plaque did not differ significantly between the placebo group and the estradiol group in either postmenopause stratum.
Oral estradiol therapy was associated with less progression of subclinical atherosclerosis (measured as CIMT) than was placebo when therapy was initiated within 6 years after menopause but not when it was initiated 10 or more years after menopause. Estradiol had no significant effect on cardiac CT measures of atherosclerosis in either postmenopause stratum.
(Funded by the National Institute on Aging, National Institutes of Health; ELITE ClinicalTrials.gov number, NCT00114517.).