Atherosclerosis
Conditions
Keywords
atherosclerosis, CAD, cardiac computed tomography, cardiovascular disease, carotid artery intima-media thickness, cognitive function, computed tomography, coronary artery calcium, coronary artery disease, coronary artery lesions, CVD, estrogen, estrogen therapy, hormone therapy, postmenopausal, subclinical vascular disease, timing hypothesis, ultrasonography, menopausal hormone replacement therapy, menopause, prevention, intervention
Brief summary
The purpose of this study is to examine the effects of oral 17B-estradiol (estrogen) on the progression of early (subclinical) atherosclerosis and cognitive decline in healthy postmenopausal women.
Detailed description
The primary hypothesis to be tested is that 17B-estradiol (estrogen) will reduce the progression of early atherosclerosis if initiated soon after menopause when the vascular endothelium (lining of blood vessels) is relatively healthy versus later when the endothelium has lost its responsiveness to estrogen. Ultrasonography will be used to measure the rate of change in the thickness of the carotid artery and cardiac computed tomography (CT) will be used to measure coronary artery calcium and coronary artery lesions. The second hypothesis to be tested is that 17B-estradiol (estrogen) will reduce the progression of cognitive decline if initiated soon after menopause when healthy brain tissue remains responsive to estrogen versus later when brain tissue has lost its responsiveness to estrogen. A total of 643 (actual; 504 initially proposed) postmenopausal women were randomized according to their number of years since menopause, less than 6 years or 10 years or more, to receive either oral 17B-estradiol 1 mg daily or matching placebo. Women with a uterus will also use vaginal progesterone gel 4% (or placebo gel) the last ten days of each month. The vaginal progesterone will be distributed in a double-blinded fashion along with the randomized treatment so that only women exposed to active treatment will receive active progesterone. As initially proposed, participants will undergo ultrasonography at baseline and every 6 months throughout the 2 to 5 years (average 3 years) of randomized treatment. Participants will also undergo cognitive testing at baseline and after 3 years of randomized treatment. The trial has been extended for an additional 2 to 2.5 years of randomized treatment (overall average randomized treatment of 5 years and range of 2 to 8.5 years). Ultrasonography will continue to be collected every 6 months and upon completion of randomized treatment, participants will undergo cardiac CT for coronary artery calcium and coronary artery lesion measurements. Participants will also undergo a third cognitive testing at the completion of randomized treatment.
Interventions
DRUG17B-estradiol
Oral 17B-estradiol 1 mg daily
OTHERPlacebo
Matching oral 17B-estradiol placebo daily
Sponsors
National Institute on Aging (NIA)
University of Southern California
Study design
Allocation
RANDOMIZED
Intervention model
PARALLEL
Primary purpose
PREVENTION
Masking
QUADRUPLE (Subject, Caregiver, Investigator, Outcomes Assessor)
Eligibility
Sex/Gender
FEMALE
Healthy volunteers
Yes
Inclusion criteria
* Women with a serum estradiol level 25 pg/ml or less * No period for 6 months or more * Postmenopausal less than 6 years, OR 10 years or longer
Exclusion criteria
* Clinical signs, symptoms, or personal history of cardiovascular disease * Women who have had a hysterectomy only and no oophorectomy (since time from menopause cannot be determined) * Diabetes mellitus or fasting serum glucose 140 mg/dL or greater * Uncontrolled hypertension (diastolic blood pressure 110 mmHg or greater) * Thyroid disease (untreated) * Serum creatinine greater than 2.0 mg/dL * Plasma triglyceride levels greater than 500 mg/dL * Life threatening disease with prognosis less than 5 years * Cirrhosis or liver disease * History of deep vein thrombosis or pulmonary embolism * History of breast cancer * Current hormone replacement therapy (HRT)
Design outcomes
Primary
| Measure | Time frame | Description |
|---|---|---|
| Progression of Subclinical Atherosclerosis | Baseline x 2 and then every 6 months up to 6.7 years | Rate of change in distal common carotid artery (CCA) far wall intima-media thickness (mm per year) in computer image processed B-mode ultrasonograms that were obtained at two baseline examinations (averaged to obtain the baseline CIMT value) and every 6 months during trial follow-up. |
Secondary
| Measure | Time frame | Description |
|---|---|---|
| Change in Neurocognitive Function (Global Cognition) | Baseline and at 2.5 years and 5 years | All neuropsychological test scores at baseline and follow-up assessments were standardized (\[raw score - mean score\]/standard deviation) using the baseline means and standard deviations from the entire ELITE sample. Each of three cognitive composite scores was calculated at baseline and follow-up assessments as the weighted average of the individual donor standardized test scores, weighted by the inverse correlation among tests.The change from baseline (endpoint minus baseline cognitive outcome) was computed for each of the cognitive scores (verbal memory, global cognition, and executive functions). Since the outcome is not a single test but a weighted average of multiple tests, the range is not standard and not reported. Higher scores mean better outcomes. |
| Coronary Artery Calcium | End of randomized treatment, up to 6.7 years | Number of participants with coronary artery calcium measured by cardiac computed tomography |
Countries
United States
Participant flow
Recruitment details
Participants were recruited from the general population through media campaigns.
Pre-assignment details
2166 individuals were screened by telephone, 1,271 were ineligible. 895 individuals were screened in research clinic, 252 were excluded (133 did not meet inclusion criteria; 119 declined to participate). 643 individuals were randomized.
Participants by arm
| Arm | Count |
|---|---|
| Early Postmenopause 17B-estradiol Early postmenopause, \<6 years-since-menopause, Oral 17B-estradiol 1 mg daily | 125 |
| Early Postmenopause Placebo Early postmenopause, \<6 years-since-menopause, Matching oral 17B-estradiol placebo daily | 123 |
| Late Postmenopause 17B-estradiol Late postmenopause, \>10 years-since-menopause, Oral 17B-estradiol 1 mg daily | 172 |
| Late Postmenopause Placebo Late postmenopause, \>10 years-since-menopause, Matching oral 17B-estradiol placebo daily | 176 |
| Total | 596 |
Withdrawals & dropouts
| Period | Reason | FG000 | FG001 | FG002 | FG003 |
|---|---|---|---|---|---|
| Overall Study | Adverse Event | 6 | 1 | 6 | 3 |
| Overall Study | Armed-services duty | 0 | 1 | 0 | 1 |
| Overall Study | Breast cancer diagnosis on baseline mammogram | 0 | 0 | 0 | 1 |
| Overall Study | Competing family issue | 0 | 1 | 0 | 1 |
| Overall Study | Concern about blood clots | 0 | 0 | 1 | 0 |
| Overall Study | Did not want estradiol | 1 | 1 | 0 | 0 |
| Overall Study | Lost interest | 0 | 0 | 1 | 0 |
| Overall Study | Lost to Follow-up | 2 | 2 | 2 | 1 |
| Overall Study | Moved from area | 0 | 3 | 2 | 1 |
| Overall Study | Physician Decision | 0 | 1 | 0 | 0 |
| Overall Study | Too busy | 3 | 1 | 1 | 2 |
| Overall Study | Weight increase | 0 | 0 | 1 | 0 |
Baseline characteristics
| Characteristic | Early Postmenopause 17B-estradiol | Early Postmenopause Placebo | Late Postmenopause 17B-estradiol | Late Postmenopause Placebo | Total |
|---|---|---|---|---|---|
| Age, Continuous | 55.4 years | 55.4 years | 64.3 years | 63.0 years | 60.0 years |
| Race/Ethnicity, Customized Asian | 14 Participants | 16 Participants | 8 Participants | 12 Participants | 50 Participants |
| Race/Ethnicity, Customized Black, non-hispanic | 7 Participants | 14 Participants | 17 Participants | 14 Participants | 52 Participants |
| Race/Ethnicity, Customized Hispanic | 16 Participants | 20 Participants | 20 Participants | 23 Participants | 79 Participants |
| Race/Ethnicity, Customized White, non-hispanic | 88 Participants | 73 Participants | 127 Participants | 127 Participants | 415 Participants |
| Sex: Female, Male Female | 125 Participants | 123 Participants | 172 Participants | 176 Participants | 596 Participants |
| Sex: Female, Male Male | 0 Participants | 0 Participants | 0 Participants | 0 Participants | 0 Participants |
Adverse events
| Event type | EG000 affected / at risk | EG001 affected / at risk |
|---|---|---|
| deaths Total, all-cause mortality | 1 / 323 | 1 / 320 |
| other Total, other adverse events | 216 / 323 | 226 / 320 |
| serious Total, serious adverse events | 43 / 323 | 45 / 320 |
Outcome results
Primary
Progression of Subclinical Atherosclerosis
Rate of change in distal common carotid artery (CCA) far wall intima-media thickness (mm per year) in computer image processed B-mode ultrasonograms that were obtained at two baseline examinations (averaged to obtain the baseline CIMT value) and every 6 months during trial follow-up.
Time frame: Baseline x 2 and then every 6 months up to 6.7 years
Population: Early postmenopause group (\<6 years-since-menopause) at baseline and late postmenopause group (\>10 years-since-menopause) at baseline.
| Arm | Measure | Group | Value (MEAN) |
|---|---|---|---|
| 17B-estradiol | Progression of Subclinical Atherosclerosis | Late postmenopause group | 0.0100 mm per year |
| 17B-estradiol | Progression of Subclinical Atherosclerosis | Early postmenopause group | 0.0044 mm per year |
| Placebo | Progression of Subclinical Atherosclerosis | Early postmenopause group | 0.0078 mm per year |
| Placebo | Progression of Subclinical Atherosclerosis | Late postmenopause group | 0.0088 mm per year |
Secondary
Change in Neurocognitive Function (Global Cognition)
All neuropsychological test scores at baseline and follow-up assessments were standardized (\[raw score - mean score\]/standard deviation) using the baseline means and standard deviations from the entire ELITE sample. Each of three cognitive composite scores was calculated at baseline and follow-up assessments as the weighted average of the individual donor standardized test scores, weighted by the inverse correlation among tests.The change from baseline (endpoint minus baseline cognitive outcome) was computed for each of the cognitive scores (verbal memory, global cognition, and executive functions). Since the outcome is not a single test but a weighted average of multiple tests, the range is not standard and not reported. Higher scores mean better outcomes.
Time frame: Baseline and at 2.5 years and 5 years
Population: Sample size represents the number of participants with analyzable data collected at baseline, 2.5 years, and 5.0 years. Early postmenopause group (\<6 years-since-menopause) at baseline and late postmenopause group (\>10 years-since-menopause) at baseline.
| Arm | Measure | Group | Value (MEAN) |
|---|---|---|---|
| 17B-estradiol | Change in Neurocognitive Function (Global Cognition) | Early postmenopause group | 0.42 units on a scale |
| 17B-estradiol | Change in Neurocognitive Function (Global Cognition) | Late postmenopause group | 0.29 units on a scale |
| Placebo | Change in Neurocognitive Function (Global Cognition) | Early postmenopause group | 0.40 units on a scale |
| Placebo | Change in Neurocognitive Function (Global Cognition) | Late postmenopause group | 0.36 units on a scale |
Secondary
Coronary Artery Calcium
Number of participants with coronary artery calcium measured by cardiac computed tomography
Time frame: End of randomized treatment, up to 6.7 years
Population: CAC data was obtained in 380 participants. Participants who were not taking the study products at the last follow-up visit, who had adherence to the study regimen that was lower than 80%, or who had a CAC scan more than 6 months after the final study visit were not included in the analysis. Early postmenopause group (\<6 years-since-menopause) at baseline and late postmenopause group (\>10 years-since-menopause) at baseline.
| Arm | Measure | Group | Value (COUNT_OF_PARTICIPANTS) |
|---|---|---|---|
| 17B-estradiol | Coronary Artery Calcium | Late postmenopause group | 57 Participants |
| 17B-estradiol | Coronary Artery Calcium | Early postmenopause group | 34 Participants |
| Placebo | Coronary Artery Calcium | Early postmenopause group | 24 Participants |
| Placebo | Coronary Artery Calcium | Late postmenopause group | 65 Participants |