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It was noted by Lemay et al that the Women's Health Initiative (WHI) had an older age distribution and a late start of hormone therapy (HT). Many of the women in the WHI had been postmenopausal and without estrogen for 10-12 years before randomization to HT or placebo. The average age was 63 years old. The women in the WHI experienced an excess of coronary events, strokes and thromboembolic disease.
The Heart and Estrogen/Progestin Replacement Study (HERS), a randomized controlled trial of secondary prevention, indicated that women with known cardiovascular disease (CVD) who received HT had slightly worse outcomes than those on placebo after 4 years.
Women in observational studies started HT during the perimenopausal at 45-55 years of age. HT was used for the relief of menopausal symptoms. These earlier studies indicated HT could be cardio-protective.
A paper published recently in the Archives of Internal Medicine/Volume 166: February 13, 2006, reviewed data from a younger group of women in the WHI. These women were age 50 to 59. After careful review of the data, there was a suggestion of lower coronary heart disease (CHD) risk among women taking estrogen.
A possible mechanism causing different cardiovascular outcomes between early and late start HT is the increase in the tendency of blood to clot produced by oral estrogens absorbed into the hepatic-portal circulation as it passes through the liver. Oral estrogens increase the hepatic production of clotting factors and decreases anti-clotting factors. This results in the greater production of fibrin split products, which is consistent with accelerated intravascular thrombus formation. These effects were not observed when estrogen was delivered systemically by the transdermal route.
The differences in results reported by the clinical trials and the observational studies may be related to the differences in clinical characteristics of the study populations or the differences in hormonal formulations, doses and/or routes of administration. The KEEPS is designed to provide new information about these issues. In addition, it evaluates the effect of oral and transdermal estrogen on cognition and quality of life issues.
KEEPS is being conducted at nine clinical centers in the United States.
Each clinical center will recruit 90 women aged 42-58 for a study total of 720 women. Eligibility criteria are:
Participants in KEEPS will have a complete medical and reproductive history, and physical exam including a breast and pelvic examination and a pap smear. Screening procedures will include a vaginal ultrasound to rule out endometrial hyperplasia. The Beck Depression Scale and the Mini-Mental State Examination will be administered to exclude depression and dementia. Participants will also have blood drawn for chemistries, receive an electrocardiogram, and undergo coronary calcium measured by x-ray tomography and a carotid intimal medial thickness (CIMT) determination done by carotid ultrasound. KEEPS will also include a comprehensive cognitive test battery and an assessment of quality of life including mood, fatigue, sleep quality and sexual function.
KEEPS will evaluate the effects of low dose oral estrogen, transdermal estrogen and placebo on the cognitive domain and cardiovascular outcomes related to atherosclerosis over a five year period. Its primary end point is atherosclerotic burden rather than clinical coronary events. It will provide important information about the effects of early initiation of HT and route of administration. The successful completion of the KEEPS will provide significant information to our current knowledge.
Kronos Early Estrogen Prevention Study (KEEPS)
KEEPS is a multicenter, four-year randomized, double-blind, placebo controlled clinical trial. It evaluates the effectiveness of oral and transdermal estrogen in preventing the progression of carotid intimal thickness and the accrual of calcium in recently menopausal women.It was noted by Lemay et al that the Women's Health Initiative (WHI) had an older age distribution and a late start of hormone therapy (HT). Many of the women in the WHI had been postmenopausal and without estrogen for 10-12 years before randomization to HT or placebo. The average age was 63 years old. The women in the WHI experienced an excess of coronary events, strokes and thromboembolic disease.
The Heart and Estrogen/Progestin Replacement Study (HERS), a randomized controlled trial of secondary prevention, indicated that women with known cardiovascular disease (CVD) who received HT had slightly worse outcomes than those on placebo after 4 years.
Women in observational studies started HT during the perimenopausal at 45-55 years of age. HT was used for the relief of menopausal symptoms. These earlier studies indicated HT could be cardio-protective.
A paper published recently in the Archives of Internal Medicine/Volume 166: February 13, 2006, reviewed data from a younger group of women in the WHI. These women were age 50 to 59. After careful review of the data, there was a suggestion of lower coronary heart disease (CHD) risk among women taking estrogen.
A possible mechanism causing different cardiovascular outcomes between early and late start HT is the increase in the tendency of blood to clot produced by oral estrogens absorbed into the hepatic-portal circulation as it passes through the liver. Oral estrogens increase the hepatic production of clotting factors and decreases anti-clotting factors. This results in the greater production of fibrin split products, which is consistent with accelerated intravascular thrombus formation. These effects were not observed when estrogen was delivered systemically by the transdermal route.
The differences in results reported by the clinical trials and the observational studies may be related to the differences in clinical characteristics of the study populations or the differences in hormonal formulations, doses and/or routes of administration. The KEEPS is designed to provide new information about these issues. In addition, it evaluates the effect of oral and transdermal estrogen on cognition and quality of life issues.
KEEPS is being conducted at nine clinical centers in the United States.
Each clinical center will recruit 90 women aged 42-58 for a study total of 720 women. Eligibility criteria are:
- Menses absent for at least 6 months and no more than 36 months
- Last spontaneous menses occurring after age 40
- Good general health
- Plasma FSH level > 35mIU/ml
- E2 levels < 40 pg/ml
- Normal mammogram within 1 year of randomization
Participants in KEEPS will have a complete medical and reproductive history, and physical exam including a breast and pelvic examination and a pap smear. Screening procedures will include a vaginal ultrasound to rule out endometrial hyperplasia. The Beck Depression Scale and the Mini-Mental State Examination will be administered to exclude depression and dementia. Participants will also have blood drawn for chemistries, receive an electrocardiogram, and undergo coronary calcium measured by x-ray tomography and a carotid intimal medial thickness (CIMT) determination done by carotid ultrasound. KEEPS will also include a comprehensive cognitive test battery and an assessment of quality of life including mood, fatigue, sleep quality and sexual function.
KEEPS will evaluate the effects of low dose oral estrogen, transdermal estrogen and placebo on the cognitive domain and cardiovascular outcomes related to atherosclerosis over a five year period. Its primary end point is atherosclerotic burden rather than clinical coronary events. It will provide important information about the effects of early initiation of HT and route of administration. The successful completion of the KEEPS will provide significant information to our current knowledge.
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