EPAT (Estrogen in the Prevention of Atherosclerosis Trial)

Howard N. Hodis, MD; Wendy J. Mack, PhD; Roger A. Lobo, MD; Donna Shoupe, MD; Alex Sevanian, PhD; Peter R. Mahrer, MD; Robert H. Selzer, MS; Chao-ran Liu, MD; Ci-hua Liu, MD; Stanley P. Azen, PhD, Estrogen in the Prevention of Atherosclerosis Trial Research Group.

Ann Intern Med. 2001 Dec 4;135(11):939-53.

BACKGROUND:
Although observational studies suggest that estrogen replacement therapy (ERT) reduces cardiovascular morbidity and mortality in postmenopausal women, use of unopposed ERT for prevention of coronary heart disease in healthy postmenopausal women remains untested.
OBJECTIVE:
To determine the effects of unopposed ERT on the progression of subclinical atherosclerosis in healthy postmenopausal women without preexisting cardiovascular disease.
DESIGN:
Randomized, double-blind, placebo-controlled trial.
SETTING:
University-based clinic.
PATIENTS:
222 postmenopausal women 45 years of age or older without preexisting cardiovascular disease and with low-density lipoprotein cholesterol levels of 3.37 mmol/L or greater (>/=130 mg/dL).
INTERVENTION:
Unopposed micronized 17beta-estradiol (1 mg/d) or placebo. All women received dietary counseling. Women received lipid-lowering medication if their low-density lipoprotein cholesterol level exceeded 4.15 mmol/L (160 mg/dL).
MEASUREMENTS:
The rate of change in intima-media thickness of the right distal common carotid artery far wall in computer image processed B-mode ultrasonograms obtained at baseline and every 6 months during the 2-year trial.
RESULTS:
In a multivariable mixed-effects model, among women who had at least one follow-up measurement of carotid intima-media thickness (n = 199), the average rate of progression of subclinical atherosclerosis was lower in those taking unopposed estradiol than in those taking placebo (-0.0017 mm/y vs. 0.0036 mm/y); the placebo-estradiol difference between average progression rates was 0.0053 mm/y (95% CI, 0.0001 to 0.0105 mm/y) (P = 0.046). Among women who did not receive lipid-lowering medication (n = 77), the placebo-estradiol difference between average rates of progression was 0.0147 mm/y (CI, 0.0055 to 0.0240) (P = 0.002). Average rates of progression did not differ between estradiol and placebo recipients who took lipid-lowering medication (n = 122) (P > 0.2).
CONCLUSIONS:
Overall, the average rate of progression of subclinical atherosclerosis was slower in healthy postmenopausal women taking unopposed ERT with 17beta-estradiol than in women taking placebo. Reduction in the progression of subclinical atherosclerosis was seen in women who did not take lipid-lowering medication but not in those who took these medications.

www.ncbi.nlm.nih.gov/pubmed/11730394

Hodis HN, Mack WJ, Azen SP, Lobo RA, Shoupe D, Mahrer PR, Faxon DP, Cashin-Hemphill L, Sanmarco ME, French WJ, Shook TL, Gaarder TD, Mehra AO, Rabbani R, Sevanian A, Shil AB, Torres M, Vogelbach KH, Selzer RH; Women’s Estrogen-Progestin Lipid-Lowering Hormone Atherosclerosis Regression Trial Research Group.

N Engl J Med. 2003 Aug 7;349(6):535-45.

BACKGROUND:
In postmenopausal women with coronary artery disease, conjugated equine estrogen with or without continuous administration of medroxyprogesterone acetate has failed to slow the progression of atherosclerosis. Whether 17beta-estradiol (the endogenous estrogen molecule) alone or administered sequentially with medroxyprogesterone acetate can slow the progression of atherosclerosis is unknown.
METHODS:
We conducted a double-blind, placebo-controlled trial in 226 postmenopausal women (mean age, 63.5 years) who had at least one coronary-artery lesion. Participants were randomly assigned to usual care (control group), estrogen therapy with micronized 17beta-estradiol alone (estrogen group), or 17beta-estradiol plus sequentially administered medroxyprogesterone acetate (estrogen-progestin group). In all patients the low-density lipoprotein (LDL) cholesterol level was reduced to a target of less than 130 mg per deciliter. The primary outcome was the average per-participant change between base-line and follow-up coronary angiograms in the percent stenosis measured by quantitative coronary angiography.
RESULTS:
After a median of 3.3 years of follow-up, the mean (+/-SE) change in the percent stenosis in the 169 participants who had a pair of matched angiograms was 1.89+/-0.78 percentage points in the control group, 2.18+/-0.76 in the estrogen group, and 1.24+/-0.80 in the estrogen-progestin group (P=0.66 for the comparison among the three groups). The mean difference in the percent stenosis between the estrogen group and the control group was 0.29 percentage point (95 percent confidence interval, -1.88 to 2.46), and the mean difference between the estrogen-progestin group and the control group was -0.65 (95 percent confidence interval, -2.87 to 1.57).
CONCLUSIONS:
In older postmenopausal women with established coronary-artery atherosclerosis, 17beta-estradiol either alone or with sequentially administered medroxyprogesterone acetate had no significant effect on the progression of atherosclerosis.

www.ncbi.nlm.nih.gov/pubmed/12904518

Mack WJ, Hameed AB, Xiang M, Roy S, Slater CC, Stanczyk FZ, Lobo RA, Liu CR, Liu CH, Hodis HN.

Atherosclerosis. 2003 May;168(1):91-8.

OBJECTIVE:
To determine whether the estrogen-related reduction in atherosclerosis progression demonstrated in the estrogen in the prevention of atherosclerosis trial (EPAT) is modified by body mass index (BMI).
STUDY DESIGN:
Subgroup analyses were performed using data from EPAT, a randomized, double-blind, placebo-controlled trial designed to determine whether unopposed 17beta-estradiol administered for a 2-year treatment period reduces the progression of subclinical atherosclerosis in healthy postmenopausal women. The primary trial endpoint was the rate of change of common carotid artery intima-media thickness (IMT). In this subgroup analysis, the sample was divided into 122 women with BMI<30 kg/m(2) and 77 women with BMI> or =30 kg/m(2). Statistical analysis was performed using mixed general linear models to evaluate whether the treatment effects on IMT progression rates differed in the two BMI groups.
RESULTS:
There was no significant difference in the estradiol treatment effect on IMT progression rates between postmenopausal women with BMI<30 vs. > or =30 kg/m(2) (P=0.52). In the 77 subjects who did not use lipid-lowering therapy, there was significant improvement in IMT with estradiol treatment that was evident in both BMI groups (P=0.48 for differences between BMI groups).
CONCLUSIONS:
In contrast to the epidemiological observation that obese postmenopausal women do not derive benefit from estrogen replacement therapy, results of this study indicate that estradiol treatment is beneficial in preventing progression of atherosclerosis regardless of initial BMI.
CONDENSATION:
Estradiol treatment is beneficial in preventing progression of atherosclerosis in postmenopausal women not receiving lipid-lowering therapy, regardless of their initial body mass index.

www.ncbi.nlm.nih.gov/pubmed/12732391

Steiner AZ, Hodis HN, Lobo RA, Shoupe D, Xiang M, Mack WJ.

Menopause. 2005 Nov-Dec;12(6):728-33.

OBJECTIVE:
To determine if 17beta-estradiol increases blood pressure in postmenopausal women.
DESIGN:
A total of 222 healthy postmenopausal women were randomly assigned to either 1 mg micronized 17beta-estradiol daily or placebo for 2 years. Blood pressure measurements were obtained every other month and common carotid artery intima-media thickness measured every 6 months. Statistical analyses comparing longitudinal changes in systolic and diastolic blood pressure between treatment groups used a mixed general linear model including interaction terms to evaluate variations by age or estradiol level.
RESULTS:
Both placebo and estradiol groups showed small declines in systolic and diastolic blood pressure during the trial among the normotensive subjects and subjects on antihypertensive medications. However, the decline did not differ significantly between the groups. Treatment effects on systolic blood pressure differed significantly by the age of the subject (interaction P value = 0.04) with younger women on estradiol showing on average a rise in systolic blood pressure, and older women a decline. The association between serum estradiol level and systolic blood pressure showed a similar modification with age (P = 0.03). Changes in systolic blood pressure in women on estradiol were positively correlated with intima-media thickness progression (P = 0.03).
CONCLUSIONS:
Overall, 17beta-estradiol did not influence changes in blood pressure in normotensive or hypertensive women. The effect of 17beta-estradiol treatment on systolic blood pressure may be influenced by a woman’s age. Estradiol may increase systolic blood pressure in younger postmenopausal women, while having the opposite effect in older postmenopausal women.

www.ncbi.nlm.nih.gov/pubmed/16278616

Hwang J, Mack WJ, Xiang M, Sevanian A, Lobo RA, Hodis HN.

Atherosclerosis. 2005 Aug;181(2):375-80.

The estrogen in the prevention of atherosclerosis trial (EPAT) was a 2-year randomized controlled trial in which unopposed 17beta-estradiol reduced subclinical atherosclerosis progression, measured as change in carotid intima-media thickness (CIMT). This study was conducted to determine whether long-term 17beta-estradiol 1mg daily increased plasma nitric oxide (NO) levels and whether this accounted for atheroprotection in EPAT. Although the on-trial serum estradiol level was significantly higher in the estradiol-treated group (n = 91 subjects) than the placebo group (n = 89 subjects) (mean (S.D.) = 59.0 (31.7) pg/ml versus 14.3 (10.4) pg/ml, p < 0.0001), there was no significant difference in the on-trial plasma NO levels, 18.5 (8.2) microM versus 20.1 (9.3) microM. Correlation between on-trial estradiol level and NO change was -0.22 (p = 0.003) in the total sample (placebo- and estradiol-treated subjects) and -0.21 (p = 0.049) in the estradiol-treated group. Change in NO levels was inversely correlated to change in LDL-cholesterol in the estradiol group (r = -0.23, p = 0.03). An NO response to 17beta-estradiol according to age, time since menopause and baseline CIMT was not found arguing against a possible NO effect in healthy versus diseased endothelium. NO levels were not related to CIMT progression. In this study, we found no evidence for an estrogen-induced effect on plasma total NO levels which unlikely accounted for the mechanism underlying the 17beta-estradiol atheroprotective effect on subclinical atherosclerosis progression.

http://www.ncbi.nlm.nih.gov/pubmed/16039293

Karim R, Mack WJ, Lobo RA, Hwang J, Liu CR, Liu CH, Sevanian A, Hodis HN.

Menopause. 2005 Jul-Aug;12(4):366-73.

OBJECTIVE:
To determine the extent to which the estrogen-induced changes in lipids and markers of carbohydrate metabolism explain the beneficial effect of estrogen therapy on the progression of carotid artery intima-media thickness (IMT) in postmenopausal women.
DESIGN:
A randomized, double-blind, placebo-controlled, single-center trial enrolling 222 postmenopausal women 45 years and older without cardiovascular disease and with low-density lipoprotein (LDL) cholesterol levels of 3.37 mmol/L or greater (> or = 130 mg/dL). Intervention was unopposed micronized 17beta-estradiol versus placebo. Measurements were made using high-resolution B-mode ultrasonography to measure carotid artery IMT at baseline and every 6 months on-trial.
RESULTS:
Progression of carotid IMT was inversely related to on-trial high-density lipoprotein (HDL) cholesterol (P = 0.04) and was directly related to on-trial LDL-cholesterol (P = 0.005). Compared with placebo, women randomized to estradiol showed a higher mean on-trial HDL-cholesterol level and a lower mean on-trial LDL-cholesterol level. In contrast, fasting glucose, insulin, and hemoglobin A1C were lowered and insulin sensitivity increased with estradiol therapy, but the changes were not related to carotid IMT progression. On-trial HDL-cholesterol and LDL-cholesterol were significant independent determinants of carotid IMT progression, jointly explaining 30% of the treatment effect of unopposed estrogen on the progression of carotid IMT.
CONCLUSION:
Unopposed 17beta-estradiol reduced carotid IMT progression in postmenopausal women in part by increasing HDL-cholesterol and decreasing LDL-cholesterol. Although women randomized to estradiol showed improvement in all the markers of carbohydrate metabolism, these factors did not play a significant role in carotid IMT progression.

www.ncbi.nlm.nih.gov/pubmed/16037751

Vigen C, Hodis HN, Chandler WL, Lobo RA, Mack WJ.

J Thromb Haemost. 2007 Jun;5(6):1201-8.

BACKGROUND:
Hemostatic factors influenced by postmenopausal hormone therapy may contribute to atherosclerosis. The Estrogen in the Prevention of Atherosclerosis Trial (EPAT), a 2-year, randomized, double-blind, placebo-controlled trial, demonstrated reduced subclinical atherosclerosis progression measured by change in common carotid artery intima-media thickness (CIMT) with unopposed oral 17beta-estradiol.
OBJECTIVES:
To assess the effect of postmenopausal hormone therapy on the levels of several hemostatic factors, and the relationship between these factors and the progression of subclinical atherosclerosis.
PATIENTS AND METHODS:
We measured tissue plasminogen activator (t-PA) antigen, factor (F) VII, D-dimer and albumin longitudinally, and plasminogen activator inhibitor type 1 (PAI-1) and fibrinogen at trial-end, in 186 postmenopausal women.
RESULTS:
Estradiol vs. placebo was associated with greater FVII and lower t-PA, albumin, PAI-1 and fibrinogen (all P < or = 0.001), with no estradiol effect on D-dimer (P = 0.42). Only mean on-trial t-PA was positively associated with the absolute level of CIMT on-trial (r = 0.29, P < 0.0001), but this was attenuated with age and body mass index adjustment. No longitudinally measured hemostatic factor was associated with CIMT progression. However, higher CIMT during the trial was significantly related to increases in t-PA.
CONCLUSIONS:
These results confirm previous findings regarding estrogen’s effect on hemostatic factors and show that albumin is negatively associated with estrogen therapy. These hemostatic factors did not account for the reduction of CIMT progression with 17beta-estradiol seen in EPAT. Atherosclerosis itself may affect levels of hemostatic factors (reverse causality), with subsequent involvement in atherosclerosis-associated thrombosis.

www.ncbi.nlm.nih.gov/pubmed/17389005

Steiner AZ, Xiang M, Mack WJ, Shoupe D, Felix JC, Lobo RA, Hodis HN.

Obstet Gynecol. 2007 Mar;109(3):581-7.

OBJECTIVE:
To estimate the rates of endometrial hyperplasia, bleeding episodes, and interventions among menopausal women receiving unopposed oral estradiol or placebo therapy with ultrasound monitoring over 3 years.
METHODS:
Two-hundred eighteen healthy women with intact uteri enrolled in the Estrogen in the Prevention of Atherosclerosis Trial (EPAT) or the Women’s Estrogen-Progestin Lipid-Lowering Hormone Atherosclerosis Regression Trial (WELL-HART) were randomly assigned to either 1 mg of micronized 17beta-estradiol (n=96) or placebo (n=122) daily for up to 3 years in a double-blind fashion. Patients were followed with annual measurement of endometrial thickness using transvaginal ultrasonography. Logistic regression was used to identify predictors of uterine bleeding and endometrial biopsy.
RESULTS:
Over the study periods, nine women (9.4% of patients, 95% confidence interval [CI] 3.6-15.2%) in the estradiol group developed hyperplasia. Eight of the nine cases (88.9%) of hyperplasia were simple without atypia. Women receiving estradiol were more likely than those receiving placebo to have at least one episode of uterine bleeding (67% versus 11% at 3 years, respectively, P<.001). Women in the estradiol group were also more likely to have an endometrial biopsy (48% versus 4% at 3 years, P<.001). Among women on estradiol, obesity (body mass index [BMI] greater than 30 kg/m(2)) significantly increased the odds of uterine bleeding compared with normal-weight patients (BMI 25 or less) (OR 3.7, 95% CI 1.2-11.8).
CONCLUSION:
Short-term, unopposed estradiol therapy with gynecologic monitoring may be an option for the treatment of menopausal symptoms. Menopausal women choosing estradiol therapy, especially if obese, should anticipate uterine bleeding and the possibility of an endometrial biopsy.

www.ncbi.nlm.nih.gov/pubmed/17329508

Hodis HN, St John JA, Xiang M, Cushman M, Lobo RA, Mack WJ.

Am J Cardiol. 2008 Apr 15;101(8):1131-3.

The objective of this study was to determine whether high-sensitivity C-reactive protein (hs-CRP) and serum soluble intercellular adhesion molecule-1 (sICAM-1) correlate with progression of subclinical atherosclerosis. Secondarily, the long-term effect of oral estradiol on hs-CRP and sICAM-1 were determined. Data were analyzed from 180 healthy postmenopausal women aged 45 to 80 years randomly assigned to either unopposed micronized 17beta-estradiol 1 mg/day or placebo in the Estrogen in the Prevention of Atherosclerosis Trial (EPAT). Carotid artery intima-media thickness (CIMT), hs-CRP, and sICAM-1 were measured at baseline and every 6 months thereafter for 2 years. Unopposed 17beta-estradiol significantly increased hs-CRP (p = 0.01) and decreased sICAM-1 compared with placebo (p = 0.04). Changes in hs-CRP and sICAM-1 did not correlate with changes in carotid artery intima-media thickness. In conclusion, although unopposed 17beta-estradiol significantly altered hs-CRP and sICAM-1, neither marker was associated with progression of subclinical atherosclerosis.

www.ncbi.nlm.nih.gov/pubmed/18394446

Karim R, Hodis HN, Stanczyk FZ, Lobo RA, Mack WJ.

J Clin Endocrinol Metab. 2008 Jan;93(1):131-8.

BACKGROUND:
Postmenopausal hormone therapy has been examined extensively in relation to cardiovascular disease. However, research relating serum levels of sex hormones to cardiovascular disease is sparse, and the results are inconclusive.
METHODS:
We measured sex hormones in longitudinally collected samples of 180 postmenopausal women, 91 randomized to 17beta-estradiol and 89 to placebo, in the Estrogen in the Prevention of Atherosclerosis Trial. Repeated measures of sex hormone levels were tested for an association with carotid artery intima-media thickness (CIMT), which was also assessed longitudinally over 2 yr.
RESULTS:
In all women, changes in serum estrone (P = 0.02), total estradiol (P = 0.01), free estradiol (P = 0.02), and SHBG (P = 0.005) were significantly inversely associated with CIMT progression, controlling for age and body mass index. All the estrogen compounds and SHBG were significantly inversely related with low-density lipoprotein cholesterol and positively associated with high-density lipoprotein cholesterol (all P < 0.0001), whereas free testosterone was positively related with low-density lipoprotein cholesterol and inversely associated with high-density lipoprotein cholesterol (P < 0.003). Despite an increase in serum-free estradiol with estradiol therapy, women with unchanged SHBG and free testosterone levels had an average (se) progression in CIMT of 8.53 (4.72) microm/yr, whereas women with increased free estradiol and SHBG and decreased free testosterone had the largest reduction in CIMT progression [-5.45 (2.77) microm/yr; trend P = 0.03].
CONCLUSION:
Estrogen and SHBG are associated with reduced subclinical atherosclerosis progression in healthy postmenopausal women. These associations are partially mediated by their beneficial effects on lipids. Among women taking estradiol, the most beneficial hormone profile for CIMT progression was increased free estradiol and SHBG with concomitant decreased free testosterone.

www.ncbi.nlm.nih.gov/pubmed/17925335

Karim R, Mack WJ, Hodis HN, Roy S, Stanczyk FZ.

J Clin Endocrinol Metab. 2009 Nov;94(11):4136-43.

OBJECTIVE:
Hormone therapy (HT) increases the risk of venous thrombosis and stroke. Risk of venous thrombosis and stroke is higher in older, overweight, and obese women using HT. However, the impact of age and obesity on estrogen concentrations among HT users is not well defined.
METHOD:
We measured serum levels of estrone, total and free estradiol, and SHBG in 180 postmenopausal women participating in the Estrogen in the Prevention of Atherosclerosis Trial (EPAT), 91 receiving estradiol therapy (ET) and 89 taking placebo, every 6 months over 2 yr. Mean on-trial levels of estrogens and SHBG were compared across age, body mass index (BMI), and waist to hip ratio categories among ET users and placebo separately.
RESULTS:
Among the ET users, total (P = 0.01) and free estradiol (P = 0.002) were significantly directly associated with BMI adjusted for age. SHBG was inversely related to waist to hip ratio adjusted for age (P = 0.005). Age was not associated with any of the estrogen or SHBG concentrations in ET or placebo groups. BMI was positively associated with estrone concentrations among older but not younger ET users (P for interaction = 0.03).
CONCLUSION:
Overweight and obese women using ET attain greater concentrations of estrogen compared to women with normal BMI, whereas ET users with abdominal obesity attain lower SHBG levels. Obese older women using ET have the highest concentration of estrone. It may be useful to consider age and obesity when prescribing HT to minimize the risk of venous thrombosis or stroke in postmenopausal women. Further research regarding relationships among circulating hormone levels and risk for these conditions is required to substantiate this conclusion.

www.ncbi.nlm.nih.gov/pubmed/19808850

Karim R, Stanczyk FZ, Hodis HN, Cushman M, Lobo RA, Hwang J, Mack WJ.

Menopause. 2010 Jul;17(4):785-90.

OBJECTIVE:
Hormone therapy has been shown to reduce markers of vascular inflammation in . C-reactive protein (CRP), a marker of generalized inflammation, is raised by oral estradiol therapy (ET). It is not known how sex hormone concentrations relate to the markers of inflammation in postmenopausal women taking or not taking hormone therapy.
METHODS:
This observational study includes postmenopausal women participating in the Estrogen in the Prevention of Atherosclerosis Trial. Multiple measures of serum sex hormone and sex hormone-binding globulin(SHBG) levels from 107 postmenopausal women taking oral ET and 109 taking placebo for 2 years were correlated with markers of inflammation over the same time period using generalized estimating equations.
RESULTS:
Levels of soluble intercellular adhesion molecule-1 were significantly inversely associated with estrone(P = 0.05), total and free estradiol (P = 0.008 and 0.02, respectively), and SHBG (P = 0.03) only among oral ET users. Serum homocysteine levels were also inversely associated with estrone (P = 0.001) and total and free estradiol (P = 0.0006 and 0.0009, respectively) in ET-treated women only. No such associations were observed among women taking placebo. CRP was positively associated with estrogens and SHBG among women taking oral ET but inversely associated with SHBG among the placebo group.
CONCLUSIONS:
The inverse associations of estrogens with soluble intercellular adhesion molecule-1 and homocysteine support an anti-inflammatory property of estrogen, which was observed only at pharmacological levels in postmenopausal women. The positive associations between estrogens and CRP in the ET-treated women can be explained by the first-pass hepatic effect rather than a proinflammatory response.

www.ncbi.nlm.nih.gov/pubmed/20632462

Peck A, Chaikittisilpa S, Mirzaei R, Wang J, Mack WJ, Hodis HN, Stanczyk FZ.

Climacteric. 2011 Feb;14(1):49-53.

OBJECTIVE:
A considerable number of postmenopausal women who receive estrogen therapy are also treated for hypercholesterolemia with cholesterol-lowering statins. Statins and steroid hormones can compete for the same steroid-metabolizing enzymes. We investigated whether long-term administration of statins had an effect on serum estrogen and androgen levels in postmenopausal women receiving and not receiving oral estrogen therapy.
METHODS:
A subgroup analysis from the Estrogen in the Prevention of Atherosclerosis Trial, a randomized, double-blind, placebo-controlled trial, was performed. A total of 222 women were randomized to receive either placebo or 1 mg of oral micronized 17β-estradiol daily for 2 years. In both the placebo and treatment groups, participants with low density lipoprotein cholesterol levels >160 mg/dl were treated with statins. Blood samples were obtained at baseline and every 6 months during the trial. Serum levels of dehydroepiandrosterone, androstenedione, testosterone, estrone and 17β-estradiol were measured by radioimmunoassay.
RESULTS:
Among 86 placebo- and 90 estradiol-treated subjects with baseline and on-trial hormone measurements, no significant differences were observed between the statin-free and statin-treated groups in mean changes from baseline to on-trial levels in any of the androgens or estrogens, whether or not the postmenopausal women were treated with estrogen.
CONCLUSION:
The results suggest that estrogen therapy and statins can be used simultaneously with no deleterious effects on circulating hormone levels.

www.ncbi.nlm.nih.gov/pubmed/20450412