Estrogen, HDL, and Coronary Heart Disease in Women

Sponsor

Tufts University (Other)

Overall Status

Completed

CT.gov ID

NCT00083824

Collaborator

National Heart, Lung, and Blood Institute (NHLBI) (NIH)

309

Enrollment

Location

Arms

35.1

Duration (Months)

8.8

Patients Per Site Per Month

Study Details

Study Description

Brief Summary

To clarify the effects of estrogen, with or without progestin, on high density lipoprotein (HDL) in postmenopausal women.

Condition or Disease	Intervention/Treatment	Phase
Cardiovascular Diseases Coronary Disease Heart Diseases Coronary Arteriosclerosis	Drug: Estrogens, Conjugated (USP) Drug: Medroxyprogesterone 17-Acetate Drug: Placebo	Phase 2/Phase 3

Detailed Description

BACKGROUND:

Coronary heart disease (CHD) is the leading cause of death and disability in postmenopausal women in the United States. Low plasma levels of high-density lipoprotein cholesterol (HDL-C) are a well-established risk factor for CHD. Elevated plasma triglyceride (TG) levels are also a risk factor for CHD in women. HDL particles are heterogeneous in composition (containing apo A-I only, LpAI, or apo A-I and apo A-II, LpAIAII) and charge and size (preBeta1, preBeta2, alpha1-3, preAlpha1-4). Different HDL subpopulations have different physiological functions and therefore may vary in their anti-atherogenic potential. Changes in alpha1 HDL subpopulations are a predictor of coronary disease progression in men. Hormonal replacement therapy (HRT) increases plasma levels of HDL-C, but has adverse effects on TG and C-reactive protein (CRP) levels. While observational studies had indicated a protective role of HRT in CHD, recent intervention studies have shown no CHD protection with the use of HRT. Our preliminary data indicate that there is a large inter-individual variability in HDL subpopulations and TG-rich lipoprotein remnants response to HRT.

The study uses the Estrogen Replacement and Atherosclerosis (ERA) trial which offers a unique opportunity to clarify the effects of estrogen with or without progestin on HDL and its subpopulation and TG-rich particles, and the effect of genetic polymorphisms on the response of these parameters to HRT. In addition, the ERA study will allow testing of the hypothesis that HRT may be of benefit to those postmenopausal women who experience large increases in HDL subpopulations (regardless of their overall effect on HDL cholesterol), without significant changes in TG levels. In addition, by looking at the TG and remnants of TG-rich lipoproteins, this study will enable a dissection of the beneficial and the adverse effects of HRT. The ERA population consists of 309 postmenopausal women who have established CHD and have participated in a randomized, placebo controlled, double-blind study of the effects of placebo (n-105), estrogen (n=100), and estrogen plus progestin (n=104) on the progression of coronary atherosclerosis, as assessed by quantitative coronary angiography. The trial showed no difference in coronary atherosclerosis progression across treatment groups after a mean follow-up of 3.2 years.

DESIGN NARRATIVE:

The study will clarify the effects of estrogen, with or without progestin, on HDL and its subpopulations and on lipoprotein remnants. It will also examine the impact of changes in HDL subpopulations and in lipoprotein remnants during HRT on progression of coronary atherosclerosis. These studies will be conducted in participants in the Estrogen Replacement and Atherosclerosis (ERA) trial, a randomized, placebo-controlled study of HRT and progression of atherosclerosis in postmenopausal women with CHD (n=309), in whom baseline and follow-up angiographic measurements of coronary artery diameter have been obtained. The following HDL parameters will be measured: preBeta1, preBeta2, alpha1-3, preAlpha1-4 HDL subpopulations by 2dGE, LpAI and LpAIAII in plasma and apo C-III in HDL and total plasma by immuno-electrophoresis, lipoprotein remnants by an immunoseparation method, and polymorphisms at gene loci involved in HDL metabolism (lipoprotein lipase, hepatic lipase, cholesteryl ester transfer protein, scavenger receptor B1, and ATPA1 receptor). Hypotheses tested are: 1) these HDL parameters and lipoprotein remnants will be significantly associated with severity of CHD at baseline; and 2) HRT-related changes in these parameters will predict coronary atherosclerosis progression in the ERA participants.

Study Design

Study Type:

Interventional

Actual Enrollment :

309 participants

Allocation:

Randomized

Intervention Model:

Parallel Assignment

Masking:

Quadruple (Participant, Care Provider, Investigator, Outcomes Assessor)

Primary Purpose:

Health Services Research

Official Title:

Estrogen, HDL, and Coronary Heart Disease in Women

Study Start Date :

Mar 1, 2004

Actual Primary Completion Date :

Feb 1, 2007

Actual Study Completion Date :

Feb 1, 2007

Arms and Interventions

Arm	Intervention/Treatment
Placebo Comparator: Sugar Pill Placebo	Drug: Placebo 2 pills/day QID for 3 years Other Names: Sugar Pill
Experimental: Estrogens, Conjugated (USP) Conjugated Equine Estrogen 0.625 mg/day for 3 years, drug	Drug: Estrogens, Conjugated (USP) 0.625 mg/day QID for 3 years Other Names: Premarin
Experimental: Medroxyprogesterone 17-acetate Conjugated Equine Estrogen 0.625 mg/day plus Medroxyprogesterone Acetate 2.5 mg/day	Drug: Estrogens, Conjugated (USP) 0.625 mg/day QID for 3 years Other Names: Premarin Drug: Medroxyprogesterone 17-Acetate 2.5 mg/day QID for 3 years Other Names: Provera

Arm

Intervention/Treatment

Placebo Comparator: Sugar Pill

Placebo

Drug: Placebo

2 pills/day QID for 3 years

Other Names:

Sugar Pill

Experimental: Estrogens, Conjugated (USP)

Conjugated Equine Estrogen 0.625 mg/day for 3 years, drug

Drug: Estrogens, Conjugated (USP)

0.625 mg/day QID for 3 years

Other Names:

Premarin

Experimental: Medroxyprogesterone 17-acetate

Conjugated Equine Estrogen 0.625 mg/day plus Medroxyprogesterone Acetate 2.5 mg/day

Drug: Estrogens, Conjugated (USP)

0.625 mg/day QID for 3 years

Other Names:

Premarin

Drug: Medroxyprogesterone 17-Acetate

2.5 mg/day QID for 3 years

Other Names:

Provera

Outcome Measures

Primary Outcome Measures

HDL subpopulation distribution and composition [1 year]
To assess the effect of hormonal replacement therapy on HDL subpopulation profile and HDL composition in postmenopausal women with established CHD

Secondary Outcome Measures

Remnant lipoprotein cholesterol [1 year]
To assess the effect of hormonal replacement therapy on remnant lipoprotein cholesterol levels in postmenopausal women with established CHD

Eligibility Criteria

Criteria

Ages Eligible for Study:

55 Years to 80 Years

Sexes Eligible for Study:

Female

Accepts Healthy Volunteers:

Inclusion criteria:

age >55 years without natural menses for at least 5 years or a serum FSH levels >40 IU/L without natural menses for at least 1 y or bilateral oophorectomy documented coronary artery disease

Exclusion criteria:

history of breast or endometrial carcinoma history of deep-vein thrombosis or pulmonary embolism previous or planned coronary bypass gallstones fasting TG levels >400 mg/dl uncontrolled diabetes uncontrolled hypertension serum creatinine >2 mg/dl a >70% stenosis of the left main coronary artery.