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; for the Estrogen in the Prevention of Atherosclerosis Trial Research Group*
Acknowledgments: The authors thank the EPAT participants and their families for their time, effort, and support, and David H. Upmalis, MD, for his insight and foresight in helping us secure funding for this study.
Grant Support: Mead Johnson Laboratories provided an investigator-initiated grant. Also supported in part by grant R01-AG-18798 from the National Institutes of Health. Mead Johnson Laboratories also supplied the micronized 17β-estradiol and placebo pills. Pharmacia & Upjohn Company provided the medroxyprogesterone acetate, Bristol-Myers Squibb Company provided the pravastatin, Merck & Co., Inc., provided the lovastatin and simvastatin, Parke-Davis provided the atorvastatin, and Novartis Pharmaceuticals Corp. provided the fluvastatin.
Requests for Single Reprints: Howard N. Hodis, MD, Atherosclerosis Research Unit, University of Southern California, 2250 Alcazar Street, CSC 132, Los Angeles, CA 90033; e-mail, firstname.lastname@example.org.
Current Author Addresses: Drs. Hodis, C.-R. Liu, and C.-H. Liu: Atherosclerosis Research Unit, University of Southern California, 2250 Alcazar Street, CSC 132, Los Angeles, CA 90033.
Drs. Mack and Azen: Department of Preventive Medicine, University of Southern California, 1540 Alcazar Street, CHP 218, Los Angeles, CA 90033.
Dr. Lobo: College of Physicians and Surgeons, Columbia University, 622 West 168th Street, New York, NY 10032.
Dr. Shoupe: Women's and Children's Hospital, University of Southern California, 1240 North Mission Road, Room 8K5, Los Angeles, CA 90033.
Dr. Sevanian: School of Pharmacy, University of Southern California, 1985 Zonal Avenue, PSC 612, Los Angeles, CA 90033.
Dr. Mahrer: Kaiser Permanente Medical Center, 1526 North Edgemont Street, Los Angeles, CA 90027.
Mr. Selzer: Jet Propulsion Laboratory, California Institute of Technology, 4800 Oak Grove Drive, Pasadena, CA 91109.
Author Contributions: Conception and design: H.N. Hodis, W.J. Mack, A. Sevanian, P.R. Mahrer, S.P. Azen.
Analysis and interpretation of the data: H.N. Hodis, W.J. Mack, R.A. Lobo, A. Sevanian, S.P. Azen.
Drafting of the article: H.N. Hodis, W.J. Mack, R.A. Lobo, A. Sevanian, S.P. Azen.
Critical revision of the article for important intellectual content: H.N. Hodis, W.J. Mack, R.A. Lobo, D. Shoupe, A. Sevanian, R.H. Selzer, C.-R. Liu, C.-H. Liu, S.P. Azen.
Final approval of the article: H.N. Hodis, W.J. Mack, R.A. Lobo, D. Shoupe, A. Sevanian, P.R. Mahrer, R.H. Selzer, C.-R. Liu, C.-H. Liu, S.P. Azen.
Provision of study materials or patients: H.N. Hodis, R.A. Lobo, P.R. Mahrer, R.H. Selzer.
Statistical expertise: W.J. Mack, S.P. Azen.
Obtaining of funding: H.N. Hodis, R.A. Lobo.
Administrative, technical, or logistic support: H.N. Hodis, D. Shoupe, A. Sevanian, P.R. Mahrer, R.H. Selzer, C.-R. Liu, C.-H. Liu.
Collection and assembly of data: H.N. Hodis, W.J. Mack, D. Shoupe, A. Sevanian, R.H. Selzer, C.-R. Liu, C.-H. Liu.
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.
To determine the effects of unopposed ERT on the progression of subclinical atherosclerosis in healthy postmenopausal women without preexisting cardiovascular disease.
Randomized, double-blind, placebo-controlled trial.
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).
Unopposed micronized 17β-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).
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.
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).
Overall, the average rate of progression of subclinical atherosclerosis was slower in healthy postmenopausal women taking unopposed ERT with 17β-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.
* For a list of members of the Estrogen in the Prevention of Atherosclerosis Trial Research Group, see the Appendix.
Hodis HN, Mack WJ, Lobo RA, Shoupe D, Sevanian A, Mahrer PR, et al. Estrogen in the Prevention of Atherosclerosis: A Randomized, Double-Blind, Placebo-Controlled Trial. Ann Intern Med. 2001;135:939–953. doi: 10.7326/0003-4819-135-11-200112040-00005
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Published: Ann Intern Med. 2001;135(11):939-953.
Cardiology, Coronary Risk Factors, Dyslipidemia, Endocrine and Metabolism.
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