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Original Research |

Arterial Imaging Outcomes and Cardiovascular Risk Factors in Recently Menopausal Women: A Randomized TrialCardiovascular Disease and Menopausal Hormone Therapy

S. Mitchell Harman, MD, PhD; Dennis M. Black, PhD; Frederick Naftolin, MD, DPhil; Eliot A. Brinton, MD; Matthew J. Budoff, MD; Marcelle I. Cedars, MD; Paul N. Hopkins, MD, MSPH; Rogerio A. Lobo, MD; JoAnn E. Manson, MD, DrPH; George R. Merriam, MD; Virginia M. Miller, PhD; Genevieve Neal-Perry, MD, PhD; Nanette Santoro, MD; Hugh S. Taylor, MD, PhD; Eric Vittinghoff, PhD; Mingzhu Yan, MD, PhD; and Howard N. Hodis, MD
[+] Article and Author Information

† Deceased.

This article was published online first at www.annals.org on 29 July 2014.


From the Kronos Longevity Research Institute and Phoenix Veterans Affairs Health Care System, Phoenix, Arizona; University of California, San Francisco, San Francisco, California; New York University College of Medicine and Columbia University College of Physicians and Surgeons, New York, New York; University of Utah School of Medicine, Salt Lake City, Utah; Los Angeles Biomedical Research Institute at Harbor–University of California, Los Angeles, Medical Center, Torrance, California; Brigham and Women's Hospital, Harvard Medical School, Boston, Massachusetts; Veterans Affairs Puget Sound Health Care System and University of Washington, Seattle, Washington; Mayo Clinic, Rochester, Minnesota; Albert Einstein College of Medicine, Bronx, New York; University of Colorado School of Medicine, Aurora, Colorado; Yale University School of Medicine, New Haven, Connecticut; and Atherosclerosis Research Unit, University of Southern California, Los Angeles, California.

Note: Drs. Harman and Black had full access to all of the data in the study and take responsibility for the integrity of the data and the accuracy of the data analysis.

Disclaimer: The contents of this article are solely the responsibility of the authors and do not necessarily represent the official view of the National Center for Advancing Translational Sciences or the National Institutes of Health.

Acknowledgment: The authors thank the investigators and staff at the KEEPS clinical centers, the KEEPS Data Coordinating Center at the Kronos Longevity Research Institute, and the National Institutes of Health institutions supporting ancillary studies (investigators and staff are listed in Appendix 2). They also thank the participants for their dedication and commitment to the KEEPS research program. The authors dedicate this publication to the memory of Dr. George R. Merriam, principal KEEPS investigator at the Veterans Affairs Puget Sound Health Care System and University of Washington study site, who consistently and cheerfully volunteered to take on many responsibilities essential to the planning, execution, and completion of KEEPS. Dr. Merriam was an outstanding researcher, consummate clinician, and dear friend and colleague and will be sorely missed by all.

Financial Support: By grants from the Aurora Foundation to the Kronos Longevity Research Institute; the National Institutes of Health (grant HL90639 to Dr. Miller); Mayo Clinic Clinical and Translational Science Award 1 UL1 RR024150; the Mayo Foundation; Brigham and Women's Hospital/Harvard Medical School Clinical and Translational Science Award UL1 RR024139; and the University of California, San Francisco, Clinical and Translational Science Award UL1 RR024131 from the National Center for Advancing Translational Sciences, a component of the National Institutes of Health and the National Institutes of Health Roadmap for Medical Research. Study medications were supplied in part by Bayer HealthCare and Abbott Pharmaceuticals.

Disclosures: Disclosures can be viewed at www.acponline.org/authors/icmje/ConflictOfInterestForms.do?msNum=M14-0353.

Reproducible Research Statement:Study protocol and statistical code: Available at www.keepstudy.org. Data set: Qualified investigators may request selected data sets for specific projects approved by the KEEPS Continuation Committee by completing the application available at www.keepstudy.org.

Requests for Single Reprints: S. Mitchell Harman, MD, PhD, Phoenix Veterans Affairs Health Care System, Mailstop 111E, 650 East Indian School Road, Phoenix, AZ 85012; e-mail, sherman.harman@va.gov.

Current Author Addresses: Dr. Harman: Phoenix Veterans Affairs Health Care System, Mailstop 111E, 650 East Indian School Road, Phoenix, AZ 85012.

Drs. Black and Vittinghoff: Department of Epidemiology and Biostatistics, University of California, San Francisco, 185 Berry Street, Suite 5700, San Francisco, CA 94107-1762.

Dr. Naftolin: Director, Reproductive Biology Research, New York University School of Medicine, First Avenue, TH528, New York, NY 10016.

Drs. Brinton and Hopkins: Metabolism Section, Cardiovascular Genetics, University of Utah College of Medicine, 420 Chipeta Way, Room 1160, Salt Lake City, UT 84108.

Dr. Budoff: St. John's Cardiovascular Research Center, Harbor–University of California, Los Angeles, Medical Center, 1124 West Canon Street RB2, Torrance, CA 90502.

Dr. Cedars: Obstetrics and Gynecology, University of California, San Francisco, UCSF Center for Reproductive Health, 2356 Sutter Street, 7th Floor, San Francisco, CA 94115-0916.

Dr. Lobo: Obstetrics and Gynecology, Columbia University College of Physicians and Surgeons, 622 West 168th Street, New York, NY 10032.

Dr. Manson: Preventive Medicine, Harvard Medical School, Brigham and Women's Hospital, 900 Commonwealth Avenue, 3rd Floor, Boston, MA 02215.

Dr. Miller: Surgery and Physiology and Biomedical Engineering, Mayo Clinic, 200 First Street SW, Rochester, MN 55905.

Dr. Neal-Perry: Department of Obstetrics, Gynecology and Women's Health, Albert Einstein College of Medicine, 1300 Morris Park Avenue, Bronx, NY 10461.

Dr. Santoro: Obstetrics and Gynecology, University of Colorado at Denver, 12631 East 17th Avenue, Mail Stop B-198/Academic Office 1, Room 4010, Aurora, CO 80045.

Dr. Taylor: Obstetrics and Gynecology, Yale University School of Medicine, 333 Cedar Street, New Haven, CT 06520.

Drs. Yan and Hodis: Atherosclerosis Research Unit, Division of Cardiovascular Medicine, University of Southern California School of Medicine, 2250 Alcazar Street, CSC 132, Los Angeles, CA 90033.

Author Contributions: Conception and design: S.M. Harman, D.M. Black, F. Naftolin, E.A. Brinton, M.I. Cedars, R.A. Lobo, J.E. Manson, G.R. Merriam, V.M. Miller, N. Santoro, H.S. Taylor, H.N. Hodis.

Analysis and interpretation of the data: S.M. Harman, D.M. Black, F. Naftolin, E.A. Brinton, M.J. Budoff, M.I. Cedars, R.A. Lobo, J.E. Manson, G.R. Merriam, V.M. Miller, N. Santoro, H.S. Taylor, E. Vittinghoff, M. Yan, H.N. Hodis.

Drafting of the article: S.M. Harman, D.M. Black, F. Naftolin, E.A. Brinton, R.A. Lobo, G.R. Merriam, V.M. Miller, G. Neal-Perry, H.N. Hodis.

Critical revision of the article for important intellectual content: S.M. Harman, D.M. Black, F. Naftolin, E.A. Brinton, M.J. Budoff, M.I. Cedars, R.A. Lobo, J.E. Manson, V.M. Miller, G. Neal-Perry, H.S. Taylor, H.N. Hodis.

Final approval of the article: S.M. Harman, D.M. Black, F. Naftolin, E.A. Brinton, M.J. Budoff, M.I. Cedars, P.N. Hopkins, R.A. Lobo, J.E. Manson, V.M. Miller, G. Neal-Perry, N. Santoro, H.S. Taylor, H.N. Hodis.

Provision of study materials or patients: F. Naftolin, E.A. Brinton, M.I. Cedars, P.N. Hopkins, R.A. Lobo, G.R. Merriam, V.M. Miller, G. Neal-Perry, N. Santoro, H.S. Taylor.

Statistical expertise: D.M. Black, F. Naftolin, E. Vittinghoff.

Obtaining of funding: S.M. Harman, F. Naftolin.

Administrative, technical, or logistic support: S.M. Harman, D.M. Black, P.N. Hopkins, J.E. Manson, N. Santoro, H.N. Hodis.

Collection and assembly of data: S.M. Harman, D.M. Black, E.A. Brinton, M.J. Budoff, M.I. Cedars, R.A. Lobo, J.E. Manson, G.R. Merriam, V.M. Miller, G. Neal-Perry, N. Santoro, H.S. Taylor, M. Yan, H.N. Hodis.


Ann Intern Med. 2014;161(4):249-260. doi:10.7326/M14-0353
Text Size: A A A

Background: Whether menopausal hormone therapy (MHT) protects against cardiovascular disease (CVD) remains unclear.

Objective: To assess atherosclerosis progression and CVD risk factors after MHT initiated in early menopause.

Design: Randomized, controlled trial. (ClinicalTrials.gov: NCT00154180)

Setting: Nine U.S. academic centers.

Participants: Healthy menopausal women aged 42 to 58 years between 6 and 36 months from last menses without prior CVD events who had a coronary artery calcium (CAC) score less than 50 Agatston units and had not received estrogen or lipid-lowering therapy for at least 90 days.

Intervention: Oral conjugated equine estrogens (o-CEE), 0.45 mg/d, or transdermal 17β-estradiol (t-E2), 50 mcg/d, each with 200 mg of oral progesterone for 12 days per month, or placebo for 48 months.

Measurements: Primary end point was annual change in carotid artery intima–media thickness (CIMT). Secondary end points included changes in markers of CVD risk.

Results: Of 727 randomly assigned women, 89.3% had at least 1 follow-up CIMT and 79.8% had CIMT at 48 months. Mean CIMT increases of 0.007 mm/y were similar across groups. The percentages of participants in whom CAC score increased did not differ significantly across groups. No changes in blood pressure were observed with o-CEE or t-E2. Low- and high-density lipoprotein cholesterol levels improved and levels of C-reactive protein and sex hormone–binding globulin but not interleukin-6 increased with o-CEE. Insulin resistance decreased with t-E2. Serious adverse events did not differ by treatment.

Limitation: Power to compare clinical events was insufficient.

Conclusion: Four years of early MHT did not affect progression of atherosclerosis despite improving some markers of CVD risk.

Primary Funding Source: Aurora Foundation.

Figures

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Figure 1.

Study flow diagram.

The number of remaining active participants receiving and not receiving drugs is shown as a denominator, and the number of CIMT scans (primary end point) obtained from those participants is shown as a numerator (i.e., “Receiving drugs: 184/198” means that, of 198 available participants receiving study medications, CIMT was measured in 184). Personal reasons for withdrawal include logistical problems, family concerns, fear of cancer, and relocation. AEs include serious and nonserious events. AE = adverse event; CIMT = carotid artery intima–media thickness; o-CEE = oral conjugated equine estrogens; t-E2 = transdermal 17β-estradiol.

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Figure 2.

Effects of treatment on CIMT.

The change in CIMT (primary end point) from baseline to 12, 24, 36, and 48 mo after randomization by treatment group is shown. Bars represent 95% CIs. All values are derived from the linear mixed-effects model for repeated measurements (see Methods section). CIMT = carotid artery intima–media thickness; o-CEE = oral conjugated equine estrogens; t-E2 = transdermal 17β-estradiol.

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Appendix Figure.

Changes in laboratory values, by treatment and duration.

CRP = C-reactive protein; HDL = high-density lipoprotein; HOMA-IR = Homeostasis Model Assessment of Insulin Resistance; LDL = low-density lipoprotein; o-CEE = oral conjugated equine estrogens; SHBG = sex hormone–binding globulin; t-E2 = transdermal 17β-estradiol. A to F. Estimated means with bars representing 95% CIs are shown for changes from baseline in measured variables. Figures are included only for variables for which at least 1 of the treatment groups differed significantly from placebo (Table 3). All values are derived from repeated measures models. Numbers for each time point vary somewhat across measurements. G and H. Plotted values are estimates based on the linear mixed-effects model fit to all observed data (see Methods section). Bars represent 95% CIs around estimated means (all values are derived from repeated measures model). Levels at baseline and 12 mo were assessed on a random sample of approximately 60% of participants (excluding those who did not complete follow-up and those without samples at these times). The line discontinuity serves to indicate that 36- and 48-mo assays were done on a random subsample of 99 participants with baseline and 12-mo values who completed the study while receiving study medications. Means for the latter subset of 99 participants at baseline and 12 mo are similar to those shown for the larger samples.

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Summary for Patients

Hormone Treatment Beginning Near the Onset of Menopause

The full report is titled “Arterial Imaging Outcomes and Cardiovascular Risk Factors in Recently Menopausal Women. A Randomized Trial.” It is in the 19 August 2014 issue of Annals of Internal Medicine (volume 161, pages 249-260). The authors are S.M. Harman, D.M. Black, F. Naftolin, E.A. Brinton, M.J. Budoff, M.I. Cedars, P.N. Hopkins, R.A. Lobo, J.E. Manson, G.R. Merriam, V.M. Miller, G. Neal-Perry, N. Santoro, H.S. Taylor, E. Vittinghoff, M. Yan, and H.N. Hodis.

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