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Women's Health Initiative clinical trials

potential interactive effect of calcium and vitamin D supplementation with hormonal therapy on cardiovascular disease

Jiang, Xuezhi MD, PhD1,2; Nudy, Matthew MD3; Aragaki, Aaron K. MS4; Robbins, John A. MD5; Manson, JoAnn E. MD, DrPH6; Stefanick, Marcia L. PhD7; O'Sullivan, David M. PhD1; Shikany, James M. DrPH8; LeBlanc, Erin S. MD, MPH9; Kelsey, Anita M. MD10; Cauley, Jane DrPH11; Martin, Lisa W. MD12; Payne, Martha E. PhD, RD, MPH13; Johnson, Karen C. MD, MPH14; Howard, Barbara PhD15; Schnatz, Peter F. DO, FACP, FACOG, NCMP1,2,16,17

doi: 10.1097/GME.0000000000001360
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Objective: Data in humans and nonhuman primates have suggested a possible synergistic effect of vitamin D and calcium (CaD) and estrogen on the cardiovascular disease (CVD) risk factors. Using randomized trial data we explored whether the effect of menopausal hormone therapy (HT) on CVD events is modified by CaD supplementation.

Methods: A prospective, randomized, double-blind, placebo-controlled trial was implemented among postmenopausal women in the Women's Health Initiative. A total of 27,347 women were randomized to the HT trials (0.625 mg/d of conjugated equine estrogens [CEE] alone for women without a uterus vs placebo; or 0.625 mg of CEE in addition to 2.5 mg of medroxyprogesterone acetate daily [CEE + MPA] for women with a uterus vs placebo). After 1 year, 16,089 women in the HT trial were randomized to the CaD trial and received either 1,000 mg of elemental calcium carbonate and 400 IU of vitamin D3 daily or placebo. The mean (SD) duration of follow-up after CaD randomization was 6.2 (1.3) years for the CEE trial and 4.6 (1.1) years for the CEE + MPA trial. CVD and venous thromboembolism events evaluated in this subgroup analysis included coronary heart disease, stroke, pulmonary embolism, all-cause mortality, plus select secondary endpoints (total myocardial infarction, coronary revascularization, deep venous thrombosis, cardiovascular death, and all CVD events). Time-to-event methods were used and models were fit with a Cox proportional hazards regression model.

Results: In the CEE trial, CaD significantly modified the effect of CEE on stroke (P interaction = 0.04). In the CaD-placebo group, CEE's effect on stroke was harmful (hazard ratio [95% confidence interval] = 2.19[1.34-3.58]); however, it was neutral in the CaD-supplement group (hazard ratio [95% confidence interval] = 1.07[0.66-1.73]). We did not observe significant CEE-CaD interactions for coronary heart disease, total CVD events, or any of the remaining endpoints. In the CEE + MPA trial, there was no evidence that the effect of CEE + MPA on any of CVD endpoints was modified by CaD supplementation.

Conclusions: CaD did not consistently modify the effect of CEE therapy or CEE + MPA therapy on CVD events. However, the increased risk of stroke due to CEE therapy appears to be mitigated by CaD supplementation. In contrast, CaD supplementation did not influence the risk of stroke due to CEE + MPA.

1Department of ObGyn, Reading Hospital, Reading, PA

2Department of ObGyn, Sidney Kimmel Medical College at Thomas Jefferson University, Philadelphia, PA

3Department of Internal Medicine, Penn State Hershey Medical Center, Hershey, PA

4Division of Public Health Sciences, Fred Hutchinson Cancer Research Center, Seattle, WA

5UC Davis Medical Center, Sacramento, CA

6Division of Preventive Medicine, Brigham and Women's Hospital/Harvard Medical School, Boston, MA

7Department of Medicine, Stanford Prevention Research Center, Stanford University School of Medicine, Stanford University, Stanford, CA

8Division of Preventive Medicine, School of Medicine, University of Alabama at Birmingham, Birmingham, AL

9Kaiser Permanente Center for Health Research NW, Portland, OR

10Division of Cardiology, Saint Francis Hospital and Medical Center, Hartford, CT

11Department of Epidemiology, Graduate School of Public Health, University of Pittsburgh, Pittsburgh, PA

12Division of Cardiology, Department of Internal Medicine, George Washington University School of Medicine and Health Sciences, Washington, DC

13Office of Research Development, Duke University School of Medicine, Durham, NC

14Department of Preventive Medicine, University of Tennessee Health Science Center, Memphis, TN

15MedStar Health Research Institute and Georgetown/Howard Universities Center for Clinical and Translational Science, Washington, DC

16Department of Internal Medicine, Reading Hospital, Reading, PA

17Department of Internal Medicine, Sidney Kimmel Medical College at Thomas Jefferson University, Philadelphia, PA.

Address correspondence to: Peter F. Schnatz, DO, FACP, FACOG, NCMP, Professor of OB/GYN and Internal Medicine, Sidney Kimmel Medical College of Thomas Jefferson University, Vice Chair and Residency Program Director, Department of OB/GYN, Reading Hospital/Tower Health, R1, P.O. Box 16052, Reading, PA 19612-6052. E-mail: Peter.Schnatz@towerhealth.org

Received 25 October, 2018

Revised 26 February, 2019

Accepted 26 February, 2019

The following data were presented as an oral presentation at the 27th Annual Scientific Meeting of The North American Menopause Society from October 5-7, 2016 in Orlando, Florida.

Funding/support: The Women's Health Initiative (WHI) program is funded by the National Heart, Lung, and Blood Institute, National Institutes of Health, US Department of Health and Human Services through contracts HHSN268201600018C, HHSN268201600001C, HHSN268201600002C, HHSN268201600003C, and HHSN268201600004C. Information about the WHI investigators, their academic centers, the program office, and the clinical coordinating center can be found online at: https://www.whi.org/researchers/Documents%20%20Write%20a%20Paper/WHI%20Investigator%20Short%20List.pdf. The research on which this publication is based was supported by R01 HL083326 from the National Heart, Lung, and Blood Institute. M.P.'s effort was supported by an NIH Building Interdisciplinary Research Careers in Women's Health (BIRCWH) K12 grant (HD043446).

Financial disclosure/conflicts of interest: E.S.L. has received grants from Merck, Inc. The other authors did not report any potential conflicts of interest.

Clinical trial registration: ClinicalTrials.gov, https://clinicaltrials.gov, NCT00000611.

© 2019 by The North American Menopause Society.