Women's Health Initiative clinical trials: potential interactive effect of calcium and vitamin D supplementation with hormonal therapy on cardiovascular disease

Xuezhi Jiang, Matthew Nudy, Aaron K. Aragaki, John A. Robbins, Jo Ann E. Manson, Marcia L. Stefanick, David M. OʼSullivan, James M. Shikany, Erin S. LeBlanc, Anita M. Kelsey, Jane Cauley, Lisa W. Martin, Martha E. Payne, Karen Johnson, Barbara Howard, Peter F. Schnatz

Research output: Contribution to journalArticle

Abstract

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.

Original languageEnglish (US)
Pages (from-to)841-849
Number of pages9
JournalMenopause (New York, N.Y.)
Volume26
Issue number8
DOIs
StatePublished - Aug 1 2019

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Conjugated (USP) Estrogens
Women's Health
Vitamin D
Cardiovascular Diseases
Clinical Trials
Calcium
Stroke
Placebos
Therapeutics
Hormones
Uterus
Coronary Disease
Confidence Intervals
Medroxyprogesterone Acetate
Calcium Carbonate
Cholecalciferol
Venous Thromboembolism
Random Allocation
Pulmonary Embolism
Proportional Hazards Models

All Science Journal Classification (ASJC) codes

  • Obstetrics and Gynecology

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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; Nudy, Matthew; Aragaki, Aaron K.; Robbins, John A.; Manson, Jo Ann E.; Stefanick, Marcia L.; OʼSullivan, David M.; Shikany, James M.; LeBlanc, Erin S.; Kelsey, Anita M.; Cauley, Jane; Martin, Lisa W.; Payne, Martha E.; Johnson, Karen; Howard, Barbara; Schnatz, Peter F.

In: Menopause (New York, N.Y.), Vol. 26, No. 8, 01.08.2019, p. 841-849.

Research output: Contribution to journalArticle

Jiang, X, Nudy, M, Aragaki, AK, Robbins, JA, Manson, JAE, Stefanick, ML, OʼSullivan, DM, Shikany, JM, LeBlanc, ES, Kelsey, AM, Cauley, J, Martin, LW, Payne, ME, Johnson, K, Howard, B & Schnatz, PF 2019, 'Women's Health Initiative clinical trials: potential interactive effect of calcium and vitamin D supplementation with hormonal therapy on cardiovascular disease', Menopause (New York, N.Y.), vol. 26, no. 8, pp. 841-849. https://doi.org/10.1097/GME.0000000000001360
Jiang, Xuezhi ; Nudy, Matthew ; Aragaki, Aaron K. ; Robbins, John A. ; Manson, Jo Ann E. ; Stefanick, Marcia L. ; OʼSullivan, David M. ; Shikany, James M. ; LeBlanc, Erin S. ; Kelsey, Anita M. ; Cauley, Jane ; Martin, Lisa W. ; Payne, Martha E. ; Johnson, Karen ; Howard, Barbara ; Schnatz, Peter F. / Women's Health Initiative clinical trials : potential interactive effect of calcium and vitamin D supplementation with hormonal therapy on cardiovascular disease. In: Menopause (New York, N.Y.). 2019 ; Vol. 26, No. 8. pp. 841-849.
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abstract = "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.",
author = "Xuezhi Jiang and Matthew Nudy and Aragaki, {Aaron K.} and Robbins, {John A.} and Manson, {Jo Ann E.} and Stefanick, {Marcia L.} and OʼSullivan, {David M.} and Shikany, {James M.} and LeBlanc, {Erin S.} and Kelsey, {Anita M.} and Jane Cauley and Martin, {Lisa W.} and Payne, {Martha E.} and Karen Johnson and Barbara Howard and Schnatz, {Peter F.}",
year = "2019",
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TY - JOUR

T1 - Women's Health Initiative clinical trials

T2 - potential interactive effect of calcium and vitamin D supplementation with hormonal therapy on cardiovascular disease

AU - Jiang, Xuezhi

AU - Nudy, Matthew

AU - Aragaki, Aaron K.

AU - Robbins, John A.

AU - Manson, Jo Ann E.

AU - Stefanick, Marcia L.

AU - OʼSullivan, David M.

AU - Shikany, James M.

AU - LeBlanc, Erin S.

AU - Kelsey, Anita M.

AU - Cauley, Jane

AU - Martin, Lisa W.

AU - Payne, Martha E.

AU - Johnson, Karen

AU - Howard, Barbara

AU - Schnatz, Peter F.

PY - 2019/8/1

Y1 - 2019/8/1

N2 - 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.

AB - 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.

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