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Review
, 342, d2040

Calcium Supplements With or Without Vitamin D and Risk of Cardiovascular Events: Reanalysis of the Women's Health Initiative Limited Access Dataset and Meta-Analysis

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Review

Calcium Supplements With or Without Vitamin D and Risk of Cardiovascular Events: Reanalysis of the Women's Health Initiative Limited Access Dataset and Meta-Analysis

Mark J Bolland et al. BMJ.

Abstract

Objectives: To investigate the effects of personal calcium supplement use on cardiovascular risk in the Women's Health Initiative Calcium/Vitamin D Supplementation Study (WHI CaD Study), using the WHI dataset, and to update the recent meta-analysis of calcium supplements and cardiovascular risk.

Design: Reanalysis of WHI CaD Study limited access dataset and incorporation in meta-analysis with eight other studies. Data source WHI CaD Study, a seven year, randomised, placebo controlled trial of calcium and vitamin D (1g calcium and 400 IU vitamin D daily) in 36,282 community dwelling postmenopausal women. Main outcome measures Incidence of four cardiovascular events and their combinations (myocardial infarction, coronary revascularisation, death from coronary heart disease, and stroke) assessed with patient-level data and trial-level data.

Results: In the WHI CaD Study there was an interaction between personal use of calcium supplements and allocated calcium and vitamin D for cardiovascular events. In the 16,718 women (46%) who were not taking personal calcium supplements at randomisation the hazard ratios for cardiovascular events with calcium and vitamin D ranged from 1.13 to 1.22 (P = 0.05 for clinical myocardial infarction or stroke, P = 0.04 for clinical myocardial infarction or revascularisation), whereas in the women taking personal calcium supplements cardiovascular risk did not alter with allocation to calcium and vitamin D. In meta-analyses of three placebo controlled trials, calcium and vitamin D increased the risk of myocardial infarction (relative risk 1.21 (95% confidence interval 1.01 to 1.44), P = 0.04), stroke (1.20 (1.00 to 1.43), P = 0.05), and the composite of myocardial infarction or stroke (1.16 (1.02 to 1.32), P = 0.02). In meta-analyses of placebo controlled trials of calcium or calcium and vitamin D, complete trial-level data were available for 28,072 participants from eight trials of calcium supplements and the WHI CaD participants not taking personal calcium supplements. In total 1384 individuals had an incident myocardial infarction or stroke. Calcium or calcium and vitamin D increased the risk of myocardial infarction (relative risk 1.24 (1.07 to 1.45), P = 0.004) and the composite of myocardial infarction or stroke (1.15 (1.03 to 1.27), P = 0.009).

Conclusions: Calcium supplements with or without vitamin D modestly increase the risk of cardiovascular events, especially myocardial infarction, a finding obscured in the WHI CaD Study by the widespread use of personal calcium supplements. A reassessment of the role of calcium supplements in osteoporosis management is warranted.

Conflict of interest statement

Competing interests: All authors have completed the Unified Competing Interest form at www.icmje.org/coi_disclosure.pdf (available on request from the corresponding author) and declare that no author has support from companies for the submitted work; IRR has received research support from and acted as a consultant for Fonterra and had study medications for clinical trials of calcium supplementation supplied by Mission Pharmacal, and AA had study medications for clinical trials of calcium supplementation supplied by Shire Pharmaceuticals and Nycomed; no other relationships or activities that could appear to have influenced the submitted work.

Figures

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Fig 1 Influence of personal calcium supplement dose at randomisation on the effect of calcium and vitamin D on cardiovascular events in the WHI CaD Study
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Fig 2 Effect of calcium and vitamin D on cardiovascular events: based on trial-level data from two randomised, placebo controlled trials of calcium and vitamin D and the WHI CaD Study participants not taking personal calcium supplements at baseline. The first two trials included calcium monotherapy and calcium and vitamin D groups: we included data only from the calcium and vitamin D group compared with the placebo group
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Fig 3 Effect of calcium supplements with or without vitamin D on cardiovascular events: based on patient-level data. The panels show the time to first event for 24 869 participants in five trials of calcium supplements, and the WHI CaD Study participants not taking personal calcium supplements at baseline
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Fig 4 Effect of calcium supplements with or without vitamin D on cardiovascular events: trial-level data. The panels show data for 28 072 participants in eight trials of calcium supplements with complete trial-level data, plus data for the WHI CaD Study participants not taking personal calcium supplements at baseline. Lappe et al randomised participants to calcium, calcium and vitamin D, or placebo: we pooled the outcomes from both the calcium and calcium and vitamin D arms. Grant et alincluded calcium v placebo arms (“Grant 2005”) and calcium plus vitamin D v vitamin D plus placebo arms (“Grant 2005 Vit D”). The composite outcome for Prince et al was myocardial infarction, stroke, or sudden death

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