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Randomized Controlled Trial
. 2023 Jun 28:381:e075230.
doi: 10.1136/bmj-2023-075230.

Vitamin D supplementation and major cardiovascular events: D-Health randomised controlled trial

Bridie Thompson  1 , Mary Waterhouse  1 , Dallas R English  2 , Donald S McLeod  1 , Bruce K Armstrong  3 , Catherine Baxter  1 , Briony Duarte Romero  1 , Peter R Ebeling  4 , Gunter Hartel  5 , Michael G Kimlin  6 , Sabbir T Rahman  1 , Jolieke C van der Pols  7 , Alison J Venn  8 , Penelope M Webb  1 , David C Whiteman  1 , Rachel E Neale  9
Affiliations
Randomized Controlled Trial

Vitamin D supplementation and major cardiovascular events: D-Health randomised controlled trial

Bridie Thompson et al. BMJ. .

Abstract

Objective: To investigate whether supplementing older adults with monthly doses of vitamin D alters the incidence of major cardiovascular events.

Design: Randomised, double blind, placebo controlled trial of monthly vitamin D (the D-Health Trial). Computer generated permuted block randomisation was used to allocate treatments.

Setting: Australia from 2014 to 2020.

Participants: 21 315 participants aged 60-84 years at enrolment. Exclusion criteria were self-reported hypercalcaemia, hyperparathyroidism, kidney stones, osteomalacia, sarcoidosis, taking >500 IU/day supplemental vitamin D, or unable to give consent because of language or cognitive impairment.

Intervention: 60 000 IU/month vitamin D3 (n=10 662) or placebo (n=10 653) taken orally for up to five years. 16 882 participants completed the intervention period: placebo 8270 (77.6%); vitamin D 8552 (80.2%).

Main outcome measures: The main outcome for this analysis was the occurrence of a major cardiovascular event, including myocardial infarction, stroke, and coronary revascularisation, determined through linkage with administrative datasets. Each event was analysed separately as secondary outcomes. Flexible parametric survival models were used to estimate hazard ratios and 95% confidence intervals.

Results: 21 302 people were included in the analysis. The median intervention period was five years. 1336 participants experienced a major cardiovascular event (placebo 699 (6.6%); vitamin D 637 (6.0%)). The rate of major cardiovascular events was lower in the vitamin D group than in the placebo group (hazard ratio 0.91, 95% confidence interval 0.81 to 1.01), especially among those who were taking cardiovascular drugs at baseline (0.84, 0.74 to 0.97; P for interaction=0.12), although the P value for interaction was not significant (<0.05). Overall, the difference in standardised cause specific cumulative incidence at five years was -5.8 events per 1000 participants (95% confidence interval -12.2 to 0.5 per 1000 participants), resulting in a number needed to treat to avoid one major cardiovascular event of 172. The rate of myocardial infarction (hazard ratio 0.81, 95% confidence interval 0.67 to 0.98) and coronary revascularisation (0.89, 0.78 to 1.01) was lower in the vitamin D group, but there was no difference in the rate of stroke (0.99, 0.80 to 1.23).

Conclusions: Vitamin D supplementation might reduce the incidence of major cardiovascular events, although the absolute risk difference was small and the confidence interval was consistent with a null finding. These findings could prompt further evaluation of the role of vitamin D supplementation, particularly in people taking drugs for prevention or treatment of cardiovascular disease.

Trial registration: ACTRN12613000743763.

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Conflict of interest statement

Competing interests: All authors have completed the ICMJE uniform disclosure form at www.icmje.org/disclosure-of-interest/ and declare: support from National Health and Medical Research Council, Metro North, Queensland Health, University of Western Australia, Western Australian State Government, Australian Federal Government, Bioplatforms Australia, National Collaborative Research Infrastructure Strategy for the submitted work. PMW has funding from AstraZeneca for an unrelated study of ovarian cancer; PRE reports grants and other from Amgen, grants from Sanofi, and grants from Alexion; REN has funding from Viatris for an unrelated study of pancreatic cancer. All other authors declare: no support from any organisation for the submitted work; no financial relationships with any organisations that might have an interest in the submitted work in the previous three years, no other relationships or activities that could appear to have influenced the submitted work.

Figures

Fig 1
Fig 1
Participant flow for analyses of major cardiovascular events (Consolidated Standards of Reporting Trials—CONSORT flow diagram). *People with self-reported history of hypercalcaemia, kidney stones, hyperarathyroidism, osteomalacia, or sarcoidosis, or those taking >500 IU/day of supplemental vitamin D were ineligible. †Withdrew consent to link to health registers
Fig 2
Fig 2
Cause specific cumulative incidence of major cardiovascular events according to randomisation group and time since randomisation. Curves estimated using Aalen-Johansen methods, treating death without previous major cardiovascular event as a competing risk. Hazard ratio (vitamin D v placebo) was estimated using a flexible parametric survival model that included randomisation group, age, sex, and state of residence at baseline. 95% CI=95% confidence interval; MACE=major cardiovascular event
Fig 3
Fig 3
Effect of vitamin D supplementation on incidence of major cardiovascular events for all participants and by selected baseline characteristics. Hazard ratios (vitamin D v placebo) were estimated using flexible parametric survival models. All models included randomisation group, age, sex, and state of residence at baseline. Models producing estimates by levels of age, sex, body mass index, predicted 25-hydroxyvitamin D (25(OH)D) concentration, use of statins, and use of (non-statin) cardiovascular drugs include the characteristic of interest and an interaction between randomisation group and the characteristic of interest. P value for interaction is from a likelihood ratio test comparing models with and without the interaction term. 95% CI=95% confidence interval
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