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

The BMJ

Jun 2023

DOI: 10.1136/bmj-2023-075230

Citations:81

Influential Citations:4

Interventional (Human) Studies

Enhanced Details

Methods

Design: Randomised, double-blind, placebo-controlled trial (D-Health Trial) conducted in Australia (2014–2020). Population: 21,315 randomised adults aged 60–84; 21,302 included in analysis; 54% men; mean age 69 years. Exclusions: hypercalcaemia, hyperparathyroidism, kidney stones, osteomalacia, sarcoidosis, or daily intake of >500 IU vitamin D. Analyses followed intention-to-treat.

Intervention

60,000 IU vitamin D3 monthly, orally, for up to five years.

Results

Vitamin D3 60,000 IU/month for up to five years showed a possible reduction in major cardiovascular events versus placebo (HR 0.91; 95% CI 0.81–1.01). Absolute risk reduction: 5.8 fewer events per 1,000 participants over five years; number needed to treat: 172. Myocardial infarction risk reduced (HR 0.81; 95% CI 0.67–0.98); coronary revascularisation reduced (HR 0.89; 95% CI 0.78–1.01); stroke effect small and not significant (HR 0.99; 95% CI 0.80–1.23). Interactions with baseline statin or cardiovascular drug use were not statistically significant, though signals suggested larger benefits in these subgroups. Conclusion: Vitamin D supplementation might reduce the incidence of major cardiovascular events, particularly MI and revascularisation, but the absolute difference is small and the confidence interval includes no effect; findings warrant further evaluation, especially in people on cardiovascular medications.

Limitations

Possible undercounting of events due to missing private-hospital data for some states; undercounting would be small and unlikely to differ between groups. Multiple tertiary outcomes raise risk of chance findings; no adjustment for multiple testing. Baseline 25(OH)D status was predicted, not measured, with limited predictive value (PPV 0.23), risking misclassification. Generalisability may be limited to populations with similar vitamin D status and not to populations with high deficiency. The monthly dosing schedule may limit extrapolation to daily regimens.

Abstract

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 show less