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Monthly super-sized vitamin D supplements failed to significantly reduce major cardiovascular events in older adults, the Australian D-Health Trial found.

Over up to 5 years of treatment, incident myocardial infarction (MI), stroke, and coronary revascularization turned up in 6% of the vitamin D group and 6.6% of the placebo group (HR 0.91, 95% CI 0.81-1.01), and that hazard ratio didn't budge over time.

There was no effect modification by age, sex, or body mass index, reported Rachel Neale, PhD, of Queensland Institute of Medical Research's Berghofer Medical Research Institute in Herston, Australia, and colleagues in .

However, some individual components of the primary outcome appeared more indicative of a clinical benefit for the monthly 60,000 IU dose of vitamin D supplementation:

• Myocardial infarction (HR 0.81, 95% CI 0.67-0.98)
• Coronary revascularisation (HR 0.89, 95% CI 0.78-1.01)
• Stroke (HR 0.99, 95% CI 0.80-1.23)

Also potentially redeeming was a signal that there was better reduction in cardiovascular events in vitamin D users who had been taking statins or other cardiovascular medications at baseline (HR 0.84, 95% CI 0.74-0.97), though the P-value for interaction was not significant.

"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," Neale and colleagues concluded.

Their findings are consistent with prior randomized trials -- and VITAL, for instance -- showing vitamin D supplementation does not prevent cardiovascular events. The D-Health investigators themselves previously reported that vitamin D3 supplements in the Australian cohort.

Yet for them, the signal of benefit in certain vitamin D recipients in the present report, along with an overall estimated number needed to treat to avoid one major cardiovascular event of 172, merits further investigation into the potential protective effects of vitamin D supplementation. Subgroup analyses in other large trials might be helpful, Neale's group said.

"In the meantime, these findings suggest that conclusions that vitamin D supplementation does not alter risk of cardiovascular disease are premature," they argued.

In current practice, clinicians may choose not to measure vitamin D levels, instead prescribing a higher supplement dose for selected patients at increased risk for vitamin D deficiency. The U.S. Preventive Services Task Force still deems the evidence insufficient to support broad screening for vitamin D deficiency in adults, partly because it is unclear what level of vitamin D is too low for a given individual.

D-Health participants were unscreened adults ages 60 to 84 years recruited from 2014 to 2015, having been selected randomly from a population register. Their cardiovascular outcomes were followed through multiple population-based databases.

Individuals were randomized to 60,000 IU/month vitamin D3 (n=10,662) or placebo (n=10,653). Blinded, all received 12 study tablets each year and were instructed to take one tablet at the beginning of each month. People were supposed to minimize the use of off-trial vitamin D supplements, with a maximum 2,000 IU per day outside the trial still acceptable to the investigators.

Study authors noted the relatively good health of D-Health participants, who were less likely to be current smokers than the general population.

Average serum 25(OH)D concentration reached 77 nmol/L in the placebo group and 115 nmol/L in the vitamin D group.

Annual self-reports and random blood sampling suggested that four out of five participants ultimately took 80% of study tablets, indicating "extremely high retention and adherence," Neale's group reported.

The incidence of adverse events was similar between groups.

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