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In the news: Overview of VITAL: Vitamin D & Omega-3 in Primary Prevention of CVD, Cancer

Overview of the VITAL Trial

Results from The Vitamin D and Omega-3 Trial (VITAL) were published in the Nov. 10th issue of the New England Journal of Medicine(1,2). Neither vitamin D nor omega-3 supplementation lowered the incidence of major cardiovascular events (a composite of heart attack, stroke or death from CVD causes) nor invasive cancer of any type, the primary endpoints evaluated in the trial.

Secondary Findings

A number of secondary findings could be viewed as encouraging, particularly the lower mortality from cancer (17% reduction in risk) seen for vitamin D vs. placebo. While omega-3 supplements didn’t lower all major cardio events as a group, a 28% reduction in risk was seen for heart attack when analyzed separately. In addition, analyses found a 50% reduced incidence of death from heart attack and 17% reduction in risk for total coronary heart disease or CHD with fish oil vs. placebo.

These secondary findings must be interpreted with caution, but do raise the question of whether supplements might be of some benefit in preventing CHD or cancer death. The study was large, and the secondary measures were built into the study design.

Low Fish Consumption

It’s worth noting that subgroup analyses showed a lower incidence of the primary cardiovascular endpoint with fish oil supplementation vs. placebo for those with low fish intake. Baseline dietary fish intake modified the fish oil’s effect on major cardiovascular events (nominally significant reduction in risk of 19%) in participants consuming less than 1½ servings weekly, while no risk reduction was observed for those with higher intake. These apparent findings could shape the design of future trials, as poor fish intake was common in VITAL and is common in the US.

Trial Design, Strengths and Safety

VITAL is a randomized, double-blind, placebo-controlled trial assessing the effects of vitamin D (2,000 IU daily) and fish oil (1,000 mg daily, 460 mg EPA/380 mg DHA, Lovaza) on the primary prevention of CVD and cancer in 25,871 men (> 50 yrs) and women (> 55 yrs). The participants, with no history of cancer or CVD at baseline, were assigned to one of four regimens: both vitamin D and fish oil, vitamin D and placebo, fish oil and placebo, or two placebos daily. Participants were followed for about 5.3 years.

The strengths of the trial include the large number of people enrolled and the applicability of the findings to many in the population as African Americans, men and women, and those with normal as well as low blood levels of vitamin D were included. Importantly, no adverse effects were seen for vitamin D or omega-3 supplementation in VITAL, including no excess bleeding or high blood levels of calcium.

Cautionary Considerations

An accompanying editorial(3) emphasized that the positive secondary results should be interpreted cautiously because there was no statistical correction for the multiple comparisons conducted (partly due to the number of secondary end points evaluated). Also for fish oil, the secondary effects (e.g. less heart attacks or fatal heart attacks) have not been consistently seen in all large, well-controlled trials.

For vitamin D and cancer, however, experimental studies consistently demonstrate an anti-cancer mechanism, and a recent meta-analysis reported a significant benefit with vitamin D and cancer mortality(4), Further, in one VITAL analysis, the rate of death from cancer was 25% lower with vitamin D vs. placebo when the first two years of the five-year study were excluded. Although this was not a “pre-planned” analysis, the apparent lower rate of cancer death with vitamin D is in line with the meta-analysis findings.

References

1. Manson JE et al. Marine n-3 fatty acids and prevention of cardiovascular disease and cancer. NEJM. Pub online Nov. 10, 2018
2. Manson JE et al. Vitamin D supplements and prevention of cancer and cardiovascular disease. NEJM. Pub online Nov. 10, 2018.
3. Keaney JF and Rosen CJ. Vital signs for dietary supplementation to prevent cancer and heart disease. NEJM. Pub online Nov. 10, 2018.
4. Vaughn-Shaw PG et al. The impact of vitamin D pathway genetic variation and circulating 25-hydroxy- vitamin D on cancer outcome: Systematic review and meta-analysis. Br J Cancer. 116:1092-110, 2017.