Fish Oil or Vitamin D Supplementation as Protection Against Cardiovascular Events or Cancer Suffers Deteriorating ‘VITAL’ Signs  AHA 2018: Vitamin D and Omega-3 Trial (VITAL)

The VITAL trial conducted by Manson et al. showed that supplementation with either n–3 fatty acids at a dose of 1 g/day or vitamin D3 at a dose of 2000 IU/day was not effective for primary prevention of cardiovascular or cancer events among healthy middle-aged men and women over 5 years of follow-up. The results were reported on Saturday at the American Heart Association Scientific Sessions meeting in Chicago and online in the New England Journal of Medicine.

In the trial with a total of 25,871 enrollees, with a 5.3-year long duration of follow up, the goal was to assess the cardiovascular (CV) and cancer benefits of n–3 (also called omega-3) fatty acid and vitamin D3 supplementation compared with placebo among healthy participants. In a 2 x 2 factorial design, healthy participants were randomized in a 1:1 fashion to either vitamin D3 (at a dose of 2000 IU per day) (n = 12,927) or placebo (n = 12,944), or n–3 fatty acids (1 g per day as a fish-oil capsule containing 840 mg of n–3 fatty acids, including 460 mg of eicosapentaenoic acid [EPA] and 380 mg of docosahexaenoic acid [DHA]) (n = 12,933) or matching placebo (n = 12,938). The primary cardiovascular (CV) outcome of CV death, nonfatal myocardial infarction (MI), or stroke, for vitamin D3 vs. placebo, was 3.1% vs. 3.2%, hazard ratio (HR) 0.97, 95% confidence interval (CI) 0.85-1.1. The rates of CV death were 1.1% vs. 1.1%, for vitamin D3 vs. placebo, respectively. Moreover, the rates of stroke, MI and primary cancer outcome were 1.1% vs. 1.1%, 1.1% vs. 1.5% (HR 0.72, 95% CI 0.59-0.90) and 6.1% vs. 6.4% (HR 0.96, 95% CI 0.88-1.06) respectively.

The investigators concluded that supplementation with either n–3 fatty acids at a dose of 1 g/day or vitamin D3 at a dose of 2000 IU/day was not effective for primary prevention of CV or cancer events among healthy middle-aged men and women over 5 years of follow-up. The finding of a lower MI risk with n–3 fatty acids was hypothesis generating and deserved further study. The authors also noted some interaction with baseline fish consumption, with greater CV benefit, observed among participants who had a low fish intake at baseline. Speaking of the results, Manson and his colleagues stated, “The observed lack of benefit of vitamin D supplementation for cardiovascular outcomes in our trial is consistent with results of previous trials of vitamin D, even at moderate or high doses. Most recently, in ViDA,  the rate of cardiovascular disease was not lower among participants who received monthly administration of high-dose vitamin D than among those who received placebo. Neither our trial nor ViDA showed that vitamin D was associated with a reduced rate of death from any cause; lower-dose vitamin D trials have shown neutral effects or at most modest reductions in this endpoint. However, detection of a decreased rate of death from any cause, if present, may require longer follow-up.”

Commenting on the new findings, the lead author Dr. JoAnn Manson, chief of the division of preventive medicine at Brigham and Women’s Hospital in Boston, noted that among fish oil recipients, the rates of death from any cause, death from cancer and death from heart disease, in general, were not significantly different than for people not taking fish oil supplements. Additionally, the collective odds of having a heart attack, stroke or death from any cardiovascular cause were essentially the same whether people were taking fish oil or placebo. The primary endpoint was attenuated by the non-coronary endpoints as, “It was only when the individual elements of heart disease were teased out – such as the rate of heart attack, the rate of fatal heart attack and the need for angioplasty – that a benefit stood out.” For people taking vitamin D who developed cancer, the death rate from cancer was 25 percent lower, possibly because the vitamin “may affect the biology of the tumor so it’s less likely to spread and become metastatic,” explained Dr. Mason.

Comparing and contrasting the results of the VITAL and REDUCE-IT trials, Dr. C Michael Gibson, CEO of Baim / PERFUSE Research Institute, Harvard Professor and Cardiologist at Beth Israel Deaconess Medical Center remarked, “The VITAL study evaluated fish oil that contained a mix of EPA and DHA at lower doses in people with no history of heart disease and was negative. REDUCE-IT evaluated purified EPA at high doses in people with heart disease or diabetes + elevated triglycerides and was positive. Many people are confused by the divergence in the VITAL & REDUCE-IT fish oil trial results but these 2 trials evaluated 2 different formulations in 2 different doses in 2 very very different populations and arrived at 2 different conclusions.” In an accompanying editorial, Dr. John F. Keaney, Jr., M.D., and Clifford J. Rosen, M.D.  wrote, “Despite the negative findings regarding the primary endpoints in VITAL, the secondary endpoints will undoubtedly draw attention. It will be tempting to note the lower incidence of myocardial infarction and of death from myocardial infarction with n−3 fatty acids than with placebo and the lower mortality from cancer with vitamin D than with placebo and then to cite these findings as evidence that these supplements can benefit some patients in preventing coronary heart disease or cancer death. However, these “positive” results need to be interpreted with caution.” They concluded, “In the absence of additional compelling data, it is prudent to conclude that the strategy of dietary supplementation with either n−3 fatty acids or vitamin D as protection against cardiovascular events or cancer suffers from deteriorating VITAL signs.”