VITAL: No CVD or Cancer Benefit From Vitamin D, Omega-3

Deborah Brauser

November 10, 2018

CHICAGO — More research is showing no significant benefit from vitamin D supplementation for the prevention of cardiovascular disease (CVD) or cancer — and little benefit from omega-3 supplements, as both therapies missed their primary endpoints.

The Vitamin D and Omega-3 Trial (VITAL) is one of the largest randomized, placebo-controlled trials to examine these associations in a diverse population. The study comprised almost 26,000 participants, of whom 5100 were black.

The two primary outcome measures were invasive cancer of any type and major CV events, which was a composite of stroke, myocardial infarction (MI), and CV-related death. Neither the participants who received vitamin D3 at 2000 IU per day nor those who received 1 g of marine n-3 fatty acids (omega-3) per day showed significantly lower incidence of either outcome over 5 years of follow-up compared with those receiving placebo.

Based on past research, these findings weren't that surprising, lead author JoAnn E. Manson, MD, Brigham and Women's Hospital and Harvard Medical School, Boston, Massachusetts, told | Medscape Cardiology.

The news was a bit more optimistic for some of the secondary outcomes, with a 28% reduction in risk for MI alone in the full group receiving omega-3 and a 77% reduction in MI risk among black participants in the omega-3 group.

"So there was a great deal of evidence from the trial that the omega-3s were reducing heart attack risk," Manson said. "They didn't reduce the risk for stroke and so the primary composite endpoint wasn't met, but I think it's important to look at the individual components."

There was also "a signal for reduction in cancer death" for the participants who received vitamin D, she added.

However, asked for comment, Steven E. Nissen, MD, chairman of the Department of Cardiovascular Medicine at the Cleveland Clinic, Ohio, said he wasn't impressed with any of the findings, noting that the only benefits from these agents were in "subanalyses of subanalyses or in secondary endpoints, and they are considered hypothesis generating rather than scientific evidence" of a benefit.

"They're interesting but speculative and should not lead to changes in guidelines or other major changes in practice," Nissen, who was not involved with the research, told | Medscape Cardiology.

That said, he noted that the trial does lay groundwork for future research looking specifically at fish oil supplementation and its effect on black participants. "I would certainly encourage that to be done. With these types of hypothesis-generating studies, whether they succeed or fail, they raise good questions," he said.

The results were presented here today at the American Heart Association (AHA) Scientific Sessions 2018 and were simultaneously published online in two articles in the New England Journal of Medicine.

Two-by-Two Factorial Design

The investigators enrolled 25,871 healthy participants (50.6% women; mean age, 67.1 years) and followed them for a mean of 5.3 years. In the two-by-two factorial design, the participants were randomly assigned to one of four treatment groups:

  • Two actives: 2000 IU/day  vitamin D3 (cholecalciferol) plus 1 g/day omega-3 fish oil supplements (Omacor/Lovaza, GlaxoSmithKline);

  • Active vitamin D plus placebo omega-3;

  • Placebo vitamin D plus active omega-3; or

  • Placebos for both.

In addition to the already-mentioned co-primary endpoints, the trial had several secondary outcomes, including individual components of the major CVD events composite; "expanded CVD events," which added coronary revascularization; and total cancer mortality.

A total of 12,933 participants received active omega-3 vs 12,938 who received placebo. Of these, 386 of the former and 419 of the latter experienced a major CVD event, which was not significantly different (hazard ratio [HR], 0.92; 95% confidence interval [CI], 0.80 - 1.06). There was no significant reduction in risk for cancer.

Among the prespecified secondary outcomes, total MI was reduced with treatment (HR, 0.72; 95% CI, 0.59 - 0.90; nominal P = .003). However, there were no significant between-group differences in the expanded CVD composite, total stroke, or CVD mortality.

In other analyses, omega-3 consumption was associated with a significant reduction in percutaneous coronary intervention (HR, 0.78), fatal MI (HR, 0.50), and total coronary heart disease (CHD), defined as MI + coronary revascularization + CHD death (HR, 0.83). Although these were considered to be "outcomes of interest," they weren't prespecified, so Manson noted that they should be interpreted with caution.

Among subgroups, there was a 40% reduction in risk for total MI among the omega-3 group members who consumed fewer than 1.5 servings of fish per week (P = .048) and a 19% reduction in major CVD events. "I think this provides further support for the biological plausibility" for the agent, Manson said.

In addition, the HR for total MI was 0.23 for black participants taking omega-3 vs placebo (number of events, 9 vs 39, respectively; P = .001).

"If this finding is confirmed and replicated, it may point to a very promising approach to reducing coronary risk among African Americans," Manson said in a press release.

Active vitamin D was given to 12,927 of the participants vs 12,944 who received placebo. There were no significant reductions in CVD outcomes or in cancer incidence. After exclusion of the first 2 years of follow-up (to account for the latency period of cancer), there was a 25% reduction in cancer death for those receiving vitamin D (number of events, 112 vs 149; nominal P = .02).

Finally, no significant adverse events occurred with either agent, including no increased risk for hypercalcemia with vitamin D and no increased risk for bleeding with omega-3. Adherence rates averaged 80% for all active and placebo treatments.

Speculative, Spurious Findings

After Manson's presentation at a press briefing, official discussant Jane Armitage, MD, University of Oxford, United Kingdom, noted that although this was a well-conducted and well-powered study with an ethnically diverse population and good follow-up, "it was robustly negative" overall.

"I think we need to accept that this was a good test of the hypothesis that universal supplementation with a decent dose of vitamin D is not worthwhile," Armitage said.

She added that before this study started, "there had been promising data" on omega-3 trials, including a meta-analysis of 10 large trials and almost 78,000 participants that was published in January in JAMA Cardiology.

Although its results didn't show a significant reduction in any CHD event, including the rate of fatal or nonfatal MI or CHD death, some outcomes "were close," Armitage said.

However, the negative endpoint of major CV events overall in the current study "was a good test of the hypothesis and pretty much refutes the benefits that were observed in observational studies," she noted.

"Although total MIs were reduced, this is a secondary endpoint and to then drill down…is cause for some concern because I think there's often the risk of getting spurious results," she added.

Nissen echoed these comments in an interview with | Medscape Cardiology, noting that the study, while conducted rigorously, showed benefits that were only speculative.

"If you study enough secondary endpoints or subgroups, you will find something that is positive. So these subgroup analyses and secondary endpoints are not reliable scientific evidence of benefit," he said.

Nissen added that the trial evaluated a low dose of omega-3 and is consistent with other studies that have shown that "low doses of fish oil given to people that are not selected for having high triglycerides don't have a favorable effect on cardiovascular outcomes."

Still, he called this trial "important" and said he was glad that it was conducted, especially because of the large number of Americans who are taking vitamin D everyday with the hope that it will protect against cancer or CVD.

He added that "the idea that low vitamin D is somehow bad may just be a reflection that people with low vitamin D don't get enough sun or don't get out enough and exercise. We don't know the answer, but we do know that giving vitamin D in this very large, very well-done study didn't show any benefits."

"Expectations Were High"

In an accompanying editorial, John F. Keaney Jr, MD, University of Massachusetts Medical School, Worcester, and Clifford J. Rosen, MD, Maine Medical Center Research Institute, Scarborough, write that the study's results are both timely and relevant, especially because of a dearth of trial data on the effects of omega-3 supplements on the primary prevention of CVD in the general population.

"VITAL has now filled this knowledge gap," they write. In addition, "expectations were high that VITAL, which was powered to detect a 15% lower incidence of new cancers with the active treatment than with placebo and which included 10 times the number of participants as other trials, would provide a definitive answer."

Although the primary endpoints weren't met, the editorialists write that "other aspects of this trial are noteworthy," including that supplementation showed no health benefits across a wide range of serum vitamin D levels.

They add that "the secondary endpoints will undoubtedly draw attention," but they caution against citing those results as evidence.

"The medical literature is replete with exciting secondary endpoints that have failed when they are subsequently formally tested as primary endpoints in adequately powered randomized trials," write Keaney and Rosen.

Therefore, "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," they write.

The study was co-sponsored by the National Cancer Institute and the National Heart, Lung, and Blood Institute, with additional funding from the Office of Dietary Supplements, the National Institute of Neurological Disorders and Stroke, and the National Center for Complementary and Integrative Health. Manson reports having received grants from the National Institutes of Health and nonfinancial support from Pharmavite LLC, Pronova BioPharma, and Quest Diagnostics. Financial relationships for the other study authors are listed in the original article. Armitage reports being chief investigator for the ASCEND trial, which assessed omega-3 vs placebo, and that research grants were given to the University of Oxford from Solvay/Abbott/Myland and Bayer for ASCEND and from The Medicines Company for the ORION 4 trial. Keaney and Rosen are associate editors at the New England Journal of Medicine. Nissen has disclosed no relevant financial relationships but notes that he is chairing a 13,000-patient study assessing large doses of a different omega-3.

American Heart Association (AHA) Scientific Sessions 2018. Session LBS.01. Presented November 10, 2018.

N Engl J Med. Published online November 10, 2018. Omega-3 full text, Vitamin D full text, Editorial

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