VITAL: No Benefits to Vitamin D and Omega-3s in Reducing Major CV Events, Cancer

Supplementation was “robustly negative” in this primary prevention group, one expert says, warning against delving too deeply into post hoc analyses.

VITAL: No Benefits to Vitamin D and Omega-3s in Reducing Major CV Events, Cancer

CHICAGO, IL—Nearly 10 years and more than $40 million dollars in the making, the VITAL trial has found no benefits to vitamin D or marine omega-3 fatty acid supplementation in the prevention of major cardiovascular disease events or cancer.

Presenting the results here at the American Heart Association (AHA) 2018 Scientific Sessions, JoAnn E Manson, MD, DrPH (Brigham and Women’s Hospital, Boston, MA), stressed that the study showed no reduction with either strategy in either primary endpoint—cardiovascular or cancer—but also that certain secondary and exploratory analyses leave the door open to further study.

Both reports were simultaneously published online, in the New England Journal of Medicine.

VITAL, launched by the US National Heart, Lung, and Blood Institute in 2009, was a nationwide, randomized, placebo-controlled trial with a 2x2 factorial design of both vitamin D at a dose of 2000 IU per day and marine n-3 fatty acids at a dose of 1 g per day. The 25,871-participant trial enrolled men ages 50 and older and women 55 and older who were free of both cancer and CVD at baseline. By design, more than 5,000 patients randomized were black, recognizing that skin pigmentation affects cutaneous absorption of vitamin D from the sun, such that black individuals are more likely than white individuals to have low blood levels of vitamin D.

After a median follow-up of 5.3 years, no differences were seen in the rates of major cardiovascular events (MI, stroke, or cardiovascular death) according to whether or not patients had been taking vitamin D versus placebo, or omega-3s versus placebo. No differences, likewise, were seen between groups for new cancer diagnoses.

Vitamin D and Omega-3 Findings

In the vitamin D analysis, no differences were seen across a wide range of secondary endpoints, including an expanded composite primary endpoint (that included revascularization), myocardial infarction, stroke, cardiovascular death, death from any cause, and a range of cancers and cancer death.

There were also no significant differences were seen between the vitamin D and placebo groups across a range of subgroups including analyses by race, serum 25-hydroxyvitamin D level, or baseline vitamin D use. The only exception was in an analysis by body mass index (BMI), wherein subjects with normal bodyweight who received vitamin D appeared to have a lower risk for new cancer than those who received a placebo. Similarly, investigators saw significant reduction in cancer deaths when the follow-up excluded years 1 and 2. Both the BMI and the censored follow-up findings should be considered “hypothesis-generating,” Manson said—the latter, in particular, were not prespecified in the trial design.

Adherence to vitamin D (or placebo) was high throughout the trial, and participants in the intervention arm achieved mean 25-hydroxyvitamin D levels within the target range, the authors note.

In the n-3 fatty acid analysis, no differences were seen between the intervention group and placebo group for the primary endpoints and across the range of secondary endpoints for cancer. For cardiovascular disease, however, investigators saw reduced risk of myocardial infarction (HR 0.72; 95% CI 0.59-0.90). Further analyses—not prespecified—showed reductions in total coronary heart disease (HR 0.93; 95% CI 0.71-0.97) and PCI (HR 0.78; 95% CI 0.63-0.95), findings that the authors term “exploratory.” No differences were seen for death from cardiovascular causes, total stroke, the expanded composite cardiovascular endpoint, or CABG.

In addition, subgroup analyses looking at participants who didn’t eat a lot of fish over the course of the trial also seemed to favor a lower incidence of the primary cardiovascular endpoint with n-3 supplementation.

Consistency in Trial Results

The results for both trial arms are consistent with those of other recent trials, Manson noted. The ViDA trial showed no impact of vitamin D on deaths from any cause. Likewise, the recent ASCEND trial of omega-3 supplementation, released earlier this year at the European Society of Cardiology Congress, also showed no benefits from daily fish oils on cardiovascular outcomes.

Lead investigator for ASCEND, Jane Armitage, MD (University of Oxford, England), who was the discussant for VITAL here today, also used the term “hypothesis-generating,” adding, “I think we need to be cautious in our interpretation.”

“The important result is that the major vascular event [endpoint] is negative overall, and that’s a good test of the hypothesis and pretty much refutes the benefits that were observed in the observational studies,” Armitage said. “While the total MIs are reduced [with omega-3 supplementation], this is a secondary endpoint, and then to drill down into the secondary endpoints is of some concern because I think there is often the risk of getting spurious results.”

The cancer findings, in addition, are “robustly negative,” Armitage added.

“Daily supplementation with high-dose vitamin D for 5 years among initially healthy adults in the United States did not reduce the incidence of cancer or major cardiovascular events,” Manson and colleagues conclude their vitamin D paper in the NEJM. A nearly identical sentence was used by way of conclusion in the second paper on n-3 fatty acids.

That takeaway is echoed in an editorial accompanying the two studies. VITAL “has convincingly shown that the use of n-3 fatty acids is not effective in preventing the combined endpoint of myocardial infarction, stroke, or death from cardiovascular causes in unselected patients,” write John F. Keaney, MD (University of Massachusetts Medical School, Worcester), and Clifford J Rosen, MD (Maine Medical Research Institute, Scarborough).  

Of note, however, there was better news for omega-3 fatty acids elsewhere in the AHA program today. In the REDUCE-IT trial, a high-dose, purified ethyl ester of eicosapentaenoic acid (EPA) derived from omega-3 fatty acids, significantly reduced the risk of hard cardiovascular events in a large, global study of statin-treated patients at elevated CV risk.  

Deepak Bhatt, MD (Brigham and Women's Hospital, Boston, MA), who presented REDUCE-IT during the same late-breaking clinical trial session, cautioned against seeing the results as contradictory, stressing that “one studied a prescription drug, the other a nutraceutical.”

“The reason the two trials are different really has to do with the drug formulation studied. In the one case that’s an over-the-counter supplement, which numerous trials have shown aren’t effective, including the ASCEND trial,” Bhatt told TCTMD. “In our trial, REDUCE-IT, we used a highly purified version of EPA called icosapent ethyl, 4 g a day, and that has properties that at least at a basic science level are quite distinct from [docosahexaenoic acid (DHA)] or an admixture of EPA and DHA, which as you know in supplements is totally unregulated: it can be whatever happens to be in that batch, with no oversight from anyone, including the FDA.”

“Don’t waste your money on those supplements,” Bhatt added during a morning press conference. “They’re not regulated, and you don’t know what’s in them.”

Donna Arnett, PhD (University of Kentucky College of Public Health, Lexington), who also addressed trial differences during the press conference, pointed out that the populations were substantially different between REDUCE-IT and VITAL. Patients enrolled in REDUCE-IT had elevated LDL cholesterol controlled by statin therapy and additional cardiovascular risk factors including persistent elevated triglycerides between 150-499 mg/dL and either established CVD or diabetes and at least one other CV risk factor. VITAL, by comparison, enrolled patients free of cardiovascular disease. “You can’t make comparisons between these trials because the populations are completely different,” she said.

Speaking with TCTMD, Manson addressed a critique of VITAL that emerged not long after the study’s launch, namely that the study dose might be too low to have an impact on cardiovascular events. Addressing that point today, she said that she did not think a higher dose of vitamin D would have made a difference, at least based on available evidence. Additional answers may come from ongoing studies testing higher doses and monthly bolus doses, she added.

Sources
  • Manson JE, Cook NR, Lee I-M, et al. Vitamin D supplements and prevention of cancer and cardiovascular disease. N Engl J Med. 2018;Epub ahead of print.

  • Manson JE, Cook NR, Lee I-M, et al. Marine n-3 fatty acids and prevention of cardiovascular disease and cancer. N Engl J Med. 2018;Epub ahead of print.

  • Keaney JF, Rosen CJ. VITAL signs for dietary supplementation to prevent cancer and cardiovascular disease. N Engl J Med. 2018;Epub ahead of print.

Disclosures
  • Manson reports no having no relevant conflicts of interest.
  • Bhatt reports receiving grants from Amarin, which makes the purified product studied in REDUCE-IT, as well as grants, fees, and/or other benefits from a wide range of pharmaceutical companies, publications, and institutions.
  • Armitage reports research grants to University of Oxford from Solvay/Abbott/Mylan, Bayer, and The Medicines Company but no personal payments.

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