Data from the VITamin D and OmegA-3 TriaL (VITAL) and Reduction of Cardiovascular Events With EPA – Intervention Trial (REDUCE-IT) were presented at the 2018 American Heart Association (AHA) Scientific Sessions on Saturday. Multiple papers were simultaneously published in the New England Journal of Medicine.
VITAL indicated that daily vitamin D3 and/or EPA+DHA in the form of omega-3-acid ethyl esters did not achieve the trial’s primary outcome of significantly reducing major cardiovascular disease (CVD) events. However, omega-3s were found to reduce total and fatal myocardial infarction risk by 28% and 50%, respectively. A 17% reduction in risk was recorded for total coronary heart disease, versus placebo.
For REDUCE-IT, which focused on people with CVD or with diabetes and other risk factors, four grams per day of Amarin’s Vascepa (icosapent ethyl) was found to reduce the risk of the primary composite end-point of cardiovascular death, nonfatal myocardial infarction, nonfatal stroke, coronary revascularization, or unstable angina by 25%, compared to placebo.
It is important to note that both studies used pharmaceuticals and not dietary supplement versions of omega-3 (VITAL used BASF/ Pronova’s Omacor/ Lovaza, while REDUCE-IT used Amarin’s Vascepa), and omega-3 supplement companies need to be careful not to link the results of these studies to their own products. The vitamin D used in VITAL was a dietary supplement, provided by Pharmavite.
Despite this, the data may still influence consumer perception of the efficacy of omega-3s and vitamin D. So far the headlines have been mixed, ranging from this positive headline in the Washington Post: Fish-oil drugs protect heart health, two studies say, to Vitamin D and Fish Oils Are Ineffective for Preventing Cancer and Heart Disease in the New York Times. The Chicago Tribune sat on the fence: Big studies give mixed news on fish oil, vitamin D.
GOED: “The VITAL results on omega-3s were more positive than we expected”
Representative from the Global Organization for EPA and DHA Omega-3 (GOED) were present at the American Heart Association sessions in Chicago on Saturday, and the organization was quick to release the following statement:
“GOED’s view is that the VITAL results on omega-3s were more positive than we expected. We attended the AHA meeting where the results were presented and also thought the presentation of VITAL by the study authors was positive in tone.
“The results showing a 28% risk reduction for myocardial infarction (MI) as well as a 17% risk reduction in Total coronary heart disease (CHD) and 50% reduction in fatal MI provide long-awaited evidence that omega-3s do provide benefits for primary prevention,” stated GOED.
“For REDUCE-IT, the additional outcomes presented at the AHA conference are in line with the topline results previously announced, all of which provide further confirmation of the importance of omega-3s for heart-related outcomes.”
Ellen Schutt, GOED’s executive director, added that they are planning to integrate the statistics from both trials into the existing data on omega-3s and heart-related outcomes to see how much it strengthens the argument.
Study details: VITAL
Harry Rice, PhD, GOED's VP of regulatory & scientific affairs, told us: "There was a statistically significant 19% reduction in the primary endpoint of major cardiovascular events (composite of myocardial infarction, stroke, or death from cardiovascular causes) in those individuals with below average fish consumption. This suggests that individuals with a lower EPA/DHA baseline can benefit from EPA/DHA supplementation. With 13,514 subjects or about 1/2 of the participants falling into this group, this is a relevant finding.
"While exciting, I have to mention that I don't know if this finding would still be statistically significant if adjusted for multiple comparisons."
VITAL included 25,871 participants who were randomly assigned to received vitamin D3 (2,000 IU per day) or a marine omega-3 (1 gram per day). The study participants were men over 50 and women over 55 in the US, and the cohort included 5,106 African Americans.
The participants were followed for an average of 5.3 years, and the data revealed no significant impact of vitamin D on the primary end-points, which included invasive cancer of any type and major cardiovascular events (consisting of myocardial infarction, stroke, or death from cardiovascular causes).
However, drilling down into the numbers revealed a reduction in total cancer mortality from vitamin D when early follow up was excluded.
In the omega-3 part of the study, there were no benefits for cancer outcomes compared to placebo.
Statistically significant reductions in secondary heart endpoints, including total and fatal MI and total CHD, which suggested that omega-3s do provide benefits for primary prevention.
It should also be noted that the greatest reductions were demonstrated among African Americans and for individuals who ate little fish.
In an accompanying editorial in the New England Journal of Medicine, John Keaney, Jr., MD, and Clifford Rosen, MD, sounded a note of caution around these results:
“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,” they wrote.
“However, these “positive” results need to be interpreted with caution. First, there was no correction for multiple comparisons, as would be required to attenuate the chance that these are spurious results, owing, in part, to the number of secondary end points. Second, these putative effects have not been consistently observed across other large, randomized trials of n−3 fatty acids.
“… the medical literature is replete with exciting secondary end points that have failed when they were subsequently formally tested as primary end points in adequately powered randomized trials. Thus, 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.”
Study details: REDUCE-IT
This study, which was funded by Amarin, included 8,179 people with established CVD or with diabetes and at least one other risk factor. Eligible participants had fasting triglyceride levels between 150 and 499 mg per deciliter and LDL cholesterol levels between 41 and 100 mg per deciliter. They were also all on a stable dose of a statin for at least one month.
The data indicated that 4 grams per day of icosapent ethyl (EPA) reduced the risk of the first occurrence of major adverse cardiovascular events (MACE), including cardiovascular death, nonfatal myocardial infarction (MI), nonfatal stroke, coronary revascularization, or unstable angina requiring hospitalization, by 25%.
A 26% reduction in the key secondary composite of CV death, MI, or stroke was also reported, while the risk of cardiovascular death or nonfatal MI were reduced by 25%.
Other reductions were observed for the risk of fatal or non-fatal MI (31% risk reduction); cardiovascular death (20% risk reduction); hospitalization or unstable angina (32%); and fatal or non-fatal stroke (28%).
“The results of REDUCE-IT stand apart from the negative findings of several contemporary trials of other agents that also lower triglyceride levels, including other n−3 fatty acids, extended-release niacin, fenofibrate, and cholesteryl ester transfer protein inhibitors,” wrote the authors, led by Deepak Bhatt, MD, MPH, from Brigham and Women’s Hospital Heart and Vascular Center and Harvard Medical School.
“It is not known whether the lack of benefit from n−3 fatty acids in previous trials may be attributable to the low dose or to the low ratio of EPA to docosahexaenoic acid (DHA).
“Both the formulation (a highly purified and stable EPA ethyl ester) and dose (total daily dose of 4 g) used in REDUCE-IT were different from those in previous outcome trials of n−3 fatty acids.”
The researchers noted that the mechanism(s) of action behind the benefits are not known and that blood samples from the study’s participants will undergo biomarker and genetic analysis to help elucidate the mechanism(s).
NutraIngredients-USA will bring additional insights and analysis of these data in the coming days as stakeholders assess the new results.
New England Journal of Medicine
Published online ahead of print, DOI: 10.1056/NEJMoa1812792
“Cardiovascular Risk Reduction with Icosapent Ethyl for Hypertriglyceridemia”
Authors: D.L. Bhatt, et al.
New England Journal of Medicine
Published online ahead of print, DOI: 10.1056/NEJMoa1811403
“Marine n−3 Fatty Acids and Prevention of Cardiovascular Disease and Cancer”
Authors: J.E. Manson et al.
New England Journal of Medicine
Published online ahead of print, DOI: 10.1056/NEJMoa1809944
“Vitamin D Supplements and Prevention of Cancer and Cardiovascular Disease”
Authors: J.E. Manson, et al.
New England Journal of Medicine
Published online ahead of print, DOI: 10.1056/NEJMe1814933
“VITAL Signs for Dietary Supplementation to Prevent Cancer and Heart Disease”
Authors: J.F. Keaney and C.J. Rosen