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Just What Did the VITAL Results Teach Us About Vitamin D and Omega-3 Supplementation?
The Vitamin D and Omega-3 Trial (VITAL) was a very large randomized placebo-controlled study (with a two-by-two factorial design), which examined the effects of vitamin D or omega-3 supplementation on the primary outcomes: major cardiovascular (CV) events (myocardial infarction (MI), stroke, CV-related death) and invasive cancer (1,2). The study included 25,871 participants, 50 years or older for men and 55 years or older for women (20% of whom were black as prespecified in the study design). Participants were given 2000 IU/day vitamin D3 and 1 g/day of marine omega-3 fatty acids (either alone or in combination) or placebos. After five years, neither supplement resulted in significantly lower incidences of the primary outcomes, major CV events or invasive cancer, compared to the placebo. The outcomes were confirmed using medical records.
The bottom line is that neither vitamin D nor omega-3 fatty acid supplements lower the incidence of any invasive cancer or reduce major CV events. Further research is needed to determine if omega-3 fatty acids have any positive influence on reducing MIs among black people (a secondary finding).
In this study, researchers also looked at several other outcomes (MIs, stroke, cardiovascular deaths and deaths from any cause), which were considered secondary analyses (1,2). While most of these secondary analyses also suggested no benefits from either of these supplements, one of the observed secondary results might suggest that there could be a beneficial effect (lower risk of MI (HR, 0.72; 95%CI, 0.59 to 0.90) with supplementation of omega-3s (particularly in black participants (HR, 0.23; 95%CI, 0.11 to 0.47)). While this sub-analysis is interesting, it was not specified as a primary outcome at the start of trial, so it is possible that this statistical significance is due to chance alone. When many statistical tests are conducted, the probability of finding positive results increases with each additional test. Before secondary analyses should be considered to have any validity, they need to be tested as primary endpoints in adequately powered RCTs.
To assess whether the secondary result might suggest a benefit, it is important to examine its numerical value. The magnitude of the results for the overall reduction in MIs was (0.72 (95%CI, 0.59 to 0.90)) with supplementation of omega-3s. While this is statistically significant (the confidence interval did not include the null value of 1), the magnitude of the hazard ratio was greater than 0.5, a value that is considered to show a sufficient magnitude of change in health outcomes to represent an important difference (3). Using this metric, the secondary finding of reduced MIs among the black people supplemented with omega-3s (HR, 0.23; 95%CI, 0.11 to 0.47) suggests that it might be worth examining as a primary outcome in a subsequent study and the result for non-Hispanic white people suggests no effect at all of omega-3s on MI risk (HR, 0.93; 95%CI, 0.73 to 1.18).
For further discussion on the findings, see:
Vital Signs for Dietary Supplementation to Prevent Cancer and Heart Disease (Editorial)
VITAL: No CVD or Cancer Benefit from Vitamin D, Omega-3 (Free Membership Required to Access).
See PEN® Practice Questions:
Are vitamin D and/or calcium supplements recommended for prevention or treatment of cardiovascular disease (CVD)?
Should omega-3 fatty acids (fish or plant-based food or supplements be recommended for the primary or secondary prevention of cardiovascular disease (CVD) in adults?
- Manson JE, Cook NR, Lee IM, Christen W, Bassuk SS, Mora S, et al.; VITAL Research Group. Vitamin D supplements and prevention of cancer and cardiovascular disease. N Engl J Med. 2018 Nov 10. doi: 10.1056/NEJMoa1809944. [Epub ahead of print]. Abstract available from: https://www.ncbi.nlm.nih.gov/pubmed/30415629
- Manson JE, Cook NR, Lee IM, Christen W, Bassuk SS, Mora S, et al.; VITAL Research Group. Marine n-3 fatty acids and prevention of cardiovascular disease and cancer. N Engl J Med. 2018 Nov 10. doi: 10.1056/NEJMoa1811403. [Epub ahead of print]. Abstract available from: https://www.ncbi.nlm.nih.gov/pubmed/30415637
- Guyatt GH, Oxman AD, Sultan S, Glasziou R, AKL EA, Alonso-Coello P, Atkins D, et al. GRADE guidelines: 9. Rating up the quality of evidence. J Clin Epidemiol. 2011 Dec;64(12):1311-6. Abstract available from: https://www.ncbi.nlm.nih.gov/pubmed/?term=21802902