Neither omega-3s, nor vitamin D, reduce major CVD events in primary prevention cohort

The VITamin D and OmegA-3 TriaL (VITAL): Principal Results for Vitamin D and Omega-3 Fatty Acid Supplementation in the Primary Prevention of Cardiovascular Disease & Cancer

Presented at the AHA congress 2018 by: JoAnn E Manson (Boston, MA, USA)

Introduction and methods

The VITAL trial was the first large-scale trial of fish oil in primary prevention, and one of the largest trials on vitamin D. It randomized over 25,000 initially healthy men and women (men ≥50 years old, women ≥55 years old) to vitamin D3 (2000 IU/d) or placebo. Within these groups, participants were further divided into receiving EPA+DHA (1gm/d, 1.3:1 ratio) or placebo. The median treatment period was 5.3 years. Over 5,000 African-Americans were included.

The primary aim of VITAL was to test whether vitamin D3 and/or omega-3 fatty acids reduce the risk of major CVD events (composite of MI, stroke, CVD death) and/or total invasive cancer. Moreover, secondary aims included testing whether these agents lower risk of MI/stroke/CVD death/PCI/CABG and/or individual components of the primary CVD outcome.

Main results

Omega-3 fatty acid results

• The primary composite outcome was not affected significantly by omega-3 supplementation (omega-3s) (386 events/12,933 participants vs. 419/12,938, HR: 0.92, 95%CI: 0.80-1.06).
• The secondary outcome of total MI was significantly reduced in the group treated with omega-3s (145/12,933 vs. 200/12,938, HR: 0.72, 95%CI: 0.59-0.90).
• Statistically significant reductions in other vascular outcomes were seen for PCI (HR: 0.78, 95%CI: 0.63-0.95), total CHD (HR: 0.83, 95%CI: 0.71-0.97) and fatal MI (HR: 0.50, 95%CI: 0.26-0.97).
• When excluding the first 2 years of follow-up to study latency, major CVD events were not significantly reduced (269/12,933 vs. 301/12,938, HR: 0.89, 95%CI: 0.76-1.05), but total MI was (94/12,933 vs 131/12,938, HR: 0.72, 95%CI: 0.55-0.93).
• In participants with lower than the median of fish consumption (<1.5 servings per week), the risk of CVD events was significantly reduced in those taking omega-3s (HR: 0.81, 95%CI: 0.67-0.98), but not in those with at least the median fish intake (HR: 1.08, 95%CI: 0.88-1.32).
• Subgroup analyses showed a strongly reduced risk of total MI in African Americans (HR: 0.23, 95%CI: 0.11-0.47), but no significantly different effect in non-Hispanic whites or other races.
• No significant effects of omega-3s on total invasive cancer (HR: 1.03), cancer death (HR: 0.97) or all-cause mortality (HR: 1.02), nor when the first 2 years of follow-up were excluded.

Vitamin D results

• No significant effects of vitamin D assignment on CVD outcomes were seen.
• No significant interactions with the relation between vitamin D and major CVD events was seen for baseline serum 25(OH) levels (< or ≥20 ng/mL or < or ≥cohort median), or omega-3s randomization status.
• Only in the latency analysis excluding the first 2 years of follow-up, vitamin D use was associated with a statistically significantly lower risk of cancer death (112/12,927 vs. 149/12,944, HR: 0.75, 95%CI: 0.59-0.96, nominal P-value 0.024), but total invasive cancer (HR: 0.94) and all-cause mortality (HR: 0.96) were not significantly affected.

Conclusion

Dr. Manson concluded that neither omega-3s, nor vitamin D, significantly reduced the primary endpoints of major CVD events or total invasive cancer. Omega-3s lowered total MI by 28%, particularly in those with low dietary fish intake and in African Americans. Other events that were reduced included PCI, fatal MI and total CHD (MI, coronary revascularization and CHD death).

Discussion

During the press conference, Jane Armitage commented on the VITAL study, which she considered a well-conducted trial. It was a large randomized trial, with an ethnically diverse population and enough women included. Adherence to the assigned supplements was good, and follow-up for mortality was almost complete.

With regard to vitamin D; while observational data had suggested a relation between vitamin D levels and (vascular) death, it was unknown whether this was causal. The VITAL trial represented a good test of the null hypothesis, providing a robust null result. Concerning omega-3, earlier studies had also suggested an effect, but a recent meta-analysis did not shown a benefit. The VITAL yielded important results, in that there is no effect on major CVD events. Dr. Armitage stressed that we should be careful when looking at secondary results, and even other outcomes; there is a risk of spurious results.

A robust conclusion that can be drawn is that the supplementations were not found to be beneficial for the primary outcomes. The other results are less robust and thus only hypothesis-generating.

- Our reporting is based on the information provided at the AHA Scientific Sessions -

Watch our video about different effects of different fish oil compounds

The omega-3 results of the VITAL study have been published simultaneously in NEJM The Vitamin D results of the VITAL study have been published simultaneously in NEJM