VITAL (Omega-3 arm)

Published

Manson JE, et al. "Marine n-3 fatty acids and prevention of cardiovascular disease and cancer". The New England Journal of Medicine. 2019. 2019(380):1.
PubMed • Full text • PDF • ClinicalTrials.gov

Clinical Question

Among adults without prior cancer or CVD, does supplementation with n-3 (also called omega-3) fatty acids reduce the risk of cardiovascular events or invasive cancer?

Bottom Line

Among adults without prior cancer or CVD, supplementation with n-3 (omega-3) fatty acids did not reduce the incidence of cardiovascular events or invasive cancer.

Major Points

The role of omega-3 (n-3) fatty acids for primary and secondary prevention of CVD is a matter of controversy, with a 2018 Cochrane review noting that there was no clear benefit for CVD risk reduction, and that prior studies implying benefit were possibly biased. Similarly, there was no clear benefit from meta analyses linking n-3 to lower cancer incidence.

The 2019 Vitamin D and Omega-3 Trial (VITAL) randomized 25,871 middle age or senior adults without prior CVD or cancer to n-3 or placebo. (This trial was a 2x2 factorial design, and there was also a vitamin D randomization that is not discussed here.) With median follow-up of 5.3 years, there was no difference in major CV events (HR 0.92; P=0.24) or invasive cancer (HR 1.03; P=0.56) when comparing n-3 to placebo. There were numerous other endpoints assessed, some of which had hazard ratios that did not include the null (e.g., MI, CHD, MI mortality). The authors did not adjust for multiple comparisons, so readers should be cautioned about interpreting these outcomes. Some subgroups might have had fewer CVD events, including those with lower dietary fish intake. Ultimately, VITAL's Omega-3 arm does not support the use of n-3 for CVD or cancer prevention.

In contrast with VITAL, the industry-sponsored 2019 REDUCE-IT trial found lower risk of CVD events when higher dose, prescription n-3 agent among persons with hypertriglyceridemia. An updated Cochrane's meta analysis concluded that higher n-3 slightly reduces risk of CVD events.

Guidelines

As of February 2024, no guidelines have been published that reflect the results of this trial.

Design

• Multicenter, randomized, double-blind, placebo-controlled trial with a two-by-two factorial design
• N=25,871
  • n-3 fatty acid (N=12,933)
  • Placebo (N=12,938)
• Setting: US-based trial, unclear how many centers participated
• Enrollment: 2011-2014
• Median follow-up: 5.3 years
• Analysis: Intention To Treat
• Primary outcome:
  • Major CV events
  • Invasive cancer

Population

Inclusion Criteria

• Men aged ≥50, women aged ≥55
• No history of cancer, except non-melanoma skin cancer
• No history of MI, stroke, TIA, or coronary revascularization

Exclusion Criteria

• Use of anticoagulation
• Renal failure
• Hypercalcemia
• Parathyroid problems
• Cirrhosis
• Sarcoidosis
• Granulomatous disease (e.g., TB, GPA)
• Fish allergy
• Illness that wuld preclude participation
• Consuming >800 units vitamin D from all supplements combined and not willing to stop supplements during the trial
• Consuming >1200 mg/D of calcium from all supplements combined

Baseline Characteristics

• Demographics: Age 67 years, 51% women, 20% African American
• BMI: 28.1
• Medical issues: Smoker 7%, hypertension on medication 50%, on cholesterol-lowering medication 38%, diabetes 14%

Interventions

• Randomized to an arm:
  • Vitamin D3 + fish oil
  • Vitamin D3 and placebo fish oil
  • Placebo vitamin D3 and fish oil
  • Placebo vitamin D3 and placebo fish oil
• Vitamin D3 dosing was 2000 units/day
• Fish oil was Omacor brand and was EPA+DHA, 840 mg/d

Outcomes

Comparisons are n-3 fatty acid vs. placebo. None of the outcomes were adjusted for multiple comparisons. Numbers here are # of participants with an event.

Primary Outcomes

Components of the CV and cancer outcomes were not themselves primary outcomes, but are shown here for simplicity.

Major CV events

MI, stroke, or CVD mortality

386 vs 419 (HR 0.92; 95% CI 0.80 to 1.06; P=0.24)

MI, total: 145 vs. 200 (HR 0.72; 95% CI 0.59-0.90)

Stroke, total: 148 vs. 142 (HR 1.04; 95% CI 0.83-1.31)

CVD mortality: 142 vs. 148 (HR 0.96; 95% CI 0.76-1.21)

Invasive cancer

Any type

820 vs. 797 (HR 1.03; 95% CI 0.93-1.13; P=0.56)

Breast cancer: 117 vs. 129 (HR 0.90; 95% CI 0.70-1.16)

Prostate cancer: 219 vs. 192 (HR 1.15; 95% CI 0.94-1.39)

Colorectal cancer: 54 vs. 44 (HR 1.23; 95% CI 0.83-1.83)

Cancer mortality: 168 vs. 173 (HR 0.97; 95% CI 0.79-1.20)

Secondary Outcomes

Expanded CVD endpoint

MI, stroke, CVD mortality, coronary revascularization

527 vs. 567 (HR 0.93; 0.82-1.04)

All cause mortality

493 vs. 485 (HR 1.02; 95% CI 0.90-1.15)

Excluding first 2 years of follow-up

Major CV events: 269 vs. 301 (HR 0.89; 95% CI 0.76-1.05)

MI, total: 94 vs. 131 (HR 0.72; 95% CI 0.55-0.93)

Invasive cancer: 536 vs. 476 (HR 1.13; 95% CI 1.00-1.28)

Cancer mortality: 126 vs. 135 (HR 0.93; 95% CI 0.73-1.19)

All-cause mortality: 371 vs. 381 (HR 0.97; 95% CI 0.84-1.12)

Other Outcomes

PCI: 162 vs. 208 (HR 0.78; 95% CI 0.63-0.95)

CABG: 85 vs. 86 (HR 0.99; 95% CI 0.73-1.33)

CHD: 308 vs. 370; 95% CI HR 0.83 (0.71-0.97)

CHD includes MI, coronary revascularization, or CHD mortality

Ischemic stroke: 111 vs. 116 (HR 0.96; 95% CI 0.74-1.24)

Hemorrhagic stroke: 25 vs. 19 (HR 1.32; 95% CI 0.72-2.39)

CHD mortality: 37 vs. 49 (HR 0.76; 95% CI 0.49-1.16)

MI mortality: 13 vs. 26 (HR 0.50; 95% CI 0.26-0.97)

Stroke mortality: 22 vs. 20 (HR 1.10; 95% CI 0.60-2.01)

Subgroup Analysis

There was a possibility of lower incidence of cardiovascular endpoints with n-3 (omega-3) supplementation among patients with a low fish consumption in their diet, Black adutls, smokers, diabetes, hypertension, and 2+ CVD risk factors. See details in Figure 2 and supplemental Figure s3. There were possibly more cancer events among men relative to women. See supplemental Table S5.

Adverse Events

There was no difference in adverse events, as is detailed in supplemental Table s7.

Criticisms

• Only one dose of n-3 (omega-3) was tested, it is possible that a higher dose might have different efficacy.
• 401,605 participants were screened for eligibility, of which only 6% of these were ultimately randomized.
• The many outcomes were not adjusted for multiple comparisons.

Funding

National Institutes of Health