Omega-3 Fatty Acid (Fish Oil) Supplements: Results from the VITAL Trial
In a major prospective National Institutes of Health (NIH)-funded study known as the VITAL trial, omega-3 fatty acid supplementation did not result in a lower incidence of major cardiovascular events or cancer compared to placebo.
Omega-3 fatty acids, also known as fish oil, are popular as supplements to reduce the incidence of chronic disease. They have been associated with reduced risks of cardiovascular disease and cancer, as reported in a variety of observational studies over the years. It was unclear whether omega-3 fatty acids have similar effects in the general population at usual risk for cardiovascular disease and cancer.
The term VITAL stands for The Vitamin D and Omega-3 Trial. (See our previous blog article reviewing the results from the vitamin D half of the trial.) According to the authors, clarifying the relation between supplemental omega-3 fatty acids and risks of cardiovascular disease and cancer and obtaining more data on the benefit-risk balance of these supplements was a high priority. The trial was conducted to add new knowledge to the use of these supplements.
The trial results can be accessed at Manson JE, et al. “Marine n-3 fatty acids and prevention of cardiovascular disease and cancer.” New Engl J Med 2019; 380:23-31.
The randomized, double-blind, placebo-controlled trial involved 25,871 participants from the general population. The intent was to test the benefits and risks of omega-3 fatty acids at a dose of 1 gram daily – comprising fish oil capsules containing 460 mg EPA (eicosapentaenoic acid) and 380 mg DHA (docosahexaenoic acid) – in the primary prevention of cardiovascular disease and cancer among men 50 years of age or older and women 55 years of age or older in the United States.
The omega-3 fatty acid dose was based on the recommendations by the American Heart Association as shown to be beneficial in a secondary prevent population.
Questionnaires were used at baseline that included participant-reported intake of fish and other foods. From there, annual questionnaires were used to collect data on adherence to and potential side effects of the trial interventions and the development of major illnesses and risk- factor updates.
The primary endpoints were major cardiovascular events consisting of heart attack, stroke, or death form cardiovascular causes and invasive cancer of any type. Secondary endpoints included individual components of the composite cardiovascular endpoint, site-specific cancers, and death from cancer.
A total of 25,871 participants underwent randomization. During a median follow up of 5.3 years:
- Major cardiovascular event occurred in 386 participants in the omega-3 fatty acid group and 419 participants in the placebo group (hazard ratio 0.92; confidence limits 0.80-1.06)
- Total myocardial infarction occurred in 145 participants in omega-3 group and 200 participants in placebo group (HR 0.72; CL 0.59-0.90)
- Total stroke occurred in 148 participants in omega-3 group and 142 participants in placebo group (HR 1.04; CL 0.83-1.31)
- Death from cardiovascular disease occurred in 142 participants in omega-3 group and 148 participants in placebo group (HR 0.96; CL 0.96-1.21)
- Invasive cancer was diagnosed in 820 participants in omega-3 group and in 797 participants in placebo group (HR 1.03; CL 0.93-1.13)
- Breast cancer was diagnosed in 117 participants in omega-3 group and 129 participants in placebo group (HR 0.90; CL 0.70-1.16)
- Prostate cancer was diagnosed in 219 participants in omega-3 group and 192 participants in placebo group (HR 1.15; CL 0.9-1.39)
- Colorectal cancer was diagnosed in 54 participants in omega-3 group and 44 participants in placebo group (HR 1.23; CL 0.83-1.83)
- Death from cancer occurred in 168 participants in omega-3 group and 173 participants in placebo group (HR 0.97; CL 0.79-1.20)
- Death from any cause occurred in 493 participants in omega-3 group and 485 participants in placebo group (HR 1.02; CL 0.90-1.15)
In this primary prevention trial using close to 26,000 participants 50 years or older with a median follow-up of 5.3 years, omega-3 fatty acid supplements at a dose of 1 gram daily did not lead to a significantly lower incidence than placebo of the primary endpoint of major cardiovascular events or invasive cancer.
Analyses of the separate components of the cardiovascular endpoints showed a lower risk of myocardial infarction in the omega-3 group than in the placebo group, but there was no significant difference in the incidence of death from overall cardiovascular causes and stroke. Also, in more detailed analysis, there was a greater cardiovascular benefit of lower myocardial infarction with omega-3 fatty acid supplements in black participants than in non-Hispanic whites.
In terms of effects on cancer, exploratory analyses that excluded the first 2 years of follow-up suggested a non-significantly higher incidence of cancer in the omega-3 group than in the placebo group, but not a higher incidence of death from cancer.
Three meta analyses reports on omega-3 fatty acid supplementation trials involving adults at high risk for cardiovascular disease have shown that supplementation had no, or at the most, weak preventive effects on major cardiovascular events, major coronary events, myocardial infarction, stroke, and revascularization. These reports can be found at:
- Rizos E.C., et al. “Association between omega-3 fatty acid supplementation and risk of major cardiovascular disease events: a systematic review and meta-analysis.” JAMA 2012; 308:1024-33.
- Aung T., et al. “Associations of omega-3 fatty acid supplement use with cardiovascular disease risk: meta-analysis of 10 trials involving 77,917 individuals.” JAMA Cardiol 2018; 3:225-34.
- Abdelhamid A.S., et al. “Omega-3 fatty acids for the primary and secondary prevention of cardiovascular diseases.” Cochrane Database Syst Rev 2018; 7:CD003177
Thus, neither this current VITAL trial, which is a primary prevention trial, nor the secondary prevention trials listed above indicate a benefit of omega-3 fatty acid supplementation with respect to composite cardiovascular endpoints.
In addition, a recent trial known as ASCEND tested omega-3 fatty acid supplements at a dose of 1 gram daily in diabetic adults, and it showed no difference in prevention of cardiovascular events compared to placebo. (For more detail: Bowman L, et al. “Effects of n-3 fatty acid supplements in diabetes mellitus.” N Engl J Med 2018; 379:540-50.)
The VITAL trial authors go on to comment on the interesting trend of fewer myocardial infarction events observed with omega-3 supplements compared with placebo, which suggests that supplemental omega-3 fatty acids conferring protection from myocardial infarction is biologically plausible. Data from laboratory studies and from studies in animals support mechanisms including reduced susceptibility to cardiac arrhythmias, anti-inflammatory effects, antithrombotic effects, and inhibition of atherosclerotic plaques.
This study showed non-significant differences between omega-3 fatty acid supplement groups and placebo groups with regard to the incidence of breast, prostate, or colorectal cancer. There was no difference in death from cancer between the two groups.
In an accompanying New England Journal of Medicine editorial by Keaney and Rosen, it stated that any long-term health benefits from omega-3 fatty acid supplementation remains in doubt.
Observational data over the years have long proposed that the consumption of fish is associated with protection from cardiovascular disease. However, evidence from trials that omega-3 fatty acid supplements may prevent coronary heart disease was not available until the late 1990s. Based on the omega- 3 fatty acid data, the American Heart Association (AHA) issued a recommendation regarding the use of omega-3 fatty acids for the secondary prevention of coronary artery disease. For clarification, secondary prevention was defined as preventing coronary artery disease in individuals having a past cardiovascular event.
That AHA recommendation has since been updated after additional trials showed no consistent effect of these supplements to reduce the incidence of cardiovascular events in populations at high risk for coronary heart disease.
Thus, the only remaining use for omega-3 fatty acids according to the AHA is an opinion that the use of omega-3 fatty acid supplements (fish oil) is reasonable (not recommended) because it may prevent death from coronary heart disease in patients with a recent myocardial infarction.
To quote the authors: “In summary, the VITAL trial has filled a knowledge gap that showed that the use of omega-3 fatty acid supplements by the general population did not result in preventing cardiovascular disease or cancer of any type.”
Richard L. Wynn, BS Pharm, PhD, is professor of pharmacology at the Baltimore College of Dental Surgery, Dental School, University of Maryland Baltimore.
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