Marine N-3 Fatty Acids and Prevention of Cardiovascular Disease and Cancer

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Clinical Question

In patients without a previous medical history of cardiovascular disease or cancer, does the use of n-3 fatty acid supplements reduce the risk for cardiovascular disease or cancer?

Bottom Line

In patients given supplementation with n-3 fatty acids as prevention for cardiovascular event or cancer, the incidence of major cardiovascular events or cancer was not significantly reduced as compared to placebo patient population.

Major Points

N-3 fatty acids (omega-3 fatty acids) are nutrients that can be obtained from consuming oily fish and supplementation. N-3 fatty acids have been associated with the reduction of cardiovascular disease/events and cancer in various studies.2 A randomized, double blind, placebo controlled trial was conducted to determine the efficacy of N-3 fatty acids, as compared to placebo, in the prevention of major cardiovascular events and cancer in patients without known cardiovascular disease or cancer. A total of 25,861 patients underwent randomization. The study occurred over approximately 2.5 years with a 5.3 year follow-up. The placebo group was given Vit D3 2000 IU per day and the n-3 group was given 1 g per day of n-3. The results of the follow-up included a major cardiovascular event occuring in 386 participants in the n-3 group and 419 in the placebo group. Confidence interval of 0.80-1.06. Invasive cancer was diagnosed in 820 participants in the n-3 group and 797 in the placebo group which led to a confidence interval of 0.93-1.13. In both cardiovascular events and cancer diagnoses, the difference between the n-3 group and placebo group was insignificant. 1 A major criticism is the study did not account for other medications the population could be taking for other diseases. Other medications could potentially dilute the n-3 fatty acid and falsely show no significant effect from the n-3 fatty acid.1

Guidelines

American Heart Association (February 2003) The mechanism of action of omega-3 fatty acids in the reduction of cardiovascular events is continuously under study. Current research suggests omega-3 fatty acids may play a role in decreasing risk for arrhythmias, thrombosis, decreasing levels of triglyceride and remnant lipoprotein, decreasing rate of growth of atherosclerotic plaque, improvement of endothelial function, decrease in blood pressure and reduction in inflammatory response. Recommendations include:

  • All adults should eat fatty fish twice per week
  • Patients with documented CHD should take 1 g of EPA and DHA combined daily from oily fish consumption or omega-3 fatty acid capsules
  • Patients with hypertriglyceridemia should take 2-4 g of EPA and DHA supplement to lower triglyceride levels

Cautions:

  • Some fish may include high levels of methylmercury, polychlorinated biphenyls, dioxins, and other contamination substances

There are no current recommendations for N-3 fatty acid consumption in prevention of cancer.

Design

  • Randomized, double blind, placebo-controlled trial
  • N=25871
    • Placebo group (n=12938)
    • N-3 group (n=12933)
  • Setting: United States
  • Enrollment: November 2011 through March 2014
  • Mean follow-up: 5.3 years
  • Analysis: intention-to-treat
  • Primary outcome: occurrence of major cardiovascular events and incidence of invasive cancer was not significant in n-3 patient population vs. placebo patient population

Population

Inclusion Criteria

  • Male patients 50 years of age or older
  • Female patients 55 years of age or older
  • Patients residing in the United States

Exclusion Criteria

  • Previous medical history of cancer
  • Previous medical history of cardiovascular disease

Baseline Characteristics

N-3 patient group

  • Population- 12933
  • Age range- 67.2+7.1
  • BMI-28.1+5.7
  • Smokers-7%
  • Patient with Diabetes- 14%
  • Treated HTN- 50%
  • Treated hyperlipidemia- 37%

Placebo patient group

  • Population- 12938
  • Age Range- 67.2+7.1
  • BMI- 28.1+5.7
  • Smokers- 7%
  • Patients with Diabetes- 14%
  • Treated HTN- 50%
  • Treated hyperlipidemia- 37%

Interventions

Patients were given one of the following regimens:

  • N-3 fatty acids dosed at 1g fish oil capsule daily (containing 840 mg of n-3 fatty acids, 460mg of eicosapentaenoic acid and 380 mg of docosahexaenoic acid) and a placebo
  • A placebo and vitamin D3 dosed at 2000 IU daily
  • N- 3 fatty acids dosed at 1g fish oil capsule daily (containing 840 mg of n-3 fatty acids, 460mg of eicosapentaenoic acid and 380 mg of docosahexaenoic acid)and vitamin D3 dosed at 2000 IU daily
  • Two placebos


Outcomes

Comparisons are N-3 Fatty Acid vs. Placebo.

Primary Outcomes

Primary Outcomes

  • Major cardiovascular events 2.9% vs 3.2% (HR 0.92, 95% CI 0.80-1.06) Not Significant
    • Includes stroke, myocardial infarction and death due to cardiovascular event
  • Invasive cancers 6.3 % vs. 6.2% (HR 1.03, 95% CI 0.93-1.13) Not significant
    • Includes breast, prostate, colorectal cancer


Secondary Outcomes

  • Major cardiovascular events plus coronary revascularization
    • Total myocardial infarction (HR 0.72, 95% CI 0.59-0.90) Significant
    • PCI (HR 0.78, 95% CI 0.63-0.95) Significant
    • Total coronary heart disease (HR 0.83, 95% CI 0.71-0.97) Significant
    • Death from myocardial infarction (HR 0.50, 95% CI 0.26-0.97) Significant
    • Death from cardiovascular causes (HR 0.96, 95% CI 0.76-1.21) Not significant
    • Stroke (HR 1.04, 95% CI 0.83-1.31) Not significant
  • Cancers
    • Colorectal Cancer (HR 1.23, 95% CI 0.83-1.83) Not significant
    • Breast Cancer (HR 0.90, 95% CI 0.70-1.16) Not significant
    • Prostate Cancer (HR 1.15, 95% CI 0.94-1.39) Not significant
    • Death from cancer (HR 0.97, 95% CI 0.79-1.20) Not significant


Subgroup Analysis

The subgroup analysis for cardiovascular events determined that the incidence of primary cardiovascular endpoint may be decreased in patients who took n-3 supplementation compared to placebo in populations who did not consume much fish. The subgroup analysis for cancer determined that the sex of the patient could possibly modify results regarding cancer incidence. There were no other significant interactions in cancer or cardiovascular endpoints.

Adverse Events

The incidence of gastrointestinal symptoms, gastrointestinal bleeding, or other serious adverse events was not significant between the placebo and n-3 fatty acid groups.

Criticisms

  • The study did not account for other medications the population could be taking. Other medications could potentially dilute the n-3 fatty acid and falsely show no significant effect from the n-3 fatty acid.
  • Patients who do not have a history of cancer or cardiovascular disease were the only population included in the trial. The study did not apply to populations seeking secondary prevention.
  • Results regarding exploratory endpoints and subgroups are to be interpreted with caution.


Funding

Supported by grants from the National Cancer Institute, the National heart, Lung, and Blood Institute, the Office of Dietary Supplements, the National Institute of Neurological Disorders and Stroke, and the National Center for Complementary and Integrative Health. N-3 fatty acids was provided by Pronova Bio-Pharma and BASF. Vitamin D was provided by Pharmavite. Both companies supplied matching placebos, packaged in calendar packs.

Further Reading

Manson, J, et al. “Marine n-3 Fatty Acids and Prevention of Cardiovascular Disease and Cancer”. The New England Journal of Medicine. 2018. 380: 23-32 Kris-Etherton, P, et. al. “Omega-3 Fatty Acids and Cardiovascular Disease”. Atherosclerosis, Thrombosis, and Vascular Biology. 2003. 23: 151-152

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