Omega-3 fatty acids may not reduce risk for cardiovascular events, deaths from coronary heart disease (CHD), strokes, or cardiac arrhythmias, new research suggests.

A Cochrane systematic review that encompassed findings of 79 studies involving more than 112,000 people found no evidence that increasing consumption of alpha ­linolenic acid (ALA) and the long-chain omega-3 fatty acids (LCn3) eicosapentaenoic acid or docosahexaenoic acid enhances cardiovascular health or protects against all-cause death or cardiovascular events.

Low/moderate-quality evidence suggests that ALA may slightly reduce cardiovascular events, mortality, and arrhythmias, and high-quality evidence suggests that LCn3 may reduce triglycerides and increase high-density lipoprotein (HDL) cholesterol.

"Clinicians need to be aware that unless there is a specific need to reduce triglycerides, then there is no reason to encourage use of omega-3 supplements," lead author Lee Hooper, PhD, SRD, from the University of East Anglia, United Kingdom, and a member of the World Health Organization Nutrition Guidance Expert Advisory Group, told theheart.org | Medscape Cardiology.

"Patients would be better advised to spend the money on eating well or keeping fit," she said.

The study was published online July 18 in the Cochrane Database of Systematic Reviews.

Previous Research Inconsistent

Many practice guidelines recommend omega-3 fats, in the form of fish oil or supplements, to enhance cardiovascular health; they are widely used for this purpose. LCn3 is derived from fish, while ALA, a shorter-chain omega-3 fatty acid, comes from plant sources and is partially converted to LCn3 fatty acids within the body.

The authors suggest possible mechanisms for a protective role of omega-3 fats against cardiovascular disease (CVD), including lowering blood pressure, altering the lipid profile, modulating arterial lipoprotein lipase levels, reducing thrombosis, producing anti-inflammatory and anti-arrhythmic effects, improving vascular endothelial function and insulin sensitivity, and increasing plaque stability and paraoxonase levels.

However, despite its putative benefits, fish oil is not without potential side effects, including toxicity and high mercury levels, and omega-3 fats themselves may extend bleeding times or suppress normal immune response.

Moreover, results of previous studies have been inconsistent and limited by possible confounding factors.

"We were asked by the World Health Organization to assess effects of polyunsaturated fats on health, and as part of this wider project, we have assessed the effects of omega-3 fats on cardiovascular outcomes," Hooper said.

"Disappointing" Results

To investigate the question, the researchers reviewed 79 trials involving 112,059 people. To be included, a study had to last at least 12 months and compare supplementation and advice to increase LCn3 or ALA intake vs usual or lower intake. Of these studies, 25 met criteria and were at low risk of bias.

The trials ranged between 12 and 72 months in duration and included adults with varying degrees of cardiovascular risk, primarily in high-income countries. While most studies assessed LCn3 supplementation taken via capsules, some trials used LCn3- or ALA-rich or enriched foods or dietary advice vs placebo or usual diet.

Using meta-analytic and sensitivity analyses, the researchers found little or no effect of increased LCn3 on all-cause mortality compared with placebo or usual diet (8% vs 9%; relative risk [RR], 0.98; 95% confidence interval [CI], 0.90 - 1.03; high-quality evidence).

Likewise, little to no effect was found for cardiovascular mortality (RR, 0.95; 95% CI, 0.87 - 1.03), cardiovascular events (RR, 0.99; 95% CI, 0.94 - 1.04, high-quality evidence), coronary heart disease (CHD) mortality (RR, 0.93; 95% CI, 0.79 - 1.09), stroke (RR, 1.06; 95% CI, 0.96 - 1.16), or arrhythmia (RR, 0.97; 95% CI, 0.90 - 1.05).

Although in the initial analysis LCn3 seemed to reduce CHD events (RR, 0.93; 95% CI, 0.88 - 0.97), the reduction was not maintained in sensitivity analyses.

"LCn3 probably makes little or no difference to CHD event risk," the authors comment.

All evidence was of moderate quality according to GRADE guidelines, unless otherwise stated.

The researchers also found that increasing ALA intake is unlikely to affect all-cause mortality (RR, 1.01; 95% CI, 0.84 - 1.20) or cardiovascular (CV) mortality (RR, 0.96; 95% CI, 0.74 - 1.25).

It also may not affect CHD events (RR, 1.00; 95% CI, 0.80 - 1.22; low-quality evidence).

On the other hand, increased ALA may slightly lower the risk for CV events (4.8% to 4.7%; RR, 0.95; 95% CI, 0.83 - 1.07; low-quality evidence) and is likely to reduce risk for CHD mortality (1.1% to 1.0%; RR, 0.95; 95% CI, 0.72 - 1.26) and arrhythmia (3.3% to 2.6%; RR, 0.79; 95% CI, 0.57 - 1.10).

The researchers call ALA's impact on stroke "unclear."

After conducting sensitivity analyses of trials only at low summary risk of bias, they found that effect sizes moved toward the null for all LCn3 primary outcomes, except arrhythmias.

However, for most ALA outcomes, effect sizes moved toward suggesting protection. By contrast, LCn3 funnel plots suggested that adding in missing studies/results would move effect sizes toward null for most primary outcomes. There were no dose or duration effects in subgrouping or meta-regression.

There was no evidence that increasing LCn3 or ALA altered serious adverse events, adiposity, or lipids, although LCn3 slightly reduced triglycerides and increased HDL cholesterol.

"We got very excited by omega-3 fats in the early 1990s, following a couple of surprising and very positive trials," Hooper recounted.

"The results in later trials have never been as positive, but somehow we owned the notion that omega-3 fats were great for us, despite disappointing results ever since," she said.

Hooper noted that omega-3 fats do lower triglycerides in the long term and also slightly increase HDL cholesterol, but "other health effects do not seem to follow."

Lifestyle Interventions

Commenting for theheart.org | Medscape Cardiology, Ian Johnson, BSc, PhD, emeritus fellow, Quadram Institute Bioscience, Norwich, United Kingdom, who was not involved with the research, said that he was "quite surprised by the outcome of this systematic review" but is "confident that it is of high quality."

"Perhaps the general message is that for fatty acids, as for many other dietary constituents, it is very difficult to reproduce epidemiological findings by means of randomized intervention trials because human diets are immensely complex and physiological effect sizes for particular nutrients are small in relation to the causation of chronic diseases," he said.

Hooper added, "I would love to see omega-3 supplements delivering — what a simple way to reduce our cardiovascular risk. But they don't, so we need to focus on the lifestyle interventions that do work — eating a high-quality diet, moderate alcohol, not smoking, and keeping fit and active."

The project was supported by the National Institute for Health Research, via Cochrane Infrastructure funding to the Heart Group. Hooper and coauthors report no conflicts of interest. Johnson declares no conflicts of interest.

Cochrane Database Syst Rev. Published online July 18, 2018. Abstract

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