More people than ever take fish oil dietary supplements—around 8% of US adults in 2012 compared with around 5% five years earlier, according to the National Center for Health Statistics. But a recent meta-analysis of 10 large clinical trials came to a disappointing conclusion: The popular capsules do little to protect patients with heart disease. The findings are at odds with advice from the American Heart Association (AHA), including a 2017 science advisory recommendation to consider fish oil supplementation for patients with a recent myocardial infarction, or heart attack.
The new meta-analysis, published in JAMA Cardiology in January, looked at randomized trials of marine-derived omega-3 fatty acid supplements involving almost 78 000 participants with a history of coronary heart disease (66%), stroke (28%), or diabetes (37%). The trials lasted an average of 4.4 years and compared fish oil with placebo or no treatment in at least 500 participants.
All told, fish oil supplements did not reduce the risk of coronary heart disease deaths, nonfatal heart attacks, fatal or nonfatal strokes, revascularization procedures, or all-cause mortality among the full study population. The supplements also didn’t protect against major vascular events in any subgroups, including people with a history of heart disease, diabetes, high cholesterol, or statin use.
Parsing the effects of fish oil supplementation in prespecified disease subtypes and participant subgroups is something that wasn’t previously possible with the published data sets, said Robert Clarke, MD, a professor of epidemiology and public health medicine at the University of Oxford who led the review. Clarke’s coauthors included principal investigators from 9 out of 10 of the included trials, who provided unpublished data necessary for the meta-analysis.
“They looked every way they could to find out if there was a signal and nothing panned out,” said Lawrence J. Appel, MD, a coauthor of last year’s AHA advisory, who was not involved with the analysis.
The findings are just the latest to cast doubt on the usefulness of fish oil supplementation for major cardiovascular disease end points. Although early trials showed a substantial mortality benefit, the supplements haven’t lived up to their promise in later studies.
Two 2012 reviews of randomized trials published in JAMA and the Archives of Internal Medicine (now JAMA Internal Medicine) by separate research teams found little benefit of fish oil supplementation for heart health. A 2016 systematic review from the Agency for Healthcare Research and Quality essentially reached the same conclusion.
The authors of the new analysis concluded that it “doesn’t provide any support for the current recommendation from the American Heart Association to use omega-3 fatty acids for the prevention of fatal coronary heart disease or any coronary heart disease in people with prior vascular disease,” Clarke told JAMA.
Despite having coauthored the conflicting AHA advisory, Appel, who is director of the Welch Center for Prevention, Epidemiology, and Clinical Research at Johns Hopkins School of Medicine and the Bloomberg School of Public Health, said he was “not at all surprised” by the results. “After a few high-profile trials done over a decade ago, … it’s really been a pretty disappointing landscape for fish oil, which [was] sort of like the supplement du jour,” he said.
The aggressive way heart disease is treated today—with statins, β-blockers, angiotensin-converting enzyme inhibitors, and aspirin, along with procedures to restore blood flow—may largely explain why the benefit of fish oil supplements appears to have dwindled over time. Trials for the most part have tested secondary prevention, which means they included participants who were already receiving treatment.
“Once you get a heavily medicated group, it’s really hard to detect further benefit,” Appel said.
Improved diets—including greater fish consumption—may have also reduced the magnitude of effect over time. The omega-3 polyunsaturated fatty acids eicosapentaenoic acid (EPA) and docosahexaenoic acid (DHA) found in cold-water fish are believed to be the main drivers of cardioprotection in seafood and are the primary components in fish oil capsules.
“Most observational studies have found that adding omega-3 supplements on top of a diet with 1 to 2 servings of fish a week will have no benefit,” said Eric Rimm, ScD, director of cardiovascular epidemiology at Harvard T.H. Chan School of Public Health.
The AHA advisory concluded that it was reasonable for physicians to consider prescribing fish oil to patients with a recent coronary heart disease event like a recent heart attack or with prevalent heart failure with reduced left ventricular function.
David Siscovick, MD, senior vice president for research at the New York Academy of Medicine and a professor emeritus of medicine and epidemiology at the University of Washington, chaired the advisory. Like his coauthor Appel, Siscovick wasn’t surprised by the results of the recent meta-analysis. But he said different research methods could explain the divergent conclusions in the analysis and the AHA advisory.
In addition to randomized trials, the advisory committee also considered meta-analyses and looked at outcomes for specific indications in individual studies rather than pooling the data. The 2 groups also defined cardiovascular mortality differently, Siscovick said. The meta-analysis included deaths related to revascularizations, for example, while the AHA advisory did not.
The AHA advisory committee estimated a reduction of around 10% in cardiovascular mortality among patients who experienced a recent heart attack and a 9% reduction in all-cause mortality among patients with heart failure.
“Given a potential modest effect [on] mortality, which is an important patient outcome, and little evidence of risk from the treatment with omega-3 supplements, we concluded that it was reasonable for physicians to consider treating in these two clinical indications,” Siscovick said.
He pointed out that the advisory and the meta-analysis are otherwise essentially in agreement. For example, both concluded that for patients at high risk of heart disease who haven’t developed it yet, the evidence from trials doesn’t suggest a benefit of fish oil treatment.
Siscovick’s bottom line: “Would I rewrite our advisory? The answer is no.”
Researchers are watching for the results of 4 large randomized trials of fish oil supplements currently under way that together will include more than 60 000 people.
An open question is whether healthy people should take fish oil for primary prevention of heart disease. The highly anticipated Vitamin D and Omega-3 Trial (VITAL), which involves almost 26 000 participants, is the first to test whether fish oil supplements reduce the risk of developing heart disease, stroke, and cancer in the general population. Another trial, A Study of Cardiovascular Events in Diabetes (ASCEND), will test if fish oil prevents serious vascular events in patients with diabetes who do not have arterial disease.
Clarke, however, doesn’t expect a different outcome in these trials because the omega-3 dosages are roughly the same as the average dose in his meta-analysis: around 1 g per day.
The 2 other trials—Reduction of Cardiovascular Events with EPA–Intervention Trial (REDUCE-IT) and Statin Residual Risk Reduction with EpaNova in High Cardiovascular Risk Patients with Hypertriglyceridemia (STRENGTH)—will test around 4 g of fish oil per day in patients at high risk of cardiovascular disease who have extremely high triglycerides and are already taking statins. This higher dosage is used to reduce hypertriglyceridemia but until now hasn’t been tested for end points such as heart attack, stroke, or mortality.
“Those results will be interesting,” Clarke said. In the meantime, patients with heart disease should focus on monitoring their blood pressure and blood lipids and making lifestyle and dietary changes, including eating 2 to 3 servings of seafood a week, he emphasized.
Most people in the United States, however, don’t eat that much fish. Although seafood consumption is on the rise, it still only makes up 5% of the protein in the US diet, far less than the 20% recommended by the Dietary Guidelines for Americans.
Those who don’t eat fish may be more likely to see a benefit from the supplements, Rimm said.