Media stories overstate the relevance of a new evidence review 03/29/2018
Jane Brody writes about nutrition and health for The New York Times.
She devoted this week's column — “Is It Time to Give Up on Fish Oil?” — to a new review of the evidence from clinical trials that tested omega-3 fish oil in heart disease patients.
The column is widely read, so it was distressing to see its misleading take on the new evidence review and absurdly broad-brush headline.
Unfortunately, most media reports were comparably off-base.
In short, the authors of the new review found no link between omega-3 fish oil and lower risk for fatal or non-fatal coronary heart disease or blood vessel problems.
As the international team wrote, “… [the outcome of our review] provides no support for current recommendations for the use of such [fish oil] supplements in people with a history of coronary heart disease.” (Aung T et al. 2018)
Critically, the conclusion only applies to people with a history of heart disease, many of whom were taking heart medications — two critically important points we will explore, among others.
Before we examine the new evidence review’s findings and their actual, limited meaning, it’s important to note the accurate and positive things Ms. Brody said about fish, their omega-3s, and heart health.
Strong evidence backs fish for heart health, likely due to their omega-3s
Ms. Brody pointed to the strong epidemiological (population) evidence linking fish-rich diets to significantly lower risks for heart disease and its adverse outcomes.
Further, as she wrote, “Omega-3s in fish clearly have effects that can account for such findings. They protect against abnormal heart rhythms, lower blood pressure and heart rate and improve the function of blood vessels. They may also lower heart-damaging triglycerides and counter inflammation, a known risk to the heart.”
As scientists from the Harvard School of Public Health concluded after reviewing the evidence, “Higher circulating individual and total omega-3 levels are associated with lower total mortality, especially CHD [coronary heart disease] death, in older adults.” (Mozaffarian D et al. 2013)
Likewise, another Harvard team concluded that if we could raise the low omega-3 blood levels typical of the average American, that alone would save many thousands of lives: see Omega-3 Deficiency May Cause 84,000 Premature Deaths.
Because it only examined trials that tested fish oil in people with diagnosed heart disease, the new evidence review has little bearing on the use of omega-3 fish oil for prevention of heart disease.
Unfortunately, no clinical trials testing the ability of fish oil to prevent heart disease have been conducted, because they’d have to last for decades and involve large numbers of people — which would make them very costly and difficult to maintain.
And prior reviews have produced much more positive conclusions. For example, see Do Fishy Omega-3s Really Cut Heart Risks?.
Ms. Brody acknowledged the substantial evidence linking fish-rich maternal and childhood diets to a variety of things:
- Enhanced child brain development
- Better brain performance in adults
- Less cognitive decline in older adults
Evidence review generated misleading headlines
The authors of the evidence review set the stage with this opening paragraph:
“Current guidelines advocate the use of marine-derived omega-3 fatty acids supplements for the prevention of coronary heart disease and major vascular events in people with prior coronary heart disease, but large trials of omega-3 fatty acids have produced conflicting results.” (Aung T et al. 2018)
This is how they summarized their study’s goals and findings in a list of “Key Points”:
- Question — Does supplementation with marine-derived omega-3 fatty acids have any associations with reductions in fatal or nonfatal coronary heart disease in people at high risk of cardiovascular disease?
- Findings — This meta-analysis of 10 trials involving 77,917 participants demonstrated that supplementation with marine-derived omega-3 fatty acids for a mean [average] of 4.4 years had no significant association with reductions in fatal or nonfatal coronary heart disease or any major vascular events.
- Meaning — The results provide no support for current recommendations to use omega-3 fatty acid supplements for the prevention of fatal coronary heart disease or any cardiovascular disease in people who have or at high risk of developing cardiovascular disease.
Specifically, the outcomes covered by the review were non-fatal heart attacks, strokes, or major vascular events, deaths from coronary heart disease, deaths from any cause.
The authors also looked for negative or positive fish oil effects that only applied to subgroups of participants with specific characteristics, and did not detect any.
Obvious reasons why the new review found no benefit
All the clinical trials included in the review involved people with diagnosed heart disease, many of whom were taking standard heart medication such as statins.
Consequently, fish oil had to pass a very tough test, making the omega-3 doses provided in a trial — and simultaneous consumption of heart medications — critically important to its outcomes and validity.
In general, clinical trials that find little or no benefit from fish oil typically used low doses and involved people with heart disease or at high risk for heart disease, who were already taking statins and/or other “standard of care” medications.
So, it’s unsurprising that from 44 to 100 percent of the participants in the trials that showed no clear benefit from fish oil were taking statins.
The American Heart Association recommends 2,000 to 4,000mg of omega-3s daily for heart patients with high triglycerides because only doses that high can reduce this major risk factor for heart disease and adverse cardiovascular events such as heart attacks.
But the doses employed in the 8 out of 10 trials in the evidence review with negative outcomes fell well below — or very far below — the 2,000 to 4,000mg per day recommended to heart patients by the AHA.
These are the AHA’s specific recommendations:
- Patients with documented CHD: Consume about 1 g [1,000mg] of [omega-3] EPA+DHA per day, preferably from fatty fish. EPA+DHA in capsule form could be considered in consultation with the physician.
- Patients who need to lower triglycerides: 2 to 4 grams [2,000 to 4,000mg] of [omega-3] EPA+DHA per day provided as capsules under a physician’s care.
And the two largest clinical trials included in the review — which found very substantial benefits from fish oil in men diagnosed with heart disease — used doses of omega-3s that were up to three times higher than the doses in the large, negative trials (i.e., GISSI vs. ORIGIN), and were at least 80 percent higher (i.e., JELIS vs. R&P).
Conversely, all but one of the negative trials involved much smaller numbers of participants, and much lower doses of omega-3s.
Large trials with positive outcomes:
- GISSI Prevenzione trial — 11,334 participants took 2,550mg of EPA + DHA daily. The results showed a 10% reduction in the risk of major cardiovascular events, compared with untreated controls. It’s not known how many of the participants were taking statins or other heart medications.
- JELIS trial — 18,645 participants took 1,800mg of EPA daily. The results showed a 19% reduction in the risk of major coronary heart disease events, compared with untreated controls. All the participants were taking statins, making this result very impressive.
Large trials with negative outcomes:
- ORIGIN trial — 12,536 participants took 840mg of EPA + DHA daily
- R&P trial — 12,505 participants took 1,000mg of EPA + DHA daily
The doses used in the negative trials were as low as 376 milligrams, with the sole exception of the DOIT trial, which involved only 563 participants who took 1,950mg of omega-3s daily.
Oddly, the authors of the evidence review failed to acknowledge the critical role that dose can play in any medical study.
They at least acknowledged that statin use muddies the waters: “... it is unclear whether the discrepant results reflect different associations of omega-3s with CHD [coronary heart disease] subtypes, different outcomes in primary vs secondary prevention of CHD, increasing use of statins with better control of lipid levels, or an artifact of chance or bias in open-label trials.”
And, as they wrote, “Previous meta-analyses of these trials of omega-3 supplements appeared to suggest a significant beneficial association of omega-3 FAs with fatal CHD but not nonfatal CHD.”
We should note that the authors didn't say whether the original clinical trials recorded their participants' intake or blood levels of omega-6 fatty acids, which compete with omega-3s — and, when consumed in the excess amounts typical of the standard American diet — tend to exert pro-inflammatory effects.
That said, a new study from Finland that followed 2,480 men for an average of 22 years linked higher omega-6 blood levels to a 43 percent lower risk for death from any cause and a 46 percent lower risk of cardiovascular death (Virtanen JK et al. 2018).
By the way, this isn’t the first time we’ve had to point out the limitations or outright errors of an evidence review or media story that generated negative headlines:
- Does Fish Oil Really Help Hearts?
- Faulty Omega-3 Heart-Health Review
- Media Misreports Omega-3 Heart Study
- Public TV Airs a Fishy Omega-3 Story
- New Evidence Analysis Supports Omega-3 Heart Benefits
- Experts Find New Fish-and-Health Review Deeply Distorting
Jane Brody missed the mark on fish and mercury
Ms. Brody was partially correct about the risk of mercury in seafood to developing children:
“For example, large predatory fish like shark, swordfish, king mackerel, tilefish and albacore tuna can contain high levels of methyl mercury, a toxin that would override any health benefit, especially for the developing brains of fetuses and young children …”.
She should not have included albacore tuna among the species that developing children and pregnant women should entirely avoid — and federal authorities don’t include albacore tuna in that list, for reasons we will explain.
As Ms. Brody acknowledged, “… in both observational studies and controlled clinical trials, eating fish was shown to foster optimal development of a baby’s brain and nervous system, prompting advice that pregnant women and nursing mothers eat more fish rich in omega-3s while avoiding species that may contain mercury or other contaminants like PCBs sometimes found in freshwater fish.”
The only thing wrong with Ms. Brody’s acknowledgment that fishy maternal and child diets enhance child development was the phrase: “avoiding species that may contain mercury”.
In fact, all fish contains some mercury, which occurs naturally in the ocean. The issue is how much mercury a given fish species contains, versus its selenium content.
The brain damage caused by excessive dietary mercury stems from the fact that it binds to selenium, which is critical to some of the body’s own antioxidant enzymes.
Accordingly, if a fish species delivers more selenium than mercury, people consuming it will suffer no harm.
Virtually all commercial species — except the four fish that young children and pregnant women should avoid (swordfish, shark, tilefish, king mackerel) — contain more selenium than mercury. In contrast, freshwater fish from certain lakes and rivers contain much more mercury than selenium, and they become the subject of local warnings.
In fact, there’s no evidence that the mercury in the vast majority of commercial fish species overrides the benefits of their omega-3s.
Why would that be?
Compelling evidence suggests it’s because almost all commercial fish species have more selenium than mercury.
For more on this widely overlooked factor, see Fish-Mercury Fears Hyped, Despite Pesky Facts, Most Fish Rank as Very Safe on New, Selenium-Based Standard and the PBS-TV documentary, Fish, Mercury & Nutrition: The Net Effects, which features the leading scientific experts on this subject.
- American Heart Association. Omega-3 Polyunsaturated Fatty Acid (Fish Oil) Supplementation and the Prevention of Clinical Cardiovascular Disease. Accessed at http://professional.heart.org/professional/ScienceNews/UCM_492507_Omega-3-Polyunsaturated-Fatty-Acid-Fish-Oil-Supplementation-and-the-Prevention.jsp
- American Heart Association. Top Ten Things to Know: n-3 Polyunsaturated Fatty Acid (“Fish Oil”) Supplementation. Accessed at http://professional.heart.org/idc/groups/ahamah-public/@wcm/@sop/@smd/documents/downloadable/ucm_492554.pdf
- Aung T, Halsey J, Kromhout D, Gerstein HC, Marchioli R, Tavazzi L, Geleijnse JM, Rauch B, Ness A, Galan P, Chew EY, Bosch J, Collins R get up out of the chair, Lewington S, Armitage J, Clarke R; Omega-3 Treatment Trialists’ Collaboration. Associations of Omega-3 Fatty Acid Supplement Use With Cardiovascular Disease Risks: Meta-analysis of 10 Trials Involving 77 917 Individuals. JAMA Cardiol. 2018 Mar 1;3(3):225-234. doi: 10.1001/jamacardio.2017.5205.
- Del Gobbo LC et al. ω-3 Polyunsaturated Fatty Acid Biomarkers and Coronary Heart Disease: Pooling Project of 19 Cohort Studies. JAMA Intern Med. 2016 Aug 1;176(8):1155-66. doi: 10.1001/jamainternmed.2016.2925.
- Marik PE, Varon J. Omega-3 dietary supplements and the risk of cardiovascular events: a systematic review. Clin Cardiol. 2009 Jul;32(7):365-72. doi: 10.1002/clc.20604. Review.
- Mozaffarian D, Lemaitre RN, King IB, Song X, Huang H, Sacks FM, Rimm EB, Wang M, Siscovick DS. Plasma phospholipid long-chain ω-3 fatty acids and total and cause-specific mortality in older adults: a cohort study. Ann Intern Med. 2013 Apr 2;158(7):515-25. doi: 10.7326/0003-4819-158-7-201304020-00003.
- Rizos EC, Ntzani EE, Bika E, Kostapanos MS, Elisaf MS. Association between omega-3 fatty acid supplementation and risk of major cardiovascular disease events: a systematic review and meta-analysis. JAMA. 2012 Sep 12;308(10):1024-33. doi: 10.1001/2012.jama.11374. Review.