Big review of the clinical evidence confirms significant cut in cardiac death risk
By Craig Weatherby
Fans of the Greatist.com lifestyle website were misled by a recent post. They posted a video asserting that fish oil is useless for heart health. We’ve no doubt of their sincerity, but the evidence clearly contradicts that claim.
Greatist did acknowledge that seafood-rich diets are strongly linked to reduced risk for cardiovascular disease. But they apparently overlooked the large amount of evidence linking fish oil to better heart, brain, and immune health. These documented benefits seem unsurprising, given the huge importance of omega-3s to human health – which Greatist also acknowledged.
Greatist also failed to put fish oil supplements in context: the average American’s woefully inadequate omega-3 intake, very low consumption of seafood (mostly unhealthful fried fish), and wildly excessive, pro-inflammatory intake of competing omega-6 fats.
Sadly, the Greatist video was just one example of scientifically fishy attacks on fish oil.
Another was an episode of PBS TV’s Frontline series, whose section on omega-3s featured selectively edited interviews and disturbing distortions: see Public TV Airs a Fishy Omega-3 Story.
Sweeping claims do a disservice
As with many nutrition-health topics, the devil lies in the details. The evidence doesn’t support broadly negative or positive claims such as “fish oil is useless for heart health”, or “fish oil is a miracle preventive aid and cure for heart problems”.
We’ll delve into the critical details below, in “Two new evidence reviews support fish oil for heart health” and “New government report partially supports fish oil for heart health”.
In short, there’s strong evidence that fish oil lowers blood levels of triglycerides and LDL cholesterol, and improves the ratio of HDL cholesterol to total cholesterol. Evidence that fish oil reduces the risk for heart-related deaths is weaker, but the evidence is significantly stronger for the many Americans with high blood triglyceride and LDL cholesterol levels — especially those who aren’t taking drugs that ease those risk factors.
Negative studies cited by Greatist don’t withstand scrutiny
Greatist cited two studies to support the assertion that fish oil is useless for heart health. But there are many positive trials and evidence reviews that they didn’t take into account.
Nor did they recognize the weaknesses of many negative trials purporting to test the efficacy of omega-3 fish oil for heart health — such as the advanced state of the participants’ disease, and/or simultaneous use of cardiac drugs proven to reduce risk of heart attacks or cardiac death.
Negative study #1
Greatist named a 2012 evidence review from Greek researchers, whose flaws we addressed in Faulty Omega-3 Heart-Health Review (Rizos EC et al. 2012). Our response featured cogent comments from Doug Bibus, Ph.D., who studied omega-3s under the renowned biochemist — professor Ralph Holman, Ph.D. — who discovered and named these essential fatty acids. (You’ll find Dr. Bibus’ comments under “Vital Choice advisor raises key questions”.)
In his commentary, Dr. Bibus noted that several major clinical trials have found omega-3s beneficial for preventing heart disease and reducing the risk of secondary heart attacks and sudden cardiac death. Further, he pointed out two fatal flaws in most trials that found no cardiac benefit from fish oil:
- The negative trials involved patients already diagnosed with cardiovascular disease.
- The participants were already taking cardiac drugs, which meant that fish oil was unlikely to further reduce the risk of heart attacks or sudden cardiac death.
In other words, fish oil was unlikely to show significant benefit in any of those negative clinical trials — something their authors should have acknowledged much more clearly.
Negative study #2
The second study cited by Greatist — a five-year Italian clinical trial — suffered from similar flaws (Risk and Prevention Study Collaborative Group et al. 2013). Its 12,513 participants had “multiple cardiovascular risk factors or atherosclerotic vascular disease” — including many diagnosed with diabetes — but had not suffered a first heart attack.
Because the fish oil group had lower rates of “adverse cardiac events” after one year, the researchers moved the goal posts. They changed the measurement of success to a longer time to death from cardiovascular causes or admission to the hospital for cardiovascular causes. Fish oil did not accomplish either of those harder goals, which fits with the negative results of trials conducted among people with cardiovascular disease who were taking standard cardiac drugs such as statins.
While fish oil does not reduce the risk for a first heart attack, large clinical trials have shown that it does reduce the risk for a second heart attack — and it reduces the risk of sudden cardiac death, which accounts for half of all heart-related deaths.
The Italian trial used a relatively modest dose of 1 gram per day, which matches the American Heart Association’s recommendation for heart patients. However, that’s much lower than the 4 grams per day the AHA advises for people with high blood triglyceride (fat) levels — one of the “multiple risk factors” affecting people in the Italian trial.
Two new evidence reviews support fish oil for heart health
Sudden cardiac death or SCD accounts for around two-thirds of heart-related deaths in the United States: some 405,000 fatalities per year. Large clinical trials have shown that high-dose fish oil reduces the risk for SCD and second heart attacks — but not the risk for non-fatal first heart attacks. And the results of two new meta-analyses — a rigorous type of evidence review — ratify those results.
Evidence review #1
The authors reviewed 14 randomized, controlled trials (RCTs) involving 71,899 people (Maki KC et al. 2017). Their conclusion — “[Fish oil] LC-OM3 supplementation is associated with a modest reduction in cardiac death” — fits with most of the available evidence.
The RCTs included in their analysis lasted longer than six months, and compared the rates of cardiac deaths between the omega-3 fish oil and control groups. The researchers reviewed studies published through December 2016, which included both over-the-counter (OTC) omega-3 fish oil supplements and the only FDA-approved prescription omega-3 fish oil, whose composition is no different from many OTC fish oils.
They calculated that omega-3 fish oil reduced the risk of cardiac death by a statistically-significant average of eight percent. Importantly, this was the first published meta-analysis to include cardiac death — also known as “coronary mortality” — as a measure of success, and it was the most comprehensive review of the clinical evidence to date.
The meta-analysis showed even greater — 17 percent — risk reduction in groups who had high triglyceride and LDL cholesterol levels, whuich are major risk factors. These results are consistent with evidence that EPA and DHA omega-3s do the most for reducing cardiac death among people with high triglyceride levels, high LDL cholesterol levels, and certain other risk factors.
The National Center for Health Statistics estimates that 25% of American adults have high triglyceride levels (150 mg/dL or more) and 27% have high LDL cholesterol levels (130 mg/dL or more).
The greatest reduction in cardiac death rates — close to 30% — was detected in trials that used daily fish oil doses that provided more than 1 gram of omega-3s (EPA and DHA) per day.
This study did not review the effects of EPA and DHA consumption from fish on cardiac death risk because no randomized, controlled trials exist — but epidemiological studies on estimated intakes of EPA and DHA from fish also show risk reductions.
As lead author Kevin Maki, M.D., said, “… these results align with the conclusions in the recent Science Advisory from the American Heart Association, which states that EPA and DHA omega-3 treatment ‘is reasonable’ for secondary prevention of coronary heart disease and sudden cardiac death.”
Dr. Maki made an important point: “One notable feature of omega-3 supplementation is the low risk associated with its use. Because of the low risk, even a modest benefit is clinically meaningful.”
We should note that several studies included in this meta-analysis were small, or had suboptimal trial designs. For example, two of the largest trials — GISSI-Prevenzione and JELIS — were controlled but did not include groups given placebo capsules. While this raises the possibility of bias or uncertainty, this is a minor concern when fatalities are the measured result … and removing individual studies from the analysis did not change its overall findings.
The new evidence review was funded by a trade association called the Global Organization for EPA and DHA Omega-3s (GOED), but it was not involved in the design or interpretation of the results.
“This study is important because it explored the effects of omega-3s on a specific outcome of coronary heart disease,” said Dr. Harry B. Rice of GOED.
And Dr. Rice added this: “A number of studies in recent years have questioned omega-3 benefits in cardiovascular diseases. In order to understand the role omega-3s play in the cardiovascular system, however, research has to focus on a specific disease rather than all cardiovascular outcomes together. This is an important nuance that this meta-analysis helps clarify.”
Evidence review #2
The second evidence review was conducted by researchers from the Mayo Clinic (Alexander DD et al. 2017). Their review covered both randomized controlled trials and prospective cohort (epidemiological) studies, and looked for any associations between intakes of omega-3 EPA+DHA and the risk for coronary heart disease (CHD).
These were their conclusions:
- The clinical trials found a statistically non-significant reduction in risk for developing CHD.
- The clinical trials found a statistically significant 16% reduction in the risk for CHD among higher-risk populations, including people with elevated triglyceride and LDL cholesterol levels.
- The prospective cohort studies found a statistically significant 18% reduction in the risk for any CHD event among people with higher intakes of omega-3 EPA+DHA.
As the authors wrote, “[The] Results indicate that EPA+DHA may be associated with reducing CHD risk, with a greater benefit observed among higher-risk populations in RCTs.” (Alexander DD et al. 2017)
New government report partially supports fish oil for heart health
Earlier this year, the U.S. Agency for Healthcare Research and Quality (AHRQ) published a report titled “Omega-3 Fatty Acids and Cardiovascular Disease: An Updated Systematic Review”. The report was compiled by researchers at Brown University’s Evidence-based Practice Center, under contract to the U.S. Department of Health and Human Services.
The AHRQ review found strong evidence for two good things: fish oil lowers blood triglyceride levels and improves the ratio of HDL to total cholesterol (AHRQ 2017).
While the review found only weak evidence that fish oil reduces the risk of cardiovascular disease and related deaths, the results from “Evidence Review #1” described above tell a different story with regard to people at higher risk. Specifically, that evidence review (Maki KC et al. 2017) found a statistically significant reduction in trial participants with high blood levels of triglycerides and LDL cholesterol.
Both conditions have become the new norm in the United States, which means that many if not most Americans should seriously consider taking fish oil.
The AHRQ review included 61 randomized clinical trials (RCT) and 37 prospective longitudinal (epidemiological) studies. Given the number of cardiovascular health outcomes the AHRQ researchers were considering, this is a relatively small number of studies. In addition, the inclusion and exclusion criteria were quite narrow, and were even described in the report as “arbitrary.”
As the report’s authors said, “Due to the very large number of potentially eligible studies (more than 400), we applied arbitrary thresholds based on sample size, follow-up duration, and whether subgroup or interaction analyses were reported.”
How much fish or fish oil should you take?
The Dietary Guidelines for Americans and the American Heart Association recommend consuming seafood every week. Public health authorities worldwide recommend getting 250-500mg of seafood-source omega-3s (EPA and DHA) every day (see Omega-3 Facts & Sources). Your best choices are fatty fish such as salmon, albacore tuna, and sardines, 3-ounce portions of which typically supply 250-500mg of omega-3s or more.
Omega-3s are associated with many other health benefits, and are widely viewed as safe, with concerns about increasing bleeding times, and advice to avoid fish oil before surgery having been persuasively refuted (see The Healthy Skeptic: Fish Oil, Bleeding, and Surgery).
The U.S. FDA allows up to 3 grams per day, the American Heart Association recommends 4 grams per day for people with high triglyceride levels, and the European Food Safety Authority reports no safety issues at intakes of up to 5 grams per day.
- Agency for Healthcare Research and Quality (AHRQ). Omega-3 Fatty Acids and Cardiovascular Disease: An Updated Systematic Review. Accessed at https://effectivehealthcare.ahrq.gov/topics/fatty-acids-cardiovascular-disease/research/
- Alexander DD, Miller PE, Van Elswyk ME, Kuratko CN, Bylsma LC. A Meta-Analysis of Randomized Controlled Trials and Prospective Cohort Studies of Eicosapentaenoic and Docosahexaenoic Long-Chain Omega-3 Fatty Acids and Coronary Heart Disease Risk. Mayo Clin Proc. 2017 Jan;92(1):15-29. doi: 10.1016/j.mayocp.2016.10.018. Review.
- Maki KC, Palacios OM, Bell M, Toth PP. Use of supplemental long-chain omega-3 fatty acids and risk for cardiac death: An updated meta-analysis and review of research gaps. J Clin Lipidol. 2017 Aug 2. pii: S1933-2874(17)30395-1. doi: 10.1016/j.jacl.2017.07.010. [Epub ahead of print]
- Risk and Prevention Study Collaborative Group, Roncaglioni MC, Tombesi M, Avanzini F, Barlera S, Caimi V, Longoni P, Marzona I, Milani V, Silletta MG, Tognoni G, Marchioli R. n-3 fatty acids in patients with multiple cardiovascular risk factors. N Engl J Med. 2013 May 9;368(19):1800-8. doi: 10.1056/NEJMoa1205409. Erratum in: N Engl J Med. 2013 May 30;368(22):2146.
- 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.
This article was originally published on Randy Hartnell’s Vital Choice blog on 31 August 2017.