Omega-3 Fatty Acids, Fish Oil Supplements and the Risk of Atrial Fibrillation

While preparing my Grand Rounds presentation on Omega-3 fatty acids and cardiovascular disease risk I reviewed in detail three recent large randomized trials which showed no benefit of fish oil supplements on cardiovascular outcomes.

These trials confirmed multiple other randomized studies in the last 20 years which have failed to show any benefit from supplementing with over-the-counter fish oil pills thus I stuck with what had I first advised in 2013:

“there is no evidence that taking over-the-counter fish oil supplements or consuming functional foods supplemented with Omega-3 fatty acids reduces your risk of cardiovascular disease”

In the past, when patients asked “are there any side effects” of taking omega-3 fatty acids (OMFAs) I would say “no, but their production wreaks havoc on the marine ecosystem and you are wasting your money and driving a multi-billion industry that should not be.”

After reviewing these recent trials in detail, however, I have realized a health hazard has been identified in the treatment arms: high dose fish oil supplements increase the risk of atrial fibrillation (AF).

This is a remarkable change from what observational studies had suggested in this area. Low blood levels of OMFAs and Vitamin D have both been associated with a higher risk of atrial fibrillation. Thus, many have advocated taking these mostly useless supplements in high doses to prevent atrial fibrillation. Of course, association does not prove causation but generates hypotheses that should be tested by the gold standard of medical science, the randomized controlled trial (RCT).

The VITAL-Rhythm RCT published last month in JAMA found no effect of supplementation with OMFAs or Vitamin D on the incidence of atrial fibrillation (or cancer or CV outcomes). The patients randomized to OMFA supplementation received low dose EPA-DHA (460 mg/d of EPA and 380 mg/d of DHA).

The vitamin D3 dose was designed to test the effect of high-dose supplementation on cancer and CVD in a primary prevention population, and the EPA-DHA dose was recommended by the American Heart Association for cardioprotection among high-risk individuals and was above the dose recommended from dietary intake for the general population. The placebo for vitamin D3 contained soybean oil, and the placebo for EPA-DHA contained olive oil.

However, 2 large RCTS using higher-dose formulations of OMFAs in patients with established cardiovascular disease found a significantly higher risk of AF in the treatment groups.

The REDUCE-IT trial randomized high CV risk individuals to 4 g/d of highly purified EPA ethyl ester (icosapent ethyl) and showed a significantly increased , 48% higher risk of hospitalization for AF compared with placebo (3.1% vs 2.1%; P = .004) over almost 5 years of follow-up. (Of note, the benefits on CV outcomes of the icosapent ethyl used in this trial have been questioned due to the use of mineral oil in the placebo arm, something I discuss in detail in my OMFA talk.)

The STRENGTH trial, randomized patients to 4 g/d of omega-3 carboxylic acid, a mixture of EPA and DHA, vs placebo over a median of 3.2 years of follow-up and found more AF developed in the active treatment arm (2.2% vs 1.3%; HR, 1.69; 95% CI,1.29-2.21; P < .001). (Of note, there was no evidence for any benefit of OMFAs in reducing CV outcomes in this trial which utilized corn oil in the placebo arm.)

A third trial, the OMEMI trial found no benefit on reducing CV outcomes from adding 1.8 g n-3 PUFA (930 mg eicosapentaenoic acid and 660 mg docosahexaenoic acid) versus placebo (corn oil) daily to standard of care in patients aged 70 to 82 years with recent (2–8 weeks) acute myocardial infarction. A nonsignificant increased risk of incident AF was found (HR, 1.84, p=.06).

The VITAL-rhythm authors concluded

Potentially, the adverse effect on AF risk may be dose related, and the higher dosages of EPA used in these other studies might account for the significant adverse effect on AF.

I agree with the conclusions of an accompanying editorial by Dr. Greg Curffman

Considered together, the data from the 4 trials suggest, but do not prove, that there may be a dose-related risk of AF with omega-3 fatty acid intake. At a dose of 4.0 g/d, there was a highly statistically significant increase in risk (nearly a doubling). With an intermediate dose of 1.8 g/d, the increase in risk (hazard ratio, 1.84) did not achieve statistical significance, and with a standard daily dose of 840 mg/d, there was no apparent increase in risk (although the data were consistent with as much as a 24% increase in risk). Patients who choose to take omega-3 fatty acids, especially in high doses, should be informed of the risk of AF and followed up for the possible development of this common and potentially hazardous arrhythmia.

A 2019 report on the global OTC OMFA supplement industry was quite enthusiastic despite the mass of scientific evidence showing no benefits to consumers, noting 4.1 billion in global sales and anticipating 8.5 billion by 2025.

This mindless consumption (my adjective), the report noted is moving beyond pills and into “functional foods”, driven by a perception of health and performance promotion.

Omega-3 increasingly finds application in dietary supplements, functional foods & beverages, pharmaceuticals, infant formula, and pet food and feed. Dietary supplements are estimated to account for the largest market due to the fast-paced and busy lifestyles; consumers prefer consuming dietary supplements to make sure that they get their optimal share of nutrients, and omega-3 supplements are used to improve the health and performance, wherein athletes are advised adequate intake of omega-3 fatty acids for fit and healthy body.

The OMFA is a huge, powerful industry intent on promoting the consumption of their useless products. In my OMFA talk I touch on what I term the “academic-industrial” complex which has resulted from physicians/scientists who are on the payroll of the fish oil industry and in some cases own, sell and shamelessly promote their own fish oil supplements. These physicians/scientists frequently publish biased analyses of the OMFA field, searching out value where there is none.

Rather than promoting or profiting from the sale of OMFAs, physicians should be actively deprescribing fish oil supplements, allowing patients to focus on taking pills which have been proven safe and beneficial.

Skeptically Your

-ACP

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37 thoughts on “Omega-3 Fatty Acids, Fish Oil Supplements and the Risk of Atrial Fibrillation”

  1. My heart has been going crazy for about 6 months. Flipping around in my chest, scaring me to death. Visits to the ER turned up nothing. Echocardiogram normal. I thought maybe it was thyroid, changed my dose a few times, nothing helped. Then I randomly found something about fish oil. Quit taking it today and today my heart feels fine. I’m pretty sure this was the cause.

    Reply
  2. And if the prospect of increased AFIB from O-3 isn’t bad enough, the likelihood of prostate cancer increases at a similar rate. The hazard ratios for low-grade, high-grade and total prostate cancer is significant.

    “Results: Compared with men in the lowest quartiles of LCω-3PUFA, men in the highest quartile had increased risks for low-grade (HR = 1.44, 95% CI = 1.08 to 1.93), high-grade (HR = 1.71, 95% CI = 1.00 to 2.94), and total prostate cancer (HR = 1.43, 95% CI = 1.09 to 1.88). Associations were similar for individual long-chain ω-3 fatty acids. Higher linoleic acid (ω-6) was associated with reduced risks of low-grade (HR = 0.75, 95% CI = 0.56 to 0.99) and total prostate cancer (HR = 0.77, 95% CI = 0.59 to 1.01); however, there was no dose response.”

    https://pubmed.ncbi.nlm.nih.gov/23843441/

    Reply
  3. Yes, I agree. Those findings have to be a tough pill to swallow for Dr. Harris.

    Do you have a theories on what the mechanism of action would be on how fish oil supplements effects the increase in AFIB?

    Reply
    • Christopher,
      I have no theories. It is interesting that some early observational studies suggested omega-3 PUFAs lowered arrhythmia risk. Papers were published on possible mechanisms. Now we know it was all BS.
      Dr P

      Reply
  4. So, It seems reasonable from these trials that if a person consumes a low enough dose of EPA/DHA there may be little to no risk of AFIB but no CV benefit either. Conversely, when a person consumes a high dose of EPA/DHA there may be some CV benefit but also comes with a high risk of AFIB. Perhaps Amarin should be required to put a black box warning on Vascepa.

    I’ve consumed daily high dose EPA/DHA for 24 years and always questioned in the back of my mind if I benefited from it or not. I took it at the advice of a retired cardiologist in Milwaukee who claimed 5 grams per day would lower my excruciatingly high Lp(a) but it didn’t have any positive effect whatsoever. Coincidentally, I acquired AFIB 5 years ago. I’m back to sardines and wild Alaskan salmon several times per week and chucked the fish oil.

    I find it interesting that Dr. Bill Harris of OmegaQuant conspicuously does not comment whatsoever on these studies on his website. As a major proponent of O3 fatty acid supplementation and his O3 Index he really should address these findings. Not commenting gives the impression that he’s more beholding to the marine oil industry and selling his O3 test kits instead of upholding current science.

    Reply
    • Christopher,
      I think Bill Harris is an honest scientist, seeking the truth but is so wedded to his omega-3 index and the value of omega-3 supplements that no amount of RCT data will dissuade him from his belief in their importance. To admit that an increased omega-3 index does not result in better cardiovascular or other health outcomes would be an evisceration of his life’s work
      Dr p

      Reply
    • I had a discussion with the presenter of that study on Twitter. It is an observational study and a more important study on that same question was presented by Dr. Nissen looking at outcomes versus EPA and DHA levels in STRENGTH.
      It didn’t matter what level of EPA or DHA was achieved, there was no benefit from the OMFAs

      Reply
  5. HELLO Dr PEARSON

    I AM A AFIB PATIENT AND AN DEDICATED FOLLOWER OF YOUR BLOG.

    I READ TODAY ON THE HEALTHLINE BLOG THE FOLLOWING. COULD YOU PLEASE INFORM YOUR READERS ON THIS PROCEDURE?

    MANY THANKS

    RICHARD HOLKAR

    The left atrial appendage is an unused, finger-like tissue that can trap blood in the heart chamber and increase the risk of clots. Removing it can cut the risk of stroke by more than a third in people whose hearts either beat too fast, too slowly, or irregularly, the researchers reported

    He said the procedure can also be done for people not needing heart surgery through less invasive methods, which will be important for research moving forward.
    “This is an inexpensive procedure that is safe, without any long-term adverse effects, and the impact is long term,” Whitlock said.”

    Reply
  6. “Omega-3 supplements”? I wonder which kind were used… The 5 studies included used synthetic omega-3 drug “Vascepa”, margarine spread with added synthetic omega-3, synthetic form ethyl ester, synthetic omega-3 drug “Epanova” and synthetic omega-3 drug “Pikasol”, respectively.

    So by using a synthetic form of omega-3, potency of EPA, DHA and/or ALA can be increased or decreased individually to possibly get benefits of reduced cardiovascular disease but it’s traded it for long term risk of atrial fibrillation? Sounds about right,

    Omega-3’s are oil, which can easily go rancid but this is no different from the oil industry lying about climate change or the food industry lying about sugars (high fructose corn syrup) or fats… Follow the money. Pharmaceutical corporations are first a business that requires profit before they are a company that cares about making life-saving or improving drug products. There’s a reason drug products are advertised to you via TV before they are recommended by your doctor…

    Anyone that has experience with a Quality Management System or cGMPs know all too well we have regulations because someone got poisoned or killed by adulterated drug products to the point where congress had to step in to make a law that the executive branch details how this should be enforced (FDA). So while the synthetic omega-3 formulas used in the study have to at least show safety and efficacy….which are now showing correlation to atrial fibrillation… those over-the-counter omega-3 supplements are far less regulated and probably have more variability, not good.

    I agree that we should be skeptical of most things… that’s how science works, question it till it stands on it’s own merit. I also agree that 99% of fish oil is bad/rancid, labelled incorrectly just like 99% of olive oil around the globe is actually found to be either mixed or bad/labelled incorrectly. We live in a capitalistic society, money talks.

    I have yet to read the studies you have listed in support of omega-3’s having no benefits but I bet they are probably using a similar synthetic form of omega-3 or adulterated.

    Until then, I’ll stick to the natural form of omega-3’s “triglyceride form” via liquid not capsules that’s noted to be refrigerated by third-party independent tested companies. This should be listed on the supplements facts on the back of your supplement bottle and usually offered by companies that spend the time and effort for purity and quality standards.

    There is a difference between “triglyceride” form and “ethyl ester” form of omega-3. One is naturally occurring, the other is not.

    Reply
  7. I raised Dr Pearson’s article with my GP (for 30+years) and he is keen to receive the link particularly in regard to AF. His own anecdote (n=1) was that whenever he ceased taking fish oil, his joint pains returned, and went away again on resumption.

    Reply
  8. This is fascinating! Unfortunately, I don’t eat fish due to allergies, and therefore have never been a fish oil devotee. (I really used to love sardines. Some of you are joking, methinks.) Just recently, someone commented, “what’s up with all the afib lately?” Hmm. Might it be our supplements? Agree about our pitiful marine ecosystem. Always appreciate your blog!?

    Reply
    • I’m putting together a post on this topic. The story is very similar to fish oil and cardiovascular disease. Lots of observational studies but well done RCTS don’t show any consistent benefit of fish oil supplementation on cognition or risk of Alzheimer’s.

      Reply
  9. Your opinion regarding redoing the Reduce-It study doesn’t make any sense. This study was done with the approval of the FDA and with its supervision. So, if your argument is that mineral oil skewed the results, why would the FDA approve mineral oil as a placebo? Also, how do you account for the Jelis study, which used no placebo? Finally, who do you think should bear the costs? The company which already spent almost half a billion on Reduce-It, or the taxpayer?

    Reply
    • Dear Herb Novo,
      Believe it or not, the FDA and brilliant study designers make mistakes. They could not have predicted that the mineral oil placebo used in REDUCE-IT (the trial establishing VASCEPA/icosapent ethyl as effective when added on to statin therapy in reducing CV events) would raise LDL-C by 10% and increase hs-cRP, a marker of inflammation, by 32%. The STRENGTH investigators were wiser and utilized a true neutral placebo.
      As to JELIS, the lack of a placebo is a strong limitation to its internal validity.
      Although promising, the JELIS trial was limited by an open-label design, lack of placebo control, and geographic limitation to patients in Japan.
      Also in JELIS LDL-C levels were much higher and the majority of patients were on low-intensity statins. This is a different population than REDUCE-IT
      It should be noted that AFib rates were not increased by the 1.8 grams of icosapent ethyl in JELIS.
      The FDA however has approved 4 grams of isocapent ethyl daily, a dosage which increases afib rates and which does not have RCT with a true neutral comparator support.

      Reply
      • Dr Pearson,
        Thanks for the reply. I agree Jellis was not a controlled study, but it was “outcome”, and begs the question what accounted for the effect on ldl-c? Further, the FDA was not passive in their monitoring of Reduce-It, so if mineral oil was as impactful as you state, don’t you think the conduct of the study would have been modified to change the placebo?
        Finally, if the use of mineral oil compromised the study results of Reduce-It as you believe, are the Europeans and the Chinese making the mistake of validating the study by accepting EPA ?

        Reply
  10. I can think of several questions to raise regarding the Welsh angina study: (1) Where did their fatty fish originate? Farms in polluted waters? (2) How was the fish prepared? Salted? Served with greasy fries? ?? (3) Did participants eating more fatty fish also eat more unhealthy foods such as rich desserts?
    There are so many variables in a study like this, it seems difficult to attribute results to the fish. When people change their diets in one way, they usually change it in many others as well. And if many of the fatty fish eaters didn’t really like the fish all that much, they were probably more likely to also consume more of their unhealthy favorites to compensate.

    Reply
      • I enjoy four to six servings a week of fresh cold-water sea catch. Sockeye salmon, cod, sometimes halibut. Oh. And sardines.
        I don’t take the oil supplements. (Whose idea was it anyway that it’s only the oil that affords the benefit?)

        How risky is that?

        Reply
  11. Second request, could you comment on the Medtronic MICRA AV approved by FDA in January 2020.

    Predecessor approved 2016 is hugely popular, but little information available on this one.

    I’m scheduled to have it June 1, together with ablation of the AV node. I’m 81. Have a persistent atrial flutter, driving me crazy, getting little sleep. Ejection fraction 55-60. Swimmer & runner. Fan for 3-4 years now.

    Reply
    • Gary,
      Sorry. I looked into your question previously but got distracted…
      My brief answer is…not a fan, definite issues.
      I also don’t think much of. AV node ablation/pacemaker therapy and have referred only a couple of patients for it in 30 years of practice.
      If time allows I’ll elaborate
      A really good resource on this would be John Mandrola. I’ll see what he thinks.

      Reply
      • My situation approaches Gary’s in that, at age 77 with increasing bouts of atrial tachycardia – 150 BPM at rest for an hour or so per episode even though I’m on flecainide – my EP talks of AV node ablation and His bundle pacing.

        Now, Dr. Mandrola is “The Medical Conservative”, so I’m eager for you to relate to us how he might address these situations before resorting to such a state-of-the-art (read: not-ready-for-prime-time?) technique.

        • Difficult placement using repurposed tools & materials.
        • Fragile His: If damaged by the lead’s “corkscrew”, then what?
        • The failure rate of the leads themselves.
        • High power demand = low battery life.

        Are swimming, running, and, in my case, chopping firewood reasonable expectations with such a pacemaker?

        The easier old standard alternative of right ventricular pacing can lead to dyssynchrony and heart failure, can it not?

        There are comparative QOL issues to consider as well as arrhythmia free longevity.
        Everything in life is chancy. Some less than others. Which?

        Reply
        • Hi Jeff, thanks for replying to a fellow sufferer. The thing that puzzles me is just how enthusiastically the leadless pacemaker, specifically Medtronic MICRA AV have been embraced by major cardio units — Mayo Clinic, Cleveland Clinic, Johns Hopkins — and many others, in the U.S and abroad. just google it & you’ll see. The MICRA AV is the second generation, FDA approved in January 2020, of their original leaderless pacemaker FDA approved in 2016.

          My A-flutter is driving me crazy, serious QOL issue as you say, and my EP, highly respected here in metro NJ, thinks it could be (makes no promises of course) for me.

          Problem is, studies for this second generation are ongoing, incomplete & I would be more comfortable w some current updates, to confirm the earlier enthusiasm.

          Medtronic is an incredible company, their accelerometer technology is cutting edge, re-invented the conventional pacemaker. Ive talked to their MICRA AV Patient Services, extremely helpful.

          I thought Dr. Pearson, also highly respected, might confirm that. Disappointed that he didn’t.

          Reply
          • Actually, Gary, I was hoping to hear back from Dr. Pearson myself about AV node ablation & pacing. Eventually perhaps?

            That said, I’m wondering if a flutter ablation would be appropriate for you. It is flutter, right? Occurring in the right atrium? That seems to me to be more conservative than destroying your AV node.
            Just a layman’s thought.

            Reply
  12. I would be interested in your thoughts on this article in the April edition of Nature Communication – https://pubmed.ncbi.nlm.nih.gov/33888689/
    Abstract: “ The health effects of omega-3 fatty acids have been controversial. Here we report the results of a de novo pooled analysis conducted with data from 17 prospective cohort studies examining the associations between blood omega-3 fatty acid levels and risk for all-cause mortality. Over a median of 16 years of follow-up, 15,720 deaths occurred among 42,466 individuals. We found that, after multivariable adjustment for relevant risk factors, risk for death from all causes was significantly lower (by 15-18%, at least p < 0.003) in the highest vs the lowest quintile for circulating long chain (20-22 carbon) omega-3 fatty acids (eicosapentaenoic, docosapentaenoic, and docosahexaenoic acids). Similar relationships were seen for death from cardiovascular disease, cancer and other causes. No associations were seen with the 18-carbon omega-3, alpha-linolenic acid.”

    Reply
    • David,
      I salute you for your ability to eat sardines!
      I’ve long been an advocate of fish consumption as part of a healthy diet.
      As part of my updated research on OMFA I was inspired to look at the data supporting fish consumption. Much of is observational, relying on the same associations report for omega-3 FAs.
      Randomized trials are few, the one I looked at in detail was the Welsh angina study and it showed those randomized to eat more fatty fish had worse outcomes!
      Before I can write about this and go against every organization/guidelines/nutritional expert I need to do a deeper drive

      Reply
  13. Dr. P, Thank you. Is there anything in this study that would less to further concussions about the efficacy or safety of Rx fish oil such as Lovaza or Vascepa?

    Reply
    • I mention the REDUCE-IT study which used VASCepa or isocapent ethyl.
      “The REDUCE-IT trial randomized high CV risk individuals to 4 g/d of highly purified EPA ethyl ester (icosapent ethyl) and showed a significantly increased , 48% higher risk of hospitalization for AF compared with placebo (3.1% vs 2.1%; P = .004) over almost 5 years of follow-up. (Of note, the benefits on CV outcomes of the icosapent ethyl used in this trial have been questioned due to the use of mineral oil in the placebo arm, something I discuss in detail in my OMFA talk.)”

      Many experts in this field, after reviewing the STRENGTH and OMEMI data are calling for a repeat of the REDUCE-IT trial with a corn oil placebo. I describe this issue in depth in my taok, Hopefully I can make that into a post soon

      Reply

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