Clinical Studies on the Effect of Omega-3 Fatty Acids on Cardiovascular Outcomes

Invited Opinion Aldo Bernasconi, Ph.D. Director of Information and Research Global Organization for EPA and DHA Omega-3s   There is a long history of clinical research showing that long-chain omega-3 fatty acids – the kind of fatty acids found at relatively high levels in fish oils - have a cardio-protective effect. This research includes several large randomized control trials (RCTs). These trials, in which participants are randomly selected to receive either a treatment or a placebo, have long been considered to be the gold standard for clinical research. One surprising aspect of this research is that while the earliest trials showed that consumption of fatty fish or fish oils have a clear benefit for cardiovascular health, later studies have found or reported either a smaller effect, or no effect at all. The first large RCT on this subject was the Diet and Reinfarction Trial (DART), whose conclusions were published in 1998 [1]. The researchers recruited 2033 men who had recovered from a myocardial infarction, and randomized them to receive advice on three possible dietary changes: to increase consumption of fatty fish, to increase the ratio of polyunsaturated to saturated fat, or to increase cereal fat consumption. The study found that consumption of two weekly servings of fatty fish not only reduced the risk of death by ischemic heart disease (IHD), but also reduced all-cause mortality by 29%. The following large RCT, the GISSI-Prevenzione trial [2], confirmed these results. In a group of 11,324 patients who had survived a recent heart attack, fish oil consumption reduced the risk of all-cause mortality, sudden death, and coronary death. The findings of these two large studies not only agreed with each other, but also with several prospective cohort studies, including Harris et al [3], which found that long-chain omega-3 consumption was associated with decreased cardiovascular risk. The accumulated evidence led to dietary recommendations, issued by multiple countries and organizations (including the World Health Organization and the American Heart Association), to eat heart-healthy fish or to increase omega-3 intake for their cardio-protective properties. Later studies, on the other hand, have failed to find the same effects ([4-6], for example), finding either evidence of a much smaller protective effect, or no effect at all. This surprising development has caused a great deal of confusion, increased by articles in the popular press and opinion pieces that exaggerate the significance of these findings as being contrary to established science and policy, and therefore more newsworthy. As a result, there is some debate about whether fish oils reduce cardiovascular risk, and even about whether the dietary recommendations to eat more fish are appropriate. These are valid concerns. The findings of the research are apparently contradictory, and one possible explanation for this could be that, somehow, all of the early research is flawed. A second possibility is that, in the intervening years, some changes in the healthcare environment or behavior have made it more difficult to conduct effective clinical trials about the cardiovascular benefits of long-chain omega-3 fatty acids. Recently, two groups of researchers, working independently, reached the conclusion that the second explanation is more likely. The results from the earlier research and subsequent dietary recommendations have had the effect of increasing the intake of omega-3s, and later studies now have study participants with a higher baseline omega-3 intake than those of the earlier trials. The participants in the newer studies already have some benefit from the cardio-protective effects of fish oils, and the study treatment only adds a smaller benefit compared to the older trials. In a way, omega-3 fatty acids are a victim of their own success as cardio-protective compounds. In addition, in the last couple of decades the standard of medical care for cardiovascular health has changed significantly, with the introduction or widespread usage of a number of medications, including aspirin, statins and beta-blockers. Participants in newer trials have better cardiovascular care and prevention, and this makes it much more difficult to isolate the protective effect of a single factor, like fish consumption or long-chain omega-3 intake. The first group was led by Dr. Michael James, of the Royal Adelaide Hospital in Adelaide, Australia. Their thoughtful review [7] was recently published by the British Journal of Nutrition, and makes the point that changes in both omega-3 intake and the standard of cardiovascular care call into question whether RCTs are the most appropriate study design. A typical clinical trial is used to study the safety and effectiveness of a candidate drug, where only the treated group receives the studied compound. In contrast, omega-3 fatty acids are nutrients that will be consumed by both the treated and the placebo groups of any clinical study, which reduces the differences between cases and controls. This makes detecting a possible beneficial effect much harder. The problem is compounded by the fact that, for a number of cardiovascular outcomes, the benefits of taking additional omega-3s strongly depend on the patients’ baseline intake of EPA and DHA [8]. This is particularly true of arrhythmia and hypertension: while a patient with an habitual low intake would see large protective benefits from eating a couple of portions of fish per week, somebody with a higher intake would see a smaller additional benefit. This creates a problem for newer clinical studies. Because omega-3 fatty acids are generally recognized to have a cardio-protective effect, their intake has increased rapidly since 2000 [9]. More recent studies not only have to deal with the fact that the subjects in the treated and placebo groups will both be taking omega-3s, but also with the fact that since everyone’s usual intake is much higher than it was two decades ago, the effect of treatment will be smaller. This makes detecting an effect all the more difficult. Newer studies need to compensate for this difficulty by enrolling a much larger number of participants, by using larger dosages (fish oils are considered safe) or by enrolling only subjects with very low habitual intake and requiring that participants maintain that low intake for the duration of the study. The second group is a panel of experts convened by GOED, the Global Organization for EPA and DHA Omega-3s. This panel, formed by a group of seven experts with different backgrounds, conducted a workshop on the Design of Clinical Studies of Omega-3 Fatty Acids with Cardiovascular Outcomes at the recent biannual meeting of ISSFAL, the International Society for the Study of Fatty Acids and Lipids, a leading organization of top scientists dedicated to the study of the health effects of dietary fats, oils and lipids. The proceedings of this workshop are being prepared for publication. While the workshop’s objective was to provide practical advice to researchers on how to design omega-3 clinical trials, the panel spent considerable time in discussing the reasons why newer trials fail to find the same cardiovascular benefits identified by the older studies. Some of the resulting conclusions and recommendations can be used as a guide to evaluate the results of cardiovascular studies involving omega-3 fatty acids:
  1. Did the study include a sufficient number of participants? Because of increases in omega-3 intake, and because of improvements in the standard of care for cardiovascular prevention, the expected effect of an omega-3 intervention will be smaller than if the study had been conducted twenty years ago. Newer clinical trials need to consider this in their design, and need to use a correspondingly larger number of participants.
  2. Did the study only include people with low omega-3 intake? Alternatively, did the study record and use the participants’ omega-3 status, both at baseline and after treatment? Higher baseline intakes would make detecting an effect much harder.
  3. Was the dosage sufficient? In general, higher doses have a more protective effect. Many studies use a low dose, which makes them more likely to return a neutral conclusion. There is no need for that. Fish oils are both easily accessible and safe.
  4. Was there concomitant medication use? Likely yes, particularly in prevention studies involving people who already had a cardiac event. But the use of modern medications makes the effect of omega-3s harder to detect, so studies need to record medication usage, and consider it explicitly during their data analysis.
  To conclude, there is an apparent contradiction between the promising results of the earlier clinical trials and the neutral findings of newer studies. This has created some controversy about whether current guidelines to eat more fish or increase the intake of long-chain omega-3 fatty acids are appropriate, which has led to calls to revert existing public health policies. We believe this would be a serious mistake. The majority of the scientific evidence shows that omega-3 fatty acids have a cardio-protective effect, and the fact that recent studies show a reduced or neutral benefit is, more likely than not explained by an increased consumption of omega-3s and by increases and changes in the usage of medications for cardiovascular disease protection (aspirin, statins, beta-blockers, ACE inhibitors, angiotensin II-receptor blockers). This does not mean that omega-3 fatty acids have no role in cardiovascular protection. Quite the contrary. Ischemic heart disease and stroke remain the two leading causes of death worldwide [10]. Unlike modern drugs, fish oils and EPA/DHA-containing dietary supplements are fundamental for early prevention — before any cardiac event or elevation of the levels of risk factors — they have a role in the reduction of the risk of both hypertriglyceridemia and hypertension, and are universally considered safe and free of side effects. They remain a safe and important tool in the prevention of cardiovascular disease.  
  1. Burr ML, Fehily AM, Gilbert JF, et al. (1989) Effects of changes in fat, fish, and fibre intakes on death and myocardial reinfarction: Diet and Reinfarction Trial (DART). Lancet 334, 757–761.
  2. GISSI Prevenzione Investigators (1999) Dietary supplementation with n-3 polyunsaturated fatty acids and vitamin E after myocardial infarction: results of the GISSI-Prevenzione trial. Lancet 354, 447–455.
  3. Harris WS, Kris-Etherton PM & Harris KA (2008) Intakes of long-chain omega-3 fatty acid associated with reduced risk for death from coronary heart disease in healthy adults. Curr Atheroscler Rep 10, 503 – 509.
  4. Rauch B, Schiele R, Schneider S, et al. (2010) OMEGA, a randomized, placebo-controlled trial to test the effect of highly purified omega-3 fatty acids on top of modern guideline- adjusted therapy after myocardial infarction. Circulation 122, 2152 – 2159.
  5. Bosch J, Gerstein HC, Dagenais GR, et al. (2012) n-3 Fatty acids and cardiovascular outcomes in patients with dysglycemia. N Engl J Med 367, 309–318.
  6. Kromhout D, Giltay EJ & Geleijnse JM (2010) n-3 Fatty acids and cardiovascular events after myocardial infarction. N Engl J Med 363, 2015–2026.
  7. James MJ, Sullivan TR, Metcalf RG & Cleland LG (2014) Pitfalls in the use of randomized control trials for fish oil studies with cardiac patients. Br J Nutr 16, 1-9
  8. Mozaffarian D & Rimm EB (2006) Fish intake, contaminants, and human health: evaluating the risks and the benefits. JAMA 296, 1885–1889.
  9. Bimbo AP (2013) The evolution of fish oils to omega 3 fatty acids and a global consumer market of US$25 billion. Paper presented at the West Virginia University Research Corporation Forum Linking Innovation, Industry, and Commercialization (LIINC), Dean’s Open Forum on Innovation and Entrepreneurship, Davis College of Agriculture, Natural Resources & Design, Morgantown, WV, USA, April 25, 2013.
  10. World Health Organization. (2014) The top 10 causes of death. .