Hitting the mark(er) for EPA and DHA omega-3s

Low EPA+DHA status should be an inclusion criterion in clinical studies with cardiovascular outcomes

Last year, the Cardiovascular Round Table of the European Society of Cardiology published the outcomes of a 2-day workshop on strategies to improve the development of effective new cardiovascular therapies, including, among others, the use of biomarkers to identify patients who will benefit from new therapies more precisely.1

Of particular interest is the alignment of this position with that of many well-respected omega-3 researchers investigating the effects of omega-3s on cardiovascular outcomes. The difference is that omega-3 researchers have a biomarker (that is, EPA+DHA omega-3 status) that is currently available, albeit underutilised.

Two years ago, GOED sponsored a workshop at the 11th International Society for the Study of Fatty Acids and Lipids (ISSFAL) Congress on conducting omega-3 clinical trials with cardiovascular endpoints.2 The goal of the workshop was to gain a better understanding, from scientific experts involved in long chain (LC) omega-3 fatty acid (EPA/DHA) research, about aspects of experimental design that should be considered when planning clinical studies related to EPA/DHA and potential cardiovascular benefits.

This topic is of particular interest because the results of recent large cardiovascular intervention trials with EPA+DHA supplements have failed to detect a benefit. In contrast, in epidemiologic studies, an inverse relation between clinical events and blood levels of EPA+DHA have been found repeatedly. For example, in the Physician’s Health Study, an inverse association was demonstrated between sudden cardiac death and blood levels of EPA+DHA, with the effect being more dramatic as the blood level of EPA+DHA increased.3

One of the issues discussed during the workshop was the utility of an omega-3 biomarker of EPA+DHA status. Drs William Harris and Clemens von Schacky spoke about the need to use low EPA+DHA status as an inclusion criterion to increase the odds of detecting an effect of LC omega-3 fatty acids in clinical studies with cardiovascular outcomes. The theory is that patients with a low omega-3 status may benefit most because they are not at cardioprotective levels.

Given that cardiovascular disease has a high prevalence and is multifactorial, individuals with cardiovascular disease are not expected to have a dramatically different EPA+DHA status than the general population. Essentially, to demonstrate a benefit between the treatment and control groups, there must be a wide enough discrepancy between the omega-3 levels in the two groups. Recruiting trial participants for LC omega-3 intervention trials without considering the baseline omega-3 status is likely to bias the results toward the null for cardiovascular outcomes.

In fact, for the majority of previous intervention trials with cardiovascular outcomes, participants were recruited regardless of their EPA+DHA baseline status. Although this is true of the earlier positive studies as well, background omega-3 intakes were not as high back then because supplementation was not as common. For trials in which a benefit was demonstrated, but omega-3 status was not considered, it is thought that the effects were substantially underestimated because omega-3 status was not considered.

Another complicating factor is that the standard of care in cardiovascular disease has advanced significantly, reducing the risk of repeat cardiovascular events and making it harder to detect an omega-3 effect. This means it is even more important to design studies and recruit patients based on low EPA+DHA status. Doing so will yield a patient population that is more likely to respond to the omega-3 treatment. If a patient is already at cardioprotective omega-3 levels and is also receiving the best standard of care, it is much less likely that an omega-3 treatment will have an effect.

In conclusion, to increase the odds of detecting an effect of LC omega-3 fatty acids in a clinical study with cardiovascular outcomes, low EPA+DHA status should be an inclusion criterion. Fortunately, simple blood tests that will allow researchers to measure these important biomarkers do exist.


1. European Society of Cardiology, 'Improving Clinical Trials for Cardiovascular Diseases: A Position Paper from the Cardiovascular Round Table of the European Society of Cardiology,' Eur. Heart J. 37, 747–754 (2016): http://eurheartj.oxfordjournals.org/content/ehj/37/9/747.full.pdf.

2. H.B. Rice, et al., 'Conducting Omega-3 Clinical Trials with Cardiovascular Outcomes: Proceedings of a Workshop Held at ISSFAL 2014,' Prostaglandins Leukot. Essent. Fatty Acids (Epub ahead of print) 25 January 2016: www.plefa.com/article/S0952-3278(15)30013-2/pdf.

3. C.M. Albert, et al., 'Blood Levels of Long-Chain n-3 Fatty Acids and the Risk of Sudden Death,' N. Engl. J. Med. 346, 1113–1118 (2002).