Why the change of heart?

Although there is no perfect experimental design, scientists need to weigh up the pros and cons when designing any experiment, according to Adam Ismail, Executive Director, and Harry Rice, VP, Regulatory and Scientific Affairs, Global Organization for EPA and DHA Omega-3s (GOED)

In contrast with earlier investigations (DART, GISSI-Prevenzione, JELIS and GISSI-HF1–4) about the effects of the long-chain omega-3s, EPA and DHA, on cardiovascular disease (CVD) risk/events, media reports about recent studies have been generally negative. This does not mean, however, that the results were negative. In general, the results of these recent studies have been either neutral (no effect[s] found) or positive (beneficial effect[s] found).

There are two things going on here. First, the reason that studies are yielding neutral results in areas where there is strong evidence that EPA and DHA have beneficial effects appears to be based in experimental design. Second, many of these studies are demonstrating positive effects, but they are understated in the conclusions and media reporting of the studies. It’s not clear why this is happening, but it is.

Although there is no perfect experimental design, scientists need to weigh up the pros and cons when designing any experiment. The following are elements of experimental design that don’t receive enough attention. They are thought to be responsible for the recent run of neutral results in omega-3 studies.

Drug Cocktails

Today’s standard of care for cardiac patients is to maintain them on aggressive drug therapy with multiple drugs. It’s difficult for omega-3s to demonstrate a benefit when patients are already taking drugs that have similar benefits. Imagine if you added another cardiac drug to an already heavy drug regime. The likelihood of demonstrating any additional benefit is on par with adding omega-3s to the mix. It’s possible that omega-3s may provide some benefit in these patients, but the additional effect on top of the drugs is likely to be small and will be difficult to detect in studies with all the extra noise presented by the drugs.

Sample Size

Too few subjects results in an underpowered study and the conclusion from such a study should not be described as a failure to have an effect, rather a failure to detect an effect. This is particularly problematic in omega-3 studies that mix healthy subjects with cardiac patients. In these populations, two large meta-analyses have shown that you could reasonably expect a 9% reduction in coronary death risk.5,6 One recent study that received a lot of media attention had a sample size that was too small to detect a change in risk reduction; therefore, it was destined to fail from the outset.7

Background Omega-3 Intake

Although people in most countries continue to fall short of ingesting a sufficient amount of EPA+DHA, average intakes have crept up in many countries. As a result, people are no longer as “deficient,” making it more difficult to demonstrate a benefit. This does not mean that omega-3s do not provide protective effects; in fact, it might mean that the subjects in the study are already protected.

Treatment Duration

Many of the neutral studies have been too short in duration. For cardioprotection, many scientists believe that most omega-3 studies need to follow patients for at least five years to see statistically significant benefits, but many have only last two to three years.

Control/Placebo

There’s some thought that olive oil, which is a popular placebo, may not be appropriate given that oleic acid, the primary fatty acid in olive oil, has been demonstrated to have heart health benefits. Is there a better choice?

Omega-3 Dosage

In general, 250–500mg/day of EPA+DHA is recommended for primary prevention (prevention of disease before it develops), whereas 1g/day or more is recommended for secondary prevention (detection and treatment of disease before it is symptomatic). It’s worth noting that many secondary prevention studies are inappropriately characterized by the media as being primary prevention; thus, the results would be applicable to the general, healthy population. Obviously, this is not true.

Endpoints

In many of the more recent omega-3 studies, a combination of endpoints has been studied as a single variable, including endpoints that omega-3s have not previously been shown to affect. The cleanest experimental design would be to study cardiovascular disease endpoints in isolation, rather than creating artificial noise by adding unreasonable endpoints.

To illustrate this problem, imagine that omega-3s are thought to reduce the risk of Condition A, but not Condition B. A study uses the incidence of either Condition A or Condition B as its primary endpoint: combined together (A+B), there is no statistically significant risk reduction seen; but in isolation, there is a reduced risk of Condition A and no effect on Condition B. Does that mean there was no benefit? Clearly not, but the poor definition of endpoints would lead you to believe there was none.

O-3 Assessment Method

These methods include, but are not inclusive of subjective measurements such as validated food frequency questionnaires and objective measurements such as plasma or RBC omega-3s. Although subjective measurements are prone to more noise, they have been used successfully for many decades. The more recent issues have been that these successful methods have limitations that are often ignored to the point of overstating the significance of the findings.

For additional insights into experimental design issues that may be contributing to neutral results, there are at least two well written articles on the subject.8,9 In addition, an upcoming ISSFAL Congress in Stockholm, Sweden (28 June–2 July), will include a GOED-sponsored workshop on conducting omega-3 clinical trials with cardiovascular endpoints. Following the workshop, GOED intends to publish guidelines to conducting cardiovascular clinical trials with omega-3s that we anticipate will serve as a valuable resource.

References

1. M.L. Burr, et al., “Effects of Changes in Fat, Fish and Fibre Intakes on Death and Myocardial Reinfarction: Diet and Reinfarction Trial (DART),” Lancet 334(8666), 757–761 (1989).

2. Gruppo Italiano per lo Studio della Sopravvivenza nell'Infarto Miocardico, “Dietary Supplementation with n-3 Polyunsaturated Fatty Acids and Vitamin E After Myocardial Infarction: Results of the GISSI-Prevenzione Trial,” Lancet 354, 447–455 (1999).

3. M. Yokoyama, et al., “Effects of Eicosapentaenoic Acid on Major Coronary Events in Hypercholesterolaemic Patients (JELIS): A Randomised Open-Label, Blinded Endpoint Analysis,” Lancet 369, 1090–1098 (2007).

4. L. Tavazzi, et al., “Effect of n-3 Polyunsaturated Fatty Acids in Patients with Chronic Heart Failure (The GISSI-HF Trial): A Randomised, Double-Blind, Placebo-Controlled Trial,” Lancet 372, 1223–1230 (2008).

5. E.C. Rizos, et al., “Association Between Omega-3 Fatty Acid Supplementation and Risk of Major Cardiovascular Disease Events: A Systematic Review and Meta-Analysis,” JAMA 308, 1024–1033 (2012).

6. S.M. Kwak, et al., “Efficacy of Omega-3 Fatty Acid Supplements (Eicosapentaenoic Acid and Docosahexaenoic Acid) in the Secondary Prevention of Cardiovascular Disease: A Meta-Analysis of Randomized, Double-Blind, Placebo-Controlled Trials,” Arch. Intern. Med. 172, 686–694 (2012).

7. Writing Group for the AREDS2 Research Group (published online 17 March 2014), “Effect of Long-Chain Omega-3 Fatty Acids and Lutein + Zeaxanthin Supplements on Cardiovascular Outcomes: Results of the Age-Related Eye Disease Study 2 (AREDS2) Randomized Clinical Trial,” JAMA Intern. Med. 309(19), 2005–2015 (2013).

8. W.S. Harris, “Are n-3 Fatty Acids Still Cardioprotective?” Curr. Opin. Clin. Nutr. Metab. Care 16, 141–149 (2013).

9. J.H.Y. Wu and D. Mozaffarian, “Omega-3 Fatty Acids, Atherosclerosis Progression and Cardiovascular Outcomes in Recent Trials: New Pieces in a Complex Puzzle,” Heart 100, 530–533 (2014).

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