Norwich, UK - Adding to the growing debate over the cardioprotective benefits of omega-3 fatty acids (FAs), a new systematic review has found that long- and short-chain omega-3s may have no effect on mortality, cardiovascular events, or cancer [1]. The finding goes against the widely held assumption that long-chain omega-3 FAs, found in oily fish and fish oils, and shorter-chain omega-3s, found in some plant oils, are protective against cardiovascular disease.

"We were sure, like many researchers and physicians working in the area of heart health, that omega-3 fats were protecting people against dying, especially those people with cardiovascular disease," lead author on the study, Dr Lee Hooper (University of East Anglia, Norwich, UK), told heartwire. "We were surprised to find that we are not so sure after all whether this protective effect occurs, and if so how big the effect is, and for whom it is protective."

Hooper et al's study appears online March 24, 2006 in the BMJ.

In their review, Hooper and colleagues looked at all randomized controlled trials and cohort studies of omega-3 intake of six months or longer that included outcome data on total mortality, cardiovascular events, or cancer. Omega-3 "exposure" was in the form of dietary supplements in most of the trials and as recommendations on consumption of oily fish in three studies, as compared with a control group taking placebo substances, dietary advice, or nothing. In total, Hooper and coauthors included a total of 48 randomized controlled trials and 41 cohort studies.

They report that, taken together, the studies showed no strong evidence of reduced total mortality risk or cardiovascular events in people adding omega-3 fats to their diets and were highly inconsistent between studies. A subset of studies deemed to be at "low risk of bias" were more consistent in their findings yet still showed no effect of omega-3s on total mortality or CV events. Analyzed separately, data from studies of long-chain omega-3 FAs showed only inconsistent effects on mortality and cardiovascular events. When randomized controlled trials were considered separately from cohort studies, neither group showed a clear impact on cardiovascular events or mortality. In terms of cancer, randomized controlled trials and cohort studies both showed no effect of high-intake omega-3s on cancer, but "clinically important harm could not be excluded" due to low numbers of events.

While an earlier meta-analysis of omega-3 effects on the heart suggested the FAs were beneficial [2], Hooper et al's study includes a subsequent study of 3114 men with angina, by Burr et al [3], which may have explained the conflicting results of Hooper et al's meta-analysis.

"[Burr et al's study] had very different results from the two other large studies and suggested that omega-3 fats, or oily fish or fish oils, may actually increase the risk of death, although this increase was not statistically significant," Hooper explained. "Other meta-analyses either did not include this study or decided not to pool the results of the studies, so that it was not clear that the overall effect was no longer statistically significant."

A number of things could explain Burr et al's findings, and by extension, the results of the meta-analysis. For one, write Hooper and colleagues, Burr et al's study had the longest follow-up of all randomized controlled trials included in the analysis, raising the possibility that the cumulative effects of methylmercury found in fish (believed to cause cancer and possibly MI) counterbalanced the benefits of omega-3 FAs. Alternatively, Burr et al's study looked exclusively at men with angina, whereas the proposed benefits of omega-3s may be strongest in people with heart failure. Different effects of fish-oil supplements vs fatty fish may also have played a role, the authors add.

Whatever the reasons, the findings provide food for thought, Hooper and colleagues write. Current dietary guidelines in the US and UK, for example, advocate regular consumption of fatty fish; the current study would suggest that such recommendations are unwarranted.

"We really need more information to be clear—and fortunately there are several large trials under way," Hooper told heartwire. "The basic information for the population in the UK is to 'eat two portions of fish a week, one of which should be oily.' This is probably sensible and fine given that omega-3 fats are essential."

What is less clear, Hooper adds, is who, if anyone, should ingest higher doses of fish oils or omega-3 supplements each week. "We were feeling that this level of omega-3 fats should be given to people post-heart attack and possibly all those with cardiovascular disease," Hooper comments. To date, studies suggest that high-dose omega-3 FAs could be recommended for secondary prevention, perhaps especially in heart-failure patients, but not for primary prevention. "But this may be too simplistic," Hooper said.

For the time being, "I think we feel that this is a caution; we shouldn't go overboard recommending omega-3 to everyone in high doses, and we need to keep an eye on emerging evidence," Hooper stated. "It may be that we should continue with oily-fish or fish-oil advice post-heart attack, but for others we should stick simply with the population levels of one portion of oily fish per week. But even this may be incorrect, and we need to know that we may need to alter our advice in the near future."

In an accompanying editorial, Dr Eric Brunner (Royal Free and University College London, UK) reviews some of the tenuous and more well-established benefits of omega-3s on human health. The review by Hooper et al, Brunner writes, "shows that the evidence for a reduction in cardiovascular events and mortality is less conclusive than we believed." The claim that omega-3s reduce cancer also is ill-supported by Hooper et al's review.

Another complicating factor is the fact that health advice is at odds with real-world availability. "We are faced with a paradox," Brunner observes. "Health recommendations advise increased consumption of oily fish and fish oils, within limits, on the grounds that intake is generally low. However, industrial fishing has depleted the world's fish stocks by some 90% since 1950, and rising fish prices reduce affordability, particularly for people with low incomes. Global production trends suggest that, although fish farming is expanding rapidly, we probably do not have a sustainable supply of long-chain omega-3 fats."