By William S. Harris, PhD
The most recent meta-analysis of omega-3 fatty acids and CVD was published in September 2012 by Rizos et al.1 These authors included 20 randomized controlled studies that primarily used omega-3 capsules whether placebo-controlled or open label. They also included the two dietary advice studies from Burr et al.2,3 This was an improvement on an earlier meta-analysis in 20124 that did not include four major non-placebo controlled trials.2,3,5,6 Nevertheless, Rizos et al. concluded that there was no statistically significant effect of omega-3 supplements on risk for cardiovascular disease. The primary reason why they reached this conclusion was because they inflated the critical value for significance to 0.006 instead of the standard 0.05. With this statistical maneuver, their conclusion – which should have been that fish oil supplementation significantly reduced risk for cardiac death by 9% (relative risk reduction of 0.91; 95% CI, 0.85 to 0.98; p=0.01) - was that there was no effect of fish oil on cardiovascular disease. The authors justified this on the basis of needing to correct for “multiple testing,” a practice rarely done in meta-analyses. In fact, 16 meta-analyses 1,7-21 were published in JAMA during the first 9 months of 2012, and Rizos et al. was the only one to adjust for multiple testing and the only one to not use the standard 95% confidence interval to draw their conclusions. Why the rules changed for this analysis is not clear, but what is clear is that their conclusion driven by a subjective interpretation of the data, not by standard statistical practices, that turned a favorable effect into a non-effect.
Even if their conclusions had been statistically sound, they should have been much more nuanced in their conclusions. They said, “Our findings do not justify the use of omega-3 as a structured intervention in everyday clinical practice or guidelines supporting dietary omega-3 PUFA administration” (and here they referenced the 2002 American Heart Association guidelines22). A more accurate and less sweeping conclusion should have been something like, “In patients of average age 63, with existing cardiovascular disease and under optimal medical care, the administration of about 1 g of EPA+DHA for about 2 years [median duration in their analysis] did not significantly reduce risk for major clinical outcomes.” Their study does not show that treating with a higher dose for a longer period of time, or treating patients earlier in the disease process or those who are not receiving “optimal medical therapy” will not be beneficial.
Other problems with their conclusions included the fact that very few people are actually “on optimal medical therapy,” with non-compliance rates around 50% within a year of getting a prescription23. So the findings of research trials cannot always be extrapolated to the real world. Finally, 84% of the subjects in the Rizos meta-analysis were taking ethyl esters. It is now becoming clear that taking ethyl esters on an empty stomach (as opposed to with a meal) results in very poor absorption24. So the true dose may have been even smaller than the average of 1 g that characterized these studies.
In summary, Rizos et al. were too conservative in their analysis and they were not circumspect in drawing their conclusions. It may be true that nowadays 1 g of EPA+DHA does not have the marked impact on heart disease risk that we came to expect after GISSI-Prevenzione, but it is still the nutritional factor with the strongest evidence for cardioprotection.
William S. Harris, PhD President, OmegaQuant Analytics 2329 N. Career Ave, Ste 113 Sioux Falls, SD 57107 (605) 271-6917 (913) 302-9433 (cell) email@example.com Professor of Medicine Sanford School of Medicine University of South Dakota Sioux Falls, SD
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