A subsequent prevention trial corroborated the benefits of fish-oil supplementation for secondary prevention in MI survivors, namely with one Lovaza capsule per day delivering 850 mg of EPA/DHA in a 1.2:1 ratio. Researchers demonstrated a 21% and a 30% reduction, respectively, in total death and cardiovascular death over the one-year duration of the study.11 These results were driven by an impressive 46% reduction in sudden cardiac death. Reductions in major clinical events continued to be demonstrated at 3.5-year follow-up.12
Additional evidence for the protective effects of omega-3 supplementation comes from the Japan EPA Lipid Intervention Study, published in 2007. In a mixed trial of primary and secondary prevention, 18,645 patients with hypercholesterolemia (70% women) were randomized to statin alone or statin and highly purified EPA 1,800 mg/day. At the end of the five-year study, those randomized to statin plus EPA had a 19% reduction in major cardiovascular events.13
How do clinicians reconcile these results with those of the Alpha Omega Trial, which demonstrated no secondary prevention benefits of supplementation with an omega-3-enriched margarine spread?
Researchers leading the Alpha Omega Trial assigned 4,837 MI survivors to one of four experimental groups. For 40 months, participants consumed either (1) placebo margarine, (2) margarine with a combined total of 400 mg of EPA/DHA, (3) margarine with 2 g of alpha-linolenic acid (ALA), a plant-derived precursor to EPA/DHA, or (4) a margarine containing a combination of EPA/DHA and ALA. State-of-the-art antihypertensive, antithrombotic, and lipid-modifying therapy was implemented in all four groups.
The results showed that neither the EPA/DHA nor the ALA (nor a combination of both) proved more beneficial than placebo. Does this constitute a repudiation of the omega-3 CVD prevention hypothesis?
Critics of the Alpha Omega Trial were quick to point out specific objections to its methodology. First, aggressive pharmacologic management may have masked some of the advantages conferred by fish oil. Additionally, it was thought that the results did not disqualify a putative benefit of omega-3-enriched margarines in primary prevention.
Some have claimed that the choice of a margarine-like spread as a delivery system might have compromised the efficacy of the active omega-3 component. The caloric load provided by daily consumption of 18.8 g of omega-6-rich vehicle and the attendant consumption of multiple slices of high glycemic index bread on which the margarine-like substance was spread, might have acted as confounders.
But most important, the low-dose of EPA/DHA (400 mg) employed in the trial is well below the threshold noted in some studies to influence cardiovascular outcome. The study might best be viewed as merely contravening the hoped-for cardio-protective role of a specific functional food—with inherent limitations to palatability attributable to fish oil’s inability to being disguised in neutral vehicles. Therefore, it would be an overstatement to claim, as some have, that the Alpha Omega Trial is the death knell for omega-3 supplementation in CVD.