Beware: I Can't Believe It's Not Better than Butter

Daan Kromhout, MPH, PhD, of Wageningen University in the Netherlands stated that, the study results are doubly disappointing since the margarine intervention did initially reduce events but by 30 months the evidence of that benefit had disappeared.

After more than 40 months, consumption of the omega-3 fatty acid fortified margarines "had no effect on the rate of major cardiovascular events," he reported at the European Society of Cardiology meeting. The findings were simultaneously published.

The ALPHA-OMEGA trial randomized 4,837 MI survivors, 60 to 80 years old, to margarine supplemented with a combination of eicosapentaenoic acid and docosahexaenoic acid (EPA and DHA), or with 2 grams of the plant-derived fatty acid alpha-linolenic acid (ALA), or a third supplemented with all three versus a placebo margarine.

The primary endpoint was the combined rate of fatal and non-fatal cardiovascular events and cardiac interventions.

Neither EPA-DHA nor ALA reduced this endpoint, the researchers reported (hazard ratio with EPA-DHA, 1.01; 95% confidence interval 0.87 to 1.17, P =0.93).

A prespecified subgroup analysis in women found that use of the ALA-fortified margarine reduced the rate of cardiovascular events compared with placebo or with the EPA-DHA margarine, but the difference failed to reach statistical significance (HR 0.73, 95% CI 0.51 to 1.03, P=0.07).

The findings were suprising to most of the attendees because most of the data on omega-3 fatty acids come from epidemiologic studies and those were positive.

That hypothesis was initially questioned when a randomized controlled trial (Estrogen/Progestin Replacement Study [HERS]) linked hormones to increased risk of events. The HERS finding was confirmed in the landmark Women's Health Initiative trial in which ischemic events were more common among women randomized to estrogen/progestin.

R. Scott Wright, MD, of the Mayo Clinic in Rochester, Minn., in an interview stated that, the design was faulty, in that margarine was a bad choice of vehicle for omega-3 fatty acids.

"It needs to be combined with another food -- bread," he said. "So this not a good option for Americans because it would mean eating more bread, which is likely to lead to weight gain and bread is high in sodium, so blood pressure would be a factor."

Wright noted that the ALPHA-OMEGA study did not include information on weight or blood pressure, so he considered the findings at best incomplete.

All of the patients received "state-of-the-art antihypertensive, antithrombotic, and lipid-modifying therapy," according to Kromhout and colleagues, in addition to margarine, and it may have been that optimal therapy that limited the potential for an omega-3 benefit.

Statin therapy, along with other improvements in cardiovascular care, means "a beneficial effect of low doses of EPA-DHA is difficult to prove," the authors wrote.

Wright said he wasn't persuaded by that explanation since, even after optimal therapy, there is about a 30% residual risk. "There is plenty of room to show a benefit," he declared.

Most of the patients in ALPHA-OMEGA were men (78%) and 24% were obese, but they differed from the typical high-risk American in at least one way: at baseline they consumed about three times more fish than does the typical American, a median of 15 grams a day.

According to a report from the Environmental Protection Agency, average fish consumption in the U.S. works out to 4.58 ± 0.42 grams a day.

The authors conducted a post hoc exploratory analysis in patients with diabetes, finding significant reductions in events among patients in the EPA-DHA group. But the authors noted that "[the] results with respect to patients with diabetes are only hypothesis-generating and do not permit definitive conclusions to be drawn."

Dr. Alfred Bove, a former president of the American College of Cardiology, added that the results from the subset analysis in diabetics was reassuring, since patients with diabetes and elevated triglycerides are the patients that "we have believed would be most likely to benefit" from omega-3 fatty acids.

The margarines used in the trial were supplied by Unilever, an international maker of food and consumer goods, and included the well-known "I Can't Believe It's Not Butter," which contains 420 mg of ALA per serving.

In a statement released after the ALPHA-OMEGA trial findings were presented, Unilever said the "study outcome for EPA and DHA is surprising considering the weight of evidence published to date. This could be the result of methodological issues such as the relatively low daily dosage compared with previous studies or the fact that in this study serious cardiovascular events were much lower than in studies performed in the past. This is probably due to extensive drug treatment that is nowadays applied. The finding needs further study, but given the totality of evidence does not immediately impact the current advice on fish and fish oil consumption for prevention of cardiovascular disease."

Practice Pearls

• Mention to patients that a recent study demonstrated that margarine supplemented with omega 3 fatty acids did not reduce the risk of second heart attacks.
• Mention that the study examined only patients living in the Netherlands and thus may not be applicable to the general United States population as our diets, lifestyles and risk factors differ.

New England Journal of Medicine, Kromhout, D et al "n-3 fatty acids and cardiovascular events after myocardial infarction" N Engl J Med 2010; DOI: 10.1056/NEJMoa1003603.