Alpha Omega Trial: N-3 Fatty Acids Fail to Reduce Cardiovascular Events in Post-MI Patients

August 29, 2010

Updated August 29, 2010 (Stockholm, Sweden) — A large trial testing the effectiveness of n-3 fatty acids has shown that low-dose supplementation with eicosapentaenoic acid (EPA), docosahexaenoic acid (DHA), or plant-derived alpha-linolenic acid (ALA) failed to reduce cardiovascular events in a large cohort of patients who had previously had a myocardial infarction (MI) [1].

The investigators, including Dr Daan Kromhout (Wageningen University, the Netherlands), who led the Alpha Omega Trial, say the negative findings are likely the result of the optimal medical therapy that patients in the trial were receiving following their index MI. All patients were treated with "state-of-the-art antihypertensive, antithrombotic, and lipid-modifying therapy," and this might explain the discrepancy with previous studies that suggested n-3 fatty acids, particularly EPA, might be cardioprotective following MI.

"Consequently, among patients who have had a myocardial infarction but who are receiving good clinical care and are at relatively low risk for future cardiovascular events, such as the patients in the Alpha Omega Trial, a beneficial effect of low doses of EPA-DHA is difficult to prove," write the authors in the New England Journal of Medicine, in a paper published online to coincide with the late-breaking clinical trial presented today here at the European Society of Cardiology 2010 Congress.

Mainly Well-Treated Men in the Study

The Alpha Omega Trial is a multicenter, double-blind, placebo-controlled study randomizing 4837 patients, aged 60 to 80 years old, to one of four treatment arms: a combination of EPA and DHA (daily dietary intake of 400 mg); ALA (daily intake of 2 g); a combination of EPA, DHA, and ALA; or placebo. Of these patients, more than 75% were men and all had a previous MI, on average, 3.7 years before enrollment into the study. The n-3 fatty acids were included in a margarine the patients consumed, and all were treated for approximately 40 months.

The primary end point of the study was the incidence of major cardiovascular events, comprising fatal and nonfatal cardiovascular disease and cardiovascular interventions such as PCI and CABG surgery.

Treatment with EPA-DHA, used alone or with ALA, did not have any impact on the primary end point when compared with patients treated with ALA or with placebo. Among patients who received ALA, there was an approximate 9% reduction in cardiovascular events compared with individuals treated with placebo or EPA-DHA, but the reduction did not achieve statistical significance. There was no benefit in any of the secondary end points, including death from ventricular arrhythmias.

Alpha Omega Trial: Primary and Secondary Outcomes in EPA-DHA Alone vs Placebo/ALA

Outcome EPA-DHA patients (n=2404), % Placebo or ALA-only patients (n=2433), % Hazard ratio (95% CI)
Major cardiovascular events* 14.0 13.8 1.01 (0.87–1.17)
Incident cardiovascular disease 7.0 7.6 0.92 (0.75–1.13)
Death from cardiovascular disease 3.3 3.4 0.98 (0.72–1.33)
Death from coronary heart diseasex 2.8 2.9 0.95 (0.68–1.32)
Ventricular arrhythmia-related events 2.8 3.0 0.90 (0.65–1.26)
Any death 7.7 7.6 1.01 (0.82–1.24)

*Primary end point

Alpha Omega Trial: Primary and Secondary Outcomes in ALA Alone vs Placebo/EPA-DHA

Outcome ALA patients (n=2428) Placebo or EPA-DHA-only patients (n=2409) Hazard ratio (95% CI)
Major cardiovascular events* 13.2 14.5 0.91 (0.78–1.05)
Incident cardiovascular disease 7.0 7.7 0.90 (0.73–1.11)
Death from cardiovascular disease 3.2 3.5 0.94 (0.69–1.27)
Death from coronary heart disease 2.7 3.0 0.92 (0.66–1.29)
Ventricular-arrhythmia-related events 2.6 3.3 0.79 (0.57–1.10)
Any death 7.6 7.7 0.97 (0.79–1.19)

*Primary end point

In a prespecified subgroup analysis that included women only, there was a 27% reduction in major cardiovascular events, although this benefit just failed to reach statistical significance (hazard ratio 0.73, 95% confidence interval [CI] 0.51–1.03). A post hoc, exploratory analysis of diabetic patients suggested that those treated with EPA-DHA had lower rates of coronary heart disease and arrhythmia-related events than those who did not receive any EPA-DHA.

Not Nearly as Many Deaths as They Thought

To heartwire , Kromhout said the overall negative findings contrast with data from the GISSI-Prevenzione study, but as the researchers point out in their paper, just 5% of patients in the GISSI trial were receiving statins at baseline and 46% receiving the lipid-lowering drugs after treatment in the study, compared with 86% of patients in the Alpha Omega Trial. Commenting on the findings, Kromhout noted that the Alpha Omega Trial was initiated in 2002, with the basic idea of the study emerging in 2000.

"That was 10 years ago now, and in that period, treatment improved very, very much," he said. "When we did our power calculations, we figured there would be about 360 patients who would die of coronary heart disease, when actually it was only 138 patients. When you look at total cardiovascular deaths, it was only 182 patients. So only half of the patients died of coronary disease, and my estimation is that this is because of the very good treatment, and at the same time, lifestyle changes, such as smoking cessation."

In addition to the differences in treatment, patients in GISSI-Prevenzione were enrolled within three months of having an MI, significantly earlier than those included in their trial, and were about 10 years younger. Similarly, the positive Japan EPA Lipid Intervention Study (JELIS) included younger patients and more women than the Alpha Omega Trial, and this too might explain the disparate results.

Speaking during the late-breaking clinical-trials session, Dr Luigi Tavazzi (Fondazione IRCCS Policlinico San Matteo, Pavia, Italy) called the hypothesis for the trial "sound" but said the relatively small sample size, especially given the lower-than-anticipated event rates, make the trial underpowered to definitively answer the question about n-3 fatty acids' role in the post-MI setting. He also questioned whether the primary end point of the study--a composite of major cardiovascular events--was sensitive enough to detect differences between the different treatments, noting that EPA, DHA, or ALA are most likely to have antiarrhythmic benefits.

In addition, Tavazzi wondered about the low dose used in the trial, given that other studies used much higher doses, especially of EPA. In the JELIS study, for example, patients were given 1800 mg of highly purified EPA capsules daily.

To heartwire , Kromhout said the group decided on 400 mg of EPA-DHA because past epidemiology studies suggested a 200-mg dose was sufficient to be protective against cardiovascular events. In later studies that used higher doses, he said, once compliance was factored in, the dose was about 600 mg. As such, they selected 400 mg, right in the middle of the 200- and 600-mg range, when the trial began in 2002.


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