Omega-3 PUFA Caps Don't Suppress Paroxysmal AF in Randomized Trial

November 15, 2010

November 15, 2010 (Chicago, Illinois) — Outcomes of studies looking at whether taking omega-3 polyunsaturated fatty acids (PUFAs) in capsules can prevent various forms of atrial fibrillation (AF) have been a mixed bag. Now, one of the largest such studies in one of the commonest forms of the arrhythmia, symptomatic paroxysmal AF, suggests that taking prescription-only omega-3 PUFA capsules (Lovaza, GlaxoSmithKline) even at the fairly high dose of 4 g/day for six months doesn't cut the risk of recurrence [1].

Although the randomized, placebo-controlled trial didn't show a fish-oil effect on the primary end point--first recurrence of symptomatic AF or atrial flutter in patients with paroxysmal AF--"we did find a reduction in average ventricular rate during the first AF recurrence, a reduction in triglyceride levels at week 24 that did not occur with placebo, and increased blood levels of the omega-3 fish oils eicosapentaenoic acid and docosahexaenoic acid compared with placebo patients," according to the study's authors, led by Dr Peter R Kowey (Lankenau Institute for Medical Research, Wynnewood, PA).

Dr Peter R Kowey

The latter observations, they write, suggest that there were indeed biologic effects, if not AF-suppressive effects, from taking the fish-oil capsules. And the supplements didn't seem to cause major adverse effects; the omega-3 and placebo groups didn't differ in rates of bleeding, "serious drug-related nonfatal events," or death.

The study also saw nonsignificant trends suggesting reduced event-free survival, as secondary end points, from omega-3 PUFA therapy in a prespecified subgroup and in the study population as a whole.

The group's report is published online today in the Journal of the American Medical Association to coincide with Kowey's scheduled presentation of the study here at the American Heart Association 2010 Scientific Sessions.

At a briefing for reporters, Kowey observed, "Many of our patients in fact do use fish-oil products, in various doses and in various preparations, in hope of preventing several cardiovascular end points. And there clearly has been equipoise in the area of atrial fibrillation, with as many studies producing positive as those producing negative results." The current study, he said, "is actually the first large randomized trial of this medication in a nonsurgical population."

The study randomized 663 outpatients with documented symptomatic paroxysmal or persistent AF (n=542 and n=121, respectively) who were without significant structural heart disease and initially in sinus rhythm to receive placebo or the prescription omega-3 PUFA capsules at 8 g/day for the first seven days followed by 4 g/day for total of 24 weeks.

Each 1-g omega-3 PUFA capsule contained about 465-mg eicosapentaenoic acid and 375-mg docosahexaenoic acid.

Persistent AF was defined as "AF that had been previously successfully treated with pharmacological or electrical cardioversion at least one time."

Rate Of First Recurrent Symptomatic AF or Atrial Flutter by AF Type and Treatment Group and Hazard Ratio (HR) for Active Therapy vs Placebo

Patient group

Placebo (%)

Omega-3 PUFA (%)

HR (95% CI)

p

Paroxysmal AF* (n=542)

48

52

1.15 (0.90–1.46)

0.26

Persistent AF (n=121)

33

50

1.64 (0.92–2.92)

0.09

Any AF (all patients)

46

52

1.22 (0.98–1.52)

0.08

*Primary end point was recurrence in this group

Similar results were seen in subgroups by age, sex, race, smoking status, alcohol consumption, and statin and ACE-inhibitor/angiotensin-receptor blocker (ARB) use.

Referring to the observed secondary-end point trends suggesting worse outcomes with active therapy, Kowey told heartwire , "My own personal opinion is that it was the play of chance. I don't think that this is a real detrimental effect of fish oil."

It's true that omega-3 PUFA supplementation carries a largely theoretical risk of causing arrhythmias, "especially from changes in autonomic tone," Kowey said. "We just haven't seen it in any other trials. The worst we've seen for fish oil is neutrality, across the board."

Dr Robert Califf

Dr Robert Califf (Duke Clinical Research Institute, Durham, NC), who wasn't involved in the study, said the observed trends were "interesting," and agreed for heartwire that "the most likely cause would be random variation or play of chance." If it turns out there really is a proarrhythmic effect, it should show up in other trials.

"So it's something to watch," he said, adding that "there may be a lesson" here regarding supplements used as drugs. "Maybe we have to test them just like we do drugs."

As for whether the omega-3 PUFA capsules at 4-g/day posed an untoward risk of adverse side effects, Kowey said, "They were extremely well tolerated. There was a very low incidence of any adverse event, and none of our adverse-event [rates], including [for] those that were serious, were any different from placebo." Only 5% of control patients and 4% of those receiving the omega-3 PUFA capsules discontinued therapy because of adverse events. The most common was diarrhea or nausea.

Although the study doesn't support using the omega-3 PUFA supplements to prevent recurrence in a paroxysmal-AF population, Kowey et al write, "Our results do not exclude potential benefit in combination with membrane-active antiarrhythmic drugs, in different patient populations such as a high-risk primary-prevention population . . . or in the absence of concomitant therapies."

Dr Christine M Albert

Dr Christine M Albert (Brigham and Women's Hospital, Boston, MA), who was later the invited discussant for Kowey's formal presentation, agreed at the press conference that the supplements could easily have different effects in different AF populations. Several smaller studies, for example, suggest that they might suppress postoperative AF, where inflammation may be a major promoter of the arrhythmia; omega-3 PUFAs are anti-inflammatory.

She described an ongoing trial called Fish Oil Research with Omega-3 for Atrial Fibrillation Recurrence Delay (FORomegaARD), which is randomizing about 1400 patients with paroxysmal or permanent AF to received fish-oil caps at 1 g/day or placebo. There are other ongoing studies in various AF populations.

Kowey said to heartwire that "there is no precedent for a drug that didn't work in the population we studied working in other populations, in atrial fibrillation. The fact that this drug failed in this population, in my mind, makes it highly unlikely that you'll see efficacy in other groups.

The study was supported by GlaxoSmithKline. Kowey reports serving as a consultant for Boehringer Ingelheim, Bristol-Myers Squibb, Blue Ash Pharmaceuticals, Gilead, HUYA Biosciences, Sanofi-Aventis, Solvay, AstraZeneca, Johnson & Johnson, Merck, Astellas, Pfizer, Sequel, Medtronic, Boston Scientific, St Jude Medical, GlaxoSmithKline, Boehringer Ingelheim, and Otsuka; serving on the speakers' bureau of Sanofi-Aventis; holding stock in Cardionet; and receiving honoraria from GlaxoSmithKline. Disclosures for the coauthors are listed in the paper. Albert reports receiving grant support from St Jude Medical, being a consultant to Novartis, and serving on an end-point committee for the ongoing OPERA trial of omega-3 PUFA capsules for postoperative AF.

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