November 05, 2012

LOS ANGELES — Short-term administration of fish oil to patients undergoing heart surgery did not reduce the incidence of postoperative atrial fibrillation (AF), a new study has shown [1]. Postoperative AF is a very common problem, affecting up to 30% of patients who undergo cardiac surgery, and is extremely debilitating, explained Dr Roberto Marchioli (Consorzio Mario Negri Sud, Santa Maria Imbaro, Italy), who presented the findings during a late-breaking clinical-trial session here at the American Heart Association 2012 Scientific Sessions today.

In the study, named Omega-3 Fatty Acids for Prevention of Postoperative AF (OPERA), there was no difference between the active-treatment and placebo groups in terms of preventing postoperative AF. And this is despite the fact that patients in this study were given fairly high doses of fish oil in the form of a prescription product. "In this setting--patients undergoing cardiac surgery--omega-3 polyunsaturated fatty acids [n3-PUFAs] may simply not be powerful enough to be effective in preventing arrhythmias," Marchioli told a media briefing, adding, "The same could be true in other settings where arrhythmias are already established."

 
                 In this setting--patients undergoing cardiac surgery--omega-3 fatty acids may simply not be powerful enough to be effective in preventing arrhythmias.                 
 

In fact, this assertion was borne out in a second trial presented in the same late-breaking session, Fish Oil Research with Omega-3 for Atrial Fibrillation Recurrence Delay (FORWARD), by Dr Alejandro Macchia (Consorzio Mario Negri Sud). This was performed in people with previous AF, to see whether 1 g per day of fish oil would prevent recurrences. It did not.

Nail in the coffin for fish oil in AF, but what about other CV indications?

Marchioli is second author on the OPERA trial, which is simultaneously published online in the Journal of the American Medical Association, with Dr Dariush Mozaffarian (Harvard Medical School, Boston, MA) as lead author. Mozaffarian told heartwire this is probably the end of the road for fish oil in AF.

"In OPERA and in FORWARD, we are setting the low-hanging fruit of people who are very high risk but are in unique settings. In FORWARD, the people have existing afib and considerable cardiac abnormalities, and one of the reasons fish oil was being tested in that setting was that many, many drugs have been tried but they did not work that well. Similarly in postoperative AF, over decades the rates are pretty much unchanged--amiodarone reduces risk a little bit, as do beta blockers--but it affects one in three, so it's a very intractable problem. Both of these populations are people at high risk, but unique. My suspicion is that fish oil won't work in established AF and that it doesn't work to prevent afib after cardiac surgery."

 
                 My suspicion is that fish oil won't work in established AF and that it doesn't work to prevent afib after cardiac surgery.                          
 

He added that patients with existing AF or those undergoing cardiac surgery hoping that fish oil might prevent postoperative AF probably shouldn't waste their money on it.

But he stressed that the trial that should be performed--although he believes it is unlikely to gain funding--is to see whether use of fish oil prevents the initial onset of AF as people age.

He also noted that OPERA "was by far the largest trial of fish oil in surgery," and it showed no evidence of an increase in bleeding with the supplement. "Many surgeons recommend that patients stop taking their fish oil before cardiac surgery, but our data suggest it's safe to continue," he observed.

And he maintains that the question of fish-oil consumption for the wider question of cardiovascular disease prevention as a whole still remains unresolved. The totality of evidence "suggests that taking fish oil compared with none reduces deaths from heart disease," he asserted.

But others are not so sure. Dr Peter Wilson (Emory University, Atlanta), an invited panel member during the press conference, said: "Every time we've had a major trial using omega-3s that was conducted as a primary purpose of the trial, we've come up short. It's very discouraging for the omega-3 story."

 
                 Every time we've had a major trial using omega-3s that was conducted as a primary purpose of the trial, we've come up short.                        
 

And Dr Elliott Antman (Brigham and Women's Hospital, Boston, MA), chair of the AHA Scientific Sessions program committee, referred journalists to a new meta-analysis in the November 2012 issue of Circulation: Cardiovascular Quality and Outcomes, which examines more than 20 trials of fish oil [2]. The authors conclude: "Omega-3 fatty acids may protect against vascular disease, but the evidence is not clear-cut, and any benefits are almost certainly not as great as previously believed."

"It was hard to find a compelling signal for a significant benefit on total mortality or coronary events" in this meta-analysis, Antman observed. But he pointed out that most individuals included were "low to moderate risk," and "perhaps some of the ongoing trials in more high-risk patients, such as ASCEND, may produce more benefit."

OPERA is largest trial of fish oil in cardiac surgery

Marchioli explained that a few small trials have evaluated whether long-chain n-3 PUFAs reduce postoperative AF, with mixed results. In OPERA, a double-blind, placebo-controlled, randomized clinical trial, a total of 1516 patients scheduled for cardiac surgery in 28 centers in Italy, Argentina, and the US were enrolled between August 2010 and June 2012. Inclusion criteria were broad; the main exclusions were regular use of fish oil, absence of sinus rhythm at enrollment, or existing heart transplant/ left ventricular assist device (LVAD) or planned surgery for this.

Patients were randomized to either olive oil (as a placebo) or supplements containing 8 to 10 g of n-3 PUFAs in the form of a prescription product, Omacor (Pronova Bio-Pharma, Norway).

Patients were given a preoperative loading dose of the fish oil of 10 g over three to five days (or 8 g over two days), followed postoperatively by 2 g daily until hospital discharge or postop day 10, whichever came first.

The highest dose of fish oil used in OPERA is the maximum that is licensed by the FDA, albeit for a different indication, that of hypertriglyceridemia.

The primary end point of OPERA was the occurrence of documented postop AF or flutter of > 30-s duration and documented by rhythm strip or 12-lead ECG. There was no difference in the primary end point between those who got fish oil, 30.0% of whom developed postoperative AF, and those who got placebo, of whom 30.7% developed it (p=0.74).

There was also no significant difference between the two groups in a number of secondary end points, including sustained postoperative AF (greater than one hour), incident postop AF, other supraventricular and ventricular tachyarrhythmias, in-hospital major adverse cardiovascular events (MACE), 30-day mortality, one-year mortality, resource utilization, significant adverse events, and bleeding.

"Postoperative AF remains an enigmatic and difficult-to-prevent complication of cardiac surgery," Marchioli commented.

FORWARD study underpowered but findings fit with OPERA

FORWARD randomized just under 600 outpatients with at least two symptomatic episodes of documented AF in the past six months or successful electrical or pharmacological cardioversion for persistent AF performed in the previous three to 90 days to 1 g daily of fish oil (n=289) or placebo (n=297). Patients were recruited from January 2008 to March 2011 and followed for 12 months or time to death or recurrent AF.

The primary end point was the time to first recurrence of symptomatic or asymptomatic AF documented by 12-lead ECG. At 12 months, 18.9% of patients on placebo had a recurrence of AF compared with 24.0% of those who took fish oil (hazard ratio 1.28, p=0.17). There was no difference between treatment with fish oil and placebo for any other prespecified end points.

Macchia, who presented the FORWARD findings, was also third author on OPERA. Mozaffarian told heartwire that FORWARD "was underpowered, because it didn't meet its target enrollment or number of events." Nevertheless, the findings support the conclusion that fish oil is probably of limited effect in established AF, he acknowledged.

Both the OPERA and FORWARD authors report no conflicts of interest.

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