New data from a small randomized trial provides further mechanistic evidence that n-3 polyunsaturated fatty acids (PUFAs) might play a role in the treatment of certain patients with heart failure (HF), with investigators showing the omega-3 fatty acids improved echocardiographic measures of systolic and diastolic function and functional capacity in patients with nonischemic cardiomyopathy and minimal symptoms [1].

Compared with patients who received placebo, treatment with a high dose of n-3 PUFAs improved ejection fraction, peak VO2, exercise duration, and mean NYHA functional class, as well as reduced hospitalizations for heart failure, report Dr Savina Nodari (University of Brescia, Italy) and colleagues in the report, published online January 5, 2011 in the Journal of the American College of Cardiology.

First presented at the Heart Failure Society of America (HFSA) 2010 Scientific Meeting in San Diego, CA, and reported by heartwire at the time, the results support the modest benefit observed in the Gruppo Italiano per lo Studio della Sopravvivenza nell’Infarto Miocardico Heart Failure (GISSI-HF) trial and provide a “compelling test case” for the dilemma facing clinicians who treat patients with heart failure, according to an editorial by Drs WH Wilson Tang and Michael Samara (Cleveland Clinic, OH) [2]. As Tang told heartwire , the results raise the possibility that n-3 PUFAs might be more beneficial if given at higher doses and earlier in the disease stages than was done in the GISSI-HF study.

“There is a lot of evolving science as we continue to try to understand whether or not we need to identify specific patients who might benefit from treatment with omega-3 fatty acids,” said Tang. “At this point, we have to rely on the fact that the treatment is safe, the treatment may be beneficial in some patients, but if the patient is very symptomatic, other things might take over and overshadow that benefit. The actual benefit is probably modest and perhaps stronger in some patients than others.”

Echocardiographic Measures of Systolic and Diastolic Function Improve

In the present study, Nodari and colleagues randomized 133 clinically stable patients with angiographically confirmed nonischemic heart failure and an LVEF <45% to take capsules containing 850 to 882 mg eicosapentaenoic acid (EPA) and docosahexaenoic acid (DHA) or a matching placebo in double-blind fashion. For the first month, patients took five capsules per day, followed by two capsules a day for 11 months. About 40% in each group had implantable defibrillators, and both groups were very well-treated with evidence-based medication, with every patient taking an ACE inhibitor/angiotensin-receptor blocker, a beta blocker, and furosemide.

As reported previously, ventricular diameters and volumes, left ventricular ejection fraction, and other echocardiographic markers of remodeling were significantly improved at 12 months among patients taking the n-3 PUFAs (p<0.001). In addition, parameters of cardiopulmonary exercise testing were also significantly improved compared with placebo, as were inflammatory markers interleukin-1 and interleukin-6. In multivariate analysis, higher baseline levels of tissue necrosis factor (TNF)-alpha were a predictor of improved left ventricular ejection fraction.

While the study was underpowered for clinical outcomes, the investigators did observe significant decreases in cardiovascular hospitalization (p=0.0029), including heart-failure hospitalization (p=0.0002), and a trend for decreased all-cause hospitalization (p=0.0599).

“From a functional standpoint, both peak VO2and NYHA functional class appear to be favorably affected by the treatment,” write Nodari and colleagues. “These benefits are consistent with the decrease of the mean furosemide dose needed to maintain a congestion-free clinical status observed in the n-3 PUFA group and may account for the lower number of cardiovascular hospitalizations and hospitalizations for heart failure recorded during the 12-month follow-up period in these patients compared with those receiving placebo.”

Compared With GISSI-HF

In their editorial, Tang and Samara contrast the patient populations in this trial with GISSI-HF, a study that included almost 7000 patients with systolic heart failure (any LVEF and either etiology) to receive omega-3 PUFAs at 1 g daily or placebo and followed them for an average of four years. As reported by heartwire , treatment with the PUFA regimen reduced all-cause mortality 9% and all-cause mortality/hospitalization for cardiovascular causes 8%, a reduction that just reached statistical significance.

Comparatively, patients in the current study were given a significantly higher dose of n-3 PUFAs, approximately 5-g EHA/DHA for one month, followed by approximately 2 g for the remaining 11 months.  In addition, they had less advanced heart failure, as assessed by mean left ventricular ejection fraction and NYHA functional class, raising the possibility that n-3 PUFAs are “most effective when introduced early in the course of cardiomyopathy,” possibly because they are better able to exert an influence on viable myocardium, according to the editorialists. In sicker patients, they might already be past the point of no return, said Tang.

To heartwire , Tang noted that the heart-failure guidelines, despite the modest level of benefit observed in clinical trials, include a section on PUFAs. In patients with class NYHA 2–4 and reduced left ventricular ejection fraction, PUFAs may be considered to reduce mortality (strength of evidence B). Although it was a modest benefit, GISSI-HF was a large trial with a significant decrease in events, and no side effects were observed, and on that basis PUFAs should be considered, said Tang.

The timing of the two studies is 180 degrees from how research is usually done, added Tang. To have the GISSI-HF study followed by a mechanistic study, such as the one done by Nodari and colleagues, might have undermined some of the benefit observed in the morbidity and mortality trial.

“We first had the large trial and then we had this mechanistic study with a much less ill population–largely nonischemic, quite well-treated–with cardiac-specific end points and using a much larger dose,” said Tang. “In general, we test the hypothesis and, based on that, try to generalize who we should treat, but a lot of the exclusion and inclusion criteria are based on an educated guess. If we did this study before GISSI-HF, we might have seen a lot more positive results.”

Tang noted that assessing the benefit of omega-3 fatty acids in a real-world setting is difficult given the different doses available to consumers. Unless studied in a clinical trial, patients purchase PUFAs over the counter, and these supplements can have as little as 300 mg or less EHA/DPA per pill.

Nodari reports no conflicts of interest, while senior author Dr Mihai Gheorghiade (Northwestern University Feinberg School of Medicine, Chicago, IL), who presented the results at the HFSA late-breaking clinical-trials session, is a consultant for Bayer Schering Pharma, Debiopharm, Medtronic, Novartis, Otsuka Pharmaceuticals, Sigma-Tau Pharmaceuticals, Solvay Pharmaceuticals (now Abbott), and PeriCor Therapeutics and has received travel compensation from Bayer Schering Pharma, Novartis, and Sigma-Tau Pharmaceuticals. Tang reports consulting for Medtronic and St Jude Medical and receives research support from Abbott Laboratories, while Samara reports no conflicts of interest.

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