Effect of N-33 Polyunsaturated Fatty Acids in Heart Failure

Abstract & Commentary

By Michael H. Crawford, MD

Source: GISSI-HF Investigators. Effect of n-3 polyunsaturated fatty acids in patients with chronic heart failure (the GISSI-HF trial): a randomised, double-blind, placebo-controlled trial. Lancet. 2008 Aug 29. [Epub ahead of print]

The Gruppo Italiano per lo Studio della Sopravvivenza nell'Infarto miocardico (GISSI)-Prevenzione trial demonstrated a lower mortality rate in post myocardial infarction patients treated with n-3 polyunsaturated fatty acids (PUFA) vs controls, which was mainly due to a reduction in sudden death. Since up to half of the deaths in chronic heart failure patients are sudden, the GISSI-heart failure trial was proposed to test the hypothesis that PUFA could reduce morbidity and mortality in symptomatic heart failure patients. The 7046 patients studied had NYHA class 11-IV heart failure of any etiology and with any left ventricular ejection fraction. The patients were randomly assigned to placebo or a 1 g capsule of PUFA in a double-blind fashion. The patients were also assigned to rosuvastatin 10 mg/day or a placebo. The primary co-endpoints were time to death and time to death or hospital admission for cardiovascular reasons. Several secondary endpoints and subgroups analyses were prespecified.

Results: Median follow-up was 3.9 years. After two years, the primary co-endpoints began to diverge in the two groups. Death occurred in 29% of the placebo patients and 27% of the PUFA group (adjusted HR 0.91, 95% CI 0.83-0.98, p = 0.04); death or hospital admission for cardiovascular disease occurred in 59% of the placebo groups and 57% of the PUFA group (HR 0.92, 0.85-0.99, p = 0.009). PUFA therapy resulted in significantly lower rates of cardiovascular death (20% vs 22%) and admission for cardiovascular reasons (47% vs 49%). Rates of acute myocardial infarction and stroke were not different. Worsening heart failure, followed by arrhythmias, were associated with most of the deaths, but were not different between the groups. No subgroup had a different response to PUFA. There was no difference in the number of patients discontinuing treatment for adverse effects between the two groups (3% in both). The authors concluded that treatment of heart failure patients with PUFA is safe and can provide a small benefit in morbidity and mortality.


The demonstrated beneficial effects of PUFA were modest and did not emerge until after two years of therapy. However, this was on top of optimal medical therapy for heart failure which included ACE1/ARBs in 93%, beta blockers in 65%, and spironolactone in 39%. Also, other therapies for heart failure have taken time to exhibit their benefits. Would a higher does of PUFA been more beneficial? This is unknown, but the 1 g dose used was well tolerated, with 3% discontinuing therapy in each group, both for gastrointestinal side effects.

Examination of secondary endpoint and subgroup results suggests that PUFA beneficially affects the progression of heart failure and, for this reason or others, reduces sudden arrhythmic death. Interestingly, there was little apparent effect on atherothrombotic events such as myocardial infarction and stroke. Also, the rosuvastatin arm of the study failed to show any benefits (Lancet. 2008;372:1231-39). These data suggest that therapies that work for atherosclerotic cardiovascular disease may have little impact once heart failure is present. Clearly, patients with non-ischemic heart failure do not need statins. Whether to discontinue statins in ischemic patients once they have heart failure is unknown, but 10 mg of rosuvastatin was well tolerated.

Only 10% of the patients in GISSI-HF had normal left ventricular ejection fractions, so conclusions about heart failure patients with preserved left ventricular systolic function are difficult to separate out. At this point, it appears that all patients with symptomatic heart failure of any cause and with any ejection fraction can benefit from daily PUFA supplementation.