Fast track — ArticlesEffect of n-3 polyunsaturated fatty acids in patients with chronic heart failure (the GISSI-HF trial): a randomised, double-blind, placebo-controlled trial
Introduction
Despite the impressive therapeutic advances made over the past 15 years, heart failure remains one of the main components of the overall burden of cardiovascular morbidity and mortality.1 Finding innovative ways to prevent cardiovascular death, including sudden cardiac death which accounts for up to half of fatal events, is a major challenge.
The results of the Gruppo Italiano per lo Studio della Sopravvivenza nell'Infarto miocardico (GISSI)-Prevenzione trial2 showed a lower mortality rate in patients taking n-3 polyunsaturated fatty acids (PUFA) after myocardial infarction than in those allocated to the control group. This finding was mainly due to the prevention of sudden death,2, 3, 4, 5, 6 and provided the first clinical controlled confirmation of the possible antiarrhythmic activity of n-3 PUFA. The properties of n-3 PUFA, suggested by observational studies,7, 8, 9, 10 have been extensively documented in cellular and animal models.11 The results of trials in primary and secondary prevention of coronary heart disease have been reviewed and overall suggest that n-3 PUFA is associated with a 20% relative risk reduction of death in high-risk populations, although their efficacy in primary prevention cannot yet be assessed since controlled trials of adequate size in primary prevention have not yet been terminated.7, 10 The potential antiarrhythmic efficacy of n-3 PUFA has been mainly assessed with controversial results in small trials with patients with implanted cardioverter defibrillators.12, 13, 14, 15
No large-scale trial has so far assessed the efficacy of n-3 PUFA in heart failure. Two reasons lent support to the interest of testing n-3 PUFA in a large population of patients with heart failure: first was the large body of experimental evidence for the favourable effects that n-3 PUFA exert on inflammatory processes (including reduction of endothelial activation and cytokine production), platelet aggregation, blood pressure, heart rate, ventricular function, and autonomic tone;16, 17, 18, 19, 20, 21, 22 and second was the safety and tolerability profile of the dose tested in the GISSI-Prevenzione trial,2 which was not expected to cause problems in patients with heart failure who were already pharmacologically treated for their index clinical disorder.
In line with previous GISSI studies,23 a large-scale, randomised, placebo-controlled trial was proposed to a nationwide representative network of hospital and ambulatory-care facilities to test the hypothesis that n-3 PUFA could improve morbidity and mortality of patients with symptomatic heart failure of any cause and with any level of left ventricular ejection fraction (LVEF).
Section snippets
Patients
We did a randomised, double-blind, placebo-controlled, multicentre study, involving 326 cardiology and 31 internal medicine centres in Italy (figure 1). The design of the GISSI-HF trial has been described in detail elsewhere, including the randomisation, monitoring, and follow-up procedures.24
Eligible patients were men and women aged 18 years or older, with clinical evidence of heart failure of any cause that was classified according to the European Society of Cardiology (ESC) guidelines as New
Results
7046 patients were randomly assigned (figure 1). We disqualified information from 71 patients at one site after randomisation, before unblinding, because the adequacy of the informed consent process and quality of data could not be ensured. Of the remaining 6975 patients, 3494 were assigned to receive n-3 PUFA and 3481 to placebo. The follow-up was concluded on March 31, 2008. The median duration of follow-up was 3·9 years (IQR 3·0–4·5).
Table 1 shows the baseline characteristics of all
Discussion
Our study shows that the long-term administration of 1 g per day n-3 PUFA was effective in reducing both all-cause mortality and admissions to hospital for cardiovascular reasons. Although this moderate benefit was smaller than was expected, we should note that it was obtained in a population already treated with recommended therapies, was consistent across all the predefined subgroups, and was further supported by the findings of the per-protocol analysis. We noted no adverse effects in the
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