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 (early online publication) 31 August 2008; DOI:10.1016/S0140-6736(08)61239-8
GISSI-HF investigators. Effect of rosuvastatin in patients with chronic heart failure (the GISSI-HF trial): a randomised, double-blind, placebo-controlled trial. Lancet (early online publication) 31 August 2008; DOI:10.1016/S0140-6736(08)61240-4
Although confirmation in further trials is necessary, the GISSI-HF study suggests that omega-3 polyunsaturated fatty acids may provide a modest benefit in people with heart failure. However, no such benefit was seen for rosuvastatin in this group, supporting the results of a previous study (CORONA).
Prescribers should continue to follow the NICE guideline for the treatment of patients with heart failure. NICE make no specific recommendations about using omega-3 poyunsaturated fatty acid supplements (PUFA) for people with heart failure and despite this study, there is still insufficient evidence to justify its routine use. However, there would appear to be no harm in patients with heart failure taking omega-3 PUFA supplements, should they wish to do so, if they are unable to obtain sufficient PUFA from their diets (e.g. by eating oily fish).
The role of statins in heart failure remains controversial. If considered appropriate for use in people with heart failure (for example in those with co-existng ischaemic heart disease), a statin proven to improve patient-oriented outcomes in other patient groups, such as simvastatin 40 mg/day, should be used as first choice. As with other indications, rosuvastatin should only be used in the minority of patients who cannot tolerate any of the other statins.
What is the background to this?
Treatments such as ACE inhibitors and beta-blockers have been proven to improve the quality of life, reduce hospital admission and delay death in people with heart failure. Despite this, prognosis is often poor and other treatments that can be shown to significantly improve outcomes should be considered as welcome additions to existing evidence-based interventions. For further information on heart failure and its treatment see the heart failure section of NPC.
The GISSI-HF study evaluated, in a large group of patients with chronic heart failure, whether addition of omega (n)-3 PUFA or rosuvastatin provided any outcome benefits in addition to that obtained from their usual treatment.
What does this study claim?
The authors claim that omega-3 PUFA provides a small advantage in terms of mortality and admission to hospital for cardiovascular reasons compared with usual care. Significantly fewer patients receiving omega-3 PUFA died during the 3.9 year study compared with placebo (27% vs. 29% NNT=56) and died or were admitted to hospital for cardiovascular causes (57% vs. 59%, NNT= 44). The authors identified no clinical benefits for rosuvastatin in patients with heart failure.
How does this relate to other studies?
Prior to this study, no large randomised controlled trials (RCTs) have evaluated the effect of omega-3 PUFA on outcomes in patients with heart failure. The only large RCT of a statin in patients with heart failure was the CORONA study – this failed to show any significant difference for rosuvastatin from placebo with regard to its primary endpoint (a composite of cardiovascular death, non-fatal myocardial infarction or non-fatal stroke).
This study found a small benefit for omega-3 PUFA over placebo in reducing important clinical outcomes in a large Italian population when added to other treatments for heart failure. The dietary habits of the patients included in the study, and in particular the amounts of dietary PUFA, was not reported. It is not known what benefits would have been obtained in people who were already receiving an adequate amount of PUFA through their normal diet. NICE make no specific recommendations about using PUFA in their current guidance and on the basis of this one study, it is not possible to recommend the routine use of PUFA supplements in patients with heart failure. Further studies are required in a population more typical of a UK population. However, as omega-3 PUFA appears to be well tolerated, there would seem no reason why patients should not take a PUFA supplement if they wish to do so, especially if patients are unable to obtain the required amount of PUFA from their diet (e.g. from eating oily fish).
As with the CORONA study, adding rosuvastatin to established therapies in a similar population of patients with heart failure who were at high risk of CV events, did not reduce the risk of the combined outcome of death from cardiovascular causes non-fatal MI or non-fatal stroke, compared with placebo. These trials do not provide sufficient evidence to discourage prescribers from continuing to use evidence-based statins, such as simvastatin 40 mg, in people with heart failure and co-existing ischaemic heart disease (such as angina or history of MI). However, it should make them pause before using rosuvastatin ahead of such statins in this or other indications, except in the minority of patients who cannot tolerate any other statin.
Patients – this was a two-armed, randomised, double-blind, placebo-controlled trial of adults (mean age 67 or 68) with confirmed chronic heart failure (NYHA class II to IV).
Interventions/comparators – patients were randomised to treatment with 1g omega-3 PUFA (850–882 mg eicosapentaenoic acid and docosahexaenoic acid as ethyl esters in the average ratio of 1:1.2) or matching placebo in the omega -3 PUFA arm, and rosuvastatin 10mg daily or placebo in the statin arm. Any other standard treatment for heart failure was given as appropriate.
Outcomes – primary outcomes were time to death, and time to death or admission to hospital for cardiovascular reasons. Median duration of follow-up was 3.9 years.
Allocation was concealed.
Results – of the 7,046 in the omega-3 PUFA arm of the study, 955 (27%) patients died from any cause in the PUFA group and 1,014 (29%) in the placebo group (adjusted hazard ratio [HR] 0.91; 95.5% CI, 0.833 to 0.998; P=0.041). There were 1,981 vs. 2,053 respectively who died or were admitted to hospital for cardiovascular reasons (57% vs. 59%; adjusted HR 0.92; 99% CI, 0.849 to 0.999; P=0.009). There were no significant differences in the proportions of patients who discontinued study treatment due to adverse reactions (omega-3 PUFA 2.9%; placebo 3.0%; P=0.87).
Of 4,574 in the statin arm of the study, there were 657 (29%) deaths from any cause in the rosuvastatin group and 644 (28%) in the placebo group (adjusted HR, 1.00; 95.5% CI, 0.898 to 1.122; P=0.943). There were 1,305 vs. 1,283 respectively who died or were admitted to hospital for cardiovascular reasons (57% vs. 56%; adjusted HR 1.01; 99% CI, 0.908 to 1.112, p=0.903). No differences in the incidences of adverse effects were reported. There were no significant differences in the proportions of patients who discontinued study treatment due to adverse reactions (rosuvastatin 4.6%; placebo 4.0%; P=0.36). There was a significant reduction in cholesterol levels in the statin group (LDL-cholesterol 3.16 to 2.15mmol/l from baseline to 1 year) with no significant change in the placebo group. All other secondary outcomes were not significantly different between the two groups.
The study was sponsored by the Società Prodotti Antibiotici (Italy), Pfizer, Sigma Tau and AstraZeneca.