Dr Alan Begg discusses results of the GISSI trials and the use of omega-3-acid ethyl esters for prevention and treatment of CHD


The The low rate of coronary heart disease (CHD) seen in the Eskimo population seems to demonstrate the apparent benefits of a diet rich in fish oils.1,2 However, the direct mechanism for this is still not clear.

Diet rich in fish

The main trial to have shown the benefit of a diet rich in oily fish was the Diet and Reinfarction Trial (DART), published in 1989.3 Patients who had suffered a myocardial infarction (MI) ate two portions of oily fish weekly and were compared with groups receiving no dietary advice, or two other different dietary regimens. Patients who could not tolerate an oily fish diet were given a total of 1.5 g/day of omega-3-acid ethyl ester capsules. The trial found that after 2 years the overall advice to eat fatty fish was associated with a 29% reduction in all-cause mortality, and the significance of the result was not affected after adjusting for ten potential confounding factors.

GISSI-Prevenzione trial

In the Gruppo Italiano per lo Studio della Sopravvivenza nell’Infarto-Prevenzione (GISSI-P) trial, which recruited 11,324 patients who had experienced an MI within the previous 3 months, one of the treatment arms compared those taking a dietary supplement of 1 g daily of omega-3-acid ethyl esters with those taking no supplementation.2 Prior to randomisation, 14% of participants had impaired left ventricular function with an ejection fraction of <40%, and more than 70% reported eating fish at least once per week.2

Substantial benefit from lower mortality rates was seen in patients taking the omega-3-acid ethyl esters supplement, which was demonstrated by a 20% decrease in total deaths, a 30% decrease in cardiovascular deaths (p=0.02), and a 45% reduction in sudden deaths (p=0.01). There was no difference across the groups for non-fatal cardiovascular events but the trial did also show the safety and tolerability of this therapy.2

GISSI-Heart Failure trial

Recently published trial data has again shown the benefits of fish oil supplements in patients with heart disease. The GISSI-Heart Failure (GISSI-HF) trial4 randomised 7046 eligible patients (6975 were analysed) with chronic heart failure classified according to the New York Heart Association grades II–IV, irrespective of the cause of the heart failure and irrespective of the left ventricular ejection fraction (LVEF), to receive 1 g daily of omega-3-acid ethyl esters or matching placebo.4 The LVEF was required to have been measured within the previous 3 months before enrolment in the trial, and if the LVEF was >40% then the patient must have been admitted to hospital with heart failure during the year prior to enrolment. Of those in the omega-3-acid ethyl esters treatment arm, 93.5% were previously taking an angiotensin-converting enzyme (ACE) inhibitor or angiotensin-receptor blocker and 65.1% were on a beta blocker.

Another arm of the trial examined the outcomes in patients with heart failure treated with a statin but the main benefit shown was that simple fish oil supplements can benefit patients with heart failure. The results revealed a 9% reduction in mortality from all causes, and an 8% reduction in all-cause mortality or hospital admission with cardiovascular problems. This overall benefit was noted to be smaller than expected as a 15% relative risk reduction had been assumed when the trial was planned.4 However, in absolute terms, the risk reduction for all-cause mortality was 1.8% (95% confidence interval [CI], 0.3–3.9), meaning that 56 patients need to be treated for 3.9 years to avoid one death, and 44 patients need to be treated over the same period to avoid a death or hospital admission from a cardiovascular cause (absolute risk reduction [ARR] 2.3%, 95% CI, 0.0–4.6).4 This modest benefit was not apparent initially as the Kaplan-Maier curves only started to diverge after 2 years of follow-up.

Of the ARR on total mortality the greatest proportion was assumed to be due to an arrhythmic death and half the ARR on first admission to hospital for cardiovascular reasons was calculated to be due to a reduction of admissions for ventricular arrhythmias. Little benefit was seen in atherothrombotic events, such as MI and stroke. Side-effects were mainly described as being due to a gastrointestinal disorder, although numbers discontinuing study treatment were only slightly larger in the active treatment group (96 versus 92).4 It has been postulated that the treatment may have an effect on the mechanisms leading to a progression of heart failure by means of a reduction of vascular resistance, attenuation of vasoconstrictive responses to angiotensin II, improvement of left ventricular diastolic function, and reduction of hypertension-related ventricular hypertrophy.

Dietary advice in patients with heart disease

An important aspect of the NICE guideline on secondary prevention after an MI is that all patients should be given advice on healthy eating, with individual consultations to discuss their current eating habits and advice on how these can be improved.5 A Mediterranean-style diet is advised, with more bread, fruit, vegetables, fish, less meat, and the replacement of butter and cheese with products based on vegetable and plant oils. This advice needs to be extended to the whole family. Patients are advised to consume at least 7 g of omega-3 fatty acids from a total of 2–4 portions of oily fish per week. However, a supplement of at least 1 g daily of omega-3-acid fatty acids should be considered for patients who have had an MI within 3 months and who are not achieving this level of oily fish intake.5 Supplements should be continued for up to 4 years in line with the evidence from the GISSI-P trial. The NICE guideline development group felt that this approach was cost-effective expressed as a quality adjusted life year when compared with no treatment.5,6

What this means for general practice

The benefits of supplementation with omega-3-acid ethyl esters have been demonstrated in patients after an MI and also in those with heart failure from any cause. Although at present this cannot be regarded as routine treatment for heart failure, the results from the GISSI-HF paper may be seen to reinforce the advice in the NICE guideline to prescribe the supplement for post-MI patients in addition to their current therapies, bearing in mind that CHD is the commonest cause of heart failure.7

It is likely that supplementation with omega-3 fatty acids in ethyl ester form will, in the future, be seen as appropriate additional therapy, with additive benefits, for patients with heart failure once the use of other therapies such as ACE inhibitors and beta blockers has been maximised.

  1. Bang H, Dyerberg J, Hjorne N. The composition of food consumed by Greenland Eskimos. Acta Med Scand 1976; 200 (1–2): 69–73.
  2. GISSI-Prevenzione Investigators (Gruppo Italiano per lo Studio della Sopravvivenza nell’Infarto Miocardico). Dietary supplementation with n-3 polyunsaturated fatty acids and vitamin E after myocardial infarction: results of the GISSI-Prevenzione trial. Lancet 1999; 354 (9177): 447–455.
  3. Burr M, Fehily A, Gilbert J et al. Effects of changes in fat, fish, and fibre intakes on death and myocardial reinfarction: Diet and Reinfarction Trial (DART). Lancet 1989; 2 (8666): 757–761.
  4. 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; 372 (9645): 1223–1230.
  5. National Institute for Health and Care Excellence. MI: Secondary prevention in primary and secondary care for patients following a myocardial infarction. Clinical Guideline 48. London: NICE, 2007.
  6. Quilici S, Martin M, McGuire A, Zoellner Y. A cost-effectiveness analysis of n-3 PUFA (Omacor) treatment in post-MI patients. Int J Clin Pract 2006; 60 (8): 922–932.
  7. McDonagh A, Morrison E, Lawrence A. Symptomatic and asymptomatic left ventricular systolic dysfunction in an urban population. Lancet 1997; 350 (9081): 829–833.G