Relative risk of mortality was reduced 9%.

BY BRUCE JANCIN (Denver Bureau)

MUNICH — Supplementation with a single daily low-dose fish oil capsule in patients with chronic heart failure resulted in modest but clinically meaningful reductions in mortality and cardiovascular hospitalization in a nearly 7,000-patient randomized trial presented at the annual congress of the European Society of Cardiology.

In a surprise finding, the same Italian study, known as GISSI-HF, concluded that rosuvastatin at 10 mg/day had no effect on mortality or hospital admission for cardiovascular events, suggesting that patients with chronic heart failure should not be started on statins (see accompanying story p. 10).

In GISSI-HF, 6,975 patients with New York Heart Association class II-IV chronic heart failure were randomized in double-blind fashion to 1 g/day of omega-3 polyunsaturated fatty acids (n-3 PUFA) in the form of eicosapentaenoic acid and docosahexaenoic acid or to placebo. The participants were on standard background therapy with the agents of proven efficacy in heart failure.

All-cause mortality after a median 3.9 years of follow-up was 27% in the n-3 PUFA group and 29% in controls, for a significant adjusted 9% relative risk reduction in the n-3 PUFA group, reported Dr. Luigi Tavazzi, chair of the GISSI-HF steering committee and professor of cardiology at the University of Pavia (Italy).

The co-primary end point in GISSI-HF was death or cardiovascular hospitalization, which occurred in 57% of the n-3 PUFA cohort and in 59% of those on placebo, for an 8% relative risk reduction that did not reach statistical significance.

In all, 44 patients needed to be treated with n-3 PUFA for 3.9 years in order to prevent one additional death or cardiovascular hospitalization, whereas 56 patients needed to be treated in order to prevent one death. Those are fairly high numbers, but it’s a trouble-free therapy, according to Dr. Tavazzi.

Among the nearly 5,000 patients who remained compliant with their treatment for the full study duration, the n-3 PUFA benefits were more pronounced: an absolute 3% difference in mortality equating to a 14% relative risk reduction, compared with placebo, and a 12% relative risk reduction in the combined end point, he added.

The benefits of n-3 PUFA supplementation were seen across the board regardless of the cause of heart failure, which was ischemia in half of subjects, dilated cardiomyopathy in 30%, and hypertension in 15%. The benefits were also consistent in the 9% who had heart failure with preserved systolic function and in the vastly greater number of patients with a low ejection fraction.

The study was undertaken in large part based upon the earlier favorable GISSI-Prevenzione trial by the same group, which showed markedly reduced mortality—mainly because of a decrease in sudden death—in patients randomized to 1 g/day of n-3 PUFA after an acute MI (Lancet 1999;354:447–55). In addition, numerous epidemiological studies have linked fish consumption to a reduced risk of cardiovascular death.

If you prescribe a ‘new drug forever, you need to have a very well-tolerated dose, and this was exceptionally well tolerated.’ DR. TAVAZZI

Dr. Tavazzi attributed the high long-term compliance rate with the n-3 PUFA regimen in GISSI-HF with the simple, once-daily, 1-g dosing, which was essentially devoid of side effects.

“If you take a large population with many elderly people, who are often frail, and all of them are already on many heart failure medications, and then you prescribe the new drug forever, you need to have a very well-tolerated dose, and this was exceptionally well tolerated,” he said.

Other studies of n-3 PUFA supplementation in cardiovascular medicine have used daily dosages of up to 24 g/day, with 3–6 g/day being most typical—and they’ve generally been brief trials that begged the issue of long-term compliance, the cardiologist continued.

“In the last 10 years or so, no new life-prolonging drugs have appeared on the scene in heart failure. The therapeutic approach to chronic heart failure has been rather static. A new drug, even if it gives only moderate benefit on top of optimal therapy, like n-3 PUFA, might be important for physicians to consider,” he added.

Dr. Michel Komajda predicted that the GISSI-HF findings could end up having a significant impact on daily practice. “Those of us who have the responsibility to draw up the next version of chronic heart failure guidelines will pay a lot of attention to the results of the GISSI-HF trial,” said Dr. Komajda of Pierre and Marie Curie University, Paris. Nevertheless, he added, there remains “a bit of mystery” regarding the mechanism of benefit. And the optimal dosage has yet to be defined.

GISSI-HF was simultaneously published online (Lancet 2008 Aug. 31 [doi:10.1016/50140–6736(08)61239–8]).

The trial was funded by the Società Prodotti Antibiotici S.p.A., Pfizer Inc., Sigma-Tau Pharmaceuticals Inc., and AstraZeneca, which provided Dr. Tavazzi with research support and honoraria.


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