Munich, Germany - Omega-3 fatty-acid supplementation improves morbidity and mortality in symptomatic heart-failure patients, while statins failed to have any beneficial effect in the same group of patients, two new studies have shown [1,2]. The long-term administration of omega-3 fatty acids reduced all-cause mortality and admission to the hospital for cardiovascular reasons, while there was no effect on these end points with 10-mg rosuvastatin (Crestor, AstraZeneca).

The Gruppo Italiano per lo Studio della Sopravvivenza nell'Infarto Miocardico Heart Failure (GISSI-HF) trial—which includes two nested studies designed to test the two hypotheses—was presented today here at the European Society of Cardiology (ESC) Congress 2008 and published online in the Lancet.

Speaking to the 9% reduction in all-cause mortality with omega-3 fatty acids in the Lancet, the GISSI-HF investigators write: "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."

Chair of the GISSI-HF steering committee, Dr Luigi Tavazzi (Fondazione IRCCS Policlinico San Matteo, Pavia, Italy), who presented the omega-3 fatty-acid data to the media during an ESC press conference, said the treatment is an "effective, safe, simple, and cheap" option for patients with chronic heart failure. In an editorial accompanying the published studies [3], Dr Gregg Fonarow (University of California, Los Angeles) echoed the sentiment, writing that while "questions remain about the mechanism of action, optimum dosing, and formulation, supplementation with n-3 polyunsaturated fatty acids [PUFA] should join the short list of evidence-based life-prolonging therapies for heart failure."

The GISSI-HF project is a large-scale, randomized, double-blind study designed to investigate the effects of omega-3 fatty acids and statin therapy on mortality and morbidity in patients with symptomatic heart failure. In the PUFA study, investigators enrolled patients with chronic heart failure—NYHA class 2-4 regardless of cause and left ventricular ejection fraction—and randomized them to treatment with n-3 PUFA 1 g daily or placebo. Patients were followed for nearly four years, with the co-primary end points being death and death or admission to the hospital for cardiovascular reasons.

After 3.9 years of follow-up, treatment with the omega-3 fatty acids reduced the risk of mortality by 9% and mortality and admission to the hospital for cardiovascular causes by 8%. The absolute reduction in risk was small, just 1.8%, but investigators report that 56 patients would need to be treated to avoid one death and 44 patients would need to be treated to avoid one death or admission for cardiovascular reasons. A per-protocol analysis that included only patients who remained on treatment for the study duration confirmed the overall findings, showing that treatment cut the absolute risk by 3.3% compared with placebo, or a 14% relative risk reduction.

Speaking to the media, Tavazzi said the advantage of n-3 PUFA, as documented by the primary end points, is that they appear to have a beneficial effect on the mechanisms leading to the progression of heart failure. Although the exact reasons are unknown, omega-3 fatty acids could possibly exert favorable effects on inflammatory processes, such as reductions in endothelial activation and cytokine production, as well as influence platelet aggregation, blood pressure, heart rate, ventricular function, and autonomic tone.

Asked about the differences in outcomes in the GISSI Prevenzione trial, a study where there was a favorable effect of omega-3 fatty acids in patients with MI, with n-3 PUFA supplementation reducing the risk of mortality 21%, Tavazzi told heartwire that fatty acids mainly influenced the risk of sudden death in the post-MI patients. In GISSI-HF, on the other hand, the risk of sudden death was not significantly different between the treated and untreated patients, suggesting the "mechanisms of action in heart-failure patients are broader than post-MI patients."

Dr Michel Komajda (Université Pierre et Marie Curie, Paris, France), who commented on the study during the late-breaking clinical trials sessions, said there "is still a bit of a mystery" regarding the observed benefit, especially as it relates to the mechanism of action. Moreover, the study included few patients with preserved ejection fractions, so further study will be needed to determine whether the benefit extends to them as well.

Cochair of the GISSI-HF steering committee, Dr Gianni Tognoni (Istituto di Ricerche Farmacologiche Mario Negri, Milan), presented the data on chronic heart-failure patients treated with rosuvastatin 10 mg. Patients were also followed for nearly four years, with the co-primary end points also being time to death and time to death or admission to the hospital for cardiovascular reasons.

After 3.9 years, there was no significant difference between arms in either of the two co-primary end points. The findings were consistent across all secondary end points as well as consistent across every subgroup analyzed, including older patients, those with left ventricular ejection >40%, and those with and without diabetes. Treatment with rosuvastatin decreased LDL cholesterol 27% at three years—down from 123 mg/dL at baseline to 90 mg/dL—and an exploratory analysis revealed no treatment effect based on achieved LDL-cholesterol reductions.

Speaking to the media, Tognoni said that the prescription of rosuvastatin or any statin to patients with heart failure should not be considered because the use of the cholesterol-lowering drugs does not translate into any clinically meaningful benefit for heart-failure patients. In his editorial, Fonarow comments that the findings from GISSI-HF, alongside the Controlled Rosuvastatin in Multinational Trial in Heart Failure (CORONA), "establish that, although statin therapy lowers concentrations of LDL cholesterol, is well tolerated, and seems reasonably safe, it does not produce meaningful improvements in survival in patients with chronic heart failure."

In CORONA, presented and published in November 2007, treatment with rosuvastatin had no significant effect on cardiovascular outcomes, as measured by the primary-end-point composite of CV death, nonfatal MI, or stroke. It did, however, significantly reduce the number of hospitalizations from CV causes and from heart failure. Commenting on the findings during the late-breaking clinical-trials session, Dr Philip Poole-Wilson (Imperial College London, UK) said GISSI-HF is an important study in light of the CORONA findings.

"What this study has done is extend what we knew from CORONA, a study where more patients had severe heart failure, to those with less severe heart failure," he said. "To that extent, the two trials are really complementary."

Poole-Wilson said that GISSI-HF is likely to generate disappointment among clinicians, as the results of the study, in light of observational and meta-analyses data, were expected to be positive. When the trial was designed, some even expressed concern that it was unethical to randomize heart-failure patients to placebo because they were so confident of the benefit of statin therapy in this patient population. The results, he said, ultimately should humble researchers, especially as they serve as reminder that medical decisions should be guided "science, and not strongly held opinion."

In terms of why the study failed to show a beneficial effect on clinical outcomes, the GISSI-HF investigators note that treatment with rosuvastatin reduced LDL cholesterol as well as high-sensitivity C-reactive protein (CRP) levels. "These effects might no longer affect the progression of coronary artery disease in patients with ischemic heart failure, perhaps because their effect is attenuated by a biological milieu not favoring the progression of coronary artery disease," they write in the Lancet. In his editorial, Fonarow states that once heart failure is established, statins may not allow patients to escape the underlying heart-disease process.

The GISSI studies are a collaboration of the Mario Negri Institute and the Associazione Nazionale dei Medici Cardiologi Ospedalieri. The GISSI-HF studies are sponsored by the Societa Prodotti Antibiotici, Pfizer, Sigma Tau, and AstraZeneca.

Sources

1) GISSI-HF investigators. Effect of n-3 polyunsaturated fatty acids in patients with chronic heart failure (the GISSI-HF trial): a randomized, double-blind, placebo-controlled trial. Lancet 2008; DOI: 10.1016/S0140-6736(08)61241-6.

2) GISSI-HF investigators. Effect of rosuvastatin in patients with chronic heart failure (the GISSI-HF trial): a randomized, double-blind, placebo-controlled trial. Lancet 2008; DOI: 10.1016/S0140-6736(08)61241-6.

3) Fonarow GC. Statins and n-3 fatty acid supplementation in heart failure. Lancet 2008; DOI: 10.1016/S0140-6736(08)61239-8.