• All-cause mortality [ Time Frame: from enrollment to 1252 deaths in R2 arm ] [ Designated as safety issue: No ]
• All cause mortality or hospitalizations for any reason [ Time Frame: from enrollment to 1252 deaths ] [ Designated as safety issue: No ]

•  All-cause mortality at the end of follow-up period
•  All cause mortality or hospitalizations for any reason at the end of follow-up period
• Since the trial is event driven, the follow-up period will be completed when 1252 deaths
• (number needed to allow a reliable evaluation of the efficacy of tested drugs for both R1 and R2) will occur.

• Cardiovascular mortality [ Time Frame: from enrollment to 1252 deaths in R2 arm ] [ Designated as safety issue: No ]
• Cardiovascular mortality or hospitalization for heart failure or for any reasons [ Time Frame: from enrollment to 1252 deaths in R2 arm ] [ Designated as safety issue: No ]
• Sudden cardiac death [ Time Frame: from enrollment to 1252 deaths in R2 arm ] [ Designated as safety issue: No ]
• Hospitalizations for any reasons [ Time Frame: from enrollment to 1252 deaths in R2 arm ] [ Designated as safety issue: No ]
• Hospitalization for Cardiovascular reasons [ Time Frame: from enrollment to 1252 deaths in R2 arm ] [ Designated as safety issue: No ]
• Hospitalization for congestive heart failure [ Time Frame: from enrollment to 1252 deaths in R2 arm ] [ Designated as safety issue: No ]
• Miocardial infarction [ Time Frame: from enrollment to 1252 deaths in R2 arm ] [ Designated as safety issue: No ]
• Stroke [ Time Frame: from enrollment to 1252 deaths in R2 arm ] [ Designated as safety issue: No ]

INTRODUCTION While pharmacological treatments specifically targeted to the cardio-circulatory system have been largely investigated, scanty controlled data are available concerning the role of dietary and metabolic approaches in the management/outcome of patients with heart failure. A large scale, randomized, clinical trial is proposed to test the effects of (a) n-3 PUFA and (b) a lipid lowering agent on top of the best recommended treatments for heart failure.

STUDY DESIGN

The GISSI-HF is a prospective, multicenter, randomized, double blind, placebo controlled study, with randomized allocation of patients with a clinical diagnosis of heart failure to:

Randomization 1 (R1): n-3 PUFA 1 g daily vs corresponding placebo; Randomization 2 (R2): rosuvastatin 10 mg daily vs corresponding placebo.

OBJECTIVES OF THE STUDY PRIMARY OBJECTIVES

To demonstrate that, in patients with heart failure treated at the best of recommended therapies, long term administration of (a) n-3 PUFA, (b) rosuvastatin is more effective than the corresponding placebo in the reduction of:

• All-cause mortality
• All-cause mortality or hospitalizations for cardiovascular reason

OTHER END-POINT MEASURES OF EFFICACY

To assess that long term administration of (a) n-3 PUFA, (b) rosuvastatin is more effective than corresponding placebo in the reduction of:

• Cardiovascular mortality
• Cardiovascular mortality or hospitalizations for any reason
• Sudden cardiac death
• Hospitalizations for any reason
• Hospitalizations for cardiovascular reasons
• Hospitalizations for congestive heart failure
• Myocardial infarction
• Stroke

The Protocol is sponsored by an independent organization and partially supported by: AstraZeneca, Società Prodotti antibiotici, Sigma Tau, Pfizer

• Drug: n-3 PUFA
• Drug: Rosuvastatin
• Drug: Placebo

• Experimental: N-3PUFA
• Experimental: Rosuvastatin

• 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 Aug 29; [Epub ahead of print]
• Gissi-Hf Investigators. Effect of rosuvastatin in patients with chronic heart failure (the GISSI-HF trial): a randomised, double-blind, placebo-controlled trial. Lancet. 2008 Aug 29; [Epub ahead of print]
• Tavazzi L, Tognoni G, Franzosi MG, Latini R, Maggioni AP, Marchioli R, Nicolosi GL, Porcu M; GISSI-HF Investigators. Rationale and design of the GISSI heart failure trial: a large trial to assess the effects of n-3 polyunsaturated fatty acids and rosuvastatin in symptomatic congestive heart failure. Eur J Heart Fail. 2004 Aug;6(5):635-41.
• Maggioni AP, Fabbri G, Lucci D, Marchioli R, Franzosi MG, Latini R, Nicolosi GL, Porcu M, Cosmi F, Stefanelli S, Tognoni G, Tavazzi L; GISSI-HF Investigators. Effects of rosuvastatin on atrial fibrillation occurrence: ancillary results of the GISSI-HF trial. Eur Heart J. 2009 Oct;30(19):2327-36. Epub 2009 Aug 30.

Inclusion Criteria:

• Clinical evidence of heart failure according to the European Society of Cardiology guidelines (New York Heart Association class II-IV) (32)
• Any left ventricular Ejection Fraction (EF) measured within 3 months from enrolment (if EF% >40%, at least 1 hospital admission for Congestive Heart Failure(CHF) in the previous year)
• No age limits
• Any etiology
• Informed consent (obtained before any study specific procedure)

Exclusion Criteria:

COMMON EXCLUSION CRITERIA (R1=n-3 PUFA vs placebo and R2=rosuvastatin vs placebo):

• Acute Myocardial Infarction, unstable angina or revascularization procedure within 1 month;
• planned cardiac surgery, expected to be performed within 3 months;
• congenital or primary valvular etiology;
• known hypersensitivity to study treatments;
• significant liver disease;
• pregnant or lactating women or women of childbearing potential who are not protected from pregnancy by an accepted method of contraception;
• any condition that in the opinion of the investigator would jeopardize the evaluation of efficacy or safety or be associated with poor adherence to the protocol;
• presence of any non-cardiac disease (e.g. cancer) that is likely to significantly shorten life expectancy;
• treatment with any investigational agent within 1 month before randomization;
• patients already on treatment with n-3 PUFA or statin for whom the prescription is confirmed.

EXCLUSION CRITERIA FOR R2 (statin hypothesis):

• current serum creatinine level >2.5 mg/dL;
• current ALT, AST level >1.5 times the upper normal limit;
• current CPK upper normal limits.