Gruppo Italiano per lo Studio della Sopravvivenza nell’Infarto Miocardico–Heart Failure: n-3 PUFA - GISSI-HF: n-3 PUFA Study

Description:

Although there are some laboratory and epidemiological data that suggest a beneficial effect of n-3 polyunsaturated fatty acids (PUFA) on ventricular function and sudden cardiac death, this has not been well studied in the setting of a randomized controlled trial. Accordingly, the GISSI-HF trial sought to study the efficacy of n-3 PUFA on mortality and morbidity in patients with symptomatic heart failure.

Hypothesis:

n-3 PUFA would be associated with lower mortality and morbidity compared with placebo in patients with symptomatic heart failure.

Study Design

Patients Enrolled: 6,975
NYHA Class: II (63.5%), III (33.9%), IV (2.6%)
Mean Follow Up: 3.9 years (median)
Mean Patient Age: 67 years
Female: 22
Mean Ejection Fraction: 33.1%

Patient Populations:

  • Age >18 years
  • Chronic symptomatic heart failure, defined as per European Society of Cardiology guidelines, provided it was measured within 3 months of enrollment
  • If EF >40%, then had to be admitted with heart failure at least once in the preceding year for heart failure

Exclusions:

  • Contraindication, existing indication, or hypersensitivity to n-3 PUFA therapy
  • Severe comorbidities precluding follow-up or requiring surgery
  • Acute coronary syndrome or cardiac procedure within the preceding 30 days
  • Planned cardiac surgery within 3 months
  • Significant liver disease
  • Pregnant or lactating women or women of childbearing potential who were not adequately protected against pregnancy

Primary Endpoints:

  • Time to death
  • Time to death or admission to hospital for cardiovascular causes

Secondary Endpoints:

  • Cardiovascular mortality
  • Cardiovascular mortality or all-cause hospital admission
  • Admission for heart failure, myocardial infarction, or stroke

Drug/Procedures Used:

n-3 PUFA 1 g daily (850-882 mg eicosapentaenoic acid and docosahexaenoic acid as ethyl esters in the average ratio of 1:1), or matching placebo

Concomitant Medications:

Angiotensin-converting enzyme inhibitor/angiotensin-receptor blocker (94%), beta-blockers (65%), spironolactone (39%), diuretics (90%), amiodarone (20%), and statin (23%)

Principal Findings:

A total of 6,975 patients were randomized, 3,494 to n-3 PUFA and 3,481 to placebo. About one-half of the patients had ischemic cardiomyopathy, and 29% had dilated cardiomyopathy. About 37% of the patients had New York Heart Association (NYHA) class III or IV symptoms, with a mean ejection fraction (EF) of about 33.1%; only about 9.4% of the patients had an EF >40%. About 49% had been hospitalized at least once for heart failure in the past year. About 12.8% of the patients had a pacemaker, and 7.2% had an implantable cardioverter defibrillator.

Although there was no difference in the unadjusted analysis between the n-3 PUFA and placebo arms for both primary endpoints—all-cause mortality (27.3% vs. 29.1%, p = 0.12), or all-cause mortality or admission for cardiovascular causes (57% vs. 59%, p = 0.06)—when adjusted for admission to the hospital for heart failure in the previous year, previous pacemaker, and the presence of aortic stenosis, both endpoints were significantly reduced in the n-3 PUFA arm compared with placebo (hazard ratio [HR] 0.91, 95.5% confidence interval [CI] 0.83-1.0; p = 0.041 for mortality, and HR 0.92, 99% CI 0.95-1.00; p = 0.009 for mortality or cardiovascular admission). This corresponded to an absolute risk reduction for mortality of about 1.8%. There was no difference between the two groups in the incidence of the first admission for heart failure (28% vs. 29%, p = 0.15), although there were fewer admissions for arrhythmia-related issues in the n-3 PUFA arm (3% vs. 4%, p = 0.013).

There was no difference in the incidence of sudden cardiac deaths or presumed arrhythmia-related deaths between the two arms. There were numerically more strokes in the n-3 PUFA arm compared with placebo (3.5% vs. 3.0%, p = 0.12).

By the end of the study, almost one-third of the patients in both arms had discontinued the study medication (28.7% vs. 29.6%, p = 0.45), although only 3% discontinued the medications permanently due to adverse reactions (2.9% vs. 3.0%, p = 0.87); the majority of them were gastrointestinal in nature.

Interpretation:

The results of the GISSI-HF trial demonstrate that 1 g per day of n-3 PUFA is associated with a small reduction in mortality (absolute risk reduction of 1.8%) and cardiovascular admissions in patients with predominantly systolic heart failure, when added to optimal medical therapy. The exact mechanism of this reduction is not very clear, although the investigators did note a beneficial effect of n-3 PUFA on admission due to arrhythmias in these patients, but not in sudden cardiac death or presumed arrhythmia-related deaths. The beneficial effect of n-3 PUFA in heart failure patients noted here is similar to that noted by the same investigators in a post-myocardial infarction population in the GISSI-Prevenzione (Prevention) study. Further studies are needed to corroborate these results in other patient populations, as well as to study the optimal duration and dose of this medication in these patients.

References:

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 31:[Epub ahead of print].

Effects of n-3 PUFA in 6,975 Patients With Chronic Heart Failure: The GISSI-HF Trial. Presented by Dr. Luigi Tavazzi at the European Society of Cardiology Congress, Munich, Germany, August/September 2008.

Clinical Topics: Arrhythmias and Clinical EP, Dyslipidemia, Heart Failure and Cardiomyopathies, Implantable Devices, SCD/Ventricular Arrhythmias, Lipid Metabolism, Nonstatins, Acute Heart Failure, Chronic Heart Failure

Keywords: Myocardial Infarction, Stroke, Fatty Acids, Omega-3, Docosahexaenoic Acids, Ventricular Function, Heart Failure, Systolic, Death, Sudden, Cardiac, Defibrillators, Implantable, Cardiomyopathy, Dilated, Eicosapentaenoic Acid


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