Title: Gruppo Italiano per lo Studio della Sopravvivenza nell’Infarto Miocardico–Heart Failure: n-3 PUFA (GISSI-HF: n-3 PUFA Study — Presented at ESC 2008)
Trial Sponsor: Società Prodotti Antibiotici (SPA; Italy), Pfizer, Sigma Tau, and AstraZeneca
Year Presented: 2008
Year Published 2008
Topic(s): General Cardiology, Heart Failure/Transplant
Summary Posted: 8/31/2008
Writer: Dharam J Kumbhani, M.D., S.M.
Author Disclosure: This author has nothing to disclose.
Reviewer: Deepak L. Bhatt, M.D., F.A.C.C.
Author Disclosure: Research Grants: The Medicines Company, Significant (>= $10,000); Research Grants: Ethicon, Significant (>= $10,000); Research Grants: Bristol Myers Squibb, Significant (>= $10,000); Research Grants: Heartscape, Significant (>= $10,000); Research Grants: Eisai, Significant (>= $10,000); Research Grants: Sanofi Aventis, Significant (>= $10,000)

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.
Drugs/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.
Conditions
• Heart failure

Therapies
• Medical

Study Design
Placebo controlled. Randomized. Blinded. Parallel. Factorial.

Patients Enrolled: 6,975
NYHA Class (% I, II, II, IV): 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%
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
Patient Population

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
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.

Source
Content provided by the American College of Cardiology Foundation