GISSI-HF

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Tavazzi L, et al. "Effect of n-3 polyunsaturated fatty acids in patients with chronic heart failure". The Lancet. 2008. 372(9645):1223-1230.
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Clinical Question

In patients with heart failure, does n-3 polyunsaturated fatty acid (PUFA) reduce all-cause mortality and hospital admission for CV disease, as compared to placebo?

Bottom Line

In patients with heart failure, n-3 polyunsaturated fatty acid (PUFA) reduces all-cause mortality and hospital admission for CV disease, as compared to placebo.

Major Points

GISSI-HF studied the effect of PUFA in patients with symptomatic heart failure (NYHA class II-IV), with the co-primary outcomes being all-cause mortality, and all-cause mortality, or hospital admission for CV reasons.[1]

Patients were randomized to receive PUFA 1 g daily (n=3,494) or placebo (n=3,481). Patients who received PUFA had a lower all-cause mortality (27% vs. 29% in placebo; adjusted HR 0·91; 95·5% CI 0·833-0·998; P=0·041; NNT=56). A benefit on all-cause mortality or hospital admission was seen as well (57% vs. 59% in placebo; adjusted HR 0·92; 99% CI 0·849-0·999; P=0·009; NNT=44). The most frequent adverse reaction, gastrointestinal symptoms, were observed equally in both group (3%).

In a substudy involving 608 heart failure patients, the authors reported that PUFA was associated with significant LVEF improvement (11.5% vs. 9.9% at 3-years in PUFA vs. placebo; P=0.005).[2] In a separate paper, the investigators also reported that rosuvastatin did not reduce all-cause mortality or hospital admission for CV reasons in patients with heart failure.[3] Similarly, the CORONA trial did not observe any benefit of rosuvastatin on the primary outcome of CV death, nonfatal MI, or nonfatal stroke.[3] However, hospitalization for CV reason was reduced.

A meta-analysis published in 2012 reported the effect of PUFA on all-cause mortality (17 trials, n=51,264; RR 0.95, 95% CI 0.89-1.01) and CV mortality (14 trials, n=48,500; RR 0.89, 95% CI 0.83-0.96). The maximal benefits were seen at a mean daily intake of 0.20 grams.

Guidelines

AHA/ACC/HFSA Guideline for the Management of Heart Failure (2022, adapted)[4]

  • In patients with HF class II to IV symptoms, PUFA supplementation may be reasonable to use as adjunctive therapy to reduce mortality and cardiovascular hospitalizations (class 2B, LOR B-R).

Design

  • Multicenter, double-blind, randomized, placebo-controlled trial
  • N=6,975
    • PUFA 1 g daily (n=3,494)
    • Placebo (n=3,481)
  • Setting: 357 centers in Italy
  • Enrollment: 2002-2005
  • Follow-up: median 3.9 years
  • Analysis: Intention-to-treat
  • Primary outcomes: All-cause mortality or CV hospitalization

Population

Inclusion Criteria

  • Age ≥18 years
  • Heart failure
    • NYHA class II-IV symptoms
    • LVEF measured within 3 months prior to enrollment. For patients with LVEF >40%, they need to have ≥1 hospital admission for heart failure in the preceding year

Exclusion Criteria

  • Indication or contraindication to PUFA
  • Hypersensitivity to PUFA
  • Noncardiac illness that may limit long-term follow-up
  • Investigational treatment within 1 month prior to randomization
  • ACS or revascularization within 1 month prior to randomization
  • Cardiac surgery scheduled within 3 months after randomization
  • Significant liver disease
  • Pregnancy or lactation

Baseline Characteristics

From the PUFA group.

  • Demographics: age 67±11 years, females 22.2%
  • Heart failure:
    • NYHA Class II (63·7%), III (33·7%), IV (2.6%)
    • LVEF 33±8.5%
    • Admission for HF in the previous year 50%
    • Etiology: ischemic 49.1%, dilatative 30.1%, hypertensive 14.1%, other 3.1%, unknown 33.6%
  • Medical history:
    • MI 41.8%, PCI 12.2%, CABG 17.6%
    • hypertension 54%, DM 28.4%, hypercholesterolemia 63.3%, peripheral vascular disease 8.4%, stroke 4.8%, current smoker 14.4%, AF 19.5%; ICD 7.1%, pacemaker 13.5%
    • COPD 21.2%, neoplasia 3.6%
  • Clinical measurements: systolic BP 126±18 mm Hg, diastolic BP 77±10 mm Hg; heart rate 72±13 beats/min; BMI 27±5 kg/m²
  • Medications: ACE inhibitor 77.2%, ARB 19.3%, antiplatelet agents 48.8%, statin 22.3%, beta-blocker 65.1%, spironolactone 38.6%, diuretics 89.5%, digoxin 37.1%, anticoagulant 29.4%, calcium-channel blocker 9.8%, nitrates 35.4%, amiodarone 19.1%

Interventions

  • Patients randomized to receive PUFA PO 1 g (850-882 mg eicosapentaenoic acid and docosahexaenoic acid as ethyl esters in 1:1·2 average ratio) or placebo.
  • Follow-up at 1, 3, 6, 12 months and every 6 months thereafter
  • Compliance was defined as administration of drug for ≥80% observed days
  • Patients also received optimal medical therapy for heart failure
  • In the study, patients were also randomized to receive rosuvastatin 10 mg PO or placebo.

Outcomes

Comparisons are PUFA vs. placebo

Primary Outcome

All-cause mortality
27% vs. 29% (adjusted HR 0·91; 95·5% CI 0·833-0·998; P=0·041; NNT=56); (unadjusted HR 0·93; 95·5% CI 0·852-1·021; P=0·124)
heart failure accounted for the most number of deaths: 9.1% vs. 9.5%
All-cause mortality or hospital admission for CV reasons
57% vs. 59% (adjusted HR 0·92; 99% CI 0·849-0·999; P=0·009; NNT=44); (unadjusted HR 0·94; 99% CI 0·869-1·022; P=0·059)

Secondary Outcomes

CV mortality
20·4% vs. 22·0% (adjusted HR 0·9; 95% CI 0·81-0·99; P=0·045); (unadjusted HR 0·92; 95% CI 0·83-1·02; P=0·121)
Sudden cardiac death
8.8% vs. 9.3% (adjusted HR 0·93; 99% CI 0·79-1.08; P=0·333); (unadjusted HR 0·94; 95% CI 0·8-1·1; P=0·413)
Hospitalization
56.8% vs. 58.3% (adjusted HR 0·94; 95% CI 0·88-1·00; P=0·049); (unadjusted HR 0·96; 95% CI 0·90-1·02; P=0·178)
Hospitalization for CV reason
46.8% vs. 48.5% (adjusted HR 0·93; 95% CI 0·87-0·99; P=0·026); (unadjusted HR 0·95; 95% CI 0·89-1·02; P=0·122)
Hospitalization for heart failure
28% vs. 28.6% (adjusted HR 0·94; 95% CI 0·86-1·02; P=147); (unadjusted HR 0·97; 95% CI 0·89-1·06; P=0·511)
CV mortality or hospitalization due to any reason
61.7% vs. 63.3% (adjusted HR 0·94; 95% CI 0·89-0.99; P=0·043); (unadjusted HR 0·96; 95% CI 0·90-1·02; P=0·159)
Fatal and non-fatal MI
3.1% vs. 3.7% (adjusted HR 0.82; 95% CI 0·63-1.06; P=0·121); (unadjusted HR 0·82; 95% CI 0·64-1·06; P=0·135)
Fatal and non-fatal stroke
3.5% vs. 3% (adjusted HR 1.16; 95% CI 0·89-1.51; P=0·271); (unadjusted HR 1.18; 95% CI 0·91-1·53; P=0·225)
Ischemic: 2.8% vs. 2.3%
Hemorrhagic: 0.4% vs. 0.3%

Subgroup Analysis

No significant interaction for age, LV function, etiology of heart failure, NYHA class, the presence of diabetes, total cholesterol level.

Adverse Events

Resulting in withdrawing from treatment
2.9% vs. 3% (P=0.87)
  • GI disorder: 96 vs. 92 patients
  • Allergy: 3 vs. 9 patients
  • Liver dysfunction: 1 vs. 1 patient
  • Lipid abnormality: 0 vs. 1 patient
  • Hepatocellular jaundice: 0 vs. 1 patient
  • Subdural hematoma: 1 vs. 0 patient
  • Muscle-related symptom: 1 vs. 0 patient
  • Subdural hematoma: 1 vs 0 patient

Criticisms

  • It has been questioned if dietary intake of PUFA may confound the study findings. Data on dietary habits of the trial patients were not published together with the main paper.[5]
  • The use of glitazones, which may increase the risk of heart failure, was not recorded in the study.[5]

Funding

  • Società Prodotti Antibiotici, Pfizer, Sigma Tau, and AstraZeneca

Further Reading