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 PUFA reduce all-cause mortality and hospital admission for CV disease, as compared to placebo?

Bottom Line

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

Major Points

The GISSI-HF trial studied the effect of n-3 polyunsaturated fatty acids (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 n-3 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 n-3 PUFA was associated with significant LVEF improvement (11.5% vs. 9.9% at 3-years in n-3 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.[4] However, hospitalization for CV reason was reduced.

A meta-analysis published in 2012 reported the effect of n-3 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).[5] The maximal benefits were seen at a mean daily intake of 0.20 grams.

Guidelines

ACCF/AHA Guideline for the Management of Heart Failure (2013, adapted)[6]

  • n-3 PUFA is reasonable as adjunctive therapy in patients HFrEF or HFpEF (NYHA class II-IV) if not contraindicated (Class IIa, Level of Evidence B)

Design

  • Multicenter, double-blind, randomized, placebo-controlled trial
  • N=6,975
    • n-3 PUFA 1 g daily (n=3,494)
    • Placebo (n=3,481)
  • Setting: 357 centers in Italy
  • Enrollment: 2002-2005
  • Follow-up: median 3.9 (3-4.5) years
  • Analysis: intention-to-treat
  • Primary outcomes:
    1. all-cause mortality
    2. all-cause mortality or hospital admission for CV reasons

Population

Inclusion Criteria

  • age ≥18 years
  • heart failure
    • NYHA class II-IV symptoms
    • LVEF measured within 3 months prior to enrolment. 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 n-3 PUFA
  • hypersensitivity to n-3 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 n-3 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 n-3 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 n-3 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

Other outcomes (presented in other papers)

LVEF increase from baseline (30%)[2]
comparisons are n-3 PUFA (n = 312) vs. placebo (n = 296):
8.1% vs. 6.3% at 1 year, 11.1% vs. 8.2% at 2 years, 11.5% vs. 9.9% at 3 years (P=0.005)
comparisons are rosuvastatin 10 mg daily (n = 212) vs. placebo (n = 207):
10.6% vs. 6.7% at 1 year, 12.9% vs. 11.2% at 2 years, 14.4% vs. 13.4% at 3 years (P=not significant)
All-cause mortality[3]
comparisons are rosuvastatin 10 mg daily (n = 2,285) vs. placebo (n = 2,289):
29% vs. 28% (adjusted HR 1·00; 95·5%CI 0·898-1·122; P=0·943)
All-cause mortality or hospitalization for CV reasons[3]
comparisons are rosuvastatin 10 mg daily (n = 2,285) vs. placebo (n = 2,289):
57% vs. 56% (adjusted HR 1·01; 95·5%CI 0·908-1·112; P=0·903)

Criticisms

  • It has been questioned if dietary intake of n-3 PUFA may confound the study findings. Data on dietary habits of the trial patients were not published together with the main paper.[7]
  • The use of glitazones, which may increase the risk of heart failure, was not recorded in the study.[7]

Funding

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

Further Reading

  1. Tavazzi L, Maggioni AP, Marchioli R,et al. 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;372(9645):1223-30
  2. 2.0 2.1 Ghio S, Scelsi L, Latini R et al. Effects of n-3 polyunsaturated fatty acids and of rosuvastatin on left ventricular function in chronic heart failure: a substudy of GISSI-HF trial. Eur J Heart Fail. 2010;12(12):1345-53
  3. 3.0 3.1 3.2 Tavazzi L, Maggioni AP, Marchioli R et al. Effect of rosuvastatin in patients with chronic heart failure (the GISSI-HF trial): a randomised, double-blind, placebo-controlled trial. Lancet. 2008;372(9645):1231-9
  4. Kjekshus J, et al. Rosuvastatin in Older Patients with Systolic Heart Failure. The New England Journal of Medicine. 2007. 357(22):2248-61.
  5. Trikalinos TA, Lee J, Moorthy D, Yu WW, Lau J, Lichtenstein AH, Chung M. Effects of Eicosapentanoic Acid and Docosahexanoic Acid on Mortality Across Diverse Settings: Systematic Review and Meta-analysis of Randomized Trials and Prospective Cohorts. Technical Review 17, Vol. 4. (Prepared by the Tufts Medical Center Evidence-based Practice Center under Contract No. HHSA 290-2007-10055-1.) AHRQ Publication No. 12-EHC040-EF. Rockville, MD: Agency for Healthcare Research and Quality; February 2012.
  6. Yancy CW, Jessup M, Bozkurt B, et al. 2013 ACCF/AHA guideline for the management of heart failure: a report of the American College of Cardiology Foundation/American Heart Association Task Force on Practice Guidelines. Circulation. 2013;128:e240-e327
  7. 7.0 7.1 Gibson LM & N-3 polyunsaturated fatty acids and statins in heart failure. Lancet 2009. 373:378; author reply 380-1.