LCZ696 in Advanced Heart Failure - LIFE

Contribution To Literature:

The LIFE trial showed that combination sacubitril/valsartan did not reduce NT-proBNP or clinical outcomes among patients with advanced HFrEF and comorbidities.


The goal of the trial was to assess the efficacy and safety of sacubitril/valsartan compared with valsartan in patients with advanced heart failure with reduced ejection fraction (HFrEF).

Study Design

Eligible patients were randomized in a 1:1 fashion to either sacubitril/valsartan (starting dose 24/26 mg or 49/51 mg BID, uptitrated to 97/103 mg BID if tolerated after 4 weeks) (n = 167), or valsartan (starting dose 40 or 80 mg BID, uptitrated to 160 mg BID if tolerated) (n = 168).

  • Total screened: 462
  • Total number of enrollees: 335
  • Duration of follow-up: 24 weeks
  • Mean patient age: 60 years
  • Percentage female: 27%

Inclusion criteria:

  • NYHA class IV symptomatology in previous 3 months
  • Receiving guideline-directed medical therapy (GDMT) for HF for ≥3 months and/or intolerant to GDMT
  • Left ventricular EF (LVEF) ≤35%
  • B-type natriuretic peptide (BNP) ≥250 pg/ml or N-terminal pro-BNP (NT-proBNP) ≥800 pg/ml
  • Systolic blood pressure ≥90 mm Hg
  • ≥1 additional objective finding of advanced HF
  • Current inotropic therapy/use of inotropes within 6 months
  • ≥1 HF hospitalization within 6 months
  • LVEF ≤25% within 12 months
  • Decreased peak VO2 within 12 months
  • 6-minute walk test distance <300 meters within 3 months

Other salient features/characteristics:

  • White race: 60%
  • LVEF: 20%
  • Systolic blood pressure: 113 mm Hg
  • Baseline medications: beta-blockers: 78%, loop diuretics: 93%, mineralocorticoid antagonists: 57%

Principal Findings:

The primary outcome, area under the curve (AUC) for the proportional change in the ratio of NT-proBNP to baseline, for sacubitril/valsartan vs. valsartan, was p = 0.45.

Secondary outcomes for sacubitril/valsartan vs. valsartan:

  • Days alive, out of hospital, or free from HF events: 103.2 vs. 111.2 days (p = 0.45)
  • CV death or hospitalization for HF: hazard ratio 1.32, 95% confidence interval 0.86-2.03 (p = 0.20)
  • Hypotension: 17% vs. 12% (p = 0.16)
  • Hyperkalemia: 17% vs. 9% (p = 0.035)


The results of this trial indicate that the combination sacubitril/valsartan did not reduce NT-proBNP or clinical outcomes among patients with advanced HFrEF and comorbidities. These data add to the available literature with angiotensin receptor-neprilysin inhibitors (ARNIs).


Presented by Dr. Douglas L. Mann at the American College of Cardiology Virtual Annual Scientific Session (ACC 2021), May 17, 2021.

Clinical Topics: Heart Failure and Cardiomyopathies, Acute Heart Failure, Heart Failure and Cardiac Biomarkers

Keywords: ACC21, ACC Annual Scientific Session, Adrenergic beta-Antagonists, Blood Pressure, Heart Failure, Hyperkalemia, Hypotension, Mineralocorticoid Receptor Antagonists, Natriuretic Peptide, Brain, Neprilysin, Receptors, Angiotensin, Sodium Potassium Chloride Symporter Inhibitors, Stroke Volume

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