Treatment With Sacubitril/Valsartan in Patients With Advanced HFrEF

Quick Takes

  • In a randomized clinical trial, NT-proBNP levels were no different with use of sacubitril/valsartan in NYHA class IV HFrEF patients compared to valsartan alone.
  • There were no clinically relevant differences between sacubitril/valsartan vs. valsartan alone in NYHA class IV patients with HFrEF.
  • Prior to randomization, 18% of eligible patients did not tolerate low-dose sacubitril/valsartan. Among those randomized, symptomatic hypotension and rates of discontinuation were not different between the two groups, but the incidence of non–life-threatening hyperkalemia was higher with sacubitril/valsartan.

Study Questions:

What is the efficacy and safety of sacubitril/valsartan compared to valsartan alone in patients with advanced heart failure with reduced ejection fraction (HFrEF) in lowering N-terminal pro–B-type natriuretic peptide (NT-proBNP) levels?


The LIFE (LCZ696 in Advanced Heart Failure) trial was a 24-week prospective, multicenter, double-blind randomized clinical trial that examined safety and efficacy of sacubitril/valsartan compared to valsartan in HFrEF patients with New York Heart Association (NYHA) class IV symptoms. All eligible patients had an initial run-in period demonstrating tolerance of sacubitril/valsartan 24-26 mg twice daily for 3-7 days prior to randomization. The primary outcome was area under the curve (AUC) of NT-proBNP levels at 2-4 weekly intervals from 2-24 weeks after randomization. Secondary endpoints included survival free of composite of transplant, left ventricular assist device, inotrope use for >7 days, or ≥2 HF hospitalizations. The trial was prematurely terminated due to the coronavirus disease 2019 (COVID-19) pandemic, reducing power to detect a 20% difference from 88% to 79%.


A total of 409 patients were eligible and consented, but 18% did not tolerate low-dose sacubitril/valsartan and hence were excluded, leading to randomization of 335 patients. Mean age was 59.4 years, 27% were women, 38% were black, with a mean LVEF of 20%. Patients were on guideline-directed medical therapy as tolerated. Median daily dose for the sacubitril/valsartan group was 178 mg and 138 mg in the valsartan group. Mean NT-proBNP levels declined below baseline in both the groups after 8 weeks of therapy. The ratio of change in AUC for NT-proBNP levels with initiation of therapy with sacubitril/valsartan was statistically not different compared to valsartan. While the number of days alive without advanced HF therapies and HF hospitalizations were numerically higher with sacubitril/valsartan, it did not meet statistical significance and the trial was underpowered. There were no differences in incidence of symptomatic hypotension between the two groups; however, hyperkalemia was more common in the sacubitril/valsartan group. Rates of discontinuation were not statistically significant between the two groups.


In a randomized trial of HFrEF patients with NYHA class IV symptoms, there was no statistically significant difference between NT-proBNP levels with sacubitril/valsartan compared to valsartan alone. The trial was underpowered to detect other clinically relevant differences because of a reduction in sample size due to the COVID-19 pandemic. Hyperkalemia was more common due to sacubitril/valsartan, but symptomatic hypotension and drug discontinuation rates were no different between the two groups.


While the benefit of angiotensin receptor-neprilysin inhibitors (ARNI) in HFrEF patients with NYHA class II-III has been established, whether this benefit extends to patients with NYHA class IV symptoms has not been evaluated previously. The LIFE study did not prove a benefit with ARNI compared to angiotensin-receptor blockers (ARB) alone in this patient population. It is noteworthy that 18% of this population did not tolerate low-dose ARNI. In addition, for both groups, the mean dose achieved was 48% of the target dose, highlighting severity of illness in this cohort. Additionally, the COVID-19 pandemic led to premature termination and hence the trial was underpowered to detect clinically significant differences. Finally, unlike the PARADIGM-HF trial, which demonstrated clinical benefit of ARNI over angiotensin-converting enzyme inhibitors in NYHA class II/III HFrEF patients, the comparator group in the LIFE trial was ARB. Accordingly, this trial does not suggest a benefit with ARNI compared to ARB in HFrEF patients with NYHA class IV symptoms with a slight increase in risk of non–life-threatening hyperkalemia with ARNI use.

Clinical Topics: Cardiac Surgery, COVID-19 Hub, Heart Failure and Cardiomyopathies, Cardiac Surgery and Heart Failure, Acute Heart Failure, Heart Failure and Cardiac Biomarkers, Mechanical Circulatory Support

Keywords: Angiotensin Receptor Antagonists, COVID-19, Heart Failure, Heart-Assist Devices, Hyperkalemia, Hypotension, Natriuretic Peptide, Brain, Neprilysin, Receptors, Angiotensin, Stroke Volume, Valsartan

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